LET-IMPT and Standard Chemotherapy in Treating Patients With Newly Diagnosed Stage I-III Anal Canal Squamous Cell Cancer

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.

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

- 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 =< 1.5mg/dL (within 14 days prior to study registration)

- Bilirubin =< 1.4mg/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