The goal of this clinical research study is to learn how safe and effective proton-beam therapy (PBT) may be in comparison to intensity modulated radiation therapy (IMRT) in combination with chemotherapy in patients with esophageal cancer.

PBT and IMRT are both forms of radiation therapy that are designed to treat a specific area of the body while affecting as little of the surrounding normal tissue as possible. PBT is a newer technology that is designed to further reduce the amount of radiation that affects the surrounding normal tissue. However, this is still being studied.

Study Treatment:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups:

• If you are in Group 1, you will receive IMRT.
• If you are in Group 2, you will receive PBT.

You will receive radiation therapy 1 time each day, 5 days a week (Monday through Friday) for up to 28 treatments.

Your doctor may think it is in your best interest to also receive chemotherapy while you are receiving radiation therapy. If this occurs, you will sign a separate consent form for these drugs with a full description of how they are given and the risks they may cause.

Study Visits:

Before you begin receiving radiation therapy, you will have a baseline visit. The following tests and procedures will be performed:

• Blood (about 1-2 tablespoons) will be drawn for routine tests.
• Your performance status will be recorded.
• You will have a PET/CT or CT scan to check the status of the disease.
• You will have lung function tests
• You will complete the symptom and quality of life questionnaires.
• Your esophagus will be examined using an endoscope. If the doctor thinks it is needed, you will have a biopsy to check the status of the disease.

You will then have a study visit every week while you are receiving radiation therapy. The following tests and procedures will be performed:

• Your medical history will be recorded.
• You will have a physical exam.
• Your performance status, weight, and vital signs will be recorded.
• Blood (about 1-2 tablespoons) will be drawn for routine tests.
• You will complete the symptom and quality of life questionnaires.

Length of Study:

You will receive radiation therapy for up to 28 treatments (about 5½ weeks). You will no longer be able to receive radiation therapy if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the follow-up visits.

Follow-Up:

After you stop receiving radiation therapy, there will be a 4-6 week break. During this time, you will contacted 2 times each week to complete the symptom and quality of life questionnaires. You will receive a call from an automated calling service or from the study staff at a scheduled time of your choosing. You will continue to be followed routinely during treatment and for follow-up visits and tests.

About 4-6 weeks after you stop receiving radiation therapy, the following tests and procedures will be performed:

• Your medical history will be recorded.
• You will have a physical exam.
• Your performance status, weight, and vital signs will be recorded.
• You will have a PET/CT scan to check the status of the disease.
• You will have lung function tests.
• Blood (about 1-2 tablespoons) will be drawn for routine tests.
• You will complete the symptom and quality of life questionnaires.
• Your esophagus will be examined using an endoscope. If the doctor thinks it is needed, you will have a biopsy to check the status of the disease.

If your doctor thinks it is in your best interest after you have completed radiation therapy, you will have surgery to remove the tumor. You will sign a separate consent form that describes the procedure and its risks. As part of this study, the study doctor will check you for side effects and discomfort after the surgery.

Every 3-4 months for 2 years, and then every 4-6 months for the next 3 years, you will have follow-up visits. The following tests and procedures will be performed:

• Your medical history will be recorded.
• You will have a physical exam.
• Your performance status, weight, and vital signs will be recorded.
• You will have either a CT or a PET/CT scan to check the status of the disease.
• You will complete the symptom and quality of life questionnaires. (If the disease gets worse, these questionnaires will no longer be completed.)

Additionally, the following tests and procedures will be performed at follow-up visits only when the doctor thinks they are needed:

• Blood (about 1-2 tablespoons) may be drawn for routine tests.
• You may have lung function tests.
• Your esophagus will be examined using an endoscope. If the doctor thinks it is needed, you will have a biopsy to check the status of the disease.

You may be contacted by the study staff to ask about your health, even if you choose not to return to MD Anderson for follow-up visits after completing treatment for esophageal cancer.

This is an investigational study. IMRT and PBT are delivered using FDA-approved and commercially available methods. It is investigational to compare IMRT to PBT.

Up to 180 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Age >/= 18
2. Histologically documented adenocarcinoma or squamous cell carcinoma of the cervical or thoracic esophagus or gastroesophageal junction or cardia of stomach.
3. Potentially resectable or unresectable esophageal cancer patients
4. Induction chemotherapy prior to concurrent chemoradiation allowed
5. Prior Endoscopic Mucosal Resection (EMR) with a diagnosis of stage II-III esophageal cancer is eligible
6. Performance status of Karnofsky Performance Scale (KPS) >/= 60 or Eastern Cooperative Oncology Group (ECOG) = 0, 1, or 2.
7. Prior thoracic radiation allowable only if there is minimal to no overlap with the treatment area estimated at the time of consultation.
8. Negative pregnancy test (serum or urine) for women of child bearing potential. All protocol participants must agree to adequate contraception.
9. Complete blood count (CBC) and complete metabolic panel (chemo-14: Glucose, Calcium, Albumin, Total Protein, Sodium, Potassium, Carbon Dioxide (CO2), Chloride, Blood Urea Nitrogen (BUN), Creatinine, Alkaline Phosphatase, Alanine Aminotransferase (ALT) Serum Glutamic Pyruvic Transaminase (SGPT), Aspartate Aminotransferase (AST) Serum Glutamic-oxaloacetic Transaminase (SGOT), and Bilirubin) to assess adequate hematologic, renal and hepatic functioning will be obtained. The values are as follows: Adequate hematologic (White Blood Count (WBC) >2,500/uL, platelets > 75,000/uL), renal (Serum creatinine </= 1.5X Upper Limit of Normal (ULN) or creatinine clearance > 50 mL/min), and liver function (bilirubin \