Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT) as a Component of Definitive Chemoradiation for Newly Diagnosed Squamous Cell Carcinoma of the Anal Canal: a Feasibility Trial

Inclusion Criteria:

* Histologically-proven, non-metastatic invasive primary squamous cell carcinoma of the anal canal (stages I, II, and III)
* History/physical examination including documentation of the primary anal lesion size, distance from the anal verge and anal sphincter tone within 60 days prior to registration
* Anal examination with biopsy on either colonoscopy, sigmoidoscopy, rigid proctoscopy or anoscopy
* Computed tomography (CT) scan of the chest and abdomen with contrast or contrast-enhanced positron emission tomography (PET)/CT scan within 60 days of registration unless the patient has a documented contrast allergy
* CT scan of pelvis with contrast or contrast-enhanced PET/CT scan within 60 days of registration unless the patient has a documented contrast allergy
* Zubrod performance status of 0-1 within 60 days prior to registration
* Absolute neutrophil count (ANC) \>=1.8 K/ul, cannot be achieved through granulocyte-colony stimulating factor (GCSF) (within 30 days prior to study registration)
* Platelets \>= 100 K/uL, cannot be achieved through transfusion (within 30 days prior to study registration)
* Hemoglobin \>= 8 g/dL, cannot be achieved through transfusion (within 30 days prior to study registration)
* Serum creatinine =\< 1.5 mg/dL (within 30 days prior to study registration)
* Bilirubin =\< 1.4 mg/dL, except in the case of patients with Gilbert's disease (within 30 days prior to study registration)
* White blood cells (WBC) \>= 3000/microliter (within 30 days prior to study registration)
* Aspartate transaminase (AST)/alanine transaminase (ALT) \< 3 x the upper limit of normal (within 30 days prior to study registration)
* International normalized ratio (INR) =\< 1.5 (within 30 days prior to study registration)
* Human Immunodeficiency Virus (HIV) test must be done within 30 days of study registration. If HIV positive, CD4 count must be obtained within 30 days of study registration

  * Note: HIV positive patients are eligible for this study if they have a CD4 count \> 400 cells/mm\^3
* The patient must either have insurance authorization or otherwise secure funding to cover IMPT
* The patient must be able to receive concurrent chemotherapy

Exclusion Criteria:

* Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years
* Prior systemic chemotherapy for anal cancer
* Prior radiotherapy to the pelvis that would result in overlap of radiation fields
* Evidence of distant metastatic disease (M1)
* Prior surgery to the anal canal that removed all macroscopic anal cancer
* Women of childbearing potential or men who do not agree to use a medically effective form of birth control throughout their participation in the treatment phase of the study
* Severe, active co-morbidity defined as follows: unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; transmural myocardial infarction within the last 6 months; acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; HIV positive with a CD4 count \< 400 cells/mm\^3; other immuno-compromised status; women who are pregnant or lactating; uncontrolled infection as deemed by the principal investigator (PI); patient incarceration