The goal of this clinical research study is to learn if a combination of the investigational drug oxaliplatin with 5-Fluorouracil (5-FU) (given at the same time as radiation therapy) is as effective as a combination of these two drugs given before and during radiation therapy in the treatment of esophageal or gastroesophageal cancers. The safety of these combinations of therapy will also be compared.

Objectives:

Primary objective:

Compare the Pathologic Complete Response rate and % of patients with <50% residual cancer in the resected surgical specimen between Arms A and B.

Secondary objectives:

1. Compare 1-year and 3-year survival rates, median survival time, R0 resection rates, safety, and local plus systemic relapse rates between Arms A and B
2. Perform exploratory correlative studies on blood, adjacent normal and cancer tissue to assess predictive markers of response and outcome.
3. Evaluate the joint effects, including possible interactive effects, of proton-versus-photon therapy and treatment arm on overall survival, R0 resection rates, safety, and local plus systemic relapse rates.

Oxaliplatin and 5-FU are chemotherapy drugs that are commonly used to treat certain kinds of cancers. 5-FU is designed to prevent cells from making DNA that is necessary for cell growth. This disrupts the growth of the cancer cells, which causes the cancer cells to start to die. Oxaliplatin is designed to damage DNA that is already formed.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to one of two groups. Participants in the first group (Arm A) will receive chemotherapy with radiation treatment. Participants in the second group (Arm B) will receive chemotherapy first then chemotherapy with radiation treatment. The chemotherapy that will be used in this study includes 5-FU and oxaliplatin. Arm B is 8 weeks longer than Arm A. Your doctor will discuss with you whether you will receive proton or photon radiation. If you receive proton radiation, it will be given in a building that is about a 5 minute drive from the main MD Anderson radiation clinic.

All participants will have had a routine upper gastrointestinal tract endoscopy and biopsy with endoscopic ultrasound examination before receiving treatment on this study. However, once you start on this study, the upper gastrointestinal tract endoscopy will be repeated before the 2nd cycle of induction chemotherapy Arm B (if needed), before chemoradiation, and before surgery. This procedure involves examination of the esophagus, stomach, and duodenum by a flexible tube. Biopsies will be taken as necessary.

Arm A:

If you are assigned to Arm A, you will receive treatment with 5-FU over 24 hours for 5 days each week for 5 weeks. It will be given as an infusion into a vein using a portable pump. This will start on Day 1 (Monday) and will continue until Day 5 (Friday) of each radiotherapy week for 5 weeks. You will need to carry this pump with you for about 96 hours. The pump is about the size of a personal compact disc player. You will also receive oxaliplatin as an infusion into a vein over 2 hours on Day 1. This will be repeated on Days 8, 15, 22, and 29. During this time you will receive radiation therapy every weekday for 5 weeks.

If the cancer gets worse or you experience intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

Each week while you are receiving chemoradiotherapy, around 1 tablespoon of blood will be drawn for routine tests. Between 5-6 weeks after the completion of chemoradiotherapy, the stage of the cancer will be evaluated. This includes drawing blood (about 1 tablespoon) for routine tests, an Electrocardiography (ECG), a Physical Fitness Testing (PFT), a computed tomography (CT) of the abdomen and chest (when necessary), a Positron emission tomography (PET) or PET/CT scan, and an upper GI endoscopy with biopsies and checking the status of your abdominal disease (if necessary).

When the evaluation of the status of your disease is complete, surgical removal of the primary tumor and lymph nodes will be attempted. All participants with no spreading disease, who are physically able to have surgery and have disease that is judged to be removable will be eligible for surgery. The tube (J-tube) will be left in your body for at least 8 weeks after the surgery to supplement your nutrition.

Arm B:

If you are assigned to Arm B, you will receive a starting (induction) course of chemotherapy before radiation therapy ever starts. You will receive 5-FU over 48 hours as an infusion into a vein using a portable pump. This will start on Day 1 and will continue over 48 hours. This will be repeated on Day 15 for another 48 hours. You will need to carry this pump with you at all times from Days 1-2 and Days 15-16. The pump is about the size of a personal compact disc player. You will also receive oxaliplatin as an infusion into a vein over 2 hours on Days 1 and 15.

One cycle is equal to 28 days, which includes 2 doses of 5-FU and oxaliplatin given on Day 1 and Day 15. Treatment is always followed by 12 days of recovery. You will receive a maximum of 2 cycles (4 doses of 5-FU and oxaliplatin).

After the first and second cycles, you will be given a full physical exam, upper GI x-rays if necessary, about 1 tablespoon of blood will be drawn for routine blood tests, and if needed, a CT scan of the abdomen and chest will be performed. You will have a PET scan or PET CT scan and upper GI endoscopy with biopsy (if needed) before the start of Cycle 2 and after the end of Cycle 2. If the disease has not gotten worse after the 1st cycle of induction chemotherapy, you will receive the 2nd cycle. An upper gastrointestinal tract endoscopy and biopsy will be performed. If the disease gets worse at any stage, you will go straight to chemoradiotherapy. If the disease starts to spread, you will be taken off study and your doctor will discuss other treatment options with you.

You will begin to receive chemoradiotherapy no more than 12 days after you complete the last dose of induction chemotherapy. You will receive treatment with 5-FU over 24 hours for 5 days each week for 5 weeks. It will be given as an infusion into a vein using a portable pump. This will start on Day 1 (Monday) and will continue until Day 5 (Friday) of each radiotherapy week for 5 weeks. You will need to carry this pump with you at all times for about 96 hours. You will also receive oxaliplatin as an infusion into a vein over 2 hours on Day 1. This will be repeated on Days 8, 15, 22, and 29. During this time you will receive radiation therapy every weekday for 5 weeks.

If the cancer gets worse or you experience intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

Each week while you are receiving chemoradiotherapy, around 1 tablespoon of blood will be drawn for routine tests. Between 5-6 weeks after the completion of chemoradiotherapy, the stage of the cancer will be evaluated. This includes drawing blood (about 1 tablespoon) for routine tests, an ECG, a PFT, a CT of the abdomen and chest (when necessary), a PET Scan or PET CT Scan, and an upper GI endoscopy with biopsies and checking the status of your abdominal disease (if necessary).

When the evaluation of the status of your disease is complete, surgical removal of the primary tumor and lymph nodes will be attempted. All participants with no spreading disease, who are physically able to have surgery and have disease that is judged to be removable will be eligible for surgery. The a tube (J-tube) will be left in your body for at least 8 weeks after the surgery to supplement your nutrition.

Arms A and B:

You will be asked to fill out side effect sheets throughout your participation in this research study. You will be asked questions regarding nausea, hair loss, fatigue, meals, and other questions regarding your daily activities. You will be asked to keep a daily calendar while receiving therapy of any type.

You will be asked to come for follow-up visits at MD Anderson at 3, 6, 9, and 12 months after surgery and then every 6 months for 2 years, and then once a year for 2 years. At these visits, you will have a full physical exam, and about 1 tablespoon of blood drawn for routine tests and a CEA test (carcinoembryonic antigen - a protein made by cancer and normal cells) if your CEA level was high in the past. You will also have a PET scan, PET CT scan, or CT of the chest and abdomen. You will have an upper GI endoscopy with biopsies 3 months after surgery and at other follow-up visits if needed. You may have a CT of the chest and abdomen at the 3 month visit if needed.

This is an investigational study. Oxaliplatin is an investigational drug and is not approved in the US for use in the treatment of esophageal and gastroesophageal cancer. The combination of these 2 drugs (oxaliplatin + 5-FU) is investigational. All procedures are standard of care. A total of up to 126 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Local regional carcinoma of the thoracic esophagus (squamous cell or adeno) or gastroesophageal junction.
2. Patients with T1N1, and T2-3 with any N (M1a only) will be eligible.
3. Normal liver (serum glutamic-pyruvic transaminase (SGPT) < 56µL, Total Bilirubin <1.5 mg/dL), kidney (Creatinine <1.75 mg/dL), and bone marrow functions (AGN >1,500µL, platelet count >100,000/µL).
4. Performance status 0 or 1.
5. Signed informed consent by the investigator or their designee and patient.
6. Medically fit for surgery.
7. No Celiac (except for the GE junction cancers), supraclavicular, or paraaortic nodal enlargement unless biopsy negative.
8. None of the celiac nodes should be larger than 2 cm
9. Male or Female but both sexes must practice adequate contraception while on therapy
10. >/=18 years but less than 76 years
11. No known allergy to any of the study drugs.
12. No prior therapy for this cancer.
13. No significant cancer (defined as non-melanomatous skin cancers and treated cervical cancers) within the past 5 years
14. New York Heart Association (NYHA) I and II

Exclusion Criteria:

1. Patients with T1N0, T4, or M1b cancer will be excluded
2. Significant comorbid conditions (defined as uncontrolled diabetes, active angina or heart failure, uncontrolled hypertension, or active psychiatric condition that prevents consistent participation and compliance).
3. More than grade 1 neuropathy
4. Unable to comprehend the requirements of the study or comply with it.