Inclusion Criteria:

• * Histologically proven, invasive primary squamous, basaloid or cloacogenic carcinoma of the anal canal.
• * American Joint Committee on Cancer (AJCC) 8th edition stage T2 \> 4 cm, T3-4 or N1.
• * Age ≥18 years.
• * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%).
• * Life expectancy of greater than 12 months.
• * Patients must have normal organ and marrow function as defined below:
• * leukocytes greater than or equal to 3,000/microliter
• * absolute neutrophil count greater than or equal to 1,500/microliter
• * platelets greater than or equal to 100,000/microliter
• * total bilirubin within normal institutional limits
• * Aspartate transaminase (AST)(SGOT)/Alanine transaminase (ALT)(SGPT) ≤ 2.5 × institutional upper limit of normal
• * creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• * Females of childbearing potential and males must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completion of study therapy. All pregnancies must be reported.
• * Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• * Prior or co-existing invasive malignancy (except non-melanomatous skin cancer) unless disease free ≥ 2 years.
• * Prior chemotherapy or radiation for anal cancer.
• * Patients who have undergone complete surgical resection.
• * Presence of recurrent/metastatic disease.
• * Prior allergic reaction to 5-Fluorouracil or mitomycin C.
• * Artificial organ prosthetics, pacemakers or other implantable devices.
• * Prior radiotherapy to the pelvis that would result in overlap of radiation therapy fields.
• * Uncontrolled inter-current illness including but not limited to known history of HIV with cluster of differentiation 4 (CD4) count less than 200 or symptomatic cardiac disease.
• * Women who are pregnant or lactating.