Esophageal and Gastric Cancer: How do we sort out the treatment options?

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

Disclosure

Research Funding

– Sanofi-aventis

– Genentech

– Bristol-Myers Squibb/Imclone

Esophageal and Gastric CarcinomaUS Incidence in 2008

37,970 new cases

– Gastric: 21,500 (57%)

– Esophagus: 16,470 (43%)

Decline in Gastric Cancer , Esophageal Squamous Cancer Incidence

Increase in Adenocarcinoma of the esophagus, GE JX, cardia

Esophageal cancer more virulent:

– 87% fatality rate

– Gastric: 52%

Jemal et al, CA 58: 71-96; 2008

Oral Presentations: Esophageal and Gastric Cancer, Phase III

Adjuvant Therapy

Igaki (Abs 4510): Esophageal Cancer

– Pre versus Post op chemo in squamous cancer

Kang (Abs LBA 4511): Gastric Cancer

– Adding IP and IV cisplatin to MMC / oral doxifluridine after resection

Advanced Disease

Ridwelski (Abs 4512): Gastric Cancer

– Docetaxel + cisplatin versus 5-FU + cisplatin

Esophageal CancerTrials of Adjuvant Therapy

Preoperative surgery

Preop Chemo Surgery

Preop Concurrent RT + Chemo + / - Surgery

6

A randomized trial of postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus neoadjuvant chemotherapy for clinical Stage II/III squamous cell carcinoma of the thoracic esophagus (JCOG 9907)

H. Igaki, N. Ando, H. Kato, M. Shinoda, H. Shimizu, T. Nakamura,

S. Ozawa, H. Yabusaki, N. Aoyama, A. Kurita, H. Fukuda

Japan Esophageal Oncology Group (JEOG) of

Japan Clinical Oncology Group (JCOG), Japan

Prior JCOG Trials in Esophageal Squamous Cancer Similar stage patients, similar sample size and design

JCOG 8806: Surgery vs post op vindesine + cisplatin, 205 pts

– Negative Trial

– OS 5 year 45% for surgery, 48% for post op chemo (NS)

JCOG 9204: Surgery vs post op 5-FU + cisplatin, 242 pts

– Primary: DFS 5 year

– Negative Trial

– DFS 45% for surgery, 55% for chemo (NS)

– OS in node + patients: 38% 52% post op chemo (P = 0.041)

Unplanned subset analysis

Ando J Card Thor S 114: 205; 1997 Ando J Clin Oncol 24: 4592;2003

8

SchemeRandomization

Balanced with minimization byinstitution, cN0 / cN1

Post-op CTx(standard arm A)

Pre-op CTx(test arm B)

Surgery

2 x FP

FP: cisplatin + 5FU5-FU 800mg/m2 d1-5 ci cisplatin 80mg/m2 d1 div

Surgery

2 x FP

Surgery-Transthoracic esophagectomy with lymphadenectomy (>D2)

In pN0,no CTx

Igaki et al, Abstract 4510

Primary Endpoint: increase PFS by 10-13% for preoperative arm

Adequately powered trial

– Protocol excluded pathologic N0 pts on post op arm (38 pts) from chemo

– Based on analysis of prior post op trial: no benefit in N0

Arms balanced by preclinical stage

Therapy tolerable and feasible

Primary endpoint not reached

Median PFS: 2 year (post op) versus 3 year (pre op, NS)

OS 5 year 38% post op 60% pre op (HR 0.64, p = 0.014)

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2nd Interim Analysis• To decide early publication or not @ Mar. 2007, all 330 pts

Years after randomization

Unadjusted one-sided stratified

logrank P = 0.0444 > 0.0254 (alpha)

Hazard ratio = 0.76 (94.91%CI: 0.56–1.04)

Years after randomization

Unadjusted two-sided logrank P = 0.013Hazard ratio by Cox model

= 0.64 (95%CI: 0.45–0.91, p=0.014)

DSMC recommended the early publication

Progression-free survival (PFS) Overall survival (OS)

PostMedian PFS=2.0y

PreMedian PFS=3.0y

Post5yOS=38.4%

Pre5yOS=60.1%

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Igaki et al, Abstract 4510

A large number of post op pts did not receive chemo

– Preop: 17 pts (10%) did not receive chemo

– Post op: 85 pts (51%) did not receive chemo Includes 38 path N0 pts excluded per protocol (23%) Another 28% failed to receive post op chemo

Trial did not reproduce results from post op arm of prior study

– 61% OS prior post op trial

– 38% OS current post op trial Different populations, pathologic staging on the prior trial

compared to clinical staging on the current trial Adequacy of clinical staging: EUS and PET scan were not

performed

– ? Treatment arms truly balanced by stage

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Subgroup Analyses: updated OSClinical

Stage

Years after randomization Years after randomization

Hazard ratio by Cox model

= 0.94 (95%CI: 0.61–1.46)

Two-sided P = 0.79

Pre-op chemotherapy may be more beneficial in Stage II

Stage II Stage III (non-T4)

Post(n=78)

5yOS=49.3%

Pre(n=80)

5yOS=69.7% Pre(n=84)

5yOS=52.1%

Post(n=88)

5yOS=36.5%

Hazard ratio by Cox model

= 0.48 (95%CI: 0.28–0.83)

Two-sided P = 0.0088

Data in Nov 2007

Igaki et al, Abstract 4510

Current Preop Trial: only Stage II patients benefit

Prior post op trial benefit limited to path N + pts

Dose this trial prove that pre op chemo is superior to post op chemo in esophageal squamous cancer?

No

Unplanned subset analyses generate hypotheses and not conclusions

Large number of pts did not receive chemotherapy

Adequacy and accuracy of pre treatment clinical staging

Esophageal Cancer: Preop Chemotherapy

Negative Trials

U.S. INT 113

– 440 pts

– Adeno 54%, Squamous 46%

– 3 pre, 3 post op cycles of 5-FU + Cisplatin

– No improvement in disease free or overall survival

0

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Kelsen et al, NEJM 339: 1979; 1998

Esophageal Cancer: Preop Chemotherapy

Positive trials

U.K. MRC OEO-2

– 802 pts

– Adeno 66%, Squamous 31%

– 2 preop cycles of 5-FU + Cisplatin

9% increase in 2 year OS

Decreased to 6% increase in 5 years OS (17%23%)

10% operative mortality

MRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006

Meta Analysis Preop Chemo in Esophageal Cancer: Thirion (ASCO 2007)

Squamous and adeno

– 9 trials OS: 2102 pts

Overall survival improvement for preop chemo (HR 0.87, p = 0.0033)

– 4% improvement in OS at 5 yrs

– Squamous 4%

– Adeno 7%

Preop Chemo in Esophageal Squamous Cancer

Marginal benefit from larger trials and meta analysis

Operative mortality risk = survival benefit

Data do no support this approach as the optimal standard of care in squamous cancer

Preop Chemo in Esophageal Squamous Cancer

Primary chemo + radiotherapy: U.S. standard of care for locally advanced disease

– Curative potential without surgery (RTOG)

– Responding patients (FFCD)

Absence of a clear survival benefit for addition of surgery

– Surgery for biopsy positive / non responding patients after therapy

– Surgery for younger, fitter patients

Early stage disease:

– Surgery alone or Chemoradiotherapy alone

Gastric Cancer:Adjuvant Therapy Standards of Care

Post op Chemo oral S-1 (Japan)– 10% improved 5 yr OS

– 1000 pts, D2 resection

Post op Chemo 5-FU / LV + radiotherapy (U.S.)– 10% improvement in 5 yr OS

– Pts with less than a D1-D2 resection

Pre and post op Chemo ECF (U.K.)– 13% improvement in 5 yr OS

– without radiotherapy

Sakuramoto NEJM 357: 1810;2007 Macdonald NEJM 345: 725; 2001 Cunningham NEJM 355: 11; 2006

Rationale: Intraperitoneal Chemotherapy

Peritoneal recurrence in up to 40-50% of patients after gastric resection

IP chemo increases exposure to chemo agents by 10-100 + fold

No confirmed phase III trials of IP therapy

Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:

A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term

doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)

(AMC 0101) (NCT00296322)

Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:

A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term

doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)

(AMC 0101) (NCT00296322)

Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang, Jae-Lyun Lee, Tae Won Kim, Dae Hyun Yang, Se Jin Jang,

Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim

Asan Medical Center, Seoul, Hallym University Hospital, Anyang, Korea

ASCO 2008 Abs 4531: Adjuvant MMC + FU + / - IV Cisplatin after D2 resection (AMC 0201)

MMC x 1, Doxifluridine orally x 3 mos

– vs

MD + IV Cisplatin x 6, Doxifluridine x 12 mos MD: 67% 3 yr relapse free survival

MDP: 65% 3 yr relapse free survival

No improvement with addition of IV cisplatin or extended therapy

Current Trial (AMC 0101) MMC + FU + IV cisplatin + extended doxifluridine

– + IP cisplatin x 1 intra op

– Mitomycin administered earlier on

– Serosa positive gastric cancer

Grossly Serosa(+), Non-Metastatic Gastric Cancer

RANDOMIZATION

Intraperitoneal CDDP

MMC

CDDP DFUR

MMC

CDDPCDDP

CDDPCDDP

CDDP

Stage I, IV(M1)

Protocol off

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFUR

Mf armMf armiceMFP armiceMFP arm

Stratified by center, stage

Treatment SchemaTreatment Schema

At surgery

DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks

100 mg for 2h before closure

15 mg/m2 iv D1

4 weeks later

3 - 6 weeks after surgery

20 mg/m2 iv

Recurrence Free SurvivalRecurrence Free Survival

0 12 24 36 48 60 720

0.25

0.50

0.75

1.00

months after randomization

Rec

urr

ence

fre

e p

rop

orti

on

N Event 3yRFSR 5yRFSR

iceMFPiceMFP 263263 103103 60.2%60.2% 50.5%50.5%

MfMf 258258 126126 50.0%50.0% 43.8%43.8%

HR 0.695 [ 95% C.I.: 0.536 - 0.902 ]P = 0.006 by log-rank test

Overall SurvivalOverall Survival

0 12 24 36 48 60 720

0.25

0.50

0.75

1.00

months after randomization

Su

rviv

ing

pro

por

tion

N Event 3yOSR 5yOSR

iceMFPiceMFP 263263 8282 71.2%71.2% 56.2%56.2%

MfMf 258258 103103 59.6%59.6% 47.0%47.0%

HR 0.710 [ 95% C.I.: 0.531-0.950 ]P = 0.02 by log-rank test

RecurrencesRecurrences

P=0.02

Intraperitoneal Cisplatin, Gastric Cancer

Well designed and conducted phase III trial

Adequately powered

Ineligible patients common

– Randomization was intraoperative prior to final pathology reading

– Appropriate exclusion of metastatic disease, positive margins

Arms balanced, therapy tolerable, no increased operative complications

Intraperitoneal Cisplatin, Gastric Cancer

Achieved primary endpoint of improved relapse free survival:

– 3 yr RFS 50% 60%

Reduced peritoneal and distant recurrence

Suggests a potential benefit for IP cisplatin, early start of mitomycin

Intraperitoneal Cisplatin, Gastric Cancer

Four variables confound conclusion that IP chemo is superior in serosa + gastric cancer

– Trial also included early MMC, extending doxifluridine, adding IV cisplatin

Companion AMC 0201 trial

– No benefit for extended chemo or addition of cisplatin

Confirmatory trial in which only variable is IP chemotherapy

Esophago-Gastric Cancer: Metastatic Disease

• CIV 5-FU + cisplatin

• 4-5 day infusion

• RR 20-30%

• Med S 8-9 months• Adding a third drug:

• Epirubicin (ECF), protracted 5-FU CIV: RR 40-45%, Med S 9 mos

• 25-40% have locally advanced, non metastatic disease

• Docetaxel (DCF): RR 36%, Med S 9 mos

• 10% increment in response rate

• 1-2 month increment in survival• Capecitabine = 5-FU, Oxaliplatin = Cisplatin

DCF vs CF: Toxicity

Grade 3/4 Toxicity DCF CF

Stomatitis 21% 27%

Diarrhea 19% 8%

Nausea/vomiting 14% 17%

Neutropenia 82% 57%

Neutropenic fever 29% 12%

Taken off toxicity of AE

49% 37%

Toxic deaths 3.6% 5.4%

Van Cutsem J Clin Oncol 2006

Docetaxel–cisplatin (DC) versus 5-fluorouracil–leucovorin–cisplatin (FLC) as

first-line treatment for locally advanced or metastatic gastric cancer: Preliminary

results of a Phase III study

4512

K Ridwelski, J Fahlke, C Schmidt, E Kettner, U Keilholz, D Quietzsch, M Assmann, M Stauch, K Zierau, H Lippert

Objectives

Primary objectiveTime to tumor progression (TTP) increase from 40% to 60% in patients without progression at 6 months

Secondary objectivesToxicityOverall response rate (ORR)Overall survival (OS)

DCDocetaxel 75 mg/m2 iv over 1 h, day 1Cisplatin 75 mg/m2 iv over 1 h, day 1 Repeated q3w for up to 6 cycles

FLC5-FU 2000 mg/m2 iv over 24 hLeucovorin 500 mg/m2 iv over 2 h Both on days 1, 8, 15, 22, 29, 36

+Cisplatin 50 mg/m2 iv over 1 h, days 1, 15, 29 Repeated q7w for up to 4 cycles

(cisplatin omitted in Cycle 4)

Chemotherapy-naïve patients with metastatic or locally advanced (stage III-IV) gastric cancer

RANDOMIZATION

Study design

273 patients randomized between October 2001 and September 2006 from 21 centers in Germany Data available for 270 patients

Results

DC

n=133

FLC

n=137Median TTP, months 5.8 6.6

Median OS, months 8.2 9.6

1-year survival data 28 % 34 %

TTP

OS

P=0.468

P=0.616

DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; OS, overall survival; TTP, time to progression

Median follow up: 8.2 months 9.5 months

Response to treatment

Response, nDC

n=133

FLC

n=137Complete response (CR) 0 4

Partial response (PR) 32 29

Stable disease 59 59

Progressive disease 26 25

Not evaluable 16 20

ORR (CR + PR), % (95% CI)p-value

24.1 (0.17-0.32) 24.1 (0.17-0.32)

DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; ORR, overall response rate

p = 0.244

Confirmed response per RECIST

Safety

Grade 3/4 adverse event (NCI-CTC)patients

DC n=127

FLC n=134

Hematologic ( % )LeukopeniaNeutropenia

Febrile NeutropeniaAnemia

45.2

46.2 5.5

15.1

8.2

12.20.0

10.4Non-hematologic ( % )

Gastrointestinal Nausea VomitingPain

Infection

18.517.3 8.713.4 5.6

29.222.215.512.6 5.2

DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin

DC vs CF

DC is not superior to CF, DC = CF

– Contrasts the V325 study: D + CF superior to CF

CF well tolerated on this dose and schedule

Use colorectal cancer like schedule for cisplatin or oxaliplatin + FU

– Weekly or two weekly infusional FU

– Single digit toxicities

Colorectal Scheduling: Gastric Cancer, Weekly infusional 5-FU + every 2 week Oxaliplatin or Cisplatin

Grade 3/4 Toxicity

FLO FLP

Stomatitis 3% 3%

Diarrhea 3% 6%

Nausea/vomiting 5% 9%

Neutropenia 5% 9%

Neuropathy 14% 2%

Off therapy due to toxicity or AE

17% 23%

Al Batran J Clin Oncol 26: 1435; 2008

DC vs CF

DC = CF, failed to achieve primary endpoint of superiority

Contrast to V325 study, three drug DCF superior to CF

– Toxicity of DCF limits its general use

If DCF is used:

– Lower starting doses

– Consider colorectal like scheduling of drugs

Marginal differences in outcome for three drugs: Doublets better platform for future study

– Adding targeted agents

– Perioperative therapy or added to radiotherapy

Gastric Cancer Chemotherapy: What regimen to use?

Oxaliplatin

EOX or EOF

Cape

ECX or EOX

XP FLO FUFIRI DCF ECF

Pts 489 513 160 109 170 221 126

%RR 44% 45% 41% 34% 32% 36% 45%

TTP, mos 6.7 6.5 5.6 5.5 5.0 5.6 7.4

OS, mos 10.9 10.4 10.5 -- 9.0 9.2 8.9