Highlights 2007: Non-colorectal GI cancer Alan P. Venook, M.D. University of California, San...
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Transcript of Highlights 2007: Non-colorectal GI cancer Alan P. Venook, M.D. University of California, San...
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