The Role of Preoperative Approaches in Localized Gastro Esophageal Cancers

David H. Ilson, MD, PhDGastrointestinal Oncology ServiceMemorial Sloan-Kettering Cancer Center

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

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

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

Esophageal CancerMULTIMODALITY STUDIES

Chemo followed by Surgery

Concurrent RT + Chemo + / - Surgery

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

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

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

ASCO 2007: Boige et al, Abs 4510: Preop Chemo in Esophageal and Gastric Cancer: FFCD / FNLCC

CT = 5-FU + Cisplatin

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.)

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

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 %

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

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

Local Recurrence: 45%

Surgeon’s argument for resection after ChemoRT

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

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

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

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

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

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

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

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

0 2 4 6

Years from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

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rtio

n S

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CALGB 9781 Overall Survival by Arm

Trimodality Arm(Cis,5FU,RT,SX)Surgery Alone

9781 Survival by ArmP =0.0130

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)

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

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

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

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

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

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

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