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Recent Advances in the Treatment of Gastric and Esophageal Cancers

Recent Advances in the Treatment of Gastric and Esophageal Cancers. Jeffrey S. Rose, MD The Ohio State University October 8, 2010. Esophageal and Gastric Cancer Incidence (US). Esophageal Cancer 2010 16,640 new cases, 14,500 deaths 89% fatality rate Over 70% adenocarcinoma

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Recent Advances in the Treatment of Gastric and Esophageal Cancers

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  1. Recent Advances in the Treatment of Gastric and Esophageal Cancers Jeffrey S. Rose, MD The Ohio State University October 8, 2010

  2. Esophageal and Gastric Cancer Incidence (US) • Esophageal Cancer 2010 • 16,640 new cases, 14,500 deaths • 89% fatality rate • Over 70% adenocarcinoma • Gastric Cancer 2009 • 21,130 new cases, 10,620 deaths • 50% fatality rate • Increasing incidence of cardia tumors American Cancer Society

  3. SEER database: 1975-2004 White males 463% increase in incidence of adenocarcinoma 1.01-5.69/100,000 50% decrease in SCC White females 335% increase in incidence of adenocarcinoma 0.17-0.74/100,000 29% decrease in SCC Incidence (cont) Brown. JNCI 2008

  4. What’s New: Gastroesophageal Junction Cancer Staging • AJCC 6 staging guideline has been criticized as a poor predictor of survival • Emphasizes the importance of depth of invasion (T) and the involvement of lymph nodes based on anatomic location • Multiple studies demonstrate the number of involved lymph nodes may better predict survival

  5. Retrospective review of 336 patients with resected ACA and SCC at MSKCC compared AJCC 6 staging with # of involved lymph nodes What’s New: Gastroesophageal Junction Cancer Staging Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

  6. Nodal Status Matters Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

  7. Survival Improves if >18 Lymph Nodes Removed Rizk N, et al. J Thorac Cardiovasc Surg. 2006.

  8. Staging: WECC/AJCC 7 • Essential changes: • Inclusion of tumor grade • Addition of N1, N2 and N3 based on # of LN involved (1-3, 4-6 or >6) • M1 changed to nonregional lymph node involvement or distant metastasis

  9. Staging: WECC/AJCC 7 • Stage 0: T0N0M0, Any Grade; TisN0M0, Any Grade • Stage IA:T1N0M0, Grade 1-2 • Stage IB: T1N0M0, Grade 3-4; T2N0M0, Grade 1-2 • Stage IIA: T2N0M0, Grade 3-4 • Stage IIB: T3N0M0/T0-2N1M0, Any Grade • Stage IIIA: T0-2N2M0, Any Grade; T3N1M0, Any Grade; T4aN0M0, Any Grade • Stage IIIB: T3N2M0, Any Grade • Stage IIIC: T4aN1-2M0, Any Grade; T4bAnyNM0, Any Grade; Any TN3M0, Any Grade • Stage IV: AnyTAnyNM1, Any Grade

  10. Staging: WECC/AJCC 7 Validation for GEJ ACA • Single institution cohort at MDACC comparing WECC/AJCC 7 to both gastric and esophageal AJCC 6 staging systems • 449 GEJ ACA patients (Siewert I-III) treated with neoadjuvant therapy followed by surgery or surgery alone • All staging systems predictive • For GEJ ACA: WECC/AJCC 7 > AJCC 6 Esoph > AJCC 6 Gastric • CONCLUSION: Incorporating the number of positive lymph nodes within the staging system appears to better predict survival Gaur P, et al. Ann Thorac Surg. 2010.

  11. Assessment of Response Following Neoadjuvant Therapy-Biopsy • Endoscopic biopsy after CRT has been used to determine response • 156 patients at MSKCC received CRT for local-regionally advanced esophageal cancer -> biopsy -> resection • 118 patients had no tumor identified on endoscopic biopsy: • 69% had local disease at time of surgery • Negative biopsy better predicted a pCR for squamous cell carcinoma versus adenocarcinoma (54.3% vs 13.6% P< 0.001). • Nodal status of surgical specimens did not correlate • Survival was equivalent • CONCLUSION: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival Sarkaria IS, et al. Ann Surg. 2009.

  12. Assessment of Response Following Neoadjuvant Therapy-PET/CT • PET is useful in restaging after CRT to exclude distant metastasis • Multiple studies are looking at prognostic value after CRT or chemotherapy • Preliminary results suggest that PET/CT can potentially be a prognosticator for OS, but data on meaningful prediction of response are lacking

  13. Assessment of Response Following Neoadjuvant Therapy-PET/CT • Retrospective analysis of 152 patients with Esoph/GEJ ACA treated with CRT and surgery • >52% SUV decrease was associated with improved OS (43% vs 72% at 3 y) • Pathologic response with <50% residual cancer associated with longer OS • % SUV decrease not associated • In multivariate analysis, SUV decrease only prognostic factor of OS Javeri H et al. Cancer. 2009

  14. Assessment of Response Following Neoadjuvant Therapy-PET/CT Javeri H et al. Cancer. 2009

  15. Assessment of Response Following Neoadjuvant Therapy • CONCLUSIONS: • No role for repeat endoscopy with biopsy • PET/CT useful for excluding distant disease, but not ready as a prognostic test

  16. Definitive Therapies:CROSS Study: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: Results from a multicenter randomized phase III study A. V. Gaast, P. van Hagen, M. Hulshof, D. Richel, M. I. van Berge Henegouwen, G. A. Nieuwenhuijzen, J. T. Plukker, J. J. Bonenkamp, E. W. Steyerberg, H. W. Tilanus, CROSS Study Group

  17. CROSS Study • Phase III study comparing preoperative chemoradiotherapy (CRT) followed by surgery versus surgery in patients with esophageal or GE junction cancer (T2-3/N0-1) • Preoperative CRT with weekly paclitaxel 50 mg/m2 and carboplatin AUC = 2 for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery versus surgery • 363 pts were enrolled with adeno/squamous/other carcinoma 273/86/4

  18. CROSS Study

  19. Overall Survival

  20. Preoperative CRT-ACA

  21. Preoperative CRT-SCC

  22. Neo-adjuvant CRT: Conclusion Neo-adjuvant CRT/trimodality therapy is the standard of care for resectable ACA of the esophagus CRT alone may be sufficient for certain patients with SCC Surgery aids in decrease of local recurrence, but does not improve survival Herskovic A et al. N Engl J Med 1992;26:1593-98, Tepper JE et al. ASCO 2006, Gaast AV et al. ASCO 2010

  23. Advanced Disease • Last Year, We Were “On Target”. One Year Later? • Yes, with Herceptin • Probably, with Cetuximab • No, with Avastin

  24. CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd, RJ Mayer, RM Goldberg

  25. Background • Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR) • EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer • EGFR expression correlates with prognosis in esophagogastric ACA and SCC • KRAS mutations occur in ~2% (0-9%) of esophageal cancers Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006

  26. Background

  27. Treatment Schema 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 Stratification: ECOG 0-1 vs 2 ADC vs. SCC 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) Primary endpoint RR

  28. Progression-Free Survival Median PFS: ECF-C 5.9 IC-C 5.0 FOLFOX-C 6.7

  29. Overall Survival Median OS: ECF-C 11.5 IC-C 8.9 FOLFOX-C 12.4

  30. P - value p=0.03 p=0.03 p=0.05 p=0.05 p=0.06 p=0.06 4% 17% 17% Pain Pain 9% 9% 1% 1% 3% 3% Pulmonary Pulmonary 4% 4% 1% 1% † † 0% 0% Vascular Vascular 6% 6% 7% 7% 4% 4% p=0.01 Death; no CTCAE defined Death; no CTCAE defined 6% 6% 0% 0% 0% 0% Total ( Total ( Heme Heme + Non + Non - - Heme Heme ) ) 75% 75% 86% 86% 79% 79% Toxicity P - value ECF ECF - - C C IC IC - - C C FOLFOX FOLFOX - - C C Non Non - - Hematologic Hematologic 66%* 66%* 77%** 77%** 65% 65% Constitutional symptoms Constitutional symptoms 13% 13% 18% 18% 17% 17% Dermatologic Dermatologic 16% 16% 11% 11% 19% 19% † † Gastrointestinal Gastrointestinal 28% 28% 42% 42% 22% 22% Infection Infection 13% 13% 8% 8% 7% 7% Metabolic Metabolic 16% 16% 34% 34% 22% 22% Neurologic Neurologic 12% 12% 4% p=0.01 * Includes 4 deaths ** Includes 2 deaths † Indicates a death

  31. Response Survival Response Survival ECF 41-45% 8.9-9.9 mos ECF-C 57.8% 11.5 mos IC (Phase II) 57-58% 9-14.6 mos IC-C 45.6% 8.9 mos FOLFOX 40-41% 7.1-10.7 mos FOLFOX-C 53.6% 12.4 mos Discussion: Is there a signal for cetuximab in esophageal cancer? 15% -10% Vs. 2.5mo -2mo *Lorenzen. Ann Oncol 2009

  32. Conclusions • All 3 regimens > 40% RR • IC-C: appeared to have lowest response and survival & most adverse events • ECF-C: appeared to have highest response, but highest treatment-related mortality and most treatment-related modifications • FOLFOX-C: good response and survival and best tolerated

  33. Studies on the Horizon EOX REAL 3* EOX + Panitumumab Cape / Cis EXPAND** Cape / Cis + Cetuximab * http://clinicaltrials.gov/ct2/show/NCT00824785 **http://clinicaltrials.gov/ct2/show/NCT00678535

  34. AVAGAST: a randomized, double-blind placebo- controlled, phase III study of first-line capecitabine and cisplatin + bevacizumab or placebo in patients with advanced gastric cancer (AGC) Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki, SR Park, H-Y Lim, J Wu, B Langer, MA Shah on behalf of AVAGAST investigators

  35. Rationale for Bevacizumab in AGC • Angiogenesis important for tumor growth, progression and metastases • Bevacizumab: • Humanized monoclonal antibody to VEGF • Promising results in Phase II studies in AGC Shah et al. 2006

  36. AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study Capecitabine*/Cisplatin (XP) + Placebo q3w Locally advanced or metastatic gastric cancer R Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Primary endpoint OS Cape 1000mg/m2 oral bid, d1–14, 1-week rest Cisplatin 80mg/m2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD

  37. Overall Response

  38. Progression-Free Survival XP + Placebo XP + Bev 1.0 0.9 0.8 0.7 HR = 0.80 95% CI 0.68–0.93 p = 0.0037 0.6 0.5 0.4 6.7 0.3 0.2 5.3 0.1 0.0 12 0 15 18 21 24 3 9 6 Study month XP + Placebo XP + Bev 387 387 279 306 145 201 86 123 55 71 32 38 15 11 3 3 0 0

  39. Overall Survival XP + Placebo XP + Bev 1.0 0.9 0.8 0.7 HR = 0.87 95% CI 0.73–1.03 p = 0.1002 0.6 0.5 12.1 0.4 0.3 10.1 0.2 0.1 0.0 12 0 15 18 21 24 3 9 6 Study month 271 291 146 178 98 104 54 50 15 19 0 0 343 355 204 232 XP + Placebo XP + Bev 387 387

  40. Regional Differences in Efficacy

  41. Conclusions • Primary endpoint of OS not met • Secondary efficacy endpoints (PFS, best ORR) significantly improved, indicating clinical activity of bev + chemo in AGC • Apparent greater benefit in America>Europe>Asia • No unexpected / new safety signals for bev • Further analysis ongoing, including preplanned biomarker analysis

  42. GE junction: FLO vs FLOT (abs 4013) Improved PFS, RR, not OS Increased, but expected, toxicity DCF vs Modified DCF (abs 4014) Improved PFS, RR and OS 53% vs 30% hospitalized for toxicity Gastric: Granite-1 study looking at Everolimus. 56% DCR in phase II study. TOGA: QoL not affected Other Therapeutic Options in Advanced Disease

  43. Conclusions • Cetuximab looks promising, not ready for clinical practice (REAL-3/EXPAND) • No role for Bevacizumab in gastric cancer • All patients with gastric and GEJ ACA should have her2neu status assessed • DCF active but still toxic, even when modified and administered with GCSF

  44. Thank You and GO BIG RED!

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