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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy after surgery may kill any remaining tumor cells following surgery. It is not yet known which chemotherapy and radiation therapy regimen is more effective in treating stomach or esophageal cancer. PURPOSE: Randomized phase III trial to compare two different chemotherapy and radiation therapy regimens in treating patients who have undergone surgery for stomach or esophageal cancer.

Detailed Description
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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.

Official Title
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Phase III Intergroup Trial of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma

Conditions
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Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Drug: leucovorin calcium
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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. 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. 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>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 to 6 weeks. Patients rest for 28-35 days between course 2 and 3. | Drug: fluorouracil<br>* Given IV<br>Drug: leucovorin calcium<br>* Given IV<br>Radiation: radiation therapy<br>* Given 5 days a week for 5 weeks<br>|
| Experimental: Arm II<br>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 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. | Drug: cisplatin<br>* Given IV<br>Drug: epirubicin hydrochloride<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>Radiation: radiation therapy<br>* Given 5 days a week for 5 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from study enrollment to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | From study enrollment until death from any cause; up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Disease free survival is defined as the time from the date of study enrollment to death or documented second primary tumor, or cancer recurrence.The distribution of disease free survival time will be estimated using the method of Kaplan-Meier. | From the date of study enrollment until death or documented second primary tumor, or cancer recurrence; up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I gastric cancer, stage II gastric cancer, stage III gastric cancer, adenocarcinoma of the stomach, adenocarcinoma of the esophagus, stage I esophageal cancer, stage II esophageal cancer, stage III esophageal cancer