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Transcript of Cco Gi 2008 Cr Slideset
CCO IndependentConference Coverageof the 2008 Gastrointestinal Cancers Symposium*
January 25-27, 2008Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by educational grants from
clinicaloptions.com/oncology
CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
About These Slides
These slides accompany CCO’s online Independent Conference Coverage of the 2008 Gastrointestinal Cancers Symposium
Our thanks to the presenters who gave permission to include their original data
The full program is available on the Clinical Care Options for Hematology/Oncology Web site: clinicaloptions.com/GI2008
Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options
clinicaloptions.com/oncology
CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
Alan P. Venook, MDProfessor of Clinical MedicineDepartment of Hematology and OncologyDivision of Medical OncologyUniversity of California, San FranciscoSan Francisco, California
Faculty Participating in Slide Development
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
Contents
Colorectal Cancers
Esophageal and Stomach Cancers
– Esophageal cancers
– Gastric Cancer
– Gastrointestinal Stromal Tumors (GIST)
Pancreas, Small Bowel, and Hepatobiliary Tract Cancers– Pancreatic Cancer
– Hepatocellular Carcinoma
– Cholangiocarcinomas
Colorectal Cancers
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial: Oxaliplatin Arm
Patients with metastatic
colorectal cancer and ECOG ≤ 1
(N = 823)Oxaliplatin-CT (eg, FOLFOX)/Bevacizumab + Panitumumab
(n = 413)
Interim analysis at 231 PFS events
Panitumumab discontinued
Oxaliplatin-CT (eg, FOLFOX)/Bevacizumab
(n = 410)
Median follow-up:54 weeks
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
11.1
9.6
PACCE Trial Oxaliplatin Arm: PFS
Regimen PFSEvents, %
HR(95% CI)
Ox-CT/Bev 52 --
Ox-CT/Bev + Pmab
591.27
(1.05-1.53)
Med
ian
(M
on
ths)
Ox-CT/Bev + Pmab Ox-CT/Bev0
2
4
6
8
12
10
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
clinicaloptions.com/oncology
CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Oxaliplatin Arm: Toxicity
More serious adverse events reported with panitumumab plus oxaliplatin chemotherapy/bevacizumab
– Skin toxicity most frequent
Grade 3/4 Toxicity, % Ox-CT/Bev + Pmab(n = 407)
Ox-CT/Bev ( n = 397)
Any serious adverse event 60 38
Grade 3/4 toxicity
Skin toxicity 36 1
Diarrhea 24 13
Neutropenia 24 24
Infections 18 10
Dehydration 17 < 6
Nausea 11 < 6
Low potassium 10 4Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Oxaliplatin Arm: Summary
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 273.
Adding panitumumab to oxaliplatin chemotherapy with bevacizumab did not prolong PFS
– 9.6 (panitumumab) vs 11.1 months (no panitumumab)
Trend toward inferior PFS and OS
Toxicity frequent in both arms; incidence of serious adverse events higher with oxaliplatin chemotherapy/ bevacizumab/panitumumab
– 60% (panitumumab) vs 38% (no panitumumab)
Majority of patients in both arms withdrew from study due to nonprogressive events
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Irinotecan Arm
Patients with metastatic
colorectal cancer and ECOG ≤ 1
(N = 230)
Irinotecan chemotherapy (eg FOLFIRI)/Bevacizumab
(n = 115)
Irinotecan chemotherapy (eg FOLFIRI)/
Bevacizumab +Panitumumab
(n = 115)
Median follow-up:9 months
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Irinotecan Arm: PFS
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
PFS Events, n (%) Median, mos (95%CI)
54 (47)
43 (37)
10.1 (8.2-13.7)
11.7 (9.0-13.2)
Pmab + Bev/Iri-CT
Bev/Iri-CT
HR: 1.21 (95% CI: 0.80-1.82)**Descriptive only
CensoredNo PmabCensored
Pmab 115 74 23 7 1 0000
4127
66
2332
34
197629
0
0115
0 5 10 15 20 25Months
0
20
40
60
80
100
Pat
ien
ts (
%)
clinicaloptions.com/oncology
CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Irinotecan Arm: Toxicity
More serious adverse events when panitumumab added to irinotecan chemotherapy/bevacizumab
Skin toxicity most frequent
Toxicity, % Iri-CT/Bev + Pmab(n = 111 )
Iri-CT/Bev( n = 113)
Any serious adverse event 54 33
Grade 3/4 toxicity
Skin toxicity 37 0 Diarrhea 28 9 Neutropenia 17 21 Dehydration 14 6 Infections 14 9 Nausea 12 6 Low potassium 11 4
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
PACCE Trial Irinotecan Arm: Summary
Adding panitumumab to irinotecan chemotherapy and bevacizumab did not prolong PFS
– 10.1 (panitumumab) vs 11.7 months (no panitumumab)
Toxicity frequent in both arms; incidence of serious adverse events higher in patients receiving panitumumab
– 54% (panitumumab) vs 33% (no panitumumab)
Hecht JR, et al. GI Cancers Symposium 2008. Abstract 279.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
FFCD 2001-02 Trial: 5-FU ± Irinotecan
One arm of a 2-arm of randomized phase III trial compared 5-FU/irinotecan with 5-FU alone in frontline therapy in elderly patients (75 years of age or older) with metastatic colorectal cancer
– Interim descriptive analysis (N = 142 patients followed ≥ 8 weeks)
Response by RECIST criteria high with a 5-FU/irinotecan regimen compared with 5-FU alone in frontline therapy
– ORR: 88% for 5-FU/irinotecan vs 69% for 5-FU alone
PD more prevalent in 5-FU-alone arm
– 25% for 5-FU vs 9% for 5-FU/irinotecan
60-day mortality: 12.7%
– Primary cause of death: disease progression
Mitry E, et al. GI Cancers Symposium 2008. Abstract 281.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
FFCD 2001-02 Trial: Toxicity
Toxicity, % 5-FU(n = 75 )
5-FU/IR(n = 67)
Any adverse event 93 98
Any grade 3/4 toxicity 16 48
Neutropenia 1 28
Neutropenia with fever 1 9
Diarrhea 0 16
Death 57 57
Neutropenia and diarrhea more frequent in 5-FU/irinotecan arm
Toxicity manageable, investigators concluded
Mitry E, et al. GI Cancers Symposium 2008. Abstract 281.
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
CONcePT Trial Design
Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.
Patients with metastatic
colorectal cancer
(N = 140)
*Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin.
Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +
placebo(n = 34)
Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +
Ca2+/Mg2+
(n = 35)
Intermittent Oxaliplatin†
mFOLFOX7 + bevacizumab +placebo(n = 36)
Intermittent Oxaliplatin†
mFOLFOX7 + bevacizumab +Ca2+/Mg2+
(n = 35)
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
CONcePT Trial Results: Sequentially Confirmed* Responses Trend toward better response with intermittent oxaliplatin
compared with continuous oxaliplatin dosing (evaluable patients)
– OR: 1.96 (95% CI: 0.86-4.54; P = .089)
Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.
2136
45 43
46
4848
39
3216 7
18
0
25
50
75
100
Placebo Ca+/Mg+ Placebo Ca+/Mg+
Continuous Oxaliplatin Intermittent Oxaliplatin
PD
SD
PR
*Responses confirmed by RECIST criteria on sequential assessments.
Pat
ient
s, %
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
CONcePT Trial: Summary
Hochster HS, et al. GI Cancers Symposium 2008. Abstract 280.
Prophylactic Ca2+/Mg2+ did not influence tumor response
Trend toward shorter time to first response with prophylactic Ca2+/Mg2+
– 32.7 weeks with placebo vs 24.0 weeks with Ca2+/Mg2+
Trend toward higher response rates with intermittent oxaliplatin (intent-to-treat population)
– Without Ca2+/Mg2+: 45% (intermittent) vs 21% (continuous)
– With Ca2+/Mg2+: 34% (intermittent) vs 29% (continuous)
Results on peripheral sensory neuropathy pending
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
X-ACT Trial Design
Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.
Bolus 5-FU/Leucovorin5-FU 425 mg/m2 +
LV 20 mg/m2 on Days 1-5, every 28 days
(n = 983)
Capecitabine1250 mg/m2 twice daily on
Days 1-14, every 21 days
(n = 1004)
Chemotherapy-naive patients with
operable stage III colorectal cancer and resection ≤ 8 weeks
(N = 1987)
Median follow-up: 6.8 years
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
X-ACT Trial: 5-Year DFS
Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months
0
0.2
0.4
0.6
0.8
1.0
Test of noninferiority: P < .0001Test of superiority: P = .0682
Est
imat
ed P
rob
abili
ty
HR: 0.88 (95% CI: 0.77-1.01)NI margin: 1.20
Capecitabine (n = 1004)5-FU/LV (n = 983)
5-Year DFS60.8%
56.7%
ITT population
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
X-ACT Trial Key Findings
Twelves C, et al. GI Cancers Symposium 2008. Abstract 274.
Trend toward superior 5-year DFS and OS with capecitabine treatment
– DFS: 60.8% vs 56.7% (P = .0682)
– OS: 68.4% vs 71.4% (P = .06)
Hand-foot syndrome common toxicity with capecitabine
– Associated with higher DFS and OS
– Possible clinical marker for optimal capecitabine exposure
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
Adherence to Follow-up Guidelines After Curative Resection
Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.
Guidelines
– ≥ 2 office visits each year
– ≥ 2 CEA tests each year
– > 1 colonoscopy within 3 years
– Yearly CT scans for poorly differentiated cancer
Medicare claims evaluated between 1992 and 2001
– Adherence to guidelines between 6 and 42 months after diagnosis
– 33,906 patients identified
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
9.9% of patients met guidelines
77.2% did not meet guidelines
12.9% of patients were in excess of guidelines; met guidelines but also had CT scan for other level of differentiation and/or PET scan
Older age and local stage cancer predicted under use of guidelines
Cooper GS, et al. GI Cancers Symposium 2008. Abstract 284.
0 20 40 60 80 100
Office Visits
Colonoscopy
CES
CT Poorly Differentiated
CT Other Level of Differentiation
PET Scan
Adherence to Follow-up Guidelines: Results
Patients, %
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
KRAS Status and Response to Panitumumab: Phase III Trial Analysis
Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
Panitumumab 6 mg/kg every 2 weeks +Best Supportive Care
(n = 231)
Best Supportive Care*(n = 232)
Colorectal cancer patients stratified by
ECOG 0-1 vs 2 and region
(N = 463)
*Optional crossover to panitumumab upon disease progression.
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PFS by KRAS Status and Treatment
Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
The relative effect of panitumumab vs best supportive care was significantly greater in patients with WT vs mutant KRAS
The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS between WT and mutant KRAS was statistically significant (P < .0001)
PFS was significantly greater for panitumumab treatment compared with best supportive care in the WT KRAS group (stratified log-rank test: P < .0001).
Mutant KRAS WT KRAS
Pmab + BSCBSC alone
7.47.3
HR: 0.99(95% CI: 0.73-1.36)
Pro
po
rtio
n E
ven
t F
ree
Weeks
00.10.20.30.40.50.60.70.80.91.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
HR: 0.45 (95% CI: 0.34-0.59)
Stratified log-rank test: P < .0001
Pro
po
rtio
n E
ven
t F
ree
Weeks
00.10.20.30.40.50.60.70.80.91.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Pmab + BSCBSC alone
12.37.3
Median PFSMedian PFS
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CCO Independent Coverage of the 2008 Gastrointestinal Cancers Symposium
OS by KRAS Status and Treatment
Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
Med
ian
OS
(M
on
ths) 8.1
7.6
4.9 4.4
0
2
4
6
8
10
WT KRAS WT KRAS Mutant KRAS Mutant KRAS
Pmab BSC Pmab BSC
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KRAS Mutation Status and Response to Panitumumab: Summary OS shorter in patients with KRAS mutation regardless of treatment
– HR: 0.67 (95% CI: 0.55-0.82)
Incidence of disease progression following panitumumab nearly 2-fold higher in patients with mutant KRAS
– 70% for mutant KRAS vs 36% for WT KRAS
Panitumumab monotherapy appears effective only in patients WT KRAS
KRAS mutational status does not influence PFS following best supportive care
KRAS genotyping recommended for metastatic colorectal cancer patients
Amado RG, et al. GI Cancers Symposium 2008. Abstract 278.
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Circulating Tumor Cells Predict Survival
Parameter n Median PFS, Mos Median OS, Mos
< 3 CTC ≥ 3CTC P Value < 3 CTC ≥ 3CTC P Value
First-line treatment 296 8.7 6.3 .0246 21.2 11.6 .0001
Second/third-line treatment 117 5.4 2.3 .0016 14.8 6.2 < .0001
Liver metastasis 302 8.5 4.2 .0002 17.3 9.5 < .0001
Oxaliplatin 242 8.7 7.5 .1200 18.1 11.6 .0008
Irinotecan 99 6.7 2.3 < .0001 15.9 5.9 .0001
Bevacizumab 235 8.6 6.3 .0178 18.6 10.5 .0005
Age ≥ 65 yrs 200 7.1 2.8 < .0001 14.8 7.4 < .0001
Age < 65 yrs 213 8.7 7.7 .0880 23.1 12.1 .0001
ECOG PS 0 187 8.5 5.6 .0008 23.6 9.5 < .0001
ECOG PS 1-2 210 7.0 4.7 .0738 15.0 9.4 .0155
Cohen SJ, et al. GI Cancers Symposium 2008. Abstract 299.
Baseline CTCs in metastatic colorectal cancer patients entering new systemic therapy predicts PFS and OS
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Genes Predictive for Colon Cancer Recurrence
Lavery I, et al. GI Cancers Symposium 2008. Abstract 302.
NSABP C-01/C-02 observational arm (N = 765)
Patients treated with surgery alone
59 genes prognostic for disease recurrence
– Up to an 11-fold difference in risk between individual expressed genes
– Genes involved in a number of biological pathways including cell cycle regulation, cell proliferation, and invasion
Multigene algorithm developed and will be validated
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Insurance Status and Colorectal Cancer Stage at Diagnosis Analysis of data from National Cancer Data Base
N = 493,419; 50 years of age or older
Uninsured and Medicaid patients 100% and 50%, respectively, more likely to be diagnosed with late-stage colorectal cancer
Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275
0.0
0.5
1.0
1.5
2.0
2.5
Uninsured Medicaid Medicare < 65 Yrs
Medicare> 65 Yrs
Stage II vs I
Stage III/IV vs I
OR
fo
r A
dva
nce
d-S
tag
e C
olo
rect
al C
ance
r D
iag
no
sis
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Insurance Status and Colorectal Cancer Stage at Diagnosis: Summary Uninsured and Medicaid patients at risk for late-stage colorectal
cancer diagnosis
Supplementing Medicare with private insurance reduces this risk
Groups more likely to be diagnosed with advanced-stage colorectal cancer include
– Blacks
– Females
– Persons with low socioeconomic or education status
– Persons receiving care at nonteaching/research hospitals
Underserved populations need better access to screening and better screening
Halpern MT, et al. GI Cancers Symposium 2008. Abstract 275
Esophagus and Stomach Cancers
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Barrett’s Esophagus and Metabolic Syndrome N = 180: 102 Barrett’s Esophagus and 78 GERD
Mean age 56 years
Power DG, et al. GI Cancers Symposium 2008. Abstract 2.
Pat
ien
ts (
%)
0
20
40
60
80
100
BMI > 25 CentralAdiposity
DeMeesterScore
MetabolicSyndrome
ElevatedCRP
Barrett’s Esophagus
GERDP = .007
P = .05
P = .04
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Barrett’s Esophagus and Metabolic Syndrome: Summary
Power DG, et al. GI Cancers Symposium 2008. Abstract 2.
Metabolic syndrome prevalent in Barrett’s Esophagus (46%) and GERD (32%) patients
High prevalence of long segment Barrett’s Esophagus (> 3 cm) in patients with
– Central adiposity (93%)
– Metabolic syndrome (62%)
– BMI > 30 (42%)
– Hyperinsulinemia (20%)
– Elevated IL-4 (4%)
Inflammation and insulin resistance due to metabolic syndrome may contribute to Barrett’s Esophagus progression to adenocarcinoma
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OE02 Update: Design
Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.
Preoperative Chemotherapy Then Surgery
Cisplatin 80 mg/m2 on Day 1 +5-FU 1 g/m2/day for 4 days,
two 4-day courses 3 weeks apart
(n = 400 )Patients with resectable
esophageal cancer
(N = 802)
Median follow-up:5.9 years
Surgery Alone(n = 402)
Median follow-up:6.1 years
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OE02 Update: DFS
Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.
0200
121162
83115
6585
5067
4154
3241
2633
1721
814
No. at risk
0.75
1.00
0.50
0.25
0
Su
rviv
al
0 1 4 6 8 9Years
DFS by Treatment Arm
HR: 0.82 (95% CI: 0.71-0.95; P = .003)
Chemotherapy then surgery
Surgery alone
Surgery aloneChemotherapy
then surgery752 3
DFS from randomization + 6 months
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OE02 Update: Results
5-year OS
– 17% surgery alone vs 23% chemotherapy then surgery (P = .03)
Survival rates dependent on resection status but not histology
3-year survival by MRC
– R0: 42%
– R1: 18%
– R2: 9%
– Unresected: 1%Allum WH, et al. GI Cancers Symposium 2008. Abstract 9.
Survival by Resection Status (All Patients)
Su
rviv
al R
ate
Months From Randomization
R0
R1
R2
Unresected
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 72 84 96 108120
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JCOG 9907: Study Design
Ando N, et al. GI Cancers Symposium 2008. Abstract 10.
Treatment-naive patients aged younger
than 75 years with squamous cell carcinoma of
thoracic esophagus,T1-3/N0-1/M0, and
ECOG PS 0-2
(N = 330)
5-FU/Cisplatin 5-FU 800 mg/m2 on
Days 1-5Cisplatin 80 mg/m2 on
Day 1(n = 164)
Surgery Transthoracic
esophagectomy with lymphadenectomy ≥ D2
(n = 166)
Postoperative chemotherapy
Preoperative chemotherapy
Surgery Transthoracic
esophagectomy with lymphadenectomy ≥ D2
5-FU/Cisplatin5-FU 800 mg/m2 on
Days 1-5Cisplatin 80 mg/m2 on
Day 1
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JCOG 9907: PFS, OS
Ando N, et al. GI Cancers Symposium 2008. Abstract 10.
Second Interim Analysis
Unadjusted 2-sided log-rank P = .013HR by Cox model: 0.64 (95% CI: 0.45-0.91; P = .014)
Unadjusted 1-sided stratifiedLog- rank P = .0444 > .0254 (alpha)HR: 0.76 (94.91% CI: 0.56-1.04)
OS
Postop5-yr OS: 38.4%
Preop 5-yr OS: 60.1%
Years After Randomization
0 1 2 3 4 5 6 70.00.10.20.30.40.50.60.70.80.91.0
PFS
Postopmedian PFS: 2 yrs
Preop median PFS: 3 yrs
Years After Randomization
0 1 2 3 4 5 6 70.00.10.20.30.40.50.60.70.80.91.0
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JCOG 9907: Summary
Ando N, et al. GI Cancers Symposium 2008. Abstract 10.
Survival benefit with preoperative chemotherapy
Fewer patients in postoperative chemotherapy arm received chemotherapy
– 70.5% postoperative vs 88.4% preoperative
2-fold greater incidence of grade 3/4 mucositis and leucopenia in postoperative chemotherapy group
Preoperative chemotherapy provided greater benefit for patients with stage II disease
Preoperative chemotherapy led to downstaging and R0 resection and therefore is recommended for patients with resectable (stage II/III) esophageal cancer
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Second-Line Cetuximab in Esophageal Cancer: SWOG Phase II Trial
Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.
Survival benefit of second-line cetuximab in patients with metastatic esophageal adenocarcinoma
Cetuximab treatment regimen
– Initial dose: 400 mg/m2 IV
– Subsequent doses: 250 mg/m2 IV over 1 hour every 7 days
Adverse events observed in 64% of patients
– Considered manageable
– Approximately 50% of patients had dose modification
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Second-Line Cetuximab in Esophageal Cancer SWOG Phase II Trial: Results
Gold PJ, et al. GI Cancers Symposium 2008. Abstract 96.
4
1.8 1.8
0
1
2
3
4
OS PFS TTF
Mo
nth
s
0
20
40
60
80
100 Not evaluablePDSDPR
Res
po
nse
Rat
e (%
)5%
7%
11%
76%
N = 55
Primary endpoint—23 patients surviving > 6 months—not met
6-month survival rate: 36%
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Phase III IRIS Study: Design
Imamura H, et al. GI Cancers Symposium 2008. Abstract 5.
S-1Oral Fluoropyrimidine
80 mg/m2/day on Days 1-28, every 6 weeks
(n = 160)Patients aged 20-75 years
with nonresectable and advanced gastric
cancer and ECOG PS 0-2
(N = 315)
Irinotecan + S-1 (IRIS)Irinotecan 80 mg/m2/day IV
on Days 1 and 15 +S-1 80 mg/m2/day given on Days 1-21, every 5 weeks
(n = 155 )
Median follow-up10.4 months
Median follow-up12.6 months
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Phase III IRIS Study: Response by RECIST 187 patients evaluated for objective response
ORR higher in IRIS (P = .035). ORR represents PR rate—no CR observed
Imamura H, et al. GI Cancers Symposium 2008. Abstract 5.
2741
38
43
3213
0
20
40
60
80
100
S-1(n = 93)
IRIS(n = 94)
Not evaluable
PD
SD
PR
Res
po
nse
Rat
e (%
)
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Phase III IRIS Study: Survival Results
Higher response rates with IRIS treatment equated to slightly longer time to treatment failure, but not to significantly longer OS
Outcome S-1(n = 160)
IRIS(n = 155)
P Value
Time to treatment failure, mos 3.6 4.5 .1565
OS, mos 10.5 12.8 .2327
1-yr survival, % 44.9 52.0
Imamura H, et al. GI Cancers Symposium 2008. Abstract 5.
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AMC 0201 Adjuvant Mitomycin C: Design
Kang Y, et al. GI Cancers Symposium 2008. Abstract 6.
MfMitomycin C 20 mg/m2 + short-term Doxifluridine600 mg/m2/day x 3 cycles
(n = 424)Chemotherapy-naive patients aged 18-70 years with
advanced gastric cancer and D2 dissection, M0
(N = 855)
MFPMitomycin C +
long-term Doxifluridine x 14 cycles +
Cisplatin 60 mg/m2 on Day 1, every 4 weeks x 6 months
(n = 431)
Median follow-up3.2 years
Randomization 3-6 weeks postsurgery
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AMC 0201 Adjuvant Mitomycin C: Recurrence-Free Survival
Kang Y, et al. GI Cancers Symposium 2008. Abstract 6.
Outcome, % Mf(n = 424)
MFP(n = 431)
3-yr RFS 67.0 64.9
5-yr RFS 63.3 58.1
Total recurrence 31.6 32.4
HR: 1.067 (95% CI: 0.845-1.346)Log-rank test: P = .59
Rec
urr
ence
-Fre
e P
rop
ort
ion
Months
00
0.2
0.4
0.6
0.8
1.0
12 24 36 48 60 72
MFPMf
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Adjuvant Mitomycin C: Summary
Extending doxifluridine and adding cisplatin to adjuvant mitomycin C safe, but efficacy not improved
5-year recurrence-free survival and OS rates similar between treatment arms
– Recurrence-free survival: 63.3% in Mf arm vs 58.1% in MFP arm
– OS: 64.5% in Mf arm vs 64.8% in MFP arm
More than 30% of patients in each arm had disease recurrences, the majority of which were distant
Kang Y, et al. GI Cancers Symposium 2008. Abstract 6.
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Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7.
31 2
14
3
11
0
5
10
15
20
Overall(N = 24)
IM-RES(n = 6)
IM/SU-RES(n = 18)
SD
PR
ORR 71%
ORR 67%
ORR 72%
ORR
Pat
ien
ts (
n)
Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST
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Survival All Patients(N = 24)
95% CI
Median PFS, mos 5.3 3.2-open
Median OS, mos 13.0 5.1-open
1-yr survival, % 62 37-78
Conclusions
Sorafenib proves active in imatinib- and imatinib/sunitinib- resistant GIST patients
Overall sorafenib well tolerated, but dose reductions frequent
Accrual ongoing
Nimeiri HS, et al. GI Cancers Symposium 2008. Abstract 7.
Phase II Trial of Sorafenib in Imatinib- and Sunitinib-Resistant GIST: PFS, OS
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ACOSOG Z9000: Phase II Study of Adjuvant Imatinib in GIST
DeMatteo RP, et al. GI Cancers Symposium 2008. Abstract 8.
High-risk GIST patients (N = 107)
– Multiple lesions or ≥ 10 cm
– KIT positive
Oral imatinib initiated after surgery (median 59 days)
– 400 mg/day for 12 months
No severe adverse events
– < 20% had grade 3 toxicity
Overall survival 99% at 1 year, 97% at 2 years and at 3 years
Recurrence-free survival 94% at 1 year, 73% at 2 years, 61% at 3 years
– Recurrence rate high among patients with KIT exon 9 mutation
Recurrence-free survival prolonged vs historical controls
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Imatinib Pharmacokinetics and Response in GIST Patients (Trial B2222)
Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
Imatinib 400 mg/day
(n = 73)GIST patients
(N = 147) Imatinib 600 mg/day
(n = 74 )
Imatinib 800 mg/day
Imatinib 800 mg/day
PD
PD
PK data collected prospectively
Correlation with clinical outcomes analyzed retrospectively
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Response to Imatinib in GIST by Cmin Quartiles
Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
Response Imatinib Cmin Quartiles (n = 73)
Q1, n (%)(n = 18)
Q2-Q3, n (%)(n = 36)
Q4, n (%)(n = 19)
CR + PR + SD 12 (67) 29 (81) 16 (84)
PD/unknown 6 (33) 7 (19) 3 (16)
Patients in lowest imatinib exposure quartile (Q1) had shorter TTP (median: 11.3 months) than patients in the upper 3 quartiles (30.6 months; P = .0029)
Patients in lowest imatinib exposure quartile (Q1) exhibited somewhat lower rates of clinical benefit (ie, CR + PR + SD) than patients in the upper 3 quartiles
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Trial B2222: Summary
Survival not different between treatment arms
– Median PFS: 57 months; median OS: 21 months
– OS varied by KIT exon 11 mutation
– OS: 63 months with KIT exon 11 and 8 months with no mutation (P = .005)
Trend toward higher rates of clinical benefit with higher imatinib exposure
– Q1: 67%; Q2/3: 81%; Q4: 84%
Higher imatinib exposure provided greater clinical benefit for patients with KIT exon 11 mutation
– Q1 67% vs Q2/3 + Q4 100% (P = .009)
Demetri GD, et al. GI Cancers Symposium 2008. Abstract 3.
Pancreas, Small Bowel, and Hepatobiliary Tract Cancers
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ACOSOG Z05031: Chemoradiation in Resected Pancreatic Cancer Patients Chemoradiation regimen
– Radiation 5040 cGy/cisplatin/5-FU
– Postchemoradiation 5-FU
Phase II study
93 patients planned; 89 patients accrued; 80 evaluable
Study accrual terminated due to toxicity concerns
Median follow-up: 28 monthsPicozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125.
Toxicity, % ACOSOG
Gastrointestinal toxicity
Nausea 36
Anorexia 30
Dehydration 27
Diarrhea 25
Stomatitis 24
Vomiting 22
Hematologic toxicity
Neutropenia 39
Febrile neutropenia 8
Thrombocytopenia 12
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Chemoradiation in Resected Pancreatic Cancer Patients: OS
Picozzi VJ, et al. GI Cancers Symposium 2008. Abstract 125.
18-month OS 67%90
100
80
70
60
50
40
30
20
10
0
Su
rviv
al (
%)
0 1 2 3
Time (Yrs)
18-month OS 67%
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Adjuvant Chemoradiation in Pancreatic Adenocarcinoma
Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.
Retrospective analysis of 2 patient arms
– Johns Hopkins (n = 618)
– Mayo Clinic (n = 474)
Patients underwent pancreaticoduodenectomy, followed by chemoradiation or observation
– One half of the patients (53.4%) received 5-FU–based adjuvant chemoradiation
Median OS: 18.8 months
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Adjuvant Chemoradiation in Pancreatic Adenocarcinoma: Survival
Hsu CC, et al. GI Cancers Symposium 2008. Abstract 124.
0
0.8
1.0
0.6
0.4
0.2Su
rviv
al, p
rop
ort
ion
0 1 2 3 4 5
Follow-up (Yrs)
mOS2-yr OS5-yr OS
CRT21.1 mo44.7%22.3%
Obs15.5 mo34.6%16.1%
(P < .001)
Observation only (n= 509) Adjuvant chemoradiation (n = 583)
RR: 0.74 (95% CI 0.62-0.87)
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CFTR Mutation and Risk of Pancreatic Cancer
McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.
CFTR gene mutations associated with other pancreatic diseases; association to pancreatic cancer unknown
Case-control study
– Patients (n = 948) recruited through Mayo Clinic Pancreas Biospecimen Resource from 2000-2006
– Controls (n = 13,340) derived from prenatal counseling samples
– Analysis limited to white patients/controls due to higher frequency of CFTR gene mutations
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CFTR Mutation and Risk of Pancreatic Cancer: Incidence and Age of Onset
McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.
CFTR carrier Noncarrier
0
12
24
36
48
60
72
Overall EverSmokers
NeverSmokers
Ag
e o
f P
ancr
eati
c C
ance
r O
nse
t (Y
rs)
0
2
4
6
8
< 60 < 55 < 50
Inci
den
ce o
f C
FT
R M
uta
tio
n (
%)
Age (Yrs)
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CFTR Mutation and Risk of Pancreatic Cancer: Summary
McWilliams RR, et al. GI Cancers Symposium 2008. Abstract 187.
Carrying just 1 CFTR mutation increases risk for pancreatic cancer
Age of onset of pancreatic cancer influenced by smoking in CFTR mutation carriers only
Known CFTR carriers should be counseled not to smoke
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Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
SNPs in 8 genes involved in gemcitabine metabolism
– Cytidine deaminase (CDA)
– Deoxycytidine kinase (dCK)
– Ribonucleotide reductase (RRM1)
– Deoxycytidylate deaminase (DCTD)
– Human concentrative (hCNT) 1, 2, and 3
– Equilibrative nucleoside transporter (hENT1)
SNPs and Gemcitabine Activity and Toxicity
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Combined SNP Genotypes and Survival
Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
Combined Genotype: hCNT1 (16AA/AG); hCNT2 (17CC);
hENT1 (913CC)Number of alleles: P = .008
Combined Genotype: CDA (111C); CDA (76AA); RRM1 (42GG); DCTD (47AG)
Number of alleles: P = .052
Cu
mu
lati
ve S
urv
ival
, %
100
80
60
40
20
00 20 40 60 80 100
Time (Mos)
Cu
mu
lati
ve S
urv
ival
, %
3 1-2
0
100
80
60
40
20
00 20 40 60 80 100
Time (Mos)
3 1-2
0
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Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
0
10
20
30
40
CC CT TT AA AG GG
CDA C111T RRM1 G42A
Med
ian
OS
(M
os)
n = 48 n = 17 n = 3n = 15n = 56 n = 97
SNPs and Gemcitabine: OS by Genotype
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SNPs and Gemcitabine Activity and Toxicity: Summary
Javle MM, et al. GI Cancers Symposium 2008. Abstract 126.
Genetic variants of genes involved in gemcitabine metabolism have prognostic value in gemcitabine treatment of pancreatic cancer
SNPs associated with lower drug toxicity correlated with poor efficacy
– CDA 111CC and dCK 1205TT alleles associated with poor survival but a lower incidence of neutropenia
Tailored therapy according to genetics on horizon
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Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Phase II study of preoperative therapy
Patients with localized pancreatic cancer (N = 29)
– ECOG PS 0-1
Small W, et al. GI Cancers Symposium 2008. Abstract 131.
Cycle 121 days
Gemcitabine Days 1 and 8 1000 mg/m2
Bevacizumab Days 1 and 15
10 mg/kg
Cycle 228 days
Gemcitabine Days 1, 8, and 15
1000 mg/m2Bevacizumab Days 8 and 21
10 mg/kgRadiotherapy
Days 1-5, 8-12, 15-19
Cycle 321 days
GemcitabineDays 1 and 81000 mg/m2
BevacizumabDay 8
10 mg/kg
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Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation
Small W, et al. GI Cancers Symposium 2008. Abstract 131.
Survival All(N = 29)
Resectable(n = 7)
Unresectable(n = 12)
Borderline(n = 10)
PFS
Median duration, mos 10.2 10.2 11.8 10.0
6-mo PFS, % 68 38 50 67
1-yr PFS, % 41 38 50 36
Progressed or died, n 15 4 5 6
OS
Median duration, mos 11.8 10.2 11.8 NA
6-mo OS, % 82 71 75 89
1-yr OS, % 45 36 48 53
Died, n 13 4 5 4
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Pancreatic Cancer: Gemcitabine and Bevacizumab Plus Radiation Chemoradiation combination of gemcitabine/
bevacizumab/radiation well tolerated
– Only 1 patient did not complete 3 cycles of therapy
Radiographic CR seen in 2 patients
– CR (2), PR (3), SD (18), PD (5)
6 patients underwent resection; 2 had pathologic CR (33%)
Small W, et al. GI Cancers Symposium 2008. Abstract 131.
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SHARP: Sorafenib in Patients With Advanced HCC and HCV Infection
Bolondi L, et al. GI Cancers Symposium 2008. Abstract 129.
Outcome
HCV-Positive Patients
Overall SHARP Population
Sorafenib(n = 93)
Placebo(n = 85)
Sorafenib(n = 299)
Placebo(n = 303)
Disease recurrence, % 44.1 30.6 43.5 31.6
Median TTP, mos 7.6 2.8 5.5 2.8
Median OS, mos 14.0 7.9 10.7 7.9
Post hoc analysis of subpopulation in phase III trial of sorafenib vs placebo
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Sorafenib in Patients With HCC and Child-Pugh A and B Cirrhosis Phase II study
Sorafenib 400 mg twice daily
Areas under the curve
– Child-Pugh A 25.4 mg/hour/L and Child-Pugh B 30.3 mg/hour/L
Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 140.
0
10
20
30
40
50
TTP OS
Child-Pugh A (n = 21)
Med
ian
(W
ks)
Child-Pugh B (n = 7)
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Sorafenib Plus Doxorubicin in HCC Phase II Study: Design
Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128.
Treatment-naive patients with advanced HCC,Child-Pugh A, and
ECOG PS 0-2
(N = 96)
Placebo/Doxorubicin*Doxorubicin 60 mg/m2 IV
every 21 days(n = 49)
Sorafenib/Doxorubicin*Sorafenib 400 mg twice daily
Doxorubicin 60 mg/m2 IV every 21 days
(n = 47)
*After 18 weeks, patients allowed to continue on single-agent sorafenib or placebo until disease progression.
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Sorafenib Plus Doxorubicin in HCC Phase II Study: Results
Abou-Alfa GK, et al. GI Cancers Symposium 2008. Abstract 128.
4.86.5
2.8
8.6
13.8
6.9
0
3
6
9
12
15
TTP OS PFS
Placebo
Sorafenib
Med
ian
(M
os)
(P = .0129)
(P = .076)
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Retrospective analysis of SEER database
Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143.
4
8
12
16
Radiationand Surgery
Surgery Radiation No Treatment
Extrahepatic CCA
Intrahepatic CCA
Med
ian
OS
(M
os)
n = 701
n = 1372 n = 475
n = 2210
n = 286
n = 948n = 396
n = 2209
0
Surgery and Adjuvant Radiation in Cholangiocarcinomas (CCA): Survival
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Surgery and Adjuvant Radiation in CCA: Prognostic Factors Treatment, race, and stage independent predictors for survival in multivariate
analysis for extrahepatic and intrahepatic CCA
Year of diagnosis independent predictor of survival for intrahepatic CCA only
Multivariate Analysis Extrahepatic CCA Intrahepatic CCA
Factor HR 95% CI HR 95% CI
Treatment vs no treatment
Radiation and surgery 0.47 0.42-0.52 0.40 0.34-0.47
Surgery 0.52 0.47-0.57 0.49 0.44-0.54
Radiation 0.66 0.58-0.75 0.68 0.59-0.77
Black vs white 1.30 1.13-1.50 1.31 1.21-1.53
Localized vs distant disease 0.48 0.43-0.53 0.51 0.46-0.56
Regional vs distant disease 0.59 0.54-0.65 0.66 0.60-0.73
Shinohara ET, et al. GI Cancers Symposium 2008. Abstract 143.
Capsule Summaries featuring expert discussion and commentary in keytopic areas in gastrointestinal cancers
Colorectal Cancers
Esophageal and Gastric Cancers
Pancreas, Small Bowel, and Hepatobiliary Tract Cancers
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