Gastric and Esophageal Cancers: ASCO 2013 Poster Discussion Section

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

Disclosure

Research Funding

– Roche-Genentech

– Bayer

Consulting

– Amgen

– Covidien

– Imclone

ASCO 2013 Gastric / Esophageal Cancer Poster Discussion

Abst 4026: Does induction chemo added to chemoradiotherapy improve response in Esophageal and GEJ Cancer?

LB Abst 4024, Abstract 4025

– S-1 in metastatic gastric cancer

Does increasing the frequency / dose of cisplatin + S-1 improve outcome?

How does S-1 + Cisplatin compare to 5-FU + Cisplatin in China?

Abst 4027: Italian Trial of D1 vs D2 surgery

– Withdrawn, Dr. Degiuli could not attend

– Data not provided for review

Esophageal and GEJ Adenocarcinoma: Consensus on Adjuvant Therapy

T2-3 or N+: Something more than surgery alone should be done

Preop chemo ECF, CF improves overall survival in some but not all trials

– MAGIC (ECF): 13% ↑ OS at 5 yr

– FFCD / FNLC (CF): 14% ↑ OS at 5 yr same as MAGIC, no epirubicin

Cunningham NEJM 355: 11; 2006, Ychou J Clin Oncol 29: 1715; 2011

Van Hagen et al NEJM 366: 2074; 2012

5 weeks of chemo + RT Surgery vs Surgery alone

Paclitaxel 50mg/m2 + Carboplatin AUC=2 weekly

RT 41.4 Gy in 23 fractions of 1.8 Gy

Surgery within 6 weeks after completion of chemoRT (THE/TTE)

CROSS Trial

HR 0.67 95% CI (.49 - .91) P=0.012

CROSS: Overall Survival

HR 0.67 95% CI (0.49 - 0.91)

CRTx

Surgery

•5-year survival 47% versus 34%, HR 0.66

•Squamous path CR 49%, Adeno 23% (p = 0.008)

Preop Chemo vs ChemoRT

Stahl J Clin Oncol: 27: 836; 2009

Preop Chemo vs Chemo RT: Stahl

Arm Pts R0 pCR N0 Median Survival

3 yr OS Local Control

Chemo 59 70% 2% 37% 21 mos 28% 59%

Chemo RT

60 72% 16% 64% 33 mos 47%P = 0.07

77%P = 0.06

Stahl J Clin Oncol: 27: 836; 2009

•EUS, laparoscopy staged pts•Siewert I-III, T3-4 adenocarcinoma

Duration of Chemo on Positive Trials MAGIC, FFCD chemo only: 4-6 months chemo

pre / post op

– 5 year OS: 13%, HR 0.69 – 0.75

Stahl, chemo vs chemoRT: 4 months chemo, vs 3 mos chemo + 1 mo chemoRT preop

– 3 year OS: 19%, HR 0.67 (p = 0.07)

CROSS, chemoRT: 5 weeks chemo during RT

– 5 year OS: 13%, HR 0.66

Duration of Chemo on Positive Trials MAGIC, FFCD chemo only: 4-6 months chemo pre / post

op

– 5 year OS: 13%, HR 0.69 – 0.75

Stahl, chemo vs chemoRT: 4 months chemo, vs 3 mos chemo + 1 mo chemoRT preop

– 3 year OS: 19%, HR 0.67 (p = 0.07)

CROSS, chemoRT: 5 weeks chemo during RT

– 5 year OS: 13%, HR 0.66

Survival benefits = for short course vs protracted chemo

Does extended chemo improve outcome?

Rationale for Induction Chemo ChemoRT

Establish safety / tolerance of chemo prior to adding RT

Improve dysphagia in 70-80% of patients

– Reduce need for feeding tube placement

Increase in pathologic response to therapy

– Increase in R0 resection

Assess response to chemo on early PET scan

– MUNICON trial: PET non responders can stop ineffective chemo and go to early surgery

– U.S. CALGB 80803: PET non responders have chemo changed during chemoRT to increase pathologic CR

Randomized Phase II Trial of Extended versus Standard Neoadjuvant Therapy

for Esophageal CancerNCCTG (Alliance) Trial N0849

SR Alberts1, GS Soori2, Q Shi1,3, DA Wigle1, RP Sticca4, RC Miller1, JL Leenstra5, PJ Peller1, T-T Wu1, HH Yoon1, TF Drevyanko6, SJ Ko7, BI

Mattar8, DA Nikcevich9, RJ Behrens10, MF Khalil11, GP Kim7

1Mayo Clinic, Rochester, MN; 2Missouri Valley Cancer Consortium, Omaha, NE; 3Alliance Statistics and Data Center, Rochester, MN; 4Meritcare Hospital CCOP, Fargo, ND; 5St. Vincent

Regional Cancer Center CCOP, Green Bay, WI; 6Iowa Oncology Research Association CCOP, Des Moines, IA; 7Mayo Clinic, Jacksonville, FL; 8Wichita Community Clinical Oncology Program, Wichita, KS; 9Essentia Health Duluth Clinic CCOP, Duluth, MN; 10Iowa Oncology Research

Association, Des Moines, IA; 11Geisinger Medical Center, Danville, PA

Abstract 4026

GoalsPrimary• To compare the pathologic complete response (PCR) rate

between patients receiving standard neoadjuvant +/- DOCSecondary• To assess and compare the adverse event (AE) profile• To assess and compare the overall survival (OS) and

disease-free survival (DFS)• To assess and compare the clinical tumor response rate

measured before surgery• To evaluate the profiles of pharmacogenetic and proteomic

biomarkers and FDG PET/CT measures

Schema

Randomization portion

Early toxicity assessment portion

DOC 5FU/Oxaliplatin/RT

Docetaxel 60 mg/m2 day 1, Oxaliplatin 85 mg/m2 day 1, and Capecitabine 1250 mg/m2/day days 1-14 x 2 cycles [DOC]; 5-FU 180 mg/m2/day continuous IV through radiation + Oxal 85 mg/m2 days 1,15,29 + 50.4 Gy radiation (chemo-RT)

DOC 5FU/Oxaliplatin/RT

5FU/Oxaliplatin/RT

R

Table 1

Table 2

Induction Chemo prior to ChemoRT

Small, underpowered study looking for a large difference in path CR (25% 45%)

No improvement in RO resection 94-100%

No improvement in pCR: higher rate, 48%, without induction chemo

– Comparison to SWOG S0356: 93 pts, CIV 5-FU, oxaliplatin, RT surgery

– Path CR 28%

Survival data pending

– 42 patient trial

Induction Chemo prior to ChemoRT

Was only 2 cycles of DOC enough?

– Data argue similar benefit for 5 weeks of chemo + RT vs 4-6 months of chemo

Is induction chemo harmful due to delay of RT?

– Anal cancer (RTOG): induction 5-FU / cisplatin prior to chemoRT worsened local control and OS

– Protracted preop chemo 3-4 months does not worsen outcome

This trial reinforces chemoRT, without added chemotherapy, as the standard or care

Advanced EsophagoGastric Cancer Chemotherapy: What regimen to use?

Oxali:

EOX or EOF

Cape:

ECX or EOX

XP FLO FUFIRI S-1 Cis

DCF ECF

Pts 489 513 160 109 170 305 221 126

%RR 44% 45% 41% 34% 32% 54% 36% 45%

TTP, mos 6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4

OS, mos 10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9

S-1

S-1: oral fluorouracil formulation

Tegafur, 5-FU prodrug +

CDHP: DPD inhibitor +

Oxo (potassium oxonate): reduces bowel toxicity, inhibiting orotate PRT

Developed as orally absorbed 5-FU preparation with potentially less bowel toxicity

Japan: toxicity hematologic, dose 80 mg/m2/d x 3 weeks + cisplatin, 2 week rest

U.S. / Europe: toxicity diarrheal, dose 50 mg/m2/d x 3 weeks + cisplatin, 2 week rest

S-1: Mechanism of Action

Gastric Cancer: S-1 vs S-1 + Cisplatin, Spirits

S-1 S-1 + Cis p

Number 150 148

RR 31% 54% 0.002

PFS 4mos 6mos 0.001

OS 11mos 13 mos 0.04, HR 0.77

1 year 47% 54%

2 year 15% 24%

Grade 3/4 Neut

11% 40%

Grade 3/4 Diarrhea

3% 4%

Grade 3/4 Nausea

1% 11%

S-1 40-60 mg/body BID x 4 weeks every 6 weeks

Vs

S-1 x 3 weeks + Cisplatin 60 mg/m2 day 8, every 5 weeks

S-1 + Cisplatin a new standard in Japan

Koizumi Lancet Oncol 9: 215; 2008

Gastric Cancer: S-1 + Cisplatin vs 5-FU + Cisplatin, FLAGS

S-1 5-FU p

Number 521 508

RR 29% 32% 0.40

OS 8.6 mos 7.9 mos 0.20

PFS 4.8 mos 5.5 mos 0.92

Second Line Chemo

29.6% 33.3%

Grade 3/4 Neut

32.3% 63.6%

Grade 3/4 Stomatitis

1.3% 13.6%

Toxic Deaths

2.5% 4.9%

S-1 50 mg/m2 x 21 days + Cisplatin 75mg/m2 every 4 weeks

vs

5-FU 1000 mg/m2 days 1-5 + Cisplatin 100 mg/m2 every 4 weeks

S-1 + Cisplatin less toxic, no difference in RR, PFS, OS

Ajani JCO 28: 1547; 2010

LB Abstract 2024, Ryu et al Non inferiority trial of escalated S-1 + cisplatin

– PFS primary endpoint

Increase cisplatin exposure by 60%

Increase S-1 exposure by 10%

Standard S-1 + Cisplatin

– Cisplatin 60 mg/m2 D-1 + S-1 80-120 mg/body/day D1-21

Cycled every 5 weeks vs

– Cisplatin 60 mg/m2 D-1 + S-1 80-120 mg/body/day D 1-14

Cycled every 3 weeks

3 week vs 5 week Schedule of S-1 + Cisplatin (Abstract LBA 4024)

Large, adequately powered and well conducted study

Non inferiority for the 3 week schedule was demonstrated

No meaningful difference in PFS (2 weeks), no improvement in OS, non significant 10% increase in RR

3 week vs 5 week Schedule of S-1 + Cisplatin (Abstract LBA 4024)

Greater hematologic toxicity, need for more frequent administration of cisplatin offer no advantage

No quality of life component

– Likely worsened QOL with a 60% increase in cisplatin exposure

Current 5 week schedule should remain standard

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER33

Rui-hua Xu*, Guo-ping Sun, Hui-shan Lu, Yun-peng Liu, Jian-ming Xu, Mei-zuo Zhong, He-long Zhang, Shi-ying Yu, Wei Li, Xiao-hua Hu, Jie-

jun Wang, Ying Cheng, Jun-tian Zhou, Zeng-qing Guo, Zhong-zhen Guan

A Phase study of S-1 Plus Cisplatin Versus ⅢA Phase study of S-1 Plus Cisplatin Versus ⅢFluorouracil Plus Cisplatin in Patients With Fluorouracil Plus Cisplatin in Patients With

Advanced Gastric or Gastro-oesophageal Junction Advanced Gastric or Gastro-oesophageal Junction AdenocarcinomaAdenocarcinoma

* Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou GD, CHINA

(Abstract 4025)

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Objectives

Primary Endpoint:

To access Progression Free Survival (PFS) in the patients with advanced dvanced

Gastric or Gastro-oesophageal Junction Adenocarcinoma Gastric or Gastro-oesophageal Junction Adenocarcinoma treated with S1 plus

Cisplatin to Fluorouracil plus Cisplatin in the first line treatment.

Second Endpoint:

To compare the two treatment arms with respect to overall survival (OS),

time to failure (TTF), overall response rate ( ORR) and safety profile.

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Methods: Study Design

5- fluorouracil ： 800 mg/m2/day CIV for 5d

Cisplatin ： 20 mg/m2 IV for 4 dA cycle of chemotherapy was 28 days， a total of 6 cycles

5- fluorouracil ： 800 mg/m2/day CIV for 5d

Cisplatin ： 20 mg/m2 IV for 4 dA cycle of chemotherapy was 28 days， a total of 6 cycles

S-1(oral drug) ： 40mg/m2 bid for 21 dCisplatin ： 20 mg/m2 IV for 4 dA cycle of chemotherapy was 35 days， a total of 6 cycles

S-1(oral drug) ： 40mg/m2 bid for 21 dCisplatin ： 20 mg/m2 IV for 4 dA cycle of chemotherapy was 35 days， a total of 6 cycles

RANDOMIZATION

RANDOMIZATION

Unresectable or recurrent Gastric or Gastro-oesophageal Gastro-oesophageal Junction Junction AdenocarcinomaAdenocarcinoma 11stst line line

Unresectable or recurrent Gastric or Gastro-oesophageal Gastro-oesophageal Junction Junction AdenocarcinomaAdenocarcinoma 11stst line line

Three stratification factors: PS Number of metastatic lesions Gastrectomy

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

S-1 ＋ Cisplatin

N=120

5- Fu ＋ Cisplatin

N=116

P value

Age Mean(Min, Max)

53

(25, 76)

55

(21, 76)

0.177

Gender Female 36 (30%) 31(27%) 0.577

Male 84(70%) 85 (73%)

History of disease

New diagnosis 77(64%) 73(63%) 0.8437

recurrence 43(36%) 43(37%)

Tissue typing Low differentiation

57(48%) 65(57%)0.1574

Moderate

differentiation28(24%) 17(15%)

High

differentiation1( 1%) 4( 3%)

History of drug allergy

Yes 13 (11%) 3 (2.6%) 0.0112

No 106(89%) 113 (97%)

Demography in two groups

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

S-1 ＋ Cisplatin

N=120

5- Fu ＋ Cisplatin

N=116

P value

ECOG PS 0 28 (23%) 29 (25%) 0.5692

1 85(71%) 83 (72%)

2 7(6 %) 4 (3 %)

The number of metastatic

lesions

1 18 (15%) 18 (16%) 0.9120

≥1 102(85%) 98 (84%)

Gastrectomy Yes 55(45.83%) 52(44.83%) 0.8767

No 65(54.17%) 64(55.17%)

The three stratification factors (general status, number of metastatic lesions, gastrectomy) between the two groups had no significant difference.

Demography in two groups

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Progression-Free Survival （ PFS）Primary endpoint:

S-1 ： 5.5 months

5-Fu ： 4.6 months

The two groups had no

significant difference

（ P=0.859 ） .

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Overall Response （ ORR）

Primary endpoint：

S-1： 32.5% 5-Fu： 30.2% The two groups had no significant difference（ P=0.7 ） .

The efficacy confirmed After 4 weeks S-1： 22.5% 5-Fu： 21.6% The two groups had no significant difference （ P=0.8605 ） .

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Overall Survival（ OS）

Secondary endpoint ：

S-1 ： 10.0 months 5-Fu ： 10.5 months The two groups had no significant difference （ P =0.820）。

中山大学肿瘤防治中心 SUN YAT-SEN UNIVERSITY CANCER CENTER

Safety Assessment

The two groups of AE and SAE had no significant difference （ P= 0.377 ， 0.948 ） .

The two groups of drug related AE/SAE had no significant difference （ P=0.292 ， 0.141 ） .

The two groups of leading the drop due to AE had no significant difference （ P=0.587 ） .

S-1 + Cisplatin vs 5-FU + Cisplatin (Abstract 4025)

Stat Design: Equivalence for PFS

– One sided alpha 0.025, 80% power: 252 pts

– Underpowered: Requires a much large sample

– Very large confidence intervals

No difference between conventional infusional 5-FU + Cisplatin vs S-1 + Cisplatin

S-1 + Cisplatin acceptable but not necessarily better than other alternatives

Less toxicity for FU/Cis than the 5-FU/Cis arm of the FLAGS trial

– Lower doses of both 5-FU and cisplatin

The Future

We do not need any more 600 pt trials with S-1!

Characterize the biologic differences and potential biomarkers in the 3 subtypes of upper GI adenocarcinoma

– Esophageal / GEJ

– Distal Gastric, Intestinal

– Distal Gastric, Diffuse

Evaluation of novel targeted agents in populations enriched for a biomarker or target

Colorectal Cancer 5-FU Dosing, Gastric Cancer: Oxaliplatin vs Cisplatin

FLO vs FLP

– Oxaliplatin 85/m2 vs Cisplatin 50/m2 q 2 weeks

24 hr CIV 5-FU 2000-2600/m2 + LV 200/m2 bi-weekly

210 pts randomized

TTP primary endpoint

Non inferiority for Oxaliplatin

Oxaliplatin superiority for patients > 65

FLO FLP P

TTP 5.8 mo

3.9 mo

.077

OS 10.7 mo

8.8 mo

NS

% RR 35 % 25% NS

Al-Batran JCO 26: 1435; 2008