Capecitabine, Oxaliplatin, and Radiation Therapy in Treating Patients With Esophageal or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying how well giving capecitabine and oxaliplatin together with radiation therapy works in treating patients with esophageal or gastroesophageal junction cancer.

Detailed Description
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OBJECTIVES: Primary Determine the pathologic complete response in patients with adenocarcinoma of the esophagus or gastroesophageal junction treated with neoadjuvant therapy comprising capecitabine, oxaliplatin, and radiotherapy. Secondary Determine the clinical response rate in patients treated with this regimen. Determine the recurrence rate, time to progression, and patterns of failure in patients treated with this regimen. Characterize the toxicity profile of this regimen in these patients. OUTLINE: Induction therapy: Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Combination chemoradiotherapy: Patients then receive oxaliplatin IV over 2 hours once weekly for 6 weeks. Patients also receive concurrent oral capecitabine twice daily and undergo radiotherapy once daily 5 days a week for 5½ weeks in the absence of disease progression or unacceptable toxicity. Surgery: Patients undergo surgical resection at 4-8 weeks after completion of chemoradiotherapy. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Phase II Study of Capecitabine and Oxaliplatin With Radiation for Esophageal and Gastroesophageal Junction Adenocarcinoma

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: Induction Therapy - Capecitabine
* Drug: Induction Therapy - Oxaliplatin
* Drug: Combination Therapy - Capecitabine
* Drug: Combination Therapy - Oxaliplatin
* Radiation: Combination Therapy - Radiation
* Procedure: Evaluation for response and surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction Stage I-IVA disease No distant metastatic disease (other than regional lymph nodes) No evidence of CNS metastases CNS metastases stable for > 3 months allowed PATIENT CHARACTERISTICS: ECOG performance status 0-2 Consuming ≥ 1,500 calories daily ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) SGOT ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No pre-existing neuropathy No prior unanticipated severe reaction to fluoropyrimidine therapy No known hypersensitivity to fluorouracil No known DPD deficiency No known hypersensitivity to any of the components of oxaliplatin No significant active infection or other severe complicated medical illness No clinically significant cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmias not well controlled with medication) No myocardial infarction within the past 12 months No history of uncontrolled seizures, CNS disorders, or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake No malabsorption syndrome No other active malignancy within the past 3 years except cervical carcinoma in situ or nonmelanoma skin cancer PRIOR CONCURRENT THERAPY: More than 4 weeks since prior participation in any investigational drug study No prior pelvic or thoracic radiotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Induction, Combination and surgery<br>Weeks 1-6: Capecitabine 1000mg/m2 twice daily Oxaliplatin 70mg/m2 on days 1 and 8 Weeks 7-12: Capecitabine 825 mg/m2 twice daily Oxaliplatin 50mg/m2 weekly Radiation 1.8 Gy Monday-Friday Evaluation for response and resection surgery | Drug: Induction Therapy - Capecitabine<br>* Two 21-day cycles will be given as induction. Capecitabine will be given at 1000 mg/m2 twice daily approximately 12 hours apart for 14 days, followed by seven days off.<br>Drug: Induction Therapy - Oxaliplatin<br>* Two 21-day cycles will be given as induction. Oxaliplatin will be given at 70 mg/m2 intravenously in 5% dextrose over two hours on days 1 and 8 of each cycle.<br>Drug: Combination Therapy - Capecitabine<br>* Two 21-day cycles will be given for combination therapy. Capecitabine will be given at 825 mg/m2 twice daily approximately 12 hours apart for five days (Monday through Friday) followed by two days off for 51/2 weeks.<br>Drug: Combination Therapy - Oxaliplatin<br>* Two 21-day cycles will be given. Oxaliplatin will be given at 50 mg/m2 intravenously in 5% dextrose over two hours on days 1, 8 and 15 of each cycle.<br>Radiation: Combination Therapy - Radiation<br>* 1.8 Gy daily Monday through Friday to a total of 50.4 Gy for 6 weeks during combination therapy.<br>Procedure: Evaluation for response and surgery<br>* Four to eight weeks following the completion of therapy subjects will undergo evaluation for response and surgical resection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Pathologic Complete Response | Pathologic response will be assessed semiquantitatively irrespective of lymph node status based on the estimated percentage of residual carcinoma in relation total carcinoma area, including amount of radiotherapy-induced tissue injury, in mural histologic sections. Pathologic response will be defined as: P0: 0% residual cancer P1: 1% to 50% residual cancer P2: more than 50% residual cancer | At time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate | Clinical response Rate will be expressed as the proportion of patients demonstrating a complete and/or partial response based on all evaluable patients treated.Clinical response will be evaluated according to Response Evaluation Criteria In Solid Tumors 1.0 (RECIST) . Complete Response (CR) is defined as the disappearance of all target lesions Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions,taking as reference the baseline sum LD | four to six weeks following completion of 4 cycles (1 cycle = 21days) of chemotherapy treatment and prior to surgery | 
| Recurrence Rate | Recurrence rate will be defined as disease recurrence, progressive disease or death. Patients will be followed for disease recurrence or death until the end of the study. | From the time of start of treatment until first documentation of disease recurrence, progression or death, whichever comes first until the end of the study, a maximum of 6 years and 7 months. | 
| Time to Progression | Time to Progression will be measured as time from the first day of therapy until death, disease progression or last contact. | From start of first treatment until time of first documentation of progression of disease or death, whichever comes first, until the study closes, up to a maximum of 6 years and 7 months. | 
| Patterns of Failure |  | At time of surgery | 
| Toxicity Profile | Toxicity will be assessed at the beginning of every cycle during chemotherapy for a total of 4 cycles (1 cycle =21 days) and then 30 days post last dose of chemotherapy. All toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Only incidents of AEs determined to be related to chemotherapy are recorded here. | During chemotherapy treatment and up to 30 days post-last dose of chemotherapy. | 
| Correlate Proteomic and Pharmacologic Characteristics With Prognosis and Response to Therapy. |  | At time of sugery | 

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