Treatment Strategies in Colorectal Cancer Patients with Initially Unresectable Liver-only Metastases CAIRO5 a Randomized Phase 3 Study of the Dutch Colorectal Cancer Group (DCCG)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 530
- 试验地点
- 55
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and no consensus exist on criteria for resectability.
In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by an expert panel according to predefined criteria, will be tested for RAS and BRAF tumor mutation status and selected by location of primary tumor. Patients with RAS or BRAF mutant and/or right sided tumors will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab (schedule 1), and triple chemotherapy (FOLFOXIRI) plus bevacizumab (schedule 2). Patients with RAS AND BRAF wildtype AND left-sided primary tumors will be randomized between doublet chemotherapy (FOLFOX or FOLFIRI) plus either bevacizumab (schedule 1) or panitumumab (schedule 3). Patient imaging will be reviewed for resectability by a central panel, consisting of at least one radiologist and three surgeons every assessment. Central panel review will be performed prior to randomization as well as during treatment, as described in the protocol.
详细描述
Patients will be stratified for resectability of liver metastases (potentially resectable versus permanently unresectable), serum lactate dehydrogenase (LDH) (normal versus abnormal), BRAF mutation status (wildtype versus mutated), type of neoadjuvant chemotherapy (FOLFIRI versus FOLFOX) and hospital of registration.
Patients with RAS and BRAF wildtype and left-sided primary tumors will be randomised between FOLFOX or FOLFIRI plus either bevacizumab or panitumumab. The choice between FOLFOX or FOLFIRI is to the discretion of the local investigator, however, the treatment is restricted to regimens that are specified in the protocol. Patients with RAS or BRAF mutated and/or right-sided primary tumors will be randomized between FOLFOX/ FOLFIRI (investigator choice) plus bevacizumab or 5FU, irinotecan, oxaliplatin (FOLFOXIRI) plus bevacizumab.
Patients will be evaluated every 8 weeks by CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months the panel concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment. These patients should continue with the targeted drug in combination with chemotherapy, but the chemotherapy may be altered into a less toxic schedule such as fluoropyrimidine monotherapy. The targeted drug should be continued until progression or unacceptable toxicity. In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months, with the chemotherapy schedule being administered according to the assigned treatment arm. However in these patients the targeted drug (bevacizumab or panitumumab) should not be continued after 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
- •Histological proof of colorectal cancer
- •Initially unresectable metastases confined to the liver according to CT scan, obtained ≤3 weeks prior to registration. Unresectability should be confirmed by the liver expertpanel. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible
- •Known mutation status of RAS and BRAF
- •WHO performance status 0-1 (Karnofsky performance status ≥ 70)
- •Age ≥ 18 years
- •No contraindications for liver surgery
- •In case of primary tumor in situ: tumor should be resectable
- •In case of resected primary tumor: adequate recovery from surgery
- •Adequate organ functions, as determined by normal bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ≥ 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 5x ULN)
- •Life expectancy > 12 weeks
- •Expected adequacy of follow-up
- •Written informed consent
排除标准
- •Extrahepatic metastases, with the exception of small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases
- •Unresectable primary tumor
- •Serious comorbidity or any other condition preventing the safe administration of study treatment (including both systemic treatment and surgery)
- •Major cardiovascular events (myocardial infarction, severe/unstable angina, congestive heart failure, CVA) within 12 months before randomisation
- •Uncontrolled hypertension, or unsatisfactory blood pressure control with ≥3 antihypertensive drugs
- •Previous systemic treatment for metastatic disease; previous adjuvant treatment is allowed if completed ≥ 6 months prior to randomisation
- •Previous surgery for metastatic disease
- •Previous intolerance of study drugs in the adjuvant setting
- •Pregnant or lactating women
- •Second primary malignancy within the past 5 years with the exception of adequately treated in situ carcinoma of any organ or basal cell carcinoma of the skin, or second primary colorectal cancer.
- •Any concomitant experimental treatment.
研究组 & 干预措施
Arm B: FOLFOXIRI & bevacizumab (inclusion completed)
Patients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab.
Intervention: FOLFOXIRI with bevacizumab
干预措施: FOLFOXIRI with bevacizumab (Drug)
Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed)
Patients with RAS or BRAF mutated and/or right-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab.
Intervention: FOLFOX/FOLFIRI with bevacizumab
干预措施: FOLFOX/ FOLFIRI with bevacizumab (Drug)
Arm D: FOLFOX/FOLFIRI & panitumumab
Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus panitumumab.
Intervention: FOLFOX/FOLFIRI with panitumumab
干预措施: FOLFOX/ FOLFIRI with panitumumab (Drug)
Arm C: FOLFOX/ FOLFIRI & bevacizumab
Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab.
Intervention: FOLFOX/FOLFIRI with bevacizumab
干预措施: FOLFOX/ FOLFIRI with bevacizumab (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: 2 years after last patient in study
Time from registration until progression or death whichever comes first
次要结局
- R0/1 secondary resection rate(2 years after last patient in study)
- Median overall survival(8 years after last patient in study)
- Toxicity (AE)(2 years after last patient in study)
- Response rate(2 years after last patient in study)
- Pathological complete response rate (pCR)(2 years after last patient in study)
- Postoperative morbidity(After surgery during two months)
- Correlation of evaluation by the panel with outcome(2 years after last patient in study)