PowerPoint Presentation

Current Trends and Future Directions in Advanced Esophagogastric Cancers Manish A. Shah, MDThe Bartlett Family Associate Professor of Gastrointestinal MalignanciesDirector, Gastrointestinal Oncology ProgramCo-Director, Center for Advanced Digestive CareWeill Cornell Medical College/New YorkPresbyterian Hospital

DisclosuresDr. Shah discloses the following commercial relationships:Consultant/Advisor: Genentech, Lilly

IARCW, 2012a.World Gastric Cancer Incidence: GLOBOCAN 2012

Disease is much more prevalent in the Far EastIARCW, 2012b.Gastric Cancer Incidence and Mortality: GLOBOCAN 2012

Esophageal and Gastric Carcinoma:US Incidence in 2016Estimated 43,280 new cases (2.5% of all cancers)Gastric: 26,370 (61%)Esophagus: 16,910 (39%)Decline in gastric cancer incidenceIncrease in esophageal, GEJ, cardia adenocarcinomaOverall survival improvement, 1975-77, 1984-86, 1999-2006Gastric: 16% 18% 27%Esophageal: 5% 10% 19%GEJ = gastroesophageal junction.Siegel et al, 2016.

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Genetic and Epidemiologic Considerations: Disease HeterogeneityGlobal heterogeneityMore prevalent in Asia, Eastern Europe, South AmericaH. pylori varianceMore advanced disease in US, WestDifferent underlying biology?Gastric cancer cannot be treated as one diseaseHistology (intestinal vs diffuse)Location(cardia/GEJ vs antrum)Biology (MET, CDH1, others?)Etiology (H. pylori related, others?)

NCCN, 2016.

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Molecular Subtypes of Gastric Cancer and Key Features

CIN = chromosome instability; EBV = Esptein-Barr virus; GS = genomically stable; MSI = microsatellite instability.Bass et al, 2014.

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Revisiting Anatomic Correlates of Gastric Cancer Subtypes

Bass et al, 2014.

Current Disease Paradigm

Genetic RiskEnvironmentBehaviorFamily History:CDH1MMRAPCTP53H. Pylori (cag A strain)

EBVTobacco useDiet ( salt, fruits/vegetables )Immune SNPsIL1, IL4, etcProximal Nondiffuse Gastric CancerChromosome instableDistal Nondiffuse Gastric CancerChromosome instableMSIDiffuse Gastric CancerGenomically stable

EBV-Associated Gastric CancerNCCN, 2016; Bass et al, 2014.

Adjuvant Therapy in Gastric Cancer Improves Overall SurvivalPostoperative RT + chemotherapy (US)Treatment: 5-FU/LV + RT (INT-0116 study)10% 5-yr OS; HR: 0.76 Preop and postop chemo (UK) without RTTreatment: ECF (MAGIC study)13% 5-yr OS; HR: 0.75Postop chemo (Asia): 2 trials, 2,000 patients, D2 resection, no RTTreatment: S-1 (oral 5-FU) (ACTS-GC study)10% 5-yr OS; HR: 0.67Treatment: postop capecitabine/oxaliplatin (CLASSIC trial) 9% 5-yr OS; HR: 0.66Survival improvements with all approaches similar, modest

RT = radiotherapy; 5-FU = 5-fluorouracil; LV, leucovorin; OS, overall survival; ECF = epirubicin, cisplatin, fluorouracil.Smalley et al, 2012; Cunningham et al, 2006; Sasako et al, 2011; Noh et al, 2014.

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Esophageal and GEJ Adenocarcinoma: Adjuvant TherapyT2-3 or N+: Something more than surgery alone should be performedPreop chemotherapy ECF, CF improves OS in some but not all trialsMAGIC (ECF): 13% OS at 5 yrs; HR: 0.75 (esophageal, 120 pts), no increase in R0 resectionFFCD/FNLC (CF): 14% OS at 5 yrs; HR: 0.69 (esophageal cancer, 180 pts) same as MAGIC, no epirubicin, increase in R0 resectionCF = cisplatin, fluorouracil.Cunningham et al, 2006; Ychou et al, 2011.

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Esophageal Adenocarcinoma: Consensus on Adjuvant TherapyPreop chemotherapyMRC OEO-2 (CF): N=8025-yr update: 6% OS increase vs resection aloneUS INT-113 (CF): N=440No impact on OS or any end point, including R0 rateMRC OEO5 (CF vs ECX): N=900, EUS stagedCF x 2 vs ECX x 4: equivalent No survival benefit with additional cycles of ECXPoor rates of R0 resection: 60% to 66%Demonstrates no role for anthracyclines in this setting

EUS = endoscopic ultrasound.Allum et al, 2009; Kelsen et al, 1998; Cunningham et al, 2015.

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Day 6Day 1Day 2Day 3Day 4Day 5Day 7Day 6Day 1Day 2Day 3Day 4Day 5Day 7Day 6Day 1Day 2Day 3Day 4Day 5Day 7Day 6Day 1Day 2Day 3Day 4Day 5Day 7Day 6Day 1Day 2Day 3Day 4Day 5Day 7

AUC = area under the curve; CRT= chemoradiotherapy; THE = transhiatal esophagectomy;TTE = transthoracic esophagectomy.van Hagen et al, 2012.Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional CancerPaclitaxel 50 mg/m2 + carboplatin AUC 2 on D 1, 8, 15, 22, 29Concurrent radiotherapy: 41.4 Gy in 23 fractions of 1.8 GySurgery within 6 weeks after completion of chemoradiotherapyChemoradiotherapy followed by surgery compared with surgery alone (N=368)MTWTFSSWk 1

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Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional Cancer: OSR0 resection increased from 69% with surgery alone to 92%5-yr OS: 47% vs 34% with surgery aloneSquamous HR: 0.453Adeno HR: 0.732Pathologic CR with CRT + surgerySquamous: 49%Adenocarcinoma: 23%Considered a new standard of care

1.00.80.60.40.201224364860MosProportion SurvivingP=0.003CRT + surgerySurgery alone01.00.80.60.40.201224364860MosProportion Surviving0OS by TreatmentOS by Tumor Type and TreatmentSCC, CRT + surgeryAC, CRT + surgeryAC, surgery aloneSCC, surgery aloneAC, P=0.049SCC, P =0.011CR = complete response; SCC = squamous cell carcinoma; AC = adenocarcinoma. van Hagen et al, 2012.

CR = complete response; SCC = squamous cell carcinoma; AC = adenocarcinoma.14

Active Chemotherapy AgentsAntimetabolites5-Fluorouracil (5-FU), S-1 (Japan/Korea)Methotrexate, leucovorin (as 5-FU modulators)DNA damagingCisplatin, oxaliplatinMitomycin-cTopoisomerase I/II inhibitorsEpirubicin, doxorubicinEtoposideIrinotecanMicrotubule inhibitorsPaclitaxel, docetaxel

NCCN, 2016.

ReferenceTrialChemo, nBSC, nHR for OS95% CIMuradCancer 1993FAMTX30100.330.17-0.64PyrhnenBJC 1995FEMTX21200.250.25-0.47Scheithauer Ann Hematol 1996ELF52510.490.33-0.74Total103810.370.24-0.55

Effective: 11 vs 4.3 mos; P