Fluorouracil, Cisplatin, Cetuximab, and Radiation Therapy in Treating Patients With Esophageal Cancer That Can Be Removed by Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as fluorouracil and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving fluorouracil and cisplatin together with cetuximab and radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of fluorouracil and cisplatin when given together with cetuximab and radiation therapy in treating patients with esophageal cancer that can be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the maximum tolerated dose of fluorouracil and cisplatin when administered with cetuximab concurrently with esophageal radiotherapy. (Phase I) To determine the complete histological response rate (after surgical resection). (Phase II) Secondary To determine progression-free survival and overall survival. (Phase II) To determine the rate of resection with negative margins (R0). (Phase II) To determine the overall tolerance to neoadjuvant therapy. (Phase II) To determine the postoperative morbidity and mortality. (Phase II) OUTLINE: This is a multicenter study. This is a dose-escalation study of cisplatin and fluorouracil. Patients receive cetuximab IV over 2 hours on day -7, then IV over 1 hour on days 1, 8, 15, 22, and 29. Patients also receive cisplatin IV over 1 hour on day 1 or 2 and fluorouracil IV continuously on days 1-4, 8-11, 15-18, 22-25, and 29-32. Patients undergo radiotherapy 5 days a week for 5 weeks, beginning on day 1 of chemotherapy. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo surgery within 6-8 weeks after completion of chemoradiotherapy. After completion of study therapy, patients are followed at 1 month, every 4 months for 2 years, and then every 6 months for 2 years.

Official Title
-----------------
Neoadjuvant Treatment for Operable Esophageal Cancer With 5-fluorouracil, Cisplatin, and Cetuximab and Concurrent Radiotherapy: Phase I/II Study

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Biological: cetuximab
* Drug: cisplatin
* Drug: fluorouracil
* Procedure: conventional surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Inclusion criteria: Histologically confirmed epidermoid or glandular carcinoma of the thoracic esophagus Invasive disease Only Siewert type I gastroesophageal carcinoma allowed Resectable disease T1N+, T2N0, T2N+, T3N0, or T3N+ (stage II or III) No visceral metastases or mediastinal extensions compromising resectability Exclusion criteria: Inoperable disease Invasion of the tracheo-bronchial tree Recurring esophageal paralysis Esopho-tracheal fistula Cervical esophageal carcinoma (< 19 cm above the dental arches) Multifocal esophageal carcinoma Superficial esophageal carcinoma (T1N0) Esophageal carcinoma in the lymph nodes that cannot be included in the radiotherapy field or cannot be completely surgically resected Proven metastatic disease PATIENT CHARACTERISTICS: Inclusion criteria: WHO performance status 0-1 Weight loss < 15% Absolute neutrophil count ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 Creatinine ≤ 1.25 times upper limit of normal PTT ≥ 80% Albumin ≥ 35 g/L FEV1 > 1 L Not pregnant or nursing Fertile patients of must use effective contraception Exclusion criteria: Known liver cirrhosis Renal insufficiency Respiratory insufficiency (i.e., severe dyspnea at rest or oxygen dependence) Progressive coronary insufficiency Myocardial infarction in the past 6 months Legally incapacitated Impossible to receive study therapy due to geographical, social, or psychological reasons Noncompliant within constraints of the study Hematologic malignancy or other cancer except carcinoma in situ of the uterine cervix, treated nonmelanoma skin cancer, or intramucous disease treated within the past 3 years PRIOR CONCURRENT THERAPY: Exclusion criteria: Prior anticancer chemotherapy or radiotherapy Treatment with endoprosthesis Surgery (esophagectomy) planned without thoracotomy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant chemoradiotherapy<br>Weekly cetuximab (400 mg/m2 one week before start of radiotherapy RT and 250 mg/m2 during radiotherapyRT), and 5 FU (500 mg/m2 per day D1-D4) combined with cisplatin CDDP (40 mg/m2 D1) on week 1 and 5 | Biological: cetuximab<br> <br> Drug: cisplatin<br> <br> Drug: fluorouracil<br> <br> Procedure: conventional surgery<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete histologic response |  | After Surgery | 
| Tolerance to neoadjuvant therapy |  | From Inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free and overall survival |  | From inclusion | 
| Mortality |  | From Inclusion | 

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