Docetaxel, Oxaliplatin, Capecitabine, Fluorouracil, and Radiation Therapy in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction

Study Overview
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Brief Summary
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This randomized phase II trial studies how well docetaxel, oxaliplatin, capecitabine, fluorouracil, and radiation therapy works compared with fluorouracil when given together with oxaliplatin and radiation therapy in treating patients with cancer of the esophagus or gastroesophageal junction that has spread from where it started to nearby tissue or lymph nodes. Drugs used in chemotherapy, such as docetaxel, oxaliplatin, capecitabine, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving more than one drug (combination chemotherapy) together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess and compare the pathologic complete response (PCR) rate of patients in Arm A receiving the sequence docetaxel, oxaliplatin, and capecitabine (DOC) followed by 5-fluorouracil (5-FU), oxaliplatin, and radiation therapy (RT) with patients in Arm B receiving only 5-FU, oxaliplatin and RT in patients with potentially resectable adenocarcinoma (ACA) of the esophagus, gastroesophageal junction (GEJ), or gastric cardia. SECONDARY OBJECTIVES: I. To assess the adverse event (AE) profile and safety of the proposed treatment in this population. II. To assess and compare the overall survival (OS) between treatment arms. III. To assess and compare the disease-free survival between treatment arms. IV. To assess and compare the clinical tumor response rate of the proposed regiments when administered before surgery between treatment arms. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive docetaxel intravenously (IV) over 1 hour and oxaliplatin IV over 2 hours on day 1. Patients also receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of the second course, patients receive fluorouracil* IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy** 5 days a week for 5.5 weeks in the absence of disease progression or unacceptable toxicity. Approximately 4-12 weeks after completion of radiotherapy, patients undergo surgery. ARM II: Patients receive fluorouracil IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy and then surgery as in Arm I. NOTE: * Fluorouracil continuous IV infusion begins within 24 hours of radiotherapy and ends within 24 hours of radiotherapy completion. NOTE: ** Radiotherapy should begin within 2-6 weeks after completion of 2 courses of docetaxel, oxaliplatin, and capecitabine. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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Randomized Phase II Trial of Extended Neoadjuvant Therapy for Locally Advanced Adenocarcinoma of the Esophagus, Gastroesophageal Junction, and Gastric Cardia

Conditions
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Esophageal Cancer, Adenocarcinoma of the Gastroesophageal Junction, Gastric Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: docetaxel
* Drug: fluorouracil
* Drug: oxaliplatin
* Radiation: radiation therapy
* Procedure: therapeutic conventional surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histological confirmation of adenocarcinoma of the esophagus, gastroesophageal (GE) junction, or gastric cardia Tumor must be considered surgically resectable; Note: patients with T4N0M0 tumors that are potentially resectable are also eligible Nodal involvement: patients with involvement of celiac nodes, (stations 15-20) are eligible if the primary lesion is mid-thoracic, distal esophagus or GE junction; patients with supraclavicular node involvement are eligible with upper thoracic esophagus primary lesions Capable of swallowing pills Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Absolute neutrophil count (ANC) >= 1500 Peripheral platelet count >= 100,000 Hemoglobin >= 9.0 g/dL Total bilirubin =< 1.5 x upper normal limit (UNL) Serum glutamic oxaloacetic transaminase (SGOT) (alanine aminotransferase [AST]) =< 3 x UNL Creatinine =< 1.5 x UNL Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Provide informed written consent Willingness to return to NCCTG enrolling institution for follow-up Patient willing to provide mandatory tissue and blood samples for research purposes Patient willing to allow use of FDG PET/CT scans for mandatory research purposes Exclusion Criteria Evidence of distant metastases Palpable supraclavicular nodes, biopsy-proven involvement of supraclavicular nodes, or radiographically involved supraclavicular nodes (> 1.5 cm in greatest dimension) for lesions in mid-thoracic, distal thoracic or GE junction T1N0M0 or T2N0M0 tumor stage Any of the following Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Uncontrolled diabetes (i.e., will interfere with the performance of the FDG PET/CT scans) Receiving current treatment or prior treatment for this malignancy Other active malignancy 5 years prior to registration, except non-melanotic skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient must not be receiving other specific treatment (other than hormonal therapy) for cancer Prior radiation to > 30% of the marrow cavity

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: Arm I (combination chemotherapy, radiation therapy, surgery)<br>Patients receive docetaxel IV over 1 hour and oxaliplatin IV over 2 hours on day 1. Patients also receive capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of the second course, patients receive fluorouracil IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy 5 days a week for 5.5 weeks in the absence of disease progression or unacceptable toxicity. Approximately 4-12 weeks after completion of radiotherapy, patients undergo surgery. | Drug: capecitabine<br>* Given PO<br>Drug: docetaxel<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>Radiation: radiation therapy<br>* Undergo radiation therapy<br>Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>|
| Active Comparator: Arm II (oxaliplatin, fluorouracil, radiation, and surgery)<br>Patients receive fluorouracil IV continuously on days 1-5 and oxaliplatin IV over 2 hours on days 1, 15, and 29. Patients also undergo radiotherapy and then surgery as in Arm I. | Drug: fluorouracil<br>* Given IV<br>Drug: oxaliplatin<br>* Given IV<br>Radiation: radiation therapy<br>* Undergo radiation therapy<br>Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathologic Complete Response (PCR) | Pathologic complete response was defined as no gross or microscopic tumor identified with the surgical specimen. All lymph nodes should be free of tumor to document a PCR. If no gross tumor is visible, section around the area of inflammation (nodularity) should be made every 2-3 cm and specimens examined. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization to the time of death from any cause. Overall survival was censored at the date of last follow-up visit for patients who are still alive or loss of follow-up. | Up to 2 years | 
| Disease-free Survival | Disease-free survival was defined as the time from randomization to the date of recurrent or death, whichever comes first. | Up to 2 years | 
| Number of Participants Who Experienced a Maximum Grade of 3 or Above Adverse Event | Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | Up to 2 years | 
| Percentage of Participants With Overall Clinical Tumor Response (CR or PR) | Overall clinical tumor response rate was defined as the percentage of evaluable participants who achieved either complete response (CR) or partial response (PR) noted on the objective status from pre-surgical staging (for arm II) or either from pre-RT or pre-surgical staging (for arm I).> CR was defined as disappearance of all non-target lesion (TL) and normalization of tumor biomarker level, all lymph nodes (LN) must be non-pathological in size (<1 cm short axis); or disappearance of all TL and normalization of tumor biomarkers, any pathological LN (whether target or non-target) must have reduction in short axis to <1 cm; or >=30% decrease in the sum of the diameters of TL taking as reference the baseline sum of the diameters. | Up to 2 years | 

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