Highlights 2007: Non-colorectal GI cancer

Transcript Highlights 2007: Non-colorectal GI cancer

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 versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma Southwest 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 Schema

Stratify Locally advanced versus metastatic Prior pancreatectomy Yes versus No Performance status 0/1 versus 2 R A N D O M I Z E Gemcitabine + Cetuximab Gemcitabine

100% 80% 60% 40% 20% 0% 0

S0205: Primary Endpoint Survival in All Patients

Overall Survival by Treatment Arm Gemcitabine Gemcitabine and Cetuximab N 369 366 P = 0.14

Events 338 331 Median in Months 6 6 HR = 1.09 (95% CI: 0.93, 1.27) 12 Months After Registration 24 36

100% 80%

S0205: Progression-Free Survival in All Patients

Progression-Free Survival by Treatment Arm Gemcitabine Gemcitabine and Cetuximab N 369 366 P = 0.058

Events 360 351 Median in Months 3 4 60% HR = 1.13 (95% CI: 0.97, 1.31) 40% 20% 0% 0 6 12 18 Months After Registration 24 30

Response CR PR SD CR + PR + SD PD

S0205: Objective Tumor Response

Gem + Cetux (%) N = 316 0 12 38 50 40 Gem (%) N = 326 1 13 30 44 47

A double-blind, placebo-controlled randomized Phase III trial of Gemcitabine plus Bevacizumab versus Gemcitabine plus placebo in Patients with Advanced Pancreatic Cancer: 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 +/- bevacizumab

Kindler, 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 cancer

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

Lowlights: pancreas cancer

Overall survival Gemcitabine +/- cetuximab: 6.4 v. 5.9 mo Gemcitabine +/- bevacizumab: 5.7 v. 6.0 mo Gemcitabine +/- 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 Carriers by Henry Lynch*, Carlos Caldas, Debrah Wirtzfeld, Carlos Vaccaro, Wendy Rubinstein, Scott Weissman, Pardeep Kaurah, Niki Boyd, Rebecca Fitzgerald, David Huntsman

-catenin binding site

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

Criteria for CDH1 mutation testing modified to reflect current data

Family with two or more cases of GC, with at least 1 DGC diagnosed before the age of 50. (>40%)* 3 or more first/second-degree relatives with confirmed diffuse gastric cancer, irrespective of age.

Isolated individual diagnosed with DGC at less than 35 years from a low incidence population (>10%)* Isolated personal history of both DGC and LBC (unknown)* 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

44-60% 3% 28-33% <1% 50-80% 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 26-43% 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

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

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

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

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

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

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

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

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

Neoadjuvant therapy v. surgery alone

Boige, 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

re

perative Chemotherapy or Radiochemotherapy in

sophago-gastric Adenocarcinoma

rial

POET

Michael Stahl on behalf of the German Oesophageal Cancer Study Group

Treatment

Arm A 1 PLF 2 x 6 weeks Week 13 PLF, 3 weeks 17 15 x 2 Gy, 3 weeks PE, 1 week Surgery 21 Surgery P: Cisplatin E: Etoposide LF: Leukovorin / 5-FU

Arm A Arm B 47.4% 27.7% Logrank p = 0.07

HR Arm B vs. A 0.67 (0.41-1.07) OS: Follow-up 45.6 mo

Abstract: 4512

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

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 patients 9 available trials (10 comparisons) - 2,102 patients (92%) Median follow up across trials: 5.3 years (range: 4.9 - 6.0)

1 st author Country/Institution

Roth USA / MD Anderson Nygaard 2 nd Scandinavian Trial Giuli International / OESO-2

Accrual Period

1982-86 1983-88 1985-89 Maipang Law Thailand / Songkla 1988-90 Hong Kong/Queen Mary 1989-95 Kelsen USA / Intergroup RTOG 1990-95 Kok Ancona MRC NL / Rotterdam E.T.S.G 1990-96 Italy UK / MRC OE-02 1992-97 1992-98

Chemotherapy regime

CDDP/Bleo/Vindesine CDDP/Bleo

36 106 + 111 CDDP/Bleo/Vindesine CDDP/Bleo/Vinblastine CDDP/5FU 122 46 147 CDDP/5FU 467 CDDP/VP16 CDDP/5FU CDDP/5FU 169 96 802

Primary End-point: Overall Survival

No. Deaths / No. Entered Chemo preop Control O-E Variance Hazard Ratio Study HR [95% CI] Queen Mary Italy Songkla MRC EO-02 RTOG 8911 MD Anderson Scandinavia 2 Scandinavia 2R Oeso-2 Rotterdam 52/74 35/48 20/24 280/400 204/233 11/17 53/56 46/53 44/58 61/85 64/73 37/48 16/22 316/402 197/234 -13.3

-2.4

5.7

-34.7

5.9

16/19 50/50 52/58 52/64 72/84 -2.7

-0.9

0.8

-3.3

-14.9

27.8

17.8

8.5

148.4

100.1

6.7

25.6

24.2

23.7

31.9

Total 806/1048 872/1054 -59.8

414.6

Test for heterogeneity: p = 0.03

0.87 [0.79;0.95] 0.25

Chemo preop better | 1.00

4.00

Control better Chemo preop effect: p = 0.003

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

Category No. Events / No. Entered Chemo preop Control O-E Var Hazard ratio HR [95% CI] Adenocarcinoma Squamous cell 282/385 315/392 -29.5

148.4

450/564 471/563 -15.0

226.7

Test for interaction: p = 0.21

0.0

0.5

1.0

1.5

2.0

Chemo preop better | Control better

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

S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur Anti-tumor activity F b -Ala Neurotoxicity DPD 5-FU OPRT GI toxicity Myelotoxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

S-1 Tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio 1 : 0.4 : 1 Tegafur Anti-tumor activity F b -Ala Neurotoxicity CDHP DPD inhibit 5-FU Oxo OPRT inhibit GI toxicity Myelotoxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

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)

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

5 800 mg/m 2 , continuous inf, days 1-5 FUci Randomization CPT-11 + CDDP CPT-11 70 mg/m 2 , div, days 1&15 CDDP 80 mg/m 2 , div, day 1 q 4 weeks Stratified by (minimization)

・

Institution

・

PS 0/1/2

・

Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx S-1 S-1 40 mg/m 2 , po, bid, days 1-28 q 6 weeks BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/day Continued until disease progression, unacceptable toxicities, patient’s refusal

(%) 100 PFS Response rate 50

CR+PR n

5-FUci CPT-11+CDDP S-1

12 24 (months)

n 234 Median HR 2.9M

236 4.8M

0.69

234 4.2M

0.75

95%C.I.

0.57-0.83

P-value † <0.001

0.62-0.90

0.001

RR 5-FUci 15 175 9% CPT-11 +CDDP 68 181 38% S-1 49 175 28%

Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment of stomach cancer H. Narahara 1

, W. Koizumi 2 , T. Hara 3 , A. Takagane 4 , T. Akiya 5 , M. Takagi 6 , K. Miyashita 7 , T. Nishizaki 8 , O. Kobayashi 9 , S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;

Central Randomization

(dynamic balancing)

Adjustment Factors:

 Institute   PS Unresectable vs Recurrent

AGC No prior Chemo.

S-1 alone

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

S-1 + CDDP

S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m 2 iv on day 8

100 80 60 40 20 0 0 No. of pts MST 1 yr survival 2 yr survival S-1 150 11.0

46.7 % 15.3 % S-1+CDDP 148 13.0

54.1 % 23.6 % Log-rank p-value: 0.0366

HR: 0.774 [ 95% CI: 0.608 – 0.985] Median follow-up time (M): 34.6

6 11.0

12 13.0

18 24 30

Months

36 42 48 54

S-1 S-1+CDDP No. 106 87 CR 1 1 PR Response SD PD 32 34 34 46 13 24 NE 5 3 Overall RR 31 % 54 % Fisher’s Exact Test p-value: 0.0018

 Criteria : RECIST (Extramural Review)

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