Recent Advances in the Treatment of Gastric and Esophageal Cancers
Jeffrey S. Rose, MDThe Ohio State UniversityOctober 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
tumorsAmerican 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
CRT+Surgery Surgery
Resection Rate 90% 86%
RO Resection Rate 92.3% 64.9%
pCR 32.6% NR
In-hospital Mortality
3.8% 3.7%
Median Overall Survival
49 months 26 months
One, 2 and 3 year survival rates
82%/67%/59% 70%/52%/48%
Overall Survival
Preoperative CRT-ACA
Trial Therapy Patients %ACA %R0 pCR Survival
Stahl Surgery 94 100 66 -- 28% 3y
CRT-S 72 16 47%
Walsh Surgery 110 100 NS -- 6% 3y
CRT-S NS 25 32%
Urba Surgery 100 75 90 -- 16% 3y
CRT-S 88 28 32%
Tepper Surgery 56 67 -- -- 16% 5 y
CRT-S -- 16 39%
Gaast Surgery 363 73 67 -- 48% 3y
CRT-S 92 32.6 59%
Preoperative CRT-SCC
Trial Therapy
Patients
%SCC %R0 pCR Survival
Le Prise Surgery
86 100 NS -- 14% 3y
CRT-S NS 25 19%
Bossett Surgery
282 100 90 -- 36% 3y
CRT-S 88 28 34%
Bedenne
CRT-S 259 100 75 23 34% 2y
CRT 40%
Stahl CRT-S 172 100 82 35 31% 3y
CRT 24%
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
BackgroundRegimen Phase Tumor
SitesResponse Survival Reference
ECF III Esoph GEJ Stomach
45% 8.9 mos Webb.J Clin Oncol 1997
ECF III Esoph GEJ Stomach
42.4% 9.4 mos Ross.J Clin Oncol 2002
ECF III Esoph GEJ Stomach
40.7% 9.9 mos Cunningham. N Engl J Med 2008
IC II EsophGEJ
57% 14.6 mos Ilson. J Clin Oncol 1999
IC II GEJ Gastric
58% 9 mos Ajani. Cancer 2002
FOLFOX II Esoph GEJ Cardia
40% 7.1 mos Mauer. Ann Oncol 2005
FLO III GEJ Gastric
41.3% 10.7 mos Al-Batran. J Clin Oncol 2008
Stratification:ECOG 0-1 vs 2ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
Treatment Schema
Primary endpoint RR
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n P
rog
res
sio
n-F
ree
ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)
Progression-Free Survival
Median PFS: ECF-C 5.9IC-C 5.0FOLFOX-C 6.7
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)
Overall Survival
Median OS: ECF-C 11.5IC-C 8.9FOLFOX-C 12.4
* Includes 4 deaths** Includes 2 deaths† Indicates a death
ECF-CECF-C IC-CIC-C FOLFOX-CFOLFOX-CNon-HematologicNon-Hematologic 66%*66%* 77%**77%** 65%65%
Constitutional symptomsConstitutional symptoms 13%13% 18%18% 17%17%DermatologicDermatologic 16%16% 11%11% 19%19%GastrointestinalGastrointestinal 28%28% 42%†42%† 22%22%InfectionInfection 13%13% 8%8% 7%7%MetabolicMetabolic 16%16% 34%34% 22%22%NeurologicNeurologic 12%12% 4%4% 17%17%PainPain 9%9% 1%1% 3%3%PulmonaryPulmonary 4%4% 1%†1%† 0%0%VascularVascular 6%6% 7%7% 4%4%Death; no CTCAE definedDeath; no CTCAE defined 6%6% 0%0% 0%0%
Total (Heme + Non-Heme)Total (Heme + Non-Heme) 75%75% 86%86% 79%79%
p=0.05
p=0.03
p=0.06
p=0.01
P-value
p=0.05
p=0.03
p=0.06
p=0.01
P-value
Toxicity
Response Survival Response Survival
ECF 41-45% 8.9-9.9 mos
ECF-C57.8% 11.5 mos
IC (Phase II)57-58% 9-14.6 mos
IC-C45.6% 8.9 mos
FOLFOX40-41% 7.1-10.7 mos
FOLFOX-C 53.6% 12.4 mos
Random Phase II* Regimen Pts Response PFS OS
1st line therapy for esophageal SCC
Cis/5-FU 30 13% 3.6 5.5
CF + Cetux 32 19% 5.9 9.5
*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
XP + PlaceboN=387
XP + BevN=387
Patients with measurable disease 297 311
Overall response 111 (37%) 143 (46%)
95% CI 0.6–16.6
P value (2) 0.0315
Complete response 3 (1%) 5 (2%)
Partial response 108 (36%) 138 (44%)
Stable disease 90 (30%) 93 (30%)
Progression-Free Survival
387387
279306
145201
86123
5571
3238
33
1511
00
XP + PlaceboXP + 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 21 240 6 12
5.3
6.7
Study month
Overall Survival
387387
343355
271291
204232
146178
98104
1519
XP + PlaceboXP + Bev
5450
00
XP + Placebo
XP + Bev
HR = 0.87
95% CI 0.73–1.03
p = 0.1002
3 9 15 18 21 240
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
RegionXP + PlaceboMedian, mo
XP + BevMedian, mo
Delta, mo
Hzrd Ratio 95% CI
OS Asia 12.1 13.9 1.8 0.97 0.75–1.25
Europe 8.6 11.1 2.5 0.85 0.63–1.14
America 6.8 11.5 4.7 0.63 0.43–0.94
PFS Asia 5.6 6.7 1.1 0.92 0.74–1.14
Europe 4.4 6.9 2.5 0.71 0.54–0.93
America 4.4 5.9 1.5 0.65 0.46–0.93
Patients enteredPatients receiving second-line
treatment (%)
Asia 376 66
Europe 249 31
Pan-America 149 21
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
Thank You and GO BIG RED!