To determine the efficacy of reduced elective nodal radiation in anal cancer patients undergoing chemoradiation in reducing toxicity compared to standard nodal irradiation.

This is a multi-center, single arm prospective trial to evaluate whether reduced elective nodal dose (30.6 Gy) reduces toxicity as defined by the CTCAE Toxicity Index compared to historic patients treated with standard nodal dose on NRG/RTOG0529 and patient reported GI toxicity using the validated PRO-CTCAE scale for diarrhea compared to historic patients treated on UC-GI-1601.

Inclusion Criteria:

1. Age ≥18 years.

2. Patients must have stage T1-4N+M0 or T3/T4N0M0 locally advanced anal cancer as evidenced by a PET scan AND either a CT with contrast of the abdomen/pelvis or an MRI with contrast of the pelvis. All imaging must be from within 60 days prior to registration.

   1. Note: Patients with T2N0 disease will be allowed if the primary tumor is >4 cm. Patients with Stage I-T1N0M0 or Stage II-T2N0M0 (tumor ≤ 4cm) will be ineligible for participation.
   2. Patients with perianal cancer that is HPV associated (P16+) will be eligible if the tumor extends to the anal verge and the CTV will include the mesorectal, internal/external iliac, and inguinal lymph nodes.
   3. Patients with excision of the primary tumor but with node positive disease or residual disease at the primary if T3T4N0 will be eligible.

3. ECOG performance status 0 or 1 (or Karnofsky ≥70, see Appendix A).

4. Patients must be able to receive concurrent treatment with capecitabine and Mitomycin C in the opinion of the investigator.

5. Creatinine Clearance must be > 30 ml/min.

6. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Any prior pelvic radiation.

2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to capecitabine.

3. Patients with uncontrolled intercurrent illness that in the opinion of the investigator would prevent receipt of radiation or capecitabine.

   a. Note: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

4. Pregnant or breastfeeding women are excluded from this study.

5. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen in the opinion of the investigator.

6. Patients with active autoimmune or connective tissue disease requiring systemic treatment are excluded from this study.