Radiotherapy,Chemotherapy,Before and After Surgery in Advanced Esophageal or Gastroesophageal Junction 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 cisplatin and fluorouracil, 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) may kill more tumor cells. Cisplatin and fluorouracil may also make tumor cells more sensitive to radiation therapy. Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving radiation therapy together with combination therapy and gefitinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving radiation therapy together with combination chemotherapy and gefitinib before and after surgery works in treating patients with advanced esophageal or gastroesophageal junction cancer.

Detailed Description
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OBJECTIVES: Primary Determine the activity of gefitinib, in terms of median survival and distant metastatic disease control, in patients treated with neoadjuvant and adjuvant cisplatin, fluorouracil, and radiotherapy who are undergoing surgery for esophageal and gastroesophageal junction cancer. Secondary Determine the pathologic complete and partial response rate in patients treated with this regimen. Determine the toxicity of this regimen in these patients and in patients who are disease free and receiving long-term maintenance gefitinib. OUTLINE: Preoperative regimen: Patients undergo radiotherapy twice a day during days 1-12 (for a total of 10 treatment days). Patients receive fluorouracil IV continuously and cisplatin IV continuously on days 1-4. Patients also receive oral gefitinib once daily on days 1-28. At 6 weeks, patients with locoregionally confined disease undergo surgical resection and then proceed to the postoperative regimen. Patients with a medical contraindication to surgery proceed directly to the postoperative regimen. Postoperative regimen: Beginning 4-10 weeks after surgery or 6 weeks after completing the first course of therapy, patients undergo radiotherapy and receive fluorouracil and cisplatin as in the preoperative regimen. Maintenance regimen: Patients receive oral gefitinib beginning on day 1 of the postoperative regimen and continuing for 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.

Official Title
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A Phase II Trial of Pre- and Postoperative Chemoradiotherapy and ZD1839 (IRESSA) Followed by Maintenance ZD1839 in Patients With Locoregionally Advanced Esophageal and Gastroesophageal Junction Carcinoma

Conditions
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Esophageal Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed squamous cell carcinoma, adenocarcinoma, or large cell undifferentiated cancer of the esophagus or gastroesophageal junction T3, N1, or M1a disease only The following types are not allowed: Small cell undifferentiated carcinomas, lymphomas, or sarcomas Small cell or mixed small cell/non-small cell histology No evidence of distant hematogenous tumor metastases (M1b) No malignant pleural effusions PATIENT CHARACTERISTICS: Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic WBC > 3,500/mm^3 Platelet count > 100,000/mm^3 Hepatic Alkaline phosphatase < 2 times normal AST < 2 times normal No unstable or uncompensated hepatic disease Renal Creatinine ≤ 2.0 mg/dL Calcium normal No unstable or uncompensated renal disease Cardiovascular No unstable or uncontrolled angina No unstable or uncompensated cardiac disease Pulmonary See Disease Characteristics No limitations to pulmonary function that would preclude study participation No evidence of clinically active interstitial lung disease (asymptomatic patients with chronic stable radiographic changes are allowed) No unstable or uncompensated respiratory disease Other Not pregnant or nursing Fertile patients must use effective contraception No evidence of severe or uncontrolled systemic disease No other uncontrolled malignancy No active infection No known severe hypersensitivity to gefitinib or any of its excipients PRIOR CONCURRENT THERAPY: Biologic therapy No prior immunotherapy for this cancer Chemotherapy No prior chemotherapy for this cancer Radiotherapy No prior radiotherapy for this cancer Surgery Recovered from any prior oncologic or other major surgery No prior surgical resection for this cancer No concurrent ophthalmic surgery Other No prior photodynamic therapy for this cancer (prior laser treatments are acceptable) More than 30 days since prior unapproved or investigational drug No concurrent phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, or Hypericum perforatum (St. John's wort)

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cisplatin|20mg/m2d/IV continuous infusion x days|
|Drug: fluorouracil|1000mg/m2/d IV continuous infusion x 4 days|
|Drug: Iressa|250mg po qd days 1-28 then x 2 years|
|Procedure: conventional surgery|conventional surgery|
|Radiation: radiation therapy|150 cGy bid|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at 1 year | Survival at 1 year | 1 year | 
| Distant metastatic control at 1 year | Distant metastatic control at 1 year | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate at 6 weeks | Response rate at 6 weeks | 6 weeks | 
| Toxicity of induction chemoradiotherapy and gefitinib as measured by CTC version 2.0 at 6 weeks | Toxicity of induction chemoradiotherapy and gefitinib as measured by CTC version 2.0 at 6 weeks | 6 weeks | 
| Toxicity of maintenance gefitinib as measured by CTC version 2.0 every 8 weeks after the completion of radiotherapy | Toxicity of maintenance gefitinib as measured by CTC version 2.0 | 8 weeks | 

 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 II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer