Recent Advances in the Treatment of Gastric and Esophageal Cancers<br />Jeffrey S. Rose, MD<br />The Ohio State University...
Esophageal and Gastric Cancer Incidence (US)<br />Esophageal Cancer 2010<br />16,640 new cases, 14,500 deaths<br />89% fat...
Incidence (cont)<br />SEER database: 1975-2004<br />White males<br />463% increase in incidence of adenocarcinoma<br />1.0...
What’s New: Gastroesophageal Junction Cancer Staging<br />AJCC 6 staging guideline has been criticized as a poor predictor...
What’s New:  Gastroesophageal Junction Cancer Staging<br />Retrospective review of 336 patients with resected ACA and SCC ...
Nodal Status Matters<br />Rizk N, et al. J Thorac Cardiovasc Surg. 2006.<br />
Survival Improves if >18 Lymph Nodes Removed<br />Rizk N, et al. J Thorac Cardiovasc Surg. 2006.<br />
Staging: WECC/AJCC 7<br />Essential changes: <br />Inclusion of tumor grade<br />Addition of N1, N2 and N3 based on # of L...
Staging: WECC/AJCC 7<br />Stage 0: T0N0M0, Any Grade; TisN0M0, Any Grade<br />Stage IA:T1N0M0, Grade 1-2<br />Stage IB: T1...
Staging: WECC/AJCC 7 Validation for GEJ ACA<br />Single institution cohort at MDACC comparing WECC/AJCC 7 to both gastric ...
Assessment of Response Following Neoadjuvant Therapy-Biopsy<br />Endoscopic biopsy after CRT has been used to determine re...
Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />PET is useful in restaging after CRT to exclude distant m...
Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />Retrospective analysis of 152 patients with Esoph/GEJ ACA...
Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />Javeri H et al. Cancer. 2009<br />
Assessment of Response Following Neoadjuvant Therapy<br />CONCLUSIONS:<br />No role for repeat endoscopy with biopsy<br />...
Definitive Therapies:CROSS Study: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resecta...
Phase III study comparing preoperative chemoradiotherapy (CRT) followed by surgery versus surgery in patients with esophag...
CROSS Study<br />
Overall Survival<br />
Preoperative CRT-ACA<br />
Preoperative CRT-SCC<br />
Neo-adjuvant CRT: Conclusion<br />Neo-adjuvant CRT/trimodality therapy is the standard of care for resectable ACA of the e...
Advanced Disease<br />Last Year, We Were “On Target”.  One Year Later? <br />Yes, with Herceptin<br />Probably, with Cetux...
CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer<b...
Background<br />Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR)<br...
Background<br />
ARM A: (ECF + cetuximab); 1 cycle = 21 days<br />Cetuximab 400  250mg/m2 IV, weekly<br />Epirubicin 50 mg/m2 IV, day 1<br...
Progression-Free Survival<br />Median PFS: <br />ECF-C 5.9<br />IC-C 5.0<br />FOLFOX-C 6.7<br />
Overall Survival<br />Median OS: <br />ECF-C 11.5<br />IC-C 8.9<br />FOLFOX-C 12.4<br />
P<br />-<br />value<br />p=0.03 <br />p=0.03 <br />p=0.05 <br />p=0.05 <br />p=0.06 <br />p=0.06 <br />4%<br />17%<br />17...
Response<br />Survival<br />Response <br />Survival<br />ECF <br />41-45%<br />8.9-9.9 mos<br />ECF-C<br />57.8%<br />11.5...
Conclusions<br />All 3 regimens > 40% RR<br />IC-C: appeared to have lowest response and survival & most adverse events<br...
EOX<br />REAL 3*<br />EOX + Panitumumab<br />Cape / Cis<br />EXPAND**<br />Cape / Cis + Cetuximab<br />*  http://clinicalt...
AVAGAST: a randomized, double-blind placebo- controlled, phase III study of first-line capecitabine and cisplatin + bevaci...
Rationale for Bevacizumab in AGC<br />Angiogenesis important for tumor growth, progression and metastases<br />Bevacizumab...
R<br />AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study<br />Capecitabine*/Cisplatin (XP) <br />+ P...
Overall Response<br />
Progression-Free Survival<br />XP + Placebo<br />XP + Bev<br />1.0<br />0.9<br />0.8<br />0.7<br />HR = 0.80<br />95% CI 0...
Overall Survival<br />XP + Placebo<br />XP + Bev<br />1.0<br />0.9<br />0.8<br />0.7<br />HR = 0.87<br />95% CI 0.73–1.03 ...
Regional Differences in Efficacy<br />
Conclusions<br />Primary endpoint of OS not met<br />Secondary efficacy endpoints (PFS, best ORR) significantly improved, ...
Other Therapeutic Options in Advanced Disease <br />GE junction:<br />FLO vs FLOT (abs 4013)<br />Improved PFS, RR, not OS...
Conclusions<br />Cetuximab looks promising, not ready for clinical practice (REAL-3/EXPAND)<br />No role for Bevacizumab i...
Thank You and GO BIG RED!<br />
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ASCO 2010 Review: Gastric and Esophageal Cancer

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ASCO 2010 Review: Gastric and Esophageal Cancer

  1. 1. Recent Advances in the Treatment of Gastric and Esophageal Cancers<br />Jeffrey S. Rose, MD<br />The Ohio State University<br />October 8, 2010<br />
  2. 2. Esophageal and Gastric Cancer Incidence (US)<br />Esophageal Cancer 2010<br />16,640 new cases, 14,500 deaths<br />89% fatality rate<br />Over 70% adenocarcinoma<br />Gastric Cancer 2009<br />21,130 new cases, 10,620 deaths<br />50% fatality rate<br />Increasing incidence of cardia tumors<br />American Cancer Society<br />
  3. 3. Incidence (cont)<br />SEER database: 1975-2004<br />White males<br />463% increase in incidence of adenocarcinoma<br />1.01-5.69/100,000<br />50% decrease in SCC<br />White females<br />335% increase in incidence of adenocarcinoma<br />0.17-0.74/100,000<br />29% decrease in SCC<br />Brown. JNCI 2008<br />
  4. 4. What’s New: Gastroesophageal Junction Cancer Staging<br />AJCC 6 staging guideline has been criticized as a poor predictor of survival<br />Emphasizes the importance of depth of invasion (T) and the involvement of lymph nodes based on anatomic location<br />Multiple studies demonstrate the number of involved lymph nodes may better predict survival<br />
  5. 5. What’s New: Gastroesophageal Junction Cancer Staging<br />Retrospective review of 336 patients with resected ACA and SCC at MSKCC compared AJCC 6 staging with # of involved lymph nodes<br />Rizk N, et al. J Thorac Cardiovasc Surg. 2006.<br />
  6. 6. Nodal Status Matters<br />Rizk N, et al. J Thorac Cardiovasc Surg. 2006.<br />
  7. 7. Survival Improves if >18 Lymph Nodes Removed<br />Rizk N, et al. J Thorac Cardiovasc Surg. 2006.<br />
  8. 8. Staging: WECC/AJCC 7<br />Essential changes: <br />Inclusion of tumor grade<br />Addition of N1, N2 and N3 based on # of LN involved (1-3, 4-6 or >6)<br />M1 changed to nonregional lymph node involvement or distant metastasis<br />
  9. 9. Staging: WECC/AJCC 7<br />Stage 0: T0N0M0, Any Grade; TisN0M0, Any Grade<br />Stage IA:T1N0M0, Grade 1-2<br />Stage IB: T1N0M0, Grade 3-4; T2N0M0, Grade 1-2<br />Stage IIA: T2N0M0, Grade 3-4<br />Stage IIB: T3N0M0/T0-2N1M0, Any Grade<br />Stage IIIA: T0-2N2M0, Any Grade; T3N1M0, Any Grade; T4aN0M0, Any Grade<br />Stage IIIB: T3N2M0, Any Grade<br />Stage IIIC: T4aN1-2M0, Any Grade; T4bAnyNM0, Any Grade; Any TN3M0, Any Grade<br />Stage IV: AnyTAnyNM1, Any Grade<br />
  10. 10. Staging: WECC/AJCC 7 Validation for GEJ ACA<br />Single institution cohort at MDACC comparing WECC/AJCC 7 to both gastric and esophageal AJCC 6 staging systems<br />449 GEJ ACA patients (Siewert I-III) treated with neoadjuvant therapy followed by surgery or surgery alone <br />All staging systems predictive<br />For GEJ ACA: WECC/AJCC 7 > AJCC 6 Esoph > AJCC 6 Gastric <br />CONCLUSION: Incorporating the number of positive lymph nodes within the staging system appears to better predict survival<br />Gaur P, et al. Ann Thorac Surg. 2010.<br />
  11. 11. Assessment of Response Following Neoadjuvant Therapy-Biopsy<br />Endoscopic biopsy after CRT has been used to determine response <br />156 patients at MSKCC received CRT for local-regionally advanced esophageal cancer -> biopsy -> resection<br />118 patients had no tumor identified on endoscopic biopsy:<br />69% had local disease at time of surgery<br />Negative biopsy better predicted a pCR for squamous cell carcinoma versus adenocarcinoma (54.3% vs 13.6% P< 0.001). <br />Nodal status of surgical specimens did not correlate <br />Survival was equivalent <br />CONCLUSION: A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival<br />Sarkaria IS, et al. Ann Surg. 2009.<br />
  12. 12. Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />PET is useful in restaging after CRT to exclude distant metastasis<br />Multiple studies are looking at prognostic value after CRT or chemotherapy<br />Preliminary results suggest that PET/CT can potentially be a prognosticator for OS, but data on meaningful prediction of response are lacking<br />
  13. 13. Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />Retrospective analysis of 152 patients with Esoph/GEJ ACA treated with CRT and surgery<br />>52% SUV decrease was associated with improved OS (43% vs 72% at 3 y)<br />Pathologic response with <50% residual cancer associated with longer OS <br />% SUV decrease not associated<br />In multivariate analysis, SUV decrease only prognostic factor of OS<br />Javeri H et al. Cancer. 2009<br />
  14. 14. Assessment of Response Following Neoadjuvant Therapy-PET/CT<br />Javeri H et al. Cancer. 2009<br />
  15. 15. Assessment of Response Following Neoadjuvant Therapy<br />CONCLUSIONS:<br />No role for repeat endoscopy with biopsy<br />PET/CT useful for excluding distant disease, but not ready as a prognostic test<br />
  16. 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<br />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 <br />
  17. 17. Phase III study comparing preoperative chemoradiotherapy (CRT) followed by surgery versus surgery in patients with esophageal or GE junction cancer (T2-3/N0-1) <br />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 <br />363 pts were enrolled with adeno/squamous/other carcinoma 273/86/4<br />CROSS Study<br />
  18. 18. CROSS Study<br />
  19. 19. Overall Survival<br />
  20. 20. Preoperative CRT-ACA<br />
  21. 21. Preoperative CRT-SCC<br />
  22. 22. Neo-adjuvant CRT: Conclusion<br />Neo-adjuvant CRT/trimodality therapy is the standard of care for resectable ACA of the esophagus<br />CRT alone may be sufficient for certain patients with SCC<br />Surgery aids in decrease of local recurrence, but does not improve survival<br />Herskovic A et al. N Engl J Med 1992;26:1593-98, Tepper JE et al. ASCO 2006, Gaast AV et al. ASCO 2010<br />
  23. 23. Advanced Disease<br />Last Year, We Were “On Target”. One Year Later? <br />Yes, with Herceptin<br />Probably, with Cetuximab<br />No, with Avastin<br />
  24. 24. CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer<br />PC Enzinger, BA Burtness, DR Hollis, <br />D Niedzwiecki, DH Ilson, AB Benson 3rd, <br />RJ Mayer, RM Goldberg<br />
  25. 25. Background<br />Cetuximab: a chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor (EGFR)<br />EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer<br />EGFR expression correlates with prognosis in esophagogastric ACA and SCC <br />KRAS mutations occur in ~2% (0-9%) of esophageal cancers<br />Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. <br />J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006<br />
  26. 26. Background<br />
  27. 27. ARM A: (ECF + cetuximab); 1 cycle = 21 days<br />Cetuximab 400  250mg/m2 IV, weekly<br />Epirubicin 50 mg/m2 IV, day 1<br />Cisplatin 60mg/m2 IV, day 1<br />Fluorouracil 200mg/m2/day, days 1-21<br />ARM B: (IC + cetuximab); 1 cycle = 21 days<br />Cetuximab 400  250mg/m2 IV, weekly<br />Cisplatin 30 mg/m2 IV, days 1 and 8<br />Irinotecan 65 mg/m2 IV, days 1 and 8<br />Stratification:<br />ECOG 0-1 vs 2<br />ADC vs. SCC<br />ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days<br />Cetuximab 400  250mg/m2 IV, weekly<br />Oxaliplatin 85 mg/m2 IV, day 1<br />Leucovorin 400 mg/m2, day 1<br />Fluorouracil 400 mg/m2 IV bolus, day 1<br />Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)<br />Treatment Schema<br />Primary endpoint RR<br />
  28. 28. Progression-Free Survival<br />Median PFS: <br />ECF-C 5.9<br />IC-C 5.0<br />FOLFOX-C 6.7<br />
  29. 29. Overall Survival<br />Median OS: <br />ECF-C 11.5<br />IC-C 8.9<br />FOLFOX-C 12.4<br />
  30. 30. P<br />-<br />value<br />p=0.03 <br />p=0.03 <br />p=0.05 <br />p=0.05 <br />p=0.06 <br />p=0.06 <br />4%<br />17%<br />17%<br />Pain<br />Pain<br />9%<br />9%<br />1%<br />1%<br />3%<br />3%<br />Pulmonary<br />Pulmonary<br />4%<br />4%<br />1%<br />†<br />1%<br />†<br />0%<br />0%<br />Vascular<br />Vascular<br />6%<br />6%<br />7%<br />7%<br />4%<br />4%<br />p=0.01 <br />Death; no CTCAE defined<br />Death; no CTCAE defined<br />6%<br />6%<br />0%<br />0%<br />0%<br />0%<br />Total (<br />Heme<br />+ Non<br />-<br />Heme<br />)<br />Total (<br />Heme<br />+ Non<br />-<br />Heme<br />)<br />75%<br />75%<br />86%<br />86%<br />79%<br />79%<br />P<br />-<br />value<br />ECF<br />-<br />C<br />ECF<br />-<br />C<br />IC<br />-<br />C<br />IC<br />-<br />C<br />FOLFOX<br />-<br />C<br />FOLFOX<br />-<br />C<br />Non<br />-<br />Hematologic<br />Non<br />-<br />Hematologic<br />66%*<br />66%*<br />77%**<br />77%**<br />65%<br />65%<br />Constitutional symptoms<br />Constitutional symptoms<br />13%<br />13%<br />18%<br />18%<br />17%<br />17%<br />Dermatologic<br />Dermatologic<br />16%<br />16%<br />11%<br />11%<br />19%<br />19%<br />†<br />†<br />Gastrointestinal<br />Gastrointestinal<br />28%<br />28%<br />42%<br />42%<br />22%<br />22%<br />Infection<br />Infection<br />13%<br />13%<br />8%<br />8%<br />7%<br />7%<br />Metabolic<br />Metabolic<br />16%<br />16%<br />34%<br />34%<br />22%<br />22%<br />Neurologic<br />Neurologic<br />12%<br />12%<br />4%<br />p=0.01 <br />* Includes 4 deaths<br />** Includes 2 deaths<br />† Indicates a death <br />Toxicity<br />
  31. 31. Response<br />Survival<br />Response <br />Survival<br />ECF <br />41-45%<br />8.9-9.9 mos<br />ECF-C<br />57.8%<br />11.5 mos<br />IC (Phase II)<br />57-58% <br />9-14.6 mos<br />IC-C<br />45.6%<br /> 8.9 mos<br />FOLFOX<br />40-41%<br />7.1-10.7 mos<br />FOLFOX-C 53.6%<br />12.4 mos<br /> 15%<br />-10%<br />Vs.<br />2.5mo<br />-2mo<br />*Lorenzen. Ann Oncol 2009<br />Discussion: Is there a signal for cetuximab in esophageal cancer?<br />
  32. 32. Conclusions<br />All 3 regimens > 40% RR<br />IC-C: appeared to have lowest response and survival & most adverse events<br />ECF-C: appeared to have highest response, but highest treatment-related mortality and most treatment-related modifications<br />FOLFOX-C: good response and survival and best tolerated<br />
  33. 33. EOX<br />REAL 3*<br />EOX + Panitumumab<br />Cape / Cis<br />EXPAND**<br />Cape / Cis + Cetuximab<br />* http://clinicaltrials.gov/ct2/show/NCT00824785<br />**http://clinicaltrials.gov/ct2/show/NCT00678535<br />Studies on the Horizon<br />
  34. 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)<br />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 <br />
  35. 35. Rationale for Bevacizumab in AGC<br />Angiogenesis important for tumor growth, progression and metastases<br />Bevacizumab:<br />Humanized monoclonal antibody to VEGF<br />Promising results in Phase II studies in AGC<br />Shah et al. 2006<br />
  36. 36. R<br />AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study<br />Capecitabine*/Cisplatin (XP) <br />+ Placebo q3w<br />Locally advanced<br /> or metastatic gastric cancer<br />Capecitabine*/Cisplatin (XP)<br />+ Bevacizumab q3w<br />Primary endpoint OS<br />Cape 1000mg/m2 oral bid, d1–14, 1-week rest<br />Cisplatin 80mg/m2 d1<br />Bevacizumab 7.5 mg/kg d1<br />Maximum of 6 cycles of cisplatin<br />Cape and bevacizumab/placebo until PD<br />
  37. 37. Overall Response<br />
  38. 38. Progression-Free Survival<br />XP + Placebo<br />XP + Bev<br />1.0<br />0.9<br />0.8<br />0.7<br />HR = 0.80<br />95% CI 0.68–0.93 <br />p = 0.0037<br />0.6<br />0.5<br />0.4<br />6.7<br />0.3<br />0.2<br />5.3<br />0.1<br />0.0<br />12<br />0<br />15<br />18<br />21<br />24<br />3<br />9<br />6<br />Study month<br />387<br />387<br />279<br />306<br />145<br />201<br />86<br />123<br />55<br />71<br />32<br />38<br />3<br />3<br />15<br />11<br />0<br />0<br />XP + Placebo<br />XP + Bev<br />
  39. 39. Overall Survival<br />XP + Placebo<br />XP + Bev<br />1.0<br />0.9<br />0.8<br />0.7<br />HR = 0.87<br />95% CI 0.73–1.03 <br />p = 0.1002<br />0.6<br />0.5<br />12.1<br />0.4<br />0.3<br />10.1<br />0.2<br />0.1<br />0.0<br />12<br />0<br />15<br />18<br />21<br />24<br />3<br />9<br />6<br />Study month<br />271<br />291<br />146<br />178<br />98<br />104<br />15<br />19<br />54<br />50<br />0<br />0<br />343<br />355<br />204<br />232<br />387<br />387<br />XP + Placebo<br />XP + Bev<br />
  40. 40. Regional Differences in Efficacy<br />
  41. 41. Conclusions<br />Primary endpoint of OS not met<br />Secondary efficacy endpoints (PFS, best ORR) significantly improved, indicating clinical activity of bev + chemo in AGC<br />Apparent greater benefit in America>Europe>Asia<br />No unexpected / new safety signals for bev<br />Further analysis ongoing, including preplanned biomarker analysis<br />
  42. 42. Other Therapeutic Options in Advanced Disease <br />GE junction:<br />FLO vs FLOT (abs 4013)<br />Improved PFS, RR, not OS<br />Increased, but expected, toxicity<br />DCF vs Modified DCF (abs 4014)<br />Improved PFS, RR and OS<br />53% vs 30% hospitalized for toxicity<br />Gastric:<br />Granite-1 study looking at Everolimus. 56% DCR in phase II study.<br />TOGA: QoL not affected<br />
  43. 43. Conclusions<br />Cetuximab looks promising, not ready for clinical practice (REAL-3/EXPAND)<br />No role for Bevacizumab in gastric cancer <br />All patients with gastric and GEJ ACA should have her2neu status assessed<br />DCF active but still toxic, even when modified and administered with GCSF<br />
  44. 44. Thank You and GO BIG RED!<br />

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