Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study

Study Overview
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Brief Summary
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This phase II trial studies how well lower-dose chemotherapy plus radiation (chemoradiation) therapy works in comparison to standard-dose chemoradiation in treating patients with early-stage anal cancer. Drugs used in chemotherapy, such as mitomycin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more tumor cells. This study may help doctors find out if lower-dose chemoradiation is as effective and has fewer side effects than standard-dose chemoradiation, which is the usual approach for treatment of this cancer type.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether de-intensified chemoradiation for early stage squamous cell carcinoma of the anal canal (SCCA) is able to maintain excellent 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose chemoradiation therapy (CRT), as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year. SECONDARY OBJECTIVES: I. To compare changes in patient-reported outcomes (as per Fecal Incontinence Severity Index [FISI], Patient Reported Outcomes Measurement Information System [PROMIS], International Index of Erectile Function [IIEF], Sexual Function-Vaginal Changes Questionnaire [SVQ], and Vaginal Assessment Scale [VAS]/Vulvar Assessment Scale [VuAS] instruments) between the experimental and control arm. II. To compare patterns of failure (local and regional relapse versus distant; in-field versus out-of-field of radiation), disease control, and overall survival between experimental and control arm. III. To correlate vaginal dilator use during radiation delivery with sexual function. IV. To measure changes in serum total testosterone from baseline to up to 12 months after radiation. V. To validate the utility of image features of inguinal and pelvic lymph nodes obtained prior to treatment as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified chemoradiation is appropriate. VI. To determine whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer. VII. To determine the incidence of and predictors for cardiovascular toxicity in patients receiving fluorouracil (5-FU) or capecitabine. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A (STANDARD-DOSE CHEMORADIATION): Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin intravenously (IV) over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine orally (PO) twice daily (BID) 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. ARM B (DE-INTENSIFIED CHEMORADIATION): Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for years 1-2, every 6 months for year 3, then annually for years 4-5.

Official Title
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A Randomized Phase II Study De-Intensified ChemoRadiation for Early-Stage Anal Squamous Cell Carcinoma (DECREASE)

Conditions
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Anal Basaloid Carcinoma, Anal Canal Cloacogenic Carcinoma, Anal Canal Squamous Cell Carcinoma, Anal Margin Squamous Cell Carcinoma, Stage I Anal Cancer AJCC v8, Stage IIA Anal Cancer AJCC v8

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Fluorouracil
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Mitomycin
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically proven T1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumors measuring =< 4 cm within 4 weeks prior to randomization. This may include tumors of non-keratinizing histology such as basaloid, transitional cell or cloacogenic histology. Patients with T1N0M0 anal margin squamous cell carcinoma who underwent surgical excision with negative margins are not eligible Patients who are human immunodeficiency virus (HIV)-negative must not have lymph nodes that are radiographically-concerning for cancer involvement using computed tomography (CT) and positron emission tomography (PET)/CT-based criteria. Measurable disease is not required Patients who are HIV-negative and do not have lymph nodes classified as lymph node positive, but are felt to be borderline for cancer involvement must undergo central imaging review NOTE: Patients requiring central imaging review will be pre-registered to Arm S. Upon central confirmation of no lymph node involvement, eligible patients may proceed to randomization on Step 1 Patients will be considered to be lymph node (LN) positive and thereby not eligible in this study if the lymph nodes meet any of the following criteria: Mesorectal, presacral, internal iliac or obturator LN with: Short axis measuring > 5 mm based on CT / magnetic resonance imaging (MRI) OR Morphologic features of irregular border or central necrosis if assessed on MRI and LN measures > 3 mm OR Fludeoxyglucose F-18 (FDG) uptake > blood pool (Deauville 3-5) based on PET/CT External Iliac and common Iliac: Short-axis measuring > 1 cm based on CT / MRI OR Morphologic features of irregular border or central necrosis based on CT / MRI OR FDG uptake > blood pool (Deauville 3-5) based on PET/CT Inguinal LN (superficial and deep) meeting any of the following criteria will be ineligible unless an FNA is performed and resulting cytology is negative. Morphologic features of irregular border or central necrosis based on CT / MRI FDG uptake > liver (Deauville 4) based on PET/CT. Patients who are HIV-negative and have inguinal lymph nodes that do not meet the above criteria must undergo fine needle aspiration and have negative histology to be eligible. Patients who are HIV-positive must have A CD4 count >= 300 Confirmation of no lymph node involvement by central real-time review of imaging NOTE: Patients will be pre-registered to Arm S. Upon central confirmation of no lymph node involvement, eligible patients may proceed to randomization on Step 1 Patient must have Eastern Cooperative Oncology Group (ECOG) - American College of Radiology Imaging Network (ACRIN) performance status of 0-2 Patient must have no history of prior radiation or chemotherapy for this malignancy Patient must not have had prior potentially curative surgery (i.e. abdominal-perineal resection) for carcinoma of the anus Patients with excisional biopsy procedure are eligible provided there was tumor involvement of the anal canal and/or anal verge prior to resection Patient must not be receiving any other standard anti-cancer therapy or experimental agent concurrently with the study drugs Patient must not have intercurrent illness including, but not limited to, ongoing or active infection or psychiatric/social situations that, in the judgement of the investigator, would limit compliance with study requirements Patient must not have had significant cardiovascular disease including myocardial infarction, unstable angina, stroke, transient ischemic attack, symptomatic coronary artery disease, symptomatic congestive heart failure, or uncontrolled cardiac arrhythmia within 6 months of randomization Patient must not have a history of a different malignancy unless they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk of recurrence Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ and basal cell or squamous cell carcinoma of the skin Patient must not have active autoimmune or connective disease Patients who are on anti-coagulation with warfarin within 2 weeks prior to registration and are considering the use of capecitabine, must use an alternative anti-coagulant NOTE: Low molecular weight heparin is permitted provided the patient's prothrombin time (PT)/international normalized ratio (INR) is < 1.5 Patients who will receive capecitabine and are on Dilantin for a seizure disorder must have Dilantin levels checked weekly Hemoglobin > 10 g/dL (within 2 weeks prior to registration) Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) Absolute neutrophil count >= 1500/mm^3 (within 2 weeks prior to registration) Serum creatinine must be < 1.5 X upper limit of normal (ULN), or calculated creatinine clearance must be > 60 ml/min (within 2 weeks prior to registration) Total bilirubin must be < 2 X ULN (within 2 weeks prior to registration) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X institutional ULN (within 2 weeks prior to registration) Albumin >= 3.0 g/dL (within 2 weeks prior to registration) Women must not be pregnant or breast-feeding because the study treatment administered may cause harm to an unborn fetus or breastfeeding child. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Women of childbearing potential and sexually active males must be strongly advised to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for at least 6 months after the completion of treatment

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (standard-dose chemoradiation)<br>Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Mitomycin<br>* Given IV<br>* Other names: NCI-C04706;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (de-intensified chemoradiation)<br>Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Mitomycin<br>* Given IV<br>* Other names: NCI-C04706;Other: 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 |
| --- | --- | --- |
| Disease control in the de-intensified chemoradiation therapy (CRT) arm | An event is local-regional failure, distant metastasis and chemoradiation-related death. Will determine if de-intensified chemoradiation achieves 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose CRT, as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year. The co-primary endpoints of disease control and FIQoL will be formally assessed in a hierarchical manner with disease control being assessed first. Will be estimated for all treatment arms using the Kaplan-Meier method (1958). | Up to 2 years | 
| Change in FIQoL in the de-intensified CRT arm | Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm. | Baseline up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in patient-reported outcomes - HRQL: Health Related Quality of Life FACT-G (Functional Assessment of Cancer Therapy-General) | Will compare changes as per HRQL: Health Related Quality of Life FACT-G (Functional Assessment of Cancer Therapy-General - Scoring: 0 - 32 with higher worse) between the experimental and control arm. Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Fecal Incontinence Severity Index [FISI] | Will compare changes as per Fecal Incontinence Severity Index [FISI - Scoring: 0 - 61 with lower better] between the experimental and control arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - International Index of Erectile Function [IIEF]: Erectile Dysfunction and Ejaculation Frequency. | Will compare changes as per International Index of Erectile Function [IIEF], Erectile Dysfunction: Scoring 7 - 35 with lower better. Ejaculation Frequency: Scoring 1 - 5 with lower better - between the experimental and control arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Orgasm ability/pleasure (PROMIS-Brief) | Will compare changes as per Orgasm ability/pleasure (PROMIS-Brief): scoring 2 - 10 with lower better - between the experimental and control arm. PROMIS = Patient Reported Outcomes Measurement Information System | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Anal Discomfort/pain (PROMIS- Full) | Will compare changes as per Anal Discomfort/pain (PROMIS- Full): scoring 3 - 15 with lower better. - between the experimental and control arm. PROMIS = Patient Reported Outcomes Measurement Information System | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Satisfaction with sex life (PROMIS-Brief): | Will compare changes as per Satisfaction with sex life (PROMIS-Brief) (scoring 2 - 10 with higher better) between the experimental and control arm. PROMIS = Patient Reported Outcomes Measurement Information System | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Therapeutic Aids for Sexual Function - Male. | Will compare changes as per Therapeutic Aids for Sexual Function - Male (Scoring 6 - 22 with lower better) between the experimental and control arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Therapeutic Aids for Sexual Function - Female. | Will compare changes as per Therapeutic Aids for Sexual Function - Female (Scoring 5 - 17 with lower better) between the experimental and control arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Sexual Function-Vaginal Changes Questionnaire [SVQ] | Will compare changes as per Sexual Function-Vaginal Changes Questionnaire [SVQ] (Scoring 5 - 26 with higher better) between the experimental and control arm. | Baseline up to 5 years | 
| Changes in patient-reported outcomes - Vaginal Assessment Scale [VAS]/Vulvar Assessment Scale [VuAS] | Will compare changes as per Vaginal Assessment Scale [VAS]/Vulvar Assessment Scale [VuAS] (Scoring:0 - 22 with lower better) between the experimental and control arm. | Baseline up to 5 years | 
| Patterns of failure (local and regional relapse versus distant; in-field versus out-of-field of radiation) | Will be compared between experimental and control arm. The cumulative incidence method will be used to estimate local-regional and distant failure rates and the failure rates for the experimental treatment will be compared against the control using a failure specific log rank test. | Up to 5 years | 
| Disease control | Will be compared between experimental and control arm. Will be estimated for all treatment arms using the Kaplan-Meier method (1958). | Up to 5 years | 
| Effect of vaginal dilator use during radiation delivery on sexual function | Vaginal dilator use during radiation delivery will be correlated with sexual function. | Up to 5 years | 
| Change in serum total testosterone |  | Baseline up to 12 months after radiation | 
| Utility of image features of inguinal and pelvic lymph nodes obtained prior to treatment | Will be validated as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified CRT is appropriate. | Baseline | 
| Effect of interactive educational tool (eContour) | Will determine whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer. | Up to 5 years | 
| Incidence of and predictors for cardiovascular toxicity in patients receiving fluorouracil or capecitabine | Rates of grade 3+ adverse events (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 5) will be estimated using a binomial distribution along with their associated 95% confidence intervals and compared using Fisher's exact test between arms. | Up to 5 years |