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Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology

Gastroesophageal Adenocarcinoma Are We on the Right Track?. Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology Abramson Cancer Center University of Pennsylvania. Abstract 4515:

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Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology

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  1. Gastroesophageal AdenocarcinomaAre We on the Right Track? Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology Abramson Cancer Center University of Pennsylvania

  2. Abstract 4515: Chemoradiation of Resected Gastric Cancer: A 10-Year Follow-up of the Phase III Trial INT-0116 (SWOG 9008). Macdonald J.S. et al. Abstract 4513: Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356). Leichman L, et al Abstract 4514: Updated results of randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG 9912). Fuse N. , et al. Abstract 4512: Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: Results of a phase II clinical trial. Kelsen D. et al

  3. Gastroesophageal Cancers • In USA: ~35,000 cases/yr; ~25,000 deaths/yr • Globally: ~1 million cases/yr; ~0.7 million deaths/yr • Decreased incidence: • ESCC and distal gastric adenocarcinomas • Increased incidence: • Adenocarcinoma of the distal esophagus • Adenocarcinoma of the GE junction • Surgery is the only potentially curative maneuver • Evidence suggests peri-operative therapy improves survival Jemal a, et al. CA Cancer J Clin, 2008 58:71-96 Parkin DM et al. CA Cancer J Clin, 2005, 55:74-108

  4. Important Factors in Therapy of Gastroesophageal Cancer • Differences in the East vs. West • Etiology • Ethnic • Pharmacogenetics • Molecular/Biology Characteristics • Bio-etiology • Carcinogenesis • Tumor biology • ‘Microenviroment’: angiogenesis vs. stroma

  5. 5-Year Survival > 15 lymph nodes resected Cancer 2000, 88:921-32

  6. Molecular Biology of Gastroesophageal Cancer • Chromosomal gains and losses • Rb mutations • Her-2 expression • EGFR overexpression • Cyclin D1 overexpression • C-Met • p16, p27 mutations • COX-2 overexpression • Adhesion proteins (E-cadherin, - & -catenin mutations)

  7. Goals in Treating Gastroesophageal Adenocarcinoma • For metastatic/advanced disease: • Increase efficacy, decrease toxicity • For locally advanced disease: • Improve cure & survival rate • Increase resectability • The extent of tumor down-staging after CTX and XRT is the most important prognostic indicator for DFS and OS

  8. Abstract 4515: INT 0116 SCHEMA RESECTED STAGE IB-IV (MO) GASTRIC ADENOCARCINOMA R A N D O M OBSERVATION 5-FU/LV 5-FU/LV 5-FU/LV RADIATION 5-FU/LV X2 4,500 cGy • Current report gives results with median follow-up 11 years • Provides expanded subset analyses: • T Stage, N Stage, Localization, D-Level of resection, Diffuse vs. Intestinal pathology, Male vs. Female, Maruyama Index

  9. 100% N Events Median in Months 5-FU+leucovorin+RT 282 211 35 Observation 277 231 27 P = .0051 80% 60% 40% 20% 0% 0 24 48 72 96 120 144 168 192 Months After Registration Overall Survival by Treatment Arm

  10. Abstract 4515: INT 0116 Macdonald JS, et al. NEJM 2001, 345:725-730 Macdonald JS, et al, ASCO 2004 Macdonald JS, ASCO 2009,

  11. (98/305=32%) (71/127=56%)

  12. Abstract 4515: INT 0116 Toxicities • Major Toxicities • Hematologic 148 (54%) • GI 89 (33%) • Flu-like 25 (9%) • Infection 16 (6%) • Neurologic 12 (4%) • Cardiovascular 11 (4%) • Pain 9 (3%) • Metabolic 5 (2%) • Hepatic 4 (1%) • Death 3 (1%) Macdonald JS, et al. NEJM 345:725-730, 2001

  13. Abstract 4515: INT 0116 Second Tumor Sites CHEMORADS (25) * CONTROL (8) Skin 6 (2 Melanoma) Pancreas 2 Colorectal 4 Basal Cell 2 Prostate 4 Breast 1 Bladder 3 Lung 1 Heme 3 (2 Lymphoma; 1 MDS) Bone Marrow 1 Breast 1 Renal 1 Lung 1 Renal Pelvis 1 Larynx 1 Unknown Primary 1 *21 Patients (no statistically significant differences)

  14. Abstract 4515: INT 0116 Summary • OS and DFS for chemoradiation remain highly significant With >11 years follow up • No significant late effects with 5-FU based Chemo/XRT • Second tumors are considered not treatment related. However, needs to be assessed in ongoing studies • Subset analyses show Diffuse histology(Women+Diffuse type) appears negative predictor for treatment benefit • Questions for improving outcome: • More effective cytotoxic regimen(s) • Histopathologic- and biologic characteristic-based-treatment • Pre-operative chemo- or chemoradiation

  15. Two Large Phase III Randomized Peri-Operative Chemotherapy Studies Cunningham D, et al. N Engl J Med. 2006;355:11-20. • MAGIC: • Operable adenocarcinoma of the stomach, gastroesophageal junction, orlower esophagus,  Stage II (M0) • ECF*  Surgery  ECF (N= 250) vs. Surgery alone (N= 253) • Epirubicin 50 mg/m² IV ,day 1;Cisplatin 60 mg/m² 4-hour infusion, day 1; 5-FU , 200 mg/m²/day CI days 1-21) • (ACTS-GC) • S-1 vs. Surgery Alone after D2 Gastrectomy Sakuramoto S N Eng J Med 2007, 357:1810-20

  16. MAGIC Trial:Pre- and Postoperative Chemotherapy

  17. There is no info about histopathology Type: Diffuse vs. intestinal

  18. ACTS-GC : S-1 vs. Surgery Alone after D2 Gastrectomy • Curative Gastrectomy (D2) Within 6 wks after Surgery • Stratify: Stage (II, IIIA, IIIB), Institution • S-1 (N=529) vs. Surgery alone (N=530). • S-1: • Tegafur –fluoropyrimidine, • Gieracil—DPD inhibitor, • Oteracil– orotate phosphoribosyltranserase (reduce GI toxicity) S-1 is effective as adjuvant for EAST ASIAN Pts. Undergone a D2 dissection Sakuramoto S N Eng J Med 2007, 357:1810-20

  19. Phase III Peri-Op Studies *S-1 efficacy has not been shown clearly in WESTERN gastroesophageal cancer patients in either adjuvant or metastatic setting (e.g. FLAGS study)

  20. C80101: Randomized Phase III Adjuvant Trial FU/LV XRT+CIFU FU/LV x2 R N=824 ECF XRT+CIFU ECF x2 Biologic markers collected: TS, ERCC-1, MSI, EGFR, COX-2 • Just closed recently (last week) at full accrual

  21. Neoadjuvant Chemoradiation • Trimodality Increases overall survival • Pathological complete response (pCR) as the predictor for overall outcome • Meta-analysis: • CALGB 9781: Trimodality vs. surgery alone in Esophageal CA • cisplatin 100 mg/m2, day 1; 5-FU 1,000 mg/m2/d x 4 days weeks 1 and 5; concurrent with radiation therapy (50.4 Gy) • Followed by esophagectomy; More chemotherapy after surgery • planned to enroll 475 pts, only 56 patients (30 in the trimodality arm and 26 in the surgery alone) • mOS 4.48 yrs vs. 1.79 yrs (p=0.002) • pCR: 10/30, PR: (micro 2/30, macro 8/30), SD: 2/30, PR: 2 Ajani JA, et al. JCO 2005:1237 Reed VK, et al. IJROBP 2008, 71:741 Gebski V, et alLancet Oncol 8:226-234, 2007 Tepper J, et al. JCO 2008; 26:1086

  22. Abstract 4513: S0356Neoadjuvant for EAAC • New agent (oxaliplatin) may improve efficacy and decrease toxicity • Pathology complete response is predictive and prognostic factor for the overall outcome. • Study design: • Assess pCR rate (>25%), PFS and OS. • Assess frequency and severity of toxicities • Explore intratumoral parameters thought to be relevant to pCR (ERCC-1, XPA, TS, γGT and γGCS)

  23. Abstract 4513: S0356 • Study design: • Chemo: • OXP 85 mg/m2 IVPB days 1, 15 and 29 • CI 5FU 180 mg/m2/days 8-43. • EBRT d 8-43 (25 fractions) • Esophagectomy 2-4 weeks after CTX/XRT • Second cycle of OXP and CI 5FU 4-6 weeks postop • Follow-up observation at 3 month intervals • Mandated central pathology review pre-op and post-op

  24. Abstract 4513: S0356 • Result (N=98): • pCR: 34% (31 pts. Central review confirmed), 9 patients (10%) had either Tin situN0M0 or T1N0M0: met the 10end point. • The regimen of OXP and CI 5FU with EBRT is safe, less toxic (gr 3/4) • 43% overall: 39% GI, 22% fatigue, 17% pulmonary,16% hematologic,14% mucositis, 3% neurologic • Surgical mortality 2.6%: acceptable • 38 patients (42%) underwent postoperative chemotherapy.(Sequence of radiation vs. chemotherapy is debatable) • (MAGIC Trial: only 54.8 % had post-surgery chemotherapy)

  25. Trimodality with newer agent (oxaliplatin/5-FU/XRT) has increased pCR and relative less toxicity, PFS and OS remain to be determined Too early to make conclusion whether this regimen is superior to cis/5-FU/XRT Molecular parameters which may help to determine how individuals should be treatedare still pending. Needs larger (randomized study) to confirm Abstract 4513: S0356Summary

  26. Abstract 4514: (JCOG 9912). • Assumed: • S-1 no-inferiority to 5-FU (+/- 5%) • CPT-11+CDDP: superior to 5-FU (+10% survival) • First reported in 2006 ASCO (N=704) • Study Design: • 5-FU (800 mg/m2/day, ci, days 1-5, q 4 wks); • CPT-11 & CDDP (CPT-11, 70 mg/m2, div, days 1&15, Cis 80 mg/m2, div, day 1, q 4 weeks); • S-1 (40 mg/m2, po, bid, days 1-28, q 6 weeks)

  27. Abstract 4514: (JCOG 9912) Gr >3 AE (%) within 6 mos 5-FUci CPT-11+CDDP S-1 234 236 234 No. of patients Leukocytes 0 41.5 0.9 Neutrophils 1.3 65.0 5.6 Hemoglobin 15.5 39.3 12.8 Platelets 0.4 4.7 1.3 Febrile neutropenia 0 9.4 0 Infection with Gr 3 or 4 neutropenia 0.4 0 7.7 Infection without neutropenia 3.9 3.8 5.6 Treatment-related death* 0 1.3 0.4

  28. Abstract 4514: (JCOG 9912) • ASCO 2006: • S-1 showed non-inferiority to 5-FU ci in survival • mild toxicities, • favorable results of RR, TTF, NHS and PFS • CPT-11+CDDP did not show superiority to 5-FU ci in survival • substantial toxicities causing treatment failure • favorable results of RR, TTF, NHS and PFS,

  29. Abstract 4514: (JCOG 9912) Update

  30. Abstract 4514: (JCOG 9912) Summary • S-1 is considered as a standard chemotherapy for East Asian patients with unresectable or recurrent gastric cancer. • S-1 has been confirmed (single agent or in combination with CDDP) in the Eastern patient population. • S-1 benefits have not been shown in Western populations including most recent FLAGS study • CP combination confirmed platinum efficacy Kiozumi W, et al: Lancet Oncol. 2008;9(3):215-21. Ajani JA, et al GI Cancer Sym 2009: Abs 8

  31. Abstract 4512: Rationale and Study Design • Combination chemotherapy with increased response rates (30-60%), Short duration of response, & increased toxicity : DCF, ECF (ECX, EOF, EOX), FP (XP), Cis-Iri • DCF improved RR, PFS, and OS • FDA and European approval in 1st line treatment • High incidence of gr 3/4 hematologic and non-hematologic (~80%) toxicity limits the use of DCF • Modified DCF regimen to reduce toxicity • Bevacizumab is approved with chemotherapy for the treatment of colorectal, lung and breast cancer • Phase II studies with different combination suggested some benefits (Cisplatin/Irinotecan & docetaxel/Irinotecan) Shah MA et al, JCO 2006 Fuchs CS et al, ASCO 2008, Abs 4552

  32. Abstract 4512: • End Points: • Primary: To improve 6-month PFS from 43% to 63%. • Secondary: RR, median PFS, 1-year Survival, and OS, the safety of mDCF + BEV in patients with unresectable or metastatic GE cancer

  33. Abstract 4512: N=44 (measurable=39) Mean follow up 13 months • 6 month PFS: 83 % (68-92%) • RR: 67% (50-81%), SD: 31% (17-48%), PD: 2% • Median PFS 12.8 month (8.9-16.4 months) • Median OS 16.3 mo (11.4 mo – not reached) • Gr 3/4 toxicity: Neutropenia 51%, Febrile Neutropenia 4%,Thrombocytopenia 16%, Anemia 11% (DCF 82%, 29 %, 8%, 28%) • Gr 3/4 DVT 31%, Gastric Perforation 2%, Bleeding 2%

  34. Other Studies Show Advances in Outcomes with Biologics Shah MA et al JCO 2006, 24:5201; El Rayes BF, et al. J Clin Oncol 2008;26 (abstract 15608). Enzinger PC, et al. J Clin Oncol 2008;26 (abstract 4552). Pinto C, et al. J Clin Oncol 2008;26 (abstract 4575). Sun W, et al. J Clin Oncol 2008;26 (abstract 4535).

  35. Summary • Both adjuvant and neoadjuvant therapy beneficial in Gastroesophageal Adenocarcinoma • Newer chemotherapy agents showed advances in systemic chemotherapy (Oxaliplatin, S-1, Docetaxel, …) • Pharmacogenetics and biology of both host and tumor are important for tailoring the patient’s needs • Biological (antiangiogenesis) agents hold promise, but phase III studies are needed.

  36. Conclusion • Peri-operative therapy is ‘standard’ approach • More effective chemotherapy regimen may benefit more at adjuvant or neoadjuvant setting (CALGB 80101) • New cytotoxic agents may increase efficacy and increase pCR in peri-operative setting and less toxicity. • Biological agents show very encouraging benefits in metastatic disease setting • Bevacizumab (Tumor environment) • Trastuzumab in Her-2+ gastric cancer (ToGA, LBA4509) (Tumor Biology)

  37. Conclusion On-going Studies: • MAGIC –B (based on data of combination with bevacizumab and other antiangiogenics) • Role of bevacizumab pre-op setting (ECF + pre-op bevacizumab) • CRITICS (based on data of INT-0116 and MAGIC; and find out the optimal sequence and duration of chemoradiation) • Preoperative chemo and post operative chemoradiation • Phase III trails of Chemo +/- antiangiogenesis • Future: individualized therapy based on natural history + individual (host and tumor) biology in both Peri-op and advanced settings.

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