The rationale of this clinical trial is to assess the feasibility of selective non-operative management for locally advanced rectal cancer using dose-escalated ultra-fractionated short course radiation therapy interdigitated with chemotherapy. We believe delivering short course radiotherapy over a prolonged interval, at escalated doses and with concurrent chemotherapy may be feasible and allow for improved clinical response.

To determine the maximal tolerated dose (MTD) of dose-escalated hypofractionated adaptive RT, in patients with locally advanced rectal cancer treated with RT, FOLFOX (5-FU, oxaliplatin, leucovorin) or CAPOX (capecitabine, oxaliplatin) chemotherapy and selective omission of surgery.

Inclusion Criteria:

1. At least 18 years of age. 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 rectal adenocarcinoma

4. T3-4 and/or N+ disease per AJCC 8th edition

5. No prior treatment for rectal adenocarcinoma

6. Eastern Cooperative Group (ECOG) performance status of 0-2.

7. Laboratory values supporting acceptable organ and marrow function within 30 days of eligibility confirmation. Defined as follows:

   • WBC ≥ 3,000/mL;
   • ANC WBC ≥ 1,000/mL;
   • PLT ≥ 75,000/mL;
   • T Bili ≤ 1.5 x upper limit of normal (ULN);
   • AST/ALT ≤ 2.5 x ULN;
   • Creatinine not above ULN, or creatinine clearance >50 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.

8. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) starting with the first dose of study therapy through 90 days after the last dose of study drugs. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

A female 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. Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any metastatic disease by CT.
2. Prior RT to the pelvis.
3. Uncontrolled comorbid illness or condition including congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would limit compliance with the study requirements.
4. Psychiatric illness/social situations that would limit consenting and compliance with study requirements.
5. Participants who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants