calgb 80101 postoperative adjuvant chemoradiation for gastric or ge junction adenocarcinoma using...
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CALGB 80101
Postoperative adjuvant chemoradiation for gastric or GE junction adenocarcinoma using ECF before and after 5-FU/radiotherapy compared to bolus 5-
FU/LV before and after 5-FU/radiotherapy: Intergroup trial CALGB 80101
CS Fuchs, JE Tepper, D Niedzwiecki, D Hollis, HJ Mamon, RS Swanson, DG Haller,
T Dragovich, SR Alberts, G Bjarnson, CG Willett, PC Enzinger, RM Goldberg, AP Venook, RJ Mayer
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CALGB 80101
CALGB 80101: Participating Groups
Cancer and Leukemia Group B
Eastern Cooperative Oncology Group
North Central Cancer Treatment Group
National Cancer Institute of Canada
Southwest Oncology Group
Radiation Treatment Oncology Group
Clinical Trials Support Unit (NCI)
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CALGB 80101
Background• INT 0116 demonstrated improved survival with post-
operative adjuvant 5-FU/LV/RT compared to surgery alone*
– Post-op 5-FU/LV/RT was associated with reduction in local-regional recurrences
– Reductions in distant relapse were less apparent
• MAGIC trial found improved outcome with perioperative ECF**
• Could the benefit associated with post-op 5-FU/LV/RT be improved with a potentially more active systemic regimen (ECF) than 5-FU/LV?
*(N Eng J Med 2001) **(N Engl J Med. 2006)
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CALGB 80101
Pre-RT Chemo (1 cycle)
Chemo with RT (45 Gy)
Post-RT Chemo (2 cycles)
Epirubicin 50 mg/m2 d1
Multicenter Pilot Study of Adjuvant Chemoradiation After Resection of Gastric or GE Junction Adenocarcinoma
Cisplatin 60 mg/m2 d1
5-FU CI 200 mg/m2
d1-21
5-FU CI 200 mg/m2/d
Epirubicin 40 mg/m2 d1
Cisplatin 50 mg/m2 d1
5-FU CI 200 mg/m2
d1-21
Grade 3 or Higher Toxicity
Pilot Study (N = 20) INT 0116 (N = 281)
Hematologic 30% (6/20) 54%
Gastrointestinal 35% (7/20) 33%
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CALGB 80101
CALGB 80101: Study Schema
R
A
N
D
O
M
I
Z
E
5-FU/LV: 5-FU 425 mg/m2 d1-5, LV 20 mg/m2 d1-5
RT: 45 Gy (1.8 Gy X 25 fractions) with 5-FU 200 mg/m2/d CI
ECF (pre-RT): Epirubicin 50 mg/m2 d1, Cisplatin 60 mg/m2 d1, &
5-FU 200 mg/m2/d CI d1-21
ECF (post-RT): Epirubicin 40 mg/m2 d1, Cisplatin 50 mg/m2 d1, &
5-FU 200 mg/m2/d CI d1-21
5-FU/LV
X1
5-FU/LV
X2
5-FU IVCI
RT
ECF
X1
ECF
X2
5-FU IVCI
RT
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CALGB 80101
CALGB 80101: Study Endpoints
Primary
• Overall survival
Secondary
• Disease-free survival
• Adverse events
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CALGB 80101
Randomization
• 1:1
• Stratification factors:
– T1/T2 vs. T3 vs. T4
– Lymph node involvement: 0 vs. 1-3 vs. ≥ 4
– ≥ 7 nodes examined vs. < 7 examined/unknown
• Sample size
– N = 540 (270 per arm)
– 80% power to detect a 30% improvement in OS comparing ECF to 5-FU/LV (Median OS: 49 versus 36 months; alpha = 0.05)
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CALGB 80101
Eligibility Criteria
• GE junction or gastric adenocarcinoma
• En bloc resection; negative resection margins
• Extension beyond muscularis propria or nodal involvement; M1 disease excluded
• No prior chemo or radiotherapy
• ECOG PS: 0-2
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CALGB 80101
Eligibility Criteria (continued)
• Adequate hematologic, renal, and hematologic function
• < 2 lbs weight loss on 2 measurements over 1 week
• 3 to 12 weeks following surgery
• Evaluation by radiation oncologist
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CALGB 80101
Study Accrual: 4/30/03 to 5/29/09
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CALGB 80101
Baseline Characteristics
Characteristic5FU/LV
N=280ECFN=266
Age (years)
Median (range) 59 (23-81) 59 (28-83)
Sex
Male 69% 67%
ECOG PS
0 47% 54%
1 50% 44%
2 3% 2%
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CALGB 80101
Baseline Characteristics5FU/LV
N=280ECFN=266
Depth of tumor
T1 or T2 47% 47%
T3 48% 49%
T4 5% 4%
Positive lymph nodes
0 16% 15%
1-3 36% 36%
≥ 4 48% 49%
Nodes examined
< 7 13% 10%
7-14 37% 29%
≥ 15 50% 61%
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CALGB 80101
Baseline Characteristics5FU/LV
N=280ECFN=266
Tumor Location
GE junction 24% 23%
Proximal 9% 6%
Corpus/Distal 47% 57%
NOS or multicentric 20% 15%
Race
White 76% 71%
Black 11% 15%
Asian 8% 9%
Other 5% 5%
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CALGB 80101
Reasons for Treatment Cessation
Reasons5FU/LV
N=280ECFN=266
Completed treatment 75% 69%
Progressive disease 5% 3%
Adverse event 10% 16%
Death 4% 1%
Withdrew 4% 8%
Other 2% 3%
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CALGB 80101
Quality Assurance for Radiotherapy
• 15% of the treatment plans were found to contain major deviations
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CALGB 80101
Major (Grade ≥ 3) Adverse Events 5FU/LV ECF
Nausea 17% 15%
Diarrhea 15% 7%
Mucositis 15% 7%
Dehydration 9% 4%
Anorexia 16% 13%
Fatigue 11% 13%
Neutropenia 52% 48%
Grade ≥ 4 Neutropenia 33% 19%
Death 3% (8) 0% (1)
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CALGB 80101
0 1 2 3 4 5 6 7
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
ECF5-FU
Overall Survival by Arm
P, log rank = 0.80
CALGB 80101Overall Survival by Treatment Arm
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CALGB 80101
Arm Median OS* 3-year OS 5-year OS Hazard Ratio (95% CI)
5-FU/LV 36.6 mos 50% 41%
ECF 37.8 mos 52% 44% 1.03 (0.80-1.34)
*P, log rank = 0.80
CALGB 80101Overall Survival by Treatment Arm
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CALGB 80101
P, log rank = 0.99
0 1 2 3 4 5 6 7
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g D
isea
se-F
ree
ECF5-FU
Disease_Free Survival by Arm
CALGB 80101Disease-Free Survival by Treatment Arm
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CALGB 80101
Arm Median DFS 3-yr DFS 5-yr DFS Hazard Ratio (95% CI)
5-FU/LV 30.1 mos 46% 35%
ECF 28.2 mos* 47% 38% 1.00 (0.79-1.27)
*P, log rank = 0.99
CALGB 80101Disease-Free Survival by Treatment Arm
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CALGB 80101
MaleFemale
Age ≥ 60
Age < 60
GE jxnProximal
Distal
T 1/2T 3/4
0 pos nodes1-3 pos nodes≥ 4 pos nodes
PS 0PS 1-2
< 7 nodes exam7-14 nodes exam≥ 15 nodes exam
Favors ECF Favors 5-FU/LV
HRs (95% CI) for Mortality According to Baseline Characteristics
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CALGB 80101
CALGB 80101 INT 0116
5-FU/LV ECF 5-FU/RT Control
Median OS(mos)
37 38 36 27
CALGB 80101 and INT 0116Overall Survival by Treatment
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CALGB 80101
Conclusion
Following curative resection of gastric or GE jxn
adenocarcinoma, post-operative chemoradiotherapy
using ECF & 5-FU/RT does not improve survival when
compared to 5-FU/LV & 5-FU/RT
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CALGB 80101
Acknowledgements
We wish to thank:
• all the patients and families who participated in the trial
and
• all the participating centers.