ΧΗΜΕΙΟΘΕΡΑΠΕΙΑ ΣΤΑ ΝΕΤ: ΝΕΩΤΕΡΕΣ ΕΞΕΛΙΞΕΙΣ ΚΑΙ ΠΡΟΒΛΗΜΑΤΙΣΜΟΙ

Transcription

1 ΧΗΜΕΙΟΘΕΡΑΠΕΙΑ ΣΤΑ ΝΕΤ: ΝΕΩΤΕΡΕΣ ΕΞΕΛΙΞΕΙΣ ΚΑΙ ΠΡΟΒΛΗΜΑΤΙΣΜΟΙ ΑΝΝΑ ΚΟΥΜΑΡΙΑΝΟΥ Ph.D ΔΙΕΥΘΥΝΤΡΙΑ ΕΣΥ, ΠΑΘΟΛΟΓΟΣ-ΟΓΚΟΛΟΓΟΣ ΑΙΜΑΤΟΛΟΓΙΚΗ-ΟΓΚΟΛΟΓΙΚΗ ΜΟΝΑΔΑ Δ ΠΑΝΕΠΙΣΤΗΜΙΑΚΗ ΠΑΘΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΕΘΝΙΚΟ ΚΑΙ ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΓΠΝΑ ΑΤΤΙΚΟΝ

2 Chemotherapy in NENs: debated points Research features: Evidence (phase III trial, control arm, homogeneous population) Predictive factors (Ki-67? FDG-PET? MGMT) Clinical features: Clinical setting 1 (high grade/low grade, primary sites) Clinical setting 2 (unresectable locally advanced, adjuvant) Clinical setting 3 (Tumor burden and site of metastases:liver tumor load, diffuse bone metastases) Histology (NEC, NET) Aim of treatment (tumor shrinkage, tumor growth control) Technical features Schedules (conventional, metronomic) Drugs (platinum derivatives, alkylating, fluoropyrimidines, other)

3 APPROVED MEDICAL THERAPIES FOR THE TREATMENT OF ADVANCED NET Octreotide Depot 9 FDA approval: Sunitinib in pnet 4 FDA approval: Lanreotide in GEP-NET FDA approval: Streptozocin in pnet 1,2 Temozolomide 8 FDA/EMA approval: Everolimus in pnet 5,6 1. Zanosar (streptozocin) SmPC 2011; 2. Blumenthal GM et al. Oncologist 2012;17: ; 3. Sutent (sunitinib) SmPC, 2014; 4. Sutent (sunitinib) PI 2011; 5. Afinitor (everolimus) PI 2011; 6. Afinitor (everolimus) SmPC 2015; 7.Somatuline depot (lanreotide) PI 2014; 8. Strosberg JR, et al. Gastrointest Cancer Res 2008;2: ; 9 Rinke JCO 2009

4 GEP NENs: classification WHO 2010 GEP NENs G1 (Ki-67 < 2% and/or MI < 2) MULTIPLE THERAPIES Well differentiated TUMOR (NET) Low/intermediate % grade (SSA, IFN, Everolimus, Sunitinib, PRRT, Chemotherapy, G2 G3 Liver-directed treatments, surgery) (Ki % and/or MI 2-20) G3 Poorly differentiated Chemotherapy G % CARCINOMA High grade (NEC) (Ki-67 > 20% and/or MI > 20)

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6 Cisplatin was identified by Barnett Rosenberg in 1965 Physicist 1926 to 2009 Rosenberg B, Van Camp L, Krigas T, Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 205: , 1965 Muggia et al., J Clin Oncol, Dec 2015

7 High grade NECs: CDDP + VP-16 Author Drugs N. pts WD PD PR/CR % RD m TTP m OS m tumors Moertel 1991 CDDP + VP mix Mitry 1999 CDDP + VP mix Fjallskog 2001 CDDP + VP Pancreas foregut midgut Hainsworth JCO 2006 Taxol + CDDP + VP nr Smallcell, Merkel, G3

8 Second-line chemotherapy in G3 NECs Hadoux et al., End Rel Cancer 2015

9 Oncologist Jun;21(6):671-5 The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors. Ramirez RA, Beyer DT, Chauhan A, Boudreaux JP, Wang YZ, Woltering EA. capecitabine and temozolomide could potentially be an option for patients with advanced neuroendocrine tumors who have progressed on standard treatment

10 J Transl Med May 3;14(1):113 Metronomic temozolomide as second line treatment for metastatic poorly differentiated pancreatic neuroendocrine carcinoma. De Divitiis et al. European Neuroendocrine Tumor Society (ENETS) Center of Excellence- Multidisciplinary Group for Neuroendocrine Tumors in Naples (Italy). Treatment with metronomic "one-week-on/onweek-off" Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pnec with MGMT methylation.

11 the clinical behavior of G3 poorly differentiated neuroendocrine carcinomas of the GEP tract does not necessarily correspond to that of small cell cancer of the lung or any other sites Rindi et al., Virchows Arch TNM staging..

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13 G3 (Ki %) GEP NECs Prognostic factors Tumor morphology: Well vs. Poorly diff. Ki-67: 20-55% vs. > 55% Primary site: pancreas vs. colon Milione et al., Neuroendocrinology 2016 Heetfeld et al., End Rel Cancer 2015 Basturk et al., Am J Clin Pathol 2015 Velayoudome-Cephise et al., End Rel Cancer 2013 Sorbye et al., Ann oncol 2013

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15 Type A Type B Overall survival of 136 patients with GEP NEC according to histological subtype Type C Figure 1: 1A + 1A1: Type A neuroendocrine carcinoma. The neoplasm is composed of relatively monomorph neoplastic cells, arranged in regular nests without necrosis, with nuclei showing finely dispersed chromatin without evidence of severe atypia. The proliferation index assessed with MIB1 Ki67 is less than 55% (1 A1). 1B + 1B1: Type B neuroendocrine carcinoma. The neoplasm is composed of atypical neoplastic cells, distributed in irregular structures for size and shape, with prominent nucleoli and intratumoral necrotic foci. The proliferation index assessed with MIB1 Ki67 is less than 55% (1 B1). 1C + 1C1: Type C neuroendocrine carcinoma. The neoplasm is composed of large and intermediate neoplastic cells, with atypical nuclei with prominent nucleoli. Abundant intratumoral necrosis is evident. The proliferation index assessed with MIB1 Ki67 is 55% or more (1 C1). Type A = well diff. + Ki % Type B = poorly diff. + Ki % Type C = poorly diff. + Ki-67 > 55% Milione et al., Neuroendocrinology Mar 2016 Downloaded by: ENETS /6/ :00:59 PM

16 Systemic therapies in GEP NECs As in G2 NETs Well differentiated with Ki-67 > 20% Poorly differentiated Ki % Poorly differentiated Ki-67 > 55% Alkylating-based chemotherapy Cisplatin/carboplatin + etoposide

17 generally not successful in the majority of G3 tumors [45]. ENETS 2016 guidelines GEP NEC Minimal consensus statement on treatment For patients with localized disease, combination of platinum-based chemotherapy with local treatment consisting of surgery, radiotherapy or both probably offers the greatest likelihood of long-term survival. Debulking or surgical resect ion of metastasis are not recommended. Systemic chemotherapy is indicated in advanced inoperable disease, provided the patient has adequate organ function and performance status and patients should be rapidly referred for consideration of palliative chemotherapy. The combination of cisplatin and etoposide, or alternative regimens substituting carboplatin for cisplatin, or irinotecan for etoposide, are recommended as first-line therapy. Since response rates of these regimens are lower in patients with Ki-67 in the lower range of G3 (20-55%), other treat ment options may be explored in these patients (especially perhaps for NEC of GI origin). While 2nd-line regimens have not been evaluated rigorously, options include temozolomide-, irinotecan- or oxaliplatinbased schedules as main alternatives. There are no data to support the use of somatostatin analogs or PRRT in patients with GEP NECs expressing so matostatin receptors. Prophylactic cranial irradiation is not indicated in patients with limited-stage disease in complete remission. Follow-up Garcia-Carbonero et al., Neuroendocrinology Jan 2016

18 Oncologist Oct;21(10): Epub 2016 Jul 8. Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. Coriat R, Walter T, Terris B, Couvelard A, Ruszniewski P. The chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 when the Ki-67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki-67 is above 55%.

19 Patient with liver mets from moderately differentiated PNET, Ki67 40% 5 weeks of Sunitinib 37.5 mg/d

20 Chemotherapy in low/intermediate grade NENs

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22 For neuroendocrine G1/G2 tumors (Ki %), streptozotocin-based combinations have been used as first-line treatment for more than 3 decades. Eriksson B., in Neuroendocrine Tumors, by Oberg & Yalcin, Springer ed. 2015

23 Streptozotocin or Streptozocin (STZ) 1968: Murray-Lyon et al., Reported effect on hypoglicaemia and tumor growth in PNET 1980: Moertel et al. published STZ +/- 5FU in PNET 1982: FDA approval of STZ in islet cell carcinoma

24 STREPTOZOTOCIN: Comparative trials in pancreatic NET Author Drug N pts RR(%) CR(%) DR(m) S(m) Moertel, STZ NEJM 1980 STZ/FU Engstrom, ADM JCO 1984 STZ/FU p 0.25 Moertel, STZ/FU NEJM 1992 STZ/ADM CLZ RR: tumor response rate; CR: complete response; DR: duration of response; S: survival STZ = streptozotocin; FU = fluorouracil; ADM = adryamicin; CLZ = clorozotocin Main toxicity: Nausea/Vomiting Nephrotoxicity - Hepatotoxicity

25 FAS regimen Fluorouracil Adriamycin Streptozotocin Author Regimen N pts PR (%) SD(%) DR(m) PFS(m) OS(m) Kouvaraki, STZ, JCO 2004 FU, (24-78) (2-51) ADM Toxicity: 20% G3-4 AEs PR: partial response; SD: stable disease; DR: duration of response; OS: overall survival; m: months; STZ: streptozotocin; FU: fluororuacil; ADM: adriamycin Retrospective analysis All pancreatic

26 Streptozocin (STZ) Dacarbazin (DTIC) Temozolomide (TMZ)

27 Table 1. Koumarianou et al., Neuroendocrinology 2015

28 Crespo et al. Future Oncol Nov 2. Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. This is the largest reported series of NETs (65pts) treated with capecitabine and temozolomide in daily practice and shows that this combination is a promising treatment option for both grade 1/2 pnets and non-pnets.

29 45 y.o. male patient symptomatic due to weight loss, low appetite, moderate pain, dyspepsia, fatigue Sinchronous liver mets from PNET G2, Ki-67 18% TMZ + CAP x 6 cycles May 2012 Nov 2012

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31 Neuroendocrinology (DOI: / ) 2016 S. Karger AG, Ba Oxaliplatin-based chemotherapy in NENs Appendix 1. Trials with oxaliplatin based chemotherapy in NENs by year of Publication (Mixed tumor population for each study) Author [Reference] Publicatio n Year Regimen Study Type No. Pts Bajetta [17] 2007 XELOX Phase II Pape [20] 2006 FOLFOX R 16 None 62 4 NR Venook [21] 2008 FOLFOX6+BEV Phase II NR NR1 9 Cassier [18] 2009 GEMOX R Kunz [22] 2010 XELOX+BEV Phase II Ferrarotto [36] 2013 XELOX R NR Dussol [19] 2015 GEMOX R Walter [37] 2015 GEMOX FOLFOX PR % SD % PFS (mo) OS (mo) R Abbreviations: Pts, Patients; R, Retrospective; PR, Partial Response; SD, Stable Disease; PFS, Progression Free Survival; OS, Overall Survival; Mo, Months; NR, Not Reached; XELOX, Xeloda/Oxaliplatin; FOLFOX, Leucovorin/Fluorouracil/Oxaliplatin; BEV, Bevacizumab; GEMOX, Gemcitabine/Oxaliplatin. Spada et al., Neuroendocrinology 2016

32 Oxaliplatin-based chemotherapy in NENs Neuroendocrinology (DOI: / ) 2016 S. Karger AG, Basel 24 TABLE 2. Activity and efficacy related to primary site. Outcome All (n=78) Pancreas (n=36) GI (n=19) Lung (n=15) Unknown (n=8) CR+PR: n (%) 20 (26) 12 (33) 5 (26) 1 (12.5) 2 (13) XELOX 12 (60) 7(58) 3 (60) 0 2 (100) FOLFOX 6 (30) 3 (25) 2 (25) 1 (100) 0 GEMOX 2 (10) 2 (60) SD : n (%) 42 (54) 19 (53) 7 (37) 6 (75) 10 (67) XELOX 30 (71) 15(52) 3(43) 4(67) 8(80) FOLFOX 11(26) 4(21) 4(57) 2(33) 1(10) GEMOX 2 (5) 1(3) 0 0 1(10) PD : n (%) 14 (18) 4 (11) 6 (31) 1 (12.5) 3 (20) XELOX 9 (64) 2 (50) 3 (50) 1 (100) 3 (100) FOLFOX 4 (29) 1 (25) 3 (50) 0 0 GEMOX 1 (7) 1 (25) NE : n (%) 1 (1) 1 (3) PFS (mo.) 8 OS (mo.) 32 Abbreviations: CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; NE, Spada et al., Neuroendocrinology 2016 Not Evaluable, Mo, Months

33 Advanced PNENs: 2015 ENETS guidelines Neuroendocrinology (DOI: / ) 2016 S. Karger AG, Basel 21 Figure 3: Therapeutic algorithm for the management of pancreatic NEN with advanced loco regional disease and/ or distant metastases

34 2015 ENETS guidelines PNETs Neuroendocrinology (DOI: / ) 2016 S. Karger AG, Basel 22 Table 1.

35 Neuroendocrinology (DOI: / ) 2016 S. Karger AG, Ba Advanced midgut NENs: 2015 ENETS guidelines Figure 2: Therapeutic algorithm for the management of intestinal (midgut) NEN with advanced loco

36 GETNE-1206 (SEQTOR): Phase III Study in Patients With Advanced GETNE pnet1206 (SEQTOR) phase III trial in patients with advanced PNETs Compare efficacy and safety of everolimus followed by chemotherapy with STZ + 5-FU upon progression, or the ongoing reverse sequence (chemotherapy with STZ + 5-FU followed by everolimus upon progression) Arm A: Everolimus Everolimus Progression Arm B: STZ + 5-FU STZ + 5-FU Primary end point: rate of second PFS at 84 weeks of treatment Unpublished data. Clinicaltrials.gov ID, NCT

37 The Cap/Tem regimen proved effective in all neuroendocrine subtypes including GI non-pnets and bronchial carcinoids No consensus about the clinical use of MGMT as a predictive factor to TMZ. Kotteas et al., Oncotargets and therapy 2016

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41 Pancreatic NETs Temozolomide and MGMT

42 Pancreatic NETs Temozolomide and MGMT

43 Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Cives M et al. Endocr Relat Cancer Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation

44 Cros et al. Endocr Relat Cancer Aug;23(8): MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. High MGMT promoter methylation was associated with longer PFS (HR=0.37 ( ), P=0.05).

45 Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours. Childs et al. Endocr Relat Cancer Jul;23(7): doi: /ERC Response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT

46 Panagiotidis et al. J Nucl Med Aug 11. Comparison of the impact of 68Ga-DOTATATE and 18F-FDG PET/CT on clinical management in patients with neuroendocrine tumors. in PD NETs, 18F-FDG PET/CT plays a significant clinical role in combination with 68Ga-DOTATATE. 68Ga DOTATATE SUVmax values relate to tumor grade and Ki67 index and can be used prognostically.

47 CRITERIA TO CHOOSE A SINGLE THERAPY IN NET

48 CHECKPOINT INHIBITORS AND IMMUNE MODULATORS

49 Precision medicine!

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