Highlights 2007:Non-colorectal GI cancer

Alan P. Venook, M.D.University of California, San Francisco

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1

Highlights: non-colorectal GI

Pancreas cancer Gemcitabine +/- cetuximab Gemcitabine +/- bevacizumab

Phase III Study Comparing Gemcitabine plus Cetuximab Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or versus Gemcitabine in Patients with Locally Advanced or

Metastatic Pancreatic AdenocarcinomaMetastatic Pancreatic Adenocarcinoma

Southwest Oncology Group Protocol S0205Southwest Oncology Group Protocol S0205

PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, E O’Reilly, R Wong, J Atkins, J Abbruzzese, C Blanke

On behalf of SWOG, CALGB, NCIC, and the CTSU

S0205 Study SchemaS0205 Study Schema

Stratify

Locally advanced versus metastatic

Prior pancreatectomyYes versus No

Performance status0/1 versus 2

Gemcitabine +

Cetuximab

Gemcitabine +

Cetuximab

GemcitabineGemcitabine

RANDOMIZE

RANDOMIZE

Overall Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 12 24 36Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events338331

Medianin Months

66

P = 0.14

5.96.4

S0205: Primary EndpointS0205: Primary EndpointSurvival in All PatientsSurvival in All Patients

HR = 1.09 (95% CI: 0.93, 1.27)

Progression-Free Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events360351

Medianin Months

34

P = 0.058

3.03.5

S0205: Progression-Free Survival in All S0205: Progression-Free Survival in All PatientsPatients

HR = 1.13 (95% CI: 0.97, 1.31)

S0205: S0205: Objective Tumor ResponseObjective Tumor Response

Response Gem + Cetux (%)N = 316

Gem (%)N = 326

CR 0 1

PR 12 13

SD 38 30

CR + PR + SD 50 44

PD 40 47

A double-blind, placebo-controlled randomized Phase III A double-blind, placebo-controlled randomized Phase III trial of Gemcitabine plus Bevacizumab versus Gemcitabine trial of Gemcitabine plus Bevacizumab versus Gemcitabine plus placebo in Patients with Advanced Pancreatic Cancer:plus placebo in Patients with Advanced Pancreatic Cancer:A preliminary analysis of Cancer and Leukemia Group B A preliminary analysis of Cancer and Leukemia Group B

H.L. Kindler, D. Niedzwiecki, D. Hollis, E. Oraefo, D. Schrag, H. Hurwitz, H.L. McLeod, M.F. Mulcahy, R. L. Schilsky, R. M. Goldberg

CALGB: Gemcitabine +/- bevacizumabKindler, et al…

Median OS: 5.7 v. 6.0 months Median failure-free survival: 4.8 v. 4.3 months RR: 13% v. 11%

Stopped and unblinded at interim analysis due to futility

Lowlights: pancreas cancerOverall survival

Gemcitabine +/- cetuximab: 6.4 v. 5.9 moGemcitabine +/- bevacizumab: 5.7 v. 6.0 mo

Lowlights: pancreas cancerOverall survival

Gemcitabine +/- cetuximab: 6.4 v. 5.9 moGemcitabine +/- bevacizumab: 5.7 v. 6.0 moGemcitabine +/- erlotinib: 6.24 v. 5.91 mo*

Moore et al, JCO, 2007

The standard is unsatisfactory and new drugs and study designs are needed

* Statistically significant

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1

Hereditary Diffuse Gastric Cancer: Natural History, Pathology, Screening Limitations, and Prophylactic Total Gastrectomy in CDH1

Mutation Carriersby

Henry Lynch*, Carlos Caldas, Debrah Wirtzfeld, Carlos Vaccaro, Wendy Rubinstein,

Scott Weissman, Pardeep Kaurah, Niki Boyd,Rebecca Fitzgerald, David Huntsman

Loss of E-cad is a defining feature of both DGC and lobular breast cancer

-catenin binding site

Criteria for CDH1 mutation testing modified to reflect current data

1. Family with two or more cases of GC, with at least 1 DGC diagnosed before the age of 50. (>40%)*

2. 3 or more first/second-degree relatives with confirmed diffuse gastric cancer, irrespective of age.

3. Isolated individual diagnosed with DGC at less than 35 years from a low incidence population (>10%)*

4. Isolated personal history of both DGC and LBC (unknown)*5. Family with multiple LBC with or without DGC in first or

second degree relatives (unknown)*

•* Percentage mutation pick up rate from low incident populations•Modified from Caldas et al. J Med Genet, 1999 and Suriano et al. Clin Can Res, 2005

Currently 31/39 (80%) of prophylactic gastrectomies reviewed in total had occult DGC’s All cancers were very superficial, the rate of progression of these lesions and the the secondary mutations required for invasion of the muscularis propria are unknown

44-60%<1%

26-43%

3%50-80%

28-33%

F Carneiro, D Huntsman et al J Pathol 2004; 203: 681–687

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1

M. A. Shah, H. Yeung, D. Coit, R. Trocola, D. Ilson, J. Randazzo, L. Tang, M. Brennan, C. Divgi, D. P. Kelsen

A phase II study of preoperative chemotherapy with irinotecan and cisplatin for gastric cancer: FDG-PET/CT predicts patient outcome

FDG-PET/CT predicts outcome in gastric ca

Shah, et al…

N = 42 locally advanced disease 31/42 PET avid Neoadjuvant irinotecan / cisplatin SUV drop from baseline to d35 correlates with

path response, but d15 does not Cut-off of 45% decrease d35 SUV:

DFS >23 months v. 14.4 months

S. Rao, D. Cunningham, M. Benson, R. Te Poele, L. Welsh, N. Starling, A. Norman, C. Saffrey, P. Workman, P. Clarke

A prospective study to evaluate the role of gene expression profiles in predicting clinical outcome of patients receiving preoperative chemoradiotherapy for

oesophagogastric cancer

Gene expression predicts outcome in gastric ca

Rao, et al…

Neoadjuvant chemotherapy N = 35 (esophagus, 23; GE junction, 12) Two distinct gene clusters: N = 17 poor prognosis -- 2 yr survival = 17% N = 18 good prognosis -- 2 yr survival = 55%

Affected pathways: tyrosine kinase signaling and cell growth

V. Boige, J. Pignon, B. Saint-Aubert, P. Lasser, T. Conroy, O. Bouche, P. Segol, L. Bedenne, P. Rougier, M. Ychou

Final results of a randomized trial comparing pre-operative 5-FU / cisplatin to

surgery alone in adenocarcinoma of stomach and lower esophagus: FNLCC ACCORDO7-

FFCD 9703 trial

Neoadjuvant therapy v. surgery aloneBoige, et al…

Neoadjuvant 5-FU/cisplatin; resectable gastric or GE junction

N = 224 (accrued over 8 years) R0 resection: 73% v. 84% favoring combined rx 5 yr DFS: 21% v. 34% OS: 24% v. 38%

Neoadjuvant 5-FU/cisplatin improves outcomes

Michael Stahlon behalf of theGerman Oesophageal Cancer Study Group

PreOperative Chemotherapy or Radiochemotherapy in Esophago-

gastric Adenocarcinoma TrialPOET

TreatmentArm A

Week

Arm B

PLF 2 x 6 weeks

PLF 2 x 6 weeks

PLF, 3 weeks

15 x 2 Gy, 3 weeks

PE, 1 week

Surgery

Surgery

1 13 17 21

P: Cisplatin E: EtoposideLF: Leukovorin / 5-FU

Logrank p = 0.07HR Arm B vs. A0.67 (0.41-1.07)

Arm B

Arm A

OS: Follow-up 45.6 mo

47.4%

27.7%

Individual patient data-based meta-analysis assessing the interest of pre-operative chemotherapy in resectable

oesophageal carcinoma

Abstract: 4512

Thirion P., Michiels S., Le Maître A., Tierney J. The Meta‑Analysis of Chemotherapy in Esophagus Cancer

Collaborative Group

Materials

12 eligible trials identified - 2,290 patients9 available trials (10 comparisons) - 2,102 patients (92%)Median follow up across trials: 5.3 years (range: 4.9 - 6.0)

1st author Country/ Institution Accrual Period

Chemotherapy regime

n

Roth USA / MD Anderson 1982-86 CDDP/Bleo/Vindesine 36

Nygaard 2nd Scandinavian Trial 1983-88 CDDP/Bleo 106 + 111

Giuli International / OESO-2 1985-89 CDDP/Bleo/Vindesine 122

Maipang Thailand / Songkla 1988-90 CDDP/Bleo/Vinblastine 46

Law Hong Kong/Queen Mary 1989-95 CDDP/5FU 147

Kelsen USA / Intergroup RTOG 1990-95 CDDP/5FU 467

Kok NL / Rotterdam E.T.S.G 1990-96 CDDP/VP16 169

Ancona I taly 1992-97 CDDP/5FU 96

MRC UK / MRC OE-02 1992-98 CDDP/5FU 802

Primary End-point: Overall Survival

Queen Mary 52/74 64/73 -13.3 27.8

StudyNo. Deaths / No. Entered

Chemo preop Control O-E Variance Hazard Ratio HR [95% CI]

Chemo preop better | Control better

Italy 35/48 37/48 -2.4 17.8

Songkla 20/24 16/22 5.7 8.5

MRC EO-02 280/400 316/402 -34.7 148.4

RTOG 8911 204/233 197/234 5.9 100.1

MD Anderson 11/17 16/19 -2.7 6.7

Scandinavia 2 53/56 50/50 -0.9 25.6

Scandinavia 2R 46/53 52/58 0.8 24.2

Oeso-2 44/58 52/64 -3.3 23.7

Rotterdam 61/85 72/84 -14.9 31.9

Total 806/1048 872/1054 -59.8 414.6

Chemo preop effect: p = 0.003

Test for heterogeneity: p = 0.03

0.87 [0.79;0.95]

0.25 1.00 4.00

Sub-group Analyses

The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across: Age (50<, 50-60, >60) Gender Initial PS Histological Type

Adenocarcinoma 282/385 315/392 -29.5 148.4

Squamous cell 450/564 471/563 -15.0 226.7

CategoryChemo preopNo. Events / No. Entered

Control O-E Var Hazard ratio HR [95% CI]

Test for interaction: p = 0.21Chemo preop better | Control better

0.0 0.5 1.0 1.5 2.0

Esophagus / GE junction conclusions

Data supports the roles of chemotherapy and radiation in the management of resectable cancers

Surgery as a single modality is probably suboptimal

F-F--Ala-Ala

NeurotoxicityNeurotoxicity

GI toxicityGI toxicity

MyelotoxicitMyelotoxicityy

5-FU5-FU

Anti-tumorAnti-tumoractivityactivity

S-1S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1

1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-77

DPDDPD

TegafurTegafur

OPRTOPRT

F-F--Ala-Ala

NeurotoxicityNeurotoxicity

GI toxicityGI toxicity

MyelotoxicitMyelotoxicityy

5-FU5-FU

Anti-tumorAnti-tumoractivityactivity

S-1S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1

1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-77

DPDDPD

TegafurTegafur

CDHPCDHP

OPRTOPRT

OxoOxo

inhibitinhibit inhibitinhibit

F-F--Ala-Ala

NeurotoxicityNeurotoxicity

GI toxicityGI toxicity

MyelotoxicitMyelotoxicityy

5-FU5-FU

Anti-tumorAnti-tumoractivityactivity

S-1S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1

1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-77

DPDDPD

TegafurTegafur

CDHPCDHP

OPRTOPRT

OxoOxo

inhibitinhibit inhibitinhibit

N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A.

Ohtsu Gastrointestinal Oncology Study Group

of Japan Clinical Oncology Group

Randomized phase III study of 5-fluorouracil (5-FU) alone versus

combination of irinotecan and cisplatin (CP)

versus S-1 alone in advanced gastric cancer (JCOG9912)

S-1 40 mg/m2, po, bid, days 1-28q 6 weeks

Stratified by (minimization) ・ Institution ・ PS 0/1/2 ・ Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx

5-FUci

CPT-11 + CDDP

S-1

Randomization

800 mg/m2, continuous inf, days 1-5q 4 weeks

CPT-11 70 mg/m2, div, days 1&15CDDP 80 mg/m2, div, day 1q 4 weeks

Continued until disease progression, unacceptable toxicities, patient’s refusal

BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day

0.0010.62-0.900.754.2M234

<0.001

-

0.57-0.83

-

95%C.I.

-2.9M234

0.694.8M236

HRMedian n P-value† 　

12 24 (months)

0

50

(%)100

Response rate

S-1

5-FUci

CPT-11+CDDP

5-FUciCPT-11+CDDP S-1

CR+PR 15 68 49

n 175 181 175

RR 9% 38% 28%

PFS

Randomized phase III study of S-1 alone versus S-1 Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastric + cisplatin in the treatment of advanced gastric

cancer cancer (The SPIRITS trial) (The SPIRITS trial)

SPIRITS: SPIRITS: SS-1 plus cis-1 plus cispplatin vs S-1 latin vs S-1 iin n RRCT CT iin the n the ttreatment of reatment of sstomach cancertomach cancer

H. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9,

S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;

AGCAGC

No priorNo priorChemo.Chemo.

RR

S-1 aloneS-1 aloneS-1: 40-60 mg BID for 28 days q6wksS-1: 40-60 mg BID for 28 days q6wks

S-1 + CDDPS-1 + CDDPS-1: 40-60 mg BID for 21 days q5wksS-1: 40-60 mg BID for 21 days q5wksCDDP: 60 mg/mCDDP: 60 mg/m22 iv on day 8 iv on day 8

Central RandomizationCentral Randomization (dynamic balancing)(dynamic balancing)Adjustment Factors:Adjustment Factors: InstituteInstitute PSPS Unresectable vs RecurrentUnresectable vs Recurrent

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54

MonthsMonths

Est

imat

ed p

roba

bilit

y E

stim

ated

pro

babi

lity

(%)

(%)

11.011.0 13.013.0

S-1S-1 S-1+CDDPS-1+CDDP

No. of ptsNo. of pts 150150 148148MST MST 11.011.0 13.013.0

1 yr survival1 yr survival 46.7 %46.7 % 54.1 %54.1 %2 yr survival2 yr survival 15.3 %15.3 % 23.6 %23.6 %

Log-rank p-value:Log-rank p-value: 0.0366 0.0366HR: HR: 0.774 0.774 [ 95% CI: 0.608 – 0.985][ 95% CI: 0.608 – 0.985]Median follow-up time (M): Median follow-up time (M): 34.634.6

No. No. ResponseResponse

Overall RR Overall RR CRCR PRPR SDSD PDPD NENE

S-1 S-1 106106 11 3232 3434 3434 55 31 %31 %S-1+CDDPS-1+CDDP 8787 11 4646 1313 2424 33 54 %54 %

Criteria : RECIST (Extramural Review)Criteria : RECIST (Extramural Review)

Fisher’s Exact Test p-value: Fisher’s Exact Test p-value: 0.00180.0018

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric Prediction of outcome Preoperative therapies S-1

Highlights: non-colorectal GI

Pancreas cancer Phase III trials

Gastric cancer Genetic risk

Esophageal / GE junction / gastric

Hepatocellular carcinoma Sorafenib