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

Study Overview
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Brief Summary
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This phase II trial studies the side effects of LET-IMPT and standard chemotherapy, and how well they work in treating patients with newly diagnosed stage I-III anal canal squamous cell cancer. LET-IMPT is a type of radiation therapy that uses high energy proton beamlets to paint the radiation dose into the target and may help to kill tumor cells and shrink tumors. Giving LET-IMPT and standard chemotherapy may work better in treating patients with anal canal squamous cell cancer.

Detailed Description
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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. 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.

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Fluorouracil
* Radiation: Linear Energy Transfer-Optimized Intensity Modulated Proton Therapy
* Procedure: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (LET-IMPT, chemotherapy)<br>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 IV weekly for up to 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Radiation: Linear Energy Transfer-Optimized Intensity Modulated Proton Therapy<br>* Undergo LET-IMPT<br>* Other names: Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT);Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Toxicity | Number (percentage) of patients with physician-reported acute G3+ GI, GU and heme toxicities | Acute physician reported toxicity from start of treatment 12 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response at 12 Weeks | Number (percentage) patients who achieved a complete clinical response of their disease by 12 weeks after chemoradiation. | 12 weeks | 
| Local Progression Free Survival at 24 Months | Patients alive without evidence of local progression 24 months after chemoradiation. | 24 months | 
| Distant Metastasis-free Survival at 24 Months. | Patients alive without evidence of distant metastases 24 months after chemoradiation. | 24 months | 
| Overall Survival at 24 Months | Patients alive 24 months after chemoradiation. | 24 months | 
| Complete Response at 24 Weeks | Number (percentage) patients who achieved a complete clinical response of their disease by 24 weeks after chemoradiation. | 24 weeks |