Radiation Therapy and Chemotherapy, With or Without Cetuximab, Followed by Surgery in Treating Patients With Locally Advanced Esophageal Cancer That Can Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays and to kill tumor cells. Drugs used in chemotherapy, such as docetaxel 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. It is not yet known whether giving radiation therapy together with chemotherapy is more effective with or without cetuximab in treating patients with esophageal cancer. PURPOSE: This randomized phase III trial is studying giving radiation therapy together with chemotherapy, with or without cetuximab, followed by surgery in treating patients with locally advanced esophageal cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To determine the efficacy of neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy in combination with cetuximab followed by surgery and adjuvant cetuximab versus neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy followed by surgery in patients with locally advanced esophageal carcinoma. Secondary To compare the toxicity of the two therapy arms. To determine patterns of failure overall and with regard to histology. To evaluate economic aspects in a subproject and to perform a radiotherapy quality assurance program. OUTLINE: This is a multicenter study. Patients are stratified according to center, histology (adenocarcinoma vs squamous cell carcinoma), primary tumor (T2 vs T3-4), and gender (male vs female). Patients are randomized to 1 of 2 treatment arms. Arm A: Induction chemotherapy (docetaxel and cisplatin) and concurrent cetuximab Patients receive docetaxel IV over 1 hour and cisplatin IV over 1 hour on day 1 and cetuximab IV over 1-2 hours on day 1, 8, and 15. Treatment repeats every 21 days for 2 courses. Chemotherapy (docetaxel and cisplatin), cetuximab, and concurrent radiotherapy Beginning in week 7, patients receive cetuximab IV over 1 hour, docetaxel IV over 30 minutes, cisplatin IV over 1 hour on days 43, 50, 57, 64, and 71 and undergo radiotherapy 5 days a week for 5 weeks. Patients then undergo surgery 4-7 weeks after completion of radiotherapy. Adjuvant cetuximab Beginning 3-6 weeks after completion of surgery, patients receive cetuximab IV over 1-2 hours once every 2 weeks for a total of 6 doses. Arm B: Patients receive induction chemotherapy comprising docetaxel IV and cisplatin IV for 2 courses as in arm A. Beginning in week 7, patients receive docetaxel IV, cisplatin IV, and concurrent radiotherapy for 5 weeks as in arm A. Patients then undergo surgery 4-7 weeks after completion of radiotherapy. After completion of study therapy, patients are followed up at 1 (arm B) or 6 (arm A) months, every 3 months for 3 years, and then every 6 months for 2 years.

Official Title
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Multimodal Therapy With and Without Cetuximab in Patients With Locally Advanced Esophageal Carcinoma - An Open-Label Phase III Trial

Conditions
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Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: cisplatin
* Drug: docetaxel
* Procedure: adjuvant therapy
* Procedure: neoadjuvant therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed esophageal carcinoma Meets the following criteria: Resectable, locally advanced disease as determined by the combination of CT scan, endoluminal ultrasound (EUS), PET scan, and a multidisciplinary team discussion T2, N1-3; T3, any N; or T4a, any N (if technically resectable with curative intent [R0] as decided by a multidisciplinary team discussion) EUS-guided fine-needle aspiration (FNA) allowed, but determines nodal status only if positive FNA No T1, any N, M0; or T2, N0, M0; T4a (due to infiltration of the trachea-bronchial tree or organ involvement that cannot be operated on with curative intent [R0] as decided by a multidisciplinary team discussion); T4b; or distant metastasis (M1) Type I or II disease according to the Siewert classification Squamous cell carcinoma (including basaloid-squamous cell and adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia) Patients with obstructive tumors are eligible (obstructive tumors will be considered as locally advanced tumors) No cervical esophageal carcinoma and tumors involving the first 5 cm of the thoracic esophagus No airway infiltration in case of tumors at or above the tracheal bifurcation No peritoneal carcinomatosis in case of adenocarcinomas infiltrating the gastric cardia (i.e., esophagogastric junction carcinoma Siewert type I or II) PATIENT CHARACTERISTICS: WHO performance status 0-1 Neutrophil count ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Creatinine clearance > 60 mL/min Bilirubin ≤ 1.0 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN AST ≤ 1.5 times ULN INR normal PTT ≤ 1.0 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 12 months after completion of study therapy FEV_1 ≥ 1.5 L OR ≥ 75% of the reference value Must be compliant and geographically proximal for staging and follow-up Considered operable (i.e., appropriate organ functions and ability to undergo general anesthesia) No other malignancies within the past 5 years except nonmelanomatous skin cancer or adequately treated carcinoma in situ of the cervix No severe or uncontrolled cardiovascular disease, including any of the following: NYHA class III-IV congestive heart failure Unstable angina pectoris Myocardial infarction within the past 12 months Significant arrhythmias No psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, and answering questionnaires No active uncontrolled infection No serious underlying medical condition that, in the opinion of the investigator, could impair the ability of the patient to participate in the trial (e.g., uncontrolled diabetes mellitus or active autoimmune disease) No preexisting peripheral neuropathy > grade 1 No definite contraindications for the use of corticosteroids and antihistamines as premedication No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy to the chest At least 30 days since prior treatment in another clinical trial No concurrent drugs contraindicated for use with the trial drugs No other concurrent anticancer treatments No other concurrent experimental drugs or investigational treatments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Additional immunotherapy (cetuximab)<br>All patients in the experimental arm will be given additional immunotherapy (cetuximab) during cycles 1 and 2, during RT and after surgery. | Biological: cetuximab<br>* Loading dose 400 mg/m2 2h infusion Weekly: 250 mg/m2 1h infusion<br>* Other names: Erbitux;Drug: cisplatin<br>* Cisplatin 75 mg/m2 1h infusion d1, 22 Cisplatin 25 mg/m2 1h infusion weekly x5<br>Drug: docetaxel<br>* Docetaxel 75 mg/m2 1h infusion d1, 22 Docetaxel 20 mg/m2 1/2h infusion weekly x5<br>* Other names: Taxotere or generic product;Procedure: adjuvant therapy<br>* During the adjuvant phase, all infusions, given every two weeks, will be at a dose of 500mg/m².<br>Procedure: neoadjuvant therapy<br>* During the neoadjuvant phase, the first infusion of cetuximab should be at a dose of 400 mg/m² administered over a period of 2 hours and all subsequent infusions, given weekly, should be of 250 mg/m² over a period of 1 hour, unless any infusion related reaction was observed at a previous infusion. (The maximum infusion rate is 10 mg/min, corresponding to 2 mL/min ready-to-use solution.<br>|
| Active Comparator: Without additional immunotherapy<br>Standard therapy without immunotherapy (cetuximab). | Drug: cisplatin<br>* Cisplatin 75 mg/m2 1h infusion d1, 22 Cisplatin 25 mg/m2 1h infusion weekly x5<br>Drug: docetaxel<br>* Docetaxel 75 mg/m2 1h infusion d1, 22 Docetaxel 20 mg/m2 1/2h infusion weekly x5<br>* Other names: Taxotere or generic product;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | time from randomization to one of the following events, whichever comes first: Tumor progression at any time (progression of primary tumor or local lymph nodes, appearance of new lesions) Recurrence at local, regional or distant site after surgery Death from any cause | time from randomization to a defined event. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival after surgery |  | from date of surgery to an event as defined in PFS. | 
| Adverse events according to CTCAE version 4.0 and major postoperative complications |  | during treatment and follow-up period. | 
| Pathological remission |  | Assessed according to the tumor regression model of Mandard | 
| Overall survival |  | time from trial randomization to the date of death from any cause | 
| Time to locoregional failure after R0 resection |  | from date of surgery to date of first documented loco-regional failure | 
| Time to systemic failure after R0 resection |  | from date of surgery to date of first documented systemic failure | 
| In-hospital mortality |  | occurring after surgery but while the patient remains in hospital | 
| Time to progression (TTP) |  | Time to progression is defined as time from randomization to one of the following events, whichever comes first: - Tumor progression at any time. - Recurrence at local, regional or distant site after surgery. - Death due to tumor | 

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