Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy in Treating Patients Who Are Undergoing Surgical Resection for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Chemoradiotherapy (combining chemotherapy with radiation therapy) before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any remaining tumor cells. PURPOSE: This randomized phase II trial is studying two different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy and comparing how well they work in treating patients who are undergoing surgical resection for locally advanced rectal cancer.

Detailed Description
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OBJECTIVES: Evaluate the pathologic complete response rate in patients with locally advanced rectal cancer undergoing surgical resection treated with 2 different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy. Evaluate the time to treatment failure and patterns of failure in patients treated with these regimens. Evaluate the incidence of hematologic and non-hematologic grade 3-4 toxicity (preoperatively, postoperatively, and overall) in patients treated with these regimens. Evaluate the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to clinical stage of tumor (T3 vs T4). Patients are randomized to 1 of 2 treatment arms. Quality of life is assessed at baseline, within 1 week after completion of radiotherapy, within 1 week after completion of adjuvant chemotherapy (12 months), and then at 24 months. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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Randomized Phase II Trial Of Neoadjuvant Combined Modality Therapy For Locally Advanced Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Radiation: Radiation Therapy
* Drug: Capecitabine 1650 mg/m^2/day
* Drug: Capecitabine 1200 mg/m^2/day
* Drug: Irinotecan
* Drug: Oxaliplatin
* Procedure: Surgery
* Drug: Folinic Acid
* Drug: Fluorouracil
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases Patient must be 18 years of age or greater. Potentially resectable en bloc based upon surgeon evaluation Clinical stages T3 or T4, based upon endorectal ultrasound, or physical examination (only acceptable for T4 lesions). Absolute neutrophil count of > 1500 per microliter and platelet count > 100,000 per microliter; aspartate aminotransferase (AST) and alkaline phosphatase < 2.5 X upper limit of normal (ULN), bilirubin < = 1.5 ULN, calculated creatinine clearance > 50 ml/min using Cockcroft-Gault formula: CrCl male = (140 - age) x (wt. in kg) / (Serum Cr) x 72 CrCl female = 0.85 x (CrCl male) Zubrod performance status 0-2 No history of other malignancies within 5 years, except non-melanoma skin cancer, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast. Previous invasive cancer permitted if disease free at least 5 years. Signed study-specific informed consent prior to randomization Exclusion Criteria: Any evidence of distant metastasis Synchronous primary colon carcinomas, except T1 lesions (full colonoscopy not required for enrollment) Extension of malignant disease to the anal canal Prior radiation therapy to the pelvis Prior chemotherapy for malignancies Pregnancy or lactation, (exclusion due to potential adverse effects of therapy). Women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline. Women/men of childbearing potential not using a reliable and appropriate contraceptive method. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered to be of non-childbearing potential.) Patients will agree to continue contraception for 30 days from the date of the last study drug administration. Serious, uncontrolled, concurrent infection(s). Participation in any investigational drug study within 4 weeks preceding the start of study treatment. Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months. Evidence of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake. Other serious uncontrolled medical conditions that the investigator feels might compromise study participation. Major surgery within 4 weeks of the study treatment. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome. Known, existing uncontrolled coagulopathy. No concurrent cimetidine allowed.

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 |
| --- | --- |
| Experimental: Neoadjuvant chemoradiation with irinotecan<br>Patients receive neoadjuvant therapy comprising 45 Gy (1.8 Gy/fx) + 5.4 Gy boost (1.8 Gy/fx) radiation therapy (RT), oral capecitabine 1200mg/m^2/day 5 days/week during RT, and irinotecan 50 mg/m^2 IV for 1 hour days 1, 8, 22, 29. Surgery 4-8 weeks after RT. Postoperative chemotherapy beginning Day 1 postoperatively for nine 14-day cycles(folinic acid 400 mg/m^2 over 2 hours Day 1; 5-fluorouracil bolus 400 mg/m^2 IV push Day 1 plus 2400 mg/m^2 IV continuous infusion over 46 hours, beginning Day 1; and oxaliplatin 85 mg/m^2 IV over 2 hours Day 1) . | Radiation: Radiation Therapy<br>* Pelvic radiation therapy given once daily 5 days a week for 6 weeks, 45 Gy in 25 fractions + boost of 5.4 Gy in 3 fractions for a total dose of 50.4 Gy.<br>Drug: Capecitabine 1200 mg/m^2/day<br>* 600 mg/m^2 q12 hours(1200 mg/m^2/day) orally 5 days per week during radiotherapy.<br>Drug: Irinotecan<br>* 50mg/m^2 IV over 1 hour on days 1, 8, 22, and 29<br>* Other names: Irinotecan Hydrochloride;Procedure: Surgery<br>* All patients will undergo surgery four to eight weeks following the completion of radiation therapy. The choice of procedure abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis is at the discretion of the surgeon.<br>Drug: Folinic Acid<br>* 400 mg/m^2 IV over 2 hours Day 1 (postoperatively) ,every 14 days, for nine 14-day cycles.<br>* Other names: Leucovorin;Drug: Fluorouracil<br>* 5-fluorouracil bolus 400 mg/m^2 IV push Day 1 (postoperatively), every 14 days, for nine 14-day cycles. 5-fluorouracil infusion 2400 mg/m^2 IV continuous infusion over 46 hours, beginning day 1, every 14 days, for nine 14-day cycles.<br>* Other names: 5-FU;Drug: Oxaliplatin<br>* 85 mg/m^2 IV over 2 hours Day 1 (postoperatively), every 14 days, for nine 14-day cycles.<br>|
| Experimental: Neoadjuvant chemoradiation with oxaliplatin<br>Patients receive neoadjuvant therapy comprising 45 Gy (1.8 Gy/fx) + 5.4 Gy boost (1.8 Gy/fx) radiation therapy (RT), oral capecitabine 1650mg/m^2/day 5 days/week during RT, and oxaliplatin 50 mg/m^2 IV for 2 hours days 1, 8, 15, 22, 29. Surgery 4-8 weeks after RT. Postoperative chemotherapy beginning Day 1 postoperatively for nine 14-day cycles(folinic acid 400 mg/m^2 over 2 hours Day 1; 5-fluorouracil bolus 400 mg/m^2 IV push Day 1 plus 2400 mg/m^2 IV continuous infusion over 46 hours, beginning Day 1; and oxaliplatin 85 mg/m^2 IV over 2 hours Day 1) . | Radiation: Radiation Therapy<br>* Pelvic radiation therapy given once daily 5 days a week for 6 weeks, 45 Gy in 25 fractions + boost of 5.4 Gy in 3 fractions for a total dose of 50.4 Gy.<br>Drug: Capecitabine 1650 mg/m^2/day<br>* 825 mg/m^2 q12 hours (1650 mg/m^2/day) orally 5 days per week during radiotherapy.<br>Drug: Oxaliplatin<br>* 50mg/m^2 IV over 2 hours on days 1, 8, 15, 22, and 29<br>Procedure: Surgery<br>* All patients will undergo surgery four to eight weeks following the completion of radiation therapy. The choice of procedure abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis is at the discretion of the surgeon.<br>Drug: Folinic Acid<br>* 400 mg/m^2 IV over 2 hours Day 1 (postoperatively) ,every 14 days, for nine 14-day cycles.<br>* Other names: Leucovorin;Drug: Fluorouracil<br>* 5-fluorouracil bolus 400 mg/m^2 IV push Day 1 (postoperatively), every 14 days, for nine 14-day cycles. 5-fluorouracil infusion 2400 mg/m^2 IV continuous infusion over 46 hours, beginning day 1, every 14 days, for nine 14-day cycles.<br>* Other names: 5-FU;Drug: Oxaliplatin<br>* 85 mg/m^2 IV over 2 hours Day 1 (postoperatively), every 14 days, for nine 14-day cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate | A pathologic complete response (pCR) was defined as no evidence of residual cancer histologically; disease progression or death before surgery was considered less than pCR (even without surgical specimen). All cases were reviewed by the study's surgical oncology co-chair for the determination of pCR. Each arm was first analyzed alone. If the arm had 9 or more pCRs in 48 evaluable pts, then the null hypothesis (H0) of 10% pCR rate would be rejected in favor of the alternative hypothesis of 25%, providing 90% power with a two-sided 10% type I error rate. If both arms reject H0, then statistical selection theory would be used to choose the arm for further study in a phase III trial. If only one arm has acceptable pCR rate, then that arm would be pursued in a phase III trial. | After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Rate at 4 Years | Survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. | From randomization to four years | 
| Local-regional Failure Rate at 4 Years | Local-regional failure is defined as any of the following: no clinical complete response (cCR) in the primary site and/or nodes at any time after treatment completion (persistence), recurrence and/or progression in the primary site and/or nodes after cCR, and nonprotocol surgery to the primary site after cCR. Time to local-regional failure is defined as time from randomization to date of failure, last known follow-up (censored), or death without local-regional failure (competing risk). Local-regional failure rates are estimated by the cumulative incidence method. | From randomization to four years | 
| Distant Failure Rate at 4 Years | Time to distant failure is defined as time from randomization to date of the appearance of distant metastases, last known follow-up (censored), or death without distant failure (competing risk). Distant failure rates are estimated by the cumulative incidence method. | From randomization to four years | 
| Second Primary Rate at 4 Years | Time to second primary is defined as time from randomization to date of the appearance of a second primary cancer, last known follow-up (censored), or death without second primary (competing risk). Second primary rates are estimated by the cumulative incidence method. | From randomization to four years | 
| Disease-free Survival Rate at 4 Years | Disease-free survival time is defined as time from randomization to date of local-regional failure, the appearance of distant metastases, the appearance of a second primary failure, or date of death from any cause/ Disease-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. | From randomization to four years | 
| Number of Participants With Grade 3+ Treatment-related Adverse Events | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (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. | From start of treatment to end of follow-up. Maximum follow-up is 5.2 years. | 
| Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (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. | From start of treatment to surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation. If no surgery, then <= 90 days from start of treatment. | 
| Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively | Highest grade adverse event per subject were counted. Adverse events were graded using the Common Terminology Criteria for Adverse Events (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. | From post-surgery to before chemotherapy (CT), or within 60 days of surgery if no postoperative CT. Approximately 10-16 weeks to 14-22 weeks from randomization based on CT starting 4-6 weeks after surgery. | 
| Tumor Marker Evaluation Using Preoperative Tissue Biopsy Specimens and Surgically Resected Tissue Specimens |  | End of study | 
| Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL. | Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization | 
| Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A positive number indicates improvement in QOL. | Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | 
| Change From Baseline in QLQ-C30 Global Health Status Score at Two Years | Global Health Status is calculated from two questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30. The question responses range from 1 very poor to 7 excellent such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates decline in quality of life. A negative number indicates improvement in symptoms. | Baseline and two years | 
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and completion of chemoradiation approximately 6-8 weeks from randomization | 
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | 
| Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years | The gastro-intestinal (GI) symptom score is calculated from five symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 (not at all) to 4 (very much) such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and two years | 
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization | 
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and completion of post-operative chemotherapy, approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy | 
| Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years | The defecation symptom score is calculated from seven symptom questions on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-CR38. The question responses range from 1 not at all to 4 very much such that a higher response indicates worse symptoms. The mean of these responses is linearly transformed to a range of 0 (best) to 100 (worst). Change from baseline is calculated as the time point value - baseline value and a decrease from baseline indicates improvement in symptoms. A negative number indicates improvement in symptoms. | Baseline and two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III rectal cancer, adenocarcinoma of the rectum, stage II rectal cancer