S0356 Oxaliplatin, 5-FU, Radiation Therapy (RT), Surgery for Pts With Stage II or III Cancer of Esophagus or Gastroesophageal (GE) Junction

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in 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. Oxaliplatin and fluorouracil may make tumor cells more sensitive to radiation therapy and may kill more tumor cells. Giving chemotherapy and radiation therapy before surgery may shrink the tumor so that it can be removed. PURPOSE: This phase II trial is studying how well giving oxaliplatin together with fluorouracil and radiation therapy works in treating patients who are undergoing surgery for stage II or stage III cancer of the esophagus or gastroesophageal junction.

Detailed Description
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OBJECTIVES: Primary Determine the pathologic complete response probability in patients with stage II or III adenocarcinoma of the esophagus or gastroesophageal junction treated with neoadjuvant oxaliplatin, fluorouracil, and radiotherapy followed by definitive surgical resection. Secondary Determine the frequency and severity of toxic effects associated with this neoadjuvant regimen in these patients. Determine the overall survival and progression-free survival of patients treated with this regimen. Exploratory Analyses (subject to funding availability) Correlate, preliminarily, initial messenger ribonucleic acid (mRNA) levels of the genes for thymidylate synthase (TS), γ-glutamyl transpeptidase (γGT), γ-glutamyl cysteine (γ-GCS), DNA excision repair cross-complementing (ERCC-1), and xeroderma pigmentosum (XPA) with response and survival of patients treated with this regimen. Correlate, preliminarily, the mRNA levels of TS, γGT, γ-GCS, ERCC-1, and XPA before and after treatment with this regimen with survival of these patients. Correlate, preliminarily, specific genetic polymorphisms of TS and ERCC-1 with tumor response and overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Neoadjuvant chemoradiotherapy: Patients receive oxaliplatin IV over 2 hours on days 1, 15, and 29 and fluorouracil (5-FU) IV continuously on days 8-43. Beginning on day 8, patients also undergo radiotherapy once daily, 5 days a week, for 5 weeks. Surgery: Patients with stable disease or better undergo surgical resection 4-10 weeks after completion of chemoradiotherapy. Adjuvant chemotherapy: Beginning 4-10 weeks after surgery, patients receive chemotherapy comprising oxaliplatin IV over 2 hours on days 1, 15, and 29 and 5-FU IV continuously on days 1-36. Treatment continues in the absence of unacceptable toxicity or disease progression. Patients are followed every 3 months for 1 year and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 45-85 patients will be accrued for this study within 17-21 months.

Official Title
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Oxaliplatin (NSC-266046) Plus Protracted Infusion 5-Fluorouracil And Radiation For Potentially Curable Esophageal Cancer: A Phase II Trial With Molecular Correlates

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: oxaliplatin
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary adenocarcinoma of the thoracic esophagus or gastroesophageal junction No recurrent disease Primary esophageal tumor at least 20 cm below the incisors (if < 26 cm below the incisors, a bronchoscopy must be performed and cytology must be negative) Esophageal disease confined to esophagus and peri-esophageal soft tissue Gastroesophageal junction disease extending ≤ 2 cm into the gastric cardia Clinical stage II or III disease by CT scan or MRI If no esophageal mass is detected by these methods, esophageal endoscopic ultrasound is required to determine stage Positron-emission tomography scan is required to confirm stage Measurable or non-measurable disease by x-ray, scanning, or physical examination No celiac axis nodes ≥ 1.5 cm Measurable regional lymph nodes ≥ 1.5 cm at stations 2-10=N1 OR subdiaphragmatic lymph nodes at stations 15-19 ≤ 1.5 cm by CT scan or MRI allowed Palpable supraclavicular lymph nodes must be free of metastatic esophageal cancer by biopsy PATIENT CHARACTERISTICS: Age Over 18 Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 White blood cell (WBC) count ≥ 3,000/mm^3 Hemoglobin ≥ 10.0 g/dL (transfusion allowed) Hepatic Albumin ≥ 3 g/dL Bilirubin normal Renal Creatinine ≤ 1.5 times upper limit of normal Cardiovascular No myocardial infarction or cerebrovascular event within the past 6 months Pulmonary No active pneumonia or inflammatory lung infiltrate Other No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No peripheral neuropathy ≥ grade 2 Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy for esophageal cancer Endocrine therapy Not specified Radiotherapy No prior radiotherapy for esophageal cancer No concurrent intensity-modulated radiotherapy Surgery No prior surgical resection or attempted surgical resection of esophageal cancer

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemo Plus RT, Surgery, Chemo<br>neoadjuvant fluorouracil, oxaliplatin and radiation therapy followed by conventional surgery and adjuvant fluoruracil and oxaliplatin | Drug: fluorouracil<br>* Before surgery: 180 mg/m2/day by 24-hour infusion days 8 through 43. After surgery:180 mg/m2/day by 24-hour infusion days 1 through 36.<br>* Other names: 5-FU;Drug: oxaliplatin<br>* Before surgery: 85 mg/m2 by 2-hour IV infusion days 1, 15, and 29. After surgery: 85 mg/m2 by 2-hour IV infusion days 1, 15, and 29.<br>* Other names: eloxatin;Procedure: conventional surgery<br>* The surgical technique will depend upon the location and extent of tumor and individual surgeon preference.<br>Radiation: radiation therapy<br>* Starting Day 8, patients will be treated 5 days/week at 180 centigray (cGy)/day times 25 fractions to a total dose of 4,500 cGy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response | Complete pathologic response assessed after chemoradiotherapy and surgery, defined as no evidence of residual disease on path review. Patients who did not receive surgery are assumed to have not responded. | 10-16 weeks after beginning study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 3 years | 
| Overall Survival | Measured from time of registration to death, or last contact date | 0-5 years | 
| Progression-free Survival | measured from date of registration to time of first documentation of progression by Response Evaluation Criteria in Solid Tumors (RECIST), death, or last contact date. | 0-3 years | 

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