• Feasibility as determined by number of patients enrolled [ Time Frame: Up to 24 months ]
  Will assess accrual at 24 months after study open to determine feasibility of enrolling 40 patients and obtaining insurance approval for intensity modulated proton therapy (IMPT) treatment over the planned 4 years.
• Guidelines and workflow development to create and deliver anal canal cancer treatments using linear energy transfer (LET)-optimized IMPT [ Time Frame: Up to 12 weeks post-treatment ]
  Will present results of workflows in a descriptive manner.
• Complete response defined as no evidence of disease by physical exam, endoscopy, and cross-sectional imaging [ Time Frame: At 12 and 24 weeks post-treatment ]
  Will be reported at 12 and 24 weeks post-treatment as determined clinically by physical exam, endoscopic examination and imaging.
• Local progression-free survival (LPFS) [ Time Frame: At 24 and 48 months ]
  LPFS is defined as either the recurrence of disease in the anal canal following clearance, progression of disease in the anal canal after completion of treatment or persistence of disease in anal canal for more than 6 months after completion of treatment. Will be estimated using the Kaplan-Meier method and estimates will be reported using 95% confidence intervals. The date of failure will be recorded as 6 months after completion of treatment in the case of persistent, biopsy-proven disease after 6 months status-post completion of all therapy.
• Distant metastatic failure as determined by the appearance of distant metastatic disease [ Time Frame: At 24 and 48 months ]
  Will be estimated using the Kaplan-Meier method and estimates will be reported using 95% confidence intervals. The date of failure will be recorded as 6 months after completion of treatment in the case of persistent, biopsy-proven disease after 6 months status-post completion of all therapy.
• Disease-free survival [ Time Frame: The time to locoregional failure, appearance of distant metastases, or death due to any cause, assessed at 24 and 48 months ]
  Will be estimated using the Kaplan-Meier method and estimates will be reported using 95% confidence intervals.
• Overall survival [ Time Frame: Baseline to death due to any cause, assessed at 24 and 48 months ]
  Will be estimated using the Kaplan-Meier method and estimates will be reported using 95% confidence intervals.
• Patient-reported acute toxicity, function, distress and quality of life (QOL) [ Time Frame: At 12 weeks post-treatment ]
  Will use Patient-Reported Outcomes (PRO) CTCAE, European Quality of Life-5 Dimensions (EQ 5D), and European Organization for Research and Treatment of Cancer Quality of Life Anal (EORTC QLQ-ANL 27), Female Sexual Function Index (FSFI), and Erectile Function Questionnaires (IIEF). The study will summarize and graph the distribution of scores for each instrument over time and analyze changes over time using mixed effects linear models.
• Patient-reported acute toxicity, function, distress and QOL [ Time Frame: Up to 24 months ]
  Will use PRO CTCAE, EQ 5D, EORTC QLQ-ANL 27, FSFI, and IIEF questionnaires. The study will summarize and graph the distribution of scores for each instrument over time and analyze changes over time using mixed effects linear models.
• Time-Driven Activity-Based Costing (TDABC) [ Time Frame: At 12 weeks post-treatment ]
  The study will evaluate the value of proton therapy by comparing Time-Driven Activity-Based Costing data from the date of consultation until the date of the 12-week follow up visit post-treatment with contemporary controls treated with VMAT. Costs will be tabulated as either treatment or toxicity-management related.

• Dose to pelvic bone marrow, bowel, bladder and genitalia [ Time Frame: Up to 12 weeks ]
  Will be compared LET-optimized IMPT, traditionally optimized IMPT and VMAT. Dosimetric studies will be performed.
• Rates of leukopenia, neutropenia and lymphopenia [ Time Frame: Up to 12 weeks ]
  Will compare the on-treatment blood count nadirs for patients treated with LET-optimized IMPT with matched historical controls treated with VMAT. Continuous variables will be compared using Wilcoxon-Rank Sum test and corresponding p-values will be reported.
• Levels of white blood cell counts, absolute neutrophil counts, and absolute lymphocyte counts [ Time Frame: Up to 12 weeks ]
  Will be correlated with dose to the pelvic bone marrow for patients treated with LET-optimized IMPT. Will use Spearman rank correlation coefficient to evaluate for correlation.
• Optional co-enrollment on study 2014-0543 [ Time Frame: Up to 12 weeks ]
  Will use descriptive statistics and graphical methods.

PRIMARY OBJECTIVES:

I. To assess physician-reported acute grade 3 or greater gastrointestinal, genitourinary and hematologic toxicities at 12 weeks post-treatment for patients treated with linear energy transfer (LET)-optimized, intensity-modulated proton therapy (IMPT) and compare to contemporary controls treated with volume modulated arc therapy (VMAT) to determine the feasibility of this outcome for a future randomized trial.

SECONDARY OBJECTIVES:

I. To assess the feasibility of enrolling patients on a prospective trial delivering LET-optimized IMPT for newly diagnosed, non-metastatic anal cancer.

II. To develop guidelines and workflow to create and deliver anal canal cancer treatments using LET-optimized IMPT.

III. To evaluate complete response rate at 12 weeks and 24 weeks post-treatment.

IV. To evaluate local progression free survival, distant metastasis-free survival and overall survival at 24 and 48 months.

V. To evaluate rates of patient-reported acute toxicity, function, distress and quality of life (QOL) at 12 weeks.

VI. To evaluate rates of patient-reported late toxicity, function, distress and QOL every 6 months for 24 months.

VII. To evaluate the value of proton therapy by comparing Time-Driven Activity-Based Costing data from the date of consultation until the date of the 12-week follow up visit post-treatment with contemporary controls treated with VMAT.

EXPLORATORY OBJECTIVES:

I. To compare dose to the pelvic bone marrow, bowel, bladder and genitalia between LET-optimized IMPT, traditionally-optimized IMPT and VMAT.

II. To assess rates of leukopenia, neutropenia and lymphopenia at 12-weeks post-treatment for patients treated with LET-optimized IMPT and compare to contemporary controls treated with VMAT.

III. To correlate white blood cell counts (WBC), absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) with dose to the pelvic bone marrow for patients treated with LET-optimized IMPT.

IV. To encourage optional co-enrollment on study 2014-0543 so that tumor deoxyribonucleic acid (DNA), rectal microbiome and magnetic resonance imaging (MRI) imaging-based biomarkers can be assessed for patients receiving LET-optimized IMPT and compared with other patients enrolled on 2014-0543 receiving VMAT-based radiation.

OUTLINE:

Patients undergo linear energy transfer-optimized intensity modulated proton therapy 5 times per week for 5-6 weeks. Patients also receive standard cisplatin and fluorouracil intravenously (IV) weekly for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 12 weeks.

• Anal Canal Squamous Cell Carcinoma
• Stage I Anal Cancer AJCC v8
• Stage II Anal Cancer AJCC v8
• Stage IIA Anal Cancer AJCC v8
• Stage IIB Anal Cancer AJCC v8
• Stage III Anal Cancer AJCC v8
• Stage IIIA Anal Cancer AJCC v8
• Stage IIIB Anal Cancer AJCC v8
• Stage IIIC Anal Cancer AJCC v8

• Drug: Cisplatin
  Given IV
  Other Names:

  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
• Drug: Fluorouracil
  Given IV
  Other Names:

  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757
• Radiation: Linear Energy Transfer-Optimized Intensity Modulated Proton Therapy
  Undergo LET-IMPT
  Other Name: LET-Optimized Intensity Modulated Proton Therapy; LET-Optimized IMPT; Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT)
• Procedure: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

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 14 days prior to registration
• Anal examination with biopsy on either colonoscopy, sigmoidoscopy, rigid proctoscopy or anoscopy within 30 days of registration
• Computed tomography (CT) scan of the chest and abdomen with contrast or contrast-enhanced positron emission tomography (PET)/CT scan within 30 days of registration unless the patient has a documented contrast allergy
• CT scan of pelvis with contrast or contrast-enhanced PET/CT scan within 30 days of registration unless the patient has a documented contrast allergy
• Zubrod Performance Status of 0-1 within 60 days prior to registration
• Age >/=18 years - 85 years
• Absolute neutrophil count (ANC) >=1800 cells/mm^3, cannot be achieved through granulocyte-colony stimulating factor (GCSF) (within 14 days prior to study registration)
• Platelets >= 100,000 cells/mm^3, cannot be achieved through transfusion (within 14 days prior to study registration)
• Hemoglobin >= 8 g/dL, cannot be achieved through transfusion (within 14 days prior to study registration)
• Serum creatinine =< 1.5 mg/dL (within 14 days prior to study registration)
• Bilirubin =< 1.4 mg/dL, except in the case of patients with Gilbert's disease (within 14 days prior to study registration)
• White blood cells (WBC) >= 3000/microliter (within 14 days prior to study registration)
• Aspartate transaminase (AST)/alanine transaminase (ALT) < 3 x the upper limit of normal (within 14 days prior to study registration)
• International normalized ratio (INR) =< 1.5 (within 14 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