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Trio of biosimilars have good showing
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
A variety of issues are influencing whether and how clinicians incorporate biosimilars into cancer care, according to Michael A. Thompson, MD, PhD, medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health Care in Milwaukee, Wis., who spoke at the annual meeting of the American Society of Clinical Oncology.
“The issue of competition is highly relevant to biosimilars,” he said. Among important questions here: Is the oncology drug market a free market? Who owns the biosimilar companies? Does competition lower drug prices? And if biosimilars don’t decrease drug cost, why bother pursuing them? “We are seeing examples where the biosimilars have been developed, they appear to work, they appear safe, and really the proof will be how much is this pushing the market to decrease cost,” he noted.
Real-world data provide some insight into how biosimilars are being incorporated into oncology care. For example, in patients with non-Hodgkin lymphoma, hematologists tend to use rituximab (Rituxan) biosimilars in later lines of therapy, in patients with a better performance status and fewer comorbidities, and in cases of indolent or incurable disease (J Clin Oncol. 2018;36[suppl; abstr 112]). “So it appears that prescribers are acting tentatively to cautiously test the waters,” Dr. Thompson said.
Use will be influenced by clinical decision support and pathways, whether those are developed by institutions or insurers. These tools generally look at efficacy first, safety second, and cost third.
The relevance of patient choice (especially when physicians decreasingly have a choice) and perception of biosimilars may, or may not, be important, according to Dr. Thompson. In some areas of medicine, there is evidence of a nocebo effect: Patients perceive worsening of symptoms when they believe they are getting a nonbranded medication. But “I am not sure if this is valid in oncology, where we are already using many older chemotherapy drugs, the generics,” he said.
The American Society of Clinical Oncology recently published a statement on the use of biosimilars and related issues, such as safety and efficacy; naming and labeling; interchangeability, switching, and substitution; and the value proposition of these agents (J Clin Oncol. 2018 Apr 20;36[12]:1260-5). “The ASCO statement and guidelines are a great resource for really digging deeply into this area,” Dr. Thompson commented.
One concern surrounding uptake of biosimilars is the possibility of an actual increase in patient cost related to single sources and potentially differing reimbursement rates, which could diminish the financial benefit of these drugs. Technically, if biosimilars have similar efficacy and safety, and lower cost, they provide greater value than the reference drugs.
But there may still be reasons for not using a higher-value drug, according to Dr. Thompson. Clinicians may have lingering questions about efficacy and safety despite trial data, a situation that is being addressed in Europe by postmarketing pharmacovigilance. Other issues include delays in pathway implementation, the contracting of pharmacies with companies, and creation of new chemotherapy builds in electronic medical records. “These are all minor but potential barriers to as fast an implementation as possible,” he said.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
CHICAGO – investigators reported at the annual meeting of the American Society of Clinical Oncology. The findings further advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous NSCLC. Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The confidence interval for the risk difference fell within the equivalence margins set by European Union regulators (–13% and +13% for the 95% confidence interval). And the confidence interval for the risk ratio fell within the equivalence margins set by the Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio, 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, Dr. Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the two agents. Patients also had similar rates of grade 3 or higher serious adverse events and of fatal (grade 5) serious adverse events (5.3% with the biosimilar and 5.9% with bevacizumab).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr. Socinski summarized.
“These results confirm similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU,” he concluded.
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer.
The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various adverse events were essentially the same.
Presence of overall response at 24 weeks correlated with duration of progression-free survival at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr. Rugo commented.
Common adverse events through week 48 were much the same as those seen at week 24, with few additional ones occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell down to a very low number and was identical between the two arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of adverse events of special interest – respiratory events, cardiac disorders, and infusion-related adverse events – and of serious adverse events were similar for the two agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr. Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr. Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.
“Trastuzumab-dkst provides an additional high-quality treatment option for patients with HER2+ breast cancers in any setting,” she added. “This study indeed shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of ob&gyn at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony–stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Dr. Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial population. Findings were similar for temperature exceeding 38.5˚ C in any cycle: 3.4% and 5.6%. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% vs. 74.3%) and higher rates of infection (15.5% vs. 7.9%) and hospitalization caused by febrile neutropenia (3.9% vs. 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 vs. 261 events, respectively) and skin/subcutaneous tissue disorders (5 vs. 258 events). “Seeing these data, you have to keep in mind first of all that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr. Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr. Harbeck commented. “Having seen the discrepancies in the data … I think it’s important to have randomized controlled trials to assess and monitor adverse events for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were both sponsored by Sandoz.
SOURCE: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
REPORTING FROM ASCO 2018
Key clinical point: Biosimilars for bevacizumab, trastuzumab, and filgrastim showed similar efficacy and safety.
Major finding: In patients with advanced nonsquamous NSCLC, the overall response rate was 45.3% with a candidate bevacizumab biosimilar and 44.6% with bevacizumab. In patients with HER2+ advanced breast cancer, 48-week median progression-free survival was 11.1 months for both trastuzumab-dkst and trastuzumab. The rate of chemotherapy-induced febrile neutropenia among breast cancer patients given a biosimilar for filgrastim was 5.1% in a trial population and 6.2% in a real-world population.
Study details: Randomized, controlled trials of first-line therapy among 719 patients with advanced nonsquamous NSCLC (REFLECTIONS trial) and among 458 patients with HER2+ advanced breast cancer (HERITAGE trial). Comparison of outcomes in a randomized, controlled trial among 217 patients with nonmetastatic breast cancer (PIONEER trial) and a real-world cohort study of 466 patients with any-stage breast cancer (MONITOR-GCSF).
Disclosures: Dr. Socinski disclosed that his institution receives research funding from Pfizer, among other disclosures; the REFLECTIONS trial was sponsored by Pfizer. Dr. Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan, among other disclosures; the HERITAGE trial was sponsored by Mylan. Dr. Harbeck disclosed that she has a consulting or advisory role with Sandoz, among other disclosures; the PIONEER and MONITOR-GCSF trials were sponsored by Sandoz.
Source: Socinski MA et al. ASCO 2018, Abstract 109. Manikhas A et al. ASCO 2018, Abstract 110. Harbeck N et al. ASCO 2018, Abstract 111.
Could High BMI Reduce Premenopausal Breast Cancer Risk?
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.
The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.
The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.
Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.
Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.
FDA expands indication for ribociclib for advanced breast cancer
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
The Food and Drug Administration has approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer, as initial endocrine-based therapy.
Ribociclib was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative advanced breast cancer in postmenopausal women.
Approval for ribociclib in combination with an AI for pre/perimenopausal women was based on progression-free survival (PFS) in MONALEESA-7, a trial of premenopausal women with HR-positive, HER2-negative, advanced breast cancer. The women received either ribociclib and an AI, or placebo and an AI, and all also received ovarian suppression with goserelin (Zoladex). Of 495 women who received nonsteroidal AIs, median PFS was 27.5 months for women also receiving ribociclib, versus 13.8 months for women who received placebo plus the AI.
Approval for ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was based on PFS results from MONALEESA-3, which enrolled 726 women with HR-positive, HER2-negative, advanced breast cancer who received no or up to one line of prior endocrine therapy. Median PFS was 20.5 months for women randomized to receive ribociclib and fulvestrant, compared with 12.8 months for women randomized to receive placebo plus fulvestrant.
The common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash. Warnings include the risk of QT prolongation, serious liver problems, low white blood cell counts, and fetal harm, the FDA said.
This is the first FDA approval as part of two new pilot programs announced earlier this year: Real-Time Oncology Review allows for the FDA to review much of the data earlier, before the information is formally submitted to the FDA, and the Assessment Aid is a structured template that offers a more streamlined approach.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information,” FDA Commissioner Scott Gottlieb, MD, said in the press statement. “This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
The two pilot programs are currently being used for supplemental applications for already approved cancer drugs and could later be expanded to original drugs and biologics, the FDA said.
Ribociclib is marketed as Kisqali by Novartis Pharmaceuticals Corporation.
ABP 980 similar to trastuzumab in HER2+ breast cancer in all but name
In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).
Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.
“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.
ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.
Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,
Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.
In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.
The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.
However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
The LILAC trial has some strengths and weaknesses and raises a curious regulatory issue. To begin with the weaknesses, only 696 of 725 randomized patients were evaluable for pathological complete response after surgery. No data about the outcomes, characteristics, or allocated treatment of the patients who did not reach surgery were provided. These lost patients should have been included in the intention-to-treat analysis and their responses classified when possible (e.g., those who did not reach surgery due to progressive disease should have been classified as nonpathological complete response). The effect of these few patients on the overall results is unknown, although it is possibly small.
Among the strengths of LILAC were that the trial was done in a sensitive population (i.e., a population in which differences in safety, immunogenicity, and efficacy could be attributed to the biosimilar or reference drug rather than patient-related or disease-related factors). Two chemotherapy choices were included that are broadly used worldwide, and thus mimicked routine clinical practice, and the study had a sensitive primary endpoint (pathological complete response). The aim of clinical trials in the regulatory pathway of biosimilars is to show an acceptable degree of similarity in clinical efficacy and safety to the reference product. For original products, endpoints in clinical trials must show benefits to patients, such as progression-free survival, disease-free survival, or overall survival, whereas for biosimilars, surrogate endpoints, such as the proportion of patients with pathological response in breast cancer neoadjuvant trials, are appropriate. The study design of LILAC, therefore, meets the main clinical requirements demanded by medicine agencies for the registration of biosimilars.
Miguel Martin, MD, PhD is with Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martin’s remarks are adapted and condensed from an editorial in The Lancet Oncology accompanying the study by von Minckwitz G et al. He disclosed grants from Novartis and Roche and personal fees from AstraZeneca, Lilly, Pfizer, and Roche.
In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).
Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.
“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.
ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.
Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,
Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.
In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.
The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.
However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).
Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.
“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.
ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.
Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,
Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.
In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.
The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.
However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.
The safety analysis showed a similar incidence of grade 3 or greater adverse events during neoadjuvant therapy (15% of patients on ABP 980 vs. 14% on trastuzumab). Grade 3 or greater neutropenia occurred in 6% of patients in each group.
During adjuvant therapy, grade 3 or greater adverse events occurred in 9% of patients continuing ABP 980, 6% continuing trastuzumab, and 8% of these switched from trastuzumab to ABP 980. The most frequent grade 3 or greater events of interest were infections and neutropenia, all occurring in 1% of patients in each arm, and infusion reaction, which occurred in 1% of patients who stayed on the assigned HER2 inhibitor and in 2% of patients who were switched to ABP 980.
There were two patient deaths from adverse events, each deemed to be unrelated to treatment. One patient died from pneumonia during neoadjuvant ABP 980 therapy, and one died from septic shock during adjuvant therapy with ABP 980 after being switch from trastuzumab.
“To our knowledge, this is the first study of a trastuzumab biosimilar encompassing a single-switch design from the reference product to a biosimilar, which allowed us to assess the clinical safety and immunogenicity of this approach to treatment. Safety and immunogenicity were similar in patients who were switched and in those who continued to receive trastuzumab as adjuvant therapy,” the investigators wrote.
SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
FROM THE LANCET ONCOLOGY
Key clinical point: The biosimilar ABP 980 appears to be comparable in efficacy and safety to trastuzumab in women with early HER2-positive breast cancer.
Major finding: According to local lab assessments, 48% of patients assigned to ABP 980 had a pathologic complete response, compared with 41% assigned to trastuzumab.
Study details: Randomized, double-blind, phase 3 trial of 696 adult women with HER2-positive breast cancer.
Disclosures: Dr. von Minckwitz is a consultant for Amgen, which funded the study. Two coauthors are employees of the company and stockholders. Other coauthors disclosed relationships with various companies.
Source: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.
Trastuzumab biosimilar is equivalent on central review
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
CHICAGO – according to a new analysis of the phase 3 LILAC trial.
The 725 women in the multinational trial received run-in, anthracycline-based chemotherapy and were then evenly randomized to receive ABP 980 or trastuzumab, each with paclitaxel, followed by surgery.
The difference in pathologic complete response (pCR) rate assessed by local pathologists has been previously reported (Lancet Oncol. 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9); those findings established non-inferiority of the biosimilar but left the matter of non-superiority inconclusive. However, in the new analysis, reported in a poster session at the ASCO Annual Meeting, the difference in pCR rate when instead assessed by a central pathologist fell within all bounds for equivalence.
“This is part of the totality of evidence in the course of approval of ABP 980,” lead author Hans-Christian Kolberg, MD, head of the department of gynecology and obstetrics of the Breast Cancer Center of the Gynecologic Cancer Center at Marien Hospital Bottrop (Germany), commented in an interview.
The new data prompted European regulators to authorize marketing of the biosimilar (branded as Kanjinti) for HER2+ early breast cancer and metastatic breast cancer, as well as HER2+ metastatic gastric cancer. (In the United States, the Food and Drug Administration recently rejected the application for ABP 980 market approval.)
“Breast cancer therapy is getting more and more expensive, and we somehow have to raise the money to pay for it. If we have a chance to make an antibody that is 20%-30% cheaper, which is what we hope it will be in Europe, we have that money for other things,” Dr. Kolberg said, reflecting on the bigger picture.
“I am also a visiting professor at a university in China, where patients who are HER2+ don’t get Herceptin because they can’t afford it. We always have to remember that in Europe and the U.S., we are kind of living on an island. If you look at Africa, Asia, and South America, making things affordable is important,” he added. “I hope and believe that this is just the beginning of the price fight. I hope that the biosimilar companies really will fight to see who will have the lowest price because that will be good for the patients. The lower the price, the better for the patients.”
Study details
Research leading up to the LILAC trial established that ABP 980 had analytic characteristics, nonclinical attributes, and pharmacokinetics similar to those of trastuzumab. The trial, conducted in 97 centers in 20 countries in western Europe, eastern Europe, and other world regions, assessed clinical similarity.
“I think central review was done in the study because we had so many centers all over the world that it was questionable as to how we could monitor the quality in dozens and dozens of pathology labs,” Dr. Kolberg explained. “So the idea was that we make it a little bit more difficult, a little bit more expensive, but more reliable if we use one pathologist.”
The central review was not without logistical issues, he acknowledged. In particular, it was challenging to ensure that all centers – including some doing so for the first time – followed a standardized procedure for sending tissue to the central lab.
The previously reported locally assessed pCR rates in breast tissue and axillary lymph nodes were 48.0% with ABP 980 and 40.5% with trastuzumab. The risk difference was 7.3% (90% confidence interval, 1.2%-13.4%) and the risk ratio was 1.188 (90% CI, 1.033-1.366), with the upper bounds of the confidence intervals exceeding the predefined equivalence margins of 13% and 1.318, respectively.
The centrally assessed pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab. The risk difference was 5.8% (90% CI, –0.5% to 12.0%), and the risk ratio was 1.14 (90% CI, 0.993 to 1.312), with the upper bounds of the confidence intervals now falling within the equivalence margins.
“This is the first study ever that used central pathology review for pCR in a neoadjuvant breast cancer study. We were really skeptical at the beginning as to whether that would work because we had a lot of centers all over the world, from Russia, Brazil, the U.S., Germany,” Dr. Kolberg commented.
“It worked, and we were very lucky that it worked because in the local review, we did not reach our biosimilar margins, our equivalence margins. In the central review, we were well within the margins,” he said. “So if we had not in the beginning planned a coprimary endpoint with local and central pathology review, the medication would never have been approved.”
Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
SOURCE: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
REPORTING FROM THE ASCO ANNUAL MEETING
Key clinical point: Central review determined that ABP 980 was neither inferior nor superior to trastuzumab in breast cancer patients.
Major finding: The centrally determined pCR rates were 47.8% with ABP 980 and 41.8% with trastuzumab, with bounds of the confidence intervals for risk difference and for risk ratio falling within the predefined equivalence margins.
Study details: An analysis of a phase 3 randomized controlled trial of neoadjuvant (and adjuvant) therapy among 725 patients with HER2+ early breast cancer (LILAC trial).
Disclosures: Dr. Kolberg disclosed that he is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GlaxoSmithKline, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, Teva Pharmaceutical Industries, and Theraclion. The trial was sponsored by Amgen.
Source: Kolberg HC et al. ASCO Annual Meeting, Abstract 583.
Does hormone therapy increase breast cancer risk in BRCA1 mutation carriers?
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
EXPERT COMMENTARY
Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.
To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.
Details of the study
The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.
Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).
During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.
When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).
Study strengths and weaknesses
This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.
The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.
Because women with BRCA1 mutations have an elevated risk of ovarian cancer, risk-reducing gynecologic surgery is recommended for these women who have completed childbearing. In young women, BO without HT is associated with severe vasomotor symptoms, osteoporosis, cardiovascular disease, and cognitive decline. The clear reduction in breast cancer risk associated with ET (vs EPT) following BO suggests that in BRCA1 carriers who have completed childbearing, hysterectomy (which precludes the need for progestogen therapy) should be considered as part of risk-reducing gynecologic surgery. Further, the findings of this prospective study in high-risk women parallels the findings of the large randomized Women's Health Initiative trial (performed in the general population of menopausal women), which found that ET (conjugated equine estrogen) reduces the risk.1
-- Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
Higher BMI tied to lower breast cancer risk in women before menopause
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
Although obesity increases the risk of breast cancer in postmenopausal women, a large multicenter analysis has confirmed the opposite effect in premenopausal women.
The association had “a greater magnitude than previously shown and across the entire distribution of body mass index,” wrote Minouk J. Schoemaker, PhD, of the Institute of Cancer Research in London, with his associates, on behalf of the Premenopausal Breast Cancer Collaborative Group. The protective effect of adiposity was strongest during young adulthood (ages 18-24 years), when it spanned breast cancer subtypes. “Understanding the biological mechanisms underlying these associations could have important preventive potential,” they wrote in JAMA Oncology.
Prior studies have linked greater body fat with reduced risk of breast cancer in younger women, but the effect has not been well characterized. For this analysis, the investigators pooled data from 19 cohort studies that included a total of 758,592 premenopausal women; median age was 40.6 years (interquartile range, 35.2-45.5 years).
For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years. There was no BMI threshold for risk reduction: the inverse correlation existed even when women were not overweight. Risk also did vary significantly among subgroups stratified by other risk factors for breast cancer. Adiposity was more protective against estrogen receptor-positive and progesterone-receptor positive breast cancers and less protective against hormone receptor–negative breast cancers, which “implies a hormonal mechanism,” the investigators said. “Body mass index at ages 25-54 years was not consistently associated with triple-negative or hormone receptor–negative breast cancer overall.”
Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
SOURCE: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
FROM JAMA ONCOLOGY
Key clinical point: In premenopausal women, adiposity inversely correlated with risk of breast cancer, and showed a stronger protective effect than previously documented.
Major finding: For each 5-unit increase in BMI, the estimated reduction in risk of breast cancer was 23% among women aged 18-24 years (hazard ratio, 0.77; 95% confidence interval, 0.73-0.80), 15% in women aged 25-34 years, 13% in women aged 35-44 years, and 12% in women aged 45-54 years.
Study details: Multicenter analysis of 19 cohort studies.
Disclosures: Funders included Breast Cancer Now, the Institute of Cancer Research, the National Institutes of Health, and many others. The researchers reported having no relevant conflicts of interest.
Source: Schoemaker MJ et al. JAMA Oncol. 2018; Jun 21. doi: 10.1001/jamaoncol.2018.1771.
ASCO 2018: Less is more as ‘tailoring’ takes on new meaning
A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.
A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.
Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.
In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.
Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.
In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.
In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.
In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.
A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.
A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.
Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.
In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.
Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.
In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.
In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.
In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.
A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.
A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.
Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.
In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.
Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.
In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.
In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.
In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.
The long-term effects of posttreatment exercise on pain in young women with breast cancer
Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.1 Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.2 Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.6 In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.7 These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,8 and can progress undetected until pain and upper-limb disability develop.
The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.9,10
The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
Methods
Design
We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
Sample
Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.18
Variables and measures
Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).
Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.16 For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.
Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.
Procedure
The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.
Intervention
The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.20 The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.
By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.
Statistical analysis
Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.
Results
A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).
The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.
Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.
The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.
Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,24 and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.
Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
Discussion
Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.
More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.
Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.
Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,31 but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.
Limitations
Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.
Conclusions
Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.
Acknowledgments
The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.
1. World Health Organization. Breast cancer: prevention and control. www.who.int/cancer/detection/breastcancer/en/. Updated 2017. Accessed September 16, 2016.
2. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain. 2011;12(7):725-746.
3. Ernst MF, Voogd AC, Balder W, Klinkenbijl JH, Roukema JA. Early and late morbidity associated with axillary levels I-III dissection in breast cancer. J Surg Oncol. 2002;79(3):151-155; discussion 156.
4. Gulluoglu BM, Cingi A, Cakir T, Gercek A, Barlas A, Eti Z. Factors related to post-treatment chronic pain in breast cancer survivors: the interference of pain with life functions. Int J Fertil Womens Med. 2006;51(2):75-82.
5. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH. Neuropathic pain following breast cancer surgery: proposed classification and research update. Pain. 2003;104(1-2):1-13.
6. Saibil S, Fitzgerald B, Freedman OC, et al. Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey. Curr Oncol. 2010;17(4):42-47.
7. Tengrup I, Tennvall-Nittby L, Christiansson I, Laurin M. Arm morbidity after breast-conserving therapy for breast cancer. Acta Oncol. 2000;39(3):393-397.
8. Johansen J, Overgaard J, Blichert-Toft M, Overgaard M. Treatment of morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol. 2000;39(3):349-354.
9. Mittmann N, Porter JM, Rangrej J, et al. Health system costs for stage-specific breast cancer: a population-based approach. Curr Oncol. 2014;21(6):281-293.
10. Page A. Keeping patients safe: transforming the work environment of nurses. Washington, DC: National Academies Press; 2004.
11. McNeely ML, Campbell K, Ospina M, et al. Exercise interventions for upper-limb dysfunction due to breast cancer treatment. Cochrane Database Syst Rev. 2010;(6):CD005211. doi:10.1002/14651858.CD005211.pub2
12. Wong P, Muanza T, Hijal T, et al. Effect of exercise in reducing breast and chest-wall pain in patients with breast cancer: a pilot study. Curr Oncol. 2012;19(3):e129-e135.
13. Fernández-Lao C, Cantarero-Villanueva I, Fernández-de-Las-Peñas C, del Moral-Ávila R, Castro-Sánchez AM, Arroyo-Morales M. Effectiveness of a multidimensional physical therapy program on pain, pressure hypersensitivity, and trigger points in breast cancer survivors: a randomized controlled clinical trial. Clin J Pain. 2012;28(2):113-121.
14. Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003;21(9):1660-1668.
15. Segal R, Evans W, Johnson D, et al. Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol. 2001;19(3):657-665.
16. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23(2):129-138.
17. Kumar SP. Utilization of Brief Pain Inventory as an assessment tool for pain in patients with cancer: a focused review. Indian J Palliat Care. 2011;17(2):108-115.
18. Van Voorhis CRW, Morgan BL. Understanding power and rules of thumb for determining sample sizes. Tutor Quant Methods Psychol. 2007;3(2):43-50.
19. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61(2):277-284.
20. Lee TS, Kilbreath SL, Refshauge KM, Pendlebury SC, Beith JM, Lee MJ. Pectoral stretching program for women undergoing radiotherapy for breast cancer. Breast Cancer Res Treat. 2007;102(3):313-321.
21. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409-1426.
22. Pollock ML, Gaesser GA, Butcher JD, et al. ACSM position stand: the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc. 1998;30(6):975-991.
23. Ibrahim M, Muanza T, Smirnow N, et al. Time course of upper limb function and return-to-work post-radiotherapy in young adults with breast cancer: a pilot randomized control trial on effects of targeted exercise program. J Cancer Surviv. 2017;11(6):791-799.
24. Ibrahim M, Muanza T, Smirnow N, et al. A pilot randomized controlled trial on the effects of a progressive exercise program on the range of motion and upper extremity grip strength in young adults with breast cancer. Clin Breast Cancer. 2018;18(1):e55-e64.
25. Gärtner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA. 2009;302(18):1985-1992.
26. Hayes SC, Johansson K, Stout NL, et al. Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. Cancer. 2012;118(suppl 8):2237-2249.
27. Kärki A, Simonen R, Mälkiä E, Selfe J. Impairments, activity limitations and participation restrictions 6 and 12 months after breast cancer operation. J Rehabil Med. 2005;37(3):180-188.
28. Katz J, Poleshuck EL, Andrus CH, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain. 2005;119(1-3):16-25.
29. Tasmuth T, von Smitten K, Hietanen P, Kataja M, Kalso E. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol. 1995;6(5):453-459.
30. Whelan TJ, Levine M, Julian J, Kirkbride P, Skingley P. The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Ontario Clinical Oncology Group. Cancer. 2000;88(10):2260-2266.
31. Harrington S, Gilchrist L, Sander A. Breast cancer EDGE task force outcomes: clinical measures of pain. Rehabil Oncol. 2014;32(1):13-21.
Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.1 Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.2 Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.6 In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.7 These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,8 and can progress undetected until pain and upper-limb disability develop.
The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.9,10
The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
Methods
Design
We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
Sample
Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.18
Variables and measures
Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).
Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.16 For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.
Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.
Procedure
The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.
Intervention
The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.20 The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.
By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.
Statistical analysis
Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.
Results
A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).
The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.
Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.
The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.
Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,24 and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.
Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
Discussion
Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.
More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.
Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.
Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,31 but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.
Limitations
Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.
Conclusions
Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.
Acknowledgments
The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.
Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.1 Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.2 Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.6 In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.7 These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,8 and can progress undetected until pain and upper-limb disability develop.
The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.9,10
The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
Methods
Design
We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
Sample
Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.18
Variables and measures
Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).
Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.16 For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.
Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.
Procedure
The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.
Intervention
The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.20 The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.
By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.
Statistical analysis
Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.
Results
A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).
The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.
Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.
The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.
Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,24 and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.
Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
Discussion
Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.
More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.
Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.
Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,31 but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.
Limitations
Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.
Conclusions
Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.
Acknowledgments
The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.
1. World Health Organization. Breast cancer: prevention and control. www.who.int/cancer/detection/breastcancer/en/. Updated 2017. Accessed September 16, 2016.
2. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain. 2011;12(7):725-746.
3. Ernst MF, Voogd AC, Balder W, Klinkenbijl JH, Roukema JA. Early and late morbidity associated with axillary levels I-III dissection in breast cancer. J Surg Oncol. 2002;79(3):151-155; discussion 156.
4. Gulluoglu BM, Cingi A, Cakir T, Gercek A, Barlas A, Eti Z. Factors related to post-treatment chronic pain in breast cancer survivors: the interference of pain with life functions. Int J Fertil Womens Med. 2006;51(2):75-82.
5. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH. Neuropathic pain following breast cancer surgery: proposed classification and research update. Pain. 2003;104(1-2):1-13.
6. Saibil S, Fitzgerald B, Freedman OC, et al. Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey. Curr Oncol. 2010;17(4):42-47.
7. Tengrup I, Tennvall-Nittby L, Christiansson I, Laurin M. Arm morbidity after breast-conserving therapy for breast cancer. Acta Oncol. 2000;39(3):393-397.
8. Johansen J, Overgaard J, Blichert-Toft M, Overgaard M. Treatment of morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol. 2000;39(3):349-354.
9. Mittmann N, Porter JM, Rangrej J, et al. Health system costs for stage-specific breast cancer: a population-based approach. Curr Oncol. 2014;21(6):281-293.
10. Page A. Keeping patients safe: transforming the work environment of nurses. Washington, DC: National Academies Press; 2004.
11. McNeely ML, Campbell K, Ospina M, et al. Exercise interventions for upper-limb dysfunction due to breast cancer treatment. Cochrane Database Syst Rev. 2010;(6):CD005211. doi:10.1002/14651858.CD005211.pub2
12. Wong P, Muanza T, Hijal T, et al. Effect of exercise in reducing breast and chest-wall pain in patients with breast cancer: a pilot study. Curr Oncol. 2012;19(3):e129-e135.
13. Fernández-Lao C, Cantarero-Villanueva I, Fernández-de-Las-Peñas C, del Moral-Ávila R, Castro-Sánchez AM, Arroyo-Morales M. Effectiveness of a multidimensional physical therapy program on pain, pressure hypersensitivity, and trigger points in breast cancer survivors: a randomized controlled clinical trial. Clin J Pain. 2012;28(2):113-121.
14. Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003;21(9):1660-1668.
15. Segal R, Evans W, Johnson D, et al. Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol. 2001;19(3):657-665.
16. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23(2):129-138.
17. Kumar SP. Utilization of Brief Pain Inventory as an assessment tool for pain in patients with cancer: a focused review. Indian J Palliat Care. 2011;17(2):108-115.
18. Van Voorhis CRW, Morgan BL. Understanding power and rules of thumb for determining sample sizes. Tutor Quant Methods Psychol. 2007;3(2):43-50.
19. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61(2):277-284.
20. Lee TS, Kilbreath SL, Refshauge KM, Pendlebury SC, Beith JM, Lee MJ. Pectoral stretching program for women undergoing radiotherapy for breast cancer. Breast Cancer Res Treat. 2007;102(3):313-321.
21. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409-1426.
22. Pollock ML, Gaesser GA, Butcher JD, et al. ACSM position stand: the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc. 1998;30(6):975-991.
23. Ibrahim M, Muanza T, Smirnow N, et al. Time course of upper limb function and return-to-work post-radiotherapy in young adults with breast cancer: a pilot randomized control trial on effects of targeted exercise program. J Cancer Surviv. 2017;11(6):791-799.
24. Ibrahim M, Muanza T, Smirnow N, et al. A pilot randomized controlled trial on the effects of a progressive exercise program on the range of motion and upper extremity grip strength in young adults with breast cancer. Clin Breast Cancer. 2018;18(1):e55-e64.
25. Gärtner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA. 2009;302(18):1985-1992.
26. Hayes SC, Johansson K, Stout NL, et al. Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. Cancer. 2012;118(suppl 8):2237-2249.
27. Kärki A, Simonen R, Mälkiä E, Selfe J. Impairments, activity limitations and participation restrictions 6 and 12 months after breast cancer operation. J Rehabil Med. 2005;37(3):180-188.
28. Katz J, Poleshuck EL, Andrus CH, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain. 2005;119(1-3):16-25.
29. Tasmuth T, von Smitten K, Hietanen P, Kataja M, Kalso E. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol. 1995;6(5):453-459.
30. Whelan TJ, Levine M, Julian J, Kirkbride P, Skingley P. The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Ontario Clinical Oncology Group. Cancer. 2000;88(10):2260-2266.
31. Harrington S, Gilchrist L, Sander A. Breast cancer EDGE task force outcomes: clinical measures of pain. Rehabil Oncol. 2014;32(1):13-21.
1. World Health Organization. Breast cancer: prevention and control. www.who.int/cancer/detection/breastcancer/en/. Updated 2017. Accessed September 16, 2016.
2. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. J Pain. 2011;12(7):725-746.
3. Ernst MF, Voogd AC, Balder W, Klinkenbijl JH, Roukema JA. Early and late morbidity associated with axillary levels I-III dissection in breast cancer. J Surg Oncol. 2002;79(3):151-155; discussion 156.
4. Gulluoglu BM, Cingi A, Cakir T, Gercek A, Barlas A, Eti Z. Factors related to post-treatment chronic pain in breast cancer survivors: the interference of pain with life functions. Int J Fertil Womens Med. 2006;51(2):75-82.
5. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH. Neuropathic pain following breast cancer surgery: proposed classification and research update. Pain. 2003;104(1-2):1-13.
6. Saibil S, Fitzgerald B, Freedman OC, et al. Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey. Curr Oncol. 2010;17(4):42-47.
7. Tengrup I, Tennvall-Nittby L, Christiansson I, Laurin M. Arm morbidity after breast-conserving therapy for breast cancer. Acta Oncol. 2000;39(3):393-397.
8. Johansen J, Overgaard J, Blichert-Toft M, Overgaard M. Treatment of morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol. 2000;39(3):349-354.
9. Mittmann N, Porter JM, Rangrej J, et al. Health system costs for stage-specific breast cancer: a population-based approach. Curr Oncol. 2014;21(6):281-293.
10. Page A. Keeping patients safe: transforming the work environment of nurses. Washington, DC: National Academies Press; 2004.
11. McNeely ML, Campbell K, Ospina M, et al. Exercise interventions for upper-limb dysfunction due to breast cancer treatment. Cochrane Database Syst Rev. 2010;(6):CD005211. doi:10.1002/14651858.CD005211.pub2
12. Wong P, Muanza T, Hijal T, et al. Effect of exercise in reducing breast and chest-wall pain in patients with breast cancer: a pilot study. Curr Oncol. 2012;19(3):e129-e135.
13. Fernández-Lao C, Cantarero-Villanueva I, Fernández-de-Las-Peñas C, del Moral-Ávila R, Castro-Sánchez AM, Arroyo-Morales M. Effectiveness of a multidimensional physical therapy program on pain, pressure hypersensitivity, and trigger points in breast cancer survivors: a randomized controlled clinical trial. Clin J Pain. 2012;28(2):113-121.
14. Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003;21(9):1660-1668.
15. Segal R, Evans W, Johnson D, et al. Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol. 2001;19(3):657-665.
16. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23(2):129-138.
17. Kumar SP. Utilization of Brief Pain Inventory as an assessment tool for pain in patients with cancer: a focused review. Indian J Palliat Care. 2011;17(2):108-115.
18. Van Voorhis CRW, Morgan BL. Understanding power and rules of thumb for determining sample sizes. Tutor Quant Methods Psychol. 2007;3(2):43-50.
19. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61(2):277-284.
20. Lee TS, Kilbreath SL, Refshauge KM, Pendlebury SC, Beith JM, Lee MJ. Pectoral stretching program for women undergoing radiotherapy for breast cancer. Breast Cancer Res Treat. 2007;102(3):313-321.
21. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409-1426.
22. Pollock ML, Gaesser GA, Butcher JD, et al. ACSM position stand: the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc. 1998;30(6):975-991.
23. Ibrahim M, Muanza T, Smirnow N, et al. Time course of upper limb function and return-to-work post-radiotherapy in young adults with breast cancer: a pilot randomized control trial on effects of targeted exercise program. J Cancer Surviv. 2017;11(6):791-799.
24. Ibrahim M, Muanza T, Smirnow N, et al. A pilot randomized controlled trial on the effects of a progressive exercise program on the range of motion and upper extremity grip strength in young adults with breast cancer. Clin Breast Cancer. 2018;18(1):e55-e64.
25. Gärtner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA. 2009;302(18):1985-1992.
26. Hayes SC, Johansson K, Stout NL, et al. Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. Cancer. 2012;118(suppl 8):2237-2249.
27. Kärki A, Simonen R, Mälkiä E, Selfe J. Impairments, activity limitations and participation restrictions 6 and 12 months after breast cancer operation. J Rehabil Med. 2005;37(3):180-188.
28. Katz J, Poleshuck EL, Andrus CH, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain. 2005;119(1-3):16-25.
29. Tasmuth T, von Smitten K, Hietanen P, Kataja M, Kalso E. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol. 1995;6(5):453-459.
30. Whelan TJ, Levine M, Julian J, Kirkbride P, Skingley P. The effects of radiation therapy on quality of life of women with breast carcinoma: results of a randomized trial. Ontario Clinical Oncology Group. Cancer. 2000;88(10):2260-2266.
31. Harrington S, Gilchrist L, Sander A. Breast cancer EDGE task force outcomes: clinical measures of pain. Rehabil Oncol. 2014;32(1):13-21.
Rural cancer patients report faster care than urban counterparts
in a survey of 6,826 Medicare beneficiaries.
Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.
“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”
In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.
The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.
Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.
For both composites, mean scores for urban and rural locations were greater than 85 out of 100.
In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.
Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.
“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”
The authors had no disclosures to report.
SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.
in a survey of 6,826 Medicare beneficiaries.
Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.
“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”
In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.
The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.
Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.
For both composites, mean scores for urban and rural locations were greater than 85 out of 100.
In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.
Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.
“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”
The authors had no disclosures to report.
SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.
in a survey of 6,826 Medicare beneficiaries.
Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.
“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”
In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.
The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.
Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.
For both composites, mean scores for urban and rural locations were greater than 85 out of 100.
In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.
Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.
“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”
The authors had no disclosures to report.
SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.
FROM CANCER
Key clinical point: Cancer patients living in rural areas reported more timely care than urban patients.
Major finding: In a Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey, urban patients rated “Getting Care Quickly” 2.27 points lower than rural patients (P = .02).
Study details: A retrospective study of 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. CAHPS patient experience surveys were conducted between 1998 and 2013, then linked with Surveillance, Epidemiology, and End Results data.
Disclosures: The authors had no disclosures to report.
Source: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.