Phase 2 Single-Arm Rectal Cancer Brachytherapy for Patients With Low-Lying Residual Adenocarcinoma After Total Neoadjuvant Therapy to Improve Organ Preservation Rates

Inclusion Criteria:

1. Provision to sign and date the consent form.

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

3. Adults (18-100 years old)

4. ECOG 0-3

5. Patients with MMR-proficient low-mid rectal adenocarcinoma cT1-4 N0-2 M0 whounderwent total neoadjuvant therapy who have not achieved complete response (i.e.incomplete or near-complete) in the rectal primary tumor such that surgicalresection, if offered presently or in the future, would be an APR or low LAR percolorectal surgeon expert opinion and central review at University of Coloradorectal tumor board. Tumor restaging will be 4-16 weeks following completion of totalneoadjuvant therapy, and no sooner than 8 weeks if patients received chemotherapyfollowed by chemoradiation/short course radiation.

6. Residual rectal disease must have its craniocaudal extent <4 cm with thickness <1.2cm. Tumor must have <50% circumferential involvement. Residual disease must be abovethe dentate line and not involving the anal canal.

7. In patients with original cN1-2 disease, restaging CT and MRI after totalneoadjuvant therapy must demonstrate at least near-complete response of the pelviclymph nodes per NCCN criteria as evaluated by central review at University ofColorado rectal tumor board.

8. Interval of time between completion of TNT and initiation of rectal brachytherapymust be between 4-16 weeks.

9. Patients must be recovered from total neoadjuvant therapy and must not havesignificant rectal incontinence at time of screening.

10. Received conventionally fractionated external beam chemoradiation between 45-56 Gyor short-course external beam radiation prescription of 25 Gy to rectal mucosa, inaddition to systemic chemotherapy before or after radiation per NationalComprehensive Cancer Network (NCCN) guidelines.

11. Women of child-bearing potential must have a negative urine or serum pregnancy testwithin 14 days of HDR treatment.

12. Men and women of reproductive potential who are sexually active must agree to followinstructions of contraception for the duration of the study and 6 months post-rectalbrachytherapy completion.

13. CBC at the time of screening must have platelets>50 10^9/L, Hemoglobin>8 g/dL andAbsolute Neutrophil Count > 500 10^9/L

Exclusion Criteria:

1. History of ulcerative colitis or Crohn's disease.

2. Pelvic radiotherapy given prior to rectal cancer external beam radiation.

3. Prior colorectal surgery in which anastomotic site is at or near HDR brachytherapytarget. o Prior local excision is not an exclusion criterion.

4. Uncontrolled intercurrent severe illness, including but not limited to, ongoing oractive infection, symptomatic congestive heart failure, uncontrolled hypertension,unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, seriouschronic gastrointestinal conditions associated with diarrhea, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs or compromise the ability of thepatient to give written informed consent.

5. Life expectancy <3 years per provider discretion.

6. Concurrent administration of any cytotoxic chemotherapy, immunotherapy, or other anytargeted oncologic agent that would impact rectal cancer is not allowed during studyprotocol.

7. If rectal cancer has been treated outside of standard total neoadjuvant therapy perNCCN guidelines, patients are ineligible for the trial. This includes if patientsreceived external beam chemoradiation dose with prescription >56 Gy or short-courseradiation to rectal mucosa prescription >30 Gy.

8. Pregnant women.