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Research and Reviews for the Practicing Oncologist
Video of the Week: More Melanoma Treatments on the Way?
A closely watched experimental drug has excited melanoma oncologists and patients with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients. Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.
The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial. We talked with Dr. Paul Chapman – lead author of the BRIM-3 study — about vemurafenib. He also hypothesized how clinicians would decide which drug — vemurafenib (assuming approval) vs. ipilimumab to use for their patients.
A closely watched experimental drug has excited melanoma oncologists and patients with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients. Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.
The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial. We talked with Dr. Paul Chapman – lead author of the BRIM-3 study — about vemurafenib. He also hypothesized how clinicians would decide which drug — vemurafenib (assuming approval) vs. ipilimumab to use for their patients.
A closely watched experimental drug has excited melanoma oncologists and patients with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients. Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.
The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial. We talked with Dr. Paul Chapman – lead author of the BRIM-3 study — about vemurafenib. He also hypothesized how clinicians would decide which drug — vemurafenib (assuming approval) vs. ipilimumab to use for their patients.
Attitudes toward Vaccination for Pandemic H1N1 and Seasonal Influenza in Patients with Hematologic Malignancies
Original research
Benjamin H. Chin-Yeea, Katherine Monkman MDa, Zafar Hussain MD, FRCP(C)a and Leonard A. Minuk MD, FRCP(C)
Background
Patients with hematologic malignancies are at increased risk of influenza and its complications. Despite current health recommendations and evidence favoring influenza vaccination, vaccination rates remain low in cancer patients.
Objective
The purpose of this study was to determine which factors influenced vaccination rates.
Methods
During the 2009–2010 pandemic H1N1 and seasonal influenza season, we surveyed patients with hematologic malignancies in a Canadian cancer center. Of the patients participating in our study (n = 129), 66% and 57% received the H1N1 pandemic influenza and seasonal influenza vaccines, respectively.
Results
A number of reasons for vaccination refusal were reported, most relating to general skepticism about the safety and efficacy of vaccination. Physician advice was also a factor influencing vaccination rates in patients. The vaccination rate for seasonal influenza was 39% in patients <65 years old, significantly lower than the rate of 73% reported for patients aged ≥65 years (P < 0.0001).
Conclusion
Future education programs should target younger patient populations and health-care workers, focusing on vaccine safety and efficacy in the high-risk cancer population.
Despite the annual development of effective influenza vaccines, influenza remains a significant cause of morbidity and mortality in Canada. In the 2009–2010 influenza season, approximately 40,000 Canadians were infected with seasonal influenza or the pandemic H1N1 influenza virus,1 and influenza has been estimated to cause 4,000–8,000 deaths in Canada each year.2 It is estimated that a severe influenza pandemic could result in a 1% reduction in annual gross domestic product in Canada.3
Patients with hematologic malignancies are known to be at increased risk of influenza and its complications, with estimated mortality rates in the range 5%–27%.[4], [5], [6], [7] and [8] Evidence for the efficacy of the influenza vaccine is limited and contradictory, and many assume that immunocompromised patients will not be able to generate a protective antibody response. Nonetheless, current evidence favors vaccination.9 Pollyea et al10 reported that eight of 15 trials on the efficacy of vaccination in patients with hematologic malignancies concluded that vaccination was beneficial. Both the Centers for Disease Control and Prevention (CDC) and the Public Health Agency of Canada (PHAC) advised that all immunocompromised patients, including those with cancer, receive both the seasonal influenza vaccine and the pandemic H1N1 influenza vaccine in the 2009–2010 influenza season.[11] and [12]
Despite these recommendations, rates of influenza vaccination remain low for the general population and cancer patients in Canada, with rates reported at 40% and 65% respectively.[13] and [14] A recent study by Yee et al15 reported similarly low influenza vaccination rates of 58% in cancer patients in the United States. Vaccination has long been a controversial public health issue, and many people choose not to be vaccinated due to fears that vaccines may not be safe and effective.[16], [17] and [18] Lack of physician recommendation has also been cited as a significant factor in the decision to decline vaccination.16
In this study, we sought to determine what percentage of patients being treated for hematologic malignancies in an Ontario, Canada, cancer center received the H1N1 pandemic influenza vaccine in the 2009–2010 influenza season and to explore the barriers to vaccination in this high-risk population. We also collected information on the percentage of patients who received the seasonal influenza vaccine. It was general practice for physicians at this center to recommend influenza vaccination in accordance with the PHAC recommendations.
Methods
Patients being treated for hematologic malignancies at the London Regional Cancer Program (London, Canada) were invited to complete a survey regarding influenza vaccination (Appendix). The London Regional Cancer Program is a tertiary care center providing specialized cancer care to a population base of 1.2 million in southwestern Ontario. The survey was administered to patients eligible to participate in another study assessing antibody levels pre- and postvaccination with the H1N1 pandemic vaccine. Eligible patients were 18 years or older and being treated or followed for hematological malignancies at the London Regional Cancer Program who attended an appointment between October 28 and November 19, 2009, and returned for a follow-up visit between January 5 and March 26, 2010 (n = 151). Patients were asked if they had received the pandemic H1N1 influenza vaccine and the seasonal influenza vaccine during the 2009–2010 influenza season. Those who had declined vaccination were asked to describe the reasons for their choice. The survey provided a list of six possible reasons for declining vaccination and gave patients the option of writing in their own responses.
The results of the study were analyzed using InStat 3 software (GraphPad, La Jolla, CA). The Mann-Whitney U-test was used to compare continuous variables, and Fisher's exact test was used to compare proportions. The study was approved by the University of Western Ontario's Institutional Research Ethics Board (IRB 16627E).
Results
Of the 151 patients invited to participate, 129 completed the survey, yielding a response rate of 85%. Patient characteristics are shown in Table 1. The respondents ranged in age from 19 to 86 years, 56% were male and 44% were female, and patients aged 65 years or older comprised 52% of the study population. The mean age of the patient group was 62.7 ± 14.8 years. Overall 119 patients (92%) had received chemotherapy at some time during their illness, with 96 patients (76%) actively receiving chemotherapy, defined as treatment within the past 3 months. Diagnoses included acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
Of the 129 patients surveyed, 85 (66%) reported that they had received the H1N1 pandemic influenza vaccine during the 2009–2010 influenza season. Fifty-seven percent had received the seasonal influenza vaccine, and 50% had received both the seasonal and the H1N1 vaccines. Of the 44 patients who did not receive the H1N1 vaccine, only three planned to receive it. Eight of the 56 patients not vaccinated with the seasonal influenza vaccine planned to receive it.
There were no significant differences in mean age, percentage of patients over 65 years old, gender, or chemotherapy status between patients who received the H1N1 vaccine and those who declined it (Table 1). The mean age of patients who received the seasonal influenza vaccine was significantly higher than that of those who did not (67.8 ±12.1 vs. 56.1 ± 15.5 years, P < 0.0001), and a significantly higher percentage of patients in the vaccinated group were over the age of 65 (67% vs. 33%, P < 0.0001).
Patient-reported reasons for not receiving the H1N1 vaccine are shown in Figure 1. The two most common reasons for declining vaccination were beliefs that “the vaccine is dangerous because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). The belief that vaccination was dangerous or not effective because of the patient's medical condition represented 16% and 12% of responses, respectively. Six percent responded that receiving the vaccine would have been too inconvenient. No patients reported concerns about pain at the injection site as a reason for avoiding vaccination. In the category of “other,” responses fell into four broad categories: “physician advised against vaccination” (8%), “vaccination is unnecessary” (8%), “previous bad experience from vaccine” (4%), and “vaccine will make me sick” (4%).
Discussion
Our study found that 66% of patients being treated for hematological malignancies at a southwestern Ontario cancer center received the H1N1 vaccine during the 2009–2010 influenza season. This was higher than the rate of H1N1 vaccination in the general Canadian population, which was reported as 41%.14 Canadian cancer patients have been previously shown to have higher rates of participation in vaccination programs. In 2005, 64% of Canadians with cancer received the seasonal influenza vaccine compared with 34% of the overall population.13 This trend may be driven in part by the higher average age of patients receiving cancer treatment as adults 65 years of age or older comprised 52% of the respondents in our study.
Worldwide, Canada ranks among the highest countries in vaccination coverage. The United Kingdom reported a vaccination rate of 28.7% during the 2007–2008 influenza season, which was at the time one of the highest in Europe.19 Other European countries, including Germany, Italy, and France, showed vaccination rates similar to that of the United Kingdom. In all of these countries vaccination coverage increased with age. The United States has vaccination rates most similar to those of Canada, estimated at 40% in the overall population and 68% in the population ≥65 years old during the 2009–2010 influenza season.20
Higher vaccination rates have been reported in the elderly compared to younger adult population,[13] and [14] and our findings prove to be consistent with this reported trend. In this study, the group vaccinated with the seasonal influenza vaccine had a mean age of 67.8 ± 12.1 years compared with the unvaccinated group aged 56.1 ± 15.5 years (P < 0.0001). Interestingly, there was no significant difference in mean age between the vaccinated and unvaccinated groups for the H1N1 pandemic influenza vaccine (P > 0.05). This was not entirely unexpected since public health campaigns during the 2009–2010 influenza season focused on the younger age group due to their increased susceptibility to severe H1N1 disease. Nonetheless, there was a trend toward an increased mean age for those who received the vaccine (64.0 ± 12.5 years) compared to those who did not (60.4 ± 18.4 years), and it is possible that statistical significance was not reached due to the small sample size. Our study reported an alarmingly low 39% vaccination rate for seasonal influenza in cancer patients <65, suggesting that the PHAC's message is not adequately reaching this potentially at-risk group.
Reasons for refusal of vaccination have been well described in previous studies.[16], [17], [18], [21], [22], [23], [24], [25] and [26] We found that the most common reasons for refusal of vaccination by cancer patients were very similar to those reported in healthy individuals. Specifically, concerns about the safety and efficacy of vaccines in general were more common than concerns related to cancer or chemotherapy. The most common reasons for refusal of vaccination were “I think the vaccine will be dangerous for people in general because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). Despite the publicity, 8% of unvaccinated patients responded that they did not feel that H1N1 influenza was a significant threat. In this study, the belief that the vaccine was dangerous because of lack of testing or a previous medical condition was responsible for 13% of patients not receiving the vaccine. Five percent of patients elected not to be vaccinated because of questions of efficacy. The H1N1 vaccine is an adjuvant with AsO3, which may cause more vaccine reactions, while the seasonal influenza vaccine is not an adjuvant. It is possible that the presence of adjuvant contributed to some patients' safety concerns, though we did not specifically ask if the adjuvant influenced their decision.
Physician advice may have played a significant role in patients' decisions to vaccinate. Eight percent of patients who did not receive the vaccine reported that they were not vaccinated due to advice from a physician. It is our routine institutional policy to recommend vaccination for all cancer patients irrespective of underlying diagnosis or treatment regimen. We do not, however, provide standardized written information to patients or referring physicians, so some patients may have been advised against vaccination by other physicians. Some primary care physicians might not have been familiar with the current PHAC recommendations or the recent literature suggesting the vaccine's potential benefits in this group. Public health campaigns should therefore seek to educate physicians as well as patients regarding the safety and efficacy of the influenza vaccine for cancer patients.
Conclusion
We found that rates of H1N1 and seasonal influenza vaccination in a southwestern Ontario cancer center were higher than those reported for the general population. Nevertheless, despite a large public health education campaign, a significant number of patients declined vaccination due to fear that it would not be safe or effective or due to a belief that vaccination was not necessary. Although the rate of seasonal influenza vaccination was high for those ≥65 years old, it was poor for those aged <65 years, despite vaccination being recommended for all adults with chronic medical conditions. Future education programs should target younger patient populations and health-care workers and focus on vaccine safety and efficacy in immunocompromised patients as well as in other high-risk groups.
References1
1 Public Health Agency of Canada, FluWatch http://www.phac-aspc.gc.ca/fluwatch/09-10/w28_10/index-eng.php Accessed August 5, 2010.
2 Public Health Agency of Canada, Influenza http://www.phac-aspc.gc.ca/influenza/index-eng.php Accessed August 5, 2010.
3 S. James and T. Sargent, The Economic Impact of an Influenza Pandemic, Department of Finance Canada, Ottawa (2006), p. 90.
4 R.F. Chemaly, S. Ghosh, G.P. Bodey, N. Rohatgi, A. Safdar, M.J. Keating, R.E. Champlin, E.A. Aguilera, J.J. Tarrand and I.I. Raad, Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center, Medicine 85 (5) (2006), pp. 278–287. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (66)
5 H.M. Yousuf, J. Englund, R. Couch, K. Rolston, M. Luna, J. Goodrich, V. Lewis, N.Q. Mirza, M. Andreeff, C. Koller, L. Elting, G.P. Bodey and E. Whimbey, Influenza among hospitalized adults with leukemia, Clin Infect Dis 24 (6) (1997), pp. 1095–1099. View Record in Scopus | Cited By in Scopus (55)
6 C.D. Cooksley, E.B. Avritscher, B.N. Bekele, K.V. Rolston, J.M. Geraci and L.S. Elting, Epidemiology and outcomes of serious influenza-related infections in the cancer population, Cancer 104 (3) (2005), pp. 618–628. View Record in Scopus | Cited By in Scopus (24)
7 L.S. Elting, E. Whimbey, W. Lo, R. Couch, M. Andreeff and G.P. Bodey, Epidemiology of influenza A virus infection in patients with acute or chronic leukemia, Support Care Cancer 3 (3) (1995), pp. 198–202. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
8 E. Whimbey, L.S. Elting, R.B. Couch, W. Lo, L. Williams, R.E. Champlin and G.P. Bodey, Influenza A virus infections among hospitalized adult bone marrow transplant recipients, Bone Marrow Transplant 13 (4) (1994), pp. 437–440. View Record in Scopus | Cited By in Scopus (110)
9 M. Tiseo, B. Calatafimi, L. Ferri, A. Menardi and A. Ardizzoni, Efficacy and safety of influenza vaccination during chemotherapy treatment, J Support Oncol 8 (6) (2010), pp. 271–272. Article | 
10 D.A. Pollyea, J.M. Brown and S.J. Horning, Utility of influenza vaccination for oncology patients, J Clin Oncol 28 (14) (2010), pp. 2481–2490. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
11 Public Health Agency of Canada, Guidance Document on the Use of Pandemic Influenza A (H1N1) 2009: Inactivated Monovalent Vaccine, Public Health Agency of Canada, Ottawa (2009).
12 Centers for Disease Control, 2009 H1N1 Vaccination Recommendations http://www.cdc.gov/h1n1flu/vaccination/acip.htm Accessed August 5, 2010.
13 J.C. Kwong, L.C. Rosella and H. Johansen, Trends in influenza vaccination in Canada, 1996/1997 to 2005, Health Rep 18 (4) (2007), pp. 9–19. View Record in Scopus | Cited By in Scopus (14)
14 Statistics Canda, Canadian Community Health Survey: H1N1 Vaccinations http://www.statcan.gc.ca/daily-quotidien/100719/dq100719b-eng.htm Accessed August 5, 2010.
15 S.S. Yee, P.R. Dutta, L.J. Solin, N. Vapiwala and G.D. Kao, Lack of compliance with national vaccination guidelines in oncology patients receiving radiation therapy, J Support Oncol 8 (1) (2010), pp. 28–34. View Record in Scopus | Cited By in Scopus (2)
16 P. Loulergue, O. Mir, J. Alexandre, S. Ropert, F. Goldwasser and O. Launay, Low influenza vaccination rate among patients receiving chemotherapy for cancer, Ann Oncol 19 (9) (2008), p. 1658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (10)
17 R.K. Zimmerman, T.A. Santibanez, J.E. Janosky, M.J. Fine, M. Raymund, S.A. Wilson, I.J. Bardella, A.R. Medsger and M.P. Nowalk, What affects influenza vaccination rates among older patients?: An analysis from inner-city, suburban, rural, and Veterans Affairs practices, Am J Med 114 (1) (2003), pp. 31–38. Article |
18 M.W. Mah, N.A. Hagen, K. Pauling-Shepard, J.S. Hawthorne, M. Mysak, T. Lye and T.J. Louie, Understanding influenza vaccination attitudes at a Canadian cancer center, Am J Infect Control 33 (4) (2005), pp. 243–250. Article |
19 P.R. Blank, M. Schwenkglenks and T.D. Szucs, Vaccination coverage rates in eleven European countries during two consecutive influenza seasons, J Infect 58 (6) (2009), pp. 446–458. Article |
20 Centers for Disease Control and Prevention, Interim Results: State-Specific Seasonal Influenza Vaccination Coverage—United States, August 2009–January 2010, MMWR Morb Mortal Wkly Rep 59 (16) (2010), pp. 477–484.
21 X. Dedoukou, G. Nikolopoulos, A. Maragos, S. Giannoulidou and H.C. Maltezou, Attitudes towards vaccination against seasonal influenza of health-care workers in primary health-care settings in Greece, Vaccine 28 (37) (2010), pp. 5931–5933. Article |
22 J.N. Kent, C.S. Lea, X. Fang, L.F. Novick and J. Morgan, Seasonal influenza vaccination coverage among local health department personnel in North Carolina, 2007–2008, Am J Prev Med 39 (1) (2010), pp. 74–77. Article |
23 M. Madjid, A. Alfred, A. Sahai, J.L. Conyers and S.W. Casscells, Factors contributing to suboptimal vaccination against influenza: results of a nationwide telephone survey of persons with cardiovascular disease, Tex Heart Inst J 36 (6) (2009), pp. 546–552. View Record in Scopus | Cited By in Scopus (5)
24 K.W. To, S. Lee, T.O. Chan and S.S. Lee, Exploring determinants of acceptance of the pandemic influenza A (H1N1) 2009 vaccination in nurses, Am J Infect Control 38 (8) (2010), pp. 623–630. Article |
25 S.D. Torun and F. Torun, Vaccination against pandemic influenza A/H1N1 among healthcare workers and reasons for refusing vaccination in Istanbul in last pandemic alert phase, Vaccine 28 (35) (2010), pp. 5703–5710. Article |
26 S. Vírseda, M.A. Restrepo, E. Arranz, P. Magán-Tapia, M. Fernández-Ruiz, A.G. de la Cámara, J.M. Aguado and F. López-Medrano, Seasonal and pandemic A (H1N1) 2009 influenza vaccination coverage and attitudes among health-care workers in a Spanish university hospital, Vaccine 28 (30) (2010), pp. 4751–4757. Article |
Appendix
Questionnaire
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
_________________________________________
5) If you are not planning to get the H1N1 vaccine, what best describes your reason for not getting vaccinated? Please circle one.
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
8) If you are not planning to get the seasonal flu vaccine, what best describes your reason for not getting vaccinated? Please circle one.
_____________________________________
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Original research
Benjamin H. Chin-Yeea, Katherine Monkman MDa, Zafar Hussain MD, FRCP(C)a and Leonard A. Minuk MD, FRCP(C)
Background
Patients with hematologic malignancies are at increased risk of influenza and its complications. Despite current health recommendations and evidence favoring influenza vaccination, vaccination rates remain low in cancer patients.
Objective
The purpose of this study was to determine which factors influenced vaccination rates.
Methods
During the 2009–2010 pandemic H1N1 and seasonal influenza season, we surveyed patients with hematologic malignancies in a Canadian cancer center. Of the patients participating in our study (n = 129), 66% and 57% received the H1N1 pandemic influenza and seasonal influenza vaccines, respectively.
Results
A number of reasons for vaccination refusal were reported, most relating to general skepticism about the safety and efficacy of vaccination. Physician advice was also a factor influencing vaccination rates in patients. The vaccination rate for seasonal influenza was 39% in patients <65 years old, significantly lower than the rate of 73% reported for patients aged ≥65 years (P < 0.0001).
Conclusion
Future education programs should target younger patient populations and health-care workers, focusing on vaccine safety and efficacy in the high-risk cancer population.
Despite the annual development of effective influenza vaccines, influenza remains a significant cause of morbidity and mortality in Canada. In the 2009–2010 influenza season, approximately 40,000 Canadians were infected with seasonal influenza or the pandemic H1N1 influenza virus,1 and influenza has been estimated to cause 4,000–8,000 deaths in Canada each year.2 It is estimated that a severe influenza pandemic could result in a 1% reduction in annual gross domestic product in Canada.3
Patients with hematologic malignancies are known to be at increased risk of influenza and its complications, with estimated mortality rates in the range 5%–27%.[4], [5], [6], [7] and [8] Evidence for the efficacy of the influenza vaccine is limited and contradictory, and many assume that immunocompromised patients will not be able to generate a protective antibody response. Nonetheless, current evidence favors vaccination.9 Pollyea et al10 reported that eight of 15 trials on the efficacy of vaccination in patients with hematologic malignancies concluded that vaccination was beneficial. Both the Centers for Disease Control and Prevention (CDC) and the Public Health Agency of Canada (PHAC) advised that all immunocompromised patients, including those with cancer, receive both the seasonal influenza vaccine and the pandemic H1N1 influenza vaccine in the 2009–2010 influenza season.[11] and [12]
Despite these recommendations, rates of influenza vaccination remain low for the general population and cancer patients in Canada, with rates reported at 40% and 65% respectively.[13] and [14] A recent study by Yee et al15 reported similarly low influenza vaccination rates of 58% in cancer patients in the United States. Vaccination has long been a controversial public health issue, and many people choose not to be vaccinated due to fears that vaccines may not be safe and effective.[16], [17] and [18] Lack of physician recommendation has also been cited as a significant factor in the decision to decline vaccination.16
In this study, we sought to determine what percentage of patients being treated for hematologic malignancies in an Ontario, Canada, cancer center received the H1N1 pandemic influenza vaccine in the 2009–2010 influenza season and to explore the barriers to vaccination in this high-risk population. We also collected information on the percentage of patients who received the seasonal influenza vaccine. It was general practice for physicians at this center to recommend influenza vaccination in accordance with the PHAC recommendations.
Methods
Patients being treated for hematologic malignancies at the London Regional Cancer Program (London, Canada) were invited to complete a survey regarding influenza vaccination (Appendix). The London Regional Cancer Program is a tertiary care center providing specialized cancer care to a population base of 1.2 million in southwestern Ontario. The survey was administered to patients eligible to participate in another study assessing antibody levels pre- and postvaccination with the H1N1 pandemic vaccine. Eligible patients were 18 years or older and being treated or followed for hematological malignancies at the London Regional Cancer Program who attended an appointment between October 28 and November 19, 2009, and returned for a follow-up visit between January 5 and March 26, 2010 (n = 151). Patients were asked if they had received the pandemic H1N1 influenza vaccine and the seasonal influenza vaccine during the 2009–2010 influenza season. Those who had declined vaccination were asked to describe the reasons for their choice. The survey provided a list of six possible reasons for declining vaccination and gave patients the option of writing in their own responses.
The results of the study were analyzed using InStat 3 software (GraphPad, La Jolla, CA). The Mann-Whitney U-test was used to compare continuous variables, and Fisher's exact test was used to compare proportions. The study was approved by the University of Western Ontario's Institutional Research Ethics Board (IRB 16627E).
Results
Of the 151 patients invited to participate, 129 completed the survey, yielding a response rate of 85%. Patient characteristics are shown in Table 1. The respondents ranged in age from 19 to 86 years, 56% were male and 44% were female, and patients aged 65 years or older comprised 52% of the study population. The mean age of the patient group was 62.7 ± 14.8 years. Overall 119 patients (92%) had received chemotherapy at some time during their illness, with 96 patients (76%) actively receiving chemotherapy, defined as treatment within the past 3 months. Diagnoses included acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
Of the 129 patients surveyed, 85 (66%) reported that they had received the H1N1 pandemic influenza vaccine during the 2009–2010 influenza season. Fifty-seven percent had received the seasonal influenza vaccine, and 50% had received both the seasonal and the H1N1 vaccines. Of the 44 patients who did not receive the H1N1 vaccine, only three planned to receive it. Eight of the 56 patients not vaccinated with the seasonal influenza vaccine planned to receive it.
There were no significant differences in mean age, percentage of patients over 65 years old, gender, or chemotherapy status between patients who received the H1N1 vaccine and those who declined it (Table 1). The mean age of patients who received the seasonal influenza vaccine was significantly higher than that of those who did not (67.8 ±12.1 vs. 56.1 ± 15.5 years, P < 0.0001), and a significantly higher percentage of patients in the vaccinated group were over the age of 65 (67% vs. 33%, P < 0.0001).
Patient-reported reasons for not receiving the H1N1 vaccine are shown in Figure 1. The two most common reasons for declining vaccination were beliefs that “the vaccine is dangerous because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). The belief that vaccination was dangerous or not effective because of the patient's medical condition represented 16% and 12% of responses, respectively. Six percent responded that receiving the vaccine would have been too inconvenient. No patients reported concerns about pain at the injection site as a reason for avoiding vaccination. In the category of “other,” responses fell into four broad categories: “physician advised against vaccination” (8%), “vaccination is unnecessary” (8%), “previous bad experience from vaccine” (4%), and “vaccine will make me sick” (4%).
Discussion
Our study found that 66% of patients being treated for hematological malignancies at a southwestern Ontario cancer center received the H1N1 vaccine during the 2009–2010 influenza season. This was higher than the rate of H1N1 vaccination in the general Canadian population, which was reported as 41%.14 Canadian cancer patients have been previously shown to have higher rates of participation in vaccination programs. In 2005, 64% of Canadians with cancer received the seasonal influenza vaccine compared with 34% of the overall population.13 This trend may be driven in part by the higher average age of patients receiving cancer treatment as adults 65 years of age or older comprised 52% of the respondents in our study.
Worldwide, Canada ranks among the highest countries in vaccination coverage. The United Kingdom reported a vaccination rate of 28.7% during the 2007–2008 influenza season, which was at the time one of the highest in Europe.19 Other European countries, including Germany, Italy, and France, showed vaccination rates similar to that of the United Kingdom. In all of these countries vaccination coverage increased with age. The United States has vaccination rates most similar to those of Canada, estimated at 40% in the overall population and 68% in the population ≥65 years old during the 2009–2010 influenza season.20
Higher vaccination rates have been reported in the elderly compared to younger adult population,[13] and [14] and our findings prove to be consistent with this reported trend. In this study, the group vaccinated with the seasonal influenza vaccine had a mean age of 67.8 ± 12.1 years compared with the unvaccinated group aged 56.1 ± 15.5 years (P < 0.0001). Interestingly, there was no significant difference in mean age between the vaccinated and unvaccinated groups for the H1N1 pandemic influenza vaccine (P > 0.05). This was not entirely unexpected since public health campaigns during the 2009–2010 influenza season focused on the younger age group due to their increased susceptibility to severe H1N1 disease. Nonetheless, there was a trend toward an increased mean age for those who received the vaccine (64.0 ± 12.5 years) compared to those who did not (60.4 ± 18.4 years), and it is possible that statistical significance was not reached due to the small sample size. Our study reported an alarmingly low 39% vaccination rate for seasonal influenza in cancer patients <65, suggesting that the PHAC's message is not adequately reaching this potentially at-risk group.
Reasons for refusal of vaccination have been well described in previous studies.[16], [17], [18], [21], [22], [23], [24], [25] and [26] We found that the most common reasons for refusal of vaccination by cancer patients were very similar to those reported in healthy individuals. Specifically, concerns about the safety and efficacy of vaccines in general were more common than concerns related to cancer or chemotherapy. The most common reasons for refusal of vaccination were “I think the vaccine will be dangerous for people in general because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). Despite the publicity, 8% of unvaccinated patients responded that they did not feel that H1N1 influenza was a significant threat. In this study, the belief that the vaccine was dangerous because of lack of testing or a previous medical condition was responsible for 13% of patients not receiving the vaccine. Five percent of patients elected not to be vaccinated because of questions of efficacy. The H1N1 vaccine is an adjuvant with AsO3, which may cause more vaccine reactions, while the seasonal influenza vaccine is not an adjuvant. It is possible that the presence of adjuvant contributed to some patients' safety concerns, though we did not specifically ask if the adjuvant influenced their decision.
Physician advice may have played a significant role in patients' decisions to vaccinate. Eight percent of patients who did not receive the vaccine reported that they were not vaccinated due to advice from a physician. It is our routine institutional policy to recommend vaccination for all cancer patients irrespective of underlying diagnosis or treatment regimen. We do not, however, provide standardized written information to patients or referring physicians, so some patients may have been advised against vaccination by other physicians. Some primary care physicians might not have been familiar with the current PHAC recommendations or the recent literature suggesting the vaccine's potential benefits in this group. Public health campaigns should therefore seek to educate physicians as well as patients regarding the safety and efficacy of the influenza vaccine for cancer patients.
Conclusion
We found that rates of H1N1 and seasonal influenza vaccination in a southwestern Ontario cancer center were higher than those reported for the general population. Nevertheless, despite a large public health education campaign, a significant number of patients declined vaccination due to fear that it would not be safe or effective or due to a belief that vaccination was not necessary. Although the rate of seasonal influenza vaccination was high for those ≥65 years old, it was poor for those aged <65 years, despite vaccination being recommended for all adults with chronic medical conditions. Future education programs should target younger patient populations and health-care workers and focus on vaccine safety and efficacy in immunocompromised patients as well as in other high-risk groups.
References1
1 Public Health Agency of Canada, FluWatch http://www.phac-aspc.gc.ca/fluwatch/09-10/w28_10/index-eng.php Accessed August 5, 2010.
2 Public Health Agency of Canada, Influenza http://www.phac-aspc.gc.ca/influenza/index-eng.php Accessed August 5, 2010.
3 S. James and T. Sargent, The Economic Impact of an Influenza Pandemic, Department of Finance Canada, Ottawa (2006), p. 90.
4 R.F. Chemaly, S. Ghosh, G.P. Bodey, N. Rohatgi, A. Safdar, M.J. Keating, R.E. Champlin, E.A. Aguilera, J.J. Tarrand and I.I. Raad, Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center, Medicine 85 (5) (2006), pp. 278–287. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (66)
5 H.M. Yousuf, J. Englund, R. Couch, K. Rolston, M. Luna, J. Goodrich, V. Lewis, N.Q. Mirza, M. Andreeff, C. Koller, L. Elting, G.P. Bodey and E. Whimbey, Influenza among hospitalized adults with leukemia, Clin Infect Dis 24 (6) (1997), pp. 1095–1099. View Record in Scopus | Cited By in Scopus (55)
6 C.D. Cooksley, E.B. Avritscher, B.N. Bekele, K.V. Rolston, J.M. Geraci and L.S. Elting, Epidemiology and outcomes of serious influenza-related infections in the cancer population, Cancer 104 (3) (2005), pp. 618–628. View Record in Scopus | Cited By in Scopus (24)
7 L.S. Elting, E. Whimbey, W. Lo, R. Couch, M. Andreeff and G.P. Bodey, Epidemiology of influenza A virus infection in patients with acute or chronic leukemia, Support Care Cancer 3 (3) (1995), pp. 198–202. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
8 E. Whimbey, L.S. Elting, R.B. Couch, W. Lo, L. Williams, R.E. Champlin and G.P. Bodey, Influenza A virus infections among hospitalized adult bone marrow transplant recipients, Bone Marrow Transplant 13 (4) (1994), pp. 437–440. View Record in Scopus | Cited By in Scopus (110)
9 M. Tiseo, B. Calatafimi, L. Ferri, A. Menardi and A. Ardizzoni, Efficacy and safety of influenza vaccination during chemotherapy treatment, J Support Oncol 8 (6) (2010), pp. 271–272. Article |
10 D.A. Pollyea, J.M. Brown and S.J. Horning, Utility of influenza vaccination for oncology patients, J Clin Oncol 28 (14) (2010), pp. 2481–2490. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
11 Public Health Agency of Canada, Guidance Document on the Use of Pandemic Influenza A (H1N1) 2009: Inactivated Monovalent Vaccine, Public Health Agency of Canada, Ottawa (2009).
12 Centers for Disease Control, 2009 H1N1 Vaccination Recommendations http://www.cdc.gov/h1n1flu/vaccination/acip.htm Accessed August 5, 2010.
13 J.C. Kwong, L.C. Rosella and H. Johansen, Trends in influenza vaccination in Canada, 1996/1997 to 2005, Health Rep 18 (4) (2007), pp. 9–19. View Record in Scopus | Cited By in Scopus (14)
14 Statistics Canda, Canadian Community Health Survey: H1N1 Vaccinations http://www.statcan.gc.ca/daily-quotidien/100719/dq100719b-eng.htm Accessed August 5, 2010.
15 S.S. Yee, P.R. Dutta, L.J. Solin, N. Vapiwala and G.D. Kao, Lack of compliance with national vaccination guidelines in oncology patients receiving radiation therapy, J Support Oncol 8 (1) (2010), pp. 28–34. View Record in Scopus | Cited By in Scopus (2)
16 P. Loulergue, O. Mir, J. Alexandre, S. Ropert, F. Goldwasser and O. Launay, Low influenza vaccination rate among patients receiving chemotherapy for cancer, Ann Oncol 19 (9) (2008), p. 1658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (10)
17 R.K. Zimmerman, T.A. Santibanez, J.E. Janosky, M.J. Fine, M. Raymund, S.A. Wilson, I.J. Bardella, A.R. Medsger and M.P. Nowalk, What affects influenza vaccination rates among older patients?: An analysis from inner-city, suburban, rural, and Veterans Affairs practices, Am J Med 114 (1) (2003), pp. 31–38. Article |
18 M.W. Mah, N.A. Hagen, K. Pauling-Shepard, J.S. Hawthorne, M. Mysak, T. Lye and T.J. Louie, Understanding influenza vaccination attitudes at a Canadian cancer center, Am J Infect Control 33 (4) (2005), pp. 243–250. Article |
19 P.R. Blank, M. Schwenkglenks and T.D. Szucs, Vaccination coverage rates in eleven European countries during two consecutive influenza seasons, J Infect 58 (6) (2009), pp. 446–458. Article |
20 Centers for Disease Control and Prevention, Interim Results: State-Specific Seasonal Influenza Vaccination Coverage—United States, August 2009–January 2010, MMWR Morb Mortal Wkly Rep 59 (16) (2010), pp. 477–484.
21 X. Dedoukou, G. Nikolopoulos, A. Maragos, S. Giannoulidou and H.C. Maltezou, Attitudes towards vaccination against seasonal influenza of health-care workers in primary health-care settings in Greece, Vaccine 28 (37) (2010), pp. 5931–5933. Article |
22 J.N. Kent, C.S. Lea, X. Fang, L.F. Novick and J. Morgan, Seasonal influenza vaccination coverage among local health department personnel in North Carolina, 2007–2008, Am J Prev Med 39 (1) (2010), pp. 74–77. Article |
23 M. Madjid, A. Alfred, A. Sahai, J.L. Conyers and S.W. Casscells, Factors contributing to suboptimal vaccination against influenza: results of a nationwide telephone survey of persons with cardiovascular disease, Tex Heart Inst J 36 (6) (2009), pp. 546–552. View Record in Scopus | Cited By in Scopus (5)
24 K.W. To, S. Lee, T.O. Chan and S.S. Lee, Exploring determinants of acceptance of the pandemic influenza A (H1N1) 2009 vaccination in nurses, Am J Infect Control 38 (8) (2010), pp. 623–630. Article |
25 S.D. Torun and F. Torun, Vaccination against pandemic influenza A/H1N1 among healthcare workers and reasons for refusing vaccination in Istanbul in last pandemic alert phase, Vaccine 28 (35) (2010), pp. 5703–5710. Article |
26 S. Vírseda, M.A. Restrepo, E. Arranz, P. Magán-Tapia, M. Fernández-Ruiz, A.G. de la Cámara, J.M. Aguado and F. López-Medrano, Seasonal and pandemic A (H1N1) 2009 influenza vaccination coverage and attitudes among health-care workers in a Spanish university hospital, Vaccine 28 (30) (2010), pp. 4751–4757. Article |
Appendix
Questionnaire
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
_________________________________________
5) If you are not planning to get the H1N1 vaccine, what best describes your reason for not getting vaccinated? Please circle one.
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
8) If you are not planning to get the seasonal flu vaccine, what best describes your reason for not getting vaccinated? Please circle one.
_____________________________________
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Original research
Benjamin H. Chin-Yeea, Katherine Monkman MDa, Zafar Hussain MD, FRCP(C)a and Leonard A. Minuk MD, FRCP(C)
Background
Patients with hematologic malignancies are at increased risk of influenza and its complications. Despite current health recommendations and evidence favoring influenza vaccination, vaccination rates remain low in cancer patients.
Objective
The purpose of this study was to determine which factors influenced vaccination rates.
Methods
During the 2009–2010 pandemic H1N1 and seasonal influenza season, we surveyed patients with hematologic malignancies in a Canadian cancer center. Of the patients participating in our study (n = 129), 66% and 57% received the H1N1 pandemic influenza and seasonal influenza vaccines, respectively.
Results
A number of reasons for vaccination refusal were reported, most relating to general skepticism about the safety and efficacy of vaccination. Physician advice was also a factor influencing vaccination rates in patients. The vaccination rate for seasonal influenza was 39% in patients <65 years old, significantly lower than the rate of 73% reported for patients aged ≥65 years (P < 0.0001).
Conclusion
Future education programs should target younger patient populations and health-care workers, focusing on vaccine safety and efficacy in the high-risk cancer population.
Despite the annual development of effective influenza vaccines, influenza remains a significant cause of morbidity and mortality in Canada. In the 2009–2010 influenza season, approximately 40,000 Canadians were infected with seasonal influenza or the pandemic H1N1 influenza virus,1 and influenza has been estimated to cause 4,000–8,000 deaths in Canada each year.2 It is estimated that a severe influenza pandemic could result in a 1% reduction in annual gross domestic product in Canada.3
Patients with hematologic malignancies are known to be at increased risk of influenza and its complications, with estimated mortality rates in the range 5%–27%.[4], [5], [6], [7] and [8] Evidence for the efficacy of the influenza vaccine is limited and contradictory, and many assume that immunocompromised patients will not be able to generate a protective antibody response. Nonetheless, current evidence favors vaccination.9 Pollyea et al10 reported that eight of 15 trials on the efficacy of vaccination in patients with hematologic malignancies concluded that vaccination was beneficial. Both the Centers for Disease Control and Prevention (CDC) and the Public Health Agency of Canada (PHAC) advised that all immunocompromised patients, including those with cancer, receive both the seasonal influenza vaccine and the pandemic H1N1 influenza vaccine in the 2009–2010 influenza season.[11] and [12]
Despite these recommendations, rates of influenza vaccination remain low for the general population and cancer patients in Canada, with rates reported at 40% and 65% respectively.[13] and [14] A recent study by Yee et al15 reported similarly low influenza vaccination rates of 58% in cancer patients in the United States. Vaccination has long been a controversial public health issue, and many people choose not to be vaccinated due to fears that vaccines may not be safe and effective.[16], [17] and [18] Lack of physician recommendation has also been cited as a significant factor in the decision to decline vaccination.16
In this study, we sought to determine what percentage of patients being treated for hematologic malignancies in an Ontario, Canada, cancer center received the H1N1 pandemic influenza vaccine in the 2009–2010 influenza season and to explore the barriers to vaccination in this high-risk population. We also collected information on the percentage of patients who received the seasonal influenza vaccine. It was general practice for physicians at this center to recommend influenza vaccination in accordance with the PHAC recommendations.
Methods
Patients being treated for hematologic malignancies at the London Regional Cancer Program (London, Canada) were invited to complete a survey regarding influenza vaccination (Appendix). The London Regional Cancer Program is a tertiary care center providing specialized cancer care to a population base of 1.2 million in southwestern Ontario. The survey was administered to patients eligible to participate in another study assessing antibody levels pre- and postvaccination with the H1N1 pandemic vaccine. Eligible patients were 18 years or older and being treated or followed for hematological malignancies at the London Regional Cancer Program who attended an appointment between October 28 and November 19, 2009, and returned for a follow-up visit between January 5 and March 26, 2010 (n = 151). Patients were asked if they had received the pandemic H1N1 influenza vaccine and the seasonal influenza vaccine during the 2009–2010 influenza season. Those who had declined vaccination were asked to describe the reasons for their choice. The survey provided a list of six possible reasons for declining vaccination and gave patients the option of writing in their own responses.
The results of the study were analyzed using InStat 3 software (GraphPad, La Jolla, CA). The Mann-Whitney U-test was used to compare continuous variables, and Fisher's exact test was used to compare proportions. The study was approved by the University of Western Ontario's Institutional Research Ethics Board (IRB 16627E).
Results
Of the 151 patients invited to participate, 129 completed the survey, yielding a response rate of 85%. Patient characteristics are shown in Table 1. The respondents ranged in age from 19 to 86 years, 56% were male and 44% were female, and patients aged 65 years or older comprised 52% of the study population. The mean age of the patient group was 62.7 ± 14.8 years. Overall 119 patients (92%) had received chemotherapy at some time during their illness, with 96 patients (76%) actively receiving chemotherapy, defined as treatment within the past 3 months. Diagnoses included acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
Of the 129 patients surveyed, 85 (66%) reported that they had received the H1N1 pandemic influenza vaccine during the 2009–2010 influenza season. Fifty-seven percent had received the seasonal influenza vaccine, and 50% had received both the seasonal and the H1N1 vaccines. Of the 44 patients who did not receive the H1N1 vaccine, only three planned to receive it. Eight of the 56 patients not vaccinated with the seasonal influenza vaccine planned to receive it.
There were no significant differences in mean age, percentage of patients over 65 years old, gender, or chemotherapy status between patients who received the H1N1 vaccine and those who declined it (Table 1). The mean age of patients who received the seasonal influenza vaccine was significantly higher than that of those who did not (67.8 ±12.1 vs. 56.1 ± 15.5 years, P < 0.0001), and a significantly higher percentage of patients in the vaccinated group were over the age of 65 (67% vs. 33%, P < 0.0001).
Patient-reported reasons for not receiving the H1N1 vaccine are shown in Figure 1. The two most common reasons for declining vaccination were beliefs that “the vaccine is dangerous because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). The belief that vaccination was dangerous or not effective because of the patient's medical condition represented 16% and 12% of responses, respectively. Six percent responded that receiving the vaccine would have been too inconvenient. No patients reported concerns about pain at the injection site as a reason for avoiding vaccination. In the category of “other,” responses fell into four broad categories: “physician advised against vaccination” (8%), “vaccination is unnecessary” (8%), “previous bad experience from vaccine” (4%), and “vaccine will make me sick” (4%).
Discussion
Our study found that 66% of patients being treated for hematological malignancies at a southwestern Ontario cancer center received the H1N1 vaccine during the 2009–2010 influenza season. This was higher than the rate of H1N1 vaccination in the general Canadian population, which was reported as 41%.14 Canadian cancer patients have been previously shown to have higher rates of participation in vaccination programs. In 2005, 64% of Canadians with cancer received the seasonal influenza vaccine compared with 34% of the overall population.13 This trend may be driven in part by the higher average age of patients receiving cancer treatment as adults 65 years of age or older comprised 52% of the respondents in our study.
Worldwide, Canada ranks among the highest countries in vaccination coverage. The United Kingdom reported a vaccination rate of 28.7% during the 2007–2008 influenza season, which was at the time one of the highest in Europe.19 Other European countries, including Germany, Italy, and France, showed vaccination rates similar to that of the United Kingdom. In all of these countries vaccination coverage increased with age. The United States has vaccination rates most similar to those of Canada, estimated at 40% in the overall population and 68% in the population ≥65 years old during the 2009–2010 influenza season.20
Higher vaccination rates have been reported in the elderly compared to younger adult population,[13] and [14] and our findings prove to be consistent with this reported trend. In this study, the group vaccinated with the seasonal influenza vaccine had a mean age of 67.8 ± 12.1 years compared with the unvaccinated group aged 56.1 ± 15.5 years (P < 0.0001). Interestingly, there was no significant difference in mean age between the vaccinated and unvaccinated groups for the H1N1 pandemic influenza vaccine (P > 0.05). This was not entirely unexpected since public health campaigns during the 2009–2010 influenza season focused on the younger age group due to their increased susceptibility to severe H1N1 disease. Nonetheless, there was a trend toward an increased mean age for those who received the vaccine (64.0 ± 12.5 years) compared to those who did not (60.4 ± 18.4 years), and it is possible that statistical significance was not reached due to the small sample size. Our study reported an alarmingly low 39% vaccination rate for seasonal influenza in cancer patients <65, suggesting that the PHAC's message is not adequately reaching this potentially at-risk group.
Reasons for refusal of vaccination have been well described in previous studies.[16], [17], [18], [21], [22], [23], [24], [25] and [26] We found that the most common reasons for refusal of vaccination by cancer patients were very similar to those reported in healthy individuals. Specifically, concerns about the safety and efficacy of vaccines in general were more common than concerns related to cancer or chemotherapy. The most common reasons for refusal of vaccination were “I think the vaccine will be dangerous for people in general because of lack of testing” (22%) and “I don't believe in vaccination in general” (18%). Despite the publicity, 8% of unvaccinated patients responded that they did not feel that H1N1 influenza was a significant threat. In this study, the belief that the vaccine was dangerous because of lack of testing or a previous medical condition was responsible for 13% of patients not receiving the vaccine. Five percent of patients elected not to be vaccinated because of questions of efficacy. The H1N1 vaccine is an adjuvant with AsO3, which may cause more vaccine reactions, while the seasonal influenza vaccine is not an adjuvant. It is possible that the presence of adjuvant contributed to some patients' safety concerns, though we did not specifically ask if the adjuvant influenced their decision.
Physician advice may have played a significant role in patients' decisions to vaccinate. Eight percent of patients who did not receive the vaccine reported that they were not vaccinated due to advice from a physician. It is our routine institutional policy to recommend vaccination for all cancer patients irrespective of underlying diagnosis or treatment regimen. We do not, however, provide standardized written information to patients or referring physicians, so some patients may have been advised against vaccination by other physicians. Some primary care physicians might not have been familiar with the current PHAC recommendations or the recent literature suggesting the vaccine's potential benefits in this group. Public health campaigns should therefore seek to educate physicians as well as patients regarding the safety and efficacy of the influenza vaccine for cancer patients.
Conclusion
We found that rates of H1N1 and seasonal influenza vaccination in a southwestern Ontario cancer center were higher than those reported for the general population. Nevertheless, despite a large public health education campaign, a significant number of patients declined vaccination due to fear that it would not be safe or effective or due to a belief that vaccination was not necessary. Although the rate of seasonal influenza vaccination was high for those ≥65 years old, it was poor for those aged <65 years, despite vaccination being recommended for all adults with chronic medical conditions. Future education programs should target younger patient populations and health-care workers and focus on vaccine safety and efficacy in immunocompromised patients as well as in other high-risk groups.
References1
1 Public Health Agency of Canada, FluWatch http://www.phac-aspc.gc.ca/fluwatch/09-10/w28_10/index-eng.php Accessed August 5, 2010.
2 Public Health Agency of Canada, Influenza http://www.phac-aspc.gc.ca/influenza/index-eng.php Accessed August 5, 2010.
3 S. James and T. Sargent, The Economic Impact of an Influenza Pandemic, Department of Finance Canada, Ottawa (2006), p. 90.
4 R.F. Chemaly, S. Ghosh, G.P. Bodey, N. Rohatgi, A. Safdar, M.J. Keating, R.E. Champlin, E.A. Aguilera, J.J. Tarrand and I.I. Raad, Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center, Medicine 85 (5) (2006), pp. 278–287. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (66)
5 H.M. Yousuf, J. Englund, R. Couch, K. Rolston, M. Luna, J. Goodrich, V. Lewis, N.Q. Mirza, M. Andreeff, C. Koller, L. Elting, G.P. Bodey and E. Whimbey, Influenza among hospitalized adults with leukemia, Clin Infect Dis 24 (6) (1997), pp. 1095–1099. View Record in Scopus | Cited By in Scopus (55)
6 C.D. Cooksley, E.B. Avritscher, B.N. Bekele, K.V. Rolston, J.M. Geraci and L.S. Elting, Epidemiology and outcomes of serious influenza-related infections in the cancer population, Cancer 104 (3) (2005), pp. 618–628. View Record in Scopus | Cited By in Scopus (24)
7 L.S. Elting, E. Whimbey, W. Lo, R. Couch, M. Andreeff and G.P. Bodey, Epidemiology of influenza A virus infection in patients with acute or chronic leukemia, Support Care Cancer 3 (3) (1995), pp. 198–202. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (32)
8 E. Whimbey, L.S. Elting, R.B. Couch, W. Lo, L. Williams, R.E. Champlin and G.P. Bodey, Influenza A virus infections among hospitalized adult bone marrow transplant recipients, Bone Marrow Transplant 13 (4) (1994), pp. 437–440. View Record in Scopus | Cited By in Scopus (110)
9 M. Tiseo, B. Calatafimi, L. Ferri, A. Menardi and A. Ardizzoni, Efficacy and safety of influenza vaccination during chemotherapy treatment, J Support Oncol 8 (6) (2010), pp. 271–272. Article |
10 D.A. Pollyea, J.M. Brown and S.J. Horning, Utility of influenza vaccination for oncology patients, J Clin Oncol 28 (14) (2010), pp. 2481–2490. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)
11 Public Health Agency of Canada, Guidance Document on the Use of Pandemic Influenza A (H1N1) 2009: Inactivated Monovalent Vaccine, Public Health Agency of Canada, Ottawa (2009).
12 Centers for Disease Control, 2009 H1N1 Vaccination Recommendations http://www.cdc.gov/h1n1flu/vaccination/acip.htm Accessed August 5, 2010.
13 J.C. Kwong, L.C. Rosella and H. Johansen, Trends in influenza vaccination in Canada, 1996/1997 to 2005, Health Rep 18 (4) (2007), pp. 9–19. View Record in Scopus | Cited By in Scopus (14)
14 Statistics Canda, Canadian Community Health Survey: H1N1 Vaccinations http://www.statcan.gc.ca/daily-quotidien/100719/dq100719b-eng.htm Accessed August 5, 2010.
15 S.S. Yee, P.R. Dutta, L.J. Solin, N. Vapiwala and G.D. Kao, Lack of compliance with national vaccination guidelines in oncology patients receiving radiation therapy, J Support Oncol 8 (1) (2010), pp. 28–34. View Record in Scopus | Cited By in Scopus (2)
16 P. Loulergue, O. Mir, J. Alexandre, S. Ropert, F. Goldwasser and O. Launay, Low influenza vaccination rate among patients receiving chemotherapy for cancer, Ann Oncol 19 (9) (2008), p. 1658. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (10)
17 R.K. Zimmerman, T.A. Santibanez, J.E. Janosky, M.J. Fine, M. Raymund, S.A. Wilson, I.J. Bardella, A.R. Medsger and M.P. Nowalk, What affects influenza vaccination rates among older patients?: An analysis from inner-city, suburban, rural, and Veterans Affairs practices, Am J Med 114 (1) (2003), pp. 31–38. Article |
18 M.W. Mah, N.A. Hagen, K. Pauling-Shepard, J.S. Hawthorne, M. Mysak, T. Lye and T.J. Louie, Understanding influenza vaccination attitudes at a Canadian cancer center, Am J Infect Control 33 (4) (2005), pp. 243–250. Article |
19 P.R. Blank, M. Schwenkglenks and T.D. Szucs, Vaccination coverage rates in eleven European countries during two consecutive influenza seasons, J Infect 58 (6) (2009), pp. 446–458. Article |
20 Centers for Disease Control and Prevention, Interim Results: State-Specific Seasonal Influenza Vaccination Coverage—United States, August 2009–January 2010, MMWR Morb Mortal Wkly Rep 59 (16) (2010), pp. 477–484.
21 X. Dedoukou, G. Nikolopoulos, A. Maragos, S. Giannoulidou and H.C. Maltezou, Attitudes towards vaccination against seasonal influenza of health-care workers in primary health-care settings in Greece, Vaccine 28 (37) (2010), pp. 5931–5933. Article |
22 J.N. Kent, C.S. Lea, X. Fang, L.F. Novick and J. Morgan, Seasonal influenza vaccination coverage among local health department personnel in North Carolina, 2007–2008, Am J Prev Med 39 (1) (2010), pp. 74–77. Article |
23 M. Madjid, A. Alfred, A. Sahai, J.L. Conyers and S.W. Casscells, Factors contributing to suboptimal vaccination against influenza: results of a nationwide telephone survey of persons with cardiovascular disease, Tex Heart Inst J 36 (6) (2009), pp. 546–552. View Record in Scopus | Cited By in Scopus (5)
24 K.W. To, S. Lee, T.O. Chan and S.S. Lee, Exploring determinants of acceptance of the pandemic influenza A (H1N1) 2009 vaccination in nurses, Am J Infect Control 38 (8) (2010), pp. 623–630. Article |
25 S.D. Torun and F. Torun, Vaccination against pandemic influenza A/H1N1 among healthcare workers and reasons for refusing vaccination in Istanbul in last pandemic alert phase, Vaccine 28 (35) (2010), pp. 5703–5710. Article |
26 S. Vírseda, M.A. Restrepo, E. Arranz, P. Magán-Tapia, M. Fernández-Ruiz, A.G. de la Cámara, J.M. Aguado and F. López-Medrano, Seasonal and pandemic A (H1N1) 2009 influenza vaccination coverage and attitudes among health-care workers in a Spanish university hospital, Vaccine 28 (30) (2010), pp. 4751–4757. Article |
Appendix
Questionnaire
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
_________________________________________
5) If you are not planning to get the H1N1 vaccine, what best describes your reason for not getting vaccinated? Please circle one.
- a) I do not think it will be effective for me because of my medical condition
b) I am concerned it might be dangerous for me because of my medical condition
c) I am concerned it might be dangerous for people in general because not enough testing has been done
d) Receiving the vaccination would be too inconvenient (long lineups, etc.)
8) If you are not planning to get the seasonal flu vaccine, what best describes your reason for not getting vaccinated? Please circle one.
_____________________________________
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Spirituality, patients' worry, and follow-up health-care utilization among cancer survivors
Background Spirituality may aid cancer survivors as they attempt to interpret the meaning of their experience.
Objective We examined the relationship between spirituality, patient-rated worry, and health-care utilization among 551 cancer survivors with different malignancies, who were evaluated prospectively.
Methods Baseline spirituality scores were categorized into low and high spirituality groups. Patient-rated worries regarding disease recurrence/progression, developing new cancer, and developing complications from treatment were collected at baseline and at 6 and 12 months. Follow-up health-care utilization was also examined at 6 and 12 months.
Results Among the survivors, 271 (49%) reported low spirituality and 280 (51%) reported high spirituality. Of the cohort, 59% had some kind of worry regarding disease recurrence/progression, development of new cancers, and treatment complications. Highly spiritual survivors were less likely to have high levels of worries at both 6 and 12 months. Highly worried survivors were significantly more likely to place phone calls to their follow-up providers and had more frequent follow-up visits at 6 and 12 months. No interactions between spirituality and level of worry were noted to affect follow-up health-care utilization.
Conclusion Given spirituality's effect on anxiety, spirituality-based intervention may have a role in addressing cancer survivors' worries but may not improve health-care utilization.
Article Outline
- Results
- Study Participation
- Characteristics of Study Participants
- Prevalence of Spirituality and Patient Worry
- Relationship Between Spirituality and Patient Worry
- Relationship Between Patient Worry and Follow-Up Health-Care Utilization
- Relationship Between Spirituality and Health-Care Utilization
- Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Receiving a diagnosis of cancer is a life-changing event. Patients commonly seek understanding of not only the medical aspects of their disease but also how the diagnosis will affect their lives. Often, this quest to understand the meaning behind the unfortunate circumstance of disease is aided by spirituality. Spirituality motivates an individual to find meaning or purpose in his or her life experience.1 Most studies indicate that spirituality gives meaningful insight to an individual's existence and aids in the interpretation of events and relationships.[2], [3], [4], [5], [6], [7], [8] and [9]
Spiritual beliefs are widespread among cancer patients. Studies have shown that a better quality of life (QOL) is achieved in patients who practice spirituality or have those needs met by their health-care providers. They require less health care as well as experience less anxiety and a greater sense of well-being.[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and [21] One may conclude that spirituality helps patients understand the meaning of their disease and provides the catalyst for significant improvement in health-related outcomes.
Vast amounts of literature affirm spirituality's positive effects on health outcomes for advanced-stage/terminally ill patients. However, very little is known about how spirituality affects the common concerns of cancer survivors. It can be inferred that spirituality continues to aid cancer survivors as they attempt to interpret the meaning of their experience during follow-up care. After completing various cancer treatments, survivors may experience worries of cancer recurrence or progression, worries of developing a different cancer, and worries of developing complications from their initial treatment.22 We explored the relationship between spirituality, patient-rated cancer-related worry, and cancer survivors' follow-up health-care utilization (follow-up doctor visits, phone calls to follow-up providers regarding medical inquiries, and emergency room visits).
Participants and Methods
Subject Selection and Eligibility
Data for this study were obtained from CANCER CARE, an observational cohort study using a self-administered questionnaire designed to evaluate follow-up care among cancer survivors.23 Participants were seen at the University of Nebraska Medical Center (UNMC) and consented to participate in a data-collection protocol (ONCOBASE) since March 2006. ONCOBASE has a 90% consent rate. To be eligible for the study, participants were at least 19 years of age (age of majority in Nebraska) and completed their cancer treatment at UNMC. Participants varied in time since completion of last cancer treatment. From a list of 5,500 eligible subjects, 2,500 were screened. The list was sorted by date of consent, and the first 2,000 subjects received the study questionnaire. Survey forms were mailed in August 2008 (baseline) and follow-up surveys were mailed in February (month 6) and August 2009 (month 12). Participants were not paid for study participation but were told that a donation to a charitable institution was made on their behalf as an altruistic incentive.23 The study was approved by the Institutional Review Board at UNMC.
Variables Analyzed
We analyzed the participants' spirituality from baseline surveys using the Functional Assessment of Cancer Therapy–Spirituality Scale (FACT-SP).24 Total spirituality scores were computed for each participant using instrument standard calculations. The cohort was categorized into two groups, consisting of low or high spirituality based on the median calculated score (<47 vs. ≥47) for the entire population. Other variables included in the analyses are shown in Table 1. Patient-rated worry pertaining to (1) disease recurrence/progression, (2) development of a new malignancy, and (3) complications related to treatment were evaluated at baseline and at 6 and 12 months. Respondents were asked to rate their level of worry for each of the above three items using a five-point Likert scale (none at all, little of the time, some of the time, most of the time, and all of the time). Each worry item was categorized as low (none at all to a little of the time) vs. high (some of the time, most of the time, all of the time). Follow-up health-care utilization was assessed at 6 and 12 months and consisted of (1) follow-up clinic visits (low, defined as none or one follow-up visit per year, vs. high, more than one follow-up visit per year), (2) phone calls to follow-up providers for medical issues (no vs. yes), and (3) emergency room visits (no vs. yes). These indices of health-care utilization were selected on the basis of whether they are discretionary (patient-driven) or nondiscretionary (physician-driven).[25] and [26] For example, follow-up clinic visits are mainly nondiscretionary in the sense that the follow-up provider primarily determines the frequency at which they are conducted, while phone calls made to follow-up providers and emergency room visits are inherently discretionary. We also evaluated the relationships between spirituality and QOL (Short Form 12 [SF-12]),27 social support,28 and religiosity (with the survey question [data not shown] “Overall, how much would you say that religious beliefs have influenced your life in the past two months?”), to establish the external validity of our spirituality cut-off score since these constructs have been associated with spirituality.[10], [15], [17], [19], [29], [30] and [31] Our analyses showed a high correlation between our categorization of low or high spirituality with QOL, social support, and religiosity.
| EVALUABLE (N) | LOW SPIRITUALITY | HIGH SPIRITUALITY | P | |||
|---|---|---|---|---|---|---|
| FREQUENCY | PERCENT | FREQUENCY | PERCENT | |||
| n | 551 | 271 | 49 | 280 | 51 | |
| Median age (range) | 59 (19–85) | 59 (22–83) | 0.99 | |||
| ≤40 | 551 | 17 | 6 | 21 | 8 | 0.78 |
| 41–60 | 137 | 51 | 135 | 48 | ||
| >60 | 117 | 43 | 124 | 44 | ||
| Sex | ||||||
| Female | 551 | 112 | 41 | 89 | 32 | 0.02 |
| Male | 159 | 59 | 191 | 68 | ||
| Race/ethnicity | ||||||
| White | 551 | 256 | 94 | 272 | 97 | 0.21 |
| Hispanic | 6 | 2 | 2 | 1 | ||
| African American | 3 | 1 | 4 | 1 | ||
| Other | 6 | 2 | 2 | 1 | ||
| Marital status | ||||||
| Single/never married | 551 | 14 | 5 | 19 | 7 | 0.67 |
| Married | 219 | 81 | 219 | 78 | ||
| Divorced/widowed | 38 | 14 | 42 | 15 | ||
| Education | ||||||
| High school | 551 | 90 | 33 | 83 | 30 | 0.49 |
| College | 105 | 39 | 122 | 44 | ||
| Postgraduate | 76 | 28 | 75 | 27 | ||
| Religion | ||||||
| Protestant | 551 | 121 | 45 | 161 | 58 | <0.01 |
| Catholic | 101 | 37 | 80 | 29 | ||
| Other | 36 | 13 | 35 | 13 | ||
| None/atheist | 13 | 5 | 4 | 1 | ||
| Income (US$) | ||||||
| <25,000 | 551 | 37 | 14 | 37 | 13 | 0.71 |
| 25,000–49,999 | 64 | 24 | 61 | 22 | ||
| 50,000–74,999 | 59 | 22 | 54 | 19 | ||
| 75,000–100,000 | 35 | 13 | 44 | 16 | ||
| >100,000 | 57 | 21 | 56 | 20 | ||
| Missing | 19 | 7 | 28 | 10 | ||
| Place of residence | ||||||
| Urban | 551 | 194 | 72 | 201 | 72 | 0.96 |
| Rural | 77 | 28 | 79 | 28 | ||
| Distance (miles) | ||||||
| ≤15 | 551 | 108 | 40 | 98 | 35 | 0.32 |
| 15–100 | 83 | 31 | 94 | 34 | ||
| 100–250 | 44 | 16 | 58 | 21 | ||
| >250 | 36 | 13 | 30 | 11 | ||
| Employment status | ||||||
| Full time | 551 | 160 | 59 | 163 | 58 | 0.93 |
| Part time | 22 | 8 | 27 | 10 | ||
| Homemaker | 25 | 9 | 26 | 9 | ||
| Student | 3 | 1 | 4 | 1 | ||
| Retired | 48 | 18 | 51 | 18 | ||
| Other | 13 | 5 | 9 | 3 | ||
| Patient is the primary income provider | 551 | 137 | 51 | 132 | 47 | 0.42 |
| Insurance | ||||||
| Employer-based | 551 | 149 | 55 | 153 | 55 | 0.95 |
| Individual-based | 47 | 17 | 48 | 17 | ||
| Medicare/Medicaid | 56 | 21 | 59 | 21 | ||
| Other | 17 | 6 | 16 | 6 | ||
| None | 2 | 1 | 4 | 1 | ||
| Prescription insurance | 551 | 239 | 88 | 242 | 86 | 0.53 |
| Type of malignancy | ||||||
| Leukemia, lymphoma, multiple myeloma | 551 | 136 | 50 | 147 | 53 | 0.86 |
| Breast, colon, prostate | 101 | 37 | 100 | 36 | ||
| Lung, pancreatic | 34 | 13 | 33 | 12 | ||
| Median time from diagnosis to study enrollment in years (range) | 4.5 (0.5–26.6) | 4.2 (0.6–26.6) | 0.28 | |||
| 0–2 years | 551 | 56 | 21 | 62 | 22 | 0.09 |
| 2–4 years | 70 | 26 | 76 | 27 | ||
| 4–8 years | 74 | 27 | 93 | 33 | ||
| >8 years | 71 | 26 | 49 | 18 | ||
| Median time from last treatment to study enrollment in years (range) | 3.6 (0.1–13.6) | 3.6 (0.4–18.7) | 0.87 | |||
| 0–2 years | 551 | 97 | 36 | 99 | 35 | 0.84 |
| 2–5 years | 83 | 31 | 92 | 33 | ||
| >5 years | 91 | 34 | 89 | 32 | ||
| Affiliation of follow-up provider | ||||||
| University-based | 551 | 193 | 71 | 190 | 68 | 0.16 |
| Community-based | 28 | 10 | 31 | 11 | ||
| Both | 50 | 18 | 54 | 19 | ||
| Missing | 0 | 0 | 5 | 2 | ||
| Treatment received | ||||||
| Chemotherapy only | 551 | 82 | 30 | 89 | 32 | 0.93 |
| Chemo + surgery + radiation | 125 | 46 | 126 | 45 | ||
| Stem cell transplantation | 64 | 24 | 65 | 23 | ||
| Prior treatment outside university | 551 | 116 | 43 | 126 | 45 | 0.60 |
Statistical Analysis
Participant characteristics were compared according to level of spirituality using a chi-square test for categorical data and the Wilcoxon test for continuous data (Table 1). Multivariate logistic regression models were fitted to evaluate separately the relationship between (1) spirituality with patient-rated worry as the outcome, (2) spirituality with follow-up health-care utilization as the outcome, and (3) patient-rated worry with follow-up health-care utilization as the outcome. In the above models, the following covariates were forced into each model: age, sex, cancer type, time from last cancer-related treatment to study start time, income, and type of medical insurance. These models were also fitted using outcomes ascertained at both 6 and 12 months. Interaction models between patient-rated worry and level of spirituality were also evaluated for an association with follow-up health-care utilization at 12 months to explore the role of spirituality in the relationship between patient-rated worry and health-care utilization. A P value of at least 0.05 was considered statistically significant.
Results
Study Participation
Of the 2,000 participants invited, 1,881 were deemed eligible (minus those who died or had wrong addresses). Baseline questionnaires were returned by 939 participants (baseline response rate of 50%). Seventeen wanted to participate only in the baseline survey. Of the 922 baseline participants, 691 returned the 6-month survey at the time of the analysis for this study, for a response rate of 76% when adjusted for deaths (182 no response, 18 deaths, 25 declined, 12 returned with wrong address). At 1 year, 691 surveys were mailed, with 588 surveys returned (58 no response, 17 deaths, 14 declined, 13 returned with wrong address, and one in hospice); a response rate of 87% was achieved after adjusting for deaths. Thirty-seven participants had missing information on spirituality, leaving a total of 551 included in this study. No differences in age, sex, and type of cancer were noted between patients included and excluded in the current analysis.
Characteristics of Study Participants
Demographic characteristics of the 551 study participants included in this study are shown in Table 1. We found that cancer survivors with low or high spirituality were more similar than different in all but two characteristics: highly spiritual survivors were more likely to be Protestant and male.
Prevalence of Spirituality and Patient Worry
Within our population, 271 (49%) survivors reported low spirituality and 280 (51%) reported high spirituality (Table 1). Also, at baseline, 277 (51%) survivors reported high levels of recurrence/progression-related worry, 190 survivors (35%) reported high levels of new malignancy–related worry, and 178 survivors (33%) reported high levels of treatment-related complication worry. As some participants may have reported one or more types of worry, this translates to 322 (59%) reporting any type of worry. Highly spiritual survivors reported significantly lower levels of high worry concerning recurrence/progression (6-month 27% vs. 38%, P < 0.01; 12-month 21% vs. 38%, P < 0.01), development of a different type of cancer (6-month 22% vs. 31%, P = 0.03; 12-month 15% vs. 26%, P < 0.01), and complications from treatment (6-month 17% vs. 30%, P < 0.01; 12-month 16% vs. 26%, P < 0.01). Highly spiritual survivors reported significantly lower levels for any type of worry at both 6 and 12 months (6 months 37% vs. 54%, P <0.01; 12 months 28% vs. 47%, P < 0.01) (Table 2).
| BASELINE | 6-MONTH | 12-MONTH | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | ||
| Recurrence/progression-related worry | Low | 106 (40) | 160 (58) | <0.01 | 154 (62) | 184 (73) | <0.01 | 166 (62) | 218 (79) | <0.01 |
| High | 160 (60) | 117 (42) | 95 (38) | 69 (27) | 103 (38) | 59 (21) | ||||
| New primary–related worry | Low | 158 (59) | 200 (72) | <0.01 | 172 (69) | 202 (78) | 0.03 | 199 (74) | 235 (85) | <0.01 |
| High | 111 (41) | 79 (28) | 76 (31) | 58 (22) | 71 (26) | 42 (15) | ||||
| Complication-related worry | Low | 166 (61) | 203 (73) | <0.01 | 175 (70) | 214 (83) | <0.01 | 200 (74) | 232 (84) | <0.01 |
| High | 104 (39) | 74 (27) | 74 (30) | 45 (17) | 69 (26) | 44 (16) | ||||
| Any worry | Low | 85 (32) | 138 (50) | <0.01 | 120 (46) | 165 (63) | <0.01 | 142 (53) | 198 (72) | <0.01 |
| High | 182 (68) | 140 (50) | 139 (54) | 97 (37) | 128 (47) | 78 (28) | ||||
Relationship Between Spirituality and Patient Worry
At the 6- and 12-month time points, after adjusting for covariates, highly spiritual survivors were significantly less likely to have worries than survivors who reported lower spirituality regarding disease recurrence/progression at 6 months (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.42–0.89, P < 0.01) and at 12 months (OR = 0.43, 95% CI 0.29–0.63, P < 0.01), complications from treatment at 6 months (OR = 0.50, 95% CI 0.33–0.76, P < 0.01) and at 12 months (OR = 0.54, 95% CI 0.35–0.83, P < 0.01), and development of a different type of cancer at 6 months (OR = 0.65, 95% CI 0.44–0.97, P = 0.04) and at 12 months (OR = 0.50, 95% CI 0.33–0.77, P < 0.01) (Table 3A).
| A | N | 6-MONTH | 12-MONTH | |||||
|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | ||
| Outcome | ||||||||
| Recurrence/progression-related worry | 502 | 1.00 | 0.61 (0.42–0.89) | 0.01 | 546 | 1.00 | 0.43 (0.29–0.63) | <0.01 |
| New primary–related worry | 508 | 1.00 | 0.65 (0.44–0.97) | 0.04 | 547 | 1.00 | 0.50 (0.33–0.77) | <0.01 |
| Complication-related worry | 508 | 1.00 | 0.50 (0.33–0.76) | <0.01 | 545 | 1.00 | 0.54 (0.35–0.83) | <0.01 |
| B | N | LOW WORRY, OR (95% CI) | HIGH WORRY, OR (95% CI) | P | N | LOW WORRY, OR (95% CI) | HIGH WORRY,OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 485 | 1.00 | 1.81 (1.04–3.12) | 0.03 | 534 | 1.00 | 1.49 (1.00–2.22) | 0.05 |
| Phone call to follow-up clinic | 504 | 1.00 | 2.21 (1.48–3.31) | <0.01 | 543 | 1.00 | 1.74 (1.20–2.53) | 0.01 |
| Emergency room visit | 503 | 1.00 | 1.75 (0.90–3.43) | 0.10 | 549 | 1.00 | 0.88 (0.52–1.51) | 0.65 |
| C | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 487 | 1.00 | 0.63 (0.37–1.10) | 0.11 | 536 | 1.00 | 0.88 (0.60–1.30) | 0.52 |
| Phone call to follow-up clinic | 506 | 1.00 | 0.77 (0.53–1.12) | 0.17 | 545 | 1.00 | 0.70 (0.49–1.00) | 0.04 |
| Emergency room visit | 505 | 1.00 | 0.56 (0.30–1.05) | 0.07 | 551 | 1.00 | 0.84 (0.50–1.41) | 0.50 |
Models adjusted for age, sex, cancer type, income, type of insurance, and time from last treatment
Relationship Between Patient Worry and Follow-Up Health-Care Utilization
Survivors who were highly worried about disease recurrence/progression, development of another type of cancer, and/or complications from treatment were more likely to visit their providers for follow-up care when compared with survivors who were less worried at 6 months (OR = 1.81, 95% CI 1.04–3.12, P = 0.03) and at 12 months (OR = 1.49, 95% CI 1.00–2.22, P = 0.05). Similarly, survivors who were highly worried were also more likely to place phone calls to their follow-up providers for medical inquiries than survivors who were less worried at 6 months (OR = 2.21, 95% CI 1.48–3.31, P < 0.01) and at 12 months (OR = 1.74, 95% CI 1.20–2.53, P = 0.01). We did not observe differences in emergency room visits between survivors with low and those with high rates of worrying at both 6 and 12 months (Table 3B).
Relationship Between Spirituality and Health-Care Utilization
No significant differences were noted for the frequency of follow-up visits, changes in follow-up providers, and emergency room visits between the levels of spirituality at both 6 and 12 months. However, at 12 months, highly spiritual survivors were less likely to call their follow-up providers for medical inquiries compared to survivors with low spirituality scores (OR = 0.70, 95% CI 0.49–1.00, P = 0.04) (Table 3C).
Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Interaction between patient-rated worry and level of spirituality as it relates to health-care utilization was not statistically significant (data not shown). This suggests that spirituality does not modify the effect of patient worry in producing change in follow-up health-care utilization.
Discussion
Our study examined the relationships between spirituality, patient-rated worry, and follow-up health-care utilization among cancer survivors and found that individuals who possess higher levels of spirituality tend to have less worry of disease recurrence/progression, development of treatment-related complications, and development of new cancers. These findings are consistent with previous research among patients with advanced or terminal cancers that consistently showed such correlations between spirituality and general measures of anxiety.[10], [15], [17], [19], [30] and [31] Additionally, our study showed that a higher degree of worry about common concerns of cancer survivors is associated with more follow-up visits and calls to health-care providers. However, our data also showed that spirituality by itself is for the most part not associated with follow-up health-care utilization.
It has been documented that psychosocial factors like anxiety and spirituality can influence behaviors.[32], [33], [34], [35] and [36] Our analysis showed that both discretionary and nondiscretionary indices of health-care utilization increased significantly among highly worried cancer survivors. However, these increases are independent of one's level of spirituality. These results suggest that cancer survivors with a high degree of worry about disease recurrence/progression, development of treatment-related complications, or development of a new cancer produce a change in care-seeking behavior and may concomitantly alter the health provider's need to see the patient. Our results also suggest that while spirituality has an impact on one's level of worry, being less spiritual does not necessarily alter a cancer survivor's care-seeking behavior.
Worried patients present a potential problem for clinicians in that they may need more attention during clinic visits,37 may result in requests for more ancillary/diagnostic tests including imaging modalities,[38] and [39] or may use more medications[40] and [41] or resort to other alternative therapies[42], [43], [44] and [45] available to reduce their worries. Given that cancer patients already receive many chemotherapeutic agents for their treatment, many of them are more inclined to undergo alternative therapies.[16], [43], [46], [47] and [48] Spirituality-based interventions shown to be effective at reducing anxiety and increasing QOL may therefore have a role among cancer survivors. And because spirituality and religiosity are closely linked,29 faith-based interventions may also benefit the patient.
Our study has several implications in the assessment of cancer survivors in multidisciplinary survivorship clinics. While much attention about assessing depression, anxiety, and QOL has been given to cancer survivors, our study shows that the evaluation of one's spirituality may have some merit as well. Participants with low spirituality and a high degree of worry may benefit from activities that enhance spirituality (e.g., yoga, meditation). Because of the increasing number of cancer survivors,[32] and [49] development of clinic-based spiritual interventions to address common worries of cancer survivors may be appropriate. In addition to the implications for clinical practice, our study has implications for future research. While the literature has shown a correlation between spirituality and religiosity,29 these two concepts are not the same.[1], [2], [50], [51] and [52] It would have been interesting to compare outcomes by level of spirituality and religiosity, but our data revealed a high degree of correlation between these two concepts. Over 90% of individuals who are spiritual are also religious.[28], [53] and [54] This may be the reason that some spirituality-based interventions have enhancement of religious activities as main approaches to improve spirituality.[28] and [53]
While our study has the strengths associated with a prospective study in a relatively large number of cancer survivors treated in a single medical center, it has several limitations. Our participation rate at baseline was only 50%, although our retention rates at 6 and 12 months were on average 80%. Another limitation of our study is that the baseline surveys were conducted at different time intervals from last treatment, although this limitation also allowed us to include all kinds of cancer survivors in terms of disease and time interval from last cancer treatment. Analysis confined to patients who received treatment within the last 5 years (n = 371) showed essentially the same results. We also compared the baseline spirituality scores of the study participants according to time from last treatment to study participation (0–2, 2–5, >5) and showed no statistically significant differences. Additionally, we adjusted for time from last treatment to study participation in the multivariate analyses. Combining all the participants into one analysis allowed for our exploratory analyses to have stronger statistical power. Another limitation of our study is the crude measurement of patient worry. However, in the absence of validated instruments to measure these worries, we felt the measures reflected subjective ratings of common worries by cancer survivors. Health-care utilization would have been ideally measured continuously to better quantify the medical services utilized. However, because we included a heterogeneous group of cancer patients, this measure would be highly variable and depend on the type of disease and treatment received by the patient. Thus, type of disease and time period from last treatment were adjusted for in the multivariate analyses.
In summary, cancer survivors who possess higher levels of spirituality tend to have a lesser degree of worry over disease recurrence/progression, development of treatment complications, and development of new cancers. A higher degree of worry about the common concerns of cancer survivors is associated with more follow-up visits and calls to health providers. However, our data showed that, for the most part, spirituality is not associated with follow-up health-care utilization.
Acknowledgments
The authors thank Linda Bauer, Garrett Frost, and Gregory McFadden for their help in coordinating the study and processing the data. This work was supported by the University of Nebraska Medical Center–Eppley Cancer Center (Support Grant P30 CA 036727) and the Medical Student Research Program. The funding source had no role in the design, collection, analysis, and interpretation of the data or in the writing of the article.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Background Spirituality may aid cancer survivors as they attempt to interpret the meaning of their experience.
Objective We examined the relationship between spirituality, patient-rated worry, and health-care utilization among 551 cancer survivors with different malignancies, who were evaluated prospectively.
Methods Baseline spirituality scores were categorized into low and high spirituality groups. Patient-rated worries regarding disease recurrence/progression, developing new cancer, and developing complications from treatment were collected at baseline and at 6 and 12 months. Follow-up health-care utilization was also examined at 6 and 12 months.
Results Among the survivors, 271 (49%) reported low spirituality and 280 (51%) reported high spirituality. Of the cohort, 59% had some kind of worry regarding disease recurrence/progression, development of new cancers, and treatment complications. Highly spiritual survivors were less likely to have high levels of worries at both 6 and 12 months. Highly worried survivors were significantly more likely to place phone calls to their follow-up providers and had more frequent follow-up visits at 6 and 12 months. No interactions between spirituality and level of worry were noted to affect follow-up health-care utilization.
Conclusion Given spirituality's effect on anxiety, spirituality-based intervention may have a role in addressing cancer survivors' worries but may not improve health-care utilization.
Article Outline
- Results
- Study Participation
- Characteristics of Study Participants
- Prevalence of Spirituality and Patient Worry
- Relationship Between Spirituality and Patient Worry
- Relationship Between Patient Worry and Follow-Up Health-Care Utilization
- Relationship Between Spirituality and Health-Care Utilization
- Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Receiving a diagnosis of cancer is a life-changing event. Patients commonly seek understanding of not only the medical aspects of their disease but also how the diagnosis will affect their lives. Often, this quest to understand the meaning behind the unfortunate circumstance of disease is aided by spirituality. Spirituality motivates an individual to find meaning or purpose in his or her life experience.1 Most studies indicate that spirituality gives meaningful insight to an individual's existence and aids in the interpretation of events and relationships.[2], [3], [4], [5], [6], [7], [8] and [9]
Spiritual beliefs are widespread among cancer patients. Studies have shown that a better quality of life (QOL) is achieved in patients who practice spirituality or have those needs met by their health-care providers. They require less health care as well as experience less anxiety and a greater sense of well-being.[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and [21] One may conclude that spirituality helps patients understand the meaning of their disease and provides the catalyst for significant improvement in health-related outcomes.
Vast amounts of literature affirm spirituality's positive effects on health outcomes for advanced-stage/terminally ill patients. However, very little is known about how spirituality affects the common concerns of cancer survivors. It can be inferred that spirituality continues to aid cancer survivors as they attempt to interpret the meaning of their experience during follow-up care. After completing various cancer treatments, survivors may experience worries of cancer recurrence or progression, worries of developing a different cancer, and worries of developing complications from their initial treatment.22 We explored the relationship between spirituality, patient-rated cancer-related worry, and cancer survivors' follow-up health-care utilization (follow-up doctor visits, phone calls to follow-up providers regarding medical inquiries, and emergency room visits).
Participants and Methods
Subject Selection and Eligibility
Data for this study were obtained from CANCER CARE, an observational cohort study using a self-administered questionnaire designed to evaluate follow-up care among cancer survivors.23 Participants were seen at the University of Nebraska Medical Center (UNMC) and consented to participate in a data-collection protocol (ONCOBASE) since March 2006. ONCOBASE has a 90% consent rate. To be eligible for the study, participants were at least 19 years of age (age of majority in Nebraska) and completed their cancer treatment at UNMC. Participants varied in time since completion of last cancer treatment. From a list of 5,500 eligible subjects, 2,500 were screened. The list was sorted by date of consent, and the first 2,000 subjects received the study questionnaire. Survey forms were mailed in August 2008 (baseline) and follow-up surveys were mailed in February (month 6) and August 2009 (month 12). Participants were not paid for study participation but were told that a donation to a charitable institution was made on their behalf as an altruistic incentive.23 The study was approved by the Institutional Review Board at UNMC.
Variables Analyzed
We analyzed the participants' spirituality from baseline surveys using the Functional Assessment of Cancer Therapy–Spirituality Scale (FACT-SP).24 Total spirituality scores were computed for each participant using instrument standard calculations. The cohort was categorized into two groups, consisting of low or high spirituality based on the median calculated score (<47 vs. ≥47) for the entire population. Other variables included in the analyses are shown in Table 1. Patient-rated worry pertaining to (1) disease recurrence/progression, (2) development of a new malignancy, and (3) complications related to treatment were evaluated at baseline and at 6 and 12 months. Respondents were asked to rate their level of worry for each of the above three items using a five-point Likert scale (none at all, little of the time, some of the time, most of the time, and all of the time). Each worry item was categorized as low (none at all to a little of the time) vs. high (some of the time, most of the time, all of the time). Follow-up health-care utilization was assessed at 6 and 12 months and consisted of (1) follow-up clinic visits (low, defined as none or one follow-up visit per year, vs. high, more than one follow-up visit per year), (2) phone calls to follow-up providers for medical issues (no vs. yes), and (3) emergency room visits (no vs. yes). These indices of health-care utilization were selected on the basis of whether they are discretionary (patient-driven) or nondiscretionary (physician-driven).[25] and [26] For example, follow-up clinic visits are mainly nondiscretionary in the sense that the follow-up provider primarily determines the frequency at which they are conducted, while phone calls made to follow-up providers and emergency room visits are inherently discretionary. We also evaluated the relationships between spirituality and QOL (Short Form 12 [SF-12]),27 social support,28 and religiosity (with the survey question [data not shown] “Overall, how much would you say that religious beliefs have influenced your life in the past two months?”), to establish the external validity of our spirituality cut-off score since these constructs have been associated with spirituality.[10], [15], [17], [19], [29], [30] and [31] Our analyses showed a high correlation between our categorization of low or high spirituality with QOL, social support, and religiosity.
| EVALUABLE (N) | LOW SPIRITUALITY | HIGH SPIRITUALITY | P | |||
|---|---|---|---|---|---|---|
| FREQUENCY | PERCENT | FREQUENCY | PERCENT | |||
| n | 551 | 271 | 49 | 280 | 51 | |
| Median age (range) | 59 (19–85) | 59 (22–83) | 0.99 | |||
| ≤40 | 551 | 17 | 6 | 21 | 8 | 0.78 |
| 41–60 | 137 | 51 | 135 | 48 | ||
| >60 | 117 | 43 | 124 | 44 | ||
| Sex | ||||||
| Female | 551 | 112 | 41 | 89 | 32 | 0.02 |
| Male | 159 | 59 | 191 | 68 | ||
| Race/ethnicity | ||||||
| White | 551 | 256 | 94 | 272 | 97 | 0.21 |
| Hispanic | 6 | 2 | 2 | 1 | ||
| African American | 3 | 1 | 4 | 1 | ||
| Other | 6 | 2 | 2 | 1 | ||
| Marital status | ||||||
| Single/never married | 551 | 14 | 5 | 19 | 7 | 0.67 |
| Married | 219 | 81 | 219 | 78 | ||
| Divorced/widowed | 38 | 14 | 42 | 15 | ||
| Education | ||||||
| High school | 551 | 90 | 33 | 83 | 30 | 0.49 |
| College | 105 | 39 | 122 | 44 | ||
| Postgraduate | 76 | 28 | 75 | 27 | ||
| Religion | ||||||
| Protestant | 551 | 121 | 45 | 161 | 58 | <0.01 |
| Catholic | 101 | 37 | 80 | 29 | ||
| Other | 36 | 13 | 35 | 13 | ||
| None/atheist | 13 | 5 | 4 | 1 | ||
| Income (US$) | ||||||
| <25,000 | 551 | 37 | 14 | 37 | 13 | 0.71 |
| 25,000–49,999 | 64 | 24 | 61 | 22 | ||
| 50,000–74,999 | 59 | 22 | 54 | 19 | ||
| 75,000–100,000 | 35 | 13 | 44 | 16 | ||
| >100,000 | 57 | 21 | 56 | 20 | ||
| Missing | 19 | 7 | 28 | 10 | ||
| Place of residence | ||||||
| Urban | 551 | 194 | 72 | 201 | 72 | 0.96 |
| Rural | 77 | 28 | 79 | 28 | ||
| Distance (miles) | ||||||
| ≤15 | 551 | 108 | 40 | 98 | 35 | 0.32 |
| 15–100 | 83 | 31 | 94 | 34 | ||
| 100–250 | 44 | 16 | 58 | 21 | ||
| >250 | 36 | 13 | 30 | 11 | ||
| Employment status | ||||||
| Full time | 551 | 160 | 59 | 163 | 58 | 0.93 |
| Part time | 22 | 8 | 27 | 10 | ||
| Homemaker | 25 | 9 | 26 | 9 | ||
| Student | 3 | 1 | 4 | 1 | ||
| Retired | 48 | 18 | 51 | 18 | ||
| Other | 13 | 5 | 9 | 3 | ||
| Patient is the primary income provider | 551 | 137 | 51 | 132 | 47 | 0.42 |
| Insurance | ||||||
| Employer-based | 551 | 149 | 55 | 153 | 55 | 0.95 |
| Individual-based | 47 | 17 | 48 | 17 | ||
| Medicare/Medicaid | 56 | 21 | 59 | 21 | ||
| Other | 17 | 6 | 16 | 6 | ||
| None | 2 | 1 | 4 | 1 | ||
| Prescription insurance | 551 | 239 | 88 | 242 | 86 | 0.53 |
| Type of malignancy | ||||||
| Leukemia, lymphoma, multiple myeloma | 551 | 136 | 50 | 147 | 53 | 0.86 |
| Breast, colon, prostate | 101 | 37 | 100 | 36 | ||
| Lung, pancreatic | 34 | 13 | 33 | 12 | ||
| Median time from diagnosis to study enrollment in years (range) | 4.5 (0.5–26.6) | 4.2 (0.6–26.6) | 0.28 | |||
| 0–2 years | 551 | 56 | 21 | 62 | 22 | 0.09 |
| 2–4 years | 70 | 26 | 76 | 27 | ||
| 4–8 years | 74 | 27 | 93 | 33 | ||
| >8 years | 71 | 26 | 49 | 18 | ||
| Median time from last treatment to study enrollment in years (range) | 3.6 (0.1–13.6) | 3.6 (0.4–18.7) | 0.87 | |||
| 0–2 years | 551 | 97 | 36 | 99 | 35 | 0.84 |
| 2–5 years | 83 | 31 | 92 | 33 | ||
| >5 years | 91 | 34 | 89 | 32 | ||
| Affiliation of follow-up provider | ||||||
| University-based | 551 | 193 | 71 | 190 | 68 | 0.16 |
| Community-based | 28 | 10 | 31 | 11 | ||
| Both | 50 | 18 | 54 | 19 | ||
| Missing | 0 | 0 | 5 | 2 | ||
| Treatment received | ||||||
| Chemotherapy only | 551 | 82 | 30 | 89 | 32 | 0.93 |
| Chemo + surgery + radiation | 125 | 46 | 126 | 45 | ||
| Stem cell transplantation | 64 | 24 | 65 | 23 | ||
| Prior treatment outside university | 551 | 116 | 43 | 126 | 45 | 0.60 |
Statistical Analysis
Participant characteristics were compared according to level of spirituality using a chi-square test for categorical data and the Wilcoxon test for continuous data (Table 1). Multivariate logistic regression models were fitted to evaluate separately the relationship between (1) spirituality with patient-rated worry as the outcome, (2) spirituality with follow-up health-care utilization as the outcome, and (3) patient-rated worry with follow-up health-care utilization as the outcome. In the above models, the following covariates were forced into each model: age, sex, cancer type, time from last cancer-related treatment to study start time, income, and type of medical insurance. These models were also fitted using outcomes ascertained at both 6 and 12 months. Interaction models between patient-rated worry and level of spirituality were also evaluated for an association with follow-up health-care utilization at 12 months to explore the role of spirituality in the relationship between patient-rated worry and health-care utilization. A P value of at least 0.05 was considered statistically significant.
Results
Study Participation
Of the 2,000 participants invited, 1,881 were deemed eligible (minus those who died or had wrong addresses). Baseline questionnaires were returned by 939 participants (baseline response rate of 50%). Seventeen wanted to participate only in the baseline survey. Of the 922 baseline participants, 691 returned the 6-month survey at the time of the analysis for this study, for a response rate of 76% when adjusted for deaths (182 no response, 18 deaths, 25 declined, 12 returned with wrong address). At 1 year, 691 surveys were mailed, with 588 surveys returned (58 no response, 17 deaths, 14 declined, 13 returned with wrong address, and one in hospice); a response rate of 87% was achieved after adjusting for deaths. Thirty-seven participants had missing information on spirituality, leaving a total of 551 included in this study. No differences in age, sex, and type of cancer were noted between patients included and excluded in the current analysis.
Characteristics of Study Participants
Demographic characteristics of the 551 study participants included in this study are shown in Table 1. We found that cancer survivors with low or high spirituality were more similar than different in all but two characteristics: highly spiritual survivors were more likely to be Protestant and male.
Prevalence of Spirituality and Patient Worry
Within our population, 271 (49%) survivors reported low spirituality and 280 (51%) reported high spirituality (Table 1). Also, at baseline, 277 (51%) survivors reported high levels of recurrence/progression-related worry, 190 survivors (35%) reported high levels of new malignancy–related worry, and 178 survivors (33%) reported high levels of treatment-related complication worry. As some participants may have reported one or more types of worry, this translates to 322 (59%) reporting any type of worry. Highly spiritual survivors reported significantly lower levels of high worry concerning recurrence/progression (6-month 27% vs. 38%, P < 0.01; 12-month 21% vs. 38%, P < 0.01), development of a different type of cancer (6-month 22% vs. 31%, P = 0.03; 12-month 15% vs. 26%, P < 0.01), and complications from treatment (6-month 17% vs. 30%, P < 0.01; 12-month 16% vs. 26%, P < 0.01). Highly spiritual survivors reported significantly lower levels for any type of worry at both 6 and 12 months (6 months 37% vs. 54%, P <0.01; 12 months 28% vs. 47%, P < 0.01) (Table 2).
| BASELINE | 6-MONTH | 12-MONTH | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | ||
| Recurrence/progression-related worry | Low | 106 (40) | 160 (58) | <0.01 | 154 (62) | 184 (73) | <0.01 | 166 (62) | 218 (79) | <0.01 |
| High | 160 (60) | 117 (42) | 95 (38) | 69 (27) | 103 (38) | 59 (21) | ||||
| New primary–related worry | Low | 158 (59) | 200 (72) | <0.01 | 172 (69) | 202 (78) | 0.03 | 199 (74) | 235 (85) | <0.01 |
| High | 111 (41) | 79 (28) | 76 (31) | 58 (22) | 71 (26) | 42 (15) | ||||
| Complication-related worry | Low | 166 (61) | 203 (73) | <0.01 | 175 (70) | 214 (83) | <0.01 | 200 (74) | 232 (84) | <0.01 |
| High | 104 (39) | 74 (27) | 74 (30) | 45 (17) | 69 (26) | 44 (16) | ||||
| Any worry | Low | 85 (32) | 138 (50) | <0.01 | 120 (46) | 165 (63) | <0.01 | 142 (53) | 198 (72) | <0.01 |
| High | 182 (68) | 140 (50) | 139 (54) | 97 (37) | 128 (47) | 78 (28) | ||||
Relationship Between Spirituality and Patient Worry
At the 6- and 12-month time points, after adjusting for covariates, highly spiritual survivors were significantly less likely to have worries than survivors who reported lower spirituality regarding disease recurrence/progression at 6 months (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.42–0.89, P < 0.01) and at 12 months (OR = 0.43, 95% CI 0.29–0.63, P < 0.01), complications from treatment at 6 months (OR = 0.50, 95% CI 0.33–0.76, P < 0.01) and at 12 months (OR = 0.54, 95% CI 0.35–0.83, P < 0.01), and development of a different type of cancer at 6 months (OR = 0.65, 95% CI 0.44–0.97, P = 0.04) and at 12 months (OR = 0.50, 95% CI 0.33–0.77, P < 0.01) (Table 3A).
| A | N | 6-MONTH | 12-MONTH | |||||
|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | ||
| Outcome | ||||||||
| Recurrence/progression-related worry | 502 | 1.00 | 0.61 (0.42–0.89) | 0.01 | 546 | 1.00 | 0.43 (0.29–0.63) | <0.01 |
| New primary–related worry | 508 | 1.00 | 0.65 (0.44–0.97) | 0.04 | 547 | 1.00 | 0.50 (0.33–0.77) | <0.01 |
| Complication-related worry | 508 | 1.00 | 0.50 (0.33–0.76) | <0.01 | 545 | 1.00 | 0.54 (0.35–0.83) | <0.01 |
| B | N | LOW WORRY, OR (95% CI) | HIGH WORRY, OR (95% CI) | P | N | LOW WORRY, OR (95% CI) | HIGH WORRY,OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 485 | 1.00 | 1.81 (1.04–3.12) | 0.03 | 534 | 1.00 | 1.49 (1.00–2.22) | 0.05 |
| Phone call to follow-up clinic | 504 | 1.00 | 2.21 (1.48–3.31) | <0.01 | 543 | 1.00 | 1.74 (1.20–2.53) | 0.01 |
| Emergency room visit | 503 | 1.00 | 1.75 (0.90–3.43) | 0.10 | 549 | 1.00 | 0.88 (0.52–1.51) | 0.65 |
| C | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 487 | 1.00 | 0.63 (0.37–1.10) | 0.11 | 536 | 1.00 | 0.88 (0.60–1.30) | 0.52 |
| Phone call to follow-up clinic | 506 | 1.00 | 0.77 (0.53–1.12) | 0.17 | 545 | 1.00 | 0.70 (0.49–1.00) | 0.04 |
| Emergency room visit | 505 | 1.00 | 0.56 (0.30–1.05) | 0.07 | 551 | 1.00 | 0.84 (0.50–1.41) | 0.50 |
Models adjusted for age, sex, cancer type, income, type of insurance, and time from last treatment
Relationship Between Patient Worry and Follow-Up Health-Care Utilization
Survivors who were highly worried about disease recurrence/progression, development of another type of cancer, and/or complications from treatment were more likely to visit their providers for follow-up care when compared with survivors who were less worried at 6 months (OR = 1.81, 95% CI 1.04–3.12, P = 0.03) and at 12 months (OR = 1.49, 95% CI 1.00–2.22, P = 0.05). Similarly, survivors who were highly worried were also more likely to place phone calls to their follow-up providers for medical inquiries than survivors who were less worried at 6 months (OR = 2.21, 95% CI 1.48–3.31, P < 0.01) and at 12 months (OR = 1.74, 95% CI 1.20–2.53, P = 0.01). We did not observe differences in emergency room visits between survivors with low and those with high rates of worrying at both 6 and 12 months (Table 3B).
Relationship Between Spirituality and Health-Care Utilization
No significant differences were noted for the frequency of follow-up visits, changes in follow-up providers, and emergency room visits between the levels of spirituality at both 6 and 12 months. However, at 12 months, highly spiritual survivors were less likely to call their follow-up providers for medical inquiries compared to survivors with low spirituality scores (OR = 0.70, 95% CI 0.49–1.00, P = 0.04) (Table 3C).
Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Interaction between patient-rated worry and level of spirituality as it relates to health-care utilization was not statistically significant (data not shown). This suggests that spirituality does not modify the effect of patient worry in producing change in follow-up health-care utilization.
Discussion
Our study examined the relationships between spirituality, patient-rated worry, and follow-up health-care utilization among cancer survivors and found that individuals who possess higher levels of spirituality tend to have less worry of disease recurrence/progression, development of treatment-related complications, and development of new cancers. These findings are consistent with previous research among patients with advanced or terminal cancers that consistently showed such correlations between spirituality and general measures of anxiety.[10], [15], [17], [19], [30] and [31] Additionally, our study showed that a higher degree of worry about common concerns of cancer survivors is associated with more follow-up visits and calls to health-care providers. However, our data also showed that spirituality by itself is for the most part not associated with follow-up health-care utilization.
It has been documented that psychosocial factors like anxiety and spirituality can influence behaviors.[32], [33], [34], [35] and [36] Our analysis showed that both discretionary and nondiscretionary indices of health-care utilization increased significantly among highly worried cancer survivors. However, these increases are independent of one's level of spirituality. These results suggest that cancer survivors with a high degree of worry about disease recurrence/progression, development of treatment-related complications, or development of a new cancer produce a change in care-seeking behavior and may concomitantly alter the health provider's need to see the patient. Our results also suggest that while spirituality has an impact on one's level of worry, being less spiritual does not necessarily alter a cancer survivor's care-seeking behavior.
Worried patients present a potential problem for clinicians in that they may need more attention during clinic visits,37 may result in requests for more ancillary/diagnostic tests including imaging modalities,[38] and [39] or may use more medications[40] and [41] or resort to other alternative therapies[42], [43], [44] and [45] available to reduce their worries. Given that cancer patients already receive many chemotherapeutic agents for their treatment, many of them are more inclined to undergo alternative therapies.[16], [43], [46], [47] and [48] Spirituality-based interventions shown to be effective at reducing anxiety and increasing QOL may therefore have a role among cancer survivors. And because spirituality and religiosity are closely linked,29 faith-based interventions may also benefit the patient.
Our study has several implications in the assessment of cancer survivors in multidisciplinary survivorship clinics. While much attention about assessing depression, anxiety, and QOL has been given to cancer survivors, our study shows that the evaluation of one's spirituality may have some merit as well. Participants with low spirituality and a high degree of worry may benefit from activities that enhance spirituality (e.g., yoga, meditation). Because of the increasing number of cancer survivors,[32] and [49] development of clinic-based spiritual interventions to address common worries of cancer survivors may be appropriate. In addition to the implications for clinical practice, our study has implications for future research. While the literature has shown a correlation between spirituality and religiosity,29 these two concepts are not the same.[1], [2], [50], [51] and [52] It would have been interesting to compare outcomes by level of spirituality and religiosity, but our data revealed a high degree of correlation between these two concepts. Over 90% of individuals who are spiritual are also religious.[28], [53] and [54] This may be the reason that some spirituality-based interventions have enhancement of religious activities as main approaches to improve spirituality.[28] and [53]
While our study has the strengths associated with a prospective study in a relatively large number of cancer survivors treated in a single medical center, it has several limitations. Our participation rate at baseline was only 50%, although our retention rates at 6 and 12 months were on average 80%. Another limitation of our study is that the baseline surveys were conducted at different time intervals from last treatment, although this limitation also allowed us to include all kinds of cancer survivors in terms of disease and time interval from last cancer treatment. Analysis confined to patients who received treatment within the last 5 years (n = 371) showed essentially the same results. We also compared the baseline spirituality scores of the study participants according to time from last treatment to study participation (0–2, 2–5, >5) and showed no statistically significant differences. Additionally, we adjusted for time from last treatment to study participation in the multivariate analyses. Combining all the participants into one analysis allowed for our exploratory analyses to have stronger statistical power. Another limitation of our study is the crude measurement of patient worry. However, in the absence of validated instruments to measure these worries, we felt the measures reflected subjective ratings of common worries by cancer survivors. Health-care utilization would have been ideally measured continuously to better quantify the medical services utilized. However, because we included a heterogeneous group of cancer patients, this measure would be highly variable and depend on the type of disease and treatment received by the patient. Thus, type of disease and time period from last treatment were adjusted for in the multivariate analyses.
In summary, cancer survivors who possess higher levels of spirituality tend to have a lesser degree of worry over disease recurrence/progression, development of treatment complications, and development of new cancers. A higher degree of worry about the common concerns of cancer survivors is associated with more follow-up visits and calls to health providers. However, our data showed that, for the most part, spirituality is not associated with follow-up health-care utilization.
Acknowledgments
The authors thank Linda Bauer, Garrett Frost, and Gregory McFadden for their help in coordinating the study and processing the data. This work was supported by the University of Nebraska Medical Center–Eppley Cancer Center (Support Grant P30 CA 036727) and the Medical Student Research Program. The funding source had no role in the design, collection, analysis, and interpretation of the data or in the writing of the article.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Background Spirituality may aid cancer survivors as they attempt to interpret the meaning of their experience.
Objective We examined the relationship between spirituality, patient-rated worry, and health-care utilization among 551 cancer survivors with different malignancies, who were evaluated prospectively.
Methods Baseline spirituality scores were categorized into low and high spirituality groups. Patient-rated worries regarding disease recurrence/progression, developing new cancer, and developing complications from treatment were collected at baseline and at 6 and 12 months. Follow-up health-care utilization was also examined at 6 and 12 months.
Results Among the survivors, 271 (49%) reported low spirituality and 280 (51%) reported high spirituality. Of the cohort, 59% had some kind of worry regarding disease recurrence/progression, development of new cancers, and treatment complications. Highly spiritual survivors were less likely to have high levels of worries at both 6 and 12 months. Highly worried survivors were significantly more likely to place phone calls to their follow-up providers and had more frequent follow-up visits at 6 and 12 months. No interactions between spirituality and level of worry were noted to affect follow-up health-care utilization.
Conclusion Given spirituality's effect on anxiety, spirituality-based intervention may have a role in addressing cancer survivors' worries but may not improve health-care utilization.
Article Outline
- Results
- Study Participation
- Characteristics of Study Participants
- Prevalence of Spirituality and Patient Worry
- Relationship Between Spirituality and Patient Worry
- Relationship Between Patient Worry and Follow-Up Health-Care Utilization
- Relationship Between Spirituality and Health-Care Utilization
- Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Receiving a diagnosis of cancer is a life-changing event. Patients commonly seek understanding of not only the medical aspects of their disease but also how the diagnosis will affect their lives. Often, this quest to understand the meaning behind the unfortunate circumstance of disease is aided by spirituality. Spirituality motivates an individual to find meaning or purpose in his or her life experience.1 Most studies indicate that spirituality gives meaningful insight to an individual's existence and aids in the interpretation of events and relationships.[2], [3], [4], [5], [6], [7], [8] and [9]
Spiritual beliefs are widespread among cancer patients. Studies have shown that a better quality of life (QOL) is achieved in patients who practice spirituality or have those needs met by their health-care providers. They require less health care as well as experience less anxiety and a greater sense of well-being.[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and [21] One may conclude that spirituality helps patients understand the meaning of their disease and provides the catalyst for significant improvement in health-related outcomes.
Vast amounts of literature affirm spirituality's positive effects on health outcomes for advanced-stage/terminally ill patients. However, very little is known about how spirituality affects the common concerns of cancer survivors. It can be inferred that spirituality continues to aid cancer survivors as they attempt to interpret the meaning of their experience during follow-up care. After completing various cancer treatments, survivors may experience worries of cancer recurrence or progression, worries of developing a different cancer, and worries of developing complications from their initial treatment.22 We explored the relationship between spirituality, patient-rated cancer-related worry, and cancer survivors' follow-up health-care utilization (follow-up doctor visits, phone calls to follow-up providers regarding medical inquiries, and emergency room visits).
Participants and Methods
Subject Selection and Eligibility
Data for this study were obtained from CANCER CARE, an observational cohort study using a self-administered questionnaire designed to evaluate follow-up care among cancer survivors.23 Participants were seen at the University of Nebraska Medical Center (UNMC) and consented to participate in a data-collection protocol (ONCOBASE) since March 2006. ONCOBASE has a 90% consent rate. To be eligible for the study, participants were at least 19 years of age (age of majority in Nebraska) and completed their cancer treatment at UNMC. Participants varied in time since completion of last cancer treatment. From a list of 5,500 eligible subjects, 2,500 were screened. The list was sorted by date of consent, and the first 2,000 subjects received the study questionnaire. Survey forms were mailed in August 2008 (baseline) and follow-up surveys were mailed in February (month 6) and August 2009 (month 12). Participants were not paid for study participation but were told that a donation to a charitable institution was made on their behalf as an altruistic incentive.23 The study was approved by the Institutional Review Board at UNMC.
Variables Analyzed
We analyzed the participants' spirituality from baseline surveys using the Functional Assessment of Cancer Therapy–Spirituality Scale (FACT-SP).24 Total spirituality scores were computed for each participant using instrument standard calculations. The cohort was categorized into two groups, consisting of low or high spirituality based on the median calculated score (<47 vs. ≥47) for the entire population. Other variables included in the analyses are shown in Table 1. Patient-rated worry pertaining to (1) disease recurrence/progression, (2) development of a new malignancy, and (3) complications related to treatment were evaluated at baseline and at 6 and 12 months. Respondents were asked to rate their level of worry for each of the above three items using a five-point Likert scale (none at all, little of the time, some of the time, most of the time, and all of the time). Each worry item was categorized as low (none at all to a little of the time) vs. high (some of the time, most of the time, all of the time). Follow-up health-care utilization was assessed at 6 and 12 months and consisted of (1) follow-up clinic visits (low, defined as none or one follow-up visit per year, vs. high, more than one follow-up visit per year), (2) phone calls to follow-up providers for medical issues (no vs. yes), and (3) emergency room visits (no vs. yes). These indices of health-care utilization were selected on the basis of whether they are discretionary (patient-driven) or nondiscretionary (physician-driven).[25] and [26] For example, follow-up clinic visits are mainly nondiscretionary in the sense that the follow-up provider primarily determines the frequency at which they are conducted, while phone calls made to follow-up providers and emergency room visits are inherently discretionary. We also evaluated the relationships between spirituality and QOL (Short Form 12 [SF-12]),27 social support,28 and religiosity (with the survey question [data not shown] “Overall, how much would you say that religious beliefs have influenced your life in the past two months?”), to establish the external validity of our spirituality cut-off score since these constructs have been associated with spirituality.[10], [15], [17], [19], [29], [30] and [31] Our analyses showed a high correlation between our categorization of low or high spirituality with QOL, social support, and religiosity.
| EVALUABLE (N) | LOW SPIRITUALITY | HIGH SPIRITUALITY | P | |||
|---|---|---|---|---|---|---|
| FREQUENCY | PERCENT | FREQUENCY | PERCENT | |||
| n | 551 | 271 | 49 | 280 | 51 | |
| Median age (range) | 59 (19–85) | 59 (22–83) | 0.99 | |||
| ≤40 | 551 | 17 | 6 | 21 | 8 | 0.78 |
| 41–60 | 137 | 51 | 135 | 48 | ||
| >60 | 117 | 43 | 124 | 44 | ||
| Sex | ||||||
| Female | 551 | 112 | 41 | 89 | 32 | 0.02 |
| Male | 159 | 59 | 191 | 68 | ||
| Race/ethnicity | ||||||
| White | 551 | 256 | 94 | 272 | 97 | 0.21 |
| Hispanic | 6 | 2 | 2 | 1 | ||
| African American | 3 | 1 | 4 | 1 | ||
| Other | 6 | 2 | 2 | 1 | ||
| Marital status | ||||||
| Single/never married | 551 | 14 | 5 | 19 | 7 | 0.67 |
| Married | 219 | 81 | 219 | 78 | ||
| Divorced/widowed | 38 | 14 | 42 | 15 | ||
| Education | ||||||
| High school | 551 | 90 | 33 | 83 | 30 | 0.49 |
| College | 105 | 39 | 122 | 44 | ||
| Postgraduate | 76 | 28 | 75 | 27 | ||
| Religion | ||||||
| Protestant | 551 | 121 | 45 | 161 | 58 | <0.01 |
| Catholic | 101 | 37 | 80 | 29 | ||
| Other | 36 | 13 | 35 | 13 | ||
| None/atheist | 13 | 5 | 4 | 1 | ||
| Income (US$) | ||||||
| <25,000 | 551 | 37 | 14 | 37 | 13 | 0.71 |
| 25,000–49,999 | 64 | 24 | 61 | 22 | ||
| 50,000–74,999 | 59 | 22 | 54 | 19 | ||
| 75,000–100,000 | 35 | 13 | 44 | 16 | ||
| >100,000 | 57 | 21 | 56 | 20 | ||
| Missing | 19 | 7 | 28 | 10 | ||
| Place of residence | ||||||
| Urban | 551 | 194 | 72 | 201 | 72 | 0.96 |
| Rural | 77 | 28 | 79 | 28 | ||
| Distance (miles) | ||||||
| ≤15 | 551 | 108 | 40 | 98 | 35 | 0.32 |
| 15–100 | 83 | 31 | 94 | 34 | ||
| 100–250 | 44 | 16 | 58 | 21 | ||
| >250 | 36 | 13 | 30 | 11 | ||
| Employment status | ||||||
| Full time | 551 | 160 | 59 | 163 | 58 | 0.93 |
| Part time | 22 | 8 | 27 | 10 | ||
| Homemaker | 25 | 9 | 26 | 9 | ||
| Student | 3 | 1 | 4 | 1 | ||
| Retired | 48 | 18 | 51 | 18 | ||
| Other | 13 | 5 | 9 | 3 | ||
| Patient is the primary income provider | 551 | 137 | 51 | 132 | 47 | 0.42 |
| Insurance | ||||||
| Employer-based | 551 | 149 | 55 | 153 | 55 | 0.95 |
| Individual-based | 47 | 17 | 48 | 17 | ||
| Medicare/Medicaid | 56 | 21 | 59 | 21 | ||
| Other | 17 | 6 | 16 | 6 | ||
| None | 2 | 1 | 4 | 1 | ||
| Prescription insurance | 551 | 239 | 88 | 242 | 86 | 0.53 |
| Type of malignancy | ||||||
| Leukemia, lymphoma, multiple myeloma | 551 | 136 | 50 | 147 | 53 | 0.86 |
| Breast, colon, prostate | 101 | 37 | 100 | 36 | ||
| Lung, pancreatic | 34 | 13 | 33 | 12 | ||
| Median time from diagnosis to study enrollment in years (range) | 4.5 (0.5–26.6) | 4.2 (0.6–26.6) | 0.28 | |||
| 0–2 years | 551 | 56 | 21 | 62 | 22 | 0.09 |
| 2–4 years | 70 | 26 | 76 | 27 | ||
| 4–8 years | 74 | 27 | 93 | 33 | ||
| >8 years | 71 | 26 | 49 | 18 | ||
| Median time from last treatment to study enrollment in years (range) | 3.6 (0.1–13.6) | 3.6 (0.4–18.7) | 0.87 | |||
| 0–2 years | 551 | 97 | 36 | 99 | 35 | 0.84 |
| 2–5 years | 83 | 31 | 92 | 33 | ||
| >5 years | 91 | 34 | 89 | 32 | ||
| Affiliation of follow-up provider | ||||||
| University-based | 551 | 193 | 71 | 190 | 68 | 0.16 |
| Community-based | 28 | 10 | 31 | 11 | ||
| Both | 50 | 18 | 54 | 19 | ||
| Missing | 0 | 0 | 5 | 2 | ||
| Treatment received | ||||||
| Chemotherapy only | 551 | 82 | 30 | 89 | 32 | 0.93 |
| Chemo + surgery + radiation | 125 | 46 | 126 | 45 | ||
| Stem cell transplantation | 64 | 24 | 65 | 23 | ||
| Prior treatment outside university | 551 | 116 | 43 | 126 | 45 | 0.60 |
Statistical Analysis
Participant characteristics were compared according to level of spirituality using a chi-square test for categorical data and the Wilcoxon test for continuous data (Table 1). Multivariate logistic regression models were fitted to evaluate separately the relationship between (1) spirituality with patient-rated worry as the outcome, (2) spirituality with follow-up health-care utilization as the outcome, and (3) patient-rated worry with follow-up health-care utilization as the outcome. In the above models, the following covariates were forced into each model: age, sex, cancer type, time from last cancer-related treatment to study start time, income, and type of medical insurance. These models were also fitted using outcomes ascertained at both 6 and 12 months. Interaction models between patient-rated worry and level of spirituality were also evaluated for an association with follow-up health-care utilization at 12 months to explore the role of spirituality in the relationship between patient-rated worry and health-care utilization. A P value of at least 0.05 was considered statistically significant.
Results
Study Participation
Of the 2,000 participants invited, 1,881 were deemed eligible (minus those who died or had wrong addresses). Baseline questionnaires were returned by 939 participants (baseline response rate of 50%). Seventeen wanted to participate only in the baseline survey. Of the 922 baseline participants, 691 returned the 6-month survey at the time of the analysis for this study, for a response rate of 76% when adjusted for deaths (182 no response, 18 deaths, 25 declined, 12 returned with wrong address). At 1 year, 691 surveys were mailed, with 588 surveys returned (58 no response, 17 deaths, 14 declined, 13 returned with wrong address, and one in hospice); a response rate of 87% was achieved after adjusting for deaths. Thirty-seven participants had missing information on spirituality, leaving a total of 551 included in this study. No differences in age, sex, and type of cancer were noted between patients included and excluded in the current analysis.
Characteristics of Study Participants
Demographic characteristics of the 551 study participants included in this study are shown in Table 1. We found that cancer survivors with low or high spirituality were more similar than different in all but two characteristics: highly spiritual survivors were more likely to be Protestant and male.
Prevalence of Spirituality and Patient Worry
Within our population, 271 (49%) survivors reported low spirituality and 280 (51%) reported high spirituality (Table 1). Also, at baseline, 277 (51%) survivors reported high levels of recurrence/progression-related worry, 190 survivors (35%) reported high levels of new malignancy–related worry, and 178 survivors (33%) reported high levels of treatment-related complication worry. As some participants may have reported one or more types of worry, this translates to 322 (59%) reporting any type of worry. Highly spiritual survivors reported significantly lower levels of high worry concerning recurrence/progression (6-month 27% vs. 38%, P < 0.01; 12-month 21% vs. 38%, P < 0.01), development of a different type of cancer (6-month 22% vs. 31%, P = 0.03; 12-month 15% vs. 26%, P < 0.01), and complications from treatment (6-month 17% vs. 30%, P < 0.01; 12-month 16% vs. 26%, P < 0.01). Highly spiritual survivors reported significantly lower levels for any type of worry at both 6 and 12 months (6 months 37% vs. 54%, P <0.01; 12 months 28% vs. 47%, P < 0.01) (Table 2).
| BASELINE | 6-MONTH | 12-MONTH | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | LOW SPIRITUALITY, N (%) | HIGH SPIRITUALITY, N (%) | P | ||
| Recurrence/progression-related worry | Low | 106 (40) | 160 (58) | <0.01 | 154 (62) | 184 (73) | <0.01 | 166 (62) | 218 (79) | <0.01 |
| High | 160 (60) | 117 (42) | 95 (38) | 69 (27) | 103 (38) | 59 (21) | ||||
| New primary–related worry | Low | 158 (59) | 200 (72) | <0.01 | 172 (69) | 202 (78) | 0.03 | 199 (74) | 235 (85) | <0.01 |
| High | 111 (41) | 79 (28) | 76 (31) | 58 (22) | 71 (26) | 42 (15) | ||||
| Complication-related worry | Low | 166 (61) | 203 (73) | <0.01 | 175 (70) | 214 (83) | <0.01 | 200 (74) | 232 (84) | <0.01 |
| High | 104 (39) | 74 (27) | 74 (30) | 45 (17) | 69 (26) | 44 (16) | ||||
| Any worry | Low | 85 (32) | 138 (50) | <0.01 | 120 (46) | 165 (63) | <0.01 | 142 (53) | 198 (72) | <0.01 |
| High | 182 (68) | 140 (50) | 139 (54) | 97 (37) | 128 (47) | 78 (28) | ||||
Relationship Between Spirituality and Patient Worry
At the 6- and 12-month time points, after adjusting for covariates, highly spiritual survivors were significantly less likely to have worries than survivors who reported lower spirituality regarding disease recurrence/progression at 6 months (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.42–0.89, P < 0.01) and at 12 months (OR = 0.43, 95% CI 0.29–0.63, P < 0.01), complications from treatment at 6 months (OR = 0.50, 95% CI 0.33–0.76, P < 0.01) and at 12 months (OR = 0.54, 95% CI 0.35–0.83, P < 0.01), and development of a different type of cancer at 6 months (OR = 0.65, 95% CI 0.44–0.97, P = 0.04) and at 12 months (OR = 0.50, 95% CI 0.33–0.77, P < 0.01) (Table 3A).
| A | N | 6-MONTH | 12-MONTH | |||||
|---|---|---|---|---|---|---|---|---|
| LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | ||
| Outcome | ||||||||
| Recurrence/progression-related worry | 502 | 1.00 | 0.61 (0.42–0.89) | 0.01 | 546 | 1.00 | 0.43 (0.29–0.63) | <0.01 |
| New primary–related worry | 508 | 1.00 | 0.65 (0.44–0.97) | 0.04 | 547 | 1.00 | 0.50 (0.33–0.77) | <0.01 |
| Complication-related worry | 508 | 1.00 | 0.50 (0.33–0.76) | <0.01 | 545 | 1.00 | 0.54 (0.35–0.83) | <0.01 |
| B | N | LOW WORRY, OR (95% CI) | HIGH WORRY, OR (95% CI) | P | N | LOW WORRY, OR (95% CI) | HIGH WORRY,OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 485 | 1.00 | 1.81 (1.04–3.12) | 0.03 | 534 | 1.00 | 1.49 (1.00–2.22) | 0.05 |
| Phone call to follow-up clinic | 504 | 1.00 | 2.21 (1.48–3.31) | <0.01 | 543 | 1.00 | 1.74 (1.20–2.53) | 0.01 |
| Emergency room visit | 503 | 1.00 | 1.75 (0.90–3.43) | 0.10 | 549 | 1.00 | 0.88 (0.52–1.51) | 0.65 |
| C | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P | N | LOW SPIRITUALITY, OR (95% CI) | HIGH SPIRITUALITY, OR (95% CI) | P |
| Outcome | ||||||||
| Follow-up frequency | 487 | 1.00 | 0.63 (0.37–1.10) | 0.11 | 536 | 1.00 | 0.88 (0.60–1.30) | 0.52 |
| Phone call to follow-up clinic | 506 | 1.00 | 0.77 (0.53–1.12) | 0.17 | 545 | 1.00 | 0.70 (0.49–1.00) | 0.04 |
| Emergency room visit | 505 | 1.00 | 0.56 (0.30–1.05) | 0.07 | 551 | 1.00 | 0.84 (0.50–1.41) | 0.50 |
Models adjusted for age, sex, cancer type, income, type of insurance, and time from last treatment
Relationship Between Patient Worry and Follow-Up Health-Care Utilization
Survivors who were highly worried about disease recurrence/progression, development of another type of cancer, and/or complications from treatment were more likely to visit their providers for follow-up care when compared with survivors who were less worried at 6 months (OR = 1.81, 95% CI 1.04–3.12, P = 0.03) and at 12 months (OR = 1.49, 95% CI 1.00–2.22, P = 0.05). Similarly, survivors who were highly worried were also more likely to place phone calls to their follow-up providers for medical inquiries than survivors who were less worried at 6 months (OR = 2.21, 95% CI 1.48–3.31, P < 0.01) and at 12 months (OR = 1.74, 95% CI 1.20–2.53, P = 0.01). We did not observe differences in emergency room visits between survivors with low and those with high rates of worrying at both 6 and 12 months (Table 3B).
Relationship Between Spirituality and Health-Care Utilization
No significant differences were noted for the frequency of follow-up visits, changes in follow-up providers, and emergency room visits between the levels of spirituality at both 6 and 12 months. However, at 12 months, highly spiritual survivors were less likely to call their follow-up providers for medical inquiries compared to survivors with low spirituality scores (OR = 0.70, 95% CI 0.49–1.00, P = 0.04) (Table 3C).
Interaction Between Spirituality and Patient Worry With Health-Care Utilization
Interaction between patient-rated worry and level of spirituality as it relates to health-care utilization was not statistically significant (data not shown). This suggests that spirituality does not modify the effect of patient worry in producing change in follow-up health-care utilization.
Discussion
Our study examined the relationships between spirituality, patient-rated worry, and follow-up health-care utilization among cancer survivors and found that individuals who possess higher levels of spirituality tend to have less worry of disease recurrence/progression, development of treatment-related complications, and development of new cancers. These findings are consistent with previous research among patients with advanced or terminal cancers that consistently showed such correlations between spirituality and general measures of anxiety.[10], [15], [17], [19], [30] and [31] Additionally, our study showed that a higher degree of worry about common concerns of cancer survivors is associated with more follow-up visits and calls to health-care providers. However, our data also showed that spirituality by itself is for the most part not associated with follow-up health-care utilization.
It has been documented that psychosocial factors like anxiety and spirituality can influence behaviors.[32], [33], [34], [35] and [36] Our analysis showed that both discretionary and nondiscretionary indices of health-care utilization increased significantly among highly worried cancer survivors. However, these increases are independent of one's level of spirituality. These results suggest that cancer survivors with a high degree of worry about disease recurrence/progression, development of treatment-related complications, or development of a new cancer produce a change in care-seeking behavior and may concomitantly alter the health provider's need to see the patient. Our results also suggest that while spirituality has an impact on one's level of worry, being less spiritual does not necessarily alter a cancer survivor's care-seeking behavior.
Worried patients present a potential problem for clinicians in that they may need more attention during clinic visits,37 may result in requests for more ancillary/diagnostic tests including imaging modalities,[38] and [39] or may use more medications[40] and [41] or resort to other alternative therapies[42], [43], [44] and [45] available to reduce their worries. Given that cancer patients already receive many chemotherapeutic agents for their treatment, many of them are more inclined to undergo alternative therapies.[16], [43], [46], [47] and [48] Spirituality-based interventions shown to be effective at reducing anxiety and increasing QOL may therefore have a role among cancer survivors. And because spirituality and religiosity are closely linked,29 faith-based interventions may also benefit the patient.
Our study has several implications in the assessment of cancer survivors in multidisciplinary survivorship clinics. While much attention about assessing depression, anxiety, and QOL has been given to cancer survivors, our study shows that the evaluation of one's spirituality may have some merit as well. Participants with low spirituality and a high degree of worry may benefit from activities that enhance spirituality (e.g., yoga, meditation). Because of the increasing number of cancer survivors,[32] and [49] development of clinic-based spiritual interventions to address common worries of cancer survivors may be appropriate. In addition to the implications for clinical practice, our study has implications for future research. While the literature has shown a correlation between spirituality and religiosity,29 these two concepts are not the same.[1], [2], [50], [51] and [52] It would have been interesting to compare outcomes by level of spirituality and religiosity, but our data revealed a high degree of correlation between these two concepts. Over 90% of individuals who are spiritual are also religious.[28], [53] and [54] This may be the reason that some spirituality-based interventions have enhancement of religious activities as main approaches to improve spirituality.[28] and [53]
While our study has the strengths associated with a prospective study in a relatively large number of cancer survivors treated in a single medical center, it has several limitations. Our participation rate at baseline was only 50%, although our retention rates at 6 and 12 months were on average 80%. Another limitation of our study is that the baseline surveys were conducted at different time intervals from last treatment, although this limitation also allowed us to include all kinds of cancer survivors in terms of disease and time interval from last cancer treatment. Analysis confined to patients who received treatment within the last 5 years (n = 371) showed essentially the same results. We also compared the baseline spirituality scores of the study participants according to time from last treatment to study participation (0–2, 2–5, >5) and showed no statistically significant differences. Additionally, we adjusted for time from last treatment to study participation in the multivariate analyses. Combining all the participants into one analysis allowed for our exploratory analyses to have stronger statistical power. Another limitation of our study is the crude measurement of patient worry. However, in the absence of validated instruments to measure these worries, we felt the measures reflected subjective ratings of common worries by cancer survivors. Health-care utilization would have been ideally measured continuously to better quantify the medical services utilized. However, because we included a heterogeneous group of cancer patients, this measure would be highly variable and depend on the type of disease and treatment received by the patient. Thus, type of disease and time period from last treatment were adjusted for in the multivariate analyses.
In summary, cancer survivors who possess higher levels of spirituality tend to have a lesser degree of worry over disease recurrence/progression, development of treatment complications, and development of new cancers. A higher degree of worry about the common concerns of cancer survivors is associated with more follow-up visits and calls to health providers. However, our data showed that, for the most part, spirituality is not associated with follow-up health-care utilization.
Acknowledgments
The authors thank Linda Bauer, Garrett Frost, and Gregory McFadden for their help in coordinating the study and processing the data. This work was supported by the University of Nebraska Medical Center–Eppley Cancer Center (Support Grant P30 CA 036727) and the Medical Student Research Program. The funding source had no role in the design, collection, analysis, and interpretation of the data or in the writing of the article.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Supporting Children's Grief within an Adult and Pediatric Palliative Care Program
Children are too often the forgotten mourners in the homes of dying patients. Children, even young children, and youth grieve and mourn the threatened and, then, actual loss of a dying parent, sibling, or other significant family member.1 At a time when the family resources and focus are pulled away and taxed, caregivers are tasked with the difficult job of sorting through their own emotions and a wealth of advice. Caregivers must decide how they will communicate with, include, and support the children/youth in their care.
Although evidence is incomplete and there is a clear need for further studies, links between unresolved childhood grief, or an inability to adequately process their grief, and subsequent psychiatric conditions such as depression and anxiety have been presented as far back as Freud.[2], [3], [4] and [5] In addition, prevalent feelings of responsibility and exclusion and poor communication are consistently identified by researchers interviewing bereaved children/youth about their own experience over the last couple of decades.[6], [7] and [8] Therefore, given the risk of negative psychological and social outcomes associated with children's grief and the struggles communicated by children themselves, it is critical to recognize the important and preventive role of supportive interventions, especially prior to the death of a significant family member.
Looking at caregivers' experiences, there is still a large divide between the advice given by many family and friends in this situation (see Table 1) and what has become accepted within the palliative and grief counseling fields as “best practice.”[6], [7] and [8] In addition, family members' access to professionals trained or knowledgeable in this area is growing but usually still limited.9 Many children/youth are left uninformed, unprepared, and cut off from their family's support.
Table 1. Myths and Realities about Speaking to Children about Grief and Dying. Adapted from MacPherson C.10
Professionals are not immune to subscribing to the myths listed in Table 1 and “are often inhibited by their anxieties about saying or doing the wrong thing and causing lasting emotional damage.”10 However, by communicating openly and honestly and including children/youth, informed care team members can offer many supportive interventions that a family can benefit from during the time leading up to and following the death. These interventions foster the best outcomes when they are offered early on in the palliative trajectory.[11] and [12]
Our Setting
The Temmy Latner Centre for Palliative Care (TLCPC) at Mount Sinai Hospital in Toronto is one of Canada's largest academic palliative care programs, incorporating a children's center, the Max and Beatrice Wolfe Children's Centre, which provides pediatric palliative care and children's grief programs (Dr. Jay Children's Grief Program). Our children's center supports children, youth, and their families when a family member is dying or has died. This support includes Canada's first Camp Erin, an overnight children's grief camp. Children are referred to these programs for grief counseling by our center's palliative care physicians, local palliative care units and hospices, and a wide variety of community agencies. Children's grief programs are very limited in our large urban setting, as is true in most communities across North America. We have four counselors devoted to child and youth grief support services.
What We Do
Action 1: Intake and Assessment
The center has an open referral policy, accepting referrals from any source, including self-referrals, regardless of the nature of the illness or cause of death.
An intake phone call, lasting between 15 and 60 minutes, is made to the family to assess their needs and to provide psychoeducation and relevant resources. Based on our belief that early intervention provides the most supportive opportunities, families in which the patient is dying are prioritized.
As a result of demand for services being greater than our resources, children and their families bereaved at the time of referral are provided with an initial psychoeducational visit and assessment and then placed on a waiting list if further counseling is deemed appropriate.
In either case, the initial assessment often reveals that what the family needs most is psychoeducation about child/youth grief, communication and development, and reassurance about the benefits of the things they are already doing. Caregivers are provided with educational materials, including a copy of the center's publication Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers,11 a list of Web resources, books, and brochures written by us. All these resources are also available to professionals.
Action 2: Counseling
If further assessment and counseling are warranted, children are seen individually, with siblings and/or with their family depending on the needs and circumstances. The bulk of our counseling services are brief, typically lasting three or four sessions in total. However, more intensive counseling is available on a case-by-case basis, with progress and needs being assessed every four sessions. Counseling techniques including expressive arts, crafts, therapeutic play, and activities are used to support children/youth and families in the grieving process. Families are able to contact counselors when issues arise for them, which often occurs around anniversaries, holidays, other important events, and as children/youth develop and experience their grief in a new light.13
The center's model is resiliency-based, nonpathological, and family-centered. Caregivers are empowered as primary and ongoing sources of support and dominant role models for the grieving child and youth in their care. In addition to conversations with their counselor, families are offered monthly opportunities forcaregiver education and peer support and various therapeutic group activities for children/youth.
Action 3: Complex Cases
Referrals to secondary children's mental health services are facilitated for families with needs beyond the scope of our supportive grief services, including children with indicators of complicated grief who need more intensive counseling. For children with severe psychological distress, referrals are made to a pediatric psychiatrist with special interest in this area.
According to Rando,14 there are a number of forms of unresolved or complicated grief which can overlap, and each has components of denial or regression. These include feelings of grief and mourning being absent, an inhibition of some of the normal symptoms of grief, putting grief on hold for any reason, and when there is a dependent or ambivalent relationship with the deceased. Two common manifestations are extreme anger and extreme guilt.
Some types of death that place children/youth at risk for complicated grief include a sudden or unexpected death, a violent death, a death involving mutilation, the death of a child, and death as the result of a prolonged illness. Also included is complicated loss associated with social stigma such as imprisonment, suicide, AIDS, abortion, severe mental illness, serious family dysfunction, or addiction. However, the presence of these factors does not necessarily lead to complicated grief. Complicated loss is known to be mediated by personal, familial, and social factors that contribute to relative risk and resilience.
What We Say
Engaging a family early in the palliative journey allows greater opportunity to prepare children/youth and prevent possible negative outcomes.[6] and [15] Christ and Weisenfluh16 tell us that the greatest need for support is found during the weeks leading up to the death. A large component of the early intervention we offer is age-appropriate psychoeducation to help caregivers conceptualize how their child/youth may be experiencing and understanding what is happening. Caregivers who anticipate some of the thoughts, feelings, questions, and struggles that their child/youth might face are empowered and children benefit.
The 3 Cs
1. Can I catch it?
2. Did I cause it?
3. Who is going to take care of me?
Julie Stokes15 was able to summarize what children/youth think and worry about most when a family member is dying into three questions. We have coined these three questions the “Three Cs”: Catch, Cause, and Care.
Catch
The first “C” relates to the fear expressed by children/youth that they could catch the illness. Melanie, a 7-year-old, explained that she would have a brain tumor soon because her sister Sarah, who was dying of brain cancer at the time, “is my sister and we lived in the same room always.” If such concerns go unexplored and children are not given clear information, caregivers may see children/youth distance themselves from their ill family member, develop a fear that they and the rest of their family will get sick and die as well, and other implications.17
The weight of language in a child's understanding of illness, death, and dying cannot be emphasized enough.11 More often than not, indirect and generic language used by adults, such as referring to someone as being “sick” or “not doing well,” complicates a child's ability to differentiate between the common cold or flu and life-threatening diseases and illnesses. “My mom was sick and she died; therefore, all people that are sick die.” Many adults believe that their child is too young to understand what cancer means. While it is true that children may not be able to grasp the complex medical information about the illness, they are able to understand a great deal more than they are given credit for, and using the word “cancer” gives them a way to distinguish their dying family member's illness from others such as the common cold or flu.
Cause
The second “C” arises from the common thought in children/youth that they somehow caused or hastened the death and/or prevented the recovery of their family member. Cause is one of the five accepted subconcepts of the developmental understanding of death8 and among the last to be mastered due to its complexity and abstract components. As she sat under her pink bunk-bed, 5-year-old Tayah told her counselor that she had cancer when she was a little girl and then her mother got it after her. Eleven-year-old Joshua shared, “I just have to get to that cancer walk thing. If I can do that, then my mom will get her cure. That is what they said on TV you know, to walk for the cure!”
There are a number of ways that children/youth may try to own responsibility for the illness and death of their family member. They may believe that things they thought or did not think, did or did not do, felt or did not feel were directly related to the cause, progression, or death of the family member.18 These thoughts are especially strong for children in the magical thinking stage of development. In Piaget's theory of cognitive development, magical thinking dominates the preoperational stage (2–7 years old) and describes thinking disconnected from the laws of nature.19 Special attention should be given to assuring children in this age group that they are in no way responsible for the illness or death of their family member, as well as to avoid minimizing these fears and beliefs of responsibility.[6] and [17] This point will need to be readdressed often, with frequent reassurance that they are not responsible.
Care
The third “C” includes concerns about what will become of them and who will take care of them as well as the desire to help care for the dying person. While it is commonly thought that this fear is felt more significantly by children/youth who have a dying or deceased parent, siblings of dying or deceased children appear to be just as challenged. They will experience the same break in their belief that their family member will always be with them.20 Also, many children worry that their surviving parent will be incapacitated and unable to care for them after the death. Four-year-old Alex looked up at his mom one night and said, “You are dying in front of me. I'm scared. Who is going to turn out the light, I can't reach it, and who will cook for me, I can't turn on the stove?” This fear extends beyond who will take over the practical parental roles, to the worry that the child or youth will be orphaned.
Children will often connect their own experience to what they have seen or heard and fear the worst.[18] and [21] Orphans are ever present in children's literature and movies and are often depicted as abandoned to fend for themselves. For many, this fear is grounded in the reality that their current caregiver may not have been emotionally able to address issues of custody or guardianship or that they do not have anyone willing or able to care for the kids after their death. As Alice lay on her bedroom floor writing notes to her dying mother in the critical care unit, she shared, “My mommy and my daddy are dying … they is both going to die,” convinced that this was the truth. Alice's dad is healthy and has been for all of Alice's life.
“Three Cs” and Adolescents
Occasionally, adults have questioned the relativity of the “Three Cs” to our adolescent (ages 13–18) population. Our clinical work has led us to conclude that indeed the “Three Cs” are very real in the lives of the youth we work with. An example of this in relation to “Catch” is Sarah, who expressed distress over the familial traits of breast cancer and the likelihood that her fate will one day mirror that of her mother, aunt, and grandmother.
With regard to “Cause,” we hear youth talk about the relationship between the quality of their caregiving efforts and the death of their family member. Many youth express a feeling that if they had done a better job caregiving, their family member would not have died, especially for youth in primary caregiving roles and single-parent homes.14
When looking at “Care,” youth are impacted by their ability to think abstractly and to experience the loss of what is yet to come. Youth understand that they depend on their caregivers for much more than their practical needs. Joshua talked to his counselor about the loss he was feeling as he searched for employment without his father's help and network. He shared, “If my Dad was here, he would know someone; he would know what I should do.” Important to note is that age is not always the best predictor of cognitive capacity as we see school-aged children grapple with many of the thoughts more commonly expressed by our older population.
Whether or not a caregiver has already spoken with a child about a diagnosis and prognosis, it is helpful to get him or her to consider what the child may be thinking about. Using the foundation of the “Three Cs” will help caregivers understand the importance of open, honest, and concrete communication, as well as feel better equipped to provide their child/youth with support.
Teaching Parents How to Communicate with Their Children
It is difficult for a parent to witness the reaction of a child/youth to such difficult information. This challenge cannot be questioned. However, the benefit to children/youth of having their parents lead or participate in communications and psychoeducation about the cancer and terminal prognosis is clear.[6], [7], [8] and [12] Caregivers are able to clarify assumptions and misperceptions while modeling that it is permissible to talk about cancer and dying together.
Medical staff can facilitate opportunities for such family communications by including children in family meetings and discussions with medical staff and by explaining complex concepts to family members in a simple, concrete fashion. Caregivers often need professionals to welcome and encourage the children to be included. Staff can reassure parents that although they may fear that their children's inclusion will be harmful, on the contrary, inclusion is helpful.
Getting Started
1 Ask what the child/youth understands about the disease/illness.
2 Fill in any gaps in their understanding and explain the treatments that were given.
3 Explain cancer treatments such as chemotherapy, radiation, and surgery.
4 Ask the child/youth what he or she thinks is going to happen.
5 Explain in terms that can be understood that the family member will die.
In any conversation with children/youth about such complex and consequential material, follow their lead in regard to the amount of detail they want. Conceptualize it as an onion: You will want to provide the child/youth with clear and simple language describing basic information. Beyond that, peel off subsequent layers as the child/youth requests more information, always using clear and concrete language. The child/youth may be uncomfortable with the material and may attempt to change the topic. This is a healthy coping mechanism; the average child is quite good at knowing when he or she has reached the limit of their emotional attention span. Allow the child to take the conversation in a different direction, periodically checking to see if he or she is ready to come back to the topic at hand. The benefit of starting this course of conversation early is that it allows children/youth the chance to receive information in small, digestible pieces and the time to process and integrate the information to begin to make meaning of it.
Summary
“What about the kids?” is a dominant and consuming question for caregivers supporting children/youth around the dying and death of a family member. The concerns and fears encompassed in this question can overwhelm caregivers as they put vast amounts of energy into trying to protect children/youth from the suffering and pain that awaits them. Perhaps the hardest lesson these caregivers must learn is that they cannot protect their child/youth from the death any more than they can stop the death from happening. Instead, what is needed most from children/youth is to be included, prepared, and provided with a safe place for emotional expression. Children, as well as adults, will grieve in their own specific way, mediated by their developmental level, circumstances of the illness and death, and protective factors available to them. Providing comprehensive, whole-person care to palliative patients with children/youth in their care ought to include psychoeducation and support for all members of the family. Our communities' bereaved children/youth will be impacted by the death of their family members in countless ways throughout their lives. As professionals caring for people who are dying, we have a responsibility to mediate this impact to the best of our ability.
References1
1 J. Bowlby, Pathological mourning and childhood mourning, J Am Psychoanal Assoc 11 (1963), pp. 500–541. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (48)
2 L. Dowdney, Annotation: childhood bereavement following parental death, J Child Psychol Psychiat 41 (7) (2000), pp. 819–830. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (68)
3 K. Kirwin and V. Hamrin, Decreasing the risk of complicated bereavement and future psych disorders in children, J Child Adolesc Psychiat Nurs 18 (2) (2005), pp. 62–78. View Record in Scopus | Cited By in Scopus (10)
4 L. Saler and N. Skoinick, Childhood parental death and depression in adulthood: roles of surviving parent and family environment, Am J Orthopsychiatry 62 (4) (1992), pp. 504–516. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (35)
5 G. Mireault and L. Bond, Parental death in childhood: perceived vulnerability, and adult depression and anxiety, Am J Orthopsychiatry 62 (4) (1992), pp. 517–524. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)
6 G. Christ and A. Christ, Current approaches to helping children cope with a parent's terminal illness, CA Cancer J Clin 56 (2006), pp. 197–212. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (13)
7 P.R. Silverman, Never Too Young to Know: Death in Children's Lives, Oxford University Press, New York (2000).
8 J.W. Warden, Children and Grief: When a Parent Dies, Guilford Press, New York (1996).
9 L. Dowdney, R. Wilson, B. Maughan, M. Allerton, P. Schofield and D. Skuse, Psychological disturbance and service provision in parentally bereaved children: prospective case–control study, BMJ 319 (7206) (1999), pp. 354–357. View Record in Scopus | Cited By in Scopus (25)
10 C. MacPherson, Telling children their ill parent is dying: a study of the factors influencing the well parent, Mortality 10 (2) (2005), pp. 113–120.
11 C. Eaton-Russell, Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers, Temmy Latner Centre for Palliative Care, Toronto (2007).
12 D. Black, Childhood bereavement: distress and long term sequelae can be lessened by early intervention, BMJ 312 (1996), p. 1496. View Record in Scopus | Cited By in Scopus (14)
13 S. Leighton, Bereavement therapy with adolescents—facilitating a process of spiritual growth, J Child Adolesc Psychiatr Nurs 21 (1) (2008), pp. 24–34. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (4)
14 T. Rando, Grief, Dying, and Death: Clinical Interventions for Caregivers, Research Press, Champaign, IL (1984).
15 J. Stokes, Anticipatory grief in families affected by HIV/AIDS, Prog Palliat Care 2 (1994), pp. 43–48.
16 C. Christ and S. Weisenfluh, Parent and child bereavement. In: D. Walsh, Editor, Palliative Medicine (1st ed.), Saunders, Philadelphia (2008).
17 L. Kroll, J. Barnes, A.L. Jones and A. Stein, Cancer in parents: telling children, BMJ 316 (1998), p. 880. View Record in Scopus | Cited By in Scopus (22)
18 J. Piaget, Piaget's theory. In: P. Mussen, Editor, Handbook of Child Psychology (4th ed.), John Wiley & Sons, New York (1970), pp. 703–732.
19 M. Van Riper, Death of a sibling: five sisters, five stories, Pediatr Nurs 23 (6) (1997), pp. 587–593.
20 F. Thompson and S. Payne, Bereaved children's questions to a doctor, Mortality 5 (1) (2000), pp. 74–96. Full Text via CrossRef
21 C.M. Burns, T.W. LeBlanc, A. Abernethy and D. Currow, Young caregivers in the end-of-life setting: a population-based profile of an emerging group, J Palliat Med 13 (10) (2010), pp. 1225–1235. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)
Children are too often the forgotten mourners in the homes of dying patients. Children, even young children, and youth grieve and mourn the threatened and, then, actual loss of a dying parent, sibling, or other significant family member.1 At a time when the family resources and focus are pulled away and taxed, caregivers are tasked with the difficult job of sorting through their own emotions and a wealth of advice. Caregivers must decide how they will communicate with, include, and support the children/youth in their care.
Although evidence is incomplete and there is a clear need for further studies, links between unresolved childhood grief, or an inability to adequately process their grief, and subsequent psychiatric conditions such as depression and anxiety have been presented as far back as Freud.[2], [3], [4] and [5] In addition, prevalent feelings of responsibility and exclusion and poor communication are consistently identified by researchers interviewing bereaved children/youth about their own experience over the last couple of decades.[6], [7] and [8] Therefore, given the risk of negative psychological and social outcomes associated with children's grief and the struggles communicated by children themselves, it is critical to recognize the important and preventive role of supportive interventions, especially prior to the death of a significant family member.
Looking at caregivers' experiences, there is still a large divide between the advice given by many family and friends in this situation (see Table 1) and what has become accepted within the palliative and grief counseling fields as “best practice.”[6], [7] and [8] In addition, family members' access to professionals trained or knowledgeable in this area is growing but usually still limited.9 Many children/youth are left uninformed, unprepared, and cut off from their family's support.
Table 1. Myths and Realities about Speaking to Children about Grief and Dying. Adapted from MacPherson C.10
Professionals are not immune to subscribing to the myths listed in Table 1 and “are often inhibited by their anxieties about saying or doing the wrong thing and causing lasting emotional damage.”10 However, by communicating openly and honestly and including children/youth, informed care team members can offer many supportive interventions that a family can benefit from during the time leading up to and following the death. These interventions foster the best outcomes when they are offered early on in the palliative trajectory.[11] and [12]
Our Setting
The Temmy Latner Centre for Palliative Care (TLCPC) at Mount Sinai Hospital in Toronto is one of Canada's largest academic palliative care programs, incorporating a children's center, the Max and Beatrice Wolfe Children's Centre, which provides pediatric palliative care and children's grief programs (Dr. Jay Children's Grief Program). Our children's center supports children, youth, and their families when a family member is dying or has died. This support includes Canada's first Camp Erin, an overnight children's grief camp. Children are referred to these programs for grief counseling by our center's palliative care physicians, local palliative care units and hospices, and a wide variety of community agencies. Children's grief programs are very limited in our large urban setting, as is true in most communities across North America. We have four counselors devoted to child and youth grief support services.
What We Do
Action 1: Intake and Assessment
The center has an open referral policy, accepting referrals from any source, including self-referrals, regardless of the nature of the illness or cause of death.
An intake phone call, lasting between 15 and 60 minutes, is made to the family to assess their needs and to provide psychoeducation and relevant resources. Based on our belief that early intervention provides the most supportive opportunities, families in which the patient is dying are prioritized.
As a result of demand for services being greater than our resources, children and their families bereaved at the time of referral are provided with an initial psychoeducational visit and assessment and then placed on a waiting list if further counseling is deemed appropriate.
In either case, the initial assessment often reveals that what the family needs most is psychoeducation about child/youth grief, communication and development, and reassurance about the benefits of the things they are already doing. Caregivers are provided with educational materials, including a copy of the center's publication Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers,11 a list of Web resources, books, and brochures written by us. All these resources are also available to professionals.
Action 2: Counseling
If further assessment and counseling are warranted, children are seen individually, with siblings and/or with their family depending on the needs and circumstances. The bulk of our counseling services are brief, typically lasting three or four sessions in total. However, more intensive counseling is available on a case-by-case basis, with progress and needs being assessed every four sessions. Counseling techniques including expressive arts, crafts, therapeutic play, and activities are used to support children/youth and families in the grieving process. Families are able to contact counselors when issues arise for them, which often occurs around anniversaries, holidays, other important events, and as children/youth develop and experience their grief in a new light.13
The center's model is resiliency-based, nonpathological, and family-centered. Caregivers are empowered as primary and ongoing sources of support and dominant role models for the grieving child and youth in their care. In addition to conversations with their counselor, families are offered monthly opportunities forcaregiver education and peer support and various therapeutic group activities for children/youth.
Action 3: Complex Cases
Referrals to secondary children's mental health services are facilitated for families with needs beyond the scope of our supportive grief services, including children with indicators of complicated grief who need more intensive counseling. For children with severe psychological distress, referrals are made to a pediatric psychiatrist with special interest in this area.
According to Rando,14 there are a number of forms of unresolved or complicated grief which can overlap, and each has components of denial or regression. These include feelings of grief and mourning being absent, an inhibition of some of the normal symptoms of grief, putting grief on hold for any reason, and when there is a dependent or ambivalent relationship with the deceased. Two common manifestations are extreme anger and extreme guilt.
Some types of death that place children/youth at risk for complicated grief include a sudden or unexpected death, a violent death, a death involving mutilation, the death of a child, and death as the result of a prolonged illness. Also included is complicated loss associated with social stigma such as imprisonment, suicide, AIDS, abortion, severe mental illness, serious family dysfunction, or addiction. However, the presence of these factors does not necessarily lead to complicated grief. Complicated loss is known to be mediated by personal, familial, and social factors that contribute to relative risk and resilience.
What We Say
Engaging a family early in the palliative journey allows greater opportunity to prepare children/youth and prevent possible negative outcomes.[6] and [15] Christ and Weisenfluh16 tell us that the greatest need for support is found during the weeks leading up to the death. A large component of the early intervention we offer is age-appropriate psychoeducation to help caregivers conceptualize how their child/youth may be experiencing and understanding what is happening. Caregivers who anticipate some of the thoughts, feelings, questions, and struggles that their child/youth might face are empowered and children benefit.
The 3 Cs
1. Can I catch it?
2. Did I cause it?
3. Who is going to take care of me?
Julie Stokes15 was able to summarize what children/youth think and worry about most when a family member is dying into three questions. We have coined these three questions the “Three Cs”: Catch, Cause, and Care.
Catch
The first “C” relates to the fear expressed by children/youth that they could catch the illness. Melanie, a 7-year-old, explained that she would have a brain tumor soon because her sister Sarah, who was dying of brain cancer at the time, “is my sister and we lived in the same room always.” If such concerns go unexplored and children are not given clear information, caregivers may see children/youth distance themselves from their ill family member, develop a fear that they and the rest of their family will get sick and die as well, and other implications.17
The weight of language in a child's understanding of illness, death, and dying cannot be emphasized enough.11 More often than not, indirect and generic language used by adults, such as referring to someone as being “sick” or “not doing well,” complicates a child's ability to differentiate between the common cold or flu and life-threatening diseases and illnesses. “My mom was sick and she died; therefore, all people that are sick die.” Many adults believe that their child is too young to understand what cancer means. While it is true that children may not be able to grasp the complex medical information about the illness, they are able to understand a great deal more than they are given credit for, and using the word “cancer” gives them a way to distinguish their dying family member's illness from others such as the common cold or flu.
Cause
The second “C” arises from the common thought in children/youth that they somehow caused or hastened the death and/or prevented the recovery of their family member. Cause is one of the five accepted subconcepts of the developmental understanding of death8 and among the last to be mastered due to its complexity and abstract components. As she sat under her pink bunk-bed, 5-year-old Tayah told her counselor that she had cancer when she was a little girl and then her mother got it after her. Eleven-year-old Joshua shared, “I just have to get to that cancer walk thing. If I can do that, then my mom will get her cure. That is what they said on TV you know, to walk for the cure!”
There are a number of ways that children/youth may try to own responsibility for the illness and death of their family member. They may believe that things they thought or did not think, did or did not do, felt or did not feel were directly related to the cause, progression, or death of the family member.18 These thoughts are especially strong for children in the magical thinking stage of development. In Piaget's theory of cognitive development, magical thinking dominates the preoperational stage (2–7 years old) and describes thinking disconnected from the laws of nature.19 Special attention should be given to assuring children in this age group that they are in no way responsible for the illness or death of their family member, as well as to avoid minimizing these fears and beliefs of responsibility.[6] and [17] This point will need to be readdressed often, with frequent reassurance that they are not responsible.
Care
The third “C” includes concerns about what will become of them and who will take care of them as well as the desire to help care for the dying person. While it is commonly thought that this fear is felt more significantly by children/youth who have a dying or deceased parent, siblings of dying or deceased children appear to be just as challenged. They will experience the same break in their belief that their family member will always be with them.20 Also, many children worry that their surviving parent will be incapacitated and unable to care for them after the death. Four-year-old Alex looked up at his mom one night and said, “You are dying in front of me. I'm scared. Who is going to turn out the light, I can't reach it, and who will cook for me, I can't turn on the stove?” This fear extends beyond who will take over the practical parental roles, to the worry that the child or youth will be orphaned.
Children will often connect their own experience to what they have seen or heard and fear the worst.[18] and [21] Orphans are ever present in children's literature and movies and are often depicted as abandoned to fend for themselves. For many, this fear is grounded in the reality that their current caregiver may not have been emotionally able to address issues of custody or guardianship or that they do not have anyone willing or able to care for the kids after their death. As Alice lay on her bedroom floor writing notes to her dying mother in the critical care unit, she shared, “My mommy and my daddy are dying … they is both going to die,” convinced that this was the truth. Alice's dad is healthy and has been for all of Alice's life.
“Three Cs” and Adolescents
Occasionally, adults have questioned the relativity of the “Three Cs” to our adolescent (ages 13–18) population. Our clinical work has led us to conclude that indeed the “Three Cs” are very real in the lives of the youth we work with. An example of this in relation to “Catch” is Sarah, who expressed distress over the familial traits of breast cancer and the likelihood that her fate will one day mirror that of her mother, aunt, and grandmother.
With regard to “Cause,” we hear youth talk about the relationship between the quality of their caregiving efforts and the death of their family member. Many youth express a feeling that if they had done a better job caregiving, their family member would not have died, especially for youth in primary caregiving roles and single-parent homes.14
When looking at “Care,” youth are impacted by their ability to think abstractly and to experience the loss of what is yet to come. Youth understand that they depend on their caregivers for much more than their practical needs. Joshua talked to his counselor about the loss he was feeling as he searched for employment without his father's help and network. He shared, “If my Dad was here, he would know someone; he would know what I should do.” Important to note is that age is not always the best predictor of cognitive capacity as we see school-aged children grapple with many of the thoughts more commonly expressed by our older population.
Whether or not a caregiver has already spoken with a child about a diagnosis and prognosis, it is helpful to get him or her to consider what the child may be thinking about. Using the foundation of the “Three Cs” will help caregivers understand the importance of open, honest, and concrete communication, as well as feel better equipped to provide their child/youth with support.
Teaching Parents How to Communicate with Their Children
It is difficult for a parent to witness the reaction of a child/youth to such difficult information. This challenge cannot be questioned. However, the benefit to children/youth of having their parents lead or participate in communications and psychoeducation about the cancer and terminal prognosis is clear.[6], [7], [8] and [12] Caregivers are able to clarify assumptions and misperceptions while modeling that it is permissible to talk about cancer and dying together.
Medical staff can facilitate opportunities for such family communications by including children in family meetings and discussions with medical staff and by explaining complex concepts to family members in a simple, concrete fashion. Caregivers often need professionals to welcome and encourage the children to be included. Staff can reassure parents that although they may fear that their children's inclusion will be harmful, on the contrary, inclusion is helpful.
Getting Started
1 Ask what the child/youth understands about the disease/illness.
2 Fill in any gaps in their understanding and explain the treatments that were given.
3 Explain cancer treatments such as chemotherapy, radiation, and surgery.
4 Ask the child/youth what he or she thinks is going to happen.
5 Explain in terms that can be understood that the family member will die.
In any conversation with children/youth about such complex and consequential material, follow their lead in regard to the amount of detail they want. Conceptualize it as an onion: You will want to provide the child/youth with clear and simple language describing basic information. Beyond that, peel off subsequent layers as the child/youth requests more information, always using clear and concrete language. The child/youth may be uncomfortable with the material and may attempt to change the topic. This is a healthy coping mechanism; the average child is quite good at knowing when he or she has reached the limit of their emotional attention span. Allow the child to take the conversation in a different direction, periodically checking to see if he or she is ready to come back to the topic at hand. The benefit of starting this course of conversation early is that it allows children/youth the chance to receive information in small, digestible pieces and the time to process and integrate the information to begin to make meaning of it.
Summary
“What about the kids?” is a dominant and consuming question for caregivers supporting children/youth around the dying and death of a family member. The concerns and fears encompassed in this question can overwhelm caregivers as they put vast amounts of energy into trying to protect children/youth from the suffering and pain that awaits them. Perhaps the hardest lesson these caregivers must learn is that they cannot protect their child/youth from the death any more than they can stop the death from happening. Instead, what is needed most from children/youth is to be included, prepared, and provided with a safe place for emotional expression. Children, as well as adults, will grieve in their own specific way, mediated by their developmental level, circumstances of the illness and death, and protective factors available to them. Providing comprehensive, whole-person care to palliative patients with children/youth in their care ought to include psychoeducation and support for all members of the family. Our communities' bereaved children/youth will be impacted by the death of their family members in countless ways throughout their lives. As professionals caring for people who are dying, we have a responsibility to mediate this impact to the best of our ability.
References1
1 J. Bowlby, Pathological mourning and childhood mourning, J Am Psychoanal Assoc 11 (1963), pp. 500–541. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (48)
2 L. Dowdney, Annotation: childhood bereavement following parental death, J Child Psychol Psychiat 41 (7) (2000), pp. 819–830. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (68)
3 K. Kirwin and V. Hamrin, Decreasing the risk of complicated bereavement and future psych disorders in children, J Child Adolesc Psychiat Nurs 18 (2) (2005), pp. 62–78. View Record in Scopus | Cited By in Scopus (10)
4 L. Saler and N. Skoinick, Childhood parental death and depression in adulthood: roles of surviving parent and family environment, Am J Orthopsychiatry 62 (4) (1992), pp. 504–516. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (35)
5 G. Mireault and L. Bond, Parental death in childhood: perceived vulnerability, and adult depression and anxiety, Am J Orthopsychiatry 62 (4) (1992), pp. 517–524. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)
6 G. Christ and A. Christ, Current approaches to helping children cope with a parent's terminal illness, CA Cancer J Clin 56 (2006), pp. 197–212. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (13)
7 P.R. Silverman, Never Too Young to Know: Death in Children's Lives, Oxford University Press, New York (2000).
8 J.W. Warden, Children and Grief: When a Parent Dies, Guilford Press, New York (1996).
9 L. Dowdney, R. Wilson, B. Maughan, M. Allerton, P. Schofield and D. Skuse, Psychological disturbance and service provision in parentally bereaved children: prospective case–control study, BMJ 319 (7206) (1999), pp. 354–357. View Record in Scopus | Cited By in Scopus (25)
10 C. MacPherson, Telling children their ill parent is dying: a study of the factors influencing the well parent, Mortality 10 (2) (2005), pp. 113–120.
11 C. Eaton-Russell, Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers, Temmy Latner Centre for Palliative Care, Toronto (2007).
12 D. Black, Childhood bereavement: distress and long term sequelae can be lessened by early intervention, BMJ 312 (1996), p. 1496. View Record in Scopus | Cited By in Scopus (14)
13 S. Leighton, Bereavement therapy with adolescents—facilitating a process of spiritual growth, J Child Adolesc Psychiatr Nurs 21 (1) (2008), pp. 24–34. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (4)
14 T. Rando, Grief, Dying, and Death: Clinical Interventions for Caregivers, Research Press, Champaign, IL (1984).
15 J. Stokes, Anticipatory grief in families affected by HIV/AIDS, Prog Palliat Care 2 (1994), pp. 43–48.
16 C. Christ and S. Weisenfluh, Parent and child bereavement. In: D. Walsh, Editor, Palliative Medicine (1st ed.), Saunders, Philadelphia (2008).
17 L. Kroll, J. Barnes, A.L. Jones and A. Stein, Cancer in parents: telling children, BMJ 316 (1998), p. 880. View Record in Scopus | Cited By in Scopus (22)
18 J. Piaget, Piaget's theory. In: P. Mussen, Editor, Handbook of Child Psychology (4th ed.), John Wiley & Sons, New York (1970), pp. 703–732.
19 M. Van Riper, Death of a sibling: five sisters, five stories, Pediatr Nurs 23 (6) (1997), pp. 587–593.
20 F. Thompson and S. Payne, Bereaved children's questions to a doctor, Mortality 5 (1) (2000), pp. 74–96. Full Text via CrossRef
21 C.M. Burns, T.W. LeBlanc, A. Abernethy and D. Currow, Young caregivers in the end-of-life setting: a population-based profile of an emerging group, J Palliat Med 13 (10) (2010), pp. 1225–1235. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)
Children are too often the forgotten mourners in the homes of dying patients. Children, even young children, and youth grieve and mourn the threatened and, then, actual loss of a dying parent, sibling, or other significant family member.1 At a time when the family resources and focus are pulled away and taxed, caregivers are tasked with the difficult job of sorting through their own emotions and a wealth of advice. Caregivers must decide how they will communicate with, include, and support the children/youth in their care.
Although evidence is incomplete and there is a clear need for further studies, links between unresolved childhood grief, or an inability to adequately process their grief, and subsequent psychiatric conditions such as depression and anxiety have been presented as far back as Freud.[2], [3], [4] and [5] In addition, prevalent feelings of responsibility and exclusion and poor communication are consistently identified by researchers interviewing bereaved children/youth about their own experience over the last couple of decades.[6], [7] and [8] Therefore, given the risk of negative psychological and social outcomes associated with children's grief and the struggles communicated by children themselves, it is critical to recognize the important and preventive role of supportive interventions, especially prior to the death of a significant family member.
Looking at caregivers' experiences, there is still a large divide between the advice given by many family and friends in this situation (see Table 1) and what has become accepted within the palliative and grief counseling fields as “best practice.”[6], [7] and [8] In addition, family members' access to professionals trained or knowledgeable in this area is growing but usually still limited.9 Many children/youth are left uninformed, unprepared, and cut off from their family's support.
Table 1. Myths and Realities about Speaking to Children about Grief and Dying. Adapted from MacPherson C.10
Professionals are not immune to subscribing to the myths listed in Table 1 and “are often inhibited by their anxieties about saying or doing the wrong thing and causing lasting emotional damage.”10 However, by communicating openly and honestly and including children/youth, informed care team members can offer many supportive interventions that a family can benefit from during the time leading up to and following the death. These interventions foster the best outcomes when they are offered early on in the palliative trajectory.[11] and [12]
Our Setting
The Temmy Latner Centre for Palliative Care (TLCPC) at Mount Sinai Hospital in Toronto is one of Canada's largest academic palliative care programs, incorporating a children's center, the Max and Beatrice Wolfe Children's Centre, which provides pediatric palliative care and children's grief programs (Dr. Jay Children's Grief Program). Our children's center supports children, youth, and their families when a family member is dying or has died. This support includes Canada's first Camp Erin, an overnight children's grief camp. Children are referred to these programs for grief counseling by our center's palliative care physicians, local palliative care units and hospices, and a wide variety of community agencies. Children's grief programs are very limited in our large urban setting, as is true in most communities across North America. We have four counselors devoted to child and youth grief support services.
What We Do
Action 1: Intake and Assessment
The center has an open referral policy, accepting referrals from any source, including self-referrals, regardless of the nature of the illness or cause of death.
An intake phone call, lasting between 15 and 60 minutes, is made to the family to assess their needs and to provide psychoeducation and relevant resources. Based on our belief that early intervention provides the most supportive opportunities, families in which the patient is dying are prioritized.
As a result of demand for services being greater than our resources, children and their families bereaved at the time of referral are provided with an initial psychoeducational visit and assessment and then placed on a waiting list if further counseling is deemed appropriate.
In either case, the initial assessment often reveals that what the family needs most is psychoeducation about child/youth grief, communication and development, and reassurance about the benefits of the things they are already doing. Caregivers are provided with educational materials, including a copy of the center's publication Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers,11 a list of Web resources, books, and brochures written by us. All these resources are also available to professionals.
Action 2: Counseling
If further assessment and counseling are warranted, children are seen individually, with siblings and/or with their family depending on the needs and circumstances. The bulk of our counseling services are brief, typically lasting three or four sessions in total. However, more intensive counseling is available on a case-by-case basis, with progress and needs being assessed every four sessions. Counseling techniques including expressive arts, crafts, therapeutic play, and activities are used to support children/youth and families in the grieving process. Families are able to contact counselors when issues arise for them, which often occurs around anniversaries, holidays, other important events, and as children/youth develop and experience their grief in a new light.13
The center's model is resiliency-based, nonpathological, and family-centered. Caregivers are empowered as primary and ongoing sources of support and dominant role models for the grieving child and youth in their care. In addition to conversations with their counselor, families are offered monthly opportunities forcaregiver education and peer support and various therapeutic group activities for children/youth.
Action 3: Complex Cases
Referrals to secondary children's mental health services are facilitated for families with needs beyond the scope of our supportive grief services, including children with indicators of complicated grief who need more intensive counseling. For children with severe psychological distress, referrals are made to a pediatric psychiatrist with special interest in this area.
According to Rando,14 there are a number of forms of unresolved or complicated grief which can overlap, and each has components of denial or regression. These include feelings of grief and mourning being absent, an inhibition of some of the normal symptoms of grief, putting grief on hold for any reason, and when there is a dependent or ambivalent relationship with the deceased. Two common manifestations are extreme anger and extreme guilt.
Some types of death that place children/youth at risk for complicated grief include a sudden or unexpected death, a violent death, a death involving mutilation, the death of a child, and death as the result of a prolonged illness. Also included is complicated loss associated with social stigma such as imprisonment, suicide, AIDS, abortion, severe mental illness, serious family dysfunction, or addiction. However, the presence of these factors does not necessarily lead to complicated grief. Complicated loss is known to be mediated by personal, familial, and social factors that contribute to relative risk and resilience.
What We Say
Engaging a family early in the palliative journey allows greater opportunity to prepare children/youth and prevent possible negative outcomes.[6] and [15] Christ and Weisenfluh16 tell us that the greatest need for support is found during the weeks leading up to the death. A large component of the early intervention we offer is age-appropriate psychoeducation to help caregivers conceptualize how their child/youth may be experiencing and understanding what is happening. Caregivers who anticipate some of the thoughts, feelings, questions, and struggles that their child/youth might face are empowered and children benefit.
The 3 Cs
1. Can I catch it?
2. Did I cause it?
3. Who is going to take care of me?
Julie Stokes15 was able to summarize what children/youth think and worry about most when a family member is dying into three questions. We have coined these three questions the “Three Cs”: Catch, Cause, and Care.
Catch
The first “C” relates to the fear expressed by children/youth that they could catch the illness. Melanie, a 7-year-old, explained that she would have a brain tumor soon because her sister Sarah, who was dying of brain cancer at the time, “is my sister and we lived in the same room always.” If such concerns go unexplored and children are not given clear information, caregivers may see children/youth distance themselves from their ill family member, develop a fear that they and the rest of their family will get sick and die as well, and other implications.17
The weight of language in a child's understanding of illness, death, and dying cannot be emphasized enough.11 More often than not, indirect and generic language used by adults, such as referring to someone as being “sick” or “not doing well,” complicates a child's ability to differentiate between the common cold or flu and life-threatening diseases and illnesses. “My mom was sick and she died; therefore, all people that are sick die.” Many adults believe that their child is too young to understand what cancer means. While it is true that children may not be able to grasp the complex medical information about the illness, they are able to understand a great deal more than they are given credit for, and using the word “cancer” gives them a way to distinguish their dying family member's illness from others such as the common cold or flu.
Cause
The second “C” arises from the common thought in children/youth that they somehow caused or hastened the death and/or prevented the recovery of their family member. Cause is one of the five accepted subconcepts of the developmental understanding of death8 and among the last to be mastered due to its complexity and abstract components. As she sat under her pink bunk-bed, 5-year-old Tayah told her counselor that she had cancer when she was a little girl and then her mother got it after her. Eleven-year-old Joshua shared, “I just have to get to that cancer walk thing. If I can do that, then my mom will get her cure. That is what they said on TV you know, to walk for the cure!”
There are a number of ways that children/youth may try to own responsibility for the illness and death of their family member. They may believe that things they thought or did not think, did or did not do, felt or did not feel were directly related to the cause, progression, or death of the family member.18 These thoughts are especially strong for children in the magical thinking stage of development. In Piaget's theory of cognitive development, magical thinking dominates the preoperational stage (2–7 years old) and describes thinking disconnected from the laws of nature.19 Special attention should be given to assuring children in this age group that they are in no way responsible for the illness or death of their family member, as well as to avoid minimizing these fears and beliefs of responsibility.[6] and [17] This point will need to be readdressed often, with frequent reassurance that they are not responsible.
Care
The third “C” includes concerns about what will become of them and who will take care of them as well as the desire to help care for the dying person. While it is commonly thought that this fear is felt more significantly by children/youth who have a dying or deceased parent, siblings of dying or deceased children appear to be just as challenged. They will experience the same break in their belief that their family member will always be with them.20 Also, many children worry that their surviving parent will be incapacitated and unable to care for them after the death. Four-year-old Alex looked up at his mom one night and said, “You are dying in front of me. I'm scared. Who is going to turn out the light, I can't reach it, and who will cook for me, I can't turn on the stove?” This fear extends beyond who will take over the practical parental roles, to the worry that the child or youth will be orphaned.
Children will often connect their own experience to what they have seen or heard and fear the worst.[18] and [21] Orphans are ever present in children's literature and movies and are often depicted as abandoned to fend for themselves. For many, this fear is grounded in the reality that their current caregiver may not have been emotionally able to address issues of custody or guardianship or that they do not have anyone willing or able to care for the kids after their death. As Alice lay on her bedroom floor writing notes to her dying mother in the critical care unit, she shared, “My mommy and my daddy are dying … they is both going to die,” convinced that this was the truth. Alice's dad is healthy and has been for all of Alice's life.
“Three Cs” and Adolescents
Occasionally, adults have questioned the relativity of the “Three Cs” to our adolescent (ages 13–18) population. Our clinical work has led us to conclude that indeed the “Three Cs” are very real in the lives of the youth we work with. An example of this in relation to “Catch” is Sarah, who expressed distress over the familial traits of breast cancer and the likelihood that her fate will one day mirror that of her mother, aunt, and grandmother.
With regard to “Cause,” we hear youth talk about the relationship between the quality of their caregiving efforts and the death of their family member. Many youth express a feeling that if they had done a better job caregiving, their family member would not have died, especially for youth in primary caregiving roles and single-parent homes.14
When looking at “Care,” youth are impacted by their ability to think abstractly and to experience the loss of what is yet to come. Youth understand that they depend on their caregivers for much more than their practical needs. Joshua talked to his counselor about the loss he was feeling as he searched for employment without his father's help and network. He shared, “If my Dad was here, he would know someone; he would know what I should do.” Important to note is that age is not always the best predictor of cognitive capacity as we see school-aged children grapple with many of the thoughts more commonly expressed by our older population.
Whether or not a caregiver has already spoken with a child about a diagnosis and prognosis, it is helpful to get him or her to consider what the child may be thinking about. Using the foundation of the “Three Cs” will help caregivers understand the importance of open, honest, and concrete communication, as well as feel better equipped to provide their child/youth with support.
Teaching Parents How to Communicate with Their Children
It is difficult for a parent to witness the reaction of a child/youth to such difficult information. This challenge cannot be questioned. However, the benefit to children/youth of having their parents lead or participate in communications and psychoeducation about the cancer and terminal prognosis is clear.[6], [7], [8] and [12] Caregivers are able to clarify assumptions and misperceptions while modeling that it is permissible to talk about cancer and dying together.
Medical staff can facilitate opportunities for such family communications by including children in family meetings and discussions with medical staff and by explaining complex concepts to family members in a simple, concrete fashion. Caregivers often need professionals to welcome and encourage the children to be included. Staff can reassure parents that although they may fear that their children's inclusion will be harmful, on the contrary, inclusion is helpful.
Getting Started
1 Ask what the child/youth understands about the disease/illness.
2 Fill in any gaps in their understanding and explain the treatments that were given.
3 Explain cancer treatments such as chemotherapy, radiation, and surgery.
4 Ask the child/youth what he or she thinks is going to happen.
5 Explain in terms that can be understood that the family member will die.
In any conversation with children/youth about such complex and consequential material, follow their lead in regard to the amount of detail they want. Conceptualize it as an onion: You will want to provide the child/youth with clear and simple language describing basic information. Beyond that, peel off subsequent layers as the child/youth requests more information, always using clear and concrete language. The child/youth may be uncomfortable with the material and may attempt to change the topic. This is a healthy coping mechanism; the average child is quite good at knowing when he or she has reached the limit of their emotional attention span. Allow the child to take the conversation in a different direction, periodically checking to see if he or she is ready to come back to the topic at hand. The benefit of starting this course of conversation early is that it allows children/youth the chance to receive information in small, digestible pieces and the time to process and integrate the information to begin to make meaning of it.
Summary
“What about the kids?” is a dominant and consuming question for caregivers supporting children/youth around the dying and death of a family member. The concerns and fears encompassed in this question can overwhelm caregivers as they put vast amounts of energy into trying to protect children/youth from the suffering and pain that awaits them. Perhaps the hardest lesson these caregivers must learn is that they cannot protect their child/youth from the death any more than they can stop the death from happening. Instead, what is needed most from children/youth is to be included, prepared, and provided with a safe place for emotional expression. Children, as well as adults, will grieve in their own specific way, mediated by their developmental level, circumstances of the illness and death, and protective factors available to them. Providing comprehensive, whole-person care to palliative patients with children/youth in their care ought to include psychoeducation and support for all members of the family. Our communities' bereaved children/youth will be impacted by the death of their family members in countless ways throughout their lives. As professionals caring for people who are dying, we have a responsibility to mediate this impact to the best of our ability.
References1
1 J. Bowlby, Pathological mourning and childhood mourning, J Am Psychoanal Assoc 11 (1963), pp. 500–541. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (48)
2 L. Dowdney, Annotation: childhood bereavement following parental death, J Child Psychol Psychiat 41 (7) (2000), pp. 819–830. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (68)
3 K. Kirwin and V. Hamrin, Decreasing the risk of complicated bereavement and future psych disorders in children, J Child Adolesc Psychiat Nurs 18 (2) (2005), pp. 62–78. View Record in Scopus | Cited By in Scopus (10)
4 L. Saler and N. Skoinick, Childhood parental death and depression in adulthood: roles of surviving parent and family environment, Am J Orthopsychiatry 62 (4) (1992), pp. 504–516. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (35)
5 G. Mireault and L. Bond, Parental death in childhood: perceived vulnerability, and adult depression and anxiety, Am J Orthopsychiatry 62 (4) (1992), pp. 517–524. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (28)
6 G. Christ and A. Christ, Current approaches to helping children cope with a parent's terminal illness, CA Cancer J Clin 56 (2006), pp. 197–212. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (13)
7 P.R. Silverman, Never Too Young to Know: Death in Children's Lives, Oxford University Press, New York (2000).
8 J.W. Warden, Children and Grief: When a Parent Dies, Guilford Press, New York (1996).
9 L. Dowdney, R. Wilson, B. Maughan, M. Allerton, P. Schofield and D. Skuse, Psychological disturbance and service provision in parentally bereaved children: prospective case–control study, BMJ 319 (7206) (1999), pp. 354–357. View Record in Scopus | Cited By in Scopus (25)
10 C. MacPherson, Telling children their ill parent is dying: a study of the factors influencing the well parent, Mortality 10 (2) (2005), pp. 113–120.
11 C. Eaton-Russell, Living Dying: A Guide for Adults Supporting Grieving Children and Teenagers, Temmy Latner Centre for Palliative Care, Toronto (2007).
12 D. Black, Childhood bereavement: distress and long term sequelae can be lessened by early intervention, BMJ 312 (1996), p. 1496. View Record in Scopus | Cited By in Scopus (14)
13 S. Leighton, Bereavement therapy with adolescents—facilitating a process of spiritual growth, J Child Adolesc Psychiatr Nurs 21 (1) (2008), pp. 24–34. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (4)
14 T. Rando, Grief, Dying, and Death: Clinical Interventions for Caregivers, Research Press, Champaign, IL (1984).
15 J. Stokes, Anticipatory grief in families affected by HIV/AIDS, Prog Palliat Care 2 (1994), pp. 43–48.
16 C. Christ and S. Weisenfluh, Parent and child bereavement. In: D. Walsh, Editor, Palliative Medicine (1st ed.), Saunders, Philadelphia (2008).
17 L. Kroll, J. Barnes, A.L. Jones and A. Stein, Cancer in parents: telling children, BMJ 316 (1998), p. 880. View Record in Scopus | Cited By in Scopus (22)
18 J. Piaget, Piaget's theory. In: P. Mussen, Editor, Handbook of Child Psychology (4th ed.), John Wiley & Sons, New York (1970), pp. 703–732.
19 M. Van Riper, Death of a sibling: five sisters, five stories, Pediatr Nurs 23 (6) (1997), pp. 587–593.
20 F. Thompson and S. Payne, Bereaved children's questions to a doctor, Mortality 5 (1) (2000), pp. 74–96. Full Text via CrossRef
21 C.M. Burns, T.W. LeBlanc, A. Abernethy and D. Currow, Young caregivers in the end-of-life setting: a population-based profile of an emerging group, J Palliat Med 13 (10) (2010), pp. 1225–1235. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)
Providing Pain and Palliative Care Education Internationally
Volume 9, Issue 4, July-August 2011, Pages 129-133
How we do it
Judith A. Paice PhD, RN
Available online 2 July 2011.
Article Outline
For many clinicians in oncology, educating other health-care professionals about cancer pain and palliative care is part of their professional life. The need for education exists across clinical settings around the world. Improved education is an urgent need as the prevalence of cancer is increasing. This burden is largely carried by the developing world, where resources are often limited.[1] Global educational efforts, including managing common symptoms, communication, care at the time of death, grief, and other topics, are imperative to reduce pain and suffering.[2] International training efforts require additional expertise and preparation beyond the standard teaching skills needed for all professional education.
The goal of international training efforts in pain and palliative care is to provide useful, culturally relevant programs while empowering participants to sustain these efforts in the long term. Global efforts in palliative care have demonstrated that sharing educational materials, resources, support and encouragement with our international colleagues can provide mentorship to go beyond simply attending a course to developing and expanding their own programs of palliative care in oncology.[3] and [4] To do this well, the following provides specific suggestions for before, during, and after international palliative care training experiences.
Do Your Homework
Before a course, it is essential to learn as much as possible about the region, the culture(s), and the health-care system. Several resources for this information are listed in Table 1. Additionally, speaking with colleagues who have traveled to the country or to those who have emigrated from the country can provide valuable insight. These individuals can provide a wealth of information to assist in developing an appropriate curriculum and specific presentations. As demographics vary, it is important to know the common cancers and other leading causes of death in the region. Issues that may be seen as “competing” issues HIV/AIDS, malaria, immunizations, lack of clean water, or maternal–infant mortality.[5] and [6] Literature, including fiction and nonfiction, as well as movies and other media, can enlighten the traveler regarding life in the region. Local consulates offer opportunities for learning, as do organizations such as the Council on Global Relations. There are rapid changes in global politics, health-care systems, and governments, so it is also vital to have current information.
| American Society for Clinical Oncology (ASCO) | Offers international cancer courses as well as fellowships and other awards. |
| Centers for Disease Control and Prevention (CDC), http://wwwnc.cdc.gov/travel/ | Provides information regarding common infectious illnesses, traveler's alerts. |
| Central Intelligence Agency (CIA), The World Factbook, https://www.cia.gov/library/publications/the-world-factbook/ | Excellent review of a country's political, demographic, geographic, and other attributes. |
| City of Hope Pain & Palliative Care Resource Center, http://prc.coh.org/ | Provides a clearinghouse that includes a wide array of resources and references to enhance pain and palliative care education and research. |
| End of Life Nursing Education Consortium (ELNEC), http://www.aacn.nche.edu/elnec/ | Includes relevant articles, resources, and a summary of current international ELNEC training programs. |
| International Association for Hospice and Palliative Care (IAHPC), http://www.hospicecare.com/ | Numerous global palliative care resources, including List of Essential Medicines, Global Directory of Educational Programs in Palliative Care, Global Directory of Palliative Care Providers/Services/Organizations, as well as Palliative Care in the Developing World: Principles and Practice. |
| International Association for the Study of Pain (IASP), http://www.iasp-pain.org/ | Strong emphasis on support of developing countries with research and educational grants; publishes a Guide to Pain Management in Low-Resource Settings offered without cost. |
| Open Society Institute–International Palliative Care Initiative, http://www.soros.org/initiatives/health/focus/ipci/about | Offers support for training, clinical care, and research in palliative care, alone and in collaboration with other organizations. |
| Pain & Policy Studies Group, http://www.painpolicy.wisc.edu/ | Excellent resource for information regarding opioid consumption by country as well as guidelines for policies that allow access to necessary medications. |
| U.S. Department of State, http://www.usembassy.gov/ Bureau of Consular Affairs, http://travel.state.gov/travel/travel_1744.html | Comprehensive lists of US embassies, consulates, and diplomatic missions; information to assist travelers from the United States to other countries, including visa requirements and safety alerts. |
| World Health Organization, http://www.who.int | Many useful resources, including Access to Analgesics and to other Controlled Medicines, as well as statistics regarding common illnesses by country. |
Health-Care Structure
Understand the existing health-care structure and what health care is available to all or for select populations. What is the extent of health-care services? Are there clinics for preventive care, or is most care obtained in the hospital? Is home care available with support from nurses and other professionals? Are emergency services available (eg, does the region have ambulances to transport and emergency departments to accept critically ill patients)? Where do patients obtain medications, and do they have to pay out of pocket for these? Do most people die in the hospital or at home? While websites and government sources are valuable, verify this information with clinicians since the clinical reality may be quite different.
Available Medications
To provide useful guidance in symptom management, it is necessary to have a list of available medications used to treat pain, nausea, dyspnea, constipation/diarrhea, wounds, and other symptoms commonly seen in oncology. Your presentation may need to be modified based upon these available drugs (Table 2). Where do patients obtain medications, and do they pay out of pocket for these? There are limitations on availability and access to opioids around the world.[7] Which opioids are available and actually used? What is the process for obtaining a supply of an opioid for a person with cancer? For example, in some countries, physicians can order only one week's worth of medication at a time. In other countries, patients must obtain opioids from the police station rather than a pharmacy. In several settings, only the patient, not family members, can pick up the medication from the dispensing site. And in a few countries, only parenteral opioids are available. It is also helpful to understand issues such as the prevalence of drug trafficking in the region and how this might affect local drug laws. Are traditional medicines, such as herbal therapies, or other techniques commonly used? It is helpful to be aware of these practices and incorporate them into teaching plans where appropriate.
Education of Health-Care Professionals
International education in palliative care should consider how physicians, nurses, pharmacists, and others are educated. Is the educational system very traditional and formal, with little interaction between students and teachers? Professionals trained in this manner may be less comfortable when faced with role-play, learning through discussion, or other Socratic educational methods. That does not mean that one should exclude these methods when planning the curriculum but, rather, be prepared for silence and possibly even discomfort when first introduced. Seek guidance from local educators as to what methods will be acceptable.
Who is included in the health-care team? Are psychologists available, and are chaplains considered part of health-care services? What is the relationship between physicians, nurses, and other team members? Is collegiality accepted, or is there a hierarchy that limits true teamwork? What is the status of physicians, nurses, and other professionals in the region? In some areas, physicians are highly regarded and financially compensated accordingly. In other parts of the world, physicians have very low social status, respect, and compensation. Within diverse cultures, compensation and acceptance of tips (or bribes) to see a patient or perform an intervention may be accepted practice. Attitudes toward work hours may differ from the Western perspective. In some cultures, socialization and development of personal relationships may be considered more important than other aspects of the workload.[8]
Planning in advance to know the targeted attendees is helpful. It is advisable to inquire if the hosts might consider inviting representatives from the ministry of health, the appropriate drug institutes, other key government officials, as well as medical, nursing, and pharmacy leaders who can become champions for access to pain relief and palliative care. Having multiple disciplines and leaders from health care and government at the same program can foster ongoing communication and understanding. Include chief educators as they can incorporate this content into their respective curricula.
Plan the Curriculum and the Program
The importance of cultural issues when developing content cannot be overstated.[9] Factors that might affect pain expression and language or cultural beliefs about death and dying will greatly impact content for teaching. Be aware of local religious and spiritual beliefs impacting pain and palliative care. Consider issues surrounding disclosure of diagnosis and prognosis. Autonomy may not be the prevailing perspective as seen in North America. Ensure that slides are culturally correct and that pictures and illustrations are appropriate. Having the host country leaders review the curriculum in advance is advisable. Avoid cartoons as these may not translate well. Use case examples, but ensure that they represent the types of patients and scenarios seen by the audience. It is also important to avoid being ethnocentric as Western medicine has much to learn from other approaches. It is very helpful to use case studies from the host country. In some settings, trainers will not have access to computers and projectors, limiting the role of PowerPoint slides. Paper presentations or the use of flip-charts may be more accessible.
Consider the need for translation and, if so, which type will be used. Simultaneous interpretation generally requires a sound booth and headphones for participants, and may be more expensive. Consecutive interpretation requires that the instructor present blocks of information, usually a sentence or two, followed by the interpreter providing the content in the appropriate language. This requires speakers to plan much shorter presentations with up to 50% less content being delivered. In either case, trained interpreters can benefit from seeing the slides in advance so they can prepare and clarify prior to the presentation.
When developing an agenda, inquire about the usual times for breaks and meals, as well as time for prayers or other activities. What is considered a “full day” varies around the world, as does the value of adhering rigidly to a schedule. International education generally means that the agenda is fluid; once you are actually in the country and providing the course, other needs may arise. A common mistake is trying to squeeze in too much content. Ask your host to meet prior to the program and, optimally, plan for time before the course to tour health-care facilities. Arrange for a time to meet with key medical, nursing, pharmacy, and governmental leaders who are not scheduled to attend the meeting but might somehow influence curricula and practice. In some settings, local media may be alerted to generate local interest in the topic. Communicate with your host about these opportunities so that arrangements can be made in advance.
For resource-poor countries, consider asking for donations from colleagues before leaving, including books, CDs, and medical supplies. Check local regulations first, particularly if bringing in medications or equipment. If sending books, some countries require high tariff fees to be paid by the receiver when accepting these packages, creating a financial burden for your hosts. Inquire ahead of time if they have to pay to accept these packages. Additionally, in some resource-poor countries, professionals do not have access to personal or work computers and internet café computers often do not have CD drives. Information on jump drives may be more easily accessible.
Finally, visiting educators may want to pack small gifts to give to hosts and others. These should be easily transported and may include items that represent your city or institution. We have also found bringing candy and small toys to be universally appreciated when visiting pediatric settings. A small portable color printer can be used to print photographs of pediatric patients as some of these children have never seen pictures of themselves. You can also print photographs of participants in the training courses.
Personal Considerations
Several months prior to departure, you should contact your traveler's health information resource to identify which vaccinations and what documents are needed to enter the country. To avoid lost time due to illness, ciprofloxacin and antidiarrheal medicines should be obtained before traveling. It is advisable to update your passport. Some countries require you to have sufficient blank pages in your passport to allow entry into their country. An entry fee paid in cash may be required upon arrival. Travelers should consider the political climate of the country and check the U.S. Department of State website (included in Table 1) for alerts or precautions.
Consider appropriate attire when packing. Clothing should reflect respect for the cultural and religious beliefs of the attendees.
During the Experience
It is very useful to meet with interpreters prior to the presentations to clarify any questions. Translation can be quite complicated. For example, a slide that used the term “caring” was interpreted as “romantic love,” and concepts about suffering and death can take on a cultural meaning. Check with interpreters regularly to determine if the speed of delivery is acceptable. Also, translators may have difficulty with this emotional content. In some instances, interpreters have become tearful and required debriefing after palliative care education events. Consider nonverbal communication and personal space. In some cultures, it may not be appropriate to shake hands or to use two hands. Gestures may have very different meanings in other cultures, so avoid these forms of communication. For example, the “OK” sign commonly used in North America, with the tip of the finger touching the tip of the thumb and the other three fingers extended, is considered an obscene gesture in Brazil.
When using teaching strategies other than lecture, respect that some students may not be comfortable at first with nontraditional approaches. Informal teaching strategies that are valued in North America may be viewed as of poor academic quality in other cultures. Debate and discussion, which may make it seem that the student is questioning a teacher's view, may be seen as disrespectful. At times, eliciting personal reflection and experience can engage the audience. For example, when introducing the topic of communication, health-care professionals in the audience can be asked the following questions:
- • If you had cancer, would you want to know?
• Would you want to know that you had a disease that you could die from?
Following these with “What do you tell your patients?” usually engenders excellent discussion.
We have also found that asking participants to do “homework” can be useful, particularly if the students have been quiet or reluctant to communicate during class. Suggested assignments might include listing the five top barriers to cancer pain management in your setting, describing a difficult death or a death that you made better, or related issues. Reticence to speak during class may be due to discomfort with language skills. Some students feel more comfortable sharing ideas in writing, and these assignments have yielded valuable stories that have helped us to understand their experiences and perspectives.
Since the goal of these educational efforts should be sustained, it is helpful to develop a plan for the future with students. Assist them in identifying goals, as well as action items to meet these goals. Allow time for individual meetings between faculty and students to fine-tune these efforts. This ensures that the educational experience will have a greater likelihood of translation into action. To provide practical assistance, if Internet access is available, spend time with small groups to demonstrate literature searches, useful websites, and other information that will foster continuity.
Faculty should meet after each day of training to modify the planned agenda as needed, to optimally meet the needs of the participants. This also provides needed time to debrief about the day's activities and provide support. Particularly when new to international education, the experience may be overwhelming as the status of health-care in developing countries can cause deep personal reflection.
Finally, celebrate. We have found that many students appreciate the opportunity to have some type of closing ceremony to receive certificates and pins, acknowledge their accomplishments, and encourage their future efforts.
Afterward
E-mail, voiceover Internet services, and videoconferencing software have significantly enhanced global communication. Faculty can make themselves available to the trainees after leaving the country using these technologies. Group conversations via e-mail can help solve problems, provide encouragement, and celebrate successes. Connect attendees with international professional organizations to support ongoing educational efforts. It is very useful to identify the leaders or champions and to plan ongoing support to help sustain their commitment. Many countries do not have professional organizations or support networks. These leaders can exist in isolation and suffer great personal sacrifice to lead palliative care efforts in their country.
Conclusion
When educating about pain and palliative care to a worldwide audience, never make assumptions, expect the unexpected, and be flexible. We have found many of these international teaching experiences to be some of the most exhilarating of our professional lives, providing insight to our own practices and creating lasting relationships with colleagues from around the globe. Ultimately, these efforts will improve care for people with cancer.
Acknowledgments
The authors acknowledge the American Association of Colleges of Nursing and the City of Hope for their ongoing support of the End-of-Life Nursing Education Consortium training activities, as well as the Oncology Nursing Society Foundation and the Open Society Institute for their support of international educational efforts. They also thank Marian Grant for her input.
References [Pub Med ID in Brackets]
1 A.L. Taylor, L.O. Gostin and K.A. Pagonis, Ensuring effective pain treatment: a national and global perspective, JAMA 299 (2008), pp. 89–91 [18167410].
2 K. Crane, Palliative care gains ground in developing countries, J Natl Cancer Inst 102 (21) (2010), pp. 1613–1615 [20966432].
3 J.A. Paice, B.R. Ferrell, N. Coyle, P. Coyne and M. Callaway, Global efforts to improve palliative care: the International End-of-Life Nursing Education Consortium training programme, J Adv Nurs 61 (2007), pp. 173–180 [18186909].
4 J.A. Paice, B. Ferrell, N. Coyle, P. Coyne and T. Smith, Living and dying in East Africa: implementing the End-of-Life Nursing Education Consortium curriculum in Tanzania, Clin J Oncol Nurs 14 (2010), pp. 161–166 [20350889].
5 C. Olweny, C. Sepulveda, A. Merriman, S. Fonn, M. Borok, T. Ngoma, A. Doh and J. Stjernsward, Desirable services and guidelines for the treatment and palliative care of HIV disease patients with cancer in Africa: a World Health Organization consultation, J Palliat Care 19 (2003), pp. 198–205 [14606333].
6 C. Sepulveda, V. Habiyatmbete, J. Amandua, M. Borok, E. Kikule, B. Mudanga and B. Solomon, Quality care at the end of life in Africa, BMJ 327 (2003), pp. 209–213 [12881267].
7 E.L. Krakauer, R. Wenk, R. Buitrago, P. Jenkins and W. Scholten, Opioid inaccessibility and its human consequences: reports from the field, J Pain Palliat Care Pharmacother 24 (2010), pp. 239–243 [20718644].
8 C.M. Bolin, Developing a postbasic gerontology program for international learners: considerations for the process, J Contin Educ Nurs 34 (2003), pp. 177–183 [12887229].
9 K.D. Meneses and C.H. Yarbro, Cultural perspectives of international breast health and breast cancer education, J Nurs Scholarsh 39 (2) (2007), pp. 105–112 [19058079].
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Paice is Director of the Cancer Pain Program, Division of Hematology-Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Carma Erickson-Hurt is a faculty member at Grand Canyon University, Phoenix, Arizona.
Dr. Ferrell is a Professor and Research Scientist at the City of Hope National Medical Center, Duarte, California.
Nessa Coyle is on the Pain and Palliative Care Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
Dr. Coyne is Clinical Director of the Thomas Palliative Care Program, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia.
Dr. Long is a geriatric nursing consultant and codirector of the Palliative Care for Advanced Dementia, Beatitudes Campus, Phoenix, Arizona.
Dr. Mazanec is a clinical nurse specialist at the University Hospitals Seidman Cancer Center, Cleveland, Ohio.
Pam Malloy is ELNEC Project Director, American Association of Colleges of Nursing, Washington, DC.
Dr. Smith is Professor of Medicine and Palliative Care Research, Virginia Commonwealth University/Massey Cancer Center, Richmond.
Volume 9, Issue 4, July-August 2011, Pages 129-133
How we do it
Judith A. Paice PhD, RN
Available online 2 July 2011.
Article Outline
For many clinicians in oncology, educating other health-care professionals about cancer pain and palliative care is part of their professional life. The need for education exists across clinical settings around the world. Improved education is an urgent need as the prevalence of cancer is increasing. This burden is largely carried by the developing world, where resources are often limited.[1] Global educational efforts, including managing common symptoms, communication, care at the time of death, grief, and other topics, are imperative to reduce pain and suffering.[2] International training efforts require additional expertise and preparation beyond the standard teaching skills needed for all professional education.
The goal of international training efforts in pain and palliative care is to provide useful, culturally relevant programs while empowering participants to sustain these efforts in the long term. Global efforts in palliative care have demonstrated that sharing educational materials, resources, support and encouragement with our international colleagues can provide mentorship to go beyond simply attending a course to developing and expanding their own programs of palliative care in oncology.[3] and [4] To do this well, the following provides specific suggestions for before, during, and after international palliative care training experiences.
Do Your Homework
Before a course, it is essential to learn as much as possible about the region, the culture(s), and the health-care system. Several resources for this information are listed in Table 1. Additionally, speaking with colleagues who have traveled to the country or to those who have emigrated from the country can provide valuable insight. These individuals can provide a wealth of information to assist in developing an appropriate curriculum and specific presentations. As demographics vary, it is important to know the common cancers and other leading causes of death in the region. Issues that may be seen as “competing” issues HIV/AIDS, malaria, immunizations, lack of clean water, or maternal–infant mortality.[5] and [6] Literature, including fiction and nonfiction, as well as movies and other media, can enlighten the traveler regarding life in the region. Local consulates offer opportunities for learning, as do organizations such as the Council on Global Relations. There are rapid changes in global politics, health-care systems, and governments, so it is also vital to have current information.
| American Society for Clinical Oncology (ASCO) | Offers international cancer courses as well as fellowships and other awards. |
| Centers for Disease Control and Prevention (CDC), http://wwwnc.cdc.gov/travel/ | Provides information regarding common infectious illnesses, traveler's alerts. |
| Central Intelligence Agency (CIA), The World Factbook, https://www.cia.gov/library/publications/the-world-factbook/ | Excellent review of a country's political, demographic, geographic, and other attributes. |
| City of Hope Pain & Palliative Care Resource Center, http://prc.coh.org/ | Provides a clearinghouse that includes a wide array of resources and references to enhance pain and palliative care education and research. |
| End of Life Nursing Education Consortium (ELNEC), http://www.aacn.nche.edu/elnec/ | Includes relevant articles, resources, and a summary of current international ELNEC training programs. |
| International Association for Hospice and Palliative Care (IAHPC), http://www.hospicecare.com/ | Numerous global palliative care resources, including List of Essential Medicines, Global Directory of Educational Programs in Palliative Care, Global Directory of Palliative Care Providers/Services/Organizations, as well as Palliative Care in the Developing World: Principles and Practice. |
| International Association for the Study of Pain (IASP), http://www.iasp-pain.org/ | Strong emphasis on support of developing countries with research and educational grants; publishes a Guide to Pain Management in Low-Resource Settings offered without cost. |
| Open Society Institute–International Palliative Care Initiative, http://www.soros.org/initiatives/health/focus/ipci/about | Offers support for training, clinical care, and research in palliative care, alone and in collaboration with other organizations. |
| Pain & Policy Studies Group, http://www.painpolicy.wisc.edu/ | Excellent resource for information regarding opioid consumption by country as well as guidelines for policies that allow access to necessary medications. |
| U.S. Department of State, http://www.usembassy.gov/ Bureau of Consular Affairs, http://travel.state.gov/travel/travel_1744.html | Comprehensive lists of US embassies, consulates, and diplomatic missions; information to assist travelers from the United States to other countries, including visa requirements and safety alerts. |
| World Health Organization, http://www.who.int | Many useful resources, including Access to Analgesics and to other Controlled Medicines, as well as statistics regarding common illnesses by country. |
Health-Care Structure
Understand the existing health-care structure and what health care is available to all or for select populations. What is the extent of health-care services? Are there clinics for preventive care, or is most care obtained in the hospital? Is home care available with support from nurses and other professionals? Are emergency services available (eg, does the region have ambulances to transport and emergency departments to accept critically ill patients)? Where do patients obtain medications, and do they have to pay out of pocket for these? Do most people die in the hospital or at home? While websites and government sources are valuable, verify this information with clinicians since the clinical reality may be quite different.
Available Medications
To provide useful guidance in symptom management, it is necessary to have a list of available medications used to treat pain, nausea, dyspnea, constipation/diarrhea, wounds, and other symptoms commonly seen in oncology. Your presentation may need to be modified based upon these available drugs (Table 2). Where do patients obtain medications, and do they pay out of pocket for these? There are limitations on availability and access to opioids around the world.[7] Which opioids are available and actually used? What is the process for obtaining a supply of an opioid for a person with cancer? For example, in some countries, physicians can order only one week's worth of medication at a time. In other countries, patients must obtain opioids from the police station rather than a pharmacy. In several settings, only the patient, not family members, can pick up the medication from the dispensing site. And in a few countries, only parenteral opioids are available. It is also helpful to understand issues such as the prevalence of drug trafficking in the region and how this might affect local drug laws. Are traditional medicines, such as herbal therapies, or other techniques commonly used? It is helpful to be aware of these practices and incorporate them into teaching plans where appropriate.
Education of Health-Care Professionals
International education in palliative care should consider how physicians, nurses, pharmacists, and others are educated. Is the educational system very traditional and formal, with little interaction between students and teachers? Professionals trained in this manner may be less comfortable when faced with role-play, learning through discussion, or other Socratic educational methods. That does not mean that one should exclude these methods when planning the curriculum but, rather, be prepared for silence and possibly even discomfort when first introduced. Seek guidance from local educators as to what methods will be acceptable.
Who is included in the health-care team? Are psychologists available, and are chaplains considered part of health-care services? What is the relationship between physicians, nurses, and other team members? Is collegiality accepted, or is there a hierarchy that limits true teamwork? What is the status of physicians, nurses, and other professionals in the region? In some areas, physicians are highly regarded and financially compensated accordingly. In other parts of the world, physicians have very low social status, respect, and compensation. Within diverse cultures, compensation and acceptance of tips (or bribes) to see a patient or perform an intervention may be accepted practice. Attitudes toward work hours may differ from the Western perspective. In some cultures, socialization and development of personal relationships may be considered more important than other aspects of the workload.[8]
Planning in advance to know the targeted attendees is helpful. It is advisable to inquire if the hosts might consider inviting representatives from the ministry of health, the appropriate drug institutes, other key government officials, as well as medical, nursing, and pharmacy leaders who can become champions for access to pain relief and palliative care. Having multiple disciplines and leaders from health care and government at the same program can foster ongoing communication and understanding. Include chief educators as they can incorporate this content into their respective curricula.
Plan the Curriculum and the Program
The importance of cultural issues when developing content cannot be overstated.[9] Factors that might affect pain expression and language or cultural beliefs about death and dying will greatly impact content for teaching. Be aware of local religious and spiritual beliefs impacting pain and palliative care. Consider issues surrounding disclosure of diagnosis and prognosis. Autonomy may not be the prevailing perspective as seen in North America. Ensure that slides are culturally correct and that pictures and illustrations are appropriate. Having the host country leaders review the curriculum in advance is advisable. Avoid cartoons as these may not translate well. Use case examples, but ensure that they represent the types of patients and scenarios seen by the audience. It is also important to avoid being ethnocentric as Western medicine has much to learn from other approaches. It is very helpful to use case studies from the host country. In some settings, trainers will not have access to computers and projectors, limiting the role of PowerPoint slides. Paper presentations or the use of flip-charts may be more accessible.
Consider the need for translation and, if so, which type will be used. Simultaneous interpretation generally requires a sound booth and headphones for participants, and may be more expensive. Consecutive interpretation requires that the instructor present blocks of information, usually a sentence or two, followed by the interpreter providing the content in the appropriate language. This requires speakers to plan much shorter presentations with up to 50% less content being delivered. In either case, trained interpreters can benefit from seeing the slides in advance so they can prepare and clarify prior to the presentation.
When developing an agenda, inquire about the usual times for breaks and meals, as well as time for prayers or other activities. What is considered a “full day” varies around the world, as does the value of adhering rigidly to a schedule. International education generally means that the agenda is fluid; once you are actually in the country and providing the course, other needs may arise. A common mistake is trying to squeeze in too much content. Ask your host to meet prior to the program and, optimally, plan for time before the course to tour health-care facilities. Arrange for a time to meet with key medical, nursing, pharmacy, and governmental leaders who are not scheduled to attend the meeting but might somehow influence curricula and practice. In some settings, local media may be alerted to generate local interest in the topic. Communicate with your host about these opportunities so that arrangements can be made in advance.
For resource-poor countries, consider asking for donations from colleagues before leaving, including books, CDs, and medical supplies. Check local regulations first, particularly if bringing in medications or equipment. If sending books, some countries require high tariff fees to be paid by the receiver when accepting these packages, creating a financial burden for your hosts. Inquire ahead of time if they have to pay to accept these packages. Additionally, in some resource-poor countries, professionals do not have access to personal or work computers and internet café computers often do not have CD drives. Information on jump drives may be more easily accessible.
Finally, visiting educators may want to pack small gifts to give to hosts and others. These should be easily transported and may include items that represent your city or institution. We have also found bringing candy and small toys to be universally appreciated when visiting pediatric settings. A small portable color printer can be used to print photographs of pediatric patients as some of these children have never seen pictures of themselves. You can also print photographs of participants in the training courses.
Personal Considerations
Several months prior to departure, you should contact your traveler's health information resource to identify which vaccinations and what documents are needed to enter the country. To avoid lost time due to illness, ciprofloxacin and antidiarrheal medicines should be obtained before traveling. It is advisable to update your passport. Some countries require you to have sufficient blank pages in your passport to allow entry into their country. An entry fee paid in cash may be required upon arrival. Travelers should consider the political climate of the country and check the U.S. Department of State website (included in Table 1) for alerts or precautions.
Consider appropriate attire when packing. Clothing should reflect respect for the cultural and religious beliefs of the attendees.
During the Experience
It is very useful to meet with interpreters prior to the presentations to clarify any questions. Translation can be quite complicated. For example, a slide that used the term “caring” was interpreted as “romantic love,” and concepts about suffering and death can take on a cultural meaning. Check with interpreters regularly to determine if the speed of delivery is acceptable. Also, translators may have difficulty with this emotional content. In some instances, interpreters have become tearful and required debriefing after palliative care education events. Consider nonverbal communication and personal space. In some cultures, it may not be appropriate to shake hands or to use two hands. Gestures may have very different meanings in other cultures, so avoid these forms of communication. For example, the “OK” sign commonly used in North America, with the tip of the finger touching the tip of the thumb and the other three fingers extended, is considered an obscene gesture in Brazil.
When using teaching strategies other than lecture, respect that some students may not be comfortable at first with nontraditional approaches. Informal teaching strategies that are valued in North America may be viewed as of poor academic quality in other cultures. Debate and discussion, which may make it seem that the student is questioning a teacher's view, may be seen as disrespectful. At times, eliciting personal reflection and experience can engage the audience. For example, when introducing the topic of communication, health-care professionals in the audience can be asked the following questions:
- • If you had cancer, would you want to know?
• Would you want to know that you had a disease that you could die from?
Following these with “What do you tell your patients?” usually engenders excellent discussion.
We have also found that asking participants to do “homework” can be useful, particularly if the students have been quiet or reluctant to communicate during class. Suggested assignments might include listing the five top barriers to cancer pain management in your setting, describing a difficult death or a death that you made better, or related issues. Reticence to speak during class may be due to discomfort with language skills. Some students feel more comfortable sharing ideas in writing, and these assignments have yielded valuable stories that have helped us to understand their experiences and perspectives.
Since the goal of these educational efforts should be sustained, it is helpful to develop a plan for the future with students. Assist them in identifying goals, as well as action items to meet these goals. Allow time for individual meetings between faculty and students to fine-tune these efforts. This ensures that the educational experience will have a greater likelihood of translation into action. To provide practical assistance, if Internet access is available, spend time with small groups to demonstrate literature searches, useful websites, and other information that will foster continuity.
Faculty should meet after each day of training to modify the planned agenda as needed, to optimally meet the needs of the participants. This also provides needed time to debrief about the day's activities and provide support. Particularly when new to international education, the experience may be overwhelming as the status of health-care in developing countries can cause deep personal reflection.
Finally, celebrate. We have found that many students appreciate the opportunity to have some type of closing ceremony to receive certificates and pins, acknowledge their accomplishments, and encourage their future efforts.
Afterward
E-mail, voiceover Internet services, and videoconferencing software have significantly enhanced global communication. Faculty can make themselves available to the trainees after leaving the country using these technologies. Group conversations via e-mail can help solve problems, provide encouragement, and celebrate successes. Connect attendees with international professional organizations to support ongoing educational efforts. It is very useful to identify the leaders or champions and to plan ongoing support to help sustain their commitment. Many countries do not have professional organizations or support networks. These leaders can exist in isolation and suffer great personal sacrifice to lead palliative care efforts in their country.
Conclusion
When educating about pain and palliative care to a worldwide audience, never make assumptions, expect the unexpected, and be flexible. We have found many of these international teaching experiences to be some of the most exhilarating of our professional lives, providing insight to our own practices and creating lasting relationships with colleagues from around the globe. Ultimately, these efforts will improve care for people with cancer.
Acknowledgments
The authors acknowledge the American Association of Colleges of Nursing and the City of Hope for their ongoing support of the End-of-Life Nursing Education Consortium training activities, as well as the Oncology Nursing Society Foundation and the Open Society Institute for their support of international educational efforts. They also thank Marian Grant for her input.
References [Pub Med ID in Brackets]
1 A.L. Taylor, L.O. Gostin and K.A. Pagonis, Ensuring effective pain treatment: a national and global perspective, JAMA 299 (2008), pp. 89–91 [18167410].
2 K. Crane, Palliative care gains ground in developing countries, J Natl Cancer Inst 102 (21) (2010), pp. 1613–1615 [20966432].
3 J.A. Paice, B.R. Ferrell, N. Coyle, P. Coyne and M. Callaway, Global efforts to improve palliative care: the International End-of-Life Nursing Education Consortium training programme, J Adv Nurs 61 (2007), pp. 173–180 [18186909].
4 J.A. Paice, B. Ferrell, N. Coyle, P. Coyne and T. Smith, Living and dying in East Africa: implementing the End-of-Life Nursing Education Consortium curriculum in Tanzania, Clin J Oncol Nurs 14 (2010), pp. 161–166 [20350889].
5 C. Olweny, C. Sepulveda, A. Merriman, S. Fonn, M. Borok, T. Ngoma, A. Doh and J. Stjernsward, Desirable services and guidelines for the treatment and palliative care of HIV disease patients with cancer in Africa: a World Health Organization consultation, J Palliat Care 19 (2003), pp. 198–205 [14606333].
6 C. Sepulveda, V. Habiyatmbete, J. Amandua, M. Borok, E. Kikule, B. Mudanga and B. Solomon, Quality care at the end of life in Africa, BMJ 327 (2003), pp. 209–213 [12881267].
7 E.L. Krakauer, R. Wenk, R. Buitrago, P. Jenkins and W. Scholten, Opioid inaccessibility and its human consequences: reports from the field, J Pain Palliat Care Pharmacother 24 (2010), pp. 239–243 [20718644].
8 C.M. Bolin, Developing a postbasic gerontology program for international learners: considerations for the process, J Contin Educ Nurs 34 (2003), pp. 177–183 [12887229].
9 K.D. Meneses and C.H. Yarbro, Cultural perspectives of international breast health and breast cancer education, J Nurs Scholarsh 39 (2) (2007), pp. 105–112 [19058079].
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Paice is Director of the Cancer Pain Program, Division of Hematology-Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Carma Erickson-Hurt is a faculty member at Grand Canyon University, Phoenix, Arizona.
Dr. Ferrell is a Professor and Research Scientist at the City of Hope National Medical Center, Duarte, California.
Nessa Coyle is on the Pain and Palliative Care Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
Dr. Coyne is Clinical Director of the Thomas Palliative Care Program, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia.
Dr. Long is a geriatric nursing consultant and codirector of the Palliative Care for Advanced Dementia, Beatitudes Campus, Phoenix, Arizona.
Dr. Mazanec is a clinical nurse specialist at the University Hospitals Seidman Cancer Center, Cleveland, Ohio.
Pam Malloy is ELNEC Project Director, American Association of Colleges of Nursing, Washington, DC.
Dr. Smith is Professor of Medicine and Palliative Care Research, Virginia Commonwealth University/Massey Cancer Center, Richmond.
Volume 9, Issue 4, July-August 2011, Pages 129-133
How we do it
Judith A. Paice PhD, RN
Available online 2 July 2011.
Article Outline
For many clinicians in oncology, educating other health-care professionals about cancer pain and palliative care is part of their professional life. The need for education exists across clinical settings around the world. Improved education is an urgent need as the prevalence of cancer is increasing. This burden is largely carried by the developing world, where resources are often limited.[1] Global educational efforts, including managing common symptoms, communication, care at the time of death, grief, and other topics, are imperative to reduce pain and suffering.[2] International training efforts require additional expertise and preparation beyond the standard teaching skills needed for all professional education.
The goal of international training efforts in pain and palliative care is to provide useful, culturally relevant programs while empowering participants to sustain these efforts in the long term. Global efforts in palliative care have demonstrated that sharing educational materials, resources, support and encouragement with our international colleagues can provide mentorship to go beyond simply attending a course to developing and expanding their own programs of palliative care in oncology.[3] and [4] To do this well, the following provides specific suggestions for before, during, and after international palliative care training experiences.
Do Your Homework
Before a course, it is essential to learn as much as possible about the region, the culture(s), and the health-care system. Several resources for this information are listed in Table 1. Additionally, speaking with colleagues who have traveled to the country or to those who have emigrated from the country can provide valuable insight. These individuals can provide a wealth of information to assist in developing an appropriate curriculum and specific presentations. As demographics vary, it is important to know the common cancers and other leading causes of death in the region. Issues that may be seen as “competing” issues HIV/AIDS, malaria, immunizations, lack of clean water, or maternal–infant mortality.[5] and [6] Literature, including fiction and nonfiction, as well as movies and other media, can enlighten the traveler regarding life in the region. Local consulates offer opportunities for learning, as do organizations such as the Council on Global Relations. There are rapid changes in global politics, health-care systems, and governments, so it is also vital to have current information.
| American Society for Clinical Oncology (ASCO) | Offers international cancer courses as well as fellowships and other awards. |
| Centers for Disease Control and Prevention (CDC), http://wwwnc.cdc.gov/travel/ | Provides information regarding common infectious illnesses, traveler's alerts. |
| Central Intelligence Agency (CIA), The World Factbook, https://www.cia.gov/library/publications/the-world-factbook/ | Excellent review of a country's political, demographic, geographic, and other attributes. |
| City of Hope Pain & Palliative Care Resource Center, http://prc.coh.org/ | Provides a clearinghouse that includes a wide array of resources and references to enhance pain and palliative care education and research. |
| End of Life Nursing Education Consortium (ELNEC), http://www.aacn.nche.edu/elnec/ | Includes relevant articles, resources, and a summary of current international ELNEC training programs. |
| International Association for Hospice and Palliative Care (IAHPC), http://www.hospicecare.com/ | Numerous global palliative care resources, including List of Essential Medicines, Global Directory of Educational Programs in Palliative Care, Global Directory of Palliative Care Providers/Services/Organizations, as well as Palliative Care in the Developing World: Principles and Practice. |
| International Association for the Study of Pain (IASP), http://www.iasp-pain.org/ | Strong emphasis on support of developing countries with research and educational grants; publishes a Guide to Pain Management in Low-Resource Settings offered without cost. |
| Open Society Institute–International Palliative Care Initiative, http://www.soros.org/initiatives/health/focus/ipci/about | Offers support for training, clinical care, and research in palliative care, alone and in collaboration with other organizations. |
| Pain & Policy Studies Group, http://www.painpolicy.wisc.edu/ | Excellent resource for information regarding opioid consumption by country as well as guidelines for policies that allow access to necessary medications. |
| U.S. Department of State, http://www.usembassy.gov/ Bureau of Consular Affairs, http://travel.state.gov/travel/travel_1744.html | Comprehensive lists of US embassies, consulates, and diplomatic missions; information to assist travelers from the United States to other countries, including visa requirements and safety alerts. |
| World Health Organization, http://www.who.int | Many useful resources, including Access to Analgesics and to other Controlled Medicines, as well as statistics regarding common illnesses by country. |
Health-Care Structure
Understand the existing health-care structure and what health care is available to all or for select populations. What is the extent of health-care services? Are there clinics for preventive care, or is most care obtained in the hospital? Is home care available with support from nurses and other professionals? Are emergency services available (eg, does the region have ambulances to transport and emergency departments to accept critically ill patients)? Where do patients obtain medications, and do they have to pay out of pocket for these? Do most people die in the hospital or at home? While websites and government sources are valuable, verify this information with clinicians since the clinical reality may be quite different.
Available Medications
To provide useful guidance in symptom management, it is necessary to have a list of available medications used to treat pain, nausea, dyspnea, constipation/diarrhea, wounds, and other symptoms commonly seen in oncology. Your presentation may need to be modified based upon these available drugs (Table 2). Where do patients obtain medications, and do they pay out of pocket for these? There are limitations on availability and access to opioids around the world.[7] Which opioids are available and actually used? What is the process for obtaining a supply of an opioid for a person with cancer? For example, in some countries, physicians can order only one week's worth of medication at a time. In other countries, patients must obtain opioids from the police station rather than a pharmacy. In several settings, only the patient, not family members, can pick up the medication from the dispensing site. And in a few countries, only parenteral opioids are available. It is also helpful to understand issues such as the prevalence of drug trafficking in the region and how this might affect local drug laws. Are traditional medicines, such as herbal therapies, or other techniques commonly used? It is helpful to be aware of these practices and incorporate them into teaching plans where appropriate.
Education of Health-Care Professionals
International education in palliative care should consider how physicians, nurses, pharmacists, and others are educated. Is the educational system very traditional and formal, with little interaction between students and teachers? Professionals trained in this manner may be less comfortable when faced with role-play, learning through discussion, or other Socratic educational methods. That does not mean that one should exclude these methods when planning the curriculum but, rather, be prepared for silence and possibly even discomfort when first introduced. Seek guidance from local educators as to what methods will be acceptable.
Who is included in the health-care team? Are psychologists available, and are chaplains considered part of health-care services? What is the relationship between physicians, nurses, and other team members? Is collegiality accepted, or is there a hierarchy that limits true teamwork? What is the status of physicians, nurses, and other professionals in the region? In some areas, physicians are highly regarded and financially compensated accordingly. In other parts of the world, physicians have very low social status, respect, and compensation. Within diverse cultures, compensation and acceptance of tips (or bribes) to see a patient or perform an intervention may be accepted practice. Attitudes toward work hours may differ from the Western perspective. In some cultures, socialization and development of personal relationships may be considered more important than other aspects of the workload.[8]
Planning in advance to know the targeted attendees is helpful. It is advisable to inquire if the hosts might consider inviting representatives from the ministry of health, the appropriate drug institutes, other key government officials, as well as medical, nursing, and pharmacy leaders who can become champions for access to pain relief and palliative care. Having multiple disciplines and leaders from health care and government at the same program can foster ongoing communication and understanding. Include chief educators as they can incorporate this content into their respective curricula.
Plan the Curriculum and the Program
The importance of cultural issues when developing content cannot be overstated.[9] Factors that might affect pain expression and language or cultural beliefs about death and dying will greatly impact content for teaching. Be aware of local religious and spiritual beliefs impacting pain and palliative care. Consider issues surrounding disclosure of diagnosis and prognosis. Autonomy may not be the prevailing perspective as seen in North America. Ensure that slides are culturally correct and that pictures and illustrations are appropriate. Having the host country leaders review the curriculum in advance is advisable. Avoid cartoons as these may not translate well. Use case examples, but ensure that they represent the types of patients and scenarios seen by the audience. It is also important to avoid being ethnocentric as Western medicine has much to learn from other approaches. It is very helpful to use case studies from the host country. In some settings, trainers will not have access to computers and projectors, limiting the role of PowerPoint slides. Paper presentations or the use of flip-charts may be more accessible.
Consider the need for translation and, if so, which type will be used. Simultaneous interpretation generally requires a sound booth and headphones for participants, and may be more expensive. Consecutive interpretation requires that the instructor present blocks of information, usually a sentence or two, followed by the interpreter providing the content in the appropriate language. This requires speakers to plan much shorter presentations with up to 50% less content being delivered. In either case, trained interpreters can benefit from seeing the slides in advance so they can prepare and clarify prior to the presentation.
When developing an agenda, inquire about the usual times for breaks and meals, as well as time for prayers or other activities. What is considered a “full day” varies around the world, as does the value of adhering rigidly to a schedule. International education generally means that the agenda is fluid; once you are actually in the country and providing the course, other needs may arise. A common mistake is trying to squeeze in too much content. Ask your host to meet prior to the program and, optimally, plan for time before the course to tour health-care facilities. Arrange for a time to meet with key medical, nursing, pharmacy, and governmental leaders who are not scheduled to attend the meeting but might somehow influence curricula and practice. In some settings, local media may be alerted to generate local interest in the topic. Communicate with your host about these opportunities so that arrangements can be made in advance.
For resource-poor countries, consider asking for donations from colleagues before leaving, including books, CDs, and medical supplies. Check local regulations first, particularly if bringing in medications or equipment. If sending books, some countries require high tariff fees to be paid by the receiver when accepting these packages, creating a financial burden for your hosts. Inquire ahead of time if they have to pay to accept these packages. Additionally, in some resource-poor countries, professionals do not have access to personal or work computers and internet café computers often do not have CD drives. Information on jump drives may be more easily accessible.
Finally, visiting educators may want to pack small gifts to give to hosts and others. These should be easily transported and may include items that represent your city or institution. We have also found bringing candy and small toys to be universally appreciated when visiting pediatric settings. A small portable color printer can be used to print photographs of pediatric patients as some of these children have never seen pictures of themselves. You can also print photographs of participants in the training courses.
Personal Considerations
Several months prior to departure, you should contact your traveler's health information resource to identify which vaccinations and what documents are needed to enter the country. To avoid lost time due to illness, ciprofloxacin and antidiarrheal medicines should be obtained before traveling. It is advisable to update your passport. Some countries require you to have sufficient blank pages in your passport to allow entry into their country. An entry fee paid in cash may be required upon arrival. Travelers should consider the political climate of the country and check the U.S. Department of State website (included in Table 1) for alerts or precautions.
Consider appropriate attire when packing. Clothing should reflect respect for the cultural and religious beliefs of the attendees.
During the Experience
It is very useful to meet with interpreters prior to the presentations to clarify any questions. Translation can be quite complicated. For example, a slide that used the term “caring” was interpreted as “romantic love,” and concepts about suffering and death can take on a cultural meaning. Check with interpreters regularly to determine if the speed of delivery is acceptable. Also, translators may have difficulty with this emotional content. In some instances, interpreters have become tearful and required debriefing after palliative care education events. Consider nonverbal communication and personal space. In some cultures, it may not be appropriate to shake hands or to use two hands. Gestures may have very different meanings in other cultures, so avoid these forms of communication. For example, the “OK” sign commonly used in North America, with the tip of the finger touching the tip of the thumb and the other three fingers extended, is considered an obscene gesture in Brazil.
When using teaching strategies other than lecture, respect that some students may not be comfortable at first with nontraditional approaches. Informal teaching strategies that are valued in North America may be viewed as of poor academic quality in other cultures. Debate and discussion, which may make it seem that the student is questioning a teacher's view, may be seen as disrespectful. At times, eliciting personal reflection and experience can engage the audience. For example, when introducing the topic of communication, health-care professionals in the audience can be asked the following questions:
- • If you had cancer, would you want to know?
• Would you want to know that you had a disease that you could die from?
Following these with “What do you tell your patients?” usually engenders excellent discussion.
We have also found that asking participants to do “homework” can be useful, particularly if the students have been quiet or reluctant to communicate during class. Suggested assignments might include listing the five top barriers to cancer pain management in your setting, describing a difficult death or a death that you made better, or related issues. Reticence to speak during class may be due to discomfort with language skills. Some students feel more comfortable sharing ideas in writing, and these assignments have yielded valuable stories that have helped us to understand their experiences and perspectives.
Since the goal of these educational efforts should be sustained, it is helpful to develop a plan for the future with students. Assist them in identifying goals, as well as action items to meet these goals. Allow time for individual meetings between faculty and students to fine-tune these efforts. This ensures that the educational experience will have a greater likelihood of translation into action. To provide practical assistance, if Internet access is available, spend time with small groups to demonstrate literature searches, useful websites, and other information that will foster continuity.
Faculty should meet after each day of training to modify the planned agenda as needed, to optimally meet the needs of the participants. This also provides needed time to debrief about the day's activities and provide support. Particularly when new to international education, the experience may be overwhelming as the status of health-care in developing countries can cause deep personal reflection.
Finally, celebrate. We have found that many students appreciate the opportunity to have some type of closing ceremony to receive certificates and pins, acknowledge their accomplishments, and encourage their future efforts.
Afterward
E-mail, voiceover Internet services, and videoconferencing software have significantly enhanced global communication. Faculty can make themselves available to the trainees after leaving the country using these technologies. Group conversations via e-mail can help solve problems, provide encouragement, and celebrate successes. Connect attendees with international professional organizations to support ongoing educational efforts. It is very useful to identify the leaders or champions and to plan ongoing support to help sustain their commitment. Many countries do not have professional organizations or support networks. These leaders can exist in isolation and suffer great personal sacrifice to lead palliative care efforts in their country.
Conclusion
When educating about pain and palliative care to a worldwide audience, never make assumptions, expect the unexpected, and be flexible. We have found many of these international teaching experiences to be some of the most exhilarating of our professional lives, providing insight to our own practices and creating lasting relationships with colleagues from around the globe. Ultimately, these efforts will improve care for people with cancer.
Acknowledgments
The authors acknowledge the American Association of Colleges of Nursing and the City of Hope for their ongoing support of the End-of-Life Nursing Education Consortium training activities, as well as the Oncology Nursing Society Foundation and the Open Society Institute for their support of international educational efforts. They also thank Marian Grant for her input.
References [Pub Med ID in Brackets]
1 A.L. Taylor, L.O. Gostin and K.A. Pagonis, Ensuring effective pain treatment: a national and global perspective, JAMA 299 (2008), pp. 89–91 [18167410].
2 K. Crane, Palliative care gains ground in developing countries, J Natl Cancer Inst 102 (21) (2010), pp. 1613–1615 [20966432].
3 J.A. Paice, B.R. Ferrell, N. Coyle, P. Coyne and M. Callaway, Global efforts to improve palliative care: the International End-of-Life Nursing Education Consortium training programme, J Adv Nurs 61 (2007), pp. 173–180 [18186909].
4 J.A. Paice, B. Ferrell, N. Coyle, P. Coyne and T. Smith, Living and dying in East Africa: implementing the End-of-Life Nursing Education Consortium curriculum in Tanzania, Clin J Oncol Nurs 14 (2010), pp. 161–166 [20350889].
5 C. Olweny, C. Sepulveda, A. Merriman, S. Fonn, M. Borok, T. Ngoma, A. Doh and J. Stjernsward, Desirable services and guidelines for the treatment and palliative care of HIV disease patients with cancer in Africa: a World Health Organization consultation, J Palliat Care 19 (2003), pp. 198–205 [14606333].
6 C. Sepulveda, V. Habiyatmbete, J. Amandua, M. Borok, E. Kikule, B. Mudanga and B. Solomon, Quality care at the end of life in Africa, BMJ 327 (2003), pp. 209–213 [12881267].
7 E.L. Krakauer, R. Wenk, R. Buitrago, P. Jenkins and W. Scholten, Opioid inaccessibility and its human consequences: reports from the field, J Pain Palliat Care Pharmacother 24 (2010), pp. 239–243 [20718644].
8 C.M. Bolin, Developing a postbasic gerontology program for international learners: considerations for the process, J Contin Educ Nurs 34 (2003), pp. 177–183 [12887229].
9 K.D. Meneses and C.H. Yarbro, Cultural perspectives of international breast health and breast cancer education, J Nurs Scholarsh 39 (2) (2007), pp. 105–112 [19058079].
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Paice is Director of the Cancer Pain Program, Division of Hematology-Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Carma Erickson-Hurt is a faculty member at Grand Canyon University, Phoenix, Arizona.
Dr. Ferrell is a Professor and Research Scientist at the City of Hope National Medical Center, Duarte, California.
Nessa Coyle is on the Pain and Palliative Care Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
Dr. Coyne is Clinical Director of the Thomas Palliative Care Program, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia.
Dr. Long is a geriatric nursing consultant and codirector of the Palliative Care for Advanced Dementia, Beatitudes Campus, Phoenix, Arizona.
Dr. Mazanec is a clinical nurse specialist at the University Hospitals Seidman Cancer Center, Cleveland, Ohio.
Pam Malloy is ELNEC Project Director, American Association of Colleges of Nursing, Washington, DC.
Dr. Smith is Professor of Medicine and Palliative Care Research, Virginia Commonwealth University/Massey Cancer Center, Richmond.
For many clinicians in oncology, educating other health-care professionals about cancer pain and palliative care is part of their professional life. The need for education exists across clinical settings around the world. Improved education is an urgent need as the prevalence of cancer is increasing.
Costs and Outcomes of Acute Kidney Injury in Critically Ill Patients with Cancer
Volume 9, Issue 4, July-August 2011, Pages 149-155
Original research
Amit Lahoti MDa,
Background
Acute kidney injury (AKI) is a common complication in critically ill patients with cancer. The RIFLE criteria define three levels of AKI based on the percent increase in serum creatinine (Scr) from baseline: risk (≥50%), injury (≥100%), and failure (≥200% or requiring dialysis). The utility of the RIFLE criteria in critically ill patients with cancer is not known.
Objective
To examine the incidence, outcomes, and costs associated with AKI in critically ill patients with cancer.
Methods
We retrospectively analyzed all patients admitted to a single-center ICU over a 13-month period with a baseline Scr ≤1.5 mg/dL (n = 2,398). Kaplan-Meier estimates for survival by RIFLE category were calculated. Logistic regression was used to determine the association of AKI on 60-day mortality. A log-linear regression model was used for economic analysis. Costs were assessed by hospital charges from the provider's perspective.
Results
For the risk, injury, and failure categories of AKI, incidence rates were 6%, 2.8%, and 3.7%; 60-day survival estimates were 62%, 45%, and 14%; and adjusted odds ratios for 60-day mortality were 2.3, 3, and 14.3, respectively (P ≤ 0.001 compared to patients without AKI). Hematologic malignancy and hematopoietic cell transplant were not associated with mortality in the adjusted analysis. Hospital cost increased by 0.16% per 1% increase in creatinine and by 21% for patients requiring dialysis.
Limitations
Retrospective analysis. Single-center study. No adjustment by cost-to-charge ratios.
Conclusions
AKI is associated with higher mortality and costs in critically ill patients with cancer.
Over the past several years, important advances have occurred in the treatment and supportive care of critically ill patients with cancer.[1] However, acute kidney injury (AKI) remains a familiar complication and is a negative prognostic factor for overall survival.[2] and [3] The development of AKI can limit further cancer treatment, increase toxicity of chemotherapy and reduce its delivery, and exclude patients from clinical trials. Further, patients with AKI have been shown to have longer hospitalizations and increased hospital costs.[4] and [5] Recognized causes of AKI include acute tubular necrosis from medications or sepsis, volume depletion, tumor lysis syndrome, abdominal compartment syndrome, and obstruction from tumor or lymphadenopathy. Elevations in serum creatinine of as little as 0.3 mg/dL, which were previously considered insignificant, have been associated with a higher mortality rate in hospitalized patients.[4] However, few of the numerous definitions of AKI used in the cancer literature incorporate these subtle declines in kidney function.
An increase in serum creatinine has traditionally been used as a reflection of AKI. However, it is well known that elevation in serum creatinine is a relatively late marker of kidney injury.[6] In addition, patients with cancer often have decreased creatinine production secondary to cachexia, which may limit the sensitivity of creatinine as a marker of kidney injury. Other variables including total body volume, ethnicity, medications, and protein intake may also vary the serum creatinine level independent of renal function. Recent studies have demonstrated that a significant number of patients with cancer and normal serum creatinine have underlying chronic kidney disease (CKD) when renal function is estimated by the Cockcroft-Gault equation.[7] and [8] Therefore, using an arbitrarily defined level of serum creatinine as an indicator of AKI (i.e. >1.5 or 2.0 mg/dL) may not be suitable.
What may be a more accurate measure of kidney injury is a classification system based on the percent increase in serum creatinine relative to baseline. One such model is the Risk, Injury, Failure, Loss, and End-Stage Kidney (RIFLE) classification, which defines three levels of severity of AKI (risk, injury, and failure).[9] Previously, over 35 different definitions of AKI were used in the literature, which has made cross-comparisons between studies difficult.[10] The RIFLE classification provides a uniform definition of AKI and has been validated in numerous studies.[11], [12], [13], [14], [15], [16], [17] and [18] The aim of this analysis was to estimate the incidence, outcomes, and costs associated with AKI as defined by the RIFLE classification in critically ill patients with cancer.
Materials and Methods
The study included all patients ≥18 years of age who were admitted to the intensive care unit (ICU) at the University of Texas M.D. Anderson Cancer Center from December 2005 through December 2006. Patients with a baseline serum creatinine >1.5 mg/dL were excluded from the analysis. The protocol was approved by the institutional review board. Demographic and clinical data were obtained from the Department of Critical Care database, the Department of Pharmacy database, and the global institutional database (Enterprise Information Warehouse). The data were incorporated into a single spreadsheet using Excel 12.2 for Mac (Microsoft, Redmond, WA).
RIFLE categories for AKI were defined by the percent increase in serum creatinine from the time of ICU admission to the maximum creatinine at any point during the ICU stay: risk (≥50% rise in serum creatinine), injury (≥100% rise in serum creatinine), and failure (≥200% rise in serum creatinine). Consistent with the Acute Kidney Injury Network modifications of the original criteria, patients who required dialysis were classified into the RIFLE failure category, irrespective of the percent rise in serum creatinine.[19] The modality for continuous renal replacement therapy used at our institution is continuous slow low-efficiency dialysis (c-SLED), which has been described previously.[20] For patients who did not have an initial creatinine available within 24 hours after ICU admission, the most recent prior creatinine within the previous 48 hours was used.
Statistics
Descriptive data are presented as medians with interquartile ranges for continuous variables and absolute numbers with percentages for categorical variables. Survival of patients with AKI as defined by the RIFLE criteria was estimated by the Kaplan-Meier method. Patients were censored at death or last known follow-up, as determined by the clinical record. Statistical significance was determined by the log-rank test.
The primary end point for logistic regression was death at 60 days after ICU admission. Two separate models were developed, examining AKI as a categorical variable (RIFLE categories) and as a continuous variable (percent increase in creatinine from baseline). The variable “age” was significantly associated in a linear fashion with log odds of death but was dichotomized to provide a more meaningful odds ratio for the reader. Correlated data were assessed by correlation coefficients, and no variables were significantly correlated >0.6. Model reduction was achieved by variable elimination using the likelihood ratio test between nested models. Predictive ability and goodness-of-fit statistics were calculated, and the model was internally validated. No significant interactions were identified in either logistic regression model.
Lastly, a multivariate log linear regression model was developed to assess the relationship of AKI and dialysis with hospital cost. Cost was defined as hospital charges from the provider perspective. Log transformation of “cost” was used to account for skewness and heteroskedasticity. Coefficients in this model were multiplied by a factor of 100 to estimate a percent change in the dependent variable (cost) associated with a unit change in the independent variable.[21]
A two-tailed P < 0.05 was considered statistically significant. No patients were excluded from the analysis because of missing data. Statistical analysis was performed with Stata 10 for Mac (StataCorp, College Station, TX).
Results
The data set included 2,398 patients. Patient characteristics are listed in Table 1. The median age was 59 years. The cohort was predominantly Caucasian (75%) and relatively balanced with respect to gender. The majority of patients on a medical service were admitted to the hospital from the emergency room (76%), compared to only 10% of patients on a surgical service. Sepsis was diagnosed in 23% of patients on a medical service vs. only 4% of patients on a surgical service. This is consistent with the large number of patients at our institution who were admitted to the ICU for routine monitoring after elective surgeries. A significant number of patients had underlying hypertension and diabetes (54% and 18%, respectively). One-third of patients had advanced malignancy by Surveillance, Epidemiology, and End Results (SEER) stage on initial presentation to our institution.
b Included if patient received therapy at any time from ICU admission to date of maximum creatinine.
The absolute number of patients developing AKI or requiring dialysis by hospital service is depicted in Figure 1. The incidence of AKI was higher among patients on a medical vs. a surgical service (21% vs. 6.6%). Patients with hematologic malignancies (leukemia, lymphoma, and myeloma) had the highest incidence of AKI and need for dialysis (28% and 9.3%, respectively). Among patients on a medical service, the odds for developing AKI or requiring dialysis were increased 1.9-fold and 5.4-fold, respectively, for patients with an underlying hematologic malignancy.
Figure 1.
Number of Patients with AKI or Needing Dialysis by Hospital Service
AKI, defined as a minimum 50% increase in serum creatinine from baseline, occurred in 301 patients (12.6%), of whom 56 (2.3%) required dialysis. By further defining AKI by the RIFLE criteria, we classified 6%, 3%, and 4% of patients into the RIFLE risk, injury, and failure categories, respectively. The median elevations in creatinine from baseline were 0.6, 1.1, and 2 mg/dL, respectively. The median time to maximum creatinine was two days for all patients with AKI. There was a stepwise decrease in estimated survival associated with each RIFLE category (Figure 2). Among patients in the RIFLE failure group, the estimated survival was similar between those who required dialysis and those who did not (P = 0.99, log-rank). Although survival for patients requiring dialysis was dismal overall, it was significantly worse for patients with underlying hematological malignancy vs. solid tumor (3% vs. 20%, respectively).
The results of the logistic regression model for predictors of death at 60 days after ICU admission is presented in Table 2. Race and gender were not significant on univariate or multivariate analyses. Although significant on univariate analysis, hematologic malignancy, prior hematopoietic cell transplant (HCT), baseline comorbidities (hypertension, diabetes, heart failure, liver disease), and sepsis were also eliminated during model reduction. After adjusting for the remaining covariates, the RIFLE risk, injury, and failure categories remained significantly associated with 60-day mortality with odds ratios of 2.3, 3.0, and 14, respectively.
| VARIABLE | UNIVARIATE | MULTIVARIATE | |||
|---|---|---|---|---|---|
| OR | P | OR | 95% CI | P | |
| Age ≥55 years | 1.2 | 0.08 | 1.5 | 1.1–1.9 | 0.007 |
| Male vs. female | 0.997 | 0.98 | |||
| Ethnicity | |||||
| Black vs. white | 2.0 | <0.001 | |||
| Hispanic vs. white | 1.1 | 0.39 | |||
| Other vs. white | 0.8 | 0.46 | |||
| Hypertension | 1.3 | 0.02 | |||
| Diabetes | 1.6 | <0.001 | |||
| Heart failure | 2.5 | <0.001 | |||
| Chronic liver disease | 1.8 | 0.02 | |||
| RIFLE category | |||||
| Risk vs. no AKI | 4.1 | <0.001 | 2.3 | 1.5–3.6 | <0.001 |
| Injury vs. no AKI | 8.1 | <0.001 | 3.0 | 1.6–5.8 | 0.001 |
| Failure vs. no AKI | 35 | <0.001 | 14.3 | 7.2–29.0 | <0.001 |
| Amphotericin | 10.9 | <0.001 | 1.9 | 1.1–3.3 | 0.03 |
| Vasopressors | 6.3 | <0.001 | 2.0 | 1.4–2.6 | <0.001 |
| Mechanical ventilation | 2.1 | <0.001 | 1.9 | 1.4–2.5 | <0.001 |
| IV diuretics | 3.8 | <0.001 | 1.4 | 1.1–1.9 | 0.015 |
| Sepsis | 5.7 | <0.001 | |||
| Medical vs. surgical service | 9.9 | <0.001 | 2.2 | 1.5–3.1 | <0.001 |
| Liquid vs. solid tumor | 5.5 | <0.001 | |||
| Prior HCT | |||||
| Autologous | 1.7 | 0.23 | |||
| Allogeneic | 6.0 | <0.001 | |||
| Advanced vs. locoregional stage (SEER) | 4.4 | <0.001 | 2.1 | 1.6–2.6 | <0.001 |
| ER admission | 11.3 | <0.001 | 5.3 | 3.7–7.6 | <0.001 |
| Pre-ICU length of stay | 1.06 | <0.001 | 1.02 | 1.0–1.03 | 0.02 |
Likelihood ratio x2(12) = 818 (P < 0.001), positive predictive value 72%, negative predictive value 88%; area under the receiver operating curve = 0.88, Hosmer-Lemeshow x2(8) = 6.8 (P = 0.56).
OR, odds ratio; AKI, acute kidney injury; HCT, hematopoietic cell transplant; ER, emergency room; ICU, intensive care unit.
To further assess the relationship between serum creatinine and mortality, a separate logistic regression was performed using “percent rise in creatinine” as a continuous predictor variable (Table 3). Need for dialysis was also included as an independent variable. Aside from “percent rise in creatinine” and dialysis, model reduction yielded the same covariates as in the initial model. Dialysis had the largest effect on the odds of 60-day mortality (odds ratio = 6.2). After adjusting for dialysis, “percent rise in creatinine” remained significantly associated with 60-day mortality. For example, a 10% rise in creatinine increased the odds of mortality by 8%. The predictive capabilities of both logistic regression models were similar.
| VARIABLE | OR | 95% CI | P |
|---|---|---|---|
| Age ≥55 years | 1.4 | 1.1–1.9 | <0.001 |
| Percent increase in creatinine | 1.008 | 1.005–1.01 | <0.001 |
| ER admission | 5.4 | 3.8–7.7 | <0.001 |
| Pre-ICU length of stay (days) | 1.02 | 1.00–1.04 | 0.016 |
| SEER stage (distant vs. other) | 2.0 | 1.6–2.7 | <0.001 |
| Medical vs. surgical service | 2.2 | 1.5–3.2 | <0.001 |
| Vasopressors | 2.0 | 1.5–2.7 | <0.001 |
| Mechanical ventilation | 1.8 | 1.4–2.5 | <0.001 |
| Amphotericin | 1.8 | 1.1–3.2 | 0.031 |
| IV diuretics | 1.4 | 1.0–1.8 | 0.024 |
| Dialysis | 6.2 | 2.3–16.5 | <0.001 |
Likelihood ratio x2(11) = 815 (P < 0.001), positive predictive value 72%, negative predictive value 88%, area under the receiver operating curve = 0.88.
OR, odds ratio; ICU, intensive care unit; AKI, acute kidney injury; ER, emergency room.
We included AKI as a continuous variable in a multivariate regression to determine the relationship of AKI and dialysis with hospital cost (Table 4). The model was adjusted for numerous clinical and demographic variables. Age, gender, race, autologous transplant, tumor grade, diabetes, and liver disease were not significant predictors of hospital cost in the final model. The need for dialysis was associated with a 21% increase in hospital cost. Each percent increase in serum creatinine was associated with a 0.16% increase in cost. An interaction was identified between mechanical ventilation and sepsis (25% increase in hospital cost).
| VARIABLE | β | SE | P |
|---|---|---|---|
| Increase in creatinine (per 1%) | 0.00156 | 0.000257 | <0.001 |
| Dialysis | 0.213 | 0.0994 | 0.032 |
| Diuretics | 0.0831 | 0.0180 | <0.001 |
| Mechanical ventilation | 0.561 | 0.0299 | <0.001 |
| Allotransplant | 0.538 | 0.0960 | <0.001 |
| Medical vs. surgical service | 0.259 | 0.0381 | <0.001 |
| Liquid vs. solid tumor | 0.227 | 0.0433 | <0.001 |
| Distant vs. locoregional stage | 0.0717 | 0.0314 | 0.023 |
| Sepsis | 0.151 | 0.0622 | 0.015 |
| ER admission | −0.246 | 0.038 | <0.001 |
| Heart failure | 0.107 | 0.0469 | 0.023 |
| Hypertension | 0.0647 | 0.0271 | 0.017 |
| Mechanical ventilation × sepsis | 0.251 | 0.0853 | 0.003 |
| Constant | 10.8 | 0.0254 | <0.001 |
R2 = 0.32.
Discussion
The incidence of AKI in our study was 12.6% of all patients admitted to the ICU, and there was a progressive decrease in survival associated with worsening kidney injury. This association remained even after adjusting for covariates. AKI and the need for dialysis were also associated with increased hospital costs. To our knowledge, this is the largest single-center study to examine the RIFLE criteria for AKI in a critically-ill population with cancer.
A striking finding in our study is the significant effect that small elevations in serum creatinine may have on survival. An increase of 0.6 mg/dL in the RIFLE risk category increased the odds for mortality by a factor of 2.3 compared to patients without AKI. The median maximum creatinine in this group was only 1.3 mg/dL, which is still within the “normal” range for males in our institution. Criteria that define mild renal toxicity as a serum greater than “1.5 × the upper limit of normal” would exclude a significant number of patients in the RIFLE risk and injury categories, although their risk of mortality was significantly increased.[22] Other criteria that define AKI by glomerular filtration rate (GFR) are also problematic as estimating equations for GFR require serum creatinine to be in steady state. This is a false assumption to make in the setting of AKI, where serum creatinine may fluctuate daily. Serum creatinine is an insensitive marker of renal injury in patients with cancer, and more sensitive and specific biomarkers of AKI are currently under development.[23], [24] and [25] Until these markers are routinely available, renal injury in oncology practice and clinical trials may be better defined as a percentage rise in serum creatinine relative to baseline, similar to the RIFLE criteria.
Out of all variables examined, it is interesting that the need for dialysis had the greatest association with 60-day mortality (Table 3). Although we adjusted for other risk factors, there may still be residual confounding to explain the strong association of dialysis with mortality. However, it is also recognized that dialysis may promote a proinflammatory state[26] and that AKI, in itself, may lead to injury of distant organs via systemic cytokine release.[27] and [28] These deleterious effects may be amplified in patients with cancer, who frequently are neutropenic and have chronic inflammation (e.g. capillary leak syndrome, diffuse alveolar hemorrhage, graft-vs.-host disease). It is known that the need for dialysis after a stem cell transplant is associated with >70% mortality.[29] Although dialysis remains pivotal for volume and metabolic clearance, a true “therapy” for AKI has unfortunately remained elusive thus far.
Our overall incidence of 12.6% for AKI is lower than the reported incidence of 13%–42% in other studies of critically ill patients with cancer.[2], [30] and [31] We excluded patients who had a serum creatinine >1.5 mg/dL on admission to the ICU as we were interested in the development of AKI after ICU admission. This likely excluded patients who already had AKI on presentation, which may have contributed to the lower incidence of AKI and the need for dialysis in our study. Unlike previous studies, our cohort included a large number of patients on a surgical service who were electively admitted to the ICU for routine postoperative care and, therefore, were at lower risk of developing AKI. However, when limited to patients on a medical service, our incidence of 21% is consistent with the results of previous studies of patients in medical ICUs.
The prognosis of patients requiring dialysis was dismal, with an estimated 89% 60-day mortality. This is somewhat higher than the reported mortality of 66%–88% in previous studies.[32], [33], [34], [35] and [36] Given that our institution also serves as a referral cancer center for patients who have had progressive disease on standard therapy, it is possible that our patient population may have been more predisposed to complications from cancer therapy. Patients with hematological malignancies had a higher incidence of AKI and need for dialysis. However, underlying hematological malignancy and HCT were no longer significantly associated with 60-day mortality in the adjusted analysis. Similar to the findings of others, this would suggest that it is not the underlying malignancy itself but rather the complications of treatment and prolonged immunosuppression that lead to decreased survival in these patients.[37] and [38] Early goal-directed intensive life support should be considered for most patients,[39] but continuation of dialysis may not be of benefit, in terms of both survival and cost, in patients with hematologic malignancy who demonstrate minimal improvement.
Our study had certain limitations. Given the retrospective design, we cannot rule out selection bias or residual confounding. We were able to adjust for several variables specific to cancer and critical care as well as pre-ICU length of stay, which may be a surrogate marker for comorbidities and functional status. Nonetheless, our conclusions should be interpreted as hypothesis-generating. Second, our study is based on a single-center experience, which may limit its generalizability. Nonetheless, our study had a large sample size that was subjected to fairly uniform management. Third, we did not have data on end-of-life decisions, which may have impacted mortality and need for dialysis. Lastly, we were unable to obtain cost-to-charge ratios, which may limit the generalizability of our findings to other institutions. However, we reported on percent increases in cost as opposed to absolute dollar figures, which may adjust for some of this variation.
Conclusions
AKI as defined by the RIFLE criteria may be predictive of short-term mortality in critically ill patients with cancer. We have demonstrated that relatively small changes in serum creatinine are associated with higher mortality and that the need for dialysis entails a very poor prognosis. The mechanism behind the increased mortality in patients with hematological malignancies appears to be secondary to the associated complications of therapy, as opposed to the underlying cancer itself. We hypothesize that strategies to prevent the development of AKI and progression to dialysis dependence may improve survival. Whether the prevention of AKI translates to cost savings is also of interest.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Volume 9, Issue 4, July-August 2011, Pages 149-155
Original research
Amit Lahoti MDa,
Background
Acute kidney injury (AKI) is a common complication in critically ill patients with cancer. The RIFLE criteria define three levels of AKI based on the percent increase in serum creatinine (Scr) from baseline: risk (≥50%), injury (≥100%), and failure (≥200% or requiring dialysis). The utility of the RIFLE criteria in critically ill patients with cancer is not known.
Objective
To examine the incidence, outcomes, and costs associated with AKI in critically ill patients with cancer.
Methods
We retrospectively analyzed all patients admitted to a single-center ICU over a 13-month period with a baseline Scr ≤1.5 mg/dL (n = 2,398). Kaplan-Meier estimates for survival by RIFLE category were calculated. Logistic regression was used to determine the association of AKI on 60-day mortality. A log-linear regression model was used for economic analysis. Costs were assessed by hospital charges from the provider's perspective.
Results
For the risk, injury, and failure categories of AKI, incidence rates were 6%, 2.8%, and 3.7%; 60-day survival estimates were 62%, 45%, and 14%; and adjusted odds ratios for 60-day mortality were 2.3, 3, and 14.3, respectively (P ≤ 0.001 compared to patients without AKI). Hematologic malignancy and hematopoietic cell transplant were not associated with mortality in the adjusted analysis. Hospital cost increased by 0.16% per 1% increase in creatinine and by 21% for patients requiring dialysis.
Limitations
Retrospective analysis. Single-center study. No adjustment by cost-to-charge ratios.
Conclusions
AKI is associated with higher mortality and costs in critically ill patients with cancer.
Over the past several years, important advances have occurred in the treatment and supportive care of critically ill patients with cancer.[1] However, acute kidney injury (AKI) remains a familiar complication and is a negative prognostic factor for overall survival.[2] and [3] The development of AKI can limit further cancer treatment, increase toxicity of chemotherapy and reduce its delivery, and exclude patients from clinical trials. Further, patients with AKI have been shown to have longer hospitalizations and increased hospital costs.[4] and [5] Recognized causes of AKI include acute tubular necrosis from medications or sepsis, volume depletion, tumor lysis syndrome, abdominal compartment syndrome, and obstruction from tumor or lymphadenopathy. Elevations in serum creatinine of as little as 0.3 mg/dL, which were previously considered insignificant, have been associated with a higher mortality rate in hospitalized patients.[4] However, few of the numerous definitions of AKI used in the cancer literature incorporate these subtle declines in kidney function.
An increase in serum creatinine has traditionally been used as a reflection of AKI. However, it is well known that elevation in serum creatinine is a relatively late marker of kidney injury.[6] In addition, patients with cancer often have decreased creatinine production secondary to cachexia, which may limit the sensitivity of creatinine as a marker of kidney injury. Other variables including total body volume, ethnicity, medications, and protein intake may also vary the serum creatinine level independent of renal function. Recent studies have demonstrated that a significant number of patients with cancer and normal serum creatinine have underlying chronic kidney disease (CKD) when renal function is estimated by the Cockcroft-Gault equation.[7] and [8] Therefore, using an arbitrarily defined level of serum creatinine as an indicator of AKI (i.e. >1.5 or 2.0 mg/dL) may not be suitable.
What may be a more accurate measure of kidney injury is a classification system based on the percent increase in serum creatinine relative to baseline. One such model is the Risk, Injury, Failure, Loss, and End-Stage Kidney (RIFLE) classification, which defines three levels of severity of AKI (risk, injury, and failure).[9] Previously, over 35 different definitions of AKI were used in the literature, which has made cross-comparisons between studies difficult.[10] The RIFLE classification provides a uniform definition of AKI and has been validated in numerous studies.[11], [12], [13], [14], [15], [16], [17] and [18] The aim of this analysis was to estimate the incidence, outcomes, and costs associated with AKI as defined by the RIFLE classification in critically ill patients with cancer.
Materials and Methods
The study included all patients ≥18 years of age who were admitted to the intensive care unit (ICU) at the University of Texas M.D. Anderson Cancer Center from December 2005 through December 2006. Patients with a baseline serum creatinine >1.5 mg/dL were excluded from the analysis. The protocol was approved by the institutional review board. Demographic and clinical data were obtained from the Department of Critical Care database, the Department of Pharmacy database, and the global institutional database (Enterprise Information Warehouse). The data were incorporated into a single spreadsheet using Excel 12.2 for Mac (Microsoft, Redmond, WA).
RIFLE categories for AKI were defined by the percent increase in serum creatinine from the time of ICU admission to the maximum creatinine at any point during the ICU stay: risk (≥50% rise in serum creatinine), injury (≥100% rise in serum creatinine), and failure (≥200% rise in serum creatinine). Consistent with the Acute Kidney Injury Network modifications of the original criteria, patients who required dialysis were classified into the RIFLE failure category, irrespective of the percent rise in serum creatinine.[19] The modality for continuous renal replacement therapy used at our institution is continuous slow low-efficiency dialysis (c-SLED), which has been described previously.[20] For patients who did not have an initial creatinine available within 24 hours after ICU admission, the most recent prior creatinine within the previous 48 hours was used.
Statistics
Descriptive data are presented as medians with interquartile ranges for continuous variables and absolute numbers with percentages for categorical variables. Survival of patients with AKI as defined by the RIFLE criteria was estimated by the Kaplan-Meier method. Patients were censored at death or last known follow-up, as determined by the clinical record. Statistical significance was determined by the log-rank test.
The primary end point for logistic regression was death at 60 days after ICU admission. Two separate models were developed, examining AKI as a categorical variable (RIFLE categories) and as a continuous variable (percent increase in creatinine from baseline). The variable “age” was significantly associated in a linear fashion with log odds of death but was dichotomized to provide a more meaningful odds ratio for the reader. Correlated data were assessed by correlation coefficients, and no variables were significantly correlated >0.6. Model reduction was achieved by variable elimination using the likelihood ratio test between nested models. Predictive ability and goodness-of-fit statistics were calculated, and the model was internally validated. No significant interactions were identified in either logistic regression model.
Lastly, a multivariate log linear regression model was developed to assess the relationship of AKI and dialysis with hospital cost. Cost was defined as hospital charges from the provider perspective. Log transformation of “cost” was used to account for skewness and heteroskedasticity. Coefficients in this model were multiplied by a factor of 100 to estimate a percent change in the dependent variable (cost) associated with a unit change in the independent variable.[21]
A two-tailed P < 0.05 was considered statistically significant. No patients were excluded from the analysis because of missing data. Statistical analysis was performed with Stata 10 for Mac (StataCorp, College Station, TX).
Results
The data set included 2,398 patients. Patient characteristics are listed in Table 1. The median age was 59 years. The cohort was predominantly Caucasian (75%) and relatively balanced with respect to gender. The majority of patients on a medical service were admitted to the hospital from the emergency room (76%), compared to only 10% of patients on a surgical service. Sepsis was diagnosed in 23% of patients on a medical service vs. only 4% of patients on a surgical service. This is consistent with the large number of patients at our institution who were admitted to the ICU for routine monitoring after elective surgeries. A significant number of patients had underlying hypertension and diabetes (54% and 18%, respectively). One-third of patients had advanced malignancy by Surveillance, Epidemiology, and End Results (SEER) stage on initial presentation to our institution.
b Included if patient received therapy at any time from ICU admission to date of maximum creatinine.
The absolute number of patients developing AKI or requiring dialysis by hospital service is depicted in Figure 1. The incidence of AKI was higher among patients on a medical vs. a surgical service (21% vs. 6.6%). Patients with hematologic malignancies (leukemia, lymphoma, and myeloma) had the highest incidence of AKI and need for dialysis (28% and 9.3%, respectively). Among patients on a medical service, the odds for developing AKI or requiring dialysis were increased 1.9-fold and 5.4-fold, respectively, for patients with an underlying hematologic malignancy.
Figure 1.
Number of Patients with AKI or Needing Dialysis by Hospital Service
AKI, defined as a minimum 50% increase in serum creatinine from baseline, occurred in 301 patients (12.6%), of whom 56 (2.3%) required dialysis. By further defining AKI by the RIFLE criteria, we classified 6%, 3%, and 4% of patients into the RIFLE risk, injury, and failure categories, respectively. The median elevations in creatinine from baseline were 0.6, 1.1, and 2 mg/dL, respectively. The median time to maximum creatinine was two days for all patients with AKI. There was a stepwise decrease in estimated survival associated with each RIFLE category (Figure 2). Among patients in the RIFLE failure group, the estimated survival was similar between those who required dialysis and those who did not (P = 0.99, log-rank). Although survival for patients requiring dialysis was dismal overall, it was significantly worse for patients with underlying hematological malignancy vs. solid tumor (3% vs. 20%, respectively).
The results of the logistic regression model for predictors of death at 60 days after ICU admission is presented in Table 2. Race and gender were not significant on univariate or multivariate analyses. Although significant on univariate analysis, hematologic malignancy, prior hematopoietic cell transplant (HCT), baseline comorbidities (hypertension, diabetes, heart failure, liver disease), and sepsis were also eliminated during model reduction. After adjusting for the remaining covariates, the RIFLE risk, injury, and failure categories remained significantly associated with 60-day mortality with odds ratios of 2.3, 3.0, and 14, respectively.
| VARIABLE | UNIVARIATE | MULTIVARIATE | |||
|---|---|---|---|---|---|
| OR | P | OR | 95% CI | P | |
| Age ≥55 years | 1.2 | 0.08 | 1.5 | 1.1–1.9 | 0.007 |
| Male vs. female | 0.997 | 0.98 | |||
| Ethnicity | |||||
| Black vs. white | 2.0 | <0.001 | |||
| Hispanic vs. white | 1.1 | 0.39 | |||
| Other vs. white | 0.8 | 0.46 | |||
| Hypertension | 1.3 | 0.02 | |||
| Diabetes | 1.6 | <0.001 | |||
| Heart failure | 2.5 | <0.001 | |||
| Chronic liver disease | 1.8 | 0.02 | |||
| RIFLE category | |||||
| Risk vs. no AKI | 4.1 | <0.001 | 2.3 | 1.5–3.6 | <0.001 |
| Injury vs. no AKI | 8.1 | <0.001 | 3.0 | 1.6–5.8 | 0.001 |
| Failure vs. no AKI | 35 | <0.001 | 14.3 | 7.2–29.0 | <0.001 |
| Amphotericin | 10.9 | <0.001 | 1.9 | 1.1–3.3 | 0.03 |
| Vasopressors | 6.3 | <0.001 | 2.0 | 1.4–2.6 | <0.001 |
| Mechanical ventilation | 2.1 | <0.001 | 1.9 | 1.4–2.5 | <0.001 |
| IV diuretics | 3.8 | <0.001 | 1.4 | 1.1–1.9 | 0.015 |
| Sepsis | 5.7 | <0.001 | |||
| Medical vs. surgical service | 9.9 | <0.001 | 2.2 | 1.5–3.1 | <0.001 |
| Liquid vs. solid tumor | 5.5 | <0.001 | |||
| Prior HCT | |||||
| Autologous | 1.7 | 0.23 | |||
| Allogeneic | 6.0 | <0.001 | |||
| Advanced vs. locoregional stage (SEER) | 4.4 | <0.001 | 2.1 | 1.6–2.6 | <0.001 |
| ER admission | 11.3 | <0.001 | 5.3 | 3.7–7.6 | <0.001 |
| Pre-ICU length of stay | 1.06 | <0.001 | 1.02 | 1.0–1.03 | 0.02 |
Likelihood ratio x2(12) = 818 (P < 0.001), positive predictive value 72%, negative predictive value 88%; area under the receiver operating curve = 0.88, Hosmer-Lemeshow x2(8) = 6.8 (P = 0.56).
OR, odds ratio; AKI, acute kidney injury; HCT, hematopoietic cell transplant; ER, emergency room; ICU, intensive care unit.
To further assess the relationship between serum creatinine and mortality, a separate logistic regression was performed using “percent rise in creatinine” as a continuous predictor variable (Table 3). Need for dialysis was also included as an independent variable. Aside from “percent rise in creatinine” and dialysis, model reduction yielded the same covariates as in the initial model. Dialysis had the largest effect on the odds of 60-day mortality (odds ratio = 6.2). After adjusting for dialysis, “percent rise in creatinine” remained significantly associated with 60-day mortality. For example, a 10% rise in creatinine increased the odds of mortality by 8%. The predictive capabilities of both logistic regression models were similar.
| VARIABLE | OR | 95% CI | P |
|---|---|---|---|
| Age ≥55 years | 1.4 | 1.1–1.9 | <0.001 |
| Percent increase in creatinine | 1.008 | 1.005–1.01 | <0.001 |
| ER admission | 5.4 | 3.8–7.7 | <0.001 |
| Pre-ICU length of stay (days) | 1.02 | 1.00–1.04 | 0.016 |
| SEER stage (distant vs. other) | 2.0 | 1.6–2.7 | <0.001 |
| Medical vs. surgical service | 2.2 | 1.5–3.2 | <0.001 |
| Vasopressors | 2.0 | 1.5–2.7 | <0.001 |
| Mechanical ventilation | 1.8 | 1.4–2.5 | <0.001 |
| Amphotericin | 1.8 | 1.1–3.2 | 0.031 |
| IV diuretics | 1.4 | 1.0–1.8 | 0.024 |
| Dialysis | 6.2 | 2.3–16.5 | <0.001 |
Likelihood ratio x2(11) = 815 (P < 0.001), positive predictive value 72%, negative predictive value 88%, area under the receiver operating curve = 0.88.
OR, odds ratio; ICU, intensive care unit; AKI, acute kidney injury; ER, emergency room.
We included AKI as a continuous variable in a multivariate regression to determine the relationship of AKI and dialysis with hospital cost (Table 4). The model was adjusted for numerous clinical and demographic variables. Age, gender, race, autologous transplant, tumor grade, diabetes, and liver disease were not significant predictors of hospital cost in the final model. The need for dialysis was associated with a 21% increase in hospital cost. Each percent increase in serum creatinine was associated with a 0.16% increase in cost. An interaction was identified between mechanical ventilation and sepsis (25% increase in hospital cost).
| VARIABLE | β | SE | P |
|---|---|---|---|
| Increase in creatinine (per 1%) | 0.00156 | 0.000257 | <0.001 |
| Dialysis | 0.213 | 0.0994 | 0.032 |
| Diuretics | 0.0831 | 0.0180 | <0.001 |
| Mechanical ventilation | 0.561 | 0.0299 | <0.001 |
| Allotransplant | 0.538 | 0.0960 | <0.001 |
| Medical vs. surgical service | 0.259 | 0.0381 | <0.001 |
| Liquid vs. solid tumor | 0.227 | 0.0433 | <0.001 |
| Distant vs. locoregional stage | 0.0717 | 0.0314 | 0.023 |
| Sepsis | 0.151 | 0.0622 | 0.015 |
| ER admission | −0.246 | 0.038 | <0.001 |
| Heart failure | 0.107 | 0.0469 | 0.023 |
| Hypertension | 0.0647 | 0.0271 | 0.017 |
| Mechanical ventilation × sepsis | 0.251 | 0.0853 | 0.003 |
| Constant | 10.8 | 0.0254 | <0.001 |
R2 = 0.32.
Discussion
The incidence of AKI in our study was 12.6% of all patients admitted to the ICU, and there was a progressive decrease in survival associated with worsening kidney injury. This association remained even after adjusting for covariates. AKI and the need for dialysis were also associated with increased hospital costs. To our knowledge, this is the largest single-center study to examine the RIFLE criteria for AKI in a critically-ill population with cancer.
A striking finding in our study is the significant effect that small elevations in serum creatinine may have on survival. An increase of 0.6 mg/dL in the RIFLE risk category increased the odds for mortality by a factor of 2.3 compared to patients without AKI. The median maximum creatinine in this group was only 1.3 mg/dL, which is still within the “normal” range for males in our institution. Criteria that define mild renal toxicity as a serum greater than “1.5 × the upper limit of normal” would exclude a significant number of patients in the RIFLE risk and injury categories, although their risk of mortality was significantly increased.[22] Other criteria that define AKI by glomerular filtration rate (GFR) are also problematic as estimating equations for GFR require serum creatinine to be in steady state. This is a false assumption to make in the setting of AKI, where serum creatinine may fluctuate daily. Serum creatinine is an insensitive marker of renal injury in patients with cancer, and more sensitive and specific biomarkers of AKI are currently under development.[23], [24] and [25] Until these markers are routinely available, renal injury in oncology practice and clinical trials may be better defined as a percentage rise in serum creatinine relative to baseline, similar to the RIFLE criteria.
Out of all variables examined, it is interesting that the need for dialysis had the greatest association with 60-day mortality (Table 3). Although we adjusted for other risk factors, there may still be residual confounding to explain the strong association of dialysis with mortality. However, it is also recognized that dialysis may promote a proinflammatory state[26] and that AKI, in itself, may lead to injury of distant organs via systemic cytokine release.[27] and [28] These deleterious effects may be amplified in patients with cancer, who frequently are neutropenic and have chronic inflammation (e.g. capillary leak syndrome, diffuse alveolar hemorrhage, graft-vs.-host disease). It is known that the need for dialysis after a stem cell transplant is associated with >70% mortality.[29] Although dialysis remains pivotal for volume and metabolic clearance, a true “therapy” for AKI has unfortunately remained elusive thus far.
Our overall incidence of 12.6% for AKI is lower than the reported incidence of 13%–42% in other studies of critically ill patients with cancer.[2], [30] and [31] We excluded patients who had a serum creatinine >1.5 mg/dL on admission to the ICU as we were interested in the development of AKI after ICU admission. This likely excluded patients who already had AKI on presentation, which may have contributed to the lower incidence of AKI and the need for dialysis in our study. Unlike previous studies, our cohort included a large number of patients on a surgical service who were electively admitted to the ICU for routine postoperative care and, therefore, were at lower risk of developing AKI. However, when limited to patients on a medical service, our incidence of 21% is consistent with the results of previous studies of patients in medical ICUs.
The prognosis of patients requiring dialysis was dismal, with an estimated 89% 60-day mortality. This is somewhat higher than the reported mortality of 66%–88% in previous studies.[32], [33], [34], [35] and [36] Given that our institution also serves as a referral cancer center for patients who have had progressive disease on standard therapy, it is possible that our patient population may have been more predisposed to complications from cancer therapy. Patients with hematological malignancies had a higher incidence of AKI and need for dialysis. However, underlying hematological malignancy and HCT were no longer significantly associated with 60-day mortality in the adjusted analysis. Similar to the findings of others, this would suggest that it is not the underlying malignancy itself but rather the complications of treatment and prolonged immunosuppression that lead to decreased survival in these patients.[37] and [38] Early goal-directed intensive life support should be considered for most patients,[39] but continuation of dialysis may not be of benefit, in terms of both survival and cost, in patients with hematologic malignancy who demonstrate minimal improvement.
Our study had certain limitations. Given the retrospective design, we cannot rule out selection bias or residual confounding. We were able to adjust for several variables specific to cancer and critical care as well as pre-ICU length of stay, which may be a surrogate marker for comorbidities and functional status. Nonetheless, our conclusions should be interpreted as hypothesis-generating. Second, our study is based on a single-center experience, which may limit its generalizability. Nonetheless, our study had a large sample size that was subjected to fairly uniform management. Third, we did not have data on end-of-life decisions, which may have impacted mortality and need for dialysis. Lastly, we were unable to obtain cost-to-charge ratios, which may limit the generalizability of our findings to other institutions. However, we reported on percent increases in cost as opposed to absolute dollar figures, which may adjust for some of this variation.
Conclusions
AKI as defined by the RIFLE criteria may be predictive of short-term mortality in critically ill patients with cancer. We have demonstrated that relatively small changes in serum creatinine are associated with higher mortality and that the need for dialysis entails a very poor prognosis. The mechanism behind the increased mortality in patients with hematological malignancies appears to be secondary to the associated complications of therapy, as opposed to the underlying cancer itself. We hypothesize that strategies to prevent the development of AKI and progression to dialysis dependence may improve survival. Whether the prevention of AKI translates to cost savings is also of interest.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Volume 9, Issue 4, July-August 2011, Pages 149-155
Original research
Amit Lahoti MDa,
Background
Acute kidney injury (AKI) is a common complication in critically ill patients with cancer. The RIFLE criteria define three levels of AKI based on the percent increase in serum creatinine (Scr) from baseline: risk (≥50%), injury (≥100%), and failure (≥200% or requiring dialysis). The utility of the RIFLE criteria in critically ill patients with cancer is not known.
Objective
To examine the incidence, outcomes, and costs associated with AKI in critically ill patients with cancer.
Methods
We retrospectively analyzed all patients admitted to a single-center ICU over a 13-month period with a baseline Scr ≤1.5 mg/dL (n = 2,398). Kaplan-Meier estimates for survival by RIFLE category were calculated. Logistic regression was used to determine the association of AKI on 60-day mortality. A log-linear regression model was used for economic analysis. Costs were assessed by hospital charges from the provider's perspective.
Results
For the risk, injury, and failure categories of AKI, incidence rates were 6%, 2.8%, and 3.7%; 60-day survival estimates were 62%, 45%, and 14%; and adjusted odds ratios for 60-day mortality were 2.3, 3, and 14.3, respectively (P ≤ 0.001 compared to patients without AKI). Hematologic malignancy and hematopoietic cell transplant were not associated with mortality in the adjusted analysis. Hospital cost increased by 0.16% per 1% increase in creatinine and by 21% for patients requiring dialysis.
Limitations
Retrospective analysis. Single-center study. No adjustment by cost-to-charge ratios.
Conclusions
AKI is associated with higher mortality and costs in critically ill patients with cancer.
Over the past several years, important advances have occurred in the treatment and supportive care of critically ill patients with cancer.[1] However, acute kidney injury (AKI) remains a familiar complication and is a negative prognostic factor for overall survival.[2] and [3] The development of AKI can limit further cancer treatment, increase toxicity of chemotherapy and reduce its delivery, and exclude patients from clinical trials. Further, patients with AKI have been shown to have longer hospitalizations and increased hospital costs.[4] and [5] Recognized causes of AKI include acute tubular necrosis from medications or sepsis, volume depletion, tumor lysis syndrome, abdominal compartment syndrome, and obstruction from tumor or lymphadenopathy. Elevations in serum creatinine of as little as 0.3 mg/dL, which were previously considered insignificant, have been associated with a higher mortality rate in hospitalized patients.[4] However, few of the numerous definitions of AKI used in the cancer literature incorporate these subtle declines in kidney function.
An increase in serum creatinine has traditionally been used as a reflection of AKI. However, it is well known that elevation in serum creatinine is a relatively late marker of kidney injury.[6] In addition, patients with cancer often have decreased creatinine production secondary to cachexia, which may limit the sensitivity of creatinine as a marker of kidney injury. Other variables including total body volume, ethnicity, medications, and protein intake may also vary the serum creatinine level independent of renal function. Recent studies have demonstrated that a significant number of patients with cancer and normal serum creatinine have underlying chronic kidney disease (CKD) when renal function is estimated by the Cockcroft-Gault equation.[7] and [8] Therefore, using an arbitrarily defined level of serum creatinine as an indicator of AKI (i.e. >1.5 or 2.0 mg/dL) may not be suitable.
What may be a more accurate measure of kidney injury is a classification system based on the percent increase in serum creatinine relative to baseline. One such model is the Risk, Injury, Failure, Loss, and End-Stage Kidney (RIFLE) classification, which defines three levels of severity of AKI (risk, injury, and failure).[9] Previously, over 35 different definitions of AKI were used in the literature, which has made cross-comparisons between studies difficult.[10] The RIFLE classification provides a uniform definition of AKI and has been validated in numerous studies.[11], [12], [13], [14], [15], [16], [17] and [18] The aim of this analysis was to estimate the incidence, outcomes, and costs associated with AKI as defined by the RIFLE classification in critically ill patients with cancer.
Materials and Methods
The study included all patients ≥18 years of age who were admitted to the intensive care unit (ICU) at the University of Texas M.D. Anderson Cancer Center from December 2005 through December 2006. Patients with a baseline serum creatinine >1.5 mg/dL were excluded from the analysis. The protocol was approved by the institutional review board. Demographic and clinical data were obtained from the Department of Critical Care database, the Department of Pharmacy database, and the global institutional database (Enterprise Information Warehouse). The data were incorporated into a single spreadsheet using Excel 12.2 for Mac (Microsoft, Redmond, WA).
RIFLE categories for AKI were defined by the percent increase in serum creatinine from the time of ICU admission to the maximum creatinine at any point during the ICU stay: risk (≥50% rise in serum creatinine), injury (≥100% rise in serum creatinine), and failure (≥200% rise in serum creatinine). Consistent with the Acute Kidney Injury Network modifications of the original criteria, patients who required dialysis were classified into the RIFLE failure category, irrespective of the percent rise in serum creatinine.[19] The modality for continuous renal replacement therapy used at our institution is continuous slow low-efficiency dialysis (c-SLED), which has been described previously.[20] For patients who did not have an initial creatinine available within 24 hours after ICU admission, the most recent prior creatinine within the previous 48 hours was used.
Statistics
Descriptive data are presented as medians with interquartile ranges for continuous variables and absolute numbers with percentages for categorical variables. Survival of patients with AKI as defined by the RIFLE criteria was estimated by the Kaplan-Meier method. Patients were censored at death or last known follow-up, as determined by the clinical record. Statistical significance was determined by the log-rank test.
The primary end point for logistic regression was death at 60 days after ICU admission. Two separate models were developed, examining AKI as a categorical variable (RIFLE categories) and as a continuous variable (percent increase in creatinine from baseline). The variable “age” was significantly associated in a linear fashion with log odds of death but was dichotomized to provide a more meaningful odds ratio for the reader. Correlated data were assessed by correlation coefficients, and no variables were significantly correlated >0.6. Model reduction was achieved by variable elimination using the likelihood ratio test between nested models. Predictive ability and goodness-of-fit statistics were calculated, and the model was internally validated. No significant interactions were identified in either logistic regression model.
Lastly, a multivariate log linear regression model was developed to assess the relationship of AKI and dialysis with hospital cost. Cost was defined as hospital charges from the provider perspective. Log transformation of “cost” was used to account for skewness and heteroskedasticity. Coefficients in this model were multiplied by a factor of 100 to estimate a percent change in the dependent variable (cost) associated with a unit change in the independent variable.[21]
A two-tailed P < 0.05 was considered statistically significant. No patients were excluded from the analysis because of missing data. Statistical analysis was performed with Stata 10 for Mac (StataCorp, College Station, TX).
Results
The data set included 2,398 patients. Patient characteristics are listed in Table 1. The median age was 59 years. The cohort was predominantly Caucasian (75%) and relatively balanced with respect to gender. The majority of patients on a medical service were admitted to the hospital from the emergency room (76%), compared to only 10% of patients on a surgical service. Sepsis was diagnosed in 23% of patients on a medical service vs. only 4% of patients on a surgical service. This is consistent with the large number of patients at our institution who were admitted to the ICU for routine monitoring after elective surgeries. A significant number of patients had underlying hypertension and diabetes (54% and 18%, respectively). One-third of patients had advanced malignancy by Surveillance, Epidemiology, and End Results (SEER) stage on initial presentation to our institution.
b Included if patient received therapy at any time from ICU admission to date of maximum creatinine.
The absolute number of patients developing AKI or requiring dialysis by hospital service is depicted in Figure 1. The incidence of AKI was higher among patients on a medical vs. a surgical service (21% vs. 6.6%). Patients with hematologic malignancies (leukemia, lymphoma, and myeloma) had the highest incidence of AKI and need for dialysis (28% and 9.3%, respectively). Among patients on a medical service, the odds for developing AKI or requiring dialysis were increased 1.9-fold and 5.4-fold, respectively, for patients with an underlying hematologic malignancy.
Figure 1.
Number of Patients with AKI or Needing Dialysis by Hospital Service
AKI, defined as a minimum 50% increase in serum creatinine from baseline, occurred in 301 patients (12.6%), of whom 56 (2.3%) required dialysis. By further defining AKI by the RIFLE criteria, we classified 6%, 3%, and 4% of patients into the RIFLE risk, injury, and failure categories, respectively. The median elevations in creatinine from baseline were 0.6, 1.1, and 2 mg/dL, respectively. The median time to maximum creatinine was two days for all patients with AKI. There was a stepwise decrease in estimated survival associated with each RIFLE category (Figure 2). Among patients in the RIFLE failure group, the estimated survival was similar between those who required dialysis and those who did not (P = 0.99, log-rank). Although survival for patients requiring dialysis was dismal overall, it was significantly worse for patients with underlying hematological malignancy vs. solid tumor (3% vs. 20%, respectively).
The results of the logistic regression model for predictors of death at 60 days after ICU admission is presented in Table 2. Race and gender were not significant on univariate or multivariate analyses. Although significant on univariate analysis, hematologic malignancy, prior hematopoietic cell transplant (HCT), baseline comorbidities (hypertension, diabetes, heart failure, liver disease), and sepsis were also eliminated during model reduction. After adjusting for the remaining covariates, the RIFLE risk, injury, and failure categories remained significantly associated with 60-day mortality with odds ratios of 2.3, 3.0, and 14, respectively.
| VARIABLE | UNIVARIATE | MULTIVARIATE | |||
|---|---|---|---|---|---|
| OR | P | OR | 95% CI | P | |
| Age ≥55 years | 1.2 | 0.08 | 1.5 | 1.1–1.9 | 0.007 |
| Male vs. female | 0.997 | 0.98 | |||
| Ethnicity | |||||
| Black vs. white | 2.0 | <0.001 | |||
| Hispanic vs. white | 1.1 | 0.39 | |||
| Other vs. white | 0.8 | 0.46 | |||
| Hypertension | 1.3 | 0.02 | |||
| Diabetes | 1.6 | <0.001 | |||
| Heart failure | 2.5 | <0.001 | |||
| Chronic liver disease | 1.8 | 0.02 | |||
| RIFLE category | |||||
| Risk vs. no AKI | 4.1 | <0.001 | 2.3 | 1.5–3.6 | <0.001 |
| Injury vs. no AKI | 8.1 | <0.001 | 3.0 | 1.6–5.8 | 0.001 |
| Failure vs. no AKI | 35 | <0.001 | 14.3 | 7.2–29.0 | <0.001 |
| Amphotericin | 10.9 | <0.001 | 1.9 | 1.1–3.3 | 0.03 |
| Vasopressors | 6.3 | <0.001 | 2.0 | 1.4–2.6 | <0.001 |
| Mechanical ventilation | 2.1 | <0.001 | 1.9 | 1.4–2.5 | <0.001 |
| IV diuretics | 3.8 | <0.001 | 1.4 | 1.1–1.9 | 0.015 |
| Sepsis | 5.7 | <0.001 | |||
| Medical vs. surgical service | 9.9 | <0.001 | 2.2 | 1.5–3.1 | <0.001 |
| Liquid vs. solid tumor | 5.5 | <0.001 | |||
| Prior HCT | |||||
| Autologous | 1.7 | 0.23 | |||
| Allogeneic | 6.0 | <0.001 | |||
| Advanced vs. locoregional stage (SEER) | 4.4 | <0.001 | 2.1 | 1.6–2.6 | <0.001 |
| ER admission | 11.3 | <0.001 | 5.3 | 3.7–7.6 | <0.001 |
| Pre-ICU length of stay | 1.06 | <0.001 | 1.02 | 1.0–1.03 | 0.02 |
Likelihood ratio x2(12) = 818 (P < 0.001), positive predictive value 72%, negative predictive value 88%; area under the receiver operating curve = 0.88, Hosmer-Lemeshow x2(8) = 6.8 (P = 0.56).
OR, odds ratio; AKI, acute kidney injury; HCT, hematopoietic cell transplant; ER, emergency room; ICU, intensive care unit.
To further assess the relationship between serum creatinine and mortality, a separate logistic regression was performed using “percent rise in creatinine” as a continuous predictor variable (Table 3). Need for dialysis was also included as an independent variable. Aside from “percent rise in creatinine” and dialysis, model reduction yielded the same covariates as in the initial model. Dialysis had the largest effect on the odds of 60-day mortality (odds ratio = 6.2). After adjusting for dialysis, “percent rise in creatinine” remained significantly associated with 60-day mortality. For example, a 10% rise in creatinine increased the odds of mortality by 8%. The predictive capabilities of both logistic regression models were similar.
| VARIABLE | OR | 95% CI | P |
|---|---|---|---|
| Age ≥55 years | 1.4 | 1.1–1.9 | <0.001 |
| Percent increase in creatinine | 1.008 | 1.005–1.01 | <0.001 |
| ER admission | 5.4 | 3.8–7.7 | <0.001 |
| Pre-ICU length of stay (days) | 1.02 | 1.00–1.04 | 0.016 |
| SEER stage (distant vs. other) | 2.0 | 1.6–2.7 | <0.001 |
| Medical vs. surgical service | 2.2 | 1.5–3.2 | <0.001 |
| Vasopressors | 2.0 | 1.5–2.7 | <0.001 |
| Mechanical ventilation | 1.8 | 1.4–2.5 | <0.001 |
| Amphotericin | 1.8 | 1.1–3.2 | 0.031 |
| IV diuretics | 1.4 | 1.0–1.8 | 0.024 |
| Dialysis | 6.2 | 2.3–16.5 | <0.001 |
Likelihood ratio x2(11) = 815 (P < 0.001), positive predictive value 72%, negative predictive value 88%, area under the receiver operating curve = 0.88.
OR, odds ratio; ICU, intensive care unit; AKI, acute kidney injury; ER, emergency room.
We included AKI as a continuous variable in a multivariate regression to determine the relationship of AKI and dialysis with hospital cost (Table 4). The model was adjusted for numerous clinical and demographic variables. Age, gender, race, autologous transplant, tumor grade, diabetes, and liver disease were not significant predictors of hospital cost in the final model. The need for dialysis was associated with a 21% increase in hospital cost. Each percent increase in serum creatinine was associated with a 0.16% increase in cost. An interaction was identified between mechanical ventilation and sepsis (25% increase in hospital cost).
| VARIABLE | β | SE | P |
|---|---|---|---|
| Increase in creatinine (per 1%) | 0.00156 | 0.000257 | <0.001 |
| Dialysis | 0.213 | 0.0994 | 0.032 |
| Diuretics | 0.0831 | 0.0180 | <0.001 |
| Mechanical ventilation | 0.561 | 0.0299 | <0.001 |
| Allotransplant | 0.538 | 0.0960 | <0.001 |
| Medical vs. surgical service | 0.259 | 0.0381 | <0.001 |
| Liquid vs. solid tumor | 0.227 | 0.0433 | <0.001 |
| Distant vs. locoregional stage | 0.0717 | 0.0314 | 0.023 |
| Sepsis | 0.151 | 0.0622 | 0.015 |
| ER admission | −0.246 | 0.038 | <0.001 |
| Heart failure | 0.107 | 0.0469 | 0.023 |
| Hypertension | 0.0647 | 0.0271 | 0.017 |
| Mechanical ventilation × sepsis | 0.251 | 0.0853 | 0.003 |
| Constant | 10.8 | 0.0254 | <0.001 |
R2 = 0.32.
Discussion
The incidence of AKI in our study was 12.6% of all patients admitted to the ICU, and there was a progressive decrease in survival associated with worsening kidney injury. This association remained even after adjusting for covariates. AKI and the need for dialysis were also associated with increased hospital costs. To our knowledge, this is the largest single-center study to examine the RIFLE criteria for AKI in a critically-ill population with cancer.
A striking finding in our study is the significant effect that small elevations in serum creatinine may have on survival. An increase of 0.6 mg/dL in the RIFLE risk category increased the odds for mortality by a factor of 2.3 compared to patients without AKI. The median maximum creatinine in this group was only 1.3 mg/dL, which is still within the “normal” range for males in our institution. Criteria that define mild renal toxicity as a serum greater than “1.5 × the upper limit of normal” would exclude a significant number of patients in the RIFLE risk and injury categories, although their risk of mortality was significantly increased.[22] Other criteria that define AKI by glomerular filtration rate (GFR) are also problematic as estimating equations for GFR require serum creatinine to be in steady state. This is a false assumption to make in the setting of AKI, where serum creatinine may fluctuate daily. Serum creatinine is an insensitive marker of renal injury in patients with cancer, and more sensitive and specific biomarkers of AKI are currently under development.[23], [24] and [25] Until these markers are routinely available, renal injury in oncology practice and clinical trials may be better defined as a percentage rise in serum creatinine relative to baseline, similar to the RIFLE criteria.
Out of all variables examined, it is interesting that the need for dialysis had the greatest association with 60-day mortality (Table 3). Although we adjusted for other risk factors, there may still be residual confounding to explain the strong association of dialysis with mortality. However, it is also recognized that dialysis may promote a proinflammatory state[26] and that AKI, in itself, may lead to injury of distant organs via systemic cytokine release.[27] and [28] These deleterious effects may be amplified in patients with cancer, who frequently are neutropenic and have chronic inflammation (e.g. capillary leak syndrome, diffuse alveolar hemorrhage, graft-vs.-host disease). It is known that the need for dialysis after a stem cell transplant is associated with >70% mortality.[29] Although dialysis remains pivotal for volume and metabolic clearance, a true “therapy” for AKI has unfortunately remained elusive thus far.
Our overall incidence of 12.6% for AKI is lower than the reported incidence of 13%–42% in other studies of critically ill patients with cancer.[2], [30] and [31] We excluded patients who had a serum creatinine >1.5 mg/dL on admission to the ICU as we were interested in the development of AKI after ICU admission. This likely excluded patients who already had AKI on presentation, which may have contributed to the lower incidence of AKI and the need for dialysis in our study. Unlike previous studies, our cohort included a large number of patients on a surgical service who were electively admitted to the ICU for routine postoperative care and, therefore, were at lower risk of developing AKI. However, when limited to patients on a medical service, our incidence of 21% is consistent with the results of previous studies of patients in medical ICUs.
The prognosis of patients requiring dialysis was dismal, with an estimated 89% 60-day mortality. This is somewhat higher than the reported mortality of 66%–88% in previous studies.[32], [33], [34], [35] and [36] Given that our institution also serves as a referral cancer center for patients who have had progressive disease on standard therapy, it is possible that our patient population may have been more predisposed to complications from cancer therapy. Patients with hematological malignancies had a higher incidence of AKI and need for dialysis. However, underlying hematological malignancy and HCT were no longer significantly associated with 60-day mortality in the adjusted analysis. Similar to the findings of others, this would suggest that it is not the underlying malignancy itself but rather the complications of treatment and prolonged immunosuppression that lead to decreased survival in these patients.[37] and [38] Early goal-directed intensive life support should be considered for most patients,[39] but continuation of dialysis may not be of benefit, in terms of both survival and cost, in patients with hematologic malignancy who demonstrate minimal improvement.
Our study had certain limitations. Given the retrospective design, we cannot rule out selection bias or residual confounding. We were able to adjust for several variables specific to cancer and critical care as well as pre-ICU length of stay, which may be a surrogate marker for comorbidities and functional status. Nonetheless, our conclusions should be interpreted as hypothesis-generating. Second, our study is based on a single-center experience, which may limit its generalizability. Nonetheless, our study had a large sample size that was subjected to fairly uniform management. Third, we did not have data on end-of-life decisions, which may have impacted mortality and need for dialysis. Lastly, we were unable to obtain cost-to-charge ratios, which may limit the generalizability of our findings to other institutions. However, we reported on percent increases in cost as opposed to absolute dollar figures, which may adjust for some of this variation.
Conclusions
AKI as defined by the RIFLE criteria may be predictive of short-term mortality in critically ill patients with cancer. We have demonstrated that relatively small changes in serum creatinine are associated with higher mortality and that the need for dialysis entails a very poor prognosis. The mechanism behind the increased mortality in patients with hematological malignancies appears to be secondary to the associated complications of therapy, as opposed to the underlying cancer itself. We hypothesize that strategies to prevent the development of AKI and progression to dialysis dependence may improve survival. Whether the prevention of AKI translates to cost savings is also of interest.
References
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12 E.A. Hoste, G. Clermont, A. Kersten, R. Venkataraman, D.C. Angus, D. De Bacquer and J.A. Kellum, RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis, Crit Care 10 (2006), p. R73.
13 A. Kuitunen, A. Vento, R. Suojaranta-Ylinen and V. Pettilä, Acute renal failure after cardiac surgery: evaluation of the RIFLE classification, Ann Thorac Surg 81 (2006), pp. 542–546.
14 J.A. Lopes, S. Jorge, S. Silva, E. de Almeida, F. Abreu, C. Martins, J.A. do Carmo, J.F. Lacerda and M.M. Prata, An assessment of the RIFLE criteria for acute renal failure following myeloablative autologous and allogeneic haematopoietic cell transplantation, Bone Marrow Transplant 38 (2006), p. 395.
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16 J.A. Lopes, S. Jorge, F.C. Neves, M. Caneira, A.G. da Costa, A.C. Ferreira and M.M. Prata, An assessment of the RIFLE criteria for acute renal failure in severely burned patients, Nephrol Dial Transplant 22 (2007), p. 285.
17 A. O'Riordan, V. Wong, R. McQuillan, P.A. McCormick, J.E. Hegarty and A.J. Watson, Acute renal disease, as defined by the RIFLE criteria, post-liver transplantation, Am J Transplant 7 (2007), pp. 168–176.
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35 T. Silfvast, V. Pettilä, A. Ihalainen and E. Elonen, Multiple organ failure and outcome of critically ill patients with haematological malignancy, Acta Anaesthesiol Scand 47 (2003), pp. 301–306.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression
Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
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2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
4 D.A. Loblaw, J. Perry, A. Chambers and N.J. Laperriere, Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group, J Clin Oncol 23 (9) (2005), pp. 2028–2037.
5 E. Maranzano, P. Latini, F. Checcaglini, S. Ricci, B.M. Panizza, C. Aristei, E. Perrucci, S. Beneventi, E. Corgna and M. Tonato, Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients, Ann Neurol 3 (1991), pp. 40–51.
6 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial, J Clin Oncol 23 (15) (2005), pp. 3358–3365.
7 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
9 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstenssf, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada
Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
1 T.N. Byrne, Spinal cord compression from epidural metastases, N Engl J Med 327 (9) (1992), pp. 614–619.
2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
4 D.A. Loblaw, J. Perry, A. Chambers and N.J. Laperriere, Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group, J Clin Oncol 23 (9) (2005), pp. 2028–2037.
5 E. Maranzano, P. Latini, F. Checcaglini, S. Ricci, B.M. Panizza, C. Aristei, E. Perrucci, S. Beneventi, E. Corgna and M. Tonato, Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients, Ann Neurol 3 (1991), pp. 40–51.
6 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial, J Clin Oncol 23 (15) (2005), pp. 3358–3365.
7 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
9 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstenssf, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada
Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
1 T.N. Byrne, Spinal cord compression from epidural metastases, N Engl J Med 327 (9) (1992), pp. 614–619.
2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
4 D.A. Loblaw, J. Perry, A. Chambers and N.J. Laperriere, Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group, J Clin Oncol 23 (9) (2005), pp. 2028–2037.
5 E. Maranzano, P. Latini, F. Checcaglini, S. Ricci, B.M. Panizza, C. Aristei, E. Perrucci, S. Beneventi, E. Corgna and M. Tonato, Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients, Ann Neurol 3 (1991), pp. 40–51.
6 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial, J Clin Oncol 23 (15) (2005), pp. 3358–3365.
7 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
9 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstenssf, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada
Treatment of Metastatic Epidural Spinal Cord Compression: The Goldilocks Principle
Volume 9, Issue 4, July-August 2011, Pages 125-126
Available online 2 July 2011.
Review
Treatment of Metastatic Epidural Spinal Cord Compression: The Goldilocks Principle
Joshua Jones MD, Erin McMenamin MSN, CRNP, Harry Quon MD, MS
Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).
Loblaw and Mitera are to be congratulated for their ongoing efforts to provide systematic guidelines in the palliative management of patients with malignant spinal cord compressions (MSCC). Highlighted in this review are recent reports that can help determine an appropriate radiotherapy (RT) dose. Loblaw and Mitera explore the various considerations important to the multidisciplinary team when reviewing treatment options. As a result of a lack of significant progress in the management of MSCC, unanswered questions remain.
When a patient is given a poor prognosis, it is difficult to modulate treatment to alleviate the side effects of MSCC and the risk of toxicity and to improve quality of life. However, many symptoms arising from a tumor's mass require some measure of tumor response to therapy. Such is the case with the neurologic compromise that arises from MSCC.
Standard palliative RT doses alleviate the pain associated with MSCC. Reversing and maintaining ambulation can be limited and is likely dependent upon achieving sufficient tumor response to therapy. RT dose intensification may provide effective tumor response and disease control at the MSCC site, preventing future loss of neurologic function. However, there are major impediments for such studies: (1) the RT toxicities associated with the use of large traditional nonconformal RT fields often used to expedite care, (2) the time required (of the patient especially), and (3) the limited prognosis of the palliative patient.
In their review, Loblaw and Mitera identify the importance of applying a risk stratification approach to guide future treatment decisions and clinical trials based on various validated scoring systems. Risk stratification offers several advantages. While these include a more homogeneous study population for future studies, it allows for the identification of a cohort of patients for whom alternative end points for palliative management can potentially be evaluated. Foremost is the issue of whether RT dose intensification improves pain control, tumor response, and disease control. There are several lines of evidence that support a possible dose–response relationship.
Maranzano et al[1] reported that even in poor-prognosis patients there was improvement in the in-field local control rates. In a relatively favorable cohort of MSCC patients prospectively treated and evaluated, Rades et al[2] reported significantly improved 12-month local control rates when comparing a short course of RT (8 Gy in one fraction or 20 Gy in five fractions) to a longer course of RT (30 Gy in 10 fractions) (P = 0.032). Univariate analysis demonstrated that local control rates were only significantly associated with the RT fractionation schedule that was used. Given the potential for selection bias, the finding that the radiation schedule continued to maintain statistical significance in the multivariate analysis (relative risk = 1.49, P = 0.035) offers greater confidence that a dose–response relationship may exist. These findings are consistent with this group's retrospective analysis when higher total doses of 30 Gy in 10 fractions or 40 Gy in 20 fractions were compared to 8 Gy in one fraction or 20 Gy in five fractions.[3] Thus, higher total doses appear to be associated with improved local control rates at the site of MSCC and may be particularly important for favorable-prognosis patients who are at risk of developing local progression and further neurologic compromise. The local control improvements appear to be the main reason that there was an improvement in progression-free survival rates.[2]
In contrast, Rades et al[2] did not find an association between higher RT doses and motor function. This may be due to the ongoing neurologic compression seen with tumor responses even at doses of 30 Gy in 10 fractions. Decompressive surgery followed by 30 Gy in 10 fractions is superior to RT alone with select patients benefiting from improved ambulatory function for a longer period of time.[4] However, other sites of MSCC or nonvertebral bone metastases can affect motor function as well and should be taken into consideration.
Modern advancements in administering palliative RT provide an opportunity for favorable therapeutic outcomes. Using image guidance, modern hypofractionated courses of RT can reduce the number of radiation fractions while achieving a higher cytotoxic effect. As a result, many of the barriers for RT dose escalation in the MSCC patient can now be overcome.
Several centers have initiated dedicated palliative care clinical services designed around the unique needs of the palliative patient. Even though analgesics can provide prompt pain relief, the literature suggests it is the addition of palliative RT that provides for the most effective and long-lasting pain relief.[5]
Loblaw and Mitera point out that the optimal fractionation schedule is not clear at this time. However, the use of 30 Gy in 10 fractions appears reasonable. The suggestion of a dose–response relationship for improved local control rates at the MSCC site also leads to questions about the optimal RT dose following surgical decompression in the favorable-prognosis patient.
The Radiation Therapy Oncology Group (RTOG) is currently conducting a prospective phase II/III RTOG 0631 study of stereotactic body radiotherapy (SBRT) for MSCC patients using image guidance to provide greater confidence in the treatment setup and dose delivered.6 The randomization is 16 vs 8 Gy, both in a single fraction. However, the primary end point is pain control, with secondary end points that do not consider the local control rates at the site of the MSCC but do consider the time to pain relief, which is often overlooked. Moreover, the eligibility criteria permit a spectrum of cancer types, including unfavorable lung cancers. These considerations are likely to limit the ability to determine if 16 Gy may offer other benefits aside from improved pain control.
For the unfavorable-prognosis patient, it is equally imperative that the right dose and the right fractionation are given. Nonconformal approaches delivering hypofractions such as 8 Gy in one fraction may offer the best option, especially when symptom management is the goal of the treatment. If local control is an important treatment goal, higher total doses may be of benefit; but the patient's prognosis must be carefully evaluated. Hypofractionation appears to be the best approach. Is this achieved with 16 Gy in two fractions?[1] Whether this requires higher total doses remains an unanswered question at this time.
In the end, while risk stratification tools can aid in deciding the optimal dose and fractionation for the MSCC patient, the best tool we have is to actively communicate with our patients. Helping the MSCC patient understand the potential goals and burdens of any treatment approach can be invaluable in deciding on the right fractionation schedule.
References
1 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
2 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
3 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstens, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
4 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
5 L.G. Soares and V.W. Chan, The rationale for a multimodal approach in the management of breakthrough cancer pain: a review, Am J Hospice Palliat Care 24 (5) (2007), pp. 430–439.
6 S. Ryu, M. Wang, P. Gerszten, F.-F. Yin and R. Timmerman et al. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&FileID=4658.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Drs. Jones, McMenamin, and Quon are from the Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
Volume 9, Issue 4, July-August 2011, Pages 125-126
Available online 2 July 2011.
Review
Treatment of Metastatic Epidural Spinal Cord Compression: The Goldilocks Principle
Joshua Jones MD, Erin McMenamin MSN, CRNP, Harry Quon MD, MS
Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).
Loblaw and Mitera are to be congratulated for their ongoing efforts to provide systematic guidelines in the palliative management of patients with malignant spinal cord compressions (MSCC). Highlighted in this review are recent reports that can help determine an appropriate radiotherapy (RT) dose. Loblaw and Mitera explore the various considerations important to the multidisciplinary team when reviewing treatment options. As a result of a lack of significant progress in the management of MSCC, unanswered questions remain.
When a patient is given a poor prognosis, it is difficult to modulate treatment to alleviate the side effects of MSCC and the risk of toxicity and to improve quality of life. However, many symptoms arising from a tumor's mass require some measure of tumor response to therapy. Such is the case with the neurologic compromise that arises from MSCC.
Standard palliative RT doses alleviate the pain associated with MSCC. Reversing and maintaining ambulation can be limited and is likely dependent upon achieving sufficient tumor response to therapy. RT dose intensification may provide effective tumor response and disease control at the MSCC site, preventing future loss of neurologic function. However, there are major impediments for such studies: (1) the RT toxicities associated with the use of large traditional nonconformal RT fields often used to expedite care, (2) the time required (of the patient especially), and (3) the limited prognosis of the palliative patient.
In their review, Loblaw and Mitera identify the importance of applying a risk stratification approach to guide future treatment decisions and clinical trials based on various validated scoring systems. Risk stratification offers several advantages. While these include a more homogeneous study population for future studies, it allows for the identification of a cohort of patients for whom alternative end points for palliative management can potentially be evaluated. Foremost is the issue of whether RT dose intensification improves pain control, tumor response, and disease control. There are several lines of evidence that support a possible dose–response relationship.
Maranzano et al[1] reported that even in poor-prognosis patients there was improvement in the in-field local control rates. In a relatively favorable cohort of MSCC patients prospectively treated and evaluated, Rades et al[2] reported significantly improved 12-month local control rates when comparing a short course of RT (8 Gy in one fraction or 20 Gy in five fractions) to a longer course of RT (30 Gy in 10 fractions) (P = 0.032). Univariate analysis demonstrated that local control rates were only significantly associated with the RT fractionation schedule that was used. Given the potential for selection bias, the finding that the radiation schedule continued to maintain statistical significance in the multivariate analysis (relative risk = 1.49, P = 0.035) offers greater confidence that a dose–response relationship may exist. These findings are consistent with this group's retrospective analysis when higher total doses of 30 Gy in 10 fractions or 40 Gy in 20 fractions were compared to 8 Gy in one fraction or 20 Gy in five fractions.[3] Thus, higher total doses appear to be associated with improved local control rates at the site of MSCC and may be particularly important for favorable-prognosis patients who are at risk of developing local progression and further neurologic compromise. The local control improvements appear to be the main reason that there was an improvement in progression-free survival rates.[2]
In contrast, Rades et al[2] did not find an association between higher RT doses and motor function. This may be due to the ongoing neurologic compression seen with tumor responses even at doses of 30 Gy in 10 fractions. Decompressive surgery followed by 30 Gy in 10 fractions is superior to RT alone with select patients benefiting from improved ambulatory function for a longer period of time.[4] However, other sites of MSCC or nonvertebral bone metastases can affect motor function as well and should be taken into consideration.
Modern advancements in administering palliative RT provide an opportunity for favorable therapeutic outcomes. Using image guidance, modern hypofractionated courses of RT can reduce the number of radiation fractions while achieving a higher cytotoxic effect. As a result, many of the barriers for RT dose escalation in the MSCC patient can now be overcome.
Several centers have initiated dedicated palliative care clinical services designed around the unique needs of the palliative patient. Even though analgesics can provide prompt pain relief, the literature suggests it is the addition of palliative RT that provides for the most effective and long-lasting pain relief.[5]
Loblaw and Mitera point out that the optimal fractionation schedule is not clear at this time. However, the use of 30 Gy in 10 fractions appears reasonable. The suggestion of a dose–response relationship for improved local control rates at the MSCC site also leads to questions about the optimal RT dose following surgical decompression in the favorable-prognosis patient.
The Radiation Therapy Oncology Group (RTOG) is currently conducting a prospective phase II/III RTOG 0631 study of stereotactic body radiotherapy (SBRT) for MSCC patients using image guidance to provide greater confidence in the treatment setup and dose delivered.6 The randomization is 16 vs 8 Gy, both in a single fraction. However, the primary end point is pain control, with secondary end points that do not consider the local control rates at the site of the MSCC but do consider the time to pain relief, which is often overlooked. Moreover, the eligibility criteria permit a spectrum of cancer types, including unfavorable lung cancers. These considerations are likely to limit the ability to determine if 16 Gy may offer other benefits aside from improved pain control.
For the unfavorable-prognosis patient, it is equally imperative that the right dose and the right fractionation are given. Nonconformal approaches delivering hypofractions such as 8 Gy in one fraction may offer the best option, especially when symptom management is the goal of the treatment. If local control is an important treatment goal, higher total doses may be of benefit; but the patient's prognosis must be carefully evaluated. Hypofractionation appears to be the best approach. Is this achieved with 16 Gy in two fractions?[1] Whether this requires higher total doses remains an unanswered question at this time.
In the end, while risk stratification tools can aid in deciding the optimal dose and fractionation for the MSCC patient, the best tool we have is to actively communicate with our patients. Helping the MSCC patient understand the potential goals and burdens of any treatment approach can be invaluable in deciding on the right fractionation schedule.
References
1 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
2 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
3 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstens, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
4 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
5 L.G. Soares and V.W. Chan, The rationale for a multimodal approach in the management of breakthrough cancer pain: a review, Am J Hospice Palliat Care 24 (5) (2007), pp. 430–439.
6 S. Ryu, M. Wang, P. Gerszten, F.-F. Yin and R. Timmerman et al. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&FileID=4658.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Drs. Jones, McMenamin, and Quon are from the Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
Volume 9, Issue 4, July-August 2011, Pages 125-126
Available online 2 July 2011.
Review
Treatment of Metastatic Epidural Spinal Cord Compression: The Goldilocks Principle
Joshua Jones MD, Erin McMenamin MSN, CRNP, Harry Quon MD, MS
Commentary on “The Optimal Dose Fractionation Schema for Malignant Extradural Spinal Cord Compression" by D. Andrew Loblaw and Gunita Mitera (page 123).
Loblaw and Mitera are to be congratulated for their ongoing efforts to provide systematic guidelines in the palliative management of patients with malignant spinal cord compressions (MSCC). Highlighted in this review are recent reports that can help determine an appropriate radiotherapy (RT) dose. Loblaw and Mitera explore the various considerations important to the multidisciplinary team when reviewing treatment options. As a result of a lack of significant progress in the management of MSCC, unanswered questions remain.
When a patient is given a poor prognosis, it is difficult to modulate treatment to alleviate the side effects of MSCC and the risk of toxicity and to improve quality of life. However, many symptoms arising from a tumor's mass require some measure of tumor response to therapy. Such is the case with the neurologic compromise that arises from MSCC.
Standard palliative RT doses alleviate the pain associated with MSCC. Reversing and maintaining ambulation can be limited and is likely dependent upon achieving sufficient tumor response to therapy. RT dose intensification may provide effective tumor response and disease control at the MSCC site, preventing future loss of neurologic function. However, there are major impediments for such studies: (1) the RT toxicities associated with the use of large traditional nonconformal RT fields often used to expedite care, (2) the time required (of the patient especially), and (3) the limited prognosis of the palliative patient.
In their review, Loblaw and Mitera identify the importance of applying a risk stratification approach to guide future treatment decisions and clinical trials based on various validated scoring systems. Risk stratification offers several advantages. While these include a more homogeneous study population for future studies, it allows for the identification of a cohort of patients for whom alternative end points for palliative management can potentially be evaluated. Foremost is the issue of whether RT dose intensification improves pain control, tumor response, and disease control. There are several lines of evidence that support a possible dose–response relationship.
Maranzano et al[1] reported that even in poor-prognosis patients there was improvement in the in-field local control rates. In a relatively favorable cohort of MSCC patients prospectively treated and evaluated, Rades et al[2] reported significantly improved 12-month local control rates when comparing a short course of RT (8 Gy in one fraction or 20 Gy in five fractions) to a longer course of RT (30 Gy in 10 fractions) (P = 0.032). Univariate analysis demonstrated that local control rates were only significantly associated with the RT fractionation schedule that was used. Given the potential for selection bias, the finding that the radiation schedule continued to maintain statistical significance in the multivariate analysis (relative risk = 1.49, P = 0.035) offers greater confidence that a dose–response relationship may exist. These findings are consistent with this group's retrospective analysis when higher total doses of 30 Gy in 10 fractions or 40 Gy in 20 fractions were compared to 8 Gy in one fraction or 20 Gy in five fractions.[3] Thus, higher total doses appear to be associated with improved local control rates at the site of MSCC and may be particularly important for favorable-prognosis patients who are at risk of developing local progression and further neurologic compromise. The local control improvements appear to be the main reason that there was an improvement in progression-free survival rates.[2]
In contrast, Rades et al[2] did not find an association between higher RT doses and motor function. This may be due to the ongoing neurologic compression seen with tumor responses even at doses of 30 Gy in 10 fractions. Decompressive surgery followed by 30 Gy in 10 fractions is superior to RT alone with select patients benefiting from improved ambulatory function for a longer period of time.[4] However, other sites of MSCC or nonvertebral bone metastases can affect motor function as well and should be taken into consideration.
Modern advancements in administering palliative RT provide an opportunity for favorable therapeutic outcomes. Using image guidance, modern hypofractionated courses of RT can reduce the number of radiation fractions while achieving a higher cytotoxic effect. As a result, many of the barriers for RT dose escalation in the MSCC patient can now be overcome.
Several centers have initiated dedicated palliative care clinical services designed around the unique needs of the palliative patient. Even though analgesics can provide prompt pain relief, the literature suggests it is the addition of palliative RT that provides for the most effective and long-lasting pain relief.[5]
Loblaw and Mitera point out that the optimal fractionation schedule is not clear at this time. However, the use of 30 Gy in 10 fractions appears reasonable. The suggestion of a dose–response relationship for improved local control rates at the MSCC site also leads to questions about the optimal RT dose following surgical decompression in the favorable-prognosis patient.
The Radiation Therapy Oncology Group (RTOG) is currently conducting a prospective phase II/III RTOG 0631 study of stereotactic body radiotherapy (SBRT) for MSCC patients using image guidance to provide greater confidence in the treatment setup and dose delivered.6 The randomization is 16 vs 8 Gy, both in a single fraction. However, the primary end point is pain control, with secondary end points that do not consider the local control rates at the site of the MSCC but do consider the time to pain relief, which is often overlooked. Moreover, the eligibility criteria permit a spectrum of cancer types, including unfavorable lung cancers. These considerations are likely to limit the ability to determine if 16 Gy may offer other benefits aside from improved pain control.
For the unfavorable-prognosis patient, it is equally imperative that the right dose and the right fractionation are given. Nonconformal approaches delivering hypofractions such as 8 Gy in one fraction may offer the best option, especially when symptom management is the goal of the treatment. If local control is an important treatment goal, higher total doses may be of benefit; but the patient's prognosis must be carefully evaluated. Hypofractionation appears to be the best approach. Is this achieved with 16 Gy in two fractions?[1] Whether this requires higher total doses remains an unanswered question at this time.
In the end, while risk stratification tools can aid in deciding the optimal dose and fractionation for the MSCC patient, the best tool we have is to actively communicate with our patients. Helping the MSCC patient understand the potential goals and burdens of any treatment approach can be invaluable in deciding on the right fractionation schedule.
References
1 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
2 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
3 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstens, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
4 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
5 L.G. Soares and V.W. Chan, The rationale for a multimodal approach in the management of breakthrough cancer pain: a review, Am J Hospice Palliat Care 24 (5) (2007), pp. 430–439.
6 S. Ryu, M. Wang, P. Gerszten, F.-F. Yin and R. Timmerman et al. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&FileID=4658.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Drs. Jones, McMenamin, and Quon are from the Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.
Growing copay crisis makes available care unattainable
Okay, so I will transfer all of my patients who cannot get care because they can’t pay their copays to you, ‘and you can watch them suffer.’ That was how a heated discussion with a respected, compassionate oncology partner ended recently,as he begged me and our practice administrator to treat one of his patients.
The patient is an otherwise healthy, active woman of 68 with stage IVA non-Hodgkin’s diffuse B-cell lymphoma that was diagnosed in March. She has a Medicare Advantage HMO with a 20% copay for chemotherapy.The total cost of eight cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) at Medicare rates is $114,271, with $22,854 in copay broken into $2,856.75 per 3-week cycle. Since she had no copay funding, our staff was able to secure a copay grant from the Leukemia & Lymphoma Society to cover her for the first two cycles in April and May, helped by free pegfilgrastim (Neulasta) from our clinic stock. She then had to delay cycle 3 until we obtained a second grant from the HealthWell Foundation in July,when she was able to resume therapy after a potentially compromising 5-week delay.
She now has coverage for cycles 3–6. We are pending reapplication to the Leukemia & Lymphoma Society for a final copay grant to cover her last two cycles. We know that for best outcomes with a curative goal in non-Hodgkin’s lymphoma,it is critical to give the full dose on time, along with white-blood-cell growth factors for patients who are older than 65 or who are at high risk for developing neutropenia. The stress of having to delay 2 extra weeks between cycles 2 and 3 and the ongoing uncertainty about cycles 7 and 8 have pushed this patient and her family, as well as our physician and clinic staff, to the breaking point.
My recent experience with one of my own patients is just as harrowing. This patient is a remarkable 60-year-old woman, who looks 40 and has been under my care for stage IV breast cancer since 2003 with an ECOG (Eastern Cooperative Oncology Group) performance status of 0. She has done remarkably well after failing to respond to hormone therapy and capecitabine (Xeloda) and being placed on a once-every-3-week regimen of IV nab-paclitaxel (Abraxane) since July 2009, coupled with ongoing control of extensive diffuse bone metastasis, as well as osteonecrosis of the jaw, from her initial 2 years of IV bisphosphonate therapy. She feels so well on this therapy that she volunteers 2 days a week at our regional psychiatric institution, despite needing methadone for pain relief. We secured a 12-month copay grant last October, which covered her costs through June of this year. She has no means of additional funding for the IV therapy that has controlled her disease for over 2 years. We also have no clinic funding for copays, so she had to stop therapy this month.
I was able to give her 4 months of samples of an aromatase inhibitor and can only pray it will hold her until we can apply for a new copay grant this October or November. The foundation that funded her, Patient Access Network, is presently out of breast cancer copay funds, and although our coordinator calls the foundations weekly for updates,we cannot be certain there will be any funding for this patient going forward. In fact, we have been notified that the major breast cancer funds (Cancer Care Foundation, Patient Advocate Foundation, Patient Access Network, and HealthWell Foundation) were out of breast cancer copay funds as of July. The remaining fund for breast cancer patients, Chronic Disease Foundation, has a list of specific drugs it covers, which does not include nab-paclitaxel.
The Patient Advocate Foundation accepts applications only on the first 3 days of each month,so that patients who are diagnosed during the remainder of the month have to wait to submit their applications during the first 3 days of the following month—and then, as with all foundations, wait another 3–5 weeks for a response, assuming their disease and therapy are on the funding list. During these weeks of waiting, it is common for our office managers to get calls from patients asking, as one put it, “What are you going to do? Watch me die?”
These are just 2 of the 15 “copay-need” patients being seen in one of our practice’s six private offices, where we treat patients from across the socioeconomic spectrum. We provide professional cancer care for indigent and low-income patients in two California counties. The uninsured rate is 26%, and unemployment is 14%, but our ability to bring cost-effective, standardized, evidenced-based care to this population has provided an important alternative for those who lose or have no insurance. In the past, like many other practices, we were able to waive copays for poor patients because we had adequately funded care. But with the underfunding of community oncology care precipitated by Medicare’s Medicare Modernization Act (MMA) of 2003 and exacerbated by private payers, the low chemotherapy drug margins, and use of the prompt pay discount in average sales price calculations, we no longer have the margins to do so.
And now a new trend is emerging—there are a growing number of patients who have health plans with high deductibles or copays of 20% or more that they cannot afford. We are being inundated with calls from these patients and their advocates. Part of our response has been to offer them individual chemotherapy and financial counseling so that they are fully informed about their copay responsibilities under their health plans before they begin therapy.The terms of their copays are often a shocking revelation to them, but being informed upfront allows for them to investigate their options for aid from personal, family, and foundation sources.
We have also tried to implement steps at the practice and office levels to help us keep tabs of all our patients’ copay needs. The practice’s copay coordinator maintains the electronic grant status records, tracking the 55 grants she is following for a total of 37 patients across the six offices. Each office manager has access to those records and, in turn,documents the office’s copay grant applications and responses to them—and whether or not the applications were successful. In addition, we maintain a custom tracking sheet for patients who receive copay grants so that we can monitor their copay balance after each cycle of therapy to ensure that patients do not continue therapy beyond the limits of the copay grants.
There are specific pharmaceutical company assistance programs for some branded drugs, but if patients have MediCal (Medicaid), Medicare, or a Medicare Advantage HMO product, they are not eligible for them. Patients can get coverage from these programs only if they have no insurance, and there is no coverage from any sources for the much cheaper, generic chemotherapy drugs. In addition,for most patients and their families, finding these grant sources, understanding the terms, and completing the applications is difficult and time consuming, so our practice hired a staff member to handle the applications (Rajurkar SP et al. J Oncol Pract 2011;7:100–102).
We are doing our part and more in community oncology, but as the cases here illustrate, we are not succeeding on behalf of all of our patients. We need patient advocates, Medicare and private health plan officials, and our elected representatives to develop a comprehensive solution to appropriately support cancer patients in the same way that those with chronic renal failure and other chronic or curable high-cost diseases are supported. We also need to urge our elected officials to ensure that the current debt crisis solution does not include further cuts to the Medicare payment system for cancer care. Physicians who have devoted years of their lives to bringing the best science to relieve suffering, prolong lives, and improve cure rates cannot realistically be expected to watch patients with curable and palliative cancers falter in their progress when effective care is available but unattainable.
Some years ago, when I was in Washington, DC,to speak to our representatives about the deleterious impact of the MMA, a prominent senator’s staffer told me “there would be no adjustments in funding until we showed them bodies in the streets.” Well, Senator, you can now see those bodies mounting.It is a sad time when clinicians are being asked to monitor patients’ cancer progression rather than their progress against cancer.
Okay, so I will transfer all of my patients who cannot get care because they can’t pay their copays to you, ‘and you can watch them suffer.’ That was how a heated discussion with a respected, compassionate oncology partner ended recently,as he begged me and our practice administrator to treat one of his patients.
The patient is an otherwise healthy, active woman of 68 with stage IVA non-Hodgkin’s diffuse B-cell lymphoma that was diagnosed in March. She has a Medicare Advantage HMO with a 20% copay for chemotherapy.The total cost of eight cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) at Medicare rates is $114,271, with $22,854 in copay broken into $2,856.75 per 3-week cycle. Since she had no copay funding, our staff was able to secure a copay grant from the Leukemia & Lymphoma Society to cover her for the first two cycles in April and May, helped by free pegfilgrastim (Neulasta) from our clinic stock. She then had to delay cycle 3 until we obtained a second grant from the HealthWell Foundation in July,when she was able to resume therapy after a potentially compromising 5-week delay.
She now has coverage for cycles 3–6. We are pending reapplication to the Leukemia & Lymphoma Society for a final copay grant to cover her last two cycles. We know that for best outcomes with a curative goal in non-Hodgkin’s lymphoma,it is critical to give the full dose on time, along with white-blood-cell growth factors for patients who are older than 65 or who are at high risk for developing neutropenia. The stress of having to delay 2 extra weeks between cycles 2 and 3 and the ongoing uncertainty about cycles 7 and 8 have pushed this patient and her family, as well as our physician and clinic staff, to the breaking point.
My recent experience with one of my own patients is just as harrowing. This patient is a remarkable 60-year-old woman, who looks 40 and has been under my care for stage IV breast cancer since 2003 with an ECOG (Eastern Cooperative Oncology Group) performance status of 0. She has done remarkably well after failing to respond to hormone therapy and capecitabine (Xeloda) and being placed on a once-every-3-week regimen of IV nab-paclitaxel (Abraxane) since July 2009, coupled with ongoing control of extensive diffuse bone metastasis, as well as osteonecrosis of the jaw, from her initial 2 years of IV bisphosphonate therapy. She feels so well on this therapy that she volunteers 2 days a week at our regional psychiatric institution, despite needing methadone for pain relief. We secured a 12-month copay grant last October, which covered her costs through June of this year. She has no means of additional funding for the IV therapy that has controlled her disease for over 2 years. We also have no clinic funding for copays, so she had to stop therapy this month.
I was able to give her 4 months of samples of an aromatase inhibitor and can only pray it will hold her until we can apply for a new copay grant this October or November. The foundation that funded her, Patient Access Network, is presently out of breast cancer copay funds, and although our coordinator calls the foundations weekly for updates,we cannot be certain there will be any funding for this patient going forward. In fact, we have been notified that the major breast cancer funds (Cancer Care Foundation, Patient Advocate Foundation, Patient Access Network, and HealthWell Foundation) were out of breast cancer copay funds as of July. The remaining fund for breast cancer patients, Chronic Disease Foundation, has a list of specific drugs it covers, which does not include nab-paclitaxel.
The Patient Advocate Foundation accepts applications only on the first 3 days of each month,so that patients who are diagnosed during the remainder of the month have to wait to submit their applications during the first 3 days of the following month—and then, as with all foundations, wait another 3–5 weeks for a response, assuming their disease and therapy are on the funding list. During these weeks of waiting, it is common for our office managers to get calls from patients asking, as one put it, “What are you going to do? Watch me die?”
These are just 2 of the 15 “copay-need” patients being seen in one of our practice’s six private offices, where we treat patients from across the socioeconomic spectrum. We provide professional cancer care for indigent and low-income patients in two California counties. The uninsured rate is 26%, and unemployment is 14%, but our ability to bring cost-effective, standardized, evidenced-based care to this population has provided an important alternative for those who lose or have no insurance. In the past, like many other practices, we were able to waive copays for poor patients because we had adequately funded care. But with the underfunding of community oncology care precipitated by Medicare’s Medicare Modernization Act (MMA) of 2003 and exacerbated by private payers, the low chemotherapy drug margins, and use of the prompt pay discount in average sales price calculations, we no longer have the margins to do so.
And now a new trend is emerging—there are a growing number of patients who have health plans with high deductibles or copays of 20% or more that they cannot afford. We are being inundated with calls from these patients and their advocates. Part of our response has been to offer them individual chemotherapy and financial counseling so that they are fully informed about their copay responsibilities under their health plans before they begin therapy.The terms of their copays are often a shocking revelation to them, but being informed upfront allows for them to investigate their options for aid from personal, family, and foundation sources.
We have also tried to implement steps at the practice and office levels to help us keep tabs of all our patients’ copay needs. The practice’s copay coordinator maintains the electronic grant status records, tracking the 55 grants she is following for a total of 37 patients across the six offices. Each office manager has access to those records and, in turn,documents the office’s copay grant applications and responses to them—and whether or not the applications were successful. In addition, we maintain a custom tracking sheet for patients who receive copay grants so that we can monitor their copay balance after each cycle of therapy to ensure that patients do not continue therapy beyond the limits of the copay grants.
There are specific pharmaceutical company assistance programs for some branded drugs, but if patients have MediCal (Medicaid), Medicare, or a Medicare Advantage HMO product, they are not eligible for them. Patients can get coverage from these programs only if they have no insurance, and there is no coverage from any sources for the much cheaper, generic chemotherapy drugs. In addition,for most patients and their families, finding these grant sources, understanding the terms, and completing the applications is difficult and time consuming, so our practice hired a staff member to handle the applications (Rajurkar SP et al. J Oncol Pract 2011;7:100–102).
We are doing our part and more in community oncology, but as the cases here illustrate, we are not succeeding on behalf of all of our patients. We need patient advocates, Medicare and private health plan officials, and our elected representatives to develop a comprehensive solution to appropriately support cancer patients in the same way that those with chronic renal failure and other chronic or curable high-cost diseases are supported. We also need to urge our elected officials to ensure that the current debt crisis solution does not include further cuts to the Medicare payment system for cancer care. Physicians who have devoted years of their lives to bringing the best science to relieve suffering, prolong lives, and improve cure rates cannot realistically be expected to watch patients with curable and palliative cancers falter in their progress when effective care is available but unattainable.
Some years ago, when I was in Washington, DC,to speak to our representatives about the deleterious impact of the MMA, a prominent senator’s staffer told me “there would be no adjustments in funding until we showed them bodies in the streets.” Well, Senator, you can now see those bodies mounting.It is a sad time when clinicians are being asked to monitor patients’ cancer progression rather than their progress against cancer.
Okay, so I will transfer all of my patients who cannot get care because they can’t pay their copays to you, ‘and you can watch them suffer.’ That was how a heated discussion with a respected, compassionate oncology partner ended recently,as he begged me and our practice administrator to treat one of his patients.
The patient is an otherwise healthy, active woman of 68 with stage IVA non-Hodgkin’s diffuse B-cell lymphoma that was diagnosed in March. She has a Medicare Advantage HMO with a 20% copay for chemotherapy.The total cost of eight cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) at Medicare rates is $114,271, with $22,854 in copay broken into $2,856.75 per 3-week cycle. Since she had no copay funding, our staff was able to secure a copay grant from the Leukemia & Lymphoma Society to cover her for the first two cycles in April and May, helped by free pegfilgrastim (Neulasta) from our clinic stock. She then had to delay cycle 3 until we obtained a second grant from the HealthWell Foundation in July,when she was able to resume therapy after a potentially compromising 5-week delay.
She now has coverage for cycles 3–6. We are pending reapplication to the Leukemia & Lymphoma Society for a final copay grant to cover her last two cycles. We know that for best outcomes with a curative goal in non-Hodgkin’s lymphoma,it is critical to give the full dose on time, along with white-blood-cell growth factors for patients who are older than 65 or who are at high risk for developing neutropenia. The stress of having to delay 2 extra weeks between cycles 2 and 3 and the ongoing uncertainty about cycles 7 and 8 have pushed this patient and her family, as well as our physician and clinic staff, to the breaking point.
My recent experience with one of my own patients is just as harrowing. This patient is a remarkable 60-year-old woman, who looks 40 and has been under my care for stage IV breast cancer since 2003 with an ECOG (Eastern Cooperative Oncology Group) performance status of 0. She has done remarkably well after failing to respond to hormone therapy and capecitabine (Xeloda) and being placed on a once-every-3-week regimen of IV nab-paclitaxel (Abraxane) since July 2009, coupled with ongoing control of extensive diffuse bone metastasis, as well as osteonecrosis of the jaw, from her initial 2 years of IV bisphosphonate therapy. She feels so well on this therapy that she volunteers 2 days a week at our regional psychiatric institution, despite needing methadone for pain relief. We secured a 12-month copay grant last October, which covered her costs through June of this year. She has no means of additional funding for the IV therapy that has controlled her disease for over 2 years. We also have no clinic funding for copays, so she had to stop therapy this month.
I was able to give her 4 months of samples of an aromatase inhibitor and can only pray it will hold her until we can apply for a new copay grant this October or November. The foundation that funded her, Patient Access Network, is presently out of breast cancer copay funds, and although our coordinator calls the foundations weekly for updates,we cannot be certain there will be any funding for this patient going forward. In fact, we have been notified that the major breast cancer funds (Cancer Care Foundation, Patient Advocate Foundation, Patient Access Network, and HealthWell Foundation) were out of breast cancer copay funds as of July. The remaining fund for breast cancer patients, Chronic Disease Foundation, has a list of specific drugs it covers, which does not include nab-paclitaxel.
The Patient Advocate Foundation accepts applications only on the first 3 days of each month,so that patients who are diagnosed during the remainder of the month have to wait to submit their applications during the first 3 days of the following month—and then, as with all foundations, wait another 3–5 weeks for a response, assuming their disease and therapy are on the funding list. During these weeks of waiting, it is common for our office managers to get calls from patients asking, as one put it, “What are you going to do? Watch me die?”
These are just 2 of the 15 “copay-need” patients being seen in one of our practice’s six private offices, where we treat patients from across the socioeconomic spectrum. We provide professional cancer care for indigent and low-income patients in two California counties. The uninsured rate is 26%, and unemployment is 14%, but our ability to bring cost-effective, standardized, evidenced-based care to this population has provided an important alternative for those who lose or have no insurance. In the past, like many other practices, we were able to waive copays for poor patients because we had adequately funded care. But with the underfunding of community oncology care precipitated by Medicare’s Medicare Modernization Act (MMA) of 2003 and exacerbated by private payers, the low chemotherapy drug margins, and use of the prompt pay discount in average sales price calculations, we no longer have the margins to do so.
And now a new trend is emerging—there are a growing number of patients who have health plans with high deductibles or copays of 20% or more that they cannot afford. We are being inundated with calls from these patients and their advocates. Part of our response has been to offer them individual chemotherapy and financial counseling so that they are fully informed about their copay responsibilities under their health plans before they begin therapy.The terms of their copays are often a shocking revelation to them, but being informed upfront allows for them to investigate their options for aid from personal, family, and foundation sources.
We have also tried to implement steps at the practice and office levels to help us keep tabs of all our patients’ copay needs. The practice’s copay coordinator maintains the electronic grant status records, tracking the 55 grants she is following for a total of 37 patients across the six offices. Each office manager has access to those records and, in turn,documents the office’s copay grant applications and responses to them—and whether or not the applications were successful. In addition, we maintain a custom tracking sheet for patients who receive copay grants so that we can monitor their copay balance after each cycle of therapy to ensure that patients do not continue therapy beyond the limits of the copay grants.
There are specific pharmaceutical company assistance programs for some branded drugs, but if patients have MediCal (Medicaid), Medicare, or a Medicare Advantage HMO product, they are not eligible for them. Patients can get coverage from these programs only if they have no insurance, and there is no coverage from any sources for the much cheaper, generic chemotherapy drugs. In addition,for most patients and their families, finding these grant sources, understanding the terms, and completing the applications is difficult and time consuming, so our practice hired a staff member to handle the applications (Rajurkar SP et al. J Oncol Pract 2011;7:100–102).
We are doing our part and more in community oncology, but as the cases here illustrate, we are not succeeding on behalf of all of our patients. We need patient advocates, Medicare and private health plan officials, and our elected representatives to develop a comprehensive solution to appropriately support cancer patients in the same way that those with chronic renal failure and other chronic or curable high-cost diseases are supported. We also need to urge our elected officials to ensure that the current debt crisis solution does not include further cuts to the Medicare payment system for cancer care. Physicians who have devoted years of their lives to bringing the best science to relieve suffering, prolong lives, and improve cure rates cannot realistically be expected to watch patients with curable and palliative cancers falter in their progress when effective care is available but unattainable.
Some years ago, when I was in Washington, DC,to speak to our representatives about the deleterious impact of the MMA, a prominent senator’s staffer told me “there would be no adjustments in funding until we showed them bodies in the streets.” Well, Senator, you can now see those bodies mounting.It is a sad time when clinicians are being asked to monitor patients’ cancer progression rather than their progress against cancer.
Underreporting of neutropenic toxicity associated with current treatment regimens for selected hematologic malignancies
Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3
1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH
Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8
Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.
Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.
Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38
Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.
We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.
Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2
The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).
The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).
Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.
Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.
A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.
Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50
Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.
A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.
In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.
The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.
Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.
Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.
A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).
Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1
Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.
Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.
In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.
Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.
Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1
Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16
Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.
Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.
Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.
For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1
Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7
The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.
Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1
Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.
Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.
Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68
A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).
Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.
A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.
Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.
Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.
Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.
Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.
Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.
Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.
Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.
Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.
Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.
For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.
The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39
Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22
Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.
Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline
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29. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with highrisk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20:727–731.
30. Johnston E, Crawford J, Blackwell S, et al. Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000;18:2522–2528.
31. Trillet-Lenoir V, Green J, Manegold C, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993;29A:319–324.
32. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double- blind, placebo-controlled phase III study. J Clin Oncol 2005;23:1178–1184.
33. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14:29–35.
34. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003;21:514–519.
35. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:3158–3167.
36. Lyman GH, Michels SL, Reynolds MW, Barron R, Tomic KS, Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 2010;116:5555– 5563.
37. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010;28:2914–2924.
38. Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev 2004:CD003189.
39. Dale DC, McCarter GC, Crawford J, Lyman GH. Myelotoxicity and dose intensity of chemotherapy: reporting practices from randomized clinical trials. J Natl Compr Canc Netw 2003;1:440–454.
40. Duff JM, Leather H, Walden EO, LaPlant KD, George TJ Jr. Adequacy of published oncology randomized controlled trials to provide therapeutic details needed for clinical application. J Natl Cancer Inst 2010;102:702– 705.
41. Freedman OC, Zimmermann C, Clemons MJ: Interpreting the results of clinical trials of cancer chemotherapy: the importance of reporting concurrent supportive care. Proceedings from 31st Annual San Antonio Breast Cancer Symposium; December 14, 2008; San Antonio, TX. Abstract 6138.
42. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235–242.
43. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105– 116.
44. Delarue R, Tilly H, Salles G, et al. RCHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03- 6B GELA study. Blood 2009;114:406.
45. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725–3732.
46. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417–1423.
47. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003–4008.
48. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non- Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-3301.
49. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858.
50. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009;27:1607–1614.
51. Salles GA, Seymour JF, Feugier P, et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010;28[15S]:8004.
52. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc.; 2010.
53. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus ritux imab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 2009;114:405.
54. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 2008;13:167–174.
55. Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2008;112:330.
56. Arzerra [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.
57. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749– 1755.
58. Straus DJ, Portlock CS, Qin J, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–3489.
59. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21:607–614.
60. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.
61. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.
62. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.
63. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607–618.
64. Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.
65. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–2498.
66. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final timeto- event results of the APEX trial. Blood 2007;110:3557–3560.
67. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–3901.
68. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.
69. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.
70. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.
71. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37.
72. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436.
73. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664–3670.
Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3
1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH
Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8
Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.
Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.
Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38
Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.
We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.
Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2
The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).
The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).
Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.
Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.
A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.
Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50
Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.
A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.
In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.
The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.
Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.
Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.
A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).
Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1
Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.
Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.
In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.
Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.
Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1
Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16
Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.
Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.
Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.
For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1
Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7
The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.
Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1
Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.
Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.
Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68
A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).
Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.
A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.
Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.
Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.
Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.
Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.
Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.
Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.
Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.
Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.
Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.
For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.
The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39
Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22
Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.
Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline
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52. Treanda [prescribing information]. Frazer, PA: Cephalon, Inc.; 2010.
53. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus ritux imab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 2009;114:405.
54. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist 2008;13:167–174.
55. Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2008;112:330.
56. Arzerra [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2010.
57. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749– 1755.
58. Straus DJ, Portlock CS, Qin J, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–3489.
59. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 2003;21:607–614.
60. Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA. Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 2002;20:630–637.
61. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478–1484.
62. Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 2009;27:805–811.
63. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607–618.
64. Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.
65. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487–2498.
66. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final timeto- event results of the APEX trial. Blood 2007;110:3557–3560.
67. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007;25:3892–3901.
68. Revlimid [prescribing information]. Summit, NJ: Celgene Corporation; 2009.
69. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142.
70. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123–2132.
71. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29–37.
72. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24:431–436.
73. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664–3670.
Stephanie A. Gregory, MD,1 Steve Abella, MD,2 and Tim Moore, MD3
1 Section of Hematology, Rush University Medical Center, Chicago, IL; 2 Global Clinical Development, Hematology/Oncology, Amgen Inc., Thousand Oaks, CA; and 3 Zangmeister Center, Columbus, OH
Most chemotherapy regimens considered standard of care for treating hematologic malignancies are myelosuppressive. They include chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN),1 such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to treat non-Hodgkin lymphoma (NHL) 2,3; fludarabine plus cyclophosphamide (FC) to treat chronic lymphocytic leukemia (CLL)4,5; and escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) or doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone (Stanford V) to treat Hodgkin lymphoma (HL).6–8
Emerging regimens that incorporate targeted therapies or other novel agents (eg, rituximab [Rituxan], lenalidomide [Revlimid], or bendamustine [Treanda]) have also been shown to be myelosuppressive, mainly because they are generally combined with myelosuppressive chemotherapy to achieve optimal efficacy. Examples include CHOP plus rituximab (R-CHOP) to treat NHL9,10; FC plus rituximab (FCR) to treat CLL11,12; or bortezomib plus melphalan-prednisone (MPB) to treat multiple myeloma.13,14 Additionally, some agents show toxicity when used as monotherapies, including bendamustine15–17 and alemtuzumab (Campath) 18 to treat CLL. Therefore, improved clinical outcomes may be achieved with concurrent increased myelosuppression.
Patients receiving myelosuppresive chemotherapy are at risk for developing chemotherapy-induced neutropenia, including severe or prolonged neutropenia and febrile neutropenia (FN). This condition often leads to treatment delays/interruptions, dose reductions, or treatment discontinuations, which can result in suboptimal treatment delivery and compromised patient outcomes.19–22 Colony-stimulating factor (CSF) has thus become an important component of many current treatment regimens for hematologic malignancies. International clinical guidelines, including those from the NCCN,1 the American Society of Clinical Oncology (ASCO),22 the European Society for Medical Oncology (ESMO),23 and the European Organization for Research and Treatment of Cancer (EORTC),24 recommend CSF use when the risk of FN is ≥ 20% and consideration of CSF use when the risk of FN is between 10% and 20%.
Numerous studies have demonstrated CSF effectiveness in decreasing the incidence of severe neutropenia and/or FN.25–34 A meta-analysis of 17 randomized controlled trials, which enrolled 3,493 cancer patients receiving chemotherapy, demonstrated that primary prophylaxis with CSF was associated with a decreased incidence of FN and reduced rates of infection-related mortality and early mortality across different tumor types.35 The occurrence of FN was associated with a 35% increase in the hazard of early mortality, and prophylactic granulocyte (G)-CSF use decreased this number by 45%.36 In a separate analysis of 25 trials (total n = 12,804), CSF support in cancer patients receiving chemotherapy was associated with a significant increase in overall survival (OS).37 Furthermore, a meta-analysis of results from 12 randomized controlled trials, which enrolled 1,823 patients with malignant lymphoma, showed that CSF prophylaxis, compared with no prophylaxis, significantly reduced the relative risk of severe neutropenia, FN, and infection.38
Evidence-based data that could guide the use of CSF in the setting of current treatment regimens for hematologic malignancies are not always readily available. Publications that report clinical trial results focus on overall efficacy and safety parameters of treatment regimens and often do not report the incidence or severity of neutropenia and/or FN.39 Similarly, these publications often do not include information on supportive care measures, including prophylaxis with antibiotics and/or CSF (primary or secondary).40,41 Also, when CSF support is reported, often the agent and dosing schedule are not provided. Many trials permit the use of CSF at the investigator’s discretion; however, the proportion of patients treated or supported with CSF and related outcomes is often not reported. These gaps in reporting neutropenic toxicity and related outcomes may result in an underestimation of the degree of significant toxicity associated with current treatment regimens for hematologic malignancies.
We conducted a comprehensive review of English-language reports published after January 2005. From the retrieved list of publications, we identified studies reporting data from trials (including phase II and III) that evaluated regimens considered NCCN Guideline recommendations for treating selected hematologic malignancies. 1 We excluded trials that enrolled patients with acute leukemia or chronic myelogenous leukemia; trials with the primary objective of assessing radiotherapy, radioimmunotherapy, stem cell transplantation, or patient-reported outcomes; and trials that described the study design but not the results. If multiple publications reported results of the same trial, we selected the publication with the most complete data on hematologic toxicity. Publications that met the inclusion criteria were retrieved and reviewed for neutropenic toxicity outcomes and the reported use of CSF or antibiotics.
Neutropenic toxicity associated with current treatment regimens for NHL
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of lymphoma generally treated with curative intent in the frontline setting. Beginning in the 1970s, the standard of care for DLBCL was CHOP, administered every 21 days (CHOP- 21).9 However, approximately half of patients > 60 years of age do not benefit from this regimen. In a study by Coiffier et al,42 3-year OS in this patient population was less than 40%. The addition of rituximab to CHOP-21 (R-CHOP-21) or CHOP-21–like regimens was subsequently shown to improve OS significantly across patient populations, with no increased neutropenic toxicity (Table 1).10 The R-CHOP regimen is now considered the standard of care for DLBCL when the goal of treatment is cure.9Another randomized study by Pfreundschuh et al compared dose-dense CHOP (given every 14 days, CHOP-14) with CHOP-21 in NHL patients ≥ 60 years of age.2 The CHOP-14 dosedense regimen required support with primary prophylactic CSF in all cycles (CHOP-14-G), whereas prophylactic CSF use with CHOP-21 was at the discretion of the treating physician, based on patient characteristics. CHOP-14-G significantly improved event-free survival (EFS) and OS. Grade 4 neutropenia was less frequent with CHOP-14-G than with CHOP-21 (24% vs 44%; P < 0.001), demonstrating that CSF support could adequately protect patients from neutropenic toxicity associated with CHOP.2
The RICOVER-60 study43 evaluated 6 or 8 cycles of dose-dense CHOP (CHOP-14-G) with or without rituximab in patients 61– 80 years of age who had aggressive B-cell lymphoma and were receiving primary prophylaxis with CSF (R-CHOP-14-G vs CHOP-14-G). R-CHOP-14-G significantly improved EFS (66.5% vs 47.2%) and OS (78.1% vs 67.7%). Leukopenia was the most common grade 3/4 toxicity, with grade 4 events occurring in 48%–52% across treatment arms. However, the incidence of leukopenia and the incidence of grade 3/4 infection were similar across the regimens (Table 1).
The Groupe d’Etude des Lymphomes de l’Adulte intergroup (GELA) study,44 compared RCHOP- 14 with R-CHOP-21 in DLBCL patients 60–80 years of age. Results from a 24-month interim analysis showed similar efficacy for R-CHOP-14 and R-CHOP-21 (2-year EFS of 48% vs 61%; P = not significant [NS]). Typically, trials of dose-dense regimens are evaluated with CSF support for all patients1,24; however, in the GELA study, patients received CSF at the physician’s discretion. Even though CSF use was higher with R-CHOP-14 than with R-CHOP-21 (90% vs 66%; Table 1), more patients in the R-CHOP-14 than in the R-CHOP-21 arm experienced grade 3/4 hematologic toxicity and FN (percentages were not reported).
Follicular lymphoma
Follicular lymphoma (FL) is usually diagnosed at an advanced stage and is incurable with current therapy.1 As shown in Table 1, current regimens for treating FL, including rituximab- and bendamustine-based regimens, are associated with neutropenic toxicity.
Rituximab-based treatment/consolidation regimens: The NCCN recommends R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for treating FL.1 A randomized phase III study by the German Low-Grade Lymphoma Study Group (GLSG) showed the superiority of first-line R-CHOP compared with CHOP in patients with untreated advanced FL.45 R-CHOP reduced the relative risk of treatment failure by 60% (28 of 223 patients vs 61 of 205 patients; P < 0.001), improved the overall response rate (ORR; 96% vs 90%; P = 0.011), and improved OS (6 deaths vs 17 deaths within the first 3 years; P = 0.016). Severe neutropenia was the most common treatment-related adverse event and occurred more often with R-CHOP than with CHOP (63% vs 53%; P = 0.01; Table 1).45 However, the incidence of severe infections was similar in the two groups (5% vs 7%; P = NS). Details of CSF use in this study were not reported.
A randomized phase III study in treatment-naive patients with advanced FL compared R-CVP with CVP.46 This study demonstrated that R-CVP significantly improved the ORR (81% vs 57%; P = 0.001), significantly prolonged the time to treatment failure (TTF; 27 months vs 7 months; P < 0.0001), and more than doubled the time to disease progression (TTP; 32 months vs 15 months; P < 0.001).46 The incidence of grade 3/4 neutropenia was higher with RCVP than with CVP (24% vs 14%), but the rates of infection and neutropenic sepsis were similar in the two treatment arms (Table 1).46 Details of CSF use were not provided in this report.
Rituximab-based maintenance regimens: Recent studies, including trials in frontline and relapsed settings, have demonstrated the benefits of rituximab maintenance after induction chemotherapy in patients with lymphoma.47–50
Two studies, one in the United States and one in Europe, randomized patients with relapsed/refractory FL to receive induction therapy with R-CHOP or CHOP; then those with a compete response (CR) or a partial response (PR) were randomized to receive rituximab maintenance (375 mg/m2 intravenously once every 3 months for up to 2 years) or no further treatment (observation group).48 Rituximab maintenance improved progression-free survival (PFS; 51.5 months vs 15.0 months; P < 0.001) and the 3-year OS rate (85% vs 77%; P = 0.011). The PFS benefit of rituximab maintenance was confirmed at a median follow-up of 6 years (3.7 years vs 1.3 years; P < 0.001; hazard ratio [HR] = 0.55), but the 5-year OS was not significantly different between the groups (74% vs 64%; P = 0.07).49 During the maintenance period, the frequency of grade 3/4 neutropenia and grade 3/4 infection was higher with rituximab than with no treatment: 12% vs 6% and 9% vs 2% (P = 0.009), respectively (Table 1).48,49 Details of CSF use during induction or maintenance therapy were not provided in the report.
A study by the GLSG group compared rituximab maintenance with no treatment following salvage therapy for patients with refractory or recurrent FL or mantle cell lymphoma.47 The maintenance regimen consisted of two courses of rituximab (4 doses of 375 mg/m2/day for 4 consecutive weeks) administered 3 months and 9 months after patients achieved a CR or a PR to induction chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) alone or in combination with rituximab (FCM-R). Rituximab maintenance significantly improved the response duration; the median response duration had not been reached in the rituximab arm vs an estimated median of 16 months in the observation arm (P < 0.001). During the maintenance period, grade 3/4 neutropenia was more common in the rituximab arm than in the observation arm (13% vs 6%; P = NS), but the incidence of grade 3/4 infection was similar in the two treatment arms (4% vs 3%; Table 1).47 Details of CSF use in both the induction and maintenance periods were not provided.
In the first-line setting, a randomized phase III study by the Eastern Cooperative Oncology Group (ECOG) evaluated the benefits of rituximab maintenance in patients with FL or small lymphocytic lymphoma following CVP treatment.50 Four weeks after the last CVP cycle, patients with responding or stable disease were randomized to receive rituximab (375 mg/m2 once per week for 4 weeks every 6 months for 2 years) or observation. Rituximab maintenance improved the 3-year PFS (68% vs 33%; HR = 0.4; P < 0.0001) and the 3-year OS (92% vs 86%; HR = 0.6; P = 0.05). During maintenance therapy, grade 3 neutropenia and grade 3 infection rates appeared to be similar in the two treatment groups (Table 1).50 Secondary CSF prophylaxis was permitted during induction chemotherapy in response to neutropenic events but not specified for the maintenance phase.
The Primary Rituximab and Maintenance (PRIMA) trial conducted by the GELA group evaluated the benefits of rituximab maintenance in previously untreated patients with indolent NHL.51 Patients who responded to one of three immunochemotherapy regimens (R-CHOP, R-CVP, or FCM with rituximab) were randomized to receive rituximab (375 mg/m2 given once every 8 weeks for 2 years) or observation. At a median followup of 2 years, maintenance rituximab significantly improved PFS (75% vs 58%; HR = 0.55; P < 0.0001). More patients in the rituximab arm than in the observation arm experienced grade 2 or higher infections (39% vs 24%), grade 3/4 infections (4% vs 1%), and grade 3/4 neutropenia (4% vs 1%). Rates of grade 3/4 FN were similar between treatment arms (< 1%); the definition of FN used in the trial was not provided.51 Details on CSF use during induction and maintenance therapies were not reported in the publication.
Ital Bendamustine-based regimens: Bendamustine, a novel bifunctional alkylating agent, was recently approved by the US Food and Drug Administration (FDA) to treat indolent NHL that has progressed after rituximab treatment.52 In a pivotal multicenter, open-label, single-arm trial, bendamustine (120 mg/m2) was administered to rituximab-refractory patients on days 1 and 2 every 21 days for 6–8 cycles.15 This study is included here because bendamustine has become an important component of regimens for the management of FL (either as monotherapy or in combination with other agents). In this study, the ORR was 74% (95% confidence interval [CI], 65%–83%), and the duration of response was 9.2 months (95% CI, 7.1–10.8 months), based on a median follow-up of 11.4 months. In 38 patients who had no objective response to their latest chemotherapy regimen, the ORR was 64%, and the median PFS was 7.5 months.
Primary CSF prophylaxis was not allowed in this study. Secondary CSF use was permitted if patients had grade 4 neutropenia that lasted at least 1 week, persistent leukopenia (grade > 2) at the next scheduled dose, or FN in any treatment cycle.15 The incidence of neutropenic complications was high (grade 3/4 neutropenia, 61%; grade 3/4 FN, 6%; and grade 3/4 infection, 21%). These findings demonstrate that when administered at the approved dose of 120 mg/m2 in the absence of primary CSF prophylaxis, bendamustine is associated with a high risk of neutropenic toxicity.
A randomized phase III trial compared bendamustine (90 mg/m2) plus rituximab (BR) with R-CHOP in patients with previously untreated indolent NHL.53 After a median observation period of 32 months, the BR regimen improved the CR rate (40% vs 31%; P = 0.03), PFS (55 vs 35 months; P = 0.0002), EFS (54 months vs 31 months; P = 0.0002), and time to next treatment (not reached vs 41 months; P = 0.0002). The rate of grade 3/4 neutropenia and number of infectious complications were significantly lower with the BR regimen than with R-CHOP: 11% vs 47% (P < 0.001) and 95 vs 121 (P < 0.04), respectively. 53 CSF was administered at the discretion of the treating physician and was used less frequently with the BR regimen than with R-CHOP (4% vs 20%).
Neutropenic toxicity associated with current treatment regimens for CLL
The NCCN recommends chemotherapy, primarily combinations containing alkylating agents and chemoimmunotherapy, as the standard of care for advanced CLL.1 Monotherapy or combination regimens with an alkylating agent or purine analog are preferred first-line therapies for elderly patients (≥ 70 years of age) and for frail patients with significant comorbidity. However, a more aggressive approach with rituximab-containing chemoimmunotherapy regimens is recommended for patients < 70 years old and for older patients with no significant comorbidities.1
Chemotherapy regimens
Two large randomized controlled trials4,5 showed that FC compared with fludarabine alone increased ORR, CR, and PFS in patients with CLL. The neutropenic toxicity of these regimens appeared similar in both studies. In Flinn et al,5 rates of grade 3/4 neutropenia, grade 3/4 FN, and grade 3–5 infection with grade 3/4 FN were similar (Table 1). CSF use was higher in the FC arm than in the fludarabine arm; however, CSF use was required in the FC arm only and not in the fludarabine arm. In Catovsky et al,4 rates of grade 3/4 neutropenia and all febrile episodes were similar (Table 1). In this study, CSF support was used according to local guidelines; however, the proportion of patients who required CSF support in the different treatment arms was not reported.
Chemoimmunotherapy regimens
In two large randomized controlled trials, FCR improved survival in patients with CLL compared with FC alone.11,12 In the CLL8 trial in chemotherapy-naive patients with advanced CLL,12 FCR was more efficacious than FC, as measured by CR rate (44% vs 22%; P < 0.001), PFS (52 vs 33 months; P < 0.001), and OS at 38 months (84% vs 79%; P = 0.01). The median OS had not been reached in either treatment arm at the time these data were published in abstract form. Hematologic adverse events, including neutropenia, were more common with FCR (percentages not reported) than with FC, but the infection rates were similar in the two treatment arms (Table 1).12 CSF use in this study was not reported.
In the REACH study, which compared FCR and FC in previously treated patients with CLL,11 FCR improved PFS (median, 31 months vs 21 months; HR = 0.65; P < 0.001) at a median follow-up of 25 months. Rates of grade 3/4 neutropenia and grade 3/4 infection were similar in the two groups (Table 1). In this study, 58% of patients in the FCR arm and 49% in the FC arm received CSF, administered at the discretion of the investigator.
Other chemoimmunotherapy regimens for CLL recommended by the NCCN include pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab.1 This recommendation was made on the basis of safety and efficacy results from nonrandomized trials.
Alemtuzumab-based regimens
In 2001, the FDA approved alemtuzumab to treat patients with CLL who had failed to respond to prior fludarabine-containing chemotherapy. 54 In an open-label, randomized controlled trial comparing alemtuzumab with chlorambucil (Leukeran) in previously untreated patients with CLL, alemtuzumab improved the ORR (83% vs 55%; P < 0.0001), PFS (15 vs 12 months; P < 0.0001), CR (24% vs 2%; P < 0.0001), and time to next treatment (23 vs 15 months; P < 0.0001).18 Grade 3/4 neutropenia was significantly more common with alemtuzumab than with chlorambucil (Table 1), but the rates of FN and serious infections were low in both treatment arms. In that study, CSF was administered to more than twice as many patients receiving alemtuzumab as receiving chlorambucil (Table 1)18; however, no further details were provided. Alemtuzumab-fludarabine and alemtuzumab with or without rituximab are regimens also recommended by the NCCN for relapsed or refractory CLL based on the results of nonrandomized trials.1
Bendamustine-based regimens
Bendamustine is recommended by the NCCN as a single agent for firstline therapy and as a single agent or in combination with rituximab for second-line therapy in patients with CLL.1 An open-label, multicenter, randomized phase III study compared bendamustine (100 mg/m2 on days 1–2 of each 28-day cycle) with chlorambucil in patients with untreated advanced CLL.16 Bendamustine significantly improved PFS (22 vs 8 months; P < 0.0001) and CR or PR (68% vs 31%; P < 0.0001). Grade 3/4 neutropenia occurred in twice as many bendamustine-treated patients as chlorambucil-treated patients (Table 1). The authors of this study report that even though the use of hematopoietic growth factors was discouraged in this study, CSF was administered in the bendamustine arm at the discretion of the treating investigator (Table 1).16
Bendamustine in combination with rituximab is also recommended for relapsed CLL.1 In a phase II study, patients with CLL were treated with bendamustine (70 mg/m2 on days 1 and 2 of each 28-day cycle) and rituximab (375 mg/m2 for the first cycle and 500 mg/m2 for subsequent cycles). 55 This single-arm study is included here because bendamustine is an important component of regimens for treating CLL. After a mean of 4.5 cycles, the ORR was 77%. Myelosup pression and infections were the most frequent severe adverse events reported, with grade 3/4 leukopenia or neutropenia observed in 12% of patients. Grade 3 or greater infections were documented in 5% of patients, and infection-related mortality occurred in 4% of patients. CSF use was not documented in this article.
Ofatumumab
Ofatumumab (Arzerra), a human monoclonal antibody directed against CD20, was recently approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab. 56 The NCCN recommends ofatumumab for relapsed or refractory disease.1 The registrational trial was a nonrandomized phase II study that evaluated safety and efficacy of ofatumumab in patients with fludarabineand alemtuzumab-refractory CLL (group A) and in patients with fludarabine- refractory CLL who were not candidates for alemtuzumab treatment because of bulky lymphadenopathy (group B).57 The study is included here because ofatumumab is a relatively new treatment option available to patients who fail to respond to other therapies. A planned interim analysis demonstrated benefits with ofatumumab in the two treatment groups (ORR, 58% and 47%; duration of response, 7.1 months and 5.6 months; PFS, 5.7 months and 5.9 months; and OS, 13.7 months and 15.4 months, respectively). 57 Grade 3/4 neutropenia was 14% in group A and 6% in group B; grade 3/4 infection was 12% and 8%, respectively. Of the 189 infectious events (all grades) with onset during treatment reported in this study, 13 (7%) were fatal. No information about CSF use was provided.
Neutropenic toxicity associated with current treatment regimens for HLThe NCCN recommends doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); Stanford V; and escalated-dose BEACOPP for the treatment of HL. ABVD was introduced in the 1990s, and Stanford V and BEACOPP were introduced in the early 2000s.8,58–61 These regimens are known to be highly myelotoxic.
For the ABVD regimen, an 18% rate of severe neutropenia was reported in one study,61 and a 57% rate of grade 3/4 neutropenia was reported in another study.58 With the Stanford V regimen, the incidence of grade 4 neutropenia and FN was as high as 82% and 14%, respectively.60 It should be noted that despite the high level of myelosuppression associated with regimens for HL, the NCCN does not recommend the routine use of CSF because neutropenia is not considered a major factor for dose reductions or dose delays.1
Trials have compared the ABVD and Stanford V regimens in patients with HL. One trial in patients with advanced disease demonstrated comparable efficacy of the two regimens.6 However, another trial in patients with intermediate- and advancedstage disease demonstrated the superiority of ABVD combined with optional limited radiotherapy over the Stanford V regimen, as measured by response rate and PFS.7 Both studies reported comparable neutropenic toxicity of the ABVD and Stanford V regimens when secondary CSF prophylaxis was permitted (Table 1).6,7
The BEACOPP regimen, which incorporates chemotherapy dose intensification and frequent scheduling, has been shown to improve patient outcomes in advanced disease.8 A relatively recent trial directly compared ABVD vs BEACOPP (four escalated-dose schedules followed by two standard-dose schedules) vs cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (CEC).62 At a median follow-up of 41 months, BEACOPP compared with ABVD significantly improved the 5-year PFS (81% vs 68%; P = 0.038) but showed no significant differences with CEC. Both the BEACOPP and CEC regimens were associated with higher rates of grade 3/4 neutropenia than ABVD; BEACOPP was also associated with higher rates of severe infections than ABVD and CEC (Table 1).62 Daily CSF was incorporated into the BEACOPP regimen and administered for at least 8 days, until an absolute neutrophil count of 500/ mm3 was reached.62 Routine CSF prophylaxis was not required with the ABVD and CEC regimens but was used at the discretion of the treating physician.
Neutropenic toxicity associated with current treatment regimens for multiple myeloma
A variety of regimens that incorporate the novel agents bortezomib (Velcade), lenalidomide (Revlimid), or thalidomide (Thalomid) have been evaluated for the treatment of multiple myeloma. These agents directly target the myeloma cells and can also interfere with the interaction of tumor cells with the bone marrow microenvironment. 63 The NCCN recommends these agents as components of combination regimens for induction chemotherapy (whether or not stem cell transplantation is indicated), as maintenance treatment after transplantation, or as salvage therapy for patients with multiple myeloma.1
Bortezomib-based regimens
Bortezomib, a member of a new class of drugs called proteasome inhibitors, is FDA approved to treat multiple myeloma.64 Patients with previously untreated myeloma are treated with bortezomib in combination with melphalan and prednisone (MPB). Results from the Velcade as Initial Standard Therapy in Multiple Myeloma trial compared MPB wit melphalan and prednisone (MP) in patients who were ineligible for transplant therapy.13,14 At a median follow-up of 37 months, MPB reduced the risk of death by 35% (HR, 0.653; P < 0.001) and improved the 3-year OS (69% vs 54%).13 The incidence of grade 3/4 neutropenia was comparable for MPB and MP (40% vs 38%; Table 1), suggesting that the MP component of the regimen is primarily responsible for the neutropenic toxicity. Information on CSF use in this study was not provided. The APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy in patients with recurrent myeloma.65,66 At a median follow-up of 22 months, bortezomib significantly improved the ORR (43% vs 18%; P < 0.0001) and the 1-year survival rates (80% vs 67%; P = 0.00002).66 Bortezomib was associated with a higher incidence of grade 3/4 neutropenia than was highdose dexamethasone (14% vs 1%; P < 0.01). However, the incidence of grade 3/4 infections was similar between the arms (13% vs 16%; P = 0.19).65 CSF use was permitted at the physician’s discretion; however, details were not provided.
Bortezomib in combination with pegylated liposomal doxorubicin (Doxil; B + PLD) is FDA approved for salvage therapy for multiple myeloma, with a category 1 recommendation from the NCCN. Interim data from a randomized phase III study67 demonstrated the superiority of B + PLD to bortezomib monotherapy (TTP, 9.3 months vs 6.5 months; P < 0.0001; PFS, 9.0 months vs 6.5 months; P < 0.0001; duration of response, 10 months vs 7 months; P < 0.001; and 15-month OS rates, 76% vs 65%; P = 0.03). Grade 3/4 neutropenia was significantly more common with the combination regimen; however, the rate of FN was similar (Table 1).67 CSF use was allowed in this study, but details were not provided.
Lenalidomide-based regimens
Lenalidomide is an immunomodulatory agent that is FDA approved for use in combination with dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy.68 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as a part of the lenalidomide-dexamethasone regimen.68
A phase III trial conducted in the US and Canada69 and a companion trial conducted in Europe, Israel, and Australia70 compared the lenalidomide- dexamethasone regimen with placebo-dexamethasone in patients with refractory or recurrent myeloma. In both trials, lenalidomidedexamethasone significantly improved the ORR, TTP, and OS.69,70 In both studies, neutropenic toxicity (including grade 3/4 neutropenia, FN, or grade 3/4 infection) was higher in the lenalidomide-dexamethasone arm than in the dexamethasone alone arm (Table 1).
Secondary CSF prophylaxis in response to neutropenic toxicity was permitted in both studies. In the Weber at al study,69 60 of the 177 patients (33.9%) in the lenalidomide- dexamethasone group received CSF support; 28 of the 60 patients (46.7%) received CSF to maintain the full lenalidomide dose, and 12 of these 28 patients (43%) were able to continue at the 25-mg dose level. In the Dimopoulos et al study,70 38 of 176 patients (22%) in the lenalidomide- dexamethasone group received CSF support; 23 of these patients (61%) needed CSF to maintain the lenalidomide dose, and 12 (52%) were able to continue on 25 mg of lenalidomide.
A recent trial evaluated lenalidomide- dexamethasone as initial therapy for patients with newly diagnosed multiple myeloma.71 In this open-label study with a noninferiority design, lenalidomide plus low-dose dexamethasone was compared with lenalidomide plus high-dose dexamethasone. The trial was stopped early because of the superior survival results with the low-dose dexamethasone regimen at a 1-year interim analysis (OS, 96% vs 87%; P = 0.0002). The NCCN now recommends lenalidomide with low-dose dexamethasone for previously untreated patients who are not candidates for transplant therapy.1 The low-dose dexamethasone regimen was associated with fewer infections than the high-dose dexamethasome regimen (9% vs 16%; P = 0.04), even though it was associated with a higher incidence of grade 3/4 neutropenia (20% vs 12%; P = 0.02). Details of CSF use were not reported for this study.
Thalidomide-based regimens
Thalidomide is also an immunomodulator that is FDA approved for use in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma. FDA approval of this regimen was supported by results from the Eastern Cooperative Oncology Group (ECOG) study, which compared thalidomidedexamethasone with dexamethasone alone.72 The response rate with thalidomide- dexamethasone was significantly higher than with dexamethasone alone (63% vs 41%; P = 0.017). The incidence of neutropenia and infection was similar between the arms (Table 1).72 Details of CSF use in this study were not provided.
Thalidomide in combination with MP (MPT) is recommended by the NCCN as a primary induction therapy for transplant-ineligible myeloma patients. The Intergroup Francophone du Myélome 01/01 Trial of MPT in patients with untreated multiple myeloma compared MPT with MP-placebo.73 MPT improved OS (44 vs 29 months; P = 0.03) and PFS (24 vs 18.5 months; P = 0.001), at a median follow-up of 47.5 months. Grade 3/4 neutropenia was significantly more common with MPT, but the incidence of severe infection was similar in the two treatment arms (Table 1). CSF use was permitted in this study; however, details were not provided.
Of note, unlike conventional chemotherapeutic agents, novel agents used to treat multiple myeloma are not administered in 14- or 21-day cycles. For example, bortezomib is initially administered twice-weekly (with rest periods) followed by weekly dosing as a component of the MPB regimen.13,14 Lenalidomide is taken orally once daily on days 1–21 of 28-day cycles as part of the lenalidomide-dexamethasone regimen. 69,70 Similarly, thalidomide is administered daily as an oral tablet.72 Furthermore, although clinical trials have integrated CSF use, no studies specifically address it with these novel agents (ie, whether CSF should be given concurrently or sequentially with the therapy). Therefore, clinical trials evaluating the safety of CSF use with these novel agents are warranted.
Quantitative analysis of underreporting of neutropenic toxicity
As previously discussed, most reports of trials evaluating therapies for treating hematologic malignancies include information about the frequency of severe neutropenia. However, our literature review showed that data on the incidence of FN and the use of CSF are frequently not provided. The omission of this information limits the comparison of results across trials and the ability to make informed decisions on the true risk of FN for a treatment modality. The objective of this quantitative analysis was to evaluate the reporting of FN and other neutropenic outcomes, as well as related CSF or antibiotic use, in randomized controlled trials that evaluated regimens for the treatment of NHL, CLL, HL, or multiple myeloma.
Selection criteria for articles included For this quantitative analysis, phase III trials published between January 2005 and June 2009 were identified from the original list of trials retrieved through the comprehensive literature search, as previously discussed. We included phase III trials only for this analysis, because most are designed to capture both safety and efficacy associated with a treatment modality, compared with phase II trials, which may sometimes primarily focus on safety parameters. We also included all articles that met the specified criteria, whether or not the treatment regimen reported in the article was recommended by the NCCN.
Articles that met the inclusion criteria were retrieved and data on myelotoxic outcomes were abstracted by two reviewers and reconciled by a third reviewer. The neutropenic outcomes included were grade 3/4 neutropenia or granulocytopenia, FN, leukopenia, all-cause hospitalization, neutropenia-related hospitalization, infection or sepsis, and infection-related mortality. Outcomes on chemotherapy delivery included dose delays, dose reductions, and dose intensity or relative dose intensity. We also collected data on CSF use defined in the methods section, CSF use presented in the results section, and antibiotic use defined in the methods and/or results section.
Results
Table 2 summarizes our findings on the reporting of neutropenic toxicity outcomes. Of the 57 trials that met the inclusion criteria, 86% reported results of at least one neutropenic endpoint. Across tumor types, 68% of trials reported on the incidence of grade 3/4 neutropenia (80%, multiple myeloma; 71%, CLL; 63%, NHL, 50%, HL). However, a few trials (19%) reported on the incidence of FN (57%, CLL; 20%, multiple myeloma; 12%, NHL). Similarly, only a few trials (4%) reported on neutropenia- related hospitalizations (8%, NHL). The incidence of infection or sepsis and infection-related mortality was reported in 79% and 60% of publications, respectively. Dose delays/interruptions were reported in 21% of trials overall. Dose reductions were reported in 30% of articles overall.
Data on the reporting of CSF and antibiotic use are shown in Table 3. About half (49%) of the publications reported planned use of CSF in the methods section (71%, CLL; 67%, HL; 50%, NHL; 35%, multiple myeloma). However, overall, only 25% of publications reported CSF use in the results section (43%, CLL; 29%, NHL; 17%, HL; 15%, multiple myeloma). Overall reporting on prophylactic antibiotic use was also low. Antibiotic use was discussed in the methods sections of only 21% of papers (71%, CLL; 17%, HL; 15%, multiple myeloma; 13%, NHL), and actual use of antibiotics was not reported in the results section of any of the publications.
Discussion
Our review shows that many phase III trials of current treatment regimens for hematologic malignancies omit important outcome data on the incidence of FN, neutropenia-related hospitalization, infection-related mortality, chemotherapy dose delays/ interruptions or dose reductions, use of primary or secondary CSF prophylaxis, or use of antibiotics. These findings are similar to recent observations by others.
For instance, Duff and colleagues40 reported that publications describing results from phase III trials fail to consistently report details that would enable clinicians in the community to translate findings to clinical practice. When these researchers asked medical oncologists and oncology pharmacists to identify the most important information necessary for clinical application of an oncology drug, 3 of the 10 most common responses were premedication, growth factor support, and dose adjustments for hematologic toxicity.
The researchers then reviewed 262 articles published in five journals (Blood, Cancer, the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and the New England Journal of Medicine) between 2005 and 2008. They found that each of these elements (premedication, growth factor support, and dose adjustments for hematologic toxicity) was reported fewer than half the time (P < 0.0001) compared with the name of the drug, which was reported 100% of the time. Duff and colleagues40 recommend that journal editors require reporting of these and other highly ranked elements in the article or in an online appendix and provide Internet- open access to the clinical trial protocol.
Dale and colleagues39 examined 58 reports on NHL therapy trials published between 1990 and 2000. They found that 34% did not include data on neutropenic toxicity and 3% included only details on clinical consequences, such as fatal infection. In the other trials, hematologic toxicity was reported 18 different ways. These authors recommend that certain details about hematologic toxicity should routinely be documented in reports on cancer chemotherapy: rates of leukopenia and neutropenia; the timing of blood cell counts used to determine these rates; protocols for antibiotics and CSF use; actual use of antibiotics and CSF; rates of all infectious complications, including hospitalizations and bacteremias; and relative dose intensity. 39
Conclusion
In addition to efficacy data, reports on clinical trials should provide details on the toxicity of treatment and requirements for supportive care. A standardized approach to collecting and reporting neutropenic outcomes and the related use of supportive care measures can assist clinicians in prospectively managing the relevant toxicities associated with treatment regimens for hematologic malignancies. This information is essential for the safe and effective transition of these regimens into broad clinical practice. These data should include all grade 3 or greater hematologic and nonhematologic toxicities in phase II, III, or IV clinical trials, as well as details on prophylactic and interventional CSF and antibiotic use. Armed with knowledge of the risk of neutropenic toxicity associated with each treatment regimen, oncologists can then focus on the patient-related risks when making decisions regarding appropriate supportive care. Mitigation of neutropenic toxicity associated with treatment regimens is important to decrease patients’ risk for treatment delays/interruptions, dose reductions, or discontinuations, which can compromise patient outcomes.19–22
Acknowledgments
Amgen sponsored an external agency for data abstraction and analysis. The authors thank Beverly A. Caley and Leta Shy for data abstraction; Supriya Srinivasan for data reconciliation; and Supriya Srinivasan and Martha Mutomba for writing assistance. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the manuscript for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit the article for publication. All authors provided comments during manuscript development and have approved the final version of the submitted article.
Conflicts of interest
Dr. Gregory has served as a consultant or in an advisory role with Amgen Inc, Genentech (Roche), Novartis, and Spectrum Pharmaceuticals; and her institution has received research funding from Astellas, Celgene, Cephalon, Genentech (Roche), GlaxoSmithKline, Immunomedics, NCIC–CTG, and Novartis. Dr. Abella is an employee and stock owner of Amgen Inc. Dr. Moore has served as a consultant or in an advisory role with Amgen Inc and is on the speakers’ bureaus of Amgen Inc, sanofi-aventis, and GlaxoSmithKline
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