Sulfasalazine in Preventing Acute Diarrhea in Patients With Cancer Who Are Undergoing Pelvic Radiation Therapy

Study Overview
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Brief Summary
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RATIONALE: Sulfasalazine may relieve diarrhea in patients with cancer who are undergoing pelvic radiation therapy. PURPOSE: This randomized phase III trial is studying sulfasalazine to see how well it works in preventing acute diarrhea in patients with cancer who are undergoing pelvic radiation therapy.

Detailed Description
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OBJECTIVES: Primary To determine whether sulfasalazine is effective in reducing the acute treatment-related diarrhea in patients receiving pelvic radiotherapy as measured by NCI CTC v4.0 in patients receiving pelvic external-beam radiotherapy as adjuvant or primary treatment for malignancy. Secondary To determine whether sulfasalazine can reduce chronic treatment-related bowel dysfunction following completion of therapy. To determine whether sulfasalazine causes any toxicity in this situation. Tertiary To bank blood products for future studies, as part of ongoing research for NCCTG studies (Mayo Clinic Rochester only). (Translational) OUTLINE: This is a multicenter study. Patients are stratified according to history of anterior resection of the rectum (yes vs no); total planned cumulative dosing, including boost fields of external-beam radiotherapy (4500-5350 cGy vs > 5350 cGy); and concurrent radiosensitizing fluorouracil, capecitabine, or oxaliplatin (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral sulfasalazine twice daily during radiotherapy* and for 4 weeks after completion of radiotherapy. Arm II: Patients receive oral placebo twice daily during radiotherapy* and for 4 weeks after completion of radiotherapy. NOTE: *Patients must start study treatment by the third radiotherapy fraction. Patients may undergo blood sample collection at baseline and then weekly during radiotherapy. All patients complete quality of life and bowel function questionnaires at baseline, weekly during radiotherapy, and at 6 weeks after completion of radiotherapy. After completion of radiotherapy, patients are followed up at 6 weeks and at 12 and 24 months.

Official Title
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Phase III, Randomized, Study of Sulfasalazine Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy

Conditions
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Diarrhea, Gastrointestinal Complications, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: sulfasalazine
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of cancer that supports the use of radiotherapy to the pelvis No current or prior metastases beyond pelvic regional lymph nodes Planning to receive a course of continuous definitive or adjuvant external-beam radiotherapy to a minimum dose of 4500 cGy with or without fluorouracil, capecitabine, or oxaliplatin Planned course of pelvic radiotherapy must fall within the following parameters: Pelvis must be encompassed by the planned radiotherapy fields Superior border may not lie superior to the L4-5 interspace and may not be inferior to the most inferior aspect of the sacroiliac joints Portions of the rectum may have special blocking, depending upon disease site Total planned dose to the central axis midplane (for AP-PA parallel opposed fields) or isocenter (for 3- or 4-field techniques) for the pelvic field must lie between 4500-5300 cGy (inclusive)* Subsequent to completion of treatment to the pelvic field, a boost to primary tumor or tumor bed may be planned Planned treatment is to be given 4-5 times per week on a one-treatment-per-day basis Daily dose (specified at central axis midplane or at isocenter for multi-field techniques) must lie between 170-210 cGy (inclusive) per day* NOTE: *For institutions that do not use midplane or isocenter as the point for specification of dose, it will be necessary to determine the dose according to the methods specified above in order to determine patient eligibility. No perineal irradiation planned (e.g., anal cancer patients, patients who have had an abdominal-perineal resection) No brachytherapy planned before the completion of all external-beam radiotherapy No planned split-course radiotherapy PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 6 months Hemoglobin ≥ 10.0 g/dL Leukocytes ≥ 3,500/mm^3 ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine ≤ 1.5 times upper limit of normal (ULN) AST ≤ 1.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to provide blood specimens as required by the study (Mayo Clinic Rochester patients only) Able to complete questionnaires alone or with assistance No history of inflammatory bowel disease No history of gastrointestinal or genitourinary obstruction or porphyria No history of G6PD deficiency No history of irritable bowel syndrome No history of blood dyscrasia No history of severe allergies or asthma No history of hepatic or renal disease No diarrhea ≥ grade 3, rectal bleeding, abdominal cramping, or incontinence of stool within the past week No medical condition that may interfere with the ability to receive study treatment No known allergy to sulfasalazine, sulfa medications, salicylates, or any known component of drug formulation PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior pelvic radiotherapy No prior abdominal-perineal resection, Hartmann procedure, or other surgical procedure leaving the patient without a functioning rectum No planned use of leucovorin or cytotoxic chemotherapeutic agents concurrent with radiotherapy (except for fluorouracil, capecitabine, or oxaliplatin) No other concurrent sulfasalazine No concurrent digoxin

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Sulfasalazine<br>Patients receive oral sulfasalazine twice daily during radiotherapy and for 4 weeks after completion of radiotherapy. | Drug: sulfasalazine<br>* Given orally<br>|
| Placebo Comparator: Arm II: Placebo<br>Patients receive oral placebo twice daily during radiotherapy and for 4 weeks after completion of radiotherapy. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Severity of Diarrhea Toxicity as Measured by the CTCAE v4.0 During and After Radiotherapy (RT) | The primary endpoint for this study is the maximal severity of diarrhea toxicity. Severity of diarrhea was graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grade 0 = None; 1=Mild; Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening as measured by the CTCAE version 4.0. Assessments were recorded during the course of RT and for 6 weeks following RT. The table below represents the worst graded diarrhea for each patient. A two-sided Wilcoxon rank-sum test will be used to test the equality of the distributions of maximum diarrhea severity grades between the two treatment arms. | During radiation therapy and up to 6 weeks post radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Severity of Each Outcome Variable (Rectal Bleeding, Abdominal Cramping, Tenesmus, Constipation, and Diarrhea) Measured During and After RT | The maximal severity of each of 5 different adverse even types (Tenesmus, Abdominal Pain, Constipation, Diarrhea, and Rectal Bleeding) were collected as a secondary endpoint. Severity of the events was graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grade 0 = None; 1=Mild; Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening. Adverse events were assessed during the course of RT and for 6 weeks following RT. The table below represents the worst grade for each patient for each type. Two-sided chi-square tests will be used to compare each percentage variable between treatment arms for each event type. | During radiation therapy and up to 6 weeks post radiation therapy | 
| Area Under the Curve That Combines the Individual Severity of Diarrhea Toxicity as Measured by the CTCAE v4.0 During and After RT | For each patient, an Area Under the Curve (AUC) summary statistic will be calculated taking into account the individual severity of diarrhea toxicity over time. Severity of diarrhea was graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grade 0 = None; 1=Mild; Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening. The curve was constructed using weekly assessments during and after RT. A separate analysis was done during the course of RT and every week for 6 weeks following RT. | During radiation therapy and up to 6 weeks post radiation therapy | 
| Average Graded Severity for Tenesmus, Abdominal Pain, Constipation, Diarrhea and Hemorrhage During and After RT as Graded by CTCAE v4.0 | Tenesmus, Abdominal pain, constipation, diarrhea and hemorrhaging were assessed during RT and up to 6 weeks after RT. Severity of these events were graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grade 0 = None; 1=Mild; Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening. For each patient, an average score for each outcome variable during and after RT calculated as follows: The sum of all severity scores for that variable divided by the number of severity scores for that variable recorded for the patient during the course of RT and for 6 weeks following RT. | During radiation therapy and up to 6 weeks post radiation therapy | 
| Percentage of Patients in Each Arm That Experience Tenesmus, Abdominal Pain, Constipation, Diarrhea and Rectal Bleeding During and After RT | The number of patients that reported any grade 1 or higher adverse event was divided by the total number of patients evaluated. The analysis was done separately for each of the 5 outcomes and separately during RT and after RT. | During radiation therapy and up to 6 weeks post radiation therapy | 
| Percent of Patients in Each Arm That Recorded Yes to Each of Questions 2-10 on the Bowel Function Questionnaire | Questions that were used in this analysis: 2. Have you had a problem causing you to get up at night to have a bowel movement? 3. Have you had a problem causing you to lose control of your bowel movements? 4. Have you had a problem causing you to have a bowel movement within 30 minutes of a prior bowel movement? 5. Have you had to wear protective clothing or a pad in case you lost control of a bowel movement? 6. Have you had a problem causing you to be unable to tell the difference between stool and gas? 7. Have you had a problem causing you to have stools that are liquid? 1=yes 2=no q08 8. Have you found that once you feel the urge to have a bowel movement, you must do so within 15 minutes to avoid an accident? 9. Have you had cramping with a bowel movement? 10. Have you had blood in your bowel movement? | Up to 6 weeks post radiation therapy | 
| Percentage of Patients in Each Arm That Require Any Type of Antidiarrheal Medications. | The number of patients reporting the use of anti-diarrheal medications divided by the number of patients evaluated for this endpoint. | Up to 24 months post radiotherapy | 
| Percentage of Patients in Each Arm That Experience Clinically Significant Deficits in Overall Quality of Life and Fatigue | For each arm, the percentage of patients experience clinically significant deficits in overall QOL and fatigue as indicated by a score of 5 or lower on the 0-10 scale. The analysis was done using the questionnaire that was completed during the first week of radiotherapy (RT) and 6 weeks after RT. | Up to 6 weeks post radiotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diarrhea, gastrointestinal complications, unspecified adult solid tumor, protocol specific