CRITICAL ANALYSIS OF NEN GUIDELINES. G Pentheroudakis Associate Professsor of Oncology Medical School, University of Ioannina Chair, ESMO Guidelines

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1 CRITICAL ANALYSIS OF NEN GUIDELINES G Pentheroudakis Associate Professsor of Oncology Medical School, University of Ioannina Chair, ESMO Guidelines

2 DISCLOSURES NO CONFLICTS OF INTEREST TO DECLARE

3 UPDATED 2018 ESMO GUIDELINES (COMING SOON)

4 Table 1. Incidence and overall survival of NEN by site of origin 2012 [1] Localization Incidence/ Median OS NEN all NEN y all localized 3.1 >30y all regional y all distant y lung 1.6 small intestine (SI) 1.3 8,6y rectum y pancreas y stomach y appendix 0.3 n/a colon/cecum m a 10 HPF: (high power fields) = 2mm 2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic density Table 2a. Pancreatic neuroendocrine neoplasms (Pan-NEN) WHO Classification 2017 [4] Well differentiated NET, G1, Ki-67 <3%, <2 mitosis Well differentiated NET, G2, Ki %, 2-20 mitosis Well differentiated NET, G3, Ki-67 >20%, >20 mitosis Poorly differentiated NEC, G3, Ki-67 >20%, >20 mitosis MiNEN Table 2b. GI neuroendocrine neoplasms (GI NEN) WHO Classification 2010 [5] Well differentiated NET, G1, Ki-67 <3%, <2 mitosis Well differentiated NET, G2, Ki %, 2-20 mitosis Poorly differentiated NEC, G3, Ki-67 >20%, >20 mitosis MANEC b MIB1 antibody; percentage of tumor cells in areas of highest nuclear labelling

5 Biomarker Method Use LOE/GOR Ki-67 (MIB1) Immunohistochemistry Prognostic relevance, established for WHO grading IV A Sstr-2/5 Immunohistochemistry Detection of Somatostatinreceptors when no functional imaging is possible DAXX/ATRX- Immunohistochemistry Prognostic relevance for PanNET P53+/Rb- Immunohistochemistry Classification of poorly differentiated PanNEC/ Distinction from PanNETG3 IV C IV C IV C

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7 Table 7. TNM classification for endocrine tumors of the Pancreas [5] T TX T0 T1 T2 T3 T4 Primary tumor a Primary tumor cannot be assessed No evidence of primary tumor Tumor limited to pancreas, b 2 cm or less in greatest dimension Tumor limited to the pancreas b more than 2 cm but less than 4 cm in greatest dimension Tumor limited to pancreas, b more than 4 cm un greatest dimension or tumour invading duodenum or bile duct. Tumor perforates visceral peritoneum (serosa) or invades other organs or adjacent structures a For any T, add (m) for multiple tumours b Invasion of adjacent peripancreatic adipose tissue is accepted but invasion of adjacent organs is excluded. N NX N0 N1 M M0 M1 Regional lymph nodes Regional lymph node cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastases No distant metastasis Distant metastasis M1a Hepatic metastasis (is) only M1b Extrahepataic metastasis (is) only M1c Hepatic and extrahepatic metastases

8 Table 8. TNM classification for endocrine tumors of Jejunum and Ileum [5] T TX T0 T1 T2 T3 T4 Primary tumor Primary tumor cannot be assessed No evidence of primary tumor Tumor invades lamina propria or submucosa and 1 cm or less in greatest dimension Tumor invades muscularis propria or is greater than 1 cm in greatest dimension Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa (jejunal or ileal) Tumor perforates visceral peritoneum (serosa) or invades other organs or adjacent structures For any T add (m) for multiple tumors N NX N0 N1 N2 M M0 M1 Regional lymph nodes Regional lymph nodes cannot be assessed No regional lymph node metastasis Less than 12 regional lymph node metastasis without mesenteric mass (es) greater than 2 cm in sizes 12 or more regional nodes and/or mesenteric mass (es) greater than 2 cm in maximum dimension Distant metastasis No distant metastasis Distant metastasis M1a Hepatic metastasis (is) only M1b Extrahepatic metastasis (is) only M1c Hepatic and extrahepatic metastases

9 I Large randomised, controlled trials of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III Prospective cohort studies IV Retrospective cohort studies or case control studies V Studies without control group, case reports, expert opinions A B C Strong evidence for efficacy with a substantial clinical benefit, strongly recommended Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,...), optional D Moderate evidence against efficacy or for adverse outcome, generally not recommended E Strong evidence against efficacy or for adverse outcome, never recommended

10 The Magnitude of Clinical Benefit Scale: ESMO-MCBS Curative setting A & B or non-curative setting 5 & 4 Curative A B C Non-curative

11 OS Median with standard therapy ESMO-MCBS Primary endpoint PFS or TTP Median with standard therapy Other than OS or PFS 6 months> 6 months 1 year > 1 year

12 Evaluation form 2a: treatments with noncurative intent,primaryendpointos IF median OS with the standard treatment is 1 year Grade 4 HR 0.65 ANDGain 3 months Increase in2 year survival alone 10% Grade 3 HR 0.65 ANDGain months Increase in2 year survival alone 5-<10% Grade 2 HR > AND Gain months Increase in2 year survival alone 3-<5% Grade 1 HR > 0.70 ORGain < 1.5 month Increase in2 year survival alone < 3% Mark with Xif relevant

13 Step 1 Evaluation form 2a: treatments withnoncurative intent, primary endpoint OS Preliminary magnitude of clinical benefit grade (highest grade scored) Step 2 Step 3 Assessment QoL & grade 3-4 toxicities Does secondary endpoint QoL show improvement Are there statistically significantly < grade 3-4 toxicities impacting daily well-being* *not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc. Adjustment: Upgrade 1 level if improved QoL or less toxicity or is shown Final adjusted magnitude of clinical benefit grade

14 Evaluation form 2b: treatments with noncurative intent, primary endpoint PFS or TTP Studies with median PFS with standard treatment 6 months Grade 3 HR 0.65 ANDGain 1.5 months Mark with Xif relevant Grade 2 HR 0.65 BUT Gain < 1.5 months Grade 1 HR > 0.65

15 Evaluation form 2b: treatmentswith noncurative intent, primaryendpointpfs or TTP Step 1 Preliminary magnitude of clinical benefit grade (highest grade scored) Toxicity and QoLadjustment when only a PFS improvement

16 What is new in v1.1 Evaluation form 2a: for therapies that are not likely to be curative with primary endpoint of OS with separate sheets for: IF median OS with the standard treatment is <12 months IF median OS with the standard treatment >12 month, <36 months IF median OS with the standard treatment >36 months Upgrade 1 level if study had early crossover because of early stopping or detection of survival advantage at interim analysis Upgrade 1 level if there is a long term plateau in the PFS curve, and there is >10% improvement in PFS at 2 years Grade 3 PFS >6 months Mark with X if relevant ORR (PR+CR) >60% ORR (PR+CR) >20% but less than 60% AND Duration of response >9 months

17 Distribution ESMO-MCBS 1.0 gradesema approvedsolidtumor drugs since2016 Vivot et al, Ann Oncol 2017

18 2018 NCCN GUIDELINES

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24 THANK YOU!