Intensity-Modulated Radiation Therapy, Fluorouracil, and Mitomycin C in Treating Patients With Invasive Anal Cancer

Study Overview
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Brief Summary
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RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as fluorouracil and mitomycin C, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with 5-fluorouracil (5-FU) and mitomycin C may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving intensity-modulated radiation therapy together with fluorouracil and mitomycin C works in treating patients with invasive anal cancer.

Detailed Description
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OBJECTIVES: Primary Determine if dose-painted, intensity-modulated radiation therapy (IMRT), fluorouracil, and mitomycin C decreases the combined rate of gastrointestinal and genitourinary adverse events (grade II or greater) by at least 15% in the first 90 days after the start of treatment in patients with primary invasive carcinoma of the anal canal compared to patients treated on the radiotherapy, fluorouracil, and mitomycin C arm on clinical trial RTOG 98-11. Secondary Determine the feasibility of performing IMRT in these patients in a cooperative group setting. Evaluate adverse events experienced by patients treated with this regimen and to decrease the grade 2 and higher and grade 3 and higher overall adverse event rates by 15% or 20% as compared to the radiotherapy and mitomycin C arm of RTOG 98-11. Evaluate the total duration of radiotherapy. Evaluate the efficacy of this regimen, in terms of locoregional failure, disease-free survival, time to colostomy, colostomy-free survival, and overall survival of these patients. Determine clinical complete response at 8 weeks after completion of study treatment. OUTLINE: This is a multicenter study. Patients receive mitomycin C IV over 10-30 minutes on days 1 and 29 and fluorouracil IV continuously over 96 hours on days 1-4 and 29-32. Patients also undergo dose-painted intensity-modulated radiation therapy once daily, 5 days a week, for 5½ to 6 weeks beginning on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 59 patients will be accrued for this study.

Official Title
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A Phase II Evaluation of Dose-Painted Intensity-Modulated Radiation Therapy (IMRT) in Combination With 5-Fluorouracil (5-FU) and Mitomycin-C for Reduction of Acute Morbidity in Carcinoma of the Anal Canal

Conditions
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Anal Cancer

Intervention / Treatment
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* Drug: fluorouracil
* Drug: mitomycin C
* Radiation: Intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed carcinoma of the anal canal, including any of the following subtypes: Squamous cell Basaloid Cloacogenic Primary invasive disease T2-4, N0-3 disease Clinically positive small inguinal nodes (i.e., < 1 cm in size) must be confirmed by biopsy (preferably fine-needle aspiration) within the past 6 weeks Biopsy is not required for enlarged inguinal, perirectal, or pelvic nodes on exam or CT scan that are found to be ≥ 1.0 cm and are considered to be clinically positive PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention allowed) ALT and AST < 3 times upper limit of normal Absolute neutrophil count ≥ 1,800/mm³ Serum creatinine ≤ 1.5 mg/dL Platelet count ≥ 100,000/mm³ Bilirubin < 1.4 mg/dL WBC ≥ 3,000/mm³ INR ≤ 1.5 No known AIDS HIV-positive patients without AIDS are eligible HIV test required for patients with clinical suspicion of AIDS No other invasive malignancy within the past 3 years except for nonmelanomatous skin cancer No severe, active comorbidity, defined as any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring IV antibiotics Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study treatment Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects Uncontrolled diabetes mellitus, uncompensated heart disease, and/or uncontrolled high blood pressure, that in the opinion of the patient's treating physician, requires an immediate change in management Patients may be eligible if appropriate changes in management have resulted in adequate control of the above mentioned conditions Other immunocompromised status (e.g., organ transplantation or chronic glucocorticoid use) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior radiation therapy to the pelvis that would result in overlap of radiation therapy fields No prior systemic chemotherapy for cancer of the anus No prior surgery for cancer of the anus that removed all macroscopic anal cancer No concurrent sargramostim (GM-CSF) No concurrent amifostine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Other: 5-FU + Mitomycin + IMRT<br>5-FU + Mitomycin + IMRT | Drug: fluorouracil<br>* 1000 mg/m^2/day 96-hour continous infusion (M-F) starting on day 1 and again on day 29 of radiation therapy.<br>Drug: mitomycin C<br>* 10 mg/m^2 intravenous therapy on day 1 and day 29 of radiation therapy.<br>Radiation: Intensity-modulated radiation therapy<br>* Prescription dose depends on tumor staging. T2N0: The primary tumor PTV (planning target volume) (PTVA) receives 50.4 Gy in 28 fractions (fx) at 1.8 Gy/fx. The nodal PTVs receive 42 Gy in 28 fx at 1.5 Gy/fx. PTVA receive 50.4 Gy in 28 fractions at 1.8 Gy/fx. PTV42 receive 42 Gy in 28 fx at 1.5 Gy/fx and will include all nodal regions. T3N0 or T4N0: The primary tumor PTV (PTVA) will receive 54 Gy in 30 fx at 1.8 Gy/fx. The nodal PTVs will receive 45 Gy in 30 fx at 1.5 Gy/fx. PTVA will receive 54 Gy in 30 fx at 1.80 Gy/fx. PTV45 will receive 45 Gy in 30 fx electively at 1.5 Gy/fx and will include all nodal regions. For N+ disease: The primary tumor PTV (PTVA) will receive 54 Gy in 30 fx at 1.8 Gy/fx. For involved nodes ≤ 3 cm in maximum dimension, the involved nodal PTV will receive 50.4 Gy in 30 fx at 1.68 Gy/fx. For involved nodes > 3 cm in maximum dimension, the involved nodal PTV will receive 54 Gy in 30 fx at 1.80 Gy/fx.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Acute Gastrointestinal (GI) and Genitourinary (GU) Adverse Events (AE) ≥ Grade 2 as Defined by CTCAE v3.0 (Common Terminology Criteria for Adverse Events) | Highest grade adverse event per subject were counted. Adverse events were graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Acute toxicities occur within 90 days of the start of treatment. | From the start of treatment to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Major Radiation Planning Deviations | Deviations in intensity-modulated radiation therapy technique (IMRT) planning were determined by central review by the radiation oncology co-chairs of the study. | Planning occurred prior to radiation therapy | 
| Percentage of Subjects With Acute Adverse Events (AE) | Highest grade adverse event per subject were counted. Adverse events were graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Acute toxicities occur within 90 days of the start of treatment. | From the start of treatment to 90 days | 
| Percentage of Subjects With Late Adverse Events (AE) | Highest grade adverse event per subject were counted. Adverse events were graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Late toxicities occur greater than 90 days from the start of treatment. | From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 9.2 years. | 
| Clinical Complete Response Rate | A complete clinical response was defined as complete resolution of all palpable tumor determined by digital rectal exam and proctosigmoidoscopy supplemented with pelvic axial imaging. | 8 and 12 weeks after treatment completion (corresponding to 14 and 18 weeks from registration) | 
| Duration of Radiotherapy Treatment | Number of days from radiotherapy treatment start to radiotherapy treatment end | From start to end of radiation therapy (6 weeks) | 
| Five-year Rate of Overall Survival | Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From registration to 5 years | 
| Five-year Rate of Disease-free Survival | Disease-free survival time is defined as time from registration to the date of local-regional failure, the appearance of distant metastases, the appearance of a second primary failure, or date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. Local failure is defined as any measurable disease after 12 weeks from the completion of chemoradiation therapy. Local failure is defined as: a) For patients with no disease in pelvic and/or groin nodes, the appearance of disease in pelvic or groin nodes; b) For patients with disease in pelvic and/or groin nodes at study entry, nodal recurrence following clearance or persistent nodal disease for more than 12 weeks after completion of treatment. | From registration to 5 years | 
| Five-Year Cumulative Incidence Rate of Local-regional Failure | Local-regional failure time is defined as time from registration to date of failure and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact. Local-regional failure is defined as a local or regional failure. Local failure is defined as any measurable disease after 12 weeks from the completion of chemoradiation therapy. Regional failure is defined as: a) For patients with no disease in pelvic and/or groin nodes, the appearance of disease in pelvic or groin nodes; b) For patients with disease in pelvic and/or groin nodes at study entry, nodal recurrence following clearance or persistent nodal disease for more than 12 weeks after completion of treatment. | From registration to 5 years | 
| Five-Year Cumulative Incidence Rate of Distant Failure | Distant failure time is defined as time from registration to the appearance of distant metastases and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact. | From registration to 5 years | 
| Five-Year Cumulative Incidence Rate of Colostomy Failure | Colostomy failure time is defined as time from registration to the date of colostomy or abdominoperineal (A-P) resection and is estimated by the cumulative incidence method. Patients last known to be alive without failure are censored at the date of last contact. | From registration to 5 years | 
| Five-Year Rate of Colostomy-free Survival | Colostomy-free survival time is defined as time from registration to date of colostomy or abdominoperineal (A-P) resection, or date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. | From registration to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, basaloid carcinoma of the anus, cloacogenic carcinoma of the anus, squamous cell carcinoma of the anus