1、肺神經內分泌腫瘤Pulmonary neuroendocrine tumors復旦大學附屬腫瘤醫院內科 王惠杰Incidence of Neuroendocrine TumorsYao, JC, et al. J Clin Oncol 2008;26:3063-3072.WHO/IASLC/ATS/ERSPreinvasive lesions Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)Carcinoid tumor Typical carcinoid (TC) Atypical carcinoid

2、 (AC)Small cell carcinoma Combined small cell carcinomaLarge cell neuroendocrine carcinoma(LCNEC)- Combined LCNECDIPNECH女性，50-70歲可無癥狀慢性干咳、呼吸困難影像表現：磨玻璃影，雙肺多發結節，細/支氣管增厚，閉塞性細支氣管炎可發展為TC/AC皮質激素、a-IFN、生長抑素，化療DIPNECH100 cases reviewedFemale 89%診斷平均年齡57.8診斷前癥狀持續3-30年63%存在通氣性障礙55例隨訪，66%病情穩定，27%緩慢進展，11%非疾病相關死

3、亡SSA 6例，SDTCACLNECSCLCNET GradeWell G1Well G2Poor G3Poor G3Mitosis/10HP22-1010often 1010often 50Ki-67%20%20%Clinical Young/male orfemale/non-smokerYoung/male orfemale/non-smokerOlder/male/smokerOlder/male/smokerLung locationCentralPeripheralMidzone orperipheralCentralRate of regionalmetastasis515%25

4、%40%90%Small Cell Lung Cell - a forgotten disease in targeted era？！病理分類WHO/IASLC肺上皮性腫瘤組織學分類 1.3.2. 小細胞癌(Small cell carcinoma) 變異(Variant) 1.3.2.1. 混合性小細胞癌(Combined small cell carcinoma) SCLC混合任何一種NSCLC成分，常見包括腺癌、鱗癌和大細胞癌（LCNEC），較少見的梭形、巨細胞癌等臨床特點男性約占80%典型表現：肺門部原發腫瘤縱隔LN形成的大腫塊、遠處轉移中央型占80%空洞少見胸腔積液發生率與其他類型相

5、近伴瘤綜合征受累器官組織診斷%尸檢%縱隔淋巴結66-8073-87肝21-2769骨27-4154腎上腺5-3135-65骨髓15-30NA腦10-1428-50腹膜后淋巴結3-1229-52鎖骨上淋巴結1742胸腔積液16-2030對側肺1-128-27軟組織519SCLC-StagingHistory and physical examinationRoutine hematologic and serum chemistry tests, LDHChest + (upper) abdomen CT scanBone scan CT with contrast or MRI of the

6、brainPET : invasive procedures/better definition of irradiation field, possible future role for better pt stagingVALG：SCLC-Staging- limited-stage disease : tumor confined to one hemithorax with or without homolateral nodes/pleural effusion that can be encompassed within a single tolerable radiation

7、therapy port - areas of controversy: contralateral hilar or supraclavicular nodes or malignant pleural or pericardial effusions - extensive disease: presence of metastatic disease 2007：SCLC Survival by TNM StageShepherd FA J Thorac Oncol 2007; 2: 1067-1077History of treatment 1969 RT 優于S CTX 優于BSC 7

8、0年代 放療更廣泛應用 聯合化療優于單藥 CAO成為標準方案 1979 EP方案出現 80年代 EP成為標準方案 90年代 化放聯合治療（LD） 新藥研究（CPT-11/ARM等） 靶向治療？治療原則Chemotherapy is the mainstay form of treatmentRadiotherapy also play a role，serving as “consolidation” therapy for individual with LDFor patients with ED，chemotherapy alone is the standard of care Ame

9、rican Cancer Society Atlas of Clinical Oncology：Lung Cancer 2002LD SCLC的治療外科化療放療外科在SCLC治療中的理論優勢 1）增加對原發腫瘤的控制率 2）切除混合的非小細胞癌成分3）化放療后長期存活者發生第二原發腫瘤的危險性增高，切除后可降低第二原發腫瘤的機會外科治療缺乏比較術后輔助治療和直接化放聯合治療可切除SCLC的RCT多項術后化療的II期研究，入選病例I-IIA期 5年生存率23-52% N % INCIDENTAL % % SURVIVAL ANY LOCALSTUDY RESECTED TREATMENT SCL

10、C p CR R0 MST % 2y % 5y RECURRENCE (mo) %Merkle et al 170 Various - - - - - 18 -Rea et al 104 Various - - - 28 - 32 24Prasad et al 97 Various 27 - - 12 37 17 -Massen et al 94 Various - - 86 - - 15 -Hage et al 74 Various 43 - - 17 35 25 -Davis et al 118 S - - - 18 39 20 -Sorensen et al 71 S - - - - -

11、 12 -Shore et al 40 S 57 - - - - 27 20Shah et al 28 S 36 - 93 34 55 43 -Shields et al 132 S-Chemo RT - - - 11 33 23 -Karrer et al 112 S-Chemo 58 - - 37 60 51 11Lucchi et al 92 S-Chemo 31 - 99 24 50 32 16 Shepherd et al 63 S-Chemo RT 64 - 90 19 45 31 11- Lad et al 70 Chemo-S RT+PCI - 19 77 15 20 10 -

12、 Shepherd et al 38 Chemo-S- RT - 8 87 21 47 36 18Eherhart et al 32 Chemo-RT-S - 34 72 36 - 46 -Holoye et al 22 Chemo-S - 19 - 25 54 33 14 Wiliams et al 21 Chemo-S - 16 84 - - - 28-Shepherd et al 28 Salvage * - - 82 24 48 23 - Average 81 22 44 28 19 * Resection of residual disease after CT +/- RTSurg

13、ery in SCLC化療或化療聯合胸部放療 A meta-analysis N Eng J Med 1992；327：161813項隨機臨床試驗共2140病例 化療 化放療 P3YS 8.9% 14.3% P=0.001 HR0.86 70歲 HR 1.07（95%CI:0.70-1.64） 結 論放療劑量和開始時間存在多種選擇 主要包括烷化劑和以ADM為基礎的方案局限期SCLC標準治療的地位 序貫或同期化放療 JCOG9104JCOG 910419.7月 27.2月Seq or Con：meta-analysis烷化劑和以ADM為基礎的聯合化療者， 同期或序貫放療結果相近選擇EP方案時 同

14、期化放療優于序貫化放療Proc Am Soc Clin Oncol 1995; 14abs早期或后期同期化放療 Systematic review:early or later radiation評價ERT和LRT對生存的影響7項隨機研究共1524病例meta分析包括了同期化放療和序貫化放療J Clin Oncol 2004;22(23):4837結 果 LRT ERT 2YS RR 1.17 P=0.033YS RR 1.13 P=0.2HFRT者2YS RR 1.44 P=0.001 3YS RR 1.39 P=0.04DDP-based 2YS RR1.30 P=0.002 3YS RR

15、1.35 P=0.01 結 論與LRT相比，ERT能提高2年生存率ERT的獲益相當于在化療基礎增加胸部放療或預防性腦放療的獲益程度獲益僅限于使用超分割放療者、選擇含DDP化療方案者ED SCLC 的治療化療放療靶向治療？EP regimen: since 1980sFirst introduced in 1979Later 1980s, extensively used the most accepted and widely used standard treatment for SCLC for the past 20 yearsEP in RCT studyregimenNRROSOnc

16、ology. 1992EPEP+IFO9278%74%2YS 15% 17%J Clin Oncol. 1992EPCAE43761%51%8.6M8.3MAnn Oncol. 2001EPEP+PTX13348%50%10.5M9.5M NSClin Lung Cancer. 2004EPEPI/DDP402NSNSJ Clin Oncol. 2005EPEP+PTX58768%75% NS9.9M10.6M NSJ Clin Oncol. 2006EPoraTPT/DDP78469%63%40.3W39.3W NSEDThorax. 2009EPGEM/DDP241NS8.1M8.0MJ

17、Natl Cancer Inst. 2009EPEP+thalidomide724NS10.5M10.1MEP or CE in SCLCJCOG9702CE方案 CBP AUC 5 d1， VP-16 80mg/m2 d1-3 q21dEP方案 DDP 25mg/m2 d1-3 VP-16 80mg/m2 d1-3 q21d JCOG9702中位年齡74歲（92% 70）男性88%PS 0-1/2-3者分別為74%/26%CE組63%、EP組67%接受4周期化療 療效 CE EP方案有效率 73% 73%中位PFS 5.3月 4.7月（p=0.20）MST 10.6月 9.8月1年生存率 4

18、1% 35%（p=0.54） 結論第一項比較CE和EP方案治療老年或PS差的III 期隨機研究 CE 和EP方案在總生存和毒性反應方面相似EP方案仍是ED SCLC的標準方案CE可作為替代選擇Irinotecan and Amrubicin myths from JapaneED-SCLC 1st Line Therapy-cisplatin basedEtoposide or Irinotecan?TRIALPATIENTSIP DOSESMedian OS (months)IP versus EPJCOG 95111154C 60 D1I 60 D1,8,15 q28d12.8 versu

19、s 9.4 (p = 0.002)Hanna2331 (2:1 IP to EP)C 30 D1,8 I 65 D1,8 q21d9.3 versus 10.2 (p = 0.74)SWOG 01243651C 60 D1I 60 D1,8,15 q28d9.9 versus 9.1 (p = 0.71)XRP4174D-3001405C 80 d1I 65 d1、8 q21d10.2 verse 9.7（P=0.07）1. Noda K, N Engl J Med 2002; 346: 85-912. Hanna N, J Clin Oncol 2006; 24: 2038-2046Nata

20、le R, J Clin Oncol 2008; 26: Abstract # 7512Zatloukal P,，Ann Oncol.2010;21(9): 1810-6Carboplatin based: Etoposide or Irinotecan?TRIALptsregimensMedian OS (months)IP versus EPHermes A,et al. J Clin Oncol.2008;26:4261IC : IRI 50mg/m2 d1、8， CBP AUC5 d1 q21dCE: CBP AUC 5 d1 VP-16 140mg/m2，d1-3 q21d10.09

21、.0個月（P=0.06）Schmittel A，et al., Ann Oncol.2011;22(8): 1798-804. 220IC：CBP AUC4 d1 IRI 175mg/m2 d1, q21dCE：CBP AUC 4 d1 VP-16 120mg/m2 口服d1-5， q21d8.57.1個月（P=0.02）ED-SCLC AmrubicinSynthetic 9-aminoantrhacyclineAntitumor effects correlated with intratumoral concentration of amrubicinolApproved in Japa

22、n for the treatment of both NSCLC and SCLC in 2002JCOG0509: Amrubicin Plus Cisplatin vs Irinotecan Plus Cisplatin in ED-SCLCProtocol amended after enrolling 191 patients to reduce amrubicin dose to 35 mg/m2 due to febrile neutropenia incidenceKotani Y, et al. ASCO 2012. Abstract 7003.Patients with u

23、ntreatedextended-stage SCLC, age 20-70, PS 0-1(N = 284)Irinotecan 60 mg/m2 on Days 1, 8, 15 +Cisplatin 60 mg/m2 on Day 1every 28 days for 4 cycles (n = 142)Amrubicin 40 mg/m2 on Days 1-3 +Cisplatin 60 mg/m2 on Day 1every 21 days for 4 cycles (n = 142)Stratified by PS 0 vs 1, institution, sexPCI give

24、n if CROutcomeIrinotecan + Cisplatin(n = 142)Amrubicin + Cisplatin(n = 142)ORR,* % CR PR SD PD Not evaluable72.31360323177.911661164Median OS, mos At second interim analysis Updated Amrubicin 40 mg/m2 Amrubicin 35 mg/m218.318.0-15.015.314.920.7Median PFS, mos5.75.1JCOG0509 : OutcomesKotani Y, et al.

25、 ASCO 2012. Abstract 7003.HR: 1.33*3 pts with no measurable lesion excluded from response analysis (irinotecan + cisplatin; n = 1; amrubicin + cisplatin: n = 2).JCOG05092013ASCO：AP&EP from ChinaSun Y, et al. ASCO 2013. Abstract 7507.Patients with untreatedextended-stage SCLC, (N = 299)VP-16 100 mg/m

26、2 on Days 1-3DDP 80 mg/m2 on Day 1every 21 days for 4-6 cycles (n = 150)Amrubicin 40 mg/m2 on Days 1-3Cisplatin 60 mg/m2 on Day 1every 21 days for 4-6 cycles (n = 149)2013 ASCO：AP&EPAmrubicin + Cisplatin(n = 149)DDP + Cisplatin(n = 150)RR %69.857.3PFS（months）7.136.37OS（months）11.7910.28gradeIII/IVne

27、utropenia54.4%44%一線治療持續時間6項隨機臨床研究4項選擇序貫化放療2項未選擇放療選擇CAV、CEV、CAE、EP等方案延長治療時間并不能獲益免疫、靶向治療不能獲益預防性腦放療Prophylactic Cranial Irradiation PCIPCI初治達CR者，2年內約有45%發生腦轉移，其中20-30%為單發轉移器官；腦轉移者中位生存期4-5個月；1999年的meta分析N Engl J Med1999;341(7): 476-84. 7項隨機臨床試驗、987病例結果： PCI減少16%的死亡危險,RR0.84(P=0.01) PCI治療組絕對提高3年生存率5.4% (

28、20.7%&15.3%)1999年的meta分析提高PFS（RR 0.75; P0.001）降低累計腦轉移發生率(RR 0.46;,P0.001)放射劑量的增加可降低腦轉移發生率（P0.05）但對總生存期無明顯意義；誘導治療結束早期給予PCI比延遲治療更能降低腦轉移危險（P=0.01） 3年生存率 PCI 20.7% No PCI 15.3%RR0.84(P=0.01)ED SCLC PCI：Study DesignPCI20-30 Gy in5-12 fractionsNo PCIRandomAny response 5 weeks4-6 weeksNo responseChemothera

29、py(4-6 cycles)Slotman et al. NEJM 2007(months)048121620242832360102030405060708090100PCIControl1 year:14.6% vs. 40.4%HR: 0.27 (0.16-0.44) p6M：original regimenRelapse 3-6MTPT，PTX，DOC，GEM，IRI，NVB，oraVP-16，TEMOZ，CAORelapse 3MTPT，PTX，DOC，GEM，IRI，IFO，TEMOZ，小 結內科治療30余年無進展生存的改善得益于RT LD RT 同期、分割以及PCI ED PCI

30、靶向治療?.問題：對治療高度敏感、快速耐藥New targets？Mutation frequenciesTP53 76.6%RB1 42.6%MYC family 12.8% PTEN 4.3%, CREBBP4.3%, EP300 4.3%, SLIT2 4.3%, MLL 4.3%, CCNE1 8.5% and SOX2 2.1%ERBB2 amplifications 5.3% mutations in PIK3CA 6.5%, HRAS 3.4%, AKT1 2.2%, BRAF 2% and KRAS 2%.Umemura S，et al 2013 ASCO abs7512Gia

31、ccone G, ，et al 2013 ASCO abs7513大細胞神經內分泌癌At the Cross Roads ofSmall and Non-small Cell Lung CancerLCNECs3-5% of all lung caner84%外周型吸煙相關老年男性多見外周大腫塊，早期區域LN及遠處受累CT：不均質強化，10%鈣化LCNECs化放療敏感性低于SCLC早期:外科仍占有重要角色回顧性研究輔助治療獲益化療方案？Stage I LCNECOverall survival of non-small cell lung carcinoma (NSCLC) n=774(84.

32、5%) large cell neuroendocrine carcinoma (LCNEC) n=27(65.4%)IP as adjuvant therapy for HGNECscompletely resected stage I-IIIA HGNEC four cycles of irinotecan (60mg/m2, day 1, 8, 15) plus cisplatin (60mg/m2, day 1).40 pts,median age 65 45-73 years male 85%; ECOG-PS 1 60% LCNEC 57% and SCLC 43% stage I

33、A/IB/IIB/IIIA 32/35/8/5%;95% received lobectomy.Lung Cancer. 2014 resultsLNECSCLCN23173-years RFS74%76%3-years OS86%74%Chemotherapy for advance LCNECChemotherapy for advance LCNECLCNECsIRI/DDPirinotecan (60 mg/m, days 1, 8, and 15) and cisplatin (60 mg/m, day 1) every 4 weeks 4 cycles30ptsRR 46.7%MS

34、T 12.6 monthsJ Thorac Oncol. 2013 Typical and atypical carcoidsindolent but not benignCarcoids12.0% of lung cancerAC 10-16% carcoids75% as intraluminal centrally locatedtypical carcinoids regional LN metastases in 1015% and distant metastases in 35%類癌綜合征少見 0.7%Chest radiographs a centrally located (

35、hilar or perihilar), well-defined solitary nodule or mass Associated postobstructive pneumonia and atelectasis may be present Most carcinoids (60%) occur in the right lung. Tumors range in size from 2 to 5 cm, with an average of about 3 cm 可切除者，外科切除輔助治療作用不明確The 5- and 10-year survival rates for pati

36、ents with typical carcinoid are 87% 100% and 82%94%, respectively, compared with 44%88% and 18%64% for patients with atypical carcinoid Advance carcoidsSimilar to Low grade neuroendocrine tumorsADM, 5-FU, dacarbazine, DDP,etoposide, streptozotocin, and CBPa-IFNSomatostatin analogues（SSA）Targeted the

37、rapyECOG 1281 trial249 cases advanced carcinoid tumors The ORR was15.9% for ADM/5-FU arm with an OS of 15.7 months 16% for the streptozotocin/5-FU group, with an OS of 24.3 monthsAt progression all patients received dacarbazine with an ORR of 8.2%J Clin Oncol 2005;23:4897904.Temozolamide10 advanced

38、TCs and 3 advanced ACs ORR of 31% and SD of 31% with a median time to progression (TTP) of 7 monthsTemozolamide + Thalidomide29 patients with neuroendocrine carcinomas received temozolamide 150 mg/M2 x 7 days q 14 days + thalidomide 50-40 mg QDAll(N=29)Carcinoid(N=15)PET(N=11)Pheo(N=3)Biochem (%)40R

39、R (%)2574533SD (%)68PD (%)7Kulke, MH, et al. J Clin Oncol 2006;24:401-406.CAPTEM for Metastatic Pancreatic Endocrine Carcinomas30 casesThe median time from diagnosis until onset of treatment 12 (1-101)monthsCapecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days

40、10-14) every 28 daysThe median duration of treatment was 8 cycles (range 3-23)Cancer 2011;117:26875.CAPTEM21 (70%) patients achieved an objective radiographic response. 27% SD Median PFS was 18 months. Median duration response 20 monthsThe rate of survival at two years was 92%.Only 4 patients (12%)

41、experienced grade 3/4 AETreatment with -Interferons(-IFN:s)Types of -IFN:SRecommended doses for classical midgut carcinoidsHuman leukocyte IFNLymphoblastoid IFN (Welferon)Recombinant IFN 2a (Roferon)Recombinant IFN 2b (Intron-A) IFNa 2b 3-5 MU x III-V/week s.c.NB! Individual dosing according to tole

42、rance and leukocyte count (3.0 x 109/l) is recommended-IFN: TreatmentSubjective ResponsesBiochemical ResponsesTumour Responses50-70%30-70%10-15%Treatment with Somatostatin Analogues (Octreotide)OctreotideCarcinoidSyndromeCarcinoid CrisesOctreotide LARRecommended dosing:100-600 g/day s.c. given as 2-

43、3 dosesExperimental: 1,500-3,000 g/day s.c. Preoperatively: 100 g s-c- 30 prior to operation and thereafter 50 g/hr i.v. infusion during op., continue postop. either with s.c. or i.v. therapyOctreotide i.v. 50-100 g/hr (Foregut carcinoid with histamine production, continue with H1 and H2 receptor bl

44、ockers)Long-acting formulation, dosing 20-30 mg i.m./4 w.Octreotide TreatmentSubjective ResponseBiochemical ResponseTumour Response30-75%(Dose dependent)30-60% (Dose dependent)0-15%(Not dose dependent)Somatostatin AnaloguesPROMID: Placebo Controlled, Double Blind, Prospective Randomized Study of the

45、 Effect of Octreotide LAR in the control of tumor growth in patients with Metastatic Neuroendocrine Midgut TumorsPrimary EndpointTime to ProgressionSecondary EndpointsOverall SurvivalResponse RatesArnold, GI ASCO 2009, abstract #121.85 patients with well-differentiatedmetastatic midgut NETsRANDOMIZE

46、Octreotide LAR 30 mg IM q4wksN=42Placebo IM q4wksN=43p=0.000072, HR 0.34 (95% CI 0.20-0.59)Time to ProgressionOverall SurvivalOctreotidePlaceboMedian OS not yet reachedSunitinib Phase III Trial-PET171 patients randomized to sunitinib 37.5 mg or placeboCrossover allowedStudy closed early due to benef

47、it of treatmentSunitinib(N=86)Placebo(N=85)HR (95%CI)P valuePFS (months)11.45.5.418 (.263, .662)6mo (%)34.924.7OSNRNR.409(.187, .894).0204Niccoli, P, et al. Proc ASCO 2010, abstract 4000. Progression-Free Survival1.00.80.60.40.20Proportion of patients051015202586391940085287210Number at riskSunitini

48、bPlaceboTime (months)Median PFSSunitinib11.4 months (95% CI 7.4, 19.8)Placebo 5.5 months (95% CI 3.6, 7.4) HR=0.418 (95% CI 0.263, 0.662)P=0.0001Overall Survival1.00.80.60.40.20Proportion of patients051015202586603816308561331230Number at riskSunitinibPlaceboTime (months)SunitinibPlacebo HR=0.409 (9

49、5% CI 0.187, 0.894)P=0.0204RADIANT-2 Phase 3 Double-Blind, Placebo-Controlled Trial: Study DesignEverolimus 10 mg/d + octreotide LAR 30 mg/28 daysn = 216Placebo + octreotide LAR 30 mg/28 daysn = 213Treatment until disease progressionPatients with advanced NET and history of symptoms attributed to ca

50、rcinoid syndrome, N = 4291:1Multiphasic CT or MRI performed every 12 weeksCrossoverPrimary endpoint: PFS (RECIST)Secondary endpoints: Tumor response, OS, biomarkers, safety, PKEnrollment January 2007March 2008CT: computed tomography; MRI: magnetic resonance imaging; OS: overall survival; PFS: progre

51、ssion-free survival; PK: pharmacokinetics; RECIST: Response Evaluation Criteria In Solid Tumors Pavel M, et al. ESMO 2010; Abstract LBA 8.RANDOMIZERADIANT-2: PFS by Central Review No. of patients still at riskE + OP + O216213202202167155129117120106102 8481726965635756505042423533242218171111 943111

52、000Kaplan-Meier median PFSEverolimus + octreotide LAR:16.4 monthsPlacebo + octreotide LAR:11.3 monthsHR = 0.77; 95% CI (0.591.00) P = .026Time (mo)02040608010002468101214161820222426283032343638% Event-freeTotal events = 223Censoring timesE + O (n/N = 103/216)P + O (n/N = 120/213)Pavel M, et al. ESMO 2010; Abstract LBA 8.*Independent adjudicated central review committee; P value obtained from one-sided log-rank test; HR obtained from unadjusted Cox model.E + O: everolimus + octreotide LAR; HR: hazard ratio; P + O: placebo +