A Randomized Phase II Study of De-Intensified ChemoRadiation for Early-Stage Anal Squamous Cell Carcinoma (DECREASE)
Overview
- Phase
- Phase 2
- Intervention
- Biopsy
- Conditions
- Anal Basaloid Carcinoma
- Sponsor
- ECOG-ACRIN Cancer Research Group
- Enrollment
- 252
- Locations
- 1314
- Primary Endpoint
- Disease control in the de-intensified chemoradiation therapy (CRT) arm
- Status
- Active, Not Recruiting
- Last Updated
- last month
Overview
Brief Summary
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
PRIMARY OBJECTIVE: 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 HRQL (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 imaging 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 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. All patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography (PET)/magnetic resonance imaging (MRI) or receive FDG and undergo PET/computed tomography (CT) during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial. 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •STEP 0 (PRE-REGISTRATION)
- •Patient must be ≥ 18 years of age
- •Patients must be English speaking to participate in the trial. (Please note that this requirement is due to the fact that the quality-of-life studies are mandatory and we currently do not have full translated versions of the questionnaires into other languages)
- •Patient must have histologically proven T1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumors measuring =\< 4 cm. This may include tumors of non-keratinizing histology such as basaloid, transitional cell or cloacogenic histology. Measurable disease is not required
- •Patients who are status/post local excision or excisional biopsy procedure are eligible provided there was tumor involvement of the anal canal and/or anal verge prior to the reaction, if the margins were positive, and/or if the stage is T2N0 based on tumor size before the procedure. This means that patients with T1N0M0 anal margin squamous cell carcinoma who underwent surgical excision with negative margins and no involvement of the anal verge and/or anal canal are not eligible
- •Tumor size must be documented based on physical examination including digital rectal exam and/or anoscopy/proctoscopy within 4 weeks prior to Step 0 pre-registration
- •Patient's human immunodeficiency virus (HIV) status must be known and documented at baseline
- •NOTE: For patients without a history of HIV infection, it is recommended (but not required) that updated HIV testing be performed within one year of study enrollment
- •Patients who are HIV-negative will be registered to Arm R. They must not have lymph nodes that are radiographically-concerning for cancer involvement using computed tomography (CT) and fludeoxyglucose F-18 (FDG) - positron emission tomography (PET)/CT-based criteria
- •NOTE: Patients who are HIV-negative and meet the below criteria may proceed directly to Step 1 Randomization
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Biopsy
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Biospecimen Collection
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Capecitabine
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Computed Tomography
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Biopsy
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Fludeoxyglucose F-18
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Fluorouracil
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Intensity-Modulated Radiation Therapy
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Magnetic Resonance Imaging
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Mitomycin
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Positron Emission Tomography
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Quality-of-Life Assessment
Arm A (standard-dose chemoradiation)
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Questionnaire Administration
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Biospecimen Collection
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Capecitabine
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Computed Tomography
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Fludeoxyglucose F-18
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Fluorouracil
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Intensity-Modulated Radiation Therapy
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Magnetic Resonance Imaging
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Mitomycin
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Positron Emission Tomography
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Quality-of-Life Assessment
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. Patients receive FDG and undergo PET/MRI or receive FDG and undergo PET/CT during baseline. Patients undergo CT or MRI on the trial. Patients also undergo tissue biopsy during screening and at the discretion of the treating physician. Additionally, patients undergo blood sample collection throughout the trial.
Intervention: Questionnaire Administration
Outcomes
Primary Outcomes
Disease control in the de-intensified chemoradiation therapy (CRT) arm
Time Frame: Up to 2 years
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).
Change in FIQoL in the de-intensified CRT arm
Time Frame: Baseline up to 1 year
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.
Secondary Outcomes
- Disease control(Up to 5 years)
- Changes in patient-reported outcomes(Baseline up to 5 years)
- Patterns of failure (local and regional relapse versus distant; in-field versus out-of-field of radiation)(Up to 5 years)
- Effect of vaginal dilator use during radiation delivery on 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(Baseline)
- Incidence of and predictors for cardiovascular toxicity in patients receiving fluorouracil or capecitabine(Up to 5 years)