The Role of Preoperative Approaches in Localized Gastro Esophageal Cancers
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The Role of Preoperative Approaches in Localized Gastro Esophageal Cancers
David H. Ilson, MD, PhDGastrointestinal Oncology ServiceMemorial Sloan-Kettering Cancer Center
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Gastric and Esophageal Cancer
Gastric and Esophageal Cancer: 1.39 million cases
– 1.09 million deaths (78%) Esophageal Cancer: 386,000 deaths
Gastric Cancer: 700,000 deaths
Estimate 50% are locally advanced (700,000)
– A 10% increment in survival = 70,000 lives saved
Kamangar et al, J Clin Oncol 24: 2137-50; 2006
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Esophageal and Gastric CancerUS Incidence in 2007
36,820 new cases
– Esophageal: 15,560
– Gastric: 21,260
Esophageal: 90% fatality rate
Decline in Gastric Cancer Incidence
Increase in Adeno of the esophagus , GE JX, cardia
Jemal et al, CA 57: 43-66; 2007
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Esophageal Cancer: Surgery 1980’s, 1990’s
Akiyama: 913 pts (Squamous), TTE (2, 3 field), 5 yr O.S. 43%
Ando: 419 pts (93% Squamous), TTE (2, 3 field) / THE, 5 yr O.S. 40%
Hulscher: 220 pts (Adeno), THE vs TTE: 5 yr O.S. 29-39%
Akiyama Ann Surg 220:364;1994 Ando Ann Surg 232:225:2000, Hulscher NEJM 347:1662;2002
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Esophageal CancerMULTIMODALITY STUDIES
Chemo followed by Surgery
Concurrent RT + Chemo + / - Surgery
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Esophageal Cancer:Adjuvant Therapy
Pre Operative—Neoadjuvant Chemotherapy
– Negative U.S., Positive U.K. trialsChemo + RT
– Most common U.S. practice
– Mixed results, Phase III
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Esophageal Cancer: Preop Chemotherapy
Negative Trials U.S. INT 113
– 3 pre, 3 post op cycles of 5-FU + Cisplatin
– 440 pts
– Adeno 54%, Squamous 46%
– No improvement in R0 resection rate, disease free or overall survival
– Path CR 2.5%
0
20
40
60
80
100
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Kelsen et al, NEJM 339: 1979; 1998
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Esophageal Cancer: Preop Chemotherapy Positive trials U.K. MRC OEO-2
– 2 preop cycles of 5-FU + Cisplatin
– 802 pts
– Adeno 66%, Squamous 31%
– 6% increase in R0 resection rate, 9% increase in 2 year OS
– Path CR 4% U.K. MAGIC: pre and post op ECF in
gastric cancer
– 25% of 500 pts had GE junction or distal esophageal adeno
– No improvement in R0 resection rate, 13% increase in 5 year OS
– No Path CRsMRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006
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ASCO 2007: Boige et al, Abs 4510: Preop Chemo in Esophageal and Gastric Cancer: FFCD / FNLCC
CT = 5-FU + Cisplatin
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Preop Chemo in Esophageal Adeno: ASCO 2007, Abs 4510
Survival benefit for preop chemo with CF (cisplatin and 5-FU)
14% improvement in 5 yr OS, HR 0.69
– Similar to survival for gastric cancer in MAGIC trial
13% rate of improvement in R0 resection rate
Major impact was reduction in systemic recurrence
– Local: 26% for surgery, 24% for chemo + surgery
– Systemic: 56% for surgery, 42% for chemo + surgery
Epirubicin (ECF in MAGIC trial) may not be needed
OEO-05 (U.K. MRC): Preop ECF versus CF in esophageal cancer (U.K.)
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Esophageal Cancer: Met Analysis Preop Chemo: ASCO 2007, Abs 4512
Individual patient data for preop chemo in squamous cell and adenocarcinoma
9 trials OS: 2102 pts
7 trials DFS: 1849 pts
Slightly more than 50% of patients had squamous ca
Primary endpoint: overall survival improved by a HR of 0.87 (p = 0.0033)
– Translates only into 4.3% improvement in OS
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Primary End-point: Overall Survival
Patients at risk
Control 1054 321 144 74 38 20Chemo pre-op 1047 361 153 90 52 31
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Time (years)
0 2 4 6 8 10
Absolute benefit at 5 years:4.3 %
Patients at risk
Control 1054 321 144 74 38 20Chemo pre-op 1047 361 153 90 52 31
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Time (years)
0 2 4 6 8 10
Absolute benefit at 5 years:4.3 %
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Meta Analysis of Preop Chemo: Esophageal Cancer (Abs 4512)
Overall Survival Benefit independent of histology– Adeno: 20% 27%
– Squamous: 16% 20%
Other endpoints:– R0 resection rate improved by 5%
Conclusions:– 4.3% OS improvement, 5% impact on resection rate
modest
– Greater effect for adeno then squamous cell carcinoma
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Chemoradiotherapy: Esophageal CancerRTOG Trial 85-01: Non operative Tial
mskcc dhi 1999
Esophageal CaSquamous Adeno
6400 cGyAlone
5000 cGy + 5FU + Cisplatin
+ 2 cycles 5FU + Cisplatin
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Local Recurrence: 45%
Surgeon’s argument for resection after ChemoRT
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RTOG 85-01: Adeno vs Squamous Carcinoma
5 year Survival:
– Squamous Cancer: 21% (107 pts)
– Adenocarcinoma: 13% (23 pts)
Differential outcome by histology
Long term survivors: Primary Chemo RT
– Adeno and Squamous Cancer
– Without surgery
Cooper et al JAMA 1999
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Chemoradiotherapy Alone (5-FU/Cis/RT) or ChemoRT Surgery: FFCD 9102
Author Pt No.
Histol. Therapy Med. Surv.
O.S. Local Control
Bedenne 259 Squam Chemo RT + S
17.7 mos
34%
2 yr
66%
Squam Chemo RT
19.3 mos
40%
2 yr
57%
455 pts treated, 259 responders randomized: Non responders excluded.
Bedenne et al JCO 25: 1160; 2007
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Preop ChemoRT Surgery: Esophageal Cancer
Path CR in 10-40%
5 yr OS 25-35%
Phase III: small, inconclusive (<100-250 patients)
– Curative Resection rates increased RT + chemo in some trials
– Local Recurrence reduced
– Trends toward ↑ Survival
– Path CR: ↑ Survival
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Prognostic Factors after Chemo RT
Patients achieving a pathologic CR have 50-70% long term survival
Some series indicate pts with 90% treatment effect have similar survival to path CR pts
Superior survival for N0 versus N1 disease
Superior survival for T0-1 versus T2-4 post treatment
Early response during induction chemotherapy on PET scan: Prognostic for improved survival
Molecular prognostic factors
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Preop ChemoRT: Phase IIITrial Therapy Patients %
Adeno%R0 Resection
Path CR
OS or Med Surv
S / CRT
FFCD Surgery 282 0% 69% -- 26% 5 yr
CRT 81% 26% 26%
Walsh* Surgery 110 100% NS -- 6% 3 yr*
CRT NS 25% 32%*
Urba Surgery 100 75% 90% -- 16% 3 yr
CRT 88% 28% 32%
Burmeister Surgery 256 80% 59% -- 19 mos
CRT 80% 16% 22 mos
*1 of 4 trials positive
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Preop ChemoRT: Phase IIITrial Therapy Patients %
Adeno%R0 Resection
Path CR
OS or Med Surv
S / CRT
FFCD Surgery 282 0% 69% -- 26% 5 yr
CRT 81% 26% 26%
Walsh* Surgery 110 100% NS -- 6% 3 yr*
CRT NS 25% 32%*
Urba Surgery 100 75% 90% -- 16% 3 yr
CRT 88% 28% 32%
Burmeister Surgery 256 80% 59% -- 19 mos
CRT 80% 16% 22 mos
*1 of 4 trials positive
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Preop ChemoRT: Phase IIITrial Therapy Patients %
Adeno%R0 Resection
Path CR
OS or Med Surv
S / CRT
FFCD Surgery 282 0% 69% -- 26% 5 yr
CRT 81% 26% 26%
Walsh* Surgery 110 100% NS -- 6% 3 yr*
CRT NS 25% 32%*
Urba Surgery 100 75% 90% -- 16% 3 yr
CRT 88% 28% 32%
Burmeister Surgery 256 80% 59% -- 19 mos
CRT 80% 16% 22 mos
*1 of 4 trials positive
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RANDOMI
Z ATION
Cisplatin + 5-FU + RT + Surgery
Cisplatin + 5-FU + RT + Surgery
SurgerySurgery
CALGB 9781: Esophageal Cancer, Preop Chemo RT vs Surgery Alone
N = 26
N= 30
Tepper JCO 24: Abs 4012, 181, 2006
Of 500 planned patients, 56 accrued
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0 2 4 6
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
CALGB 9781 Overall Survival by Arm
Trimodality Arm(Cis,5FU,RT,SX)Surgery Alone
9781 Survival by ArmP =0.0130
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Preop Chemo versus Preop Chemo RT: ASCO 2007, Abs 4511
Trial limited to esophageal adenocarcinoma
– Siewert’s I-III, distal esophagus, GE JX, cardia
Careful preop staging by EUS and laparoscopy
Only high risk T3-4 pts treated
Balance of pts by pre therapy stage
Therapy was feasible and tolerable
Accrual goal was not met (33% planned)
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Preop Chemo, Preop Chemo RT feasible
No difference in rate of R0 resection, + RT
Higher post op mortality, + RT in multi institution trial
Strong trend favoring improved OS, + RT
– 20% at 3 years (p = 0.07)
Strong trend favoring improved local PFS, + RT
– 18% at 3 years (p = 0.06)
Preop Chemo versus Preop Chemo RT: ASCO 2007, Abs 4511
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Esophageal Cancer: Preop Chemo, RT, or Both? Esophageal Adeno: Preop Chemo
– Improves survival
– More feasible in a community setting
– Higher op mortality with preop chemort Esophageal Adeno: Combined Preop RT + Chemo
– Trends toward improved OS
– Significant rate of pathologic CR
– Cost of greater toxicity
– Treated at high volume centersOperative mortality not increased with preop
therapy
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Esophageal Cancer: Preop Chemo, RT, or Both? Esophageal Squamous
– Preop Chemo: less certain survival benefit
– RT + Chemo:As primary therapy without surgery is
acceptableSurgery after chemo rt: in selected patients,
as the improved local control no improvement in survival
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Preop Chemo vs Chemo RT: Meta Analysis
Gebski et al, Lancet Oncol 8: 226-234; 2007
Trials Pts Mort. Reduc
HR P value
2 yr OS
Chemo 8 1724 10% 0.90 0.05 7%
Adeno 22% 0.78 0.024
Squam 12% 0.88 0.12
Chemo RT 10 1209 19% 0.81 0.002 13%
Adeno 25% 0.75 0.02
Squam 16% 0.84 0.04
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Preop Therapy in Esophageal Cancer
Is radiotherapy required as part of adjuvant therapy?
Future Trial Questions
– Preop Chemo + / - RT Surgery
– Preop Chemo Surgery , Post op Chemo + / - RTCRITICS Trial: the Netherlands; ECXKorean adjuvant trial: Capecitabine + Cisplatin
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New Agents In Combined ChemoRT
CALGB: Irinotecan/Cisplatin Irino/Cis/RT Surgery
– Phase II 80302, serial PET scan
ECOG: Irinotecan/Cis vs Paclitaxel/Cis + RT surgery
– Path CR’s 15%
– Adenocarcinoma
RTOG 04026: Paclitaxel, Cisplatin, RT + / - Cetuximab
SWOG S0-356: Oxaliplatin + 5-FU + XRT: preop
U.K.: MAGIC 2 Trial: Pre and post ECF + / - Bevacizumab, without RT
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The Future?
Better ID of patients achieving path CR: Surgery
PET Scan: early response at 2-6 weeks during induction chemo is prognostic for improved survival
– Treatment failures referred for surgery (MUNICON)
– Failures change chemotherapy during subsequent RT
Targeted agents:
– Cetuximab: RTOG 04026, Chemort + / - Cetuximab
– Bevacizumab: MAGIC 2, ECX + / - Bevacizumab
Pharmacogenetics: chemo target polymorphisms (TS, ERCC-1)
Pharmacogenomics: patient drug metabolism
DNA Array