The goal of this clinical trial is to learn the safety of the addition of PULSAR radiation to standard of care chemotherapy and immunotherapy in people with esophageal and gastroesophageal junction cancer and to determine the safest dose of radiation that can be used.

Participants in this study will be undergoing clinically scheduled procedures. In addition to the standard of care visits and treatments, there will be additional visits and assessments with radiation.

Participants with resectable locally advanced esophageal or gastro-esophageal junction cancer will enroll to receive perioperative FLOT or FLOT(D) (standard of care) and will receive interdigitated neoadjuvant PULSAR delivered at one of three possible dose levels in four total fractions. Following completion of neoadjuvant portion of the study, patients will undergo re-evaluation for resectability and proceed to resection if it remains feasible. Following resection, patients will complete all planned curative intent therapy with four adjuvant cycles of FLOT or FLOT(D). Those who receive FLOT(D) will subsequently receive 10 cycles of adjuvant durvalumab monotherapy per standard of care1. All patients will enter follow-up on completion of FLOT chemotherapy.

Inclusion Criteria:

1. At least 18 years of age at date of enrollment. Both men and women and members of all races and ethnic groups will be included.

2. Willing and able to provide written informed consent.

3. Pathologic diagnosis of esophageal or gastroesophageal junction adenocarcinoma. GEJ cancer includes Siewart types 1 and 2 tumors. Siewart type 3 is also eligible as long as the patient is intended to be treated in the same way as for type 1 and 2 tumors (i.e. candidate for FLOT-(D), resectable, amenable to radiation)

4. T1N+ or T2-4N(any) by the American Joint Committee on Cancer staging manual 8th edition

5. Primary tumor (and lymph nodes) that appear to be resectable in the opinion of an experienced thoracic surgeon or surgical oncologist 19.

6. Measurable disease by RECIST 1.1 is not a requirement in order to enroll on this study. Those who have measurable disease at baseline will be followed by RECIST 1.1 criteria at time of restaging.

7. Primary tumor (and applicable nodal sites) that appears amenable to radiation in the opinion of an experienced radiation oncologist.

8. Eastern cooperative Oncology Group (ECOG) performance status of 0-1

9. No prior systemic treatment or radiation for esophageal/GEJ adenocarcinoma. Patients who have received prior endoscopic therapies with subsequent recurrence necessitating curative-intent surgery will be eligible for enrollment.

10. Adequate organ and marrow function as defined below:

    10.0 ANC ≥1500/mL 10.1 Platelet ≥100,000/mL 10.2 Total Bilirubin ≤ 1.0 x the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician.

    10.3 AST and/or ALT both ≤ 1.5x ULN with alkaline phosphatase ≤2.5x ULN 10.4 Creatinine Clearance ≥ 30 mL/min by Cockroft Gault

11. All men, as well as women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) starting with the first dose of radiation through 120 days after completion of adjuvant chemotherapy or immunotherapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

11a. A woman of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

1. Patients with adenosquamous cell carcinoma, squamous cell carcinoma, GI stromal tumor, or neuroendocrine tumor (any grade) of the esophagus or GEJ.
2. Receipt of prior chemotherapy, radiotherapy, or both for esophageal or gastroesophageal junction cancer (any type).
3. Any other active malignancies besides localized skin cancers or in situ carcinomas. Patients with localized prostate or breast cancers who have been stable for ≥ 6 months on adjuvant therapy without evidence of active disease will be eligible to enroll on this study. Patients with a history of cancer that has not been active in the last 5 years may be included but only after consultation with the principal investigator.
4. Prior RT to the chest or abdomen (not esophagus/GEJ) that would, in the opinion of a radiation oncologist, limit the safety of PULSAR.
5. Known dihydropyrimidine dehydrogenase (DPYD) intermediate or poor metabolizer phenotype where administration of full dose 5-fluoruracil would be prohibitively toxic. It is not a requirement to test DPYD deficiency prior to enrollment. Patients found to be DPYD intermediate or poor metabolizers through the course of standard of care evaluation will be removed from the protocol and followed for DLTs. These patients will be replaced.
6. Uncontrolled comorbid illness or condition including congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements or that would be prohibitive of a surgical resection in the opinion of a surgical oncologist or thoracic surgeon.
7. Chemotherapy, or other systemic cancer therapy for non-esophageal or GEJ cancer within 52 weeks prior to starting study treatment (with the exception of long-term adjuvant therapy for curative-intent prostate or breast cancer, as defined above).
8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to FLOT chemotherapy, durvalumab or other agents used in study.
9. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
10. Unwilling or unable to undergo placement of chest wall mediport for chemotherapy administration.
11. Any autoimmune condition requiring immunosuppression beyond physiologic doses of steroids will not be eligible for receipt of durvalumab. Patient would still be eligible for enrollment for receipt of perioperative FLOT only and can enroll on this study while receiving FLOT.
12. Requirement of prednisone 10 mg (or prednisone equivalent) or more daily for any reason (Inhalational steroids for chronic obstructive pulmonary disease, asthma, or the like, is allowable). Patient would still be eligible for enrollment for receipt of perioperative FLOT only if they are meeting all other eligibility criteria.
13. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.