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Hydroxyurea-induced palmar-plantar erythrodysesthesia in an adult with sickle cell disease

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Ramandeep K. Bambrah, MD

Fauzia Rana, MD

Dat C. Pham, MD

Sickle cell disease consists of hemolytic anemia and episodes of vaso-occlusion, which are caused by sickling of red blood cells (RBCs) precipitated by deoxygenation. The change in shape of the RBCs is what causes vascular occlusion, leading to acute sickle crisis.

Hydroxyurea has been approved by the US Food and Drug Administration for the treatment of adult patients with clinically severe disease. Hydroxyurea blocks DNA synthesis via enzymatic inhibition of ribonucleotide reductase.1 Administration of hydroxyurea is associated with an increase in HbF (fetal hemoglobin) levels,2 thereby reducing the severity of vaso-occlusive crises, acute pain, acute chest syndrome, transfusion requirements, and hospitalizations. 3 As a cytotoxic, cell cycle–specific agent, hydroxyurea is associated with several adverse reactions, namely bone marrow suppression.4 Other side effects associated with hydroxyurea use include gastrointestinal upset, mild dermatologic reactions, alopecia, and leg ulcers.

The case study presented here focuses on an adult with sickle cell disease who complained of painful discoloration and edema of his hands and feet with blisters about 1 week after starting hydroxyurea therapy.

Case presentation

A 50-year-old black man with a history of atrial fibrillation, avascular necrosis of the shoulder, and sickle cell disease had frequent hospitalizations for acute crises requiring multiple packed RBC transfusions. He had no known history of leukemia/ lymphoma or exposure to other cytotoxic drugs. The patient was placed on hydroxyurea to reduce the frequency of sickle cell crises. Once hydroxyurea was begun, the patient noticed a decrease in acute pain and improvement in his general well-being.

Approximately 1 week after initiation of hydroxyurea therapy, the patient started noticing darkening of his hands. Two weeks later, hyperpigmentation of the palmar creases was noted. Three weeks after hydroxyurea was started, the patient had edema and blisters of his hands and feet with associated desquamation. Symptoms were severe and painful and interfered with activities of daily living (Figure 1). The patient’s fingers were so swollen that he was unable to make a fist. His feet were so edematous that it was difficult to walk. After these signs of hand-foot syndrome developed, his hematologist discontinued hydroxyurea, and the edema and pain gradually improved. Three months after hydroxyurea discontinuation, the edema and erythema had resolved, but the patient still had some hyperpigmentation.

Discussion

Palmar-plantar erythrodysesthesia, also known as hand-foot syndrome or acral erythema, is a known adverse reaction of several antineoplastic medications, although few published articles mention hand-foot syndrome as a common adverse effect of hydroxyurea therapy.3–5 The incidence of hand-foot syndrome in patients being treated with 5-fluorouracil, capecitabine (Xeloda), or liposomal doxorubicin (Doxil) ranges from 7% to 63%.6 It is a known adverse event of hydroxyurea therapy, although its exact frequency has not been established.

In a study examining mucocutaneous changes in 158 patients with chronic myeloid leukemia (CML) and long-term hydroxyurea therapy, 21 had severe changes and acral erythema.7 In these CML patients acral persistent erythema involved palmar, plantar, and facial areas, with less frequent involvement of the scrotum. 7 Symptoms were described as a burning sensation associated with redness, scaling, and fissuring.7 Acral erythema was noted to disappear gradually after studies are needed to further support this use.6 Another agent to consider for hand-foot syndrome is topical 99% dimethyl sulfoxide (DMSO). Case descriptions have reported improvement with DMSO in soft-tissue damage and edema in patients being treated with liposomal doxorubicin.8

In conclusion, hand-foot syndrome is a potentially reversible condition that is a common complication of certain chemotherapeutic drugs. However, it is not frequently reported with the use of hydroxyurea in adult patients with sickle cell disease.

References

1. Navarra P, Preziosi P. Hydroxyurea: new insights on an old drug. Crit Rev Oncol Hematol 1999;29:249–255.
2. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood 1997;89:1078–1088.
3. Kovacic P. Hydroxyurea (therapeutics and mechanism): metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling, and clinical applications. Med Hypotheses 2011;76:24–31.
4. Singh H, Dulhani N, Kumar BN, Singh P, Tiwari P. Effective control of sickle cell disease with hydroxyurea therapy. Indian J Pharmacol 2010;42:32–35.
5. Steinberg MH, McCarthy WF, Castro O, et al; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients’ Follow-Up. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 2010;85:403–408.
6. Clark AS, Vahdat LT. Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome: etiology and emerging therapies. Support Cancer Ther 2004;1:213–218.
7. Vassallo C, Passamonti F, Merante S, et al. Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia. Clin Exp Dermatol 2001;26:141–148.
8. Lopez AM, Wallace L, Dorr RT, Koff M, Hersh EM, Alberts DS. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol 1999;44:303–306.

ABOUT THE AUTHORS

Affiliations: Dr. Bambrah is a medical resident; Dr. Rana is Assistant Professor of Medicine and Chief, Division of Hematology and Medical Oncology; and Dr. Pham is Assistant Professor of Medicine and Program Director for Medical Oncology, University of Florida College of Medicine, Jacksonville, FL. Conflicts of interest: The authors have nothing to disclose.

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Read more about Hydroxyurea-induced palmar-plantar erythrodysesthesia in an adult with sickle cell disease

Author(s)

Ramandeep K. Bambrah, MD

Fauzia Rana, MD

Dat C. Pham, MD

Author(s)

Ramandeep K. Bambrah, MD

Fauzia Rana, MD

Dat C. Pham, MD

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ABOUT THE AUTHORS

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Hydroxyurea-induced palmar-plantar erythrodysesthesia in an adult with sickle cell disease

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Combining sorafenib with chemoembolization for hepatocellular cancer

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Jeffrey J. Critchfield, MD

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Combining sorafenib with chemoembolization for hepatocellular cancer

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Minsig Choi, MD

Philip A. Philip, MD, PhD, FRCP

The incidence of hepatocellular carcinoma (HCC) has increased over the past decade, with an estimated 1 million new cases per year worldwide. In 2010 in the United States alone, it was expected that over 24,000 new cases would be diagnosed, with approximately 19,000 deaths.1 The incidence of HCC in the Western world is expected to rise until 2020 because of the large population of patients infected with the hepatitis C virus. 2 Furthermore, epidemiologic data suggest that many patients with cryptogenic cirrhosis have nonalcoholic steatohepatitis (NASH) as the cause of their chronic liver disease.3 Due to the rise in obese patient populations, NASH could be an important risk factor for patients with cirrhosis.

Surgical resection and liver transplantation are the preferred treatments of HCC, because they both are potentially curative. Unfortunately, only 10%–15% of patients are candidates for either of these approaches.4 Patients with liver-limited disease who are not candidates for liver transplantation or resection may be managed by liver-directed therapies. Common treatment modalities include ablation (eg, microwave ablation, radiofrequency ablation, and cryoablation), chemoembolization, and radioembolization.

Systemic therapy for HCC

HCC is considered a chemotherapy-resistant malignancy. Systemic chemotherapy approaches have been ineffective in patients with HCC, with increased toxicities.5 However, the introduction of sorafenib (Nexavar) has changed the landscape of systemic therapy for HCC and opened up opportunities for development of new drug regimens and multidisciplinary approaches in the treatment of those patients. Sorafenib is a smallmolecule kinase inhibitor that blocks multiple intracellular and cell-surface kinases (KIT, FLT3, RET, VEGFR- 1, VEGFR-2, VEGFR-3, and PDGFR- b) involved in cell signaling, angiogenesis, and apoptosis.6

In two large international studies (SHARP and Asia-Pacific) in patients with advanced HCC, sorafenib showed improvement in time to tumor progression (TTP) as well as in overall survival compared with placebo.7,8 Patients in these two studies had a Child-Pugh classification of A and a favorable performance status. The hypervascularity of HCC and the predominant effect of sorafenib of vascular endothelial growth factor receptor (VEGFR)-related tyrosine kinase activity provided the proof of principle for targeting angiogenesis in this disease.

In the multicenter, phase III, double-blinded, placebo-controlled SHARP trial,7 602 patients with advanced HCC who had not received previous systemic treatment were given either sorafenib (400 mg twice daily) or placebo. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group.7 In 2007, sorafenib was granted US Food and Drug Administration approval for the treatment of patients with advanced HCC.

Overview of chemoembolization

Transarterial chemoembolization (TACE) is the most widely used approach in the palliative setting and in some patients considered for liver transplantation. Embolization of the hepatic artery and its branches causes ischemic necrosis in the tumor cells that derive their blood supply predominantly from the hepatic artery. In contrast, the normal liver parenchyma is fed primarily by the portal system. The additional mechanism of action of chemoembolization is the trapping of cytotoxic agents within the embolized tissue. This process occurs because the lipiodol, which is used in most regimens, flows through the malignant tissues and parenchyma to obstruct portal vein inflow and hepatic vein washout, whereas particulate material employed near the end of the embolization procedure acts by entrapping the agents through blocking the hepatic arterial supply inflow.

Doxorubicin is the most commonly used cytotoxic drug in conjunction with embolization. Other agents used include mitomycin C and cisplatin. Partial responses in the range of 20%– 50% have been reported in the literature. 9,10 Two randomized trials and meta-analyses of chemoembolization in approximately 500 patients showed clinical benefit of this approach when compared with conservative management in patients with HCC.9,10 These patients were not candidates for either resection or transplantation.

Mild systemic toxicity continues to be an advantageous part of chemoembolization. Although upward of 90% of patients experience the symptoms of postembolization syndrome, which include fever, nausea, vomiting, and abdominal pain, they are generally self-limited and confined to the immediate acute postprocedure period. More serious toxicities such as anemia, liver decompensation, and infection (including cholecystitis) are rare and mostly encountered in patients with more advanced disease.11

Rationale for combining sorafenib with TACE

Treatment with TACE alone causes necrosis of tumor tissue, with transient elevations of levels of many angiogenic growth factors (such as VEGF and plasma insulin-like growth factor 2 [IGF-2]).12,13 High expression of stem cell likeness and tumor angiogenesis results in a poor prognosis. 14,15 Emerging clinical data also suggest that increased VEGF levels post TACE may be associated with an increased chance of disease progression. 16 These angiogenic factors may be responsible for the limited longterm benefit of TACE seen in patients with HCC. Therefore, the combination of sorafenib with TACE may have the potential to improve clinical outcomes in patients with HCC by blocking this angiogenic signaling activated by the chemoembolization.

Current status of studies combining sorafenib with TACE

Multiple clinical trials in the United States and around the world are examining this novel approach in treating patients with HCC (Table 1). Chung and colleagues presented the interim analysis of a phase II trial using the combination of sorafenib and TACE in patients with unresectable HCC at the 2010 American Society of Clinical Oncology meeting.17 Eligibility criteria included intermediate stage of HCC (BCLC stage B) and a Child-Pugh score ≤ 7 in candidates for TACE therapy. The objective of the study was to evaluate the safety and efficacy of sorafenib after TACE.

Patients were treated with sorafenib (400 mg twice daily initiated on day 4) after the first TACE treatment (day 1). Sorafenib was interrupted 4 days before TACE and 4 days after the next TACE treatment. TACE was performed using lipiodol and doxorubicin (30–60 mg), for a maximum of 6 cycles. A computed tomography (CT) scan of the abdomen and serum alpha-fetoprotein (AFP) measurements were performed 4 weeks after each TACE procedure. Patients remained on sorafenib and underwent CT and AFP analysis every 3 months.

Preliminary data suggest that this approach is feasible, with expected side effects including hand-foot syndrome, fatigue, and neutropenia. Among the 50 patients who had at least two tumor assessments and were available for efficacy analysis, 18 patients (36%) achieved a complete response (CR), 30 patients (60%) had a partial response (PR) or stable disease (SD), and 2 patients (4%) had progressive disease.12

Another multicenter, phase II study was conducted by Erhardt and colleagues. 18 This study also investigated the combination of sorafenib and TACE for the treatment of HCC. Eligibility criteria were similar to the previous study. The primary study endpoint was TTP. Enrolled in the study were 44 patients, with a mean age of 67 years. The majority of patients had Child-Pugh A status (87%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (79%). Disease etiology included hepatitis C (21%) and hepatitis B (23%), respectively.

Patients were treated with sorafenib (400 mg twice daily continuously), starting 2 weeks before the first TACE procedure. Sorafenib was stopped at least 3 days prior to TACE and could be resumed 1 day after improvement in liver function. TACE was performed using lipiodol and 50 mg of doxorubicin and was repeated at 6-week intervals if necessary. Patients received a mean of two TACE procedures (range, 1–10) and were treated for 6 cycles (range, 1–20).

TTP was estimated to be 491 days, progression-free survival was 242 days, and overall survival was estimated to be 356 days.18 Thirty-one patients received at least one TACE procedure and were evaluable for response. The disease control rate was 90% (28 of 31 patients), according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria.

A large phase III study of sorafenib in patients who had responded to prior TACE was reported by Okita et al.19 A total of 552 patients with advanced HCC received TACE and were assessed by CT scan for response. Those who responded to TACE were stratified according to the type of response (CR vs non-CR), ECOG perperformance status (0 vs 1), and number of prior TACE procedures (1 vs 2) and randomized in a 1:1 ratio to receive either sorafenib (n = 229) or placebo (n = 229). The median time from TACE to receiving sorafenib was 9.3 weeks. The most common adverse events were hand-foot syndrome and elevated lipase levels.

In the analysis of the data, the median TTP was 5.4 months in the sorafenib group versus 3.7 months in the placebo group (hazard ratio [HR] = 0.87; P = 0.252). The median overall survival was 29.7 months in the sorafenib group and had not been reached (due to immaturity of the data) in the placebo group (HR = 1.06; P = 0.790).19 Hence, the addition of sorafenib did not significantly prolong the median TTP or overall survival in patients with HCC who had previously responded to TACE. The study was criticized on a number of accounts, including the delay in initiation of sorafenib and the relatively short duration of its use in most patients. Exploratory subgroup analysis showed that clinical benefit was noted in a younger Korean population.

More to learn from ongoing clinical trials

Currently, there are several multicenter clinical trials investigating the benefit of adding sorafenib to chemoembolization in patients with advanced HCC. SPACE is a multinational, randomized, double-blind, placebo-controlled study in patients with intermediate- stage HCC (BCLC stage B; defined as the presence of asymptomatic, unresectable, multinodular tumors without vascular invasion or extrahepatic spread). Major eligibility also includes Child-Pugh class A status without ascites. Eligible patients undergoing TACE with doxorubicin-eluting beads (loaded with 150 mg of doxorubicin) are randomized 1:1 to receive sorafenib (400 mg twice daily) or matching placebo orally on a continuous basis. Treatment cycles are repeated every 4 weeks until disease progression. TACE is performed on day 1 of cycles 1, 3, 7, and 13 and every 6 cycles thereafter. All endpoints will be assessed on an intent-to-treat analysis. The primary study endpoint is TTP. Secondary endpoints are overall survival, time to untreatable tumor progression, time to vascular invasion/extrahepatic tumor spread, and safety. Estimated overall accrual is 300 patients.

The HeiLivCa study,20 ECOG 1208, and the TACE-2 study are also addressing similar questions with slightly different patient populations. For example, the open ECOG 1208 study randomizes patients to receive sorafenib or placebo in conjunction with TACE and allows the interventionalist to choose one of a few different chemoembolization methods. Liver-directed therapy can take the form of conventional TACE, using the mixture of doxorubicin, mitomycin, and cisplatin described previously. However, embolization may also be completed by employing conventional Ethiodol (ethiodized oil) TACE, using only doxorubicin or doxorubicin-loaded beads. This varied approach may provide an analytic advantage, because the design better mirrors what is happening at institutions around the world.

The optimal scheduling of sorafenib in relation to TACE has yet to be determined, but with these trials, the elucidation of combination therapy will be discovered. For instance, the TACE-2 trial is not only comparing drug-eluting beads with and without sorafenib but is also additionally randomizing patients into two arms. One arm starts sorafenib or placebo at day 0, whereas the other arm begins with sorafenib or placebo at day 7 after TACE (2–5 weeks post randomization). This study will help to clarify the timing of combination therapy for HCC.

Conclusion

With increased angiogenic factors following embolization and the emergence of specific agents to target those factors, a potential benefit of targeting angiogenesis as an adjunct to TACE may be expected. Although the rationale is sound and safety has been demonstrated in preliminary studies,21,22 using sorafenib in patients with HCC receiving chemoembolization is not yet recommended outside the clinical trial setting. Over the coming years, efficacy data from ongoing randomized studies will be available. It is best to support the current ongoing clinical trials so we may reach a definitive answer. With the increasing awareness among community oncologists and their participation in clinical trials, we should be able to optimize the use of sorafenib in combination with TACE and extend its use in conjunction with other locoregional therapies.

References

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
2. El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230.
3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664–669.
4. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol 2004;7:431–441.
5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907– 1917.
6. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/ PRF/5. Cancer Res 2006;66:11851–11858.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinomacarcinoma. N Engl J Med 2008;359:378–390.
8. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.
9. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–442.
10. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002;224:47–54.
11. Leung DA, Goin JE, Sickles C, Raskay BJ, Soulen MC. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol 2001;12:321–326.
12. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914–921.
13. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878–2882.
14. Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010;59:953–962.
15. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein- negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 2009;135:1359–1367.
16. Xiong ZP, Yang SR, Liang ZY, et al. Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2004;3:386–390.
17. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transarterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma trial (START): second interim safety and efficacy analysis. J Clin Oncol 2010;28[15S]:4026.
18. Erhardt A, Kolligs FT, Dollinger MM, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30–November 3, 2009; Boston, MA.
19. Okita K, Imanaka K, Chida N, et al. Phase III study of sorafenib in patients in Japan and South Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE). Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract LBA128.
20. Hoffmann K, Glimm H, Radeleff B, et al. Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation–HeiLivCa [ISRCTN24081794]. BMC Cancer 2008;8:349.
21. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): interim safety and efficacy analysis. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract 254.
22. Valenti DA, Cabrera T, Khankan A, et al. Combined sorafenib and yttrium-90 radioembolization in the treatment of advanced HCC: preliminary results. J Vasc Interv Radiol 2009;20(suppl):S65–S66. Abstract 169.

ABOUT THE AUTHORS

Affiliations: Dr. Choi is Assistant Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI. Dr. Critchfield is Assistant Professor of Radiology and Chief of Interventional Oncology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI. Dr. Philip is Professor of Medicine, Wayne State University School of Medicine, and Clinical Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI. Conflicts of interest: The authors have no conflicts of interest to disclose.

¹ Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, and ² Department of Radiology, Section of Interventional Radiology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI

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Systemic therapy for HCC

Overview of chemoembolization

Rationale for combining sorafenib with TACE

Current status of studies combining sorafenib with TACE

More to learn from ongoing clinical trials

Conclusion

References

ABOUT THE AUTHORS

Systemic therapy for HCC

Overview of chemoembolization

Rationale for combining sorafenib with TACE

Current status of studies combining sorafenib with TACE

More to learn from ongoing clinical trials

Conclusion

References

ABOUT THE AUTHORS

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Publications

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Update on romiplostim therapy for immune thrombocytopenic purpura

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Update on romiplostim therapy for immune thrombocytopenic purpura

Thrombopoietin mimetic is superior to standard of care in adults with immune thrombocytopenic purpura (ITP) and demonstrates activity and tolerability in pediatric ITP patients

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Matt Stenger, MS

Romiplostim (Nplate) is a thrombopoietin receptor agonist that is currently indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. In a recently reported phase III trial,1 romiplostim treatment was associated with a number of benefits compared with the standard of care in nonsplenectomized ITP patients: higher platelet response rate, lower rates of treatment failure and splenectomy, fewer bleeding events, and fewer blood transfusions.

The safety and efficacy of romiplostim in children with ITP have not yet been established. A recently reported placebo-controlled trial indicates good response and good tolerability of romiplostim in children with chronic refractory ITP.2

Romiplostim versus standard of care in adult nonsplenectomized patients

In a 52-week, multicenter, openlabel trial,1 patients with ITP who had not undergone splenectomy, had received at least one prior treatment for ITP, and had a platelet count of less than 50 × 109/L were randomized to receive weekly SC injections of romiplostim (n = 157) or standard-ofcare treatment (n = 77). Romiplostim was started at a dose of 3 μg/kg, which could be increased up to a maximum of 10 μg/kg to achieve a target platelet count of 50–200 × 109/L. Standardof- care treatment was selected by the treating physician based on standard institutional practices or therapeutic guidelines. Throughout the study, patients in either treatment group could receive additional therapies for ITP, including short-term rescue therapy, such as IV immune globulin (IVIG), but excluding other thrombopoietin mimetics, as deemed medically necessary by investigators.

Study population, endpoints, other treatments

The median ages of patients in the romiplostim and standard-of-care groups were 58 and 57 years, respectively; 54% and 60% were women; the median duration since ITP diagnosis was 2.1 and 2.3 years; baseline median platelet counts were 33 × 109/L and 27 × 109/L; and 13% and 6% were receiving medications, primarily glucocorticoids (11% and 3%), for ITP at baseline. Splenectomy could be performed if study therapy was considered to be ineffective or was associated with severe side effects.

The primary endpoints of the trial were the incidence of splenectomy and the incidence of treatment failure, with treatment failure defined as a platelet count of 20 × 109/L or lower for 4 consecutive weeks, a major bleeding event, or a requirement for a change in therapy (including splenectomy) due to an adverse event or bleeding. In primary endpoint analyses, patients who received any study treatment and then discontinued study participation were counted as having both treatment failure and splenectomy.

During the study, ITP treatments other than romiplostim were received by 44% of patients in the romiplostim group and 79% of patients in the standard- of-care group, including glucocorticoids in 37% versus 63%, IVIG in 7% versus 33%, rituximab (Rituxan) in 1% versus 20%, azathioprine in 1% versus 9%, danazol in 2% versus 7%, other medications in 6% versus 19%, and platelet transfusions in 6% versus 16%.

Efficacy

The incidence of treatment failure was 11% in the romiplostim group versus 30% in the standard-of-care group (P < 0.001). Time to treatment failure was significantly prolonged in the romiplostim group (Figure 1a). The incidence of splenectomy was 9% in the romiplostim group versus 36% in the standard-of-care group (P < 0.001), and time to splenectomy was significantly prolonged in the include bleeding, thrombosis, hematologic cancer or myelodysplastic syndromes, and increased bone marrow reticulin.

After adjustment for duration of study-drug exposure, the romiplostim group had significantly fewer incidences of overall bleeding (P = 0.001) and grade 3 or higher bleeding (P = 0.02); no significant difference between the two treatment groups was observed for less severe bleeding. Overall, 260 bleeding events occurred in 80 patients (52%) in the romiplostim group, for a bleeding rate of 3.56 events/100 patient-weeks; 153 events occurred in 40 patients (53%) in the standard-of-care group, for a rate of 5.02 events/100 patient-weeks. Eight grade 3 or higher bleeding events occurred in five romiplostim-treated patients (3%), a rate of 0.11 events/100 patient weeks; 10 events occurred in five patients (7%) in the standard-ofcare group, a rate of 0.33 events/100 patient-weeks.

A total of 41 blood transfusions were given to 12 patients (8%) in the romiplostim group, whereas a total of 76 transfusions were given to 13 patients (17%) in the standard-of-care group. There was no significant difference between the two groups with regard to the occurrence of thrombotic events. A total of 11 thrombotic events occurred in six patients (4%) in the romiplostim group, yielding a rate of 0.15 events/100 patientweeks, whereas two events occurred in two patients (3%) in the standardof- care group, yielding a rate of 0.07 events/100 patient-weeks.

Two cases of hematologic cancer were observed, consisting of lymphoma and myelodysplastic syndrome in one patient each in the standard-ofcare group. Bone marrow reticulin was found in one romiplostim-treated patient during 6 months posttreatment follow up, with the level being within the normal range (grade 2).

Thrombopoietin mimetics challenge the conventional wisdom about controlling ITP

Chronic immune thrombocytopenic purpura (ITP) affects 60,000 adults in the United States and is associated with the risk of life-threatening hemorrhage. For decades, the standard treatments included glucocorticoids and splenectomy. The advent and subsequent regulatory approval of the thrombopoietin mimetics romiplostim (Nplate) and eltrombopag (Promacta) have not only added to the therapeutic arsenal for this orphan disease but also successfully challenged the conventional wisdom that the key to controlling ITP is to reduce platelet destruction. Instead, these agents work by increasing intramedullary platelet production and are thus able to outpace the rate of peripheral destruction.

As reported by Kuter and colleagues last November in The New England Journal of Medicine, romiplostim is safe, well tolerated, and highly effective in the adult population with chronic ITP, including individuals with an intact spleen. Among the remaining questions regarding its use are: Where in the sequence of treatments for ITP do thrombopoietin mimetics belong? What is the long-term safety of these agents, given the changes to the bone marrow microenvironment that they induce? And, what will the cost impact be of a treatment that is designed for disease maintenance as opposed to providing a cure.

Thrombopoietin mimetics have not been widely tested for the treatment of pediatric ITP. Two small trials have shown that in children with disease that has been refractory to all standard approaches (with the exception of splenectomy), romiplostim is well tolerated, effective, and results in a meaningful reduction of clinically significant bleeding episodes. These data are preliminary but nevertheless provocative, and they offer the potential for new hope to children with chronic refractory ITP. Additional experience will be required to prove long-term safety and tolerability in the pediatric population before these new agents will be adopted into standard practice.

— David M.J. Hoffman, MD, FACP
Tower Hematology Oncology Medical Group
Beverly Hills, CA

Three deaths occurred during the study treatment period, including one death due to pneumonia in one romiplostim-treated patient and two deaths due to hepatic failure and cardiorespiratory arrest, respectively, in two patients in the standard-of-care group. Three additional deaths due to metastatic lung cancer, left ventricular failure, and hepatic neoplasm occurred in the standard-of-care group during the 6-month posttreatment follow up. None of the deaths was attributed to study treatment. No neutralizing antibodies to romiplostim or thrombopoietin were detected.

Quality of life

Quality of life was assessed by the ITP Patient Assessment Questionnaire, consisting of 44 ITP-specific items on each of 10 scales ranging from 0 to 100 points each (with higher scores indicating better quality of life). Scores on two scales (Women’s Reproductive Health and Work Quality of Life) could not be assessed due to inadequacies of the statistical model used in the analysis. Of the eight scales assessed, clinically significant increases of 8–15 points were observed for both treatment groups on all but the Fatigue scale. The romiplostim treatment group showed statistically greater improvements on the Symptoms (P = 0.01), Bother (P = 0.008), Activity (P = 0.02), Psychological (P = 0.049), Fear (P < 0.001), Social Quality of Life (P = 0.002), and Overall Quality of Life (P = 0.02) scales compared with the standard-of-care group, although the between-group differences of 2–8 points on these scales are of uncertain clinical significance.

Romiplostim in children with chronic refractory ITP

Few data exist on the effects of romiplostim therapy in pediatric ITP patients. In a recent single-blind, placebo-controlled trial,2 18 patients aged 2.5 to 16 years with chronic refractory ITP (baseline platelet count < 20 × 109/L) who had not undergone splenectomy were randomized to receive weekly SC injections of romiplostim (n = 12) or placebo (n = 6) for 12 weeks. Romiplostim was started at a dose of 1 μg/kg, escalated to 5 μg/kg at 5 weeks, and tapered afterward.

All patients had either no response or failed to maintain a response to at least two prior treatment modalities for ITP. All had received prior steroid treatment; 44% had received corticosteroids, IVIG, and anti-D immunogloblin in combination or sequentially; and 22% had received cytotoxic or immune-modulating agents. All such treatments were stopped 2 weeks prior to the study.

For patients in the romiplostim versus placebo group, mean age was 9.5 versus 7.0 years, 10 (83%) versus 3 (50%) were male, and median disease duration was 2.3 versus 3.0 years. Median baseline platelet counts were 10.5 × 109/L in both groups.

The median platelet count in the romiplostim group was significantly higher (P = 0.039) than that in the placebo group within 1 week of the first dose of romiplostim (1 μg/kg) and remained so at 3 weeks after the end of treatment (15 weeks total; median platelet count of 47.5 × 109/L vs 19.0 × 109/L; P = 0.001). Changes in platelet count in the romiplostim group were dose-dependent, with a median peak platelet count of 73.5 × 109/L reached after 5 weeks, when the dose was 5 μg/kg. Eleven of the 12 patients in the romiplostim group (93%) reached the target range of greater than 50 × 109/L by the fifth week. At week 12 (end of treatment), 10 romiplostim patients (83%) versus no placebo patients were at target levels. Six romiplostim-treated patients (50%) maintained target platelet count levels at 3 weeks after treatment.

Adverse events occurred in 50% of patients in each group. The most frequent adverse events were headache, epistaxis, cough, and vomiting, which occurred in one patient each in the romiplostim group (8%) and placebo group (17%). Two romiplostim-treated patients (17%) developed a skin rash. None of the patients had thrombocytosis or rebound thrombocytopenia, and none of the romiplostim-treated patients developed bone marrow fibrosis by week 18 of follow up.

How I treat ITP Immune thrombocytopenic purpura (ITP) and its associated problems are frequently encountered by the practicing hematologist. When it comes treatment, there are several options:

If the platelet count is at least 30,000/μL and there is no active bleeding, close observation is the most prudent approach. In anticipation of the possibility of splenectomy at some point in their course, patients are offered immunization against Streptococcus pneumoniae, Hemophilus influenza, and Neisseria meningitides. In addition, I screen for exposure to hepatitis B virus (HBV), because patients may at some point receive treatment with rituximab (Rituxan), which is associated with HBV reactivation.
For patients with a platelet count below 30,000/μL, evidence of impending bleeding (such as wet purpura), or frank bleeding, treatment is indicated. Typically, this involves the use of glucocorticoids, often in combination with IV gamma globulin (IVIG) or, occasionally, anti-D immunoglobulin.
For a platelet count below 10,000/μL, I give methylprednisolone, 1,000 mg/d IV, for 5 consecutive days with IVIG, 1 g/kg daily, for 2 consecutive days. I then shift the patient to oral prednisone, 1 mg/kg daily, for 1 week, followed by tapering the dose by 10 mg/wk, as allowed by the platelet count, which should remain at ≥ 30,000/μL. Failure of this approach, or the inability to reduce the prednisone dose to 10 mg/d or less, would raise the options of either giving rituximab, 375 mg/m2 per week, for 4 weeks or performing a therapeutic, laparoscopic-assisted splenectomy, the single intervention still the most likely to provide meaningful, long-lasting benefit.
In the setting of asplenia (including the absence of accessory splenic tissue), I favor a trial of a thrombopoietin mimetic, either romiplostim (Nplate) or eltrombopag (Promacta).

In the truly refractory patient, other options include calcineurin inhibitors, cytotoxic agents, danazol, tumor necrosis factor-alpha inhibitors, and staphylococcal A column immunoadsorption.

— David M.J. Hoffman, MD, FACP

Rescue medication, consisting of IVIG 1 g/kg for two doses, was given to one romiplostim-treated patient (8%) due to head trauma and loss of consciousness and two placebo-treated patients (33%) during the 12-week study period, with no interruption of study drug being required. The number of romiplostim-treated patients with grade 3 bleeding decreased from four (33%) prior to the study to none during the study, and the number with grade 2 bleeding decreased from six (50%) to two (17%; P = 0.002).

These findings are similar to results observed in another small study of romiplostim in children with ITP.3,4 An open-label phase III study designed to study the long-term safety of romiplostim and the durability of platelet responses to the drug in pediatric patients currently is in the recruitment stage.5 In this extension trial, approximately 20 patients aged 1 to 18 years with ITP are to receive weekly SC injections of romiplostim, starting at 1 μg/kg (or prior dose) and escalated to 10 μg/kg (based on the platelet count) over a period of 3 years. The primary outcome measure is the incidence of adverse events, including significant changes in laboratory values and the incidence of antibody formation. Secondary outcome measures include the platelet response (> 50 × 109/L) in the absence of rescue medication and the need for concurrent ITP medication (corticosteroids, danazol, or azathioprine) over the duration of the study.

References

1. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889–1899.
2. Elalfy MS, Abdelmaksoud AA, Eltonbary KY. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study. Ann Hematol 2011;doi10.1007/s00277- 011-1172-9.
3. Buchanan GR, Bomgaars L, Bussel JB, et al. A randomized, double-blind, placebo-controlled phase 1/2 study to determine the safety and efficacy of romiplostim in children with chronic immune (idiopathic) thrombocytopenic purpura (ITP). Blood 2009;114(22):680.
4. Safety and efficacy study of AMG 531 to treat ITP in pediatric subjects. ClinicalTrials. gov Web site. http://clinicaltrials.gov/ct2/ show/NCT00515203. Accessed May 12, 2011.
5. A study evaluating the safety and efficacy of long-term dosing of romiplostim in thrombocytopenic pediatric subjects with immune (idiopathic) thrombocytopenia purpura. ClinicalTrials. gov Web site. http://clinicaltrials. gov/ct2/show/study/NCT01071954. Accessed May 12, 2011.

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Matt Stenger, MS

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Matt Stenger, MS

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Thrombopoietin mimetic is superior to standard of care in adults with immune thrombocytopenic purpura (ITP) and demonstrates activity and tolerability in pediatric ITP patients

Romiplostim versus standard of care in adult nonsplenectomized patients

Study population, endpoints, other treatments

Efficacy

Thrombopoietin mimetics challenge the conventional wisdom about controlling ITP

Quality of life

Romiplostim in children with chronic refractory ITP

How I treat ITP Immune thrombocytopenic purpura (ITP) and its associated problems are frequently encountered by the practicing hematologist. When it comes treatment, there are several options:

If the platelet count is at least 30,000/μL and there is no active bleeding, close observation is the most prudent approach. In anticipation of the possibility of splenectomy at some point in their course, patients are offered immunization against Streptococcus pneumoniae, Hemophilus influenza, and Neisseria meningitides. In addition, I screen for exposure to hepatitis B virus (HBV), because patients may at some point receive treatment with rituximab (Rituxan), which is associated with HBV reactivation.
For patients with a platelet count below 30,000/μL, evidence of impending bleeding (such as wet purpura), or frank bleeding, treatment is indicated. Typically, this involves the use of glucocorticoids, often in combination with IV gamma globulin (IVIG) or, occasionally, anti-D immunoglobulin.
For a platelet count below 10,000/μL, I give methylprednisolone, 1,000 mg/d IV, for 5 consecutive days with IVIG, 1 g/kg daily, for 2 consecutive days. I then shift the patient to oral prednisone, 1 mg/kg daily, for 1 week, followed by tapering the dose by 10 mg/wk, as allowed by the platelet count, which should remain at ≥ 30,000/μL. Failure of this approach, or the inability to reduce the prednisone dose to 10 mg/d or less, would raise the options of either giving rituximab, 375 mg/m2 per week, for 4 weeks or performing a therapeutic, laparoscopic-assisted splenectomy, the single intervention still the most likely to provide meaningful, long-lasting benefit.
In the setting of asplenia (including the absence of accessory splenic tissue), I favor a trial of a thrombopoietin mimetic, either romiplostim (Nplate) or eltrombopag (Promacta).

References

Romiplostim versus standard of care in adult nonsplenectomized patients

Study population, endpoints, other treatments

Efficacy

Thrombopoietin mimetics challenge the conventional wisdom about controlling ITP

Quality of life

Romiplostim in children with chronic refractory ITP

How I treat ITP Immune thrombocytopenic purpura (ITP) and its associated problems are frequently encountered by the practicing hematologist. When it comes treatment, there are several options:

If the platelet count is at least 30,000/μL and there is no active bleeding, close observation is the most prudent approach. In anticipation of the possibility of splenectomy at some point in their course, patients are offered immunization against Streptococcus pneumoniae, Hemophilus influenza, and Neisseria meningitides. In addition, I screen for exposure to hepatitis B virus (HBV), because patients may at some point receive treatment with rituximab (Rituxan), which is associated with HBV reactivation.
For patients with a platelet count below 30,000/μL, evidence of impending bleeding (such as wet purpura), or frank bleeding, treatment is indicated. Typically, this involves the use of glucocorticoids, often in combination with IV gamma globulin (IVIG) or, occasionally, anti-D immunoglobulin.
For a platelet count below 10,000/μL, I give methylprednisolone, 1,000 mg/d IV, for 5 consecutive days with IVIG, 1 g/kg daily, for 2 consecutive days. I then shift the patient to oral prednisone, 1 mg/kg daily, for 1 week, followed by tapering the dose by 10 mg/wk, as allowed by the platelet count, which should remain at ≥ 30,000/μL. Failure of this approach, or the inability to reduce the prednisone dose to 10 mg/d or less, would raise the options of either giving rituximab, 375 mg/m2 per week, for 4 weeks or performing a therapeutic, laparoscopic-assisted splenectomy, the single intervention still the most likely to provide meaningful, long-lasting benefit.
In the setting of asplenia (including the absence of accessory splenic tissue), I favor a trial of a thrombopoietin mimetic, either romiplostim (Nplate) or eltrombopag (Promacta).

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A Phase II Tolerability Trial of Neoadjuvant Docetaxel with Carboplatin and Capecitabine in Locally Advanced Breast Cancer

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A Phase II Tolerability Trial of Neoadjuvant Docetaxel with Carboplatin and Capecitabine in Locally Advanced Breast Cancer

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Aruna Mani, MD

The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,¹ with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).²,³ A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).⁴

At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.¹ Numerous phase II and III trials have evaluated single-agent^5–8 and combination^{9– 32} chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.⁴

Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.³³ Expanded clinical trials of this approach are in progress.

The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine.^34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.^6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.^37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami^{39– 41} suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.^27,42–44

Patients and methods

Study design

In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.

Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.^9,32

Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.

Patients

Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.

Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.

Study endpoints

The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.⁴⁵

The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.

Statistical analysis

Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).

Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.

Tolerability assessment

At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.

Ethical considerations

The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.

Literature review

The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.

Results Patients

Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.

The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.

The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.

Clinical response

At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.

Pathologic response

After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.

The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.

Biologic features of responders

Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.

One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.

Conversion to breast conservation

Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.

Time to disease progression

At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.

Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).

Disease-free and overall survival

Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.

Adverse events

Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.

Discussion

The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42

The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based^34–36 has since been disputed.⁴⁷ The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.

Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.⁴⁸.

The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.⁴⁹ The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.

It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.⁵¹ A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).⁵² Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.⁴³ In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.

The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.^53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.⁵⁵

The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.⁵⁶

Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.

Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

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ABOUT THE AUTHORS

Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.

Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.

Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.

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Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

ABOUT THE AUTHORS

Patients and methods

Study design

Patients

Study endpoints

Statistical analysis

Tolerability assessment

At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.

Ethical considerations

Literature review

Results Patients

Clinical response

Pathologic response

Biologic features of responders

Conversion to breast conservation

Time to disease progression

Disease-free and overall survival

Adverse events

Discussion

Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

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Facilitating hospice discussions: a six-step roadmap

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Jennifer Shin and David Casarett

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Facilitating hospice discussions: a six-step roadmap

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Mr. C is a 54-year-old man with metastatic lung adenocarcinoma who presented 1 year ago with multiple lung nodules and hepatic metastases. His tumor responded to initial treatment with four cycles of carboplatin and pemetrexed, and he was treated with maintenance pemetrexed for 5 months before his liver lesions progressed. Despite treatment with docetaxel and then erlotinib, his liver and lung tumors progressed rapidly. He has lost 10 pounds in the last few weeks and is now so fatigued that he spends most of his day resting in his recliner. He has been admitted to the hospital twice in the last month for worsening dyspnea in the setting of progressive pulmonary metastases.

Introduction

Hospice programs provide high-quality, compassionate care to dying patients and their families through an interdisciplinary team specializing in pain and symptom management.^[1]^and ^[2] These patients also receive medications and supplies, durable medical equipment, and home health aide services. Patients and their families receive support from a chaplain, social worker, physician, nurse, and volunteer. Families are offered bereavement services for at least 13 months following the patient's death (Table 1).³

Table 1. Hospice Services and Team Members

Services

• Pain and symptom management

• 24-hour telephone access to a clinician

• Assistance with personal care needs

• Help with errands and light housework

• Spiritual support

• Companionship for the patient and family

• Bereavement counseling before and after the patient's death

• Patient and family education and counseling

• Case management and coordination

• Advance care planning

• Medications and supplies related to the hospice diagnosis

• Durable medical equipment

• Child bereavement services

• Respite services (up to 5 consecutive days of inpatient care to allow families a needed break)

• Inpatient hospice (for treatment of severe symptoms that cannot be managed at home)

Team members

• Physician

• Nurse

• Social worker

• Home health aide

• Chaplain

• Bereavement counselor

• Physical therapist

• Occupational therapist

• Volunteer

National Hospice and Palliative Care Organization. NHPCO Facts and Figures: Hospice Care in America.³

Families report high levels of satisfaction with hospice and are more likely to describe high-quality care.¹ Despite this, only 40% of people in the United States die while receiving hospice care.³ Although longer hospice stays are associated with better quality of life in patients and less depression in bereaved family members,^[4]^and ^[5] many patients enroll very late in the course of illness. In fact, the median length of stay is just over 3 weeks, and a third of patients die or are discharged within 1 week of hospice enrollment.³ The result is that brief exposures to hospice at the end of life do not allow patients and families to take full advantage of the benefits.⁶

There are several explanations for why people enroll in hospice so late. The Medicare Hospice Benefit requires hospice patients to choose a plan of comfort care, which means that they must usually forgo disease-directed therapies unless they provide a specific palliative benefit. Furthermore, the financial per diem payment structure of hospice means that patients may need to forgo palliative treatments that cannot be covered under the typical hospice reimbursement (approximately $150/day for routine home care). Patients may not be willing to give up these therapies or may be reluctant to transition from a model of care focusing on disease-directed therapies to one with palliation as the goal.

Patients may also enroll in hospice later if their physicians do not discuss hospice or if they have these discussions in the last few weeks of the patient's life.^[7]^and ^[8] Physicians may delay hospice discussions because they are unsure of the patient's prognosis,⁹ although the disease trajectory in patients with cancer is often more straightforward than in patients with non-oncologic diagnoses. Studies have documented deficiencies in doctor–patient communication regarding prognosis and end-of-life issues,¹⁰ and patients report inadequate communication with physicians about shared decision making at the end of life.¹ Another study found that about half of patients diagnosed with metastatic lung cancer reported not having discussed hospice with a provider within 4–7 months after diagnosis.¹¹

Although these discussions may be delayed or avoided altogether, seriously ill patients value the ability to prepare for the end of life.^[12]^and ^[13] Patients rely on their physicians to discuss hospice and other end-of-life care options. Furthermore, most family caregivers report that communication with their oncologists was important in helping them to understand the patient's prognosis and to see the role that hospice could play as a treatment alternative.⁷

These conversations are often difficult for patients and families and can also be challenging for physicians. Nevertheless, communication skills in discussing transitions to palliative care can be learned.^[14]^and ^[15] Although these discussions are not nearly as straightforward as a medical or surgical procedure, one can approach them with the same methodical preparation and careful consideration of the steps involved.

When Is a Hospice Discussion Appropriate?

To be eligible for the Medicare Hospice Benefit, a patient must have a prognosis of 6 months or less if his or her illness runs its usual course; also, the patient needs to be willing to accept the hospice philosophy of comfort care. This second criterion is not formally defined but is generally accepted to mean that the patient must be willing to forgo disease-directed therapies related to the hospice admitting diagnosis.

These eligibility criteria should not be used to define the patients for whom a hospice discussion is appropriate however. When a patient's goals and values reflect a desire to focus on palliation, it is time for the physician to initiate a hospice discussion. Other triggers for early hospice discussions can include a change in clinical status, recent hospitalization, decline in performance status, new weight loss, or complication of treatment. Although these factors may prompt a discussion of options for care, including hospice,^[16]^and ^[17] not all discussions will lead to a hospice enrollment decision. Nevertheless, earlier discussions that prompt conversations about a patient's needs, goals, and preferences can facilitate later decisions about hospice and other treatment options.

A Six-Step Roadmap

We provide a Six-Step Roadmap for navigating discussions about hospice adapted from the SPIKES protocol for delivering bad news.¹⁸ This strategy is comprised of six communication steps that can be remembered by using the mnemonic SPIKES: setting up the discussion, assessing the patient's perception, inviting a patient to discuss individual goals and needs, sharing knowledge, empathizing with the patient's emotions, and summarizing and strategizing the next steps.

Step 1: Set Up the Discussion About Hospice

Before discussing hospice with a patient and family, it is important to communicate with other members of the medical team to ensure an understanding of the patient's prognosis and treatment options. It is also helpful to find out what the patient and family may have expressed to other providers regarding these issues and how they have been coping. Any provider who has been in contact with the patient may be able to contribute to this consensus, including the medical oncologist, radiation oncologist, palliative care physician, primary care physician, home nurse, and social worker. A clear, unified message from the team decreases confusion for the patient and family.

Once a common agreement has been established regarding the patient's prognosis and treatment options, physicians can schedule a time and arrange for a place to allow for an uninterrupted conversation. Scheduling a patient at the end of a clinic day or visiting a patient in the hospital during an admission are potential ways to do this. Before scheduling a meeting, however, it is essential to know who the patient would like to be present at the meeting. One approach may be to tell the patient that there are important options to discuss regarding the next steps in his or her care and find out who may be able to help the patient with such decisions (Table 2). Additionally, a palliative care physician may cofacilitate these discussions. If the patient already has a palliative care physician, it may be helpful to have him or her involved in the meeting. If the patient has not yet been evaluated by a palliative care team, it may be possible to consult a palliative care specialist who can attend the meeting or follow up with the patient afterward.

Table 2. Useful Language for Hospice Discussions

Adapted from Cassett et al ⁸ and Baille et al ¹⁵

Invite other decision makers	“Who do you usually rely on to help you make important decisions?” “When we discuss your results, who would you like to be present?”
Assess understanding of prognosis	“Tell me about your understanding of the most recent tests/studies.” “Can you share with me what you think is happening with your cancer and the treatments?”
Identify goals of care	“What is most important to you right now?” “What are your biggest concerns right now?” “What are your hopes for the coming weeks/months?” “What do you enjoy doing now?” “What is most important to you now?” “What are you worried about now? In the future?”
Reframe goals (“wish” statements)	“I wish I could promise you that you will be able to make it to your daughter's wedding, but unfortunately I can't. What do you think about writing a letter for her to read on her wedding day? We can also think about other ways to let her know that you will always be with her, even if you cannot physically be there.” “I wish that we could find a new chemotherapy that could cure your cancer. Even though cure is not possible, I think that we can meet some of your other goals, like staying at home to spend time with your children.”
Identify needs for care	“What has been hard for you and your family?” “What is your life like when you are at home? How are you and your family managing?” “Are you experiencing pain or other symptoms that are bothering you?” “Have you been feeling sad or anxious lately?” “Would it be helpful to have a visiting nurse come to your home to assist you with your medications?”
Introduce hospice	“One of the best ways to give you the help that you need to stay at home is through hospice.” “The hospice team specializes in caring for seriously ill patients at home.” “Hospice can provide you and your family with more services and support.”
Recommend hospice	“From what you have shared with me today, I recommend hospice as a way of helping you meet the goals that are important to you.” “I feel that hospice is the best option for you and your family. I know this is a big decision, and I want you to know that the decision is yours.”

Full-size table

Mr. C's medical oncologist, Dr. A, contacted Mr. C's radiation oncologist as well as his primary care physician. They all agreed that his prognosis could be measured in weeks to months and that his performance status precluded any further chemotherapy. Dr. A also spoke with the hospital social worker who met Mr. C and his wife during his most recent hospitalization. The social worker said that Mr. C's wife has been very distressed, particularly about his increasing debility and her difficulty in caring for him at home. When Dr. A visited Mr. C during his hospitalization, Dr. A explained to Mr. C that they would be making some decisions about the next steps in his care and asked who might be able to help with these decisions. When Mr. C said his wife would be this person, Dr. A asked that she come to his next visit. Dr. A decided to schedule Mr. C for an appointment at the end of his clinic session the following week.

Step 2: Assess the Patient's Perception

The physician can begin this discussion by asking the patient to describe his or her current medical situation (Table 2). Although the physician may have provided this information on prior occasions, it is important to hear the patient's perception of the diagnosis and prognosis. Patients with advanced cancer often overestimate their prognosis and are more likely to favor life-extending therapies over hospice.¹⁹ These questions provide an opportunity to address any misconceptions or gaps in understanding that the patient may have. When the physician, patient, and family are in agreement with the patient's current medical situation it allows for further exploration of the patient's hopes and concerns.

This part of the discussion should rely on open-ended questions designed to elicit the patient's perspective. In particular, an invitation to “tell me more” encourages patients to explore how they are thinking or feeling and can yield more information than closed-ended or leading questions. This phrase can also help redirect the conversation when necessary (“You mentioned before that you are worried that the chemotherapy is not working anymore. Tell me more about your concerns.”).

Dr. A asked Mr. C how he was doing overall and to describe his understanding of whether the erlotinib had been working. In response, Mr. C expressed his concern about his recent weight loss and lethargy. Dr. A asked Mr. C to tell him more about these concerns, and Mr. C said that he thought his symptoms were a sign that the erlotinib was not helping him. He said he knew that the CT scans showed progression of disease, and he wondered whether chemotherapy could help. Dr. A confirmed there was progression of cancer in his lungs and liver. Dr. A also expressed his concern that more chemotherapy would not provide additional benefit for him and may harm him. Mr. C and his wife were tearful and agreed that he was too weak for more chemotherapy. Dr. A acknowledged that the disease had progressed quickly and must be very upsetting to them.

Step 3: Invite the Patient to Discuss Goals of Care and Needs for Care

Before sharing information about hospice with a patient, it is important to understand the patient's hopes and fears about the future, goals of care, and needs for care. It is helpful to start with learning about the patient's perspectives on the future and linking that to the patient's goals of care. Once the goals are clear, it is easier to match the patient's needs with his or her goals.

One way to elicit patients' goals of care is by asking them to describe their hopes and fears about their cancer in the context of their life (Table 2). Patients may volunteer information about their hopes (eg, attending their daughter's wedding) or fears (eg, worrying about pain) that provide insight into their more global goals of care. Again, the “tell me more” phrase can be helpful (“Tell me more about what you mean when you say you are a burden on your family.”).

Once the patient and family express their thoughts, it is useful to restate the patient's goals by asking a question that summarizes the patient's statements (“From what you and your family have just shared with me, I hear that the most important thing to you is … . Did I understand you correctly?”). It is often challenging for patients to specifically articulate their goals of care. Asking a question allows the patient and family the chance to elaborate or offer corrections.

If a patient expresses unrealistic expectations (eg, a cure, years of life), “wish” statements can be helpful in providing gentle redirection. These statements express empathy while also communicating that the wished-for outcome is unlikely (“I wish that we could guarantee that … but unfortunately we can't.”). These statements can explain the reality of the situation in a compassionate manner (Table 2). Patients and families who have unrealistic goals of care may need time to readjust their expectations, and in these cases it may be prudent to revisit the discussion of hospice at a later date.

Once the goals of care have been established, it is important to further explore the needs for care. Although some of these needs may have been mentioned during the goals discussion, it is helpful to directly ask the patient and family about their needs. General questions about what has been hard for the patient and the family can be useful in eliciting needs, as are questions about what life has been like at home and how they are managing (Table 2). It is also important to ask more specific questions that pertain to the patient's symptoms such as pain or depression and those that address the family's needs for help around the house (Table 2). Once this information has been shared, it is often useful to repeat a summary back to the patient and family (“From what we have just discussed, it may be helpful to have a visiting nurse to assist with his medications and a home health aide to dress and bathe him … . Does it sound like this could be helpful to you?”). Often, these needs can be addressed by the multidisciplinary hospice team, and it is important to understand what needs exist in preparation for a discussion about how hospice might be helpful.

Mr. C shares with you that his two hospitalizations for dyspnea have been frustrating because he feels that they have prevented him from spending quality time with his daughters. Although he did not want to be admitted to the hospital, he tearfully expressed that he was worried about “suffocating to death” and did not want to die at home in front of his wife and children. Mr. C's wife also shares that it has been harder to bathe and dress him because he is becoming so weak. Mr. and Mrs. C agree that it would be helpful to have the support of a visiting nurse and a home health aide.

Step 4: Share Knowledge

Once the patient's goals and needs for care have been clarified, physicians can introduce hospice as a way of achieving their goals and meeting their needs. In presenting hospice in this transparent manner, patients and families can better understand how hospice is part of a plan of care that addresses their individualized goals and needs. Most family caregivers report that communication with their oncologists was critical in their understanding the patient's prognosis and hospice as a treatment alternative.⁷ In one survey, the majority of caregivers did not realize that their loved ones could benefit from hospice until their physicians first discussed it with them.⁷

A discussion of hospice should offer concrete information about the services provided to patients and their families (Table 1). Many patients and families do not understand the benefits, such as a visiting nurse for frequent symptom management or a home health aide to assist with daily patient care, until after enrollment. Many say they wish they had known sooner.²⁰ By providing this information earlier, patients and families may make more informed decisions about hospice. This description also makes clear to the patient and family that hospice is not simply a generic recommendation but rather the physician's recommendation of a program that is the best fit for their specific goals and needs.

Given the emotional nature of these discussions and the large amount of information involved, it is important to ask the patient to explain in his or her own words how hospice could help (“To make sure I did a good job of explaining things, can you tell me what we just talked about in your own words?” and “How do you think hospice might help you?”). This provides the opportunity to assess understanding and clarify any confusion.

Since not all patients are best served by hospice, the discussion may also be expanded to include other options for palliative care. For example, hospice is not equipped to care for debilitated patients at home who do not have a caretaker, nor is it usually able to absorb the costs of expensive palliative treatments. Sometimes, larger hospices may be able to make exceptions on a case-by-case basis, but it is helpful to be aware of other options for palliative care like bridge-to-hospice home care and outpatient palliative care programs.

Dr. A explained that hospice could provide intensive management of his dyspnea with the assistance of a visiting nurse and a 24-hour phone line to call for assistance. With these measures in place, Dr. A said that he hoped hospitalizations could be avoided, allowing him more time at home with his family. Dr. A addressed Mr. C's concern about dying at home and shared with him that he could be transferred to an inpatient hospice if death seemed imminent. Dr. A shared with Mrs. C that hospice could provide the services of a home health aide, which seemed to reduce her concerns about being able to care for her husband as he became weaker.

Step 5: Empathize With the Patient's Emotion

In discussions regarding end-of-life care, patients and families value empathy, compassion, and honesty balanced with sensitivity and hope.²¹ Throughout the conversation, it is likely that the patient and family will express a range of emotions. Rather than providing immediate reassurance or trying to “fix” the emotion, it can be helpful to use an empathic statement to let the patient know that his or her emotions are recognized.¹⁵ Empathic responses address and validate a patient's emotions and encourage further disclosure.²² The NURSE mnemonic summarizes ways in which to respond to emotions: naming, understanding, respecting, supporting, and exploring the feelings the patient has shared (Table 3).^[15]^and ^[23]

Table 3. NURSE Statements for Expressing Empathy

Adapted from Back et al ^[15]^and ^[23]

N = Naming	“It sounds like you are worried about how fast the cancer has been progressing.” “Some people in this situation would feel frustrated.”
U = Understanding	“My understanding of what you have told me is that you are worried about being able to live independently at home.” “I can see how difficult this has been for you and your family.”
R = Respecting	“It is very clear to me how supportive your family has been.” “I can see how hard you have worked to understand the treatment options for your cancer.”
S = Supporting	“I will support the decisions that you make, no matter what you decide.” “I will always be your doctor.”
E = Exploring	“Could you tell me more about what you mean when you say that you don't want to give up?” “I sense that you may be feeling anxious about stopping chemotherapy. Can you share with me what you are feeling?”

Some of the emotions arising during a hospice discussion may stem from preconceived notions or a prior experience. Therefore, it may be helpful to specifically ask patients and families about these perceptions and experiences. Common misperceptions may include the concern that hospice hastens death. Other patients view hospice as “giving up” and worry about being abandoned by their physicians. A hospice discussion provides the opportunity to directly address these concerns and provide clarification (“No, hospice does not hasten death. Hospice helps you have the best quality of life for whatever time you have.”).

Ultimately, some patients and families may decide that hospice is not the right choice for them. It is important to recognize that the time invested has not been wasted. Instead, if done well, these discussions offer an opportunity for the physician to align his or her goals and understanding with those of the patient and family. Specifically, these discussions are a chance to demonstrate a desire to understand the patient's individualized goals and to share concerns about disease progression. In essence, it is a valuable opportunity to establish a collective understanding about the patient's current situation while also laying important groundwork for future discussions.

Mr. C tearfully shared his concern about being a burden to his wife and about how his daughters would handle his progressive decline. Dr. A sat quietly, allowed Mr. C to fully detail his worries, and then said, “I can see how worried you are about your family and understand that you want to make sure that their needs are also addressed.”

Step 6: Summarize the Discussion and Strategize Next Steps

In all stages of cancer, patients and families rely on their oncologist for information about treatment options. This is particularly important when a patient's cancer has progressed despite therapy and when the focus of care may be shifting from disease-directed therapies to palliation. Just as a physician may have previously recommended a chemotherapeutic option for a patient, so should he or she recommend the therapeutic option of focusing on quality of life. If hospice appears consistent with the patient's and family's goals and needs, the physician should make this recommendation. It may be helpful for the patient and family to hear a summary of how hospice will meet their needs. If the patient is amenable to learning more about hospice but is not yet ready to enroll, the physician can arrange for an informational visit with the hospice team.

Dr. A recommends hospice and emphasizes that hospice would provide services that meet Mr. C's goals of symptom management, avoiding hospitalizations, and providing support for his family. Mr. C and his wife agree that hospice is the best option for them. They would like to enroll after they have spoken with their children about their decision.

Conclusion

Discussions about goals of care and hospice are not easy. They are rarely as straightforward as presented in this case, and an oncologist may face numerous barriers when attempting to have these discussions. For instance, treating physicians may have differing opinions on therapeutic options. Patients and family members may have different goals and may be in different stages of accepting a life-limiting cancer diagnosis. Additionally, these discussions take preparation, time, and skill. Although there are no easy solutions to these issues, the general guidance provided in this article focuses on suggesting tools and techniques that can make these discussions easier for oncologists, patients, and families. By increasing our competence and comfort with these conversations, we can reduce delays in offering patients the benefits of hospice as they near the end of life.

Although no algorithm will fully address the complexities and nuances of these conversations, this approach provides a general framework and offers tools to use while speaking with patients and families. Conversations about hospice do not begin with the recommendation of hospice but rather with an honest discussion of the goals and needs of a patient and family. If these goals and needs can be met with the services that hospice can provide, the physician has the opportunity to educate the patient and to make the recommendation as they would for any other therapeutic option.

Patients and families consider communication to be one of the most important facets of end-of-life care.²⁴ Seriously ill patients value being able to prepare for death,¹³ and physicians have the duty to help patients and families prepare for the end of life.²⁵ Physicians can help increase the time patients have to plan for the last phase of their lives by having honest and open discussions about hospice and other alternatives. Oncologists have the responsibility to present patients with the benefits and burdens of therapies throughout the trajectory of their illness, and it is critically important during the transition from disease-directed to palliative care. By exploring the option of hospice, patients and families can make informed decisions about whether hospice may meet their needs. Equally important, patients are given the control to choose how they would like to live the final phase of their lives.

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Dr. Casarett's research is funded by grants from the Commonwealth Fund, the Greenwall Foundation, the VistaCare Foundation, and the Department of Veterans' Affairs. Dr. Shin has nothing to disclose.

Correspondence to: Jennifer Shin, MD, Division of Hematology–Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

¹ PubMed ID in brackets

Vitae

Dr. Shin is from the Division of Hematology–Oncology, University of Pennsylvania School of Medicine, Philadelphia

Dr. Casarett is from the Division of Geriatric Medicine and the Penn-Wissahickon Hospice, University of Pennsylvania School of Medicine, Philadelphia

The Journal of Supportive Oncology
Volume 9, Issue 3, May-June 2011, Pages 97-102

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