Radiation Therapy + Combination Chemotherapy as 1st-Line Therapy for Patients With Inoperable Esophageal Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, leucovorin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with radiation therapy may kill more tumor cells. PURPOSE: This randomized phase II/III trial is studying radiation therapy and two different combination chemotherapy regimens to compare how well they work as first-line therapy in treating patients with esophageal cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To assess the feasibility of radiochemotherapy comprising oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX regimen) vs fluorouracil and cisplatin (Herskovic regimen) in patients with inoperable esophageal cancer. (Phase II) To assess the endoscopic complete response rate in patients treated with these regimens. (Phase II) To compare the event-free survival of patients treated with these regimens. (Phase III) Secondary To assess the toxicity profile of these regimens using the NCI CTC v2.0 criteria. (Phase II) To compare the overall survival, endoscopic complete response rate, incidence of grade 3-4 toxicities, and time to treatment failure in patients treated with these regimens. (Phase III) To evaluate the quality of life of these patients using EORTC QLQ-C30 (version 3) and a validated disease-specific module EORTC QLQ-OES18. (Phase III) OUTLINE: This is a multicenter study. Patients are stratified according to histological type (adenocarcinoma or adenosquamous carcinoma vs squamous cell carcinoma), pretreatment weight loss within the past 6 months (grade 1 [< 10%] vs grade 2 [≥ 10%]), ECOG performance status (0 vs 1 vs 2), and participating center. Patients are randomized to 1 of 2 treatment arms. Arm I (modified FOLFOX 4 regimen): Patients undergo radiotherapy 5 days a week for 5 weeks. Beginning concurrently with radiotherapy, patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment with chemotherapy repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Arm II (Herskovic regimen): Patients undergo radiotherapy as in arm I. Patients also receive cisplatin IV continuously over 24 hours on day 1 and fluorouracil IV continuously over 96 hours on days 1-4 of weeks 1, 5, 8, and 11 in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, periodically during study therapy, and then every 6 months for 1 year and annually for 3 years after completion of study therapy. After completion of study therapy, patients are followed at 4 weeks and then every 3-6 months until disease progression. PROJECTED ACCRUAL: A total of 97 patients will be accrued for the phase II portion of the study. A total of 169 patients will be accrued for the phase III portion of the study.

Official Title
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Phase II-III Study Comparing Radiochemotherapy With the FOLFOX Regimen Versus Radiochemotherapy With 5FU-cisplatin (Herskovic Regimen) in First Line Treatment of Patients With Inoperable Oesophageal Cancer.

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: 5-FU
* Drug: oxaliplatin
* Radiation: radiation therapy
* Drug: Folinic Acid


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma of the esophagus Locally advanced disease (any T, N0 or N1, M0 or M1a) No metastatic disease, except for tumor involvement of the upper third of the esophagus or cervical esophageal tumor with regional nodes, or tumor involvement of the lower third of the esophagus with celiac nodes (M1a) Cervical primary tumor with positive supraclavicular or cervical lymph nodes (defined as N1) allowed No radiographic evidence of enlarged (≥ 1.5 cm) celiac lymph nodes by CT scan or echography No small cell or undifferentiated carcinoma of the esophagus No multiple carcinomas of the esophagus (i.e., > 1 esophageal tumor) No cardia tumor (Siewert II) or gastric tumor extension to the esophagus (Siewert III) Esophageal tumor extension to the cardia (Siewert I) (center of the tumor lying > 1 cm-5 cm above gastroesophageal junction) allowed Inoperable disease OR surgery is contraindicated No tracheo-esophageal fistula or invasion of the tracheo-bronchial tree PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 3 months Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL (transfusion allowed) Creatinine < 15 mg/L Total bilirubin < 1.5 times upper limit of normal (ULN) ALT and AST < 2.5 times ULN Prothrombin time ≥ 60% Not pregnant or nursing Fertile patients must use effective contraception Caloric intake sufficient (i.e., > 1,000 Kcal/m²/day) (orally or with gastrostomy) No weight loss > 20% normal body weight within the past 3 months No complete dysphagia No exclusive requirement for parenteral nutrition No peripheral neuropathy > grade 1 No sensitive peripheral neuropathy with functional impairment No auditory disorders No other prior malignancies except curatively treated nonmelanoma skin cancer or carcinoma in situ of the cervix or stage I or II node-negative head and neck cancer that was curatively treated > 3 years ago No myocardial infarction within the past 6 months Patients who have had a myocardial infarction > 6 months ago are eligible provided there is no transient ischemia by thallium myocardial scintigraphy and patient is able to undergo chemotherapy , as determined by a cardiologist No other serious illness or medical condition (e.g., symptomatic coronary disease, left ventricular failure, or uncontrolled infection) No stage II-IV arterial disease, according to the DE LERICHE and FONTAINE classification No geographical, social, or psychological circumstances preventing regular follow-up PRIOR CONCURRENT THERAPY: No prior treatment for esophageal cancer (e.g., surgery, chemotherapy, or radiotherapy) No prior cervical, thoracic, or abdominal radiotherapy with field overlapping the proposed esophageal radiotherapy field More than 30 days since prior experimental drugs or participation in another clinical trial No other concurrent anticancer therapy No concurrent phenytoin or yellow fever vaccine No concurrent high-dose, long-term corticosteroids No concurrent calcium gluconate/magnesium sulfate infusions No concurrent hematopoietic growth factors No concurrent esophageal dilatation

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 |
| --- | --- |
| Experimental: FOLFOX and radiotherapy<br>Oxaliplatin (85mg/m2); Folinic Acid (200mg/m2); 5-FU (400mg/m2-Bolus and 1600mg/m2 over 46h)- once every two weeks for six cycles | Drug: 5-FU<br> <br> * Other names: 5-Fluorouracil;Drug: oxaliplatin<br> <br> Radiation: radiation therapy<br> <br> Drug: Folinic Acid<br> <br> |
| Experimental: 5-FU / cisplatin and radiotherapy<br>5-FU (100mg/m2); Cisplatin (75mg/m2) | Drug: cisplatin<br> <br> Drug: 5-FU<br> <br> * Other names: 5-Fluorouracil;Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients who complete the full study treatment (Phase II) |  | 12 weeks | 
| Endoscopic complete response rate (Phase II) |  | 12 weeks | 
| Progression-free survival (Phase III) |  | Until progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile as assessed by NCI CTC v2.0 (Phase II) |  | Total duration of the trial | 
| Overall survival (Phase III) |  | Total duration of the trial | 
| Complete response rate (Phase III) |  | Total duration of the trial | 
| Time to treatment failure (Phase III) |  | Total duration of the trial | 
| Incidence of grade 3-4 toxicities (Phase III) |  | Total duration of the trial | 
| Quality of life as assessed by EORTC QLQ-C30 (version 3) and EORTC QLQ-OES18 (Phase III) |  | Total duration of the trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the esophagus, squamous cell carcinoma of the esophagus, stage IIA esophageal cancer, stage IIB esophageal cancer, stage IIIA esophageal cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer, stage IV esophageal cancer