Non Inferiority Multicenter Phase III Randomized Trial Comparing Preoperative Chemotherapy Only to Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer (Intergroup FRENCH-GRECCAR- PRODIGE)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 540
- 试验地点
- 2
- 主要终点
- Survival
研究概览
简要总结
This study is a non-inferiority phase III randomised trial comparing preoperative chemotherapy alone (modified FOLFIRINOX) to chemotherapy followed by chemoradiotherapy in patients with primary resectable locally advanced rectal cancer. The primary endpoint of the study is 3-year progression free survival.
Expected 3 year PFS rate in the preoperative chemotherapy followed by chemoradiotherapy arm is 75%. This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 67%. The study will randomize 540 patients (270 in the chemotherapy group and 270 in the chemoradiotherapy group) in 42 french academic centers.
详细描述
This study is a national, multicenter, open-label randomized, 2-arm phase III non-inferiority trial.
Patients with mid or low LARC (cT3N0 or cT1-T3N+ with CRM > 2 mm on pretreatment MRI) will be randomized to two arms of treatment: one experimental arm with systemic FOLFIRINOX chemotherapy for 3 months and one control arm with systemic FOLFIRINOX chemotherapy for 3 months followed by conventional standardized radiochemotherapy (intensified-modulated radiotherapy 50Gy + capecitabine). The choice of FOLFIRINOX for preoperative chemotherapy is based on recent data regarding its safety and efficacy rectal cancer with or without metastatic disease. Since the annual world meeting of ASCO 2020, a new standard of treatment has been adopted using the combination of chemotherapy followed by radiochemotherapy that has been show to improve disease free survival in phase III controlled randomized trial (Conroy et al, J Clin Oncol 38: 2020 (suppl; abstr 4007).
All patients will have reassessment MRI after preoperative treatment and before surgery.
Objectives and study endpoints
- primary endpoint : 3-year progression-free survival (PFS) from the time to randomization. In this trial, a modified definition of PFS will be used for the primary endpoint. The rationale for using this modified definition of PFS is to better assess time to failure of the whole treatment strategy (preoperative treatment and surgery).
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
- •Histologically proven middle or low rectal carcinoma, ≤ 10 cm from the anal verge on MRI (sagittal slide)
- •cT3N0 and/or cT1-T3N+ on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound),
- •Pretreatment predictive circumferential margin > 2mm on pretreatment imaging work up (pelvic contrast enhanced MRI)
- •Patients must be 18 years old or older
- •A World Health Organization (WHO/ECOG) performance status of 0 or 1
- •Informed consent signed
- •Patients of childbearing / reproductive potential should use adequate birth control measures during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
排除标准
- •Rectal tumor > 10 cm from the anal verge on MRI (sagittal slide)
- •cT4 tumor on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound) or involvement of external sphincter
- •Circumferential margin ≤ 2 mm on pretreatment imaging work up (pelvic contrast enhanced MRI)
- •Metastatic disease
- •Prior pelvic irradiation or any contraindication to pelvic irradiation
- •Contraindication to oxaliplatin or irinotecan or 5FU based chemotherapy
- •Concomitant treatment with warfarin is contraindicated and warafarin must be replaced whenever possible to allow for inclusion.
- •Recent or concomitant treatment with brivudine is contraindicated
- •contraindications to 5-FU: complete and permanent insufficiency in dihydropyrimidine dehydrogenase, bone marrow insufficiency, chronic and severe infection
- •contraindication to irinotecan : inflammatory bowel disease, bilirubin serum level > 3 times the upper limit of the normal rate, severe bone marrow insufficiency, WHO/ECOG performence status > 2,
- •Concomitant treatment with millepertuis.
- •contraindication to oxaliplatin :
- •*bone marrow insufficiency before treatment initiation (neutrophil count <2x109/L and/or platelet count <100x109/L), peripheral neuropathy with permanent invalidity before treatment initiation
- •severe renal insufficiency (Creatinin clearance <30 ml/min)
- •contraindications to folinic acid : Biermer anemia and other anemia related to B12 vitamin insufficiency
- •contraindications to capecitabin : severe renal insufficiency (Creatinin clearance <30 ml/min), complete and permanent insufficiency in dihydropyrimidine dehydrogenase
- •live attenuated vaccine should not be used during and 6 months after preoperative treatment.
- •Previous colorectal cancer
- •Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years
- •Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- •protected adults
- •Pregnancy or breastfeeding
- •Patient with no national health or universal plan affiliation coverage.
研究组 & 干预措施
A: Modified Folfirinox
Experimental : preoperative chemotherapy:
Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.
干预措施: Chemotherapy (Drug)
B: Modified Folfirinox followed by Radiochemotherapy
Active comparator: preoperative chemotherapy : Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively FOLLOWED BY Preoperative radiochemotherapy with concurrent capecitabine 825 mg/m2/12h 5 days/week and intensity modulated radiation therapy using a simultaneous integrated boost technique with 45 Gy in 25 fractions in pelvic volume and 50 Gy in 25 fractions to the tumor
干预措施: Radiochemotherapy (Drug)
结局指标
主要结局
Survival
时间窗: 3 years
3-year progression-free survival
次要结局
- Size of circumferential margin(4 weeks after surgery)
- Acute treatment toxicity(Up to 1 month after the end of preoperative treatment)
- Late toxicity related to treatment(3 years after surgery)
- Radiological response(28±5 days after the end of preoperative treatment)
- The rate of R0 resection(4 weeks after surgery)
- Quality of mesorectal excision: 3-grades Quirke scoring system(4 weeks after surgery)
- Postoperative morbidity(30 days after resection)
- Uncontrolled local recurrence(At 3 years)
- Compliance to treatment(Up to 1 month after the end of preoperative treatment)
- Size of longitudinal margin(4 weeks after surgery)
- Postoperative mortality(30 days after resection)
- Number of lymph nodes harvested(4 weeks after surgery)
- Sphincter saving surgery rate(4 weeks after surgery)
- EORTC QLQ-CR29(1 year after surgery)
- LARS Scores(1 year after surgery)
- Pathologic response after chemotherapy(4 weeks after surgery)
- Quality of life - physical functioning: QLQ-C30(1 year after surgery)
- Pathologic response after chemoradiotherapy(4 weeks after surgery)
- Loco-regional recurrence free survival(At 3 years)
- Overall survival(At 5 years)
- Overall survival(At 3 years)
- EORTC QLQ-CR29(Diagnosis time)
- EORTC QLQ-CR29(28±5 days after the end of preoperative treatment)
- EORTC QLQ-CR29(At 6 months after surgery)
- LARS Scores(Diagnosis time)
- LARS Scores(28±5 days after the end of preoperative treatment)
- LARS Scores(6 months after surgery)
- Quality of life - physical functioning: QLQ-C30(At diagnosis)
- Quality of life - physical functioning: QLQ-C30(28±5 days after the end of preoperative treatment)
- Quality of life - physical functioning: QLQ-C30(6 months after surgery)