This is a prospective observational study designed to observe the toxicity and efficacy of PBS proton RT for patients with esophageal cancer undergoing trimodality therapy. The investigators hypothesize that PBS proton RT will be associated with a favorable adverse event profile and quality of life, with similar disease control outcomes, relative to historical comparisons of patients treated with photon RT.

Inclusion Criteria:

• Age ≥ 18 years.
• Histological confirmation of adenocarcinoma or squamous cell carcinoma of the esophagus (mid, distal, or GE junction)
• Stage T1N1-3M0 or T2-4N0-3M0 by American Joint Commission on Cancer (AJCC) 7th edition
• Tumor extends ≤ 5 cm into gastric cardia, based on EGD and PET/CT
• ECOG Performance Status (PS) 0-2 (Appendix I)
• Surgical consultation to confirm that patient is an appropriate candidate for esophagectomy
• Medical oncology consultation to confirm that patient is an appropriate candidate for chemotherapy
• Planned to receive standard of care neoadjuvant CRT, consisting of PBS proton RT (50 Gy/25 fractions) and concurrent chemotherapy (weekly carboplatin and paclitaxel), followed by surgical resection
• Ability to complete questionnaire(s) by themselves or with assistance.
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Note: During the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up.

• Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB number 15-000136

Exclusion Criteria:

• Cervical or upper esophageal tumors with any part of tumor < 24 cm from incisors
• Prior chemotherapy or RT for esophageal cancer
• History of RT to the thorax
• 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 adverse events.
• Immunocompromised patients and patients known to be HIV positive and not currently receiving antiretroviral therapy. NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• 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.
• Receiving any investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 1 year prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
• History of myocardial infarction ≤6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.

Adult patients with non-metastatic esophageal cancer who are candidates for neoadjuvant chemoradiotherapy followed by surgery