Upper GI Cancers: Risk Stratification and Treatment Selection David H. Ilson, MD, PhD Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center

Disclosure Research Funding – Roche-Genentech – Bayer – sanofi-aventis – BMS-Imclone

UGI Cancers, Risk Stratification and Therapy Staging of Gastric and Esophageal Cancer for treatment selection Benefits of adjuvant chemotherapy and radiation therapy Appropriate selection of chemotherapy for Stage IV disease Pancreatic Cancer adjuvant and advanced disease therapy

Esophageal and Gastric Carcinoma US Incidence in ,500 new cases Decline in Gastric Cancer Incidence Increase in Esophageal, GE JX, cardia adeno OS improvement, , , – Gastric: 16%  18%  27% – Esophageal: 5%  10%  19% Highly virulent diseases with poor outcome Jemal et al, CA 61: ; 2011

New AJCC Staging: Survival in over 13,000 pts with gastric cancer, SEER database McGhan J Gastro Surg 16: 53; 2012

Gastric Cancer Preop therapy: T3 or N+ T1A: EMR T1B, T2: Primary resection

New AJCC Staging: Survival in over 4600 pts with esophageal and GEJ cancer Rice Cancer 2010

Esophagus, GEJ Preop therapy: T2-3 or N+ T1A: EMR T1B: Primary resection

PET SCAN: Staging (15% occult mets), and Determine Response to Preop Chemo SUV = 10.6 SUV = 2.2

Laparoscopy in Gastric Cancer CT and PET scan may miss small volume liver or peritoneal disease For gastric cancer, laparoscopy detects peritoneal or liver disease in 20-30% of patients – Not mandated for GEJ cancers: < 5% positive lap findings A positive cytology = Stage IV disease – Patients do not benefit from immediate gastrectomy – They should be treated with palliative chemotherapy – ? Reassess response and consider selective surgery No long term survivors with + cytology

Adjuvant Therapy in Gastric Cancer Improves OS Pre and post op chemo (U.K.) – ECF, MAGIC: 13% 5 yr OS, HR 0.75 Post op chemo (Asia): 2 trials, 2000 pts, D2 resection – S-1, ACTS-GC: 13% 5 yr OS, HR 0.67 (2011 update) – Post op Cape-Oxali, CLASSIC Trial: 14% 3 yr DFS, HR 0.56 Post op RT + chemo (U.S.), less than a D1-2 resection – 5FU-LV + RT, INT 116: 10% 5 yr OS, HR 0.65 Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 Bang LBA 4002, Proc ASCO 2011 Macdonald NEJM 345:725; 2001

Optimal Surgery for Gastric Cancer? D2 resection is the standard of care in Asia Increasingly in the West D2 resection is considered the standard Update of Dutch D1 vs D2 resection at 15 years supports D2: Songun I et al Lancet Oncol 11: 439; 2010

Optimal Adjuvant Chemotherapy? Support of 5-FU monotherapy – ACTS-GC: S-1 – CALGB 80101: ECF no better than 5-FU/LV, when given post op with FU + RT Support for 5-FU + platinum agent – CLASSIC: Capecitabine-Oxaliplatin – FNCLCC-FFCD and MAGIC: CF and ECF Fuchs Abs 4003, Proc ASCO 2011 Bang LBA 4002, Proc ASCO 2011 Ychou J Clin Oncol 29: 1715; 2011

Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=1035 Capecitabine: 1,000mg/m 2 bid, d1–14, q3w Oxaliplatin: 130mg/m 2, d1, q3w RANDOMIZATIONRANDOMIZATION 1:1 † n=520 n=515 Primary endpoint: 3-year DFS ‡ Secondary endpoints: overall survival and safety profile † Stratified by stage and country with age, sex, and nodal status as covariates ‡ GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009 CLASSIC study design 8 cycles of XELOX (6 months) Observation: No adjuvant therapy

Primary endpoint (3-year DFS) met at interim analysis ITT population; DFS = disease-free survival Median follow-up 34.4 months (range 16–51) year DFS 74% 60% HR=0.56 (95% CI 0.44–0.72) P< Time (months) Observation, n=515 XELOX, n= XELOX Observation No. left

Regional Therapies as Adjuvant? Role of post op RT – U.S. INT 116: < D1-2 resection, RT reduced local recurrence – ARTIST (Korea, JCO in press), D2 resection Cape-Cis vs Cape-Cis + RT DFS benefit in node + patients for adding RT  5% improvement in 3 year DFS, HR 0.69 Ongoing Trials – CRITICS: Preop ECX, post op ECX + / - RT – TOPGEAR: Preop ECX + / - RT

Esophageal Adenocarcinoma: Adjuvant Therapy Improves OS T2-3 or N1: Something more than surgery alone should be done Preoperative chemotherapy ECF, CF improves overall survival in some but not all trials – MAGIC (ECF): 13% ↑ OS at 5 yr (75% gastric, 25% esophageal) – FFCD / FNLC (CF): 14% ↑ OS at 5 yr (gastric and esophageal cancer)  same as MAGIC, no epirubicin – MRC 0E0-2 (CF): Esophageal 5 year update: 6%, no impact on distant recurrence – U.S. INT 113 (CF): no impact on OS – EORTC (CF): no impact on OS MRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006 Schumacher JCO 28: 5210; 2010

Meta Analysis of Preop Chemo: Overall Survival (Thirion, ASCO 2007) Squamous: 4% Adeno: 7%

CROSS Active Treatment Arm  Paclitaxel 50mg/m 2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29  Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy  Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)  Major eligibility: Adeno- or squamous histology; N1 or >T2, PS < 2  Primary objective: Median overall survival 22 months (versus 16)

20 CROSS: Major Results EUS staged patients T3N0-1 75%, median age 60 74% Adenocarcinoma 93% received all courses chemotherapy –23% had > = grade 3 toxicity from pre-op therapy Post-operative morbidity and mortality almost identical (mortality %) Path CR rate of nearly 30% with chemo RT

Resection rate and resection margins Resection rate of all randomised patients Surgery aloneCRT + surgery 162/188 (86%)157/175 (90%) Resection margins Surgery aloneCRT + surgery R0110 (67%)145 (92.3%) p<0.002 R1 52 (33%) 12 (7.6%) R0 = no tumor within 1 mm of the resection margins CROSS study 21

HR % CI ( ) P=0.012 CROSS: Overall Survival HR % CI ( ) CRTx Surgery Adapted van der Gaast 1-year survival 82 versus 70% 2-year survival 67 versus 52% 3-year survival 59 versus 48% Median survival 49 versus 26 months, HR 0.67, p = 0.011) Squamous HR 0.24, Adeno HR 0.82

Preop Chemo vs ChemoRT

Preop Chemo vs Chemo RT: Stahl ArmPtsR0pCRN0Median Survival 3 yr OSLocal Control Chemo5970%2%37%21 mos28%59% Chemo RT 6072%16%64%33 mos47% P = % P = 0.06 Stahl J Clin Oncol: 27: 836; 2009 EUS, laparoscopy staged pts Siewert I-III, T3-4 adenocarcinoma

MUNICON-1 trial: PET scan response during Induction Chemo AEG type I-II CTx Resection Non-Responder Responder CTx: 3 months PET d0 PET d14 Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24: Response definition: Decrease of the SUV mean PET d14 / PET baseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24:4692-8

Comparison with historic cohort Ott et al. J Clin Oncol 2006;24: CTx for 12 weeks in all patients Survival (median) Responders: not reached Non-Responders: 18 months MUNICON-1 study; 2007 CTx stopped after 2wks in Non-Responders Survival (median) Responders: not reached Non-Responders: 26 months PET-Responder PET-Non-Responder Survival Survival time [months]

PET Scan Directed Therapy Trial Design: CALGB / RTOG T3/4 or N1 Esophageal Adenoca PET/CT: Induction Chemo: modified FOLFOX6 days 1,15, 22 or Carbo/Taxol days 1,8,22,29 PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx) PET Scan day Surgical resection 6 weeks post-RT PET- nonresponders: < 35% SUV decrease: Cross over to alternate chemo + RT (5040cGy in 180cGy fx) Hypothesis: changing chemo in PET non responding patients will improve pCR during chemo + RT

Best Supportive Care vs Chemotherapy Wagner J Clin Oncol 24: 2903; 2006

Advanced Gastric Cancer Chemotherapy: What regimen to use? Oxali: EOX or EOF Cape: ECX or EOX XPFLOFUFIRIS-1 Cis DCFECF Pts %RR44%45%41%34%32%54%36%45% TTP, mos OS, mos

Patient Selection for Chemotherapy Assess age, functional status, comorbidites Combination chemotherapy preferred over single agents – Monotherapy with 5-FU, capecitabine, taxanes in elderly, poor PS patients 3 drug regimens (DCF, mDCF) – High functional status, younger patients without comorbidities – Willingness to tolerate side effects – Access to frequent follow up and toxicity assessment

CALGB / ECOG E1206: Comparison of ECF, FOLFOX, Irino/Cis Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400  250mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Response *RECIST - confirmed; restaging every 6 weeks

CALGB 80403/ECOG 1206: Survival

CALGB 80403: Esophageal, GE Junction Cancers Phase II trial of Chemo + Cetuximab FOLFOX behaved as well as ECF with less toxicity – Irinotecan and cisplatin had lowest efficacy and highest toxicity Optimal irinotecan combination? – Irinotecan + cisplatin; significant second line activity – First Line: Irinotecan + infusional 5-FU preferred

Colorectal Style Chemotherapy and Gastric Cancer Both FOLFOX and FOLFIRI like regimens have acceptable activity in gastric cancer – Can be considered first line therapy Toxicity profiles favor these regimens over conventional high dose cisplatin + 5 day infusion 5-FU

Molecular Targets: Gastric Cancer KRAS mutation: < 5-10% BRAF mutation: < 5% EGFr IHC over expression: 50-80% – EGFr mutation: < 5% CMET amplification: < 10% – IHC over expression 40% HER2 over expression: 10-25% – Trastuzumab + chemo improves OS in HER2+ disease Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006 Gold GI CA Symp 2008 Abs 96

Targeted Agents Phase III: Met Disease REAL 3: ECX + / - Panitumumab (U.K.) EXPAND: Cape-Cis + / Cetuximab LOGIC: Cape-Ox + / - Lapatinib (HER2+) TYTAN: second line, paclitaxel + / - Lapatinib (HER2+) Paclitaxel + / - Everolimus – GRANITE: Single agent Everolimus inactive, no improvement in OS, 656 patients

Resected Pancreatic Cancer OS (MSK) , N= year OS N= 75, 12% 10-year OS N= 18, 5% Predictors of Survival Negative margins AJCC stage Ferrone, et al. J Gast Surg, 2008

Adjuvant Chemoradiation Trials Randomized Phase III TrialTherapyNMed Surv 2-Yr Surv 5-Yr Surv GITSG 1985FU+RT+FU2120 mths43%19% Observation2211 mths18%5% EORTC 1999FU + RT mths37%20% Observation mths26%10% Kalser. GITSG. Arch Surg, Klikenbilj. EORTC. Ann Surg, 1999.

ESPAC-1 Update (NEJM, 2004) 289 pts (53% of all enrollee’s) 237 deaths (82%); median follow-up 47 mths Med Surv5-Yr SurvP-Value Chemo20.1 mths21%0.09 No chemo15.5 mths8%HR 0.71 ChemoRT15.9 mths10%0.05 No chemoRT17.9 mths20%HR 1.28

Neuhaus, et al. ASCO, 2008 (Abst #4504) Resected Pancreatic Cancer N= 368 Observation D1 q 4 weeks CONKO-001 Randomized Phase III Gemcitabine D 1, 8, 15 q 28 x 6 cycles Stratification ₋ R0 vs R1 resection; T stage; N(+) vs N(-) ₋ Ca 19-9 < 2.5x ULN (eligibility) Primary Endpoint: Disease-Free Survival Secondary Endpoints: Overall Survival, Toxicity RANDOMIZERANDOMIZE

Neuhaus, et al. ASCO, 2008 (LBA #4504) CONKO-001: Efficacy Results Gemcitabine (N= 179) Observation (N= 175) P-value Median DFS13.4 mths6.9 mths< Median OS22.8 mths20.2 mths Year OS72%72.5%- 3-year OS36.5%19.5%- 5-Year OS21%9%-

ESPAC-3 (v2) Neoptolemos, et al. JAMA, 2010 Resected PC R0/R1 N= 1,030 5-FU + LV Observation RANDOMIZERANDOMIZE Gemcitabine Primary Endpoint: 10% improvement in 2-year OS

LCTU Liverpool Cancer Trials Unit ESPAC-3 Overall Survival Median OS= 23 months Median OS= 23.6 months  2 LR =0.74, p=0.39, HR GEM VS 5FU/FA =0.94 (95%CI: 0.81, 1.08)

ESPAC-4: Phase III (recruiting) Primary Endpoint: Overall Survival Resected PC N= 1,080 Gemcitabine + Capecitabine Gemcitabine RANDOMIZERANDOMIZE Neoptolemos, J (PI)

Resected PC N= 518 R0/R1 5-FU infusion ↓ 5-FU + RT ↓ 5-FU infusion US Intergroup RTOG Gemcitabine ↓ 5-FU + RT ↓ Gemcitabine RANDOMIZERANDOMIZE Regine, et al. JAMA, 2008

Pancreatic Head Tumors (N= 388) Gemcitabine Arm5-FU Arm Median OS20.5 mths16.9 mths 3-Year Survival31%21% HR 0.82 (CI ), p= 0.09 Survival trend for gemcitabine, but not significant Body/tail tumors included (N= 451, p= 0.013)

Resected Pancreas Cancer N= 952 Gemcitabine + Erlotinib x 4 US Intergroup/RTOG 0848 Gemcitabine x 4 cycles Stratification ₋ R0 vs R1 resection; T stage; N(+) vs N(-) Primary Endpoint: Overall Survival +/- Erlotinib, +/- RT Secondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicity Tissue acquistion/ correlative science RANDOMIZERANDOMIZE 2 nd Randomization +/- ChemoRT

Burris, et al. J Clin Oncol, 1997 Gemcitabine vs 5-FU, Advanced pancreatic cancer Median Survival Gemcitabine 5.6 months 5-FU 4.3 months

Randomized Phase III Trials: Gemcitabine

Gemcitabine vs Gemcitabine + Another Drug? Heinemann, BMC Cancer 8:82;2008: Meta Analysis HR Survival P-ValueN Gem + platinum , 5 trials Gem + 5-FU , 6 trials Good PS 90%+ Poor PS % < ,108, 5 trials 574 Gemcitabine combination therapy: 10-15% OS improvement

Prodige 4 - ACCORD 11 trial design Stratification : center performance status: 0 versus 1 location of the tumor: head versus other location of the primary Metastatic pancreatic cancer RANDOMIZERANDOMIZE Folfirinox Gemcitabine 6 months of chemotherapy recommended CT scans: obtained every 2 months for both arms:

Objective Response Rate Folfirinox N=171 Gemcitabine N=171 p Complete response0.6% 0% Partial response31%9.4% CR/PR 95% CI[ ][ ] Stable disease38.6%41.5% Disease control CR+PR+SD 70.2%50.9% Progression15.2%34.5% Not assessed14.6% Median duration of response 5.9 mo. 4 mo.ns

Progression-Free Survival Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

Overall Survival Folfirinox N=171 Gemcitabine N=171 pHR Median survival [CI 95%] 11.1 mo. [ ] 6.8 mo. [ ] < yr. survival48.4%20.6% 18-mo. survival18.6%6% Median follow up: 26.6 months [95% CI: 20.5 – 44.9]

Overall Survival

Time to definitive QoL degradation

Pancreatic Cancer Chemotherapy with Gemcitabine has modest improvement in OS and QOL Good PS patients may benefit for Gem + platin or Gem + 5-FU FOLFIRINOX is the new standard for good PS patients Targeted Agents –Marginal benefit for Erlotinib –Negative results for Bevacizumab and Cetuximab

Pancreatic Cancer Adjuvant chemotherapy with 5-FU or Gemcitabine improves OS –Role of RT unclear –Current RTOG trial delivers RT at the end of chemo to select patients to best benefit –Locally unresectable disease Similar approach of chemo first, selective use of RT if no POD