This is a prospective, randomized, open-label, two-arm phase 2 trial that will evaluate whether the use of Pulsed Low-Dose-Rate radiation technique, as compared to standard radiation, is associated with reduced rates of clinically significant esophagitis during and following chemoradiation.

PLDR radiation technique has been shown to kill cancer cells while limiting normal tissue toxicity. In PLDR, subjects receive the same total dose of radiation for each treatment, but the treatment is delivered in a series of low-dose pulses which are separated by timed pauses. Radiation given with this approach may be less toxic but appears to be equally effective. This trial will evaluate the PLDR technique in combination with standard chemotherapy as part of definitive or curative treatment for locally advanced esophageal cancer.

Inclusion Criteria:

A potential study subject who meets all of the following inclusion criteria is eligible to participate in the study.

1. Age ≥ 18 years.

2. Stage II-IVb adenocarcinoma of the esophagus (if IVb, oligometastatic only, felt to be eligible for definitive dose CRT treatment by treating physician).

3. Currently receiving or have received induction chemotherapy and planned for definitive dose chemoradiation (+/- esophagectomy).

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

5. Adequate hematologic function within 30 days prior to registration defined as follows:

   1. Absolute Neutrophil Count ≥ 1,500/mcg
   2. Hemoglobin ≥ 8 gm/dL
   3. Platelets ≥ 100,000/mcL.

6. Adequate renal function within 30 days prior to registration, defined as a creatinine clearance of ≥ 50 ml/min as calculated by the Cockcroft-Gault equation.

7. Adequate hepatic function within 30 days prior to registration, defined as total bilirubin ≤ 1.5 x ULN

   a. Note: patients with known Gilbert Syndrome can have a total bilirubin < 2.5 x upper limit of normal (ULN).

8. Female patients <65 years of age and of childbearing potential must have a negative serum/urine pregnancy test within 14 days prior to study entry. A female not of childbearing potential is one who has undergone a hysterectomy, bilateral oophorectomy, tubal ligation, or who has had no menses for 12 consecutive months.

9. Patients of reproductive potential must agree to use effective contraception for the duration of study treatment. Effective contraception includes oral contraceptives, implantable hormonal contraception, double-barrier method, or intrauterine device.

10. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

11. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

A potential study subject who meets any of the following exclusion criteria is ineligible to participate in the study.

1. Age < 18 years.

2. Extensive distant metastatic cancer, defined as >5 metastases.

3. Recurrent esophageal cancer.

   a. Note: prior or concurrent malignancies are allowed if they do not impact the study's primary endpoint (i.e., treatment-associated toxicity).

4. Prior non-approved chemotherapy for the treatment of cancer.

5. Prior radiotherapy to the region of the study cancer that would result in an overlap of radiation therapy fields.

6. Women must not be pregnant or breast-feeding.