Intergroup Randomized Phase III Study of Postoperative Irinotecan, 5-Fluorouracil and Leucovorin vs. Oxaliplatin, 5-Fluorouracil and Leucovorin vs. 5-Fluorouracil and Leucovorin for Patients With Stage II or III Rectal Cancer Receiving Either Preoperative Radiation and 5-Fluorouracil or Postoperative Radiation and 5-Fluorouracil
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 225
- 试验地点
- 1
- 主要终点
- 3-year Overall Survival Rate
研究概览
简要总结
This randomized phase III trial is comparing the effectiveness of three adjuvant combination chemotherapy regimens in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for stage II or stage III rectal cancer. Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, and oxaliplatin, use 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. It is not yet known which adjuvant combination chemotherapy regimen is more effective in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for rectal cancer.
详细描述
PRIMARY OBJECTIVES:
I. To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin versus those treated with oxaliplatin, leucovorin and 5-FU versus those treated with leucovorin and 5-FU for patients with stage II and III rectal cancer.
SECONDARY OBJECTIVES:
I. To determine sphincter preservation, tolerance of treatment and patterns of failure.
II. To describe patterns of failures
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
- •Patients must have histologically proven adenocarcinoma of the rectum with no distant metastases. Clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0).
- •Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.
- •The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 cm of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of surgery are eligible regardless of the distance determined by endoscopy.
- •Transmural penetration of tumor through the muscularis propria must be demonstrated by CT scan, endo-rectal ultrasound or MRI.
- •Tumors must be defined prospectively by the surgeon as clinically resectable or not.
- •Clinically resectable tumors will be defined by the surgeon as not fixed and completely resectable with negative margins based on the routine examination of the non-anesthetized patient.
- •Before pre-op treatment, the surgeon should estimate and record the type of resection anticipated: APR, LAR or LAR/coloanal anastomosis.
- •The tumor may be clinically fixed or initially not completely resectable, clinical stage T4 N0-2 M0 based on the presence of at least one of the following criteria:
- •Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum.
- •Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into prostate.
- •Vaginal or uterine involvement.
- •Patients must not have a previous or concurrent malignancy, with the exception of:
- •Nonmelanoma skin cancer or in situ cervical cancer.
- •Treated non-pelvic cancer from which the patient has been continuously disease-free for >5 years.
- •Patients must have ECOG performance status 0-
- •Patients must be > 18 years of age.
- •All females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy.
- •Sexually-active women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception
排除标准
- •Patients have received prior chemotherapy or pelvic irradiation therapy.
- •Female patients must not be pregnant or breast-feeding.
- •Patients have an active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy.
- •Group II (Post-operative) Registration
- •Inclusion Criteria:
- •Patients must have had histologically proven adenocarcinoma of the rectum with no distant metastases. Pathologic staging is required (T3N0M0, T4N0M0, TanyN1-3M0).
- •Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.
- •The distal border of the tumor must have been at or below the peritoneal reflection, defined as within 12 centimeters of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of the surgery are eligible regardless of the distance determined by endoscopy.
- •Patients must not have received prior chemotherapy or pelvic irradiation therapy.
- •Patients must not have a previous or concurrent malignancy, with the exception of:
- •Non-melanoma skin cancer or in situ cervical cancer.
- •Treated non-pelvic cancer from which the patient has been continuously disease-free for >5 years.
- •Patients must have ECOG performance status 0-
- •Patients must be > 18 years of age.
- •All females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy.
- •Sexually active women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception.
- •Exclusion Criteria:
- •Patients have an active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy.
- •Female patients are pregnant or breast-feeding.
- •Randomization (Groups I and II)
- •Inclusion Criteria:
- •Patients must have a completely resected tumor and be within 21-56 days from the date of surgery.
- •Patients who received combination chemotherapy/XRT prior to randomization (Group I) must have had a minimum radiation dose of 50.4 Gy.
- •Patients must have ECOG performance status 0-
- •Patients must have adequate renal function (creatinine < 1.5 x ULN) obtained < 4 weeks prior to randomization.
- •Patients must have adequate hepatic function (bilirubin < 1.5 x ULN, SGOT (AST) < 3 x ULN) obtained < 4 weeks prior to randomization).
- •Patients must have absolute neutrophil count > 1500/mm3 and platelet count > 100,000/mm3 < 4 weeks prior to randomization.
- •Exclusion Criteria:
- •Patients have an active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy.
研究组 & 干预措施
Group I, Arm I
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group I, Arm I
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group I, Arm I
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
Group I, Arm I
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Irinotecan (Drug)
Group I, Arm II
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group I, Arm II
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group I, Arm II
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
Group I, Arm II
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Group I, Arm III
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group I, Arm III
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group I, Arm III
Patients receive 1 of 3 preoperative chemo and radiotherapy treatment regimens, determined by the treating physician. Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
Group II, Arm I
Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group II, Arm I
Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group II, Arm I
Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
Group II, Arm I
Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Irinotecan (Drug)
Group II, Arm II
Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group II, Arm II
Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group II, Arm II
Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
Group II, Arm II
Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.
Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Oxaliplatin (Drug)
Group II, Arm III
Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Radiotherapy (Radiation)
Group II, Arm III
Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Fluorouracil (Drug)
Group II, Arm III
Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemo and radiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity.
干预措施: Leucovorin Calcium (Drug)
结局指标
主要结局
3-year Overall Survival Rate
时间窗: assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years
Overall survival (OS) was defined as time from randomization to death from any cause. 3-year OS rate was estimated using Kaplan-Meier method.
次要结局
- Proportion of Sphincter Preservation(assessed at primary surgery time)
- 3-year Disease Free Survival(assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years)
- Failure Pattern(assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years)