胰腺神经内分泌肿瘤中山大学附属第三医院肿瘤内科 陈展洪2011年10月19日ASCO2011信息传达会胰腺神经内分泌肿瘤的治疗进展2003年10月 超声内镜确诊胰岛细胞瘤 试图饮食 控制 2004年7月31日，斯坦福大学医疗中心， whipple手术 2006年8月起日益消瘦 肿瘤复发？药物治疗？ 2009年4月田 肝脏移植手术 并长期服用免疫抑制 剂抗排斥 2011年 肿瘤进展 接受放疗 化疗、靶向？ （脱 发明显） 2011年10月6日 死于呼吸衰竭 OS：96个月Pancreatic Endocrine TumorsnAccount for 3-5% of all pancreatic neoplasmsnMost are sporadicnFamilial Syndromesn多发性内分泌瘤病1型 MEN-1n结节性硬化症n神经纤维瘤病n林-希氏病(视网膜血管瘤病)nHormonal secretion: insulin, gastrin, glucagon, VIP, serotonin, ACTHnUsually metastasize to liverIncreasing Incidence Better prognosis than pancreatic cancerLoalized、regional、distant mOS：124m,70m, and 23 m Yao, JC, et al., Annals of Surg Oncol 2007;14:3492-3500. Pancreatic Endocrine Tumors-Survival by SEER 2005局限期肿瘤手术原则n尽可能切除肿瘤病灶n伴有多发性内分泌瘤病1型、卓艾综合症的 肿瘤应行whipple手术治疗n其余情况多采用局部切除或摘除n暂无辅助治疗临床试验数据卓艾综合症又称佐林格一埃利森综合征(Zollinger-Ellison syndrome), 来源于G细胞， 是一种以消化道溃疡为主要表现的综合病症Management of Metastatic DiseasenSystemic therapynSomatostatin analoguesnInterferonnChemotherapyn“Targeted” AgentsnPeptide receptor therapynLiver metastasis：Surgical Intervention、TACEOctreotide Symptoms of flushing and diarrhea relieved in 75-80% 50% become refractory Stabilize disease in 50% Tumor regression in 4%Arnold R et al. Digestion. 1993;54(suppl 1):72-75.Interferon Interferon alpha Biochemical response in 40% Stabilizes tumor in 15-40% Tumor regression in 12% Toxicity: Fatigue、Myelosuppression、Fever、Flu-like illness Depressionberg K. Ann Oncol. 2001;12(suppl 2):S111-S114. Shnirer, II, et al. Acta Oncol 2003;42:672-692.ChemotherapynGenerally ineffectivenLow mitotic ratenHigh bcl-2 expressionnMDR gene expressionnAgentsnStreptozocin+Doxorubicin+Fluoropyrimidines RR30%nDTIC：First line RR33% Second line 8%nTemozolamidexeloda RR35-40%nPoor-differentiaed CIS/L-OHP+VP-16 RR40-60% with short PFSTargeted AgentsnVEGFnBevacizumabnPazopanibnSorafenibnSunitinib nmTORnEverolimusTemozolamide + Bevacizumabn34 patients with neuroendocrine carcinomas received temozolamide 150 mg/M2 BID x 7d q 14 days + bevacizumab 5 mg/kg IV q 14 daysCarcinoidPETPR (%)024SD (%)9270PD (%)86Kulke, MH, et al. ProcASCO 2006, abstract 4044.XELOX + Bevacizumabn40 patients with NETs received capecitabine 850 mg/M2 BID x 14d, oxaliplatin 130 mg/M2 + bevacizumab 7.5 mg/kg q 21dPET (N=19)SB (N=5)Unknown (N=11)Other (N=5)Total (N=40)DOR PR6-1-7 (18%)3-27mSD1147325 (63%)3-27PD-112 (5%)-NE21216 (15%)-Kuntz, PL, et al. ProcASCO 2010, abstract 4104.Sorafenibn93 patients received sorafenib 400 mg BIDnKi-67 correlates with response (2% RR 22%)n2/3 of patients discontinued for reasons other than progression (toxicity)PET (N=35)Carcinoid (N=42)PR (%)117MR (%)147PFS-6months (%)7258PFS (months)11.97.8Hobday, TJ, et al. ProcASCO 2007, abstract 4504.Pazopanib + Sandostatin LAR Pazopanib 800 mg orally QD + octreotide LAR Carcinoid enrollment stopped earlyOverall (N=51)Carcinoid (N=20)PNET (N=31) PR (%)12019MR (%)182016SD (%)697068PD (%)121510Unknown (%)8153PFS (months)14.21214.2OS (months)25.619.625.61y (%)737571Phan, AT. ProcASCO 2010, abstract 4001.SunitinibRAD001：依维莫斯RADIANT-1: Everolimus in PETnPET patients who progressed on or after chemotherapy, stratified by prior octreotideEverolimus (N=115)Everolimus + Octreotide LAR (N=45) PR (%)9.64.4SD (%)67.880PR + SD (%)77.484.4PD (%)13.90PFS (months)9.716.7Yao, JC, et al. J Clin Oncol 2010;28:69-76.RADIANT-3 Phase 3 Double-Blind, Placebo- Controlled Trial: Study DesignEverolimus 10 mg/d + BSC* n = 207Placebo + BSC* n = 203Treatment until disease progressionPatients with advanced pNET N = 410Stratified by: WHO PS Prior chemotherapy1:1Multi-phasic CT or MRI performed every 12 weeksCrossoverPrimary endpoint: PFS (RECIST)Secondary endpoints: Response, OS, biomarkers, safety, and PKR A N D O M I Z EYao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.Randomization August 2007May 2009PFS&OSToxicity：Aware of pneumonitisnAcceptable safety profile: stomatitis, rash, infection, infrequent pneumonitis结论n依维莫斯显著延长PFS（延长6.4m）n可用做进展的低或中分级的胰腺神经内分 泌肿瘤的标准治疗n注意肺毒性Bevacizumab + Everolimusn39 patients with low or intermediate grade NETnPR/PR confirmed26%/21%nSD69%nPD3%nPFS14.6 monthsn6/12 month92%/74%nOSNRn1y/2y92%/80%Yao, JC, et al. ProcASCO 2010, abstract 4002.Peptide receptor therapy:PPRT 多肽受体放射性核素治疗生长抑素受体显像技术呈高摄取的患者可以选择多肽受体靶向放射治疗 仍需随机临床试验确定其疗效，通常用于二线治疗肝转移灶的处理n最常见的死亡原因：肝转移n治疗方案：肝叶切除、不规则的转移瘤切除 术、术中射频消融或冷冻治疗、多种方法联 合n介入栓塞Take home messagen胰腺神经内分泌肿瘤，散发，约占胰腺恶 性肿瘤3-5%，发病率呈上升趋势。n多伴有激素异常释放。经常转移到肝脏。n预后较胰腺癌好，局限期、局部晚期、晚 期mOS：124m,70m, and 23 mn尽可能切除肿瘤病灶；伴有多发性内分泌 瘤病1型、卓艾综合症的肿瘤应行whipple手 术治疗；其余情况多采用局部切除或摘除 。n积极处理患者肝转移病灶可能改善生存n晚期患者多采用生长抑素、化疗或靶向治 疗n生长抑素ORR低4%，以缓解症状、稳定肿 瘤为主n化疗有效的药物：链脲霉素+5Fu+ADM、 替莫唑胺（或DTIC）联合卡培他滨、CIS/L -OHP+VP-16n靶向治疗：舒尼替尼、依维莫斯，延长PFS 为主 注意依维莫斯肺毒性