Chemotherapy, Surgery, and Radiation Therapy in Treating Patients With Gastric Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy, radiation therapy, and surgery may kill more tumor cells. E7296 was conducted to study neoadjuvant chemotherapy and postoperative chemoradiation therapy in patients diagnosed with high-risk gastric cancer using a new neoadjuvant regimen: paclitaxel plus cisplatin. It was hypothesized that this new neoadjuvant chemotherapy followed by surgery and chemoradiation therapy would be well tolerated and would have a high curative resection rate.

Detailed Description
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OBJECTIVES: Primary objective: To evaluate the tolerability and toxicity of neoadjuvant cisplatin plus paclitaxel and postoperative chemoradiation therapy with fluorouracil plus leucovorin calcium in patients with high-risk gastric cancer. Secondary objectives: To assess the pathologic response of gastric tumors to neoadjuvant cisplatin plus paclitaxel chemotherapy, and preliminarily assess the patterns of failure and disease free and overall survival. OUTLINE: Patients receive 3 courses of preoperative neoadjuvant chemotherapy given on day 1 every 21 days. Courses consist of an intravenous infusion of cisplatin and a 3 hour intravenous infusion of paclitaxel on day 1. Patients then undergo surgery for tumor removal on day 63, followed 4-6 weeks later by one course of daily intravenous bolus leucovorin calcium and fluorouracil for 5 days. Chemotherapy is repeated 4-6 weeks later for the first 4 days of week 1 and the last 3 days of week 5 of radiation therapy given 5 days a week for 5 weeks. Patients receive two more courses, 4 weeks apart, of fluorouracil and leucovorin calcium for 5 days 4-6 weeks after completing radiation treatment. Patients are followed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter. PROJECTED ACCRUAL: Approximately 30-42 patients will be accrued over 18 months.

Official Title
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A Phase II Trial of Neoadjuvant Paclitaxel - Cisplatin Chemotherapy, Surgery and Adjuvant Radiation Therapy and 5-FU/Leucovorin for Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: paclitaxel
* Procedure: surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction Localized cancer that is potentially curable by surgery (T2, N1-2, M0 or T3-4, any N, M0) No metastatic cancer to the ovaries Age: 18 and over Easter Cooperative Oncology Group (ECOG) performance status 0-2 White blood cell (WBC) count at least 4,000 cells/mm3 Platelet count at least 150,000/mm3 Bilirubin less than 2 mg/dL Creatinine no greater than 1.5 mg/dL Creatinine clearance greater than 50 mL/min Caloric intake must be at least 1500 kcal/day No prior history of cancer within the past 5 years except for basal cell carcinoma of the skin or in situ carcinoma of the cervix No prior radiation therapy, except for skin cancer Fertile patients must use adequate contraception Met criteria for re-registration after surgery T1N1-2M0, T2N1-2M0 or T3-4NanyM0 at time of initial re-registration. No evidence of metastatic disease from postoperative pathologic staging. ECOG performance status of 0, 1, or 2 at re-registration Curative resection performed Re-registered 4 - 6 weeks from the date of surgery WBC ≥ 4000 cells/mm³, platelets ≥ 150,000/mm³, creatinine ≤ 1.5 mg/dl or creatinine clearance of > 50 ml/min (measured or calculated) and total serum bilirubin < 2 mg/dl, all within four weeks prior to re-registration Exclusion Criteria: Prior chemotherapy Clinically significant auditory impairment Significant heart disease Pregnant or lactating

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Patients receive 3 courses of preoperative neoadjuvant chemotherapy given on day 1 every 21 days. Courses consist of an intravenous infusion of cisplatin and a 3 hour intravenous infusion of paclitaxel on day 1. Patients then undergo surgery for tumor removal on day 63, followed 4-6 weeks later by one course of daily intravenous bolus leucovorin calcium and fluorouracil for 5 days. Chemotherapy is repeated 4-6 weeks later for the first 4 days of week 1 and the last 3 days of week 5 of radiation therapy given 5 days a week for 5 weeks. Patients receive two more courses, 4 weeks apart, of fluorouracil and leucovorin calcium for 5 days 4-6 weeks after completing radiation treatment. | Drug: cisplatin<br>* Cisplatin was administered as part of the neoadjuvant regimen. It was given at a dose of 75 mg/m² via IV over approximately one hour, on day 1 of each cycle. Three cycles were given.<br>* Other names: DDP;Drug: fluorouracil<br>* Postoperative regimen 5-FU, along with Leucovorin, was given by IV bolus, with 5-FU given immediately after the Leucovorin<br>* Other names: Efudex;Drug: leucovorin calcium<br>* Both 5-FU and Leucovorin will be given via IV bolus, with Leucovorin given immediately before 5-FU.<br>* Other names: LCV;Drug: paclitaxel<br>* Paclitaxel was administered as part of the neoadjuvant regimen. It was given at a dose of 175 mg/m² as a 3 hour continuous intravenous infusion on day 1. Three cycles were given.<br>* Other names: NSC 125973;Procedure: surgery<br>* The surgical procedure performed involved a radical subtotal or total gastrectomy. A complete surgical resection was required<br>Radiation: radiation therapy<br>* Concomitant chemotherapy and radiation therapy course: 5-FU 400 mg/m²/day + Leucovorin 20 mg/m²/day on days 1-4 of week one and days 1-3 of week 5 of XRT. Combined chemotherapy and radiation therapy were to begin 4 weeks after day 1 of the initial course of chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or Higher Toxicity Incidence on Step 1 | Incidence is defined as proportion of patients with any grade 3 or higher treatment-related toxicities among all treated patients. | assessed at the end of every cycle (cycle=21 days) during treatment (3 cycles in total) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Confirmed Response to Neoadjuvant Therapy | Response was based on pathology at surgery. A patient achieved complete response if no gross or microscopic tumor were identified with the surgical specimen and nodal tissue. Stable response was defined as a response that did not qualify as complete response or progressive disease (PD), where PD indicated metastatic spread. Best confirmed response rate was defined as the proportion of patients with complete response (CR). A patient was considered unevaluable if the patient did not have surgery, the pathologist did not examine at least 15 lymph nodes, or the pathology report was unavailable. | Assessed at surgery time (surgery performed during week 8-10 after registration to the study) | 
| Overall Survival | Overall survival was defined as the time from registration to death, where a subject was censored on date of last record alive. | assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10 | 
| Progression Free Survival | Progression-free survival (PFS) was defined as time from registration until progression, recurrence, or death, whichever occurred first. If date of death occurred beyond three months from the date of last disease assessment, then PFS was censored at date of last disease assessment. Patients who were alive and progression-free were censored at the date of last disease evaluation. | assessed every month for the first 3 months, every 3 months for the next 21 months, every 6 months for the next year, and annually thereafter up to year 10 | 

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