Randomized Phase II Trial Of Neoadjuvant Combined Modality Therapy For Locally Advanced Rectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 146
- 试验地点
- 5
- 主要终点
- Pathologic Complete Response Rate
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Radiation Therapy (Radiation)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Capecitabine 1200 mg/m^2/day (Drug)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Irinotecan (Drug)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Surgery (Procedure)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Folinic Acid (Drug)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Fluorouracil (Drug)
Neoadjuvant chemoradiation with irinotecan
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) .
干预措施: Oxaliplatin (Drug)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Radiation Therapy (Radiation)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Capecitabine 1650 mg/m^2/day (Drug)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Oxaliplatin (Drug)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Surgery (Procedure)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Folinic Acid (Drug)
Neoadjuvant chemoradiation with oxaliplatin
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) .
干预措施: Fluorouracil (Drug)
结局指标
主要结局
Pathologic Complete Response Rate
时间窗: After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation
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.
次要结局
- Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively(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(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(Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy)
- Survival Rate at 4 Years(From randomization to four years)
- Distant Failure Rate at 4 Years(From randomization to four years)
- Second Primary Rate at 4 Years(From randomization to four years)
- Local-regional Failure Rate at 4 Years(From randomization to four years)
- Disease-free Survival Rate at 4 Years(From randomization to four years)
- Number of Participants With Grade 3+ Treatment-related Adverse Events(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(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.)
- Change From Baseline in QLQ-C30 Global Health Status Score at Two Years(Baseline and two years)
- Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation(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(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(Baseline and two years)
- Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation(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(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(Baseline and two years)