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

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)

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)

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%

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

CALGB 80101

CALGB 80101: Study Endpoints

Primary

• Overall survival

Secondary

• Disease-free survival

• Adverse events

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)

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

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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%

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%

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%

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%

CALGB 80101

Quality Assurance for Radiotherapy

• 15% of the treatment plans were found to contain major deviations

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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)

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

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

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

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

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

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

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

CALGB 80101

Acknowledgements

We wish to thank:

• all the patients and families who participated in the trial

and

• all the participating centers.