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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
Gastric Cancer 2009
21,130 new cases, 10,620 deaths
50% fatality rate
Increasing incidence of cardia tumors American Cancer Society Incidence (cont) 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
Brown. JNCI 2008 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
What’s New: Gastroesophageal Junction Cancer Staging Retrospective review of 336 patients with resected ACA and SCC at MSKCC compared AJCC 6 staging with # of involved lymph nodes
Rizk N, et al. J Thorac Cardiovasc Surg. 2006. Nodal Status Matters Rizk N, et al. J Thorac Cardiovasc Surg. 2006. Survival Improves if >18 Lymph Nodes Removed Rizk N, et al. J Thorac Cardiovasc Surg. 2006. 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 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 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. 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. 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
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 Assessment of Response Following Neoadjuvant Therapy-PET/CT Javeri H et al. Cancer. 2009 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 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 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 CROSS Study CROSS Study Overall Survival Preoperative CRT-ACA Preoperative CRT-SCC 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 Advanced Disease Last Year, We Were “On Target”. One Year Later?
Yes, with Herceptin
Probably, with Cetuximab
No, with Avastin
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 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 Background 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) Treatment Schema Primary endpoint RR Progression-Free Survival Median PFS:
ECF-C 5.9
IC-C 5.0
FOLFOX-C 6.7 Overall Survival Median OS:
ECF-C 11.5
IC-C 8.9
FOLFOX-C 12.4
* Includes 4 deaths
** Includes 2 deaths
† Indicates a death ECF - C ECF - C IC - C IC - C FOLFOX - C FOLFOX - C Non - Hematologic Non - 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 P - value Toxicity *Lorenzen. Ann Oncol 2009 15% 2.5mo -10% -2mo Vs. Discussion: Is there a signal for cetuximab in esophageal cancer? 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 * http://clinicaltrials.gov/ct2/show/NCT00824785
**http://clinicaltrials.gov/ct2/show/NCT00678535 REAL 3* EXPAND** EOX EOX + Panitumumab Cape / Cis Cape / Cis + Cetuximab Studies on the Horizon 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 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 R AVAGAST: A Randomized Double-Blind, Placebo- Controlled Phase III Study Capecitabine*/Cisplatin (XP)
+ Placebo q3w Capecitabine*/Cisplatin (XP)
+ Bevacizumab q3w Locally advanced
or metastatic gastric cancer Cape 1000 mg/m2 oral bid, d1–14, 1-week rest
Cisplatin 80 mg/m2 d1
Bevacizumab 7.5 mg/kg d1
Maximum of 6 cycles of cisplatin
Cape and bevacizumab/placebo until PD Primary endpoint OS Overall Response Progression-Free Survival 387
387 279
306 145
201 86
123 55
71 32
38 3
3 15
11 0
0 XP + Placebo
XP + Bev XP + Placebo
XP + Bev HR = 0.80
95% CI 0.68–0.93
p = 0.0037 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 9 15 18 21 24 0 6 12 5.3 6.7 Study month Overall Survival 387
387 343
355 271
291 204
232 146
178 98
104 15
19 XP + Placebo
XP + Bev 54
50 0
0 XP + Placebo
XP + Bev HR = 0.87
95% CI 0.73–1.03
p = 0.1002 3 9 15 18 21 24 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 12 Study month 10.1 12.1 Regional Differences in Efficacy 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 Other Therapeutic Options in Advanced Disease 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 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
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