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Soild Tumors Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727-1733. 6. International Agency for Research on Cancer. WHO Classification of Tumours of the Digestive System. 2000. www.iarc.fr/en/publications/pdfs-online/pat-gen/bb2/ BB2.pdf. Accessed April 7, 2011. 7. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 8. Franko J, Feng W, Yip L, et al. Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2,158 patients. J Gastrointes Surg. 2010;14:541-548. 9. Fazio N, Cinieri S, Lorizzo K, et al. Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas. Cancer Treat Rev. 2010;36(suppl 3):S87-S94. 10. Hemming AW, Magliocca JF, Fujita S, et al. Combined resection of liver and pancreas for malignancy. J Am Coll Surg. 2010;210:808-816. 11. Glazer ES, Tseng JF, Al-Refaie W, et al. Long-term survival after surgical management of neuroendocrine hepatic metastases. HPB (Oxford). 2010;12:427-433. 12. Gamblin TC, Christians K, Pappas SG. Radiofrequency ablation of neuroendocrine hepatic metastasis. Surg Oncol Clin N Am. 2011;20:273-279. 13. Akyildiz HY, Mitchell J, Milas M, et al. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: a long-term follow-up. Surgery. 2010;148:1288-1293. 14. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation micro-
spheres for neuroendocrine liver metastases. Cancer. 2008;113:921-929. 15. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol. 2008;31: 271-279. 16. Varker K, Martin EW, Klemanski D, et al. Repeat transarterial chemoembolization (TACE) for progressive hepatic carcinoid metastases provides results similar to first TACE. J Gastrointest Surg. 2007;11:1680-1685. 17. Pascher A, Klupp J, Neuhaus P. Endocrine tumours of the gastrointestinal tract. Transplantation in the management of metastatic endocrine tumours. Best Pract Res Clin Gastroenterol. 2005;19:637-648. 18. Le Treut YP, Grégoire E, Belghiti J, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report. Am J Transplant. 2008;8:1205-1213. 19. Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl. 2007;13:327-333. 20. Grégoire E, Le Treut YP. Liver transplantation for primary or secondary endocrine tumors. Transplant Int. 2010;23:704-711. 21. Stauffer JA, Steers JL, Bonatti H, etal. Liver transplantation and pancreatic resection: a single-center experience and a review of the literature. Liver Transpl. 2009;15:1728-1737. 22. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980;303:1189-1194. 23. Moertel CG, Lefkopoulo M, Lipsitz S, et al.
Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519-523. 24. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762-4771. 25. Turner NC, Strauss SJ, Sarker D, et al. Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. Br J Cancer. 2010;102: 1106-1112. 26. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68:227-232. 27. Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999;81:1351-1355. 28. Fjallskog ML, Granberg DP, Welin SL, et al. Treatment with cisplatin and etoposide in patients with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer. 2001;92:1101-1107. 29. Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986-2991. 30. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268-275. 31. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401-406.
Eribulin: A New Option in the Treatment of Metastatic Breast Cancer By Georgia Litsas, RN, NP Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts
reast cancer is the most common cancer among women. In 2010, there were an estimated 207,090 new cases and 39,840 deaths.1 Despite many improvements in the treatment of breast cancer, about 20% to 30% of women with the disease will progress to metastatic breast cancer (MBC). Although MBC remains incurable, a variety of treatment options are available. The US Food and Drug Administration (FDA) recently approved eribulin (Halaven), providing an exciting new option for women with heavily pretreated MBC. Eribulin is a synthetic analog of halichondrin B, a nontaxane microtubule dynamics inhibitor originally isolated from a sea sponge. Eribulin inhibits the growth phase of microtubules and sequesters tubulin into nonproductive aggregates, resulting in G2/M cellcycle block, by disrupting mitotic spindles. It exerts its action at a site on the cellular level that is distinct from that targeted by taxanes, vinca alkaloids, and other existing microtubulin inhibitors. FDA approval was based on data from the international, phase 3 EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin) clinical trial, which had a primary end point of overall survival (OS). To be eligible, all the women had to have been treated with 2
to 5 prior chemotherapy regimens and to have experienced disease progression within 6 months of completing their most recent chemotherapy regimen. Of the regimens administered previously in the adjuvant or metastatic setting, at least 1 had to have been anthracycline based and 1 had to have been taxane based to be eligible for enrollment. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and patients with preexisting neuropathy >grade 2 were ineligible.
Median OS was significantly prolonged for patients randomized to receive eribulin.
Investigators randomized 762 patients with MBC at a 2:1 ratio to eribulin (n = 508) or a single-agent therapy selected by their physician prior to randomization (n = 254). Randomization was stratified by geographic region, HER2 status, and prior capecitabine exposure. The physician’s choice of treatment consisted of any single agent, whether a chemotherapy, hormonal, or biologic therapy, or supportive care only. Randomization was stratified by geographic region, HER2
status, and prior capecitabine exposure. Eribulin 1.4 mg/m2 was administered on days 1 and 8 every 21 days, with dose reductions and delays for predetermined toxicities. The control arm therapies consisted of the following agents: vinorelbine (Navelbine; 26%), gemcitabine (Gemzar; 18%), a taxane (16%), capecitabine (18%), an anthracycline (9%), other chemotherapy (10%), and hormonal therapy (3%). Median OS was significantly prolonged for patients randomized to receive eribulin compared with those who received the physician’s choice of treatment (13.1 vs 10.6 mo, respectively; hazard ratio, 0.809; 95% confidence interval, 0.660-0.991; P = .041). Eribulin treatment had a manageable safety profile. The most common adverse reactions in the eribulin arm, occurring in >25% of patients, were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common treatment-related adverse reactions ≥grade 3 experienced by >5% of patients were neutropenia (57%), asthenia/fatigue (10%), and peripheral neuropathy (8%). The most common serious adverse reactions reported in eribulin-treated patients were febrile neutropenia (4%) and neutropenia (2%). The most common toxicity leading to discontinuation of eribulin was peripheral neuropathy (5%).
32. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009;15:338-345. 33. Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28: 245-255. 34. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311-4318. 35. Yao JC, Shah MH, Ito T, et al; for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523. 36. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-513. 37. Faivre S, Sablin MP, Dreyer C, Raymond E. Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors. Endocrinol Metab Clin North Am. 2010;39:811-826. 38. Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316-1323. 39. Raymond E, Hobday T, Castellano D, et al. Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. Cancer Metastasis Rev. 2011;30(suppl 1):19-26.
These results were discussed at the 2010 ASCO Annual Meeting and published in The Lancet in March 2011.2 These results are especially noteworthy because this is the first time a single agent has demonstrated survival benefit in this population. The recommended dosage of eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. Eribulin may be administered undiluted or diluted in 100 mL of 0.9% sodium chloride injection, USP. The drug should not be administered through an intravenous line that is delivering a dextrose-containing solution.3 Eribulin offers new promise for women with heavily pretreated MBC. The results of the EMBRACE trial demonstrate that cytotoxic therapies directed at a well-defined target remain a viable area of continued study. Given the favorable results of the EMBRACE trial, future studies will examine the use of eribulin in the adjuvant setting and also as frontline therapy in the metastatic setting. It is important for nurses to be aware of the FDA’s approval of eribulin, its mechanism of action, and its safety profile. Nurses are in a pivotal position to advocate for their patients, to provide consistent patient education, and to monitor adverse reactions. ● References 1. Breast cancer overview. American Cancer Society. http://www.cancer.org/Cancer/BreastCancer/Overview Guide/breast-cancer-overview-key-statistics. Updated September 2010. Accessed April 12, 2011. 2. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet. 2011;377 (9769):914-923. 3. Halaven [package insert]. Woodcliff Lake, NJ: Eisai, Inc.; 2010.
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