Radiation Therapy and Chemotherapy Before and After Surgery in Treating Patients With Esophageal Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy before and after surgery may kill more tumor cells. PURPOSE: Randomized phase II trial to compare the effectiveness of combining radiation therapy with two different chemotherapy regimens before and after surgery in treating patients who have esophageal cancer.

Detailed Description
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OBJECTIVES: Compare the pathologic complete response rate in patients with adenocarcinoma of the esophagus or gastroesophageal junction treated with radiotherapy with pre- and post-operative cisplatin plus paclitaxel versus cisplatin plus irinotecan. Compare the survival outcome in patients treated with these regimens. Compare the toxicity of these regimens in these patients. Compare the tolerability of these adjuvant chemotherapy regimens after neoadjuvant chemoradiotherapy in these patients. Compare time to progression or recurrence in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs. 1) and stage of disease (T2-3, N0, M0 vs. T1-3, N0-1, M0 or M1A). Patients are randomized to 1 of 2 treatment arms. Arm A: Patients receive neoadjuvant radiotherapy once daily, 5 days a week, for 5 weeks beginning on day 1 concurrently with neoadjuvant chemotherapy comprising cisplatin IV (Intravenous) over 2-3 hours followed by irinotecan IV over 30-60 minutes once daily on days 1, 8, 22, and 29. Four to six weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgical resection. A minimum of 4 weeks after resection, patients receive adjuvant chemotherapy comprising cisplatin and irinotecan as above on days 1 and 8. Treatment with adjuvant chemotherapy repeats every 3 weeks for 3 courses. Arm B: Patients receive neoadjuvant radiotherapy as in arm A concurrently with neoadjuvant chemotherapy comprising paclitaxel IV (Intravenous) over 1 hour followed by cisplatin IV over 2-3 hours once daily on days 1, 8, 15, 22, and 29. Patients then undergo surgical resection as in arm A. A minimum of 4 weeks after resection, patients receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours followed by cisplatin as above on day 1. Treatment with adjuvant chemotherapy repeats every 3 weeks for 3 courses. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed at 1 month, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years. ACCRUAL: A total of 97 patients (50 on Arm A and 47 on Arm B) were accrued for this study.

Official Title
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Randomized Phase II Study of Preoperative Combined Modality Paclitaxel / Cisplatin / RT or Irinotecan / Cisplatin / RT Followed by Postoperative Chemotherapy With the Same Agents in Operable Adenocarcinoma of the Esophagus

Conditions
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Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: irinotecan hydrochloride
* Drug: paclitaxel
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed adenocarcinoma of the esophagus (20 cm below incisors) or gastroesophageal junction Stage T2-3, N0, M0 OR Stage T1-3, N0-1, M0 or M1A (celiac nodal metastasis) Tumor must be considered surgically resectable (T1-3, but not T4) Age>=18 years ECOG Performance status 0-1 Adequate hematopoietic, hepatic, renal functions defined by the following within 4 weeks prior to randomization: Granulocyte count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min Prior curatively treated malignancy allowed if currently disease-free and survival prognosis is more than 5 years Fertile patients must use effective contraception Endoscopy with biopsy and dilation allowed Exclusion Criteria: Tumor extends more than 2 cm into the cardia Pregnant or nursing Other concurrent illness that would preclude study therapy or surgical resection Concurrent filgrastim (G-CSF) during study radiotherapy Prior chemotherapy Prior radiotherapy Prior surgery

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: Cisplatin / Irinotecan / Radiation therapy (Arm A)<br>Days 1 - 35 : Concurrent radiation therapy (RT) and Cisplatin / Irinotecan Chemotherapy. Radiotherapy 45 Gy administered at 1.8 Gy per day, 5 days a week for 5 weeks. Cisplatin 30 mg/m² days 1, 8, 22, 29. Irinotecan 65 mg/m² days 1, 8, 22, 29. Chemotherapy should begin within 24 hours of start of radiotherapy Days 63 - 77 : Surgical Resection At least 28 days after surgical resection, begin adjuvant chemotherapy: cisplatin 30 mg/m² and irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles | Drug: cisplatin<br>* Days 1 - 35 : Cisplatin 30 mg/m² days 1, 8, 15, 22, 29 Days 63 - 77 : cisplatin 30 mg/m² and irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles<br>* Other names: NSC 119875;Drug: irinotecan hydrochloride<br>* Days 1 - 35 : Irinotecan 65 mg/m² days 1, 8, 22, 29 Days 63 - 77 : irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles<br>* Other names: Camptosar;Procedure: conventional surgery<br>* The type of resection (lvor-Lewis, Transhiatal, etc.) was left to the discretion of the operating surgeon. One lymph node dissection was required.<br>Radiation: radiation therapy<br>* The total dose to the prescription point was 4500 cGy given in 25 fractions. The patient was treated with one fraction per day with all fields treated per day. 180 cGy was delivered to the isocenter. If the dose to the supraclavicular fossa (SCF) was less than 4500 cGy, a localized photon or electron boost was allowed in order to increase the SCF dose to 4500 cGy, specified at 3 cm depth from the anterior skin surface.<br>|
| Experimental: Paclitaxel / Cisplatin / Radiation therapy (Arm B)<br>Days 1 - 35 : Concurrent radiation therapy (RT) and Paclitaxel/Cisplatin Chemotherapy. Radiotherapy 45 Gy administered at 1.8 Gy per day, 5 days a week for 5 weeks. Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29. Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Chemotherapy should begin within 24 hours of start of radiotherapy. Days 63 - 77 : Surgical Resection At least 28 days after surgical resection, begin adjuvant chemotherapy: paclitaxel 175 mg/m² and cisplatin 75 mg/m² day 1 of three 3-week cycles. | Drug: cisplatin<br>* Days 1 - 35 : Cisplatin 30 mg/m² days 1, 8, 15, 22, 29 Days 63 - 77 : cisplatin 30 mg/m² and irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles<br>* Other names: NSC 119875;Drug: paclitaxel<br>* Days 1 - 35 : Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29 Days 63 - 77 : paclitaxel 175 mg/m² and cisplatin 75 mg/m² day 1 of three 3-week cycles<br>* Other names: NSC 125973;Procedure: conventional surgery<br>* The type of resection (lvor-Lewis, Transhiatal, etc.) was left to the discretion of the operating surgeon. One lymph node dissection was required.<br>Radiation: radiation therapy<br>* The total dose to the prescription point was 4500 cGy given in 25 fractions. The patient was treated with one fraction per day with all fields treated per day. 180 cGy was delivered to the isocenter. If the dose to the supraclavicular fossa (SCF) was less than 4500 cGy, a localized photon or electron boost was allowed in order to increase the SCF dose to 4500 cGy, specified at 3 cm depth from the anterior skin surface.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate | A patient would have achieved a pathologic complete response if no histopathological evidence of residual tumor is found in the resected esophageal specimen and nodal tissue. | approximately 1 month after completing all treatments, then every 3 months up to 2 years, every 6 months from 2-5 years of study entry and annually 6-10 years from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | Survival was measured from the date of randomization onto study to death from any cause.Patients who were still alive at the end of the study were censored at the last date of known alive. Median survival time was calculated in the 81 eligible and treated patients. | Approximately 1 month after completing all treatments, then every 3 months up to 2 years, every 6 months from 2-5 years of study entry and annually 6-10 years from study entry | 
| Recurrence-free Survival Time | Recurrence-free survival is measured from the date of complete response to recurrence of the cancer. Patients without recurrence were censored at the last date of known recurrence-free. Median recurrence-free survival time was calculated in the eligible and treated patients. | Approximately 1 month after completing all treatments, then every 3 months up to 2 years, every 6 months from 2-5 years of study entry and annually 6-10 years from study entry | 

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