The proposed study is a phase II, single arm, open-label trial of MR-guided radiation therapy (RT) with risk stratified RT dose selection in patients with anal cancer. Based on previous data, a risk adaptive treatment approached is proposed in 4 groups: Low risk, standard risk, intermediate risk, and high risk. Human papillomavirus (HPV) DNA will be analyzed to identify novel biomarkers that predict chemoradiotherapy (CRT) response and toxicity.

After being informed about the study and potential risks, all patients giving written informed consent will undergo a risk-stratified dose of treatment (radiation dose and chemotherapy number of cycles) based on predefined clinical and biological biomarkers for anal squamous cell carcinoma (SCC). Radiotherapy will be delivered on the MR-Linac for image-guided-radiation therapy (IGRT). Patients will be followed for up to 5 years after radiotherapy and be required to complete questionnaires and clinic visits. Patients have the option to complete blood and tissue samples during the study.

Inclusion Criteria:

• Patients with pathologically proven diagnosis of anal SCC. This may include tumors of non-keratinizing histology such as basoloid or cloacogenic histology. Individuals with squamous cell carcinoma of the anal margin are eligible.
• Clinical stage T1-4 N0-1 M0 (the Union for International Cancer Control (UICC) / the American Joint Committee on Cancer (AJCC) 8th Ed)
• Patients must be eligible for definitive RT or CRT
• Must be ≥ 18 years of age
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Exclusion Criteria:

• Previous chemotherapy, RT or curative-intent surgical treatment (i.e. APR) for anal cancer.
• Any previous RT to the abdomino-pelvic region that would result in overlap of RT volume for the current study.
• Individuals with a history of a different malignancy except if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.