1. Intergroup trial 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

2. 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)

3. 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)

4. Grade 3 or Higher Toxicity
Multicenter Pilot Study of Adjuvant Chemoradiation After Resection of Gastric or GE Junction Adenocarcinoma
Pre-RT Chemo
Chemo with RT
Post-RT Chemo
(1 cycle)
(45 Gy)
(2 cycles)
Epirubicin
50 mg/m2 d1
Epirubicin
40 mg/m2 d1
Cisplatin
60 mg/m2 d1
Cisplatin
50 mg/m2 d1
5-FU CI
200 mg/m2/d
5-FU CI
200 mg/m2
d1-21
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%

5. CALGB 80101: Study Schema 5-FU/LV X1 5-FU IVCI RT 5-FU/LV X2 ECF X1N D O M I Z E
5-FU/LV X1
5-FU IVCI RT
5-FU/LV X2
ECF X1
5-FU IVCI RT
ECF X2
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, &

6. CALGB 80101: Study Endpoints
Primary
Overall survival
Secondary
Disease-free survival
Adverse events

7. 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)

8. 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

9. 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

10. Study Accrual: 4/30/03 to 5/29/09

11. Baseline Characteristics
5FU/LV N=280
ECF N=266
Age (years)
       Median (range)
59 (23-81)
59 (28-83)
Sex
       Male
69%
67%
ECOG PS
47%
54% 1
50%
44% 2 3% 2%

12. Baseline Characteristics
5FU/LV N=280
ECF N=266
Depth of tumor
T1 or T2
47% T3
48%
49% T4 5% 4%
Positive lymph nodes
16%
15%
1-3
36%
≥ 4
Nodes examined
< 7
13%
10%
7-14
37%
29%
≥ 15
50%
61%

13. Baseline Characteristics
5FU/LV N=280
ECF N=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%
Asian 8%
Other 5%

14. Reasons for Treatment Cessation
5FU/LV N=280
ECF N=266
Completed treatment
75%
69%
Progressive disease 5% 3%
Adverse event
10%
16%
Death 4% 1%
Withdrew 8%
Other 2%

15. Quality Assurance for Radiotherapy
15% of the treatment plans were found to contain major deviations

16. Major (Grade ≥ 3) Adverse Events
5FU/LV
ECF
Nausea
17%
15%
Diarrhea 7%
Mucositis
Dehydration 9% 4%
Anorexia
16%
13%
Fatigue
11%
Neutropenia
52%
48%
Grade ≥ 4 Neutropenia
33%
19%
Death
3% (8)
0% (1)

17. Overall Survival by Treatment Arm
CALGB 80101
Overall Survival by Treatment Arm
P, log rank = 0.80

18. Overall Survival by Treatment Arm
CALGB 80101
Overall Survival by Treatment Arm
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%
( )
*P, log rank = 0.80

19. Disease-Free Survival by Treatment Arm
CALGB 80101
Disease-Free Survival by Treatment Arm
P, log rank = 0.99

20. Disease-Free Survival by Treatment Arm
CALGB 80101
Disease-Free Survival by Treatment Arm
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%
( )
*P, log rank = 0.99

21. HRs (95% CI) for Mortality According to Baseline Characteristics
Male
Female
Age ≥ 60
Age < 60
GE jxn
Proximal
Distal
T 1/2
T 3/4
0 pos nodes
1-3 pos nodes
≥ 4 pos nodes
PS 0
PS 1-2
< 7 nodes exam
7-14 nodes exam
≥ 15 nodes exam
Favors ECF
Favors 5-FU/LV
HRs (95% CI) for Mortality According to Baseline Characteristics

22. Overall Survival by Treatment
CALGB and INT 0116
Overall Survival by Treatment
CALGB 80101
INT 0116
5-FU/LV
ECF
5-FU/RT
Control
Median OS
(mos) 37 38 36 27

23. 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

24. Acknowledgements We wish to thank:
all the patients and families who participated in the trial
and
all the participating centers.