提示: 手机请竖屏浏览!

¹⁷⁷Lu-Dotatate治疗中肠神经内分泌肿瘤的三期临床试验
Phase 3 Trial of ¹⁷⁷Lu-Dotatate for Midgut Neuroendocrine Tumors


Jonathan Strosberg ... 肿瘤 • 2017.01.12

神经内分泌肿瘤治疗进入新的时代

 

邱海波,周志伟,徐瑞华*

中山大学肿瘤防治中心

* 通讯作者


神经内分泌肿瘤(neuroendocrine neoplasm,NEN)是一组起源于肽能神经元和神经内分泌细胞的高度异质性肿瘤,包括分化好的神经内分泌瘤(neuroendocrine tumor,NET)和分化差的神经内分泌癌(neuroendocrine carcinoma,NEC)。肝脏和淋巴结是NEN最常见的转移部位。根据肿瘤分泌的激素是否能引起临床相关症状分为功能性和非功能性NEN。目前,不可切除或转移性中肠NET的基础治疗是生长抑素类似物(SSA)。因多数NET会表达生长抑素受体,SSA不仅可以控制功能性NEN的症状,还可以延缓肿瘤的进展。前瞻性的研究(PROMID研究)表明,长效奥曲肽与安慰剂对比,明显延长患者的至肿瘤进展时间(time to progression,TTP)1。来自 CLARINET 研究的类似证据表明,兰瑞肽Autogel组与安慰剂组相比,明显延长局部进展或转移性的、无功能的胰腺或中肠神经内分泌肿瘤患者的无进展生存时间(progress free survival,PFS)2。2016年,mTOR抑制剂维莫司被证实可明显延长晚期分化良好的肺和胃肠道NET患者的PFS3。自1992年以来,肽受体放射性核素治疗(PRRT)就被认为是治疗的有效办法,通过生长抑素类似物导入高剂量的放射性核素至肿瘤细胞内,从而杀死肿瘤细胞,不同的放射性核素在不断地测试,试图寻找一个最佳的放射性核素4,5

查看更多

摘要


背景

晚期中肠神经内分泌肿瘤患者在接受一线生长抑素类似物治疗期出现疾病进展时,可供选择的治疗方案有限。本项随机对照临床试验以晚期进展性且生长抑素受体阳性的中肠神经内分泌肿瘤患者为研究对象,对镥-177(177Lu)-Dotatate的有效性与安全性进行了评估。


方法

我们将229例分化良好的转移性中肠神经内分泌肿瘤患者随机分配至177Lu-Dotatate组(116例)或对照组(113例);177Lu-Dotatate组患者每8周接受7.4 GBq的177Lu-Dotatate治疗(4次静脉输注,联合最佳的支持治疗,包括肌内给予30 mg的奥曲肽长效缓释制剂[long-acting repeatableLAR]),对照组患者仅接受奥曲肽LAR治疗(每4周肌内给予60 mg药物)。主要终点为无进展生存期。次要终点包括客观缓解率、总生存期、安全性以及副作用特征。按照研究方案的规定,总生存期的最终分析将在以后进行。本文报道了对预设的总生存期的中期分析结果。


结果

在主要分析的数据截至日期,177Lu-Dotatate组的20个月无进展生存率估计为65.2%(95%置信区间[CI]为50.0~76.8),对照组为10.8%(95% CI为3.5~23.0)。缓解率为177Lu-Dotatate组的18%对比对照组的3%(P<0.001)。在计划的针对总生存期的中期分析中,177Lu-Dotatate组有14例、对照组有26例患者死亡(P=0.004)。在177Lu-Dotatate组中,有1%、2%和9%的患者分别发生3或4级中性粒细胞减少、血小板减少以及淋巴细胞减少,而对照组患者未发生这些事件;我们在观察期间未发现肾毒性作用的证据。


结论

在晚期中肠神经内分泌肿瘤患者中,与大剂量奥曲肽LAR治疗相比,177Lu-Dotatate治疗可以显著延长患者的无进展生存期,且缓解率显著升高。我们在中期分析中观察到总生存期获益的初步证据;但这还需要在计划的最终分析中证实。在177Lu-Dotatate组中,<10%的患者发生了有临床意义的骨髓抑制(由Advanced Accelerator Applications公司资助,NETTER-1在ClinicalTrials.gov编号为NCT01578239,在EudraCT编号为2011-005049-11)。





作者信息

Jonathan Strosberg, M.D., Ghassan El-Haddad, M.D., Edward Wolin, M.D., Andrew Hendifar, M.D., James Yao, M.D., Beth Chasen, M.D., Erik Mittra, M.D., Ph.D., Pamela L. Kunz, M.D., Matthew H. Kulke, M.D., Heather Jacene, M.D., David Bushnell, M.D., Thomas M. O’Dorisio, M.D., Richard P. Baum, M.D., Harshad R. Kulkarni, M.D., Martyn Caplin, M.D., Rachida Lebtahi, M.D., Timothy Hobday, M.D., Ebrahim Delpassand, M.D., Eric Van Cutsem, M.D., Ph.D., Al Benson, M.D., Rajaventhan Srirajaskanthan, M.D., Marianne Pavel, M.D., Jaime Mora, M.D., Jordan Berlin, M.D., Enrique Grande, M.D., Nicholas Reed, M.D., Ettore Seregni, M.D., Kjell Öberg, M.D., Ph.D., Maribel Lopera Sierra, M.D., Paola Santoro, Ph.D., Thomas Thevenet, Pharm.D., Jack L. Erion, Ph.D., Philippe Ruszniewski, M.D., Ph.D., Dik Kwekkeboom, M.D., Ph.D., and Eric Krenning, M.D., Ph.D., for the NETTER-1 Trial Investigators*
Address reprint requests to Dr. Strosberg at the Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612, or at jonathan.strosberg@moffitt.org. *A complete list of investigators in the Neuroendocrine Tumors Therapy (NETTER-1) trial is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;340:858-868

2. Strosberg JR, Weber JM, Feldman M, Coppola D, Meredith K, Kvols LK. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol 2013;31:420-425

3. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072

4. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934-959

5. Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;315:663-666

6. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-4663

7. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-233

8. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387:968-977

9. Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 2011;29:934-943

10. Krenning EP, Kooij PP, Bakker WH, et al. Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide: a case history. Ann N Y Acad Sci 1994;733:496-506

11. Krenning EP, de Jong M, Kooij PP, et al. Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy. Ann Oncol 1999;10:Suppl 2:S23-9

12. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008;26:2124-2130

13. Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging 2011;38:2125-2135

14. Hörsch D, Ezziddin S, Haug A, et al. Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: a multi-institutional registry study with prospective follow-up. Eur J Cancer 2016;58:41-51

15. Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011;29:2416-2423

16. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716-731

17. Valkema R, Pauwels S, Kvols LK, et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med 2006;36:147-156

18. van der Zwan WA, Bodei L, Mueller-Brand J, de Herder WW, Kvols LK, Kwekkeboom DJ. GEPNETs update: radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol 2015;172:R1-8

19. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205-216

20. Bodei L, Kidd M, Paganelli G, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging 2015;42:5-19

21. Sabet A, Ezziddin K, Pape UF, et al. Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med 2013;54:1857-1861

22. Janson ET, Oberg K. Long-term management of the carcinoid syndrome: treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol 1993;32:225-229

23. Ducreux M, Ruszniewski P, Chayvialle JA, et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 2000;95:3276-3281

24. Pavel M, O’Toole D, Costa F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016;103:172-185

25. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011;378:2005-2012

26. Bodei L, Kwekkeboom DJ, Kidd M, Modlin IM, Krenning EP. Radiolabeled somatostatin analogue therapy of gastroenteropancreatic cancer. Semin Nucl Med 2016;46:225-238

27. Bergsma H, Konijnenberg MW, Kam BLR, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging 2016;43:453-463

28. Bergsma H, Konijnenberg MW, van der Zwan WA, et al. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 2016;43:1802-1811

29. Ezziddin S, Khalaf F, Vanezi M, et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2014;41:925-933

30. Delpassand ES, Samarghandi A, Zamanian S, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas 2014;43:518-525

服务条款 | 隐私政策 | 联系我们