Chemotherapy and Radiation Therapy After Surgery in Treating Patients With Stomach or Esophageal Cancer

OBJECTIVES:

- Compare overall survival in patients with resected gastric adenocarcinoma treated with
epirubicin, cisplatin, and infusional fluorouracil (5-FU) vs 5-FU bolus and leucovorin
calcium before and after 5-FU plus radiotherapy.

- Compare disease-free survival and local and distant recurrence rates in these patients
treated with these regimens.

- Correlate the expression of putative prognostic markers (including TS, ERCC-1, MSI,
E-cadherin, EGFR, p27, COX-2, and c-erbB-2) with overall survival of patients treated
with these regimens.

- Correlate specific germline polymorphisms related to chemotherapy metabolism and
resistance (including UGT2B7 [epirubicin], GST [cisplatin], ERCCI [cisplatin], XRCC1
[cisplatin], TS [5-FU], DPD [5-FU], and EGFR polymorphisms) with treatment-related
toxicity and overall survival of these patients.

- Correlate serum levels of insulin-like growth factor-1 (IGF-1), IGF-2, and IGF-binding
protein 3 with overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to depth
of tumor penetration (T1 or T2 vs T3 vs T4), lymph node involvement (0 vs 1-3), and extent of
lymphadenectomy (D1 or D2 vs D0 or unknown). Patients are randomized to 1 of 2 treatment
arms.

- Arm I: Patients receive leucovorin calcium IV and fluorouracil (5-FU) IV on days 1-5 of
courses 1, 3, and 4. Courses repeat every 28 days. During course 2, patients undergo
radiotherapy 5 days a week and receive 5-FU IV continuously for 5 weeks. Patients rest
for 28-35 days between course 2 and 3.

- Arm II: Patients receive epirubicin IV over 3-15 minutes and cisplatin IV over 1 hour on
day 1 and 5-FU IV continuously on days 1-21 during course 1. Beginning 1 week later,
patients undergo radiotherapy 5 days a week and receive 5-FU IV continuously for 5
weeks. Patients rest for 28-35 days before beginning course 2 of chemotherapy. Patients
then receive epirubicin, cisplatin, and 5-FU as in course 1. Treatment repeats every 21
days for 2 courses.

Patients are followed every 3 months for 2 years, every 4 months for 2 years, and then
annually for 3 years.

PROJECTED ACCRUAL: A total of 824 patients will be accrued for this study.

1. Required Tumor Parameters

1.1 Patients must have histologically diagnosed adenocarcinoma of the stomach or
gastroesophageal junction. Adenocarcinomas of the esophagus that are not involving the
gastroesophageal junction are not eligible.

1.2 Patients must have had en bloc resection of all known tumor. The surgical
resection must have been done with a curative intent.

1.3 Patients must have tumor extension beyond muscularis propria and/or nodal
involvement without evidence of M1 disease.

- Patients can have stages IB if there is evidence of either node-positive (N1)
disease or tumor extension beyond the muscularis propria (i.e., T1, N1, M0
patients are eligible but patients with T2, N0, M0 are allowed only if there is
extension beyond the muscularis propria).

- Patients can have stages II, IIIA, IIIB or stage IV with M0 (i.e., T4N2M0).

- Stages 0, IA, or any stage with M1 are not allowed. (see Appendix I for TNM
staging guide).

1.4 Patients with known unresected cancer, recurrent cancer, microscopic evidence of
tumor at the distal or proximal line of stomach resection, noncontiguous resection of
tumor, or M1 (metastatic) disease are ineligible.

2. Prior Therapy

2.1 No prior therapy (except hormonal or biologic) for other malignancies is allowed
except for adequately treated basal cell or squamous cell skin cancer, noninvasive
carcinoma in situ which has been fully resected, or other cancer for which the patient
has been disease free for five years.

2.2 Patients who have had any previous chemotherapy or radiotherapy are ineligible.

3. Patient Characteristics

3.1 Patients must have an ECOG (CTC) performance status of 0, 1 or 2.

3.2 Patients are required to have an adequate total caloric intake to allow them to
maintain their post-surgical body weight. Patients must have documentation of stable
weight (or less than 2 pounds weight loss) for at least one week prior to
registration.

3.3 All patients must be evaluated by a radiation oncologist (prior to enrollment) to
ensure that the patient is an appropriate candidate for radiation therapy.

3.4 Patients may not have unilateral renal function (only one functioning kidney) as
determined by CT scan with contrast, urogram, renal scan, or other study.

3.5 Pregnant or lactating women may not participate. Men and women of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method or practice abstinence while in this study.

- The effects of therapeutic radiotherapy are known to be teratogenic.

- The effects of Epirubicin, Cisplatin, and 5-FU on a developing human fetus at the
recommended therapeutic dose are less well known.

- For this reason and because DNA alkylating agents are known to be teratogenic,
women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation.

- Should a woman become pregnant or suspect she is pregnant while participating on
this study, she should inform her treating physician immediately. Because the
risk of toxicity in nursing infants secondary to Epirubicin, Cisplatin, and 5-FU
treatment of the mother is unknown but may be harmful, breastfeeding should be
discontinued.

3.6 Patients with any of the following cardiac conditions are ineligible:

- Uncontrolled high blood pressure

- Unstable angina

- Symptomatic congestive heart failure

- Myocardial infarction < 6 months prior to registration

- Serious uncontrolled cardiac arrhythmia

- New York Heart Association classification III or IV.

3.7 No uncontrolled serious medical or psychiatric illness which would prevent
compliance with treatment or adequate informed consent.

3.8 Patients with active infectious process are ineligible.

3.9 Patients with grade 2 or greater peripheral neuropathy at baseline are ineligible.

4. Required Initial Laboratory Values:

- Granulocytes ≥ 1,500/μl

- Platelet count ≥ 100,000/μl

- Creatinine ≤ 1.5 mg/dl

- Bilirubin ≤ 2.0 mg/dl

- AST ≤ 3x upper limits of normal