OUTLINE. Background. What in NEC. What in NET G3. What in Minen/Manec. Future prospective. Conclusions

Transcription

1

2 OUTLINE Background What in NEC What in NET G3 What in Minen/Manec Future prospective Conclusions

3 Median OS of poorly differentiated neuroendocrine carcinomas (NECs) The median survival for all cases was 7.7 months. Dasari A, et al. JAMA Oncol 2017 Dasari A, et al. Cancer. 2017

4 38.7% 95.2% Dasari A, et al. Cancer. 2017

5 Things To Keep In Mind Before Starting High-quality data regarding poorly differentiated NECs are lacking due to the rare incidence of these malignancies outside of the lung and diverse primary sites Significant differences in demographics, stage at diagnosis, and survival were noted based on the primary site and morphological subtype Lung and Extrapulmonary Poorly Differentiated Neuroendocrine Carcinomas are not the same Ideally, future studies therefore should distinguish between lung NECs and extrapulmonary NECs and should consider stratifying patients according to the different primary sites

6 OUTLINE 1 2 What in NEC

7 Garcia-Carbonero R, et al. Neuroendocrinology 2016

8 Cisplatinum and Etoposide 67% with anaplastic neuroendocrine pathologic findings had objective tumor regression The median OS for was 19 months The overall OR rate was 41.5% Median PFS was 8.9 months for poorly differentiated tumours Moertel CG, et al. Cancer 1991 Mitry E, et al. Br J Cancer 1999

9 Recent large retrospective 1-line chemotherapy studies in metastatic GEP NEN G3 Treatment No Diff RR% OS% PFS mos Sorbye et al Ann Oncol 2013 Cis or Carbo + VP16 252? m 11 m Yamaguchi et al Cancer Sci 2014 CIS + CPT 11 or VP Poorly? m 11.5 m Heetfeld et al Endo Rel Cancer 2015 Walter et al Eur J Can 2017 Platinum/ VP Poorly m 16.4 m Platinum/VP Poorly m 11.6 m

10 Does platinum/vp 16 fit all NEC? PR/CR SD PD PFS OS All Pts 31% 33% 36% 4m 11 m Colon 16% 28% 56% 3 m 8 m Sorbye H. et al. Ann of Oncol 2013

11

12 Evidences i.v. vs oral Cisplatin vs Carboplatin Etoposide vs Irinotecan Significant variation?

13 Patients were collected from the Nordic NEC study. Patients were given etoposide as short infusion ( 5 h), long infusion (24 h), or oral tablet (O.E.). No statistically signifcant diferences between the three administration groups Ali AS, et al. Med Oncol. 2018

14 Imai H, et al. Chemotherapy 2015

15 Irinotecan plus Cisplatin Garcia-Carbonero R, et al. Neuroendocrinology 2016; Yamaguchi T,et al. Cancer Sci 2014; Li J, et al. Oncotarget 2017

16 Is 3 better than 2? Hainsworth JD, et al.jco 2006

17 CT vs Immuno in I L Metastatic MCC m PFS 4.6 months mpfs 9.1 months (range, 1.9 to NE) D Angelo SP, et al. JAMA Oncol 2018 Cowey LC, et al. Future Oncol.2017

18 In Pretreated Metastatic MCC Cowey LC, et al. Future Oncol.2017 Kaufmanet HLal. J Immunother Cancer 2018

19 Second line Chemotherapy in PDNEC Hadoux et al. (2015) Hadoux J, et al. Endocrine-Related Cancer 2015

20 Randomized Phase II Trials: Chemotherapy in NECs Study Design Phase II NCT Phase II NCT Phase I/II NCT Phase II NCT Phase II NCT Phase II NCT Phase I/II NCT Phase II NCT Phase II NCT Phase II NCT Tumor Origin Line of Treatment Treatment Primary Endpoint Status NEC of I Everolimus + CIS DCR recruiting Extrapulmonary GEP-NEC Ki % I Everolimus + TMZ DCR recruiting SCLC, LC (NSCLC), SC extrapulmonary I Cis + VP16 + Veliparib MTD, PFS Active Not recruiting NEC I Cis + CPT11 vs Cis + VP16 ORR recruiting GEP-NEC Ki % I CAPTEM vs CIS/CARBO + VP16 PFS recruiting NEC I Carbo + Nabpaclitaxel ORR Active Not recruiting SCLC, NSCLC, ovarian cancer, cervical cancer, and NECs NEC from GEP or an unknown primary I Topotecan + VX-970 MTD, Clinical RR recruiting II Folfiri Bevacizumab vs Folfiri Proportion of pts alive 6 mo after treatment recruiting NEC II S1+ Oxaliplatin ORR recruiting NEC II FOLFIRI ORR recruiting

21 Randomized Phase II Trials: Chemotherapy in NECs

22 Garcia-Carbonero R, et al. Neuroendocrinology 2016

23 Prospective studies evaluating the outcomes of adjuvant therapy following surgery for SCLC Authors N Stage ADJ Regimen Overall survival Macchiarini et al. Am J Clin Oncol Karrer et al. Acta Oncol Rea et al. Eur J Cardiothorac Surg Tsuchiya et al. J Thorac Cardiovasc Surg T1-3N0M0 CT Cyclophosphamide + epirubicin + etoposide at 3-week intervals 6 cycles 183 T1-2N0M0 CT + PCI Cyclophosphamide + doxorubicin + vincristine at 3-week intervals x 8 cycles, or alternating chemotherapy using 3 different drug combination for 6 months 51 of 104 I-II CT + RT Doxorubicin + cyclophosphamide + vincristine on day 1 alternating with courses of cisplatin on day 1 and etoposide on days 1, 3, and 5 (DDP/VP16); Cisplatin day 1, etoposide days 1-3, and epirubicin day 1 62 I-II-IIIa CT Cisplatin + etoposide (days 1 3) 4 cycles 5-year survival rate: 36% 4-year survival rate: 56% 5-year survival rate: 52% 5-year survival rate is 73% for IA and 67% for IB. 3-year survival rate is 61% (68% for stage I, 56% for stage II, and 13% for stage IIIa)

24 OUTLINE What in NET G

25 WHO Classification 2017 for Pancreatic Neuroendocrine Neoplasms NET G3?

26 Sorbye H. et al. Ann of Oncol 2013 Milione M. et al. Neuroendocrinology 2017

27

28 Characteristics and treatment of patients with G3 GEP neuroendocrine neoplasms Two hundred and four patients with NET G3 and NEC from eight European centers were analyzed (37 NET G3 and 167 NEC) First, Second and Third line of treatment NEC G3 NET G3 Regimen Number (%) Regimen Number (%) Platinum + VP (84%) Platinum + VP16 7 (24%) FOLFOX/XELOX 10 (7%) Temozolomide-based 5 (17%) FOLFIRI 2 (1%) Dacarbazine-based 4 (14%) TXT/CIS/5FU 2 (1%) FOLFOX/XELOX 3 (10%) Other 6 (4%) Other 10 (35%) Heetfeld M, et al. Endocrine-Related Cancer 2015

29 HOW TO PICK THE RIGHT ROAD? Until better classification and more treatment data are avalaible for NEN G3 pts several factors should be considered: Differentation Ki 67% Clinical presentation (tumor buden/growth)

30 Randomized Phase II Trials: Chemotherapy in NETs G3 Study Design Phase II NCT Phase II NCT Tumor Origin GEP G3 Ki67% 20-60% GEP-NETs Ki % Line of Treatment Treatment Primary Endpoint Status Any TEMCAP ORR recruiting I line CAPTEM vs CIS + VP16 PFS recruiting Phase II NCT Well-differentiated GEP-NET Any CAPTEM vs Cape + Dacarbazine ORR Recruiting Phase II NCT Extrapancreatice NET (G1, G2 or G3) No more than two Tegafur + Temozolomide vs Tegafur + Temozolomide combined with Thalidomide ORR recruiting

31 OUTLINE What in Minen/Manec 5 6

32 MANEC/MiNEN Juxtaposition without mixing Not common precursor two components that coexist in: an intermingled population one predominant + focal area phenotypes of at least two neoplasms De Mestier L, et al.neuroendocrinology 2017

33 Ki67 proliferative index of the neuroendocrine component drives MANEC prognosis Milione M, et al. Endocr Relat Cancer 2018

34 MANEC/MiNEN De Mestier L, et al.neuroendocrinology 2017

35 Expression Analysis of Genes involved in DNA Repair or Synthesis in Manec Volante M, et al.neuroendocrinology 2015

36 Duodenocefalopancreasectomia. Caso clinico

37 DCP Xelox (3 cicli) CPT11 (3 cicli) CapTem

38 OUTLINE Future prospective 6

39 Predictive Biomarkers Surrogate markers of cell kinetics or cell biology Tumor differentiation Ki67 index Tumor site (pancreatic vs non-pancreatic) Drug-specific markers Temozolomide: MGMT 5FU: TS Platinum agents: BRCA

40 Temozolomide and MGMT TMZ Methylation To remove the O6-alkylguanine adducts Repaired DNA breaks Apoptosis

41 Retrospective, Pts 28; IHC and PCR Retrospective, Pts 20, IHC Retrospective, Pts 24; IHC Retrospective, Pts 95; MS-PCR or pyrosequencing Retrospective, Pts 52; IHC Retrospective, Pts 43; IHC and PCR Italian phase II study testing TEM and lanreotide in bronchial carcinoid tumors American randomized phase II studycomparing TEMcapecitabine vs. TEM alone in pancreatic NET Retrospective, Pts 47; IHC and MS-PCR 41

42 IHC MGMT expression was evaluated in 52 pnets Cives M et al. Endocrine-Related Cancer 2016

43 MGMTpromoter methylation status was evaluated using two techniques: methylation specificpolymerase chain reaction (MS-PCR) or pyrosequencing (PSQ) The presence of MGMT promoter methylation represented a strong predictive factor for response at univariate and multivariate analysis Median PFS was found to be significantly longer in patients with MGMT promoter methylation (21.0 vs. 8.0,p=0.017 Campana D, et al. Endocrine 2017

44 WD PD Ceppi P, et al. Clin Cancer Res. 2008

45 Scarpa A et al. Nature 2017

46

47 Conclusions Besides recent advantages in the pathogenesis of NETs and the introduction of targeted therapies, chemotherapy still remains an important therapeutic modality, as it is associated with clinically meaningful responses in a number of patients. Chemotherapy is currently the only available treatment for poorly- or well-differentiated G3 tumors Advances in predictive biomarkers, ideally molecular markers, may help identify suitable patients, stratify treatment and minimize toxicity Multicentre prospective studies will help identify the place of chemotherapy and its sequencing along with other existing therapies

48 No two zebra stripes are alike Grazie!

49 La chemioterapia nell alto grado A cura di Valeria Smiroldo Carlo Carnaghi 06 Giugno 2018