Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait. A Multi-center Prospective Randomized Controlled Trial. (CCHOWW)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 216
- 试验地点
- 24
- 主要终点
- Decision to Watch and Wait due to clinical complete response
研究概览
简要总结
Background: Neoadjuvant chemoradiation (nCRT) has been considered the preferred initial treatment strategy for distal rectal cancer. Advantages of this approach include improved local control after radical surgery but also the opportunity for organ preserving strategies (Watch and Wait - WW). Consolidation chemotherapy (cCT) regimens using fluoropyrimidine-based with or without oxaliplatin following nCRT have demonstrated to increase complete response and organ preservation rates among these patients. However, the benefit of adding oxaliplatin to cCt compared to fluoropyrimidine alone regimens in terms of primary tumor response remains unclear. Since oxaliplatin-treatment may be associated with considerable toxicity, it becomes imperative to understand the benefit of its incorporation into standard cCT regimens in terms of primary tumor response. The aim of the present trial is to compare the outcomes of 2 different cCT regimens following nCRT (fluoropyrimidine-alone versus fluoropyrimidine+oxaliplatin) for patients with distal rectal cancer.
Methods: In this multi-centre study, patients with magnetic resonance-defined distal rectal tumors will be randomized on a 1:1 ratio to receive long-course chemoradiation (54Gy) followed by cCT with fluoropyrimidine alone versus fluoropyrimidine+oxaliplatin. Magnetic resonance (MR) will be analyzed centrally prior to patient inclusion and randomization. mrT2-3N0-1 tumor located no more than 1cm above the anorectal ring determined by sagittal views on MR will be eligible for the study. Tumor response will be assessed after 12 weeks from radiotherapy (RT) completion. Patients with clinical complete response (clinical, endoscopic and radiological) will be enrolled in an organ-preservation program (WW). The primary endpoint of this trial is decision to organ-preservation surveillance (WW) at 18 weeks from RT completion.
Discussion: Long-course nCRT with cCT is associated with improved complete response rates and may be a very attractive alternative to increase the chances for organ-preservation strategies. Fluoropyrimidine-based cCT with or without oxaliplatin has never been investigated in the setting of a randomized trial to compare clinical response rates and the possibility of organ-preservation. The outcomes of this study may significantly impact clinical practice of patients with distal rectal cancer interested in organ-preservation.
详细描述
Patients and Methods
Patients with distal rectal cancer will be eligible for the study after initial clinical, endoscopic and radiological assessment. At this point, patients will be offered to participate in the study and after informed consent, randomized to control or experimental arms as follows.
Endpoints
Primary endpoint: Decision to Watch and Wait due to clinical complete response achieved at 18 weeks from last date of radiation using clinical (DRE), endoscopic and radiological criteria (mrTRG grade) or near-complete clinical response (no progressive disease clinically, endoscopically or radiologically)
Definition of clinical complete response (cCR) available below and at the discretion of the attending surgeon.
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
- Single (Investigator)
盲法说明
Patients and attending phisicians will not be blinded to the treatment arm randomized for each patient. However, as a strategy to reduce investigator's expectations and reduce inherent bias, the central committee will be blinded to the treatment arm. It is expected that blinding the central committee, who will be responsible for assessing the primary endpoint, any bias related to the investigator's expectation about the treatment arm and the chances of Watch and Wait will be nulled.
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
- •Age ≥18 years;
- •ECOG 0-2 or KPS≥70;
- •Primary rectal adenocarcinoma (biopsy confirmed) within the reach of digital rectal examination (at least lower tip/border) by the attending colorectal surgeon;
- •Endoscopic documentation;
- •Abdominal and chest CT scans showing no evidence of metastatic disease;
- •High-resolution magnetic resonance images performed at either 1.5T or 3.0T system using a phased array surface coil with: sagittal T2 images including the anal verge and the sacrum; axial oblique T2 weighted images acquired in a plane perpendicular to the long axis of the rectal wall guided by the sagittal images; coronal images acquired in parallel to the anal canal plane. Small field of view (16-18cm), 3mm section thickness, increased matrix size and increased number of signal averages are required;
- •Radiological defining criteria (centralized):
- •Lower edge of tumor at the level (max. 1cm distance) or below the anorectal ring defined at sagittal or coronal views;
- •mrT2, mrT3 (any subclassification)
- •mrN0-1 (≤3 radiologically positive lymph nodes)
- •mrEMVI: any status
- •mrMRF: any status
排除标准
- •ECOG ≥3 or KPS<70
- •Unwilling to consent
- •Metastatic disease (any kind; internal iliac and obturator nodes are considered local disease and not metastatic disease and therefore will not be considered as exclusion criteria)
- •mrT4 or mrN2
- •Previous pelvic irradiation
- •Baseline neuropathy
- •Receiving treatment of other anti-cancer drug or methods
- •Presence of uncontrolled life threatening diseases
研究组 & 干预措施
Arm 1 - 5FU + Oxaliplatin
- RT (54Gy) plus daily concomitant capecitabine 825mg/m2 bid, followed by mFOLFOX6 or XELOX for 4 cycles (12 weeks), starting 1 week after radiotherapy ended;
干预措施: Oxaliplatin (Drug)
Arm 1 - 5FU + Oxaliplatin
- RT (54Gy) plus daily concomitant capecitabine 825mg/m2 bid, followed by mFOLFOX6 or XELOX for 4 cycles (12 weeks), starting 1 week after radiotherapy ended;
干预措施: 5FU (Drug)
Arm 2 - 5FU Only
- RT (54Gy) plus daily concomitant capecitabine 825mg/m2 bid, followed by capecitabine 2000mg/m2/day for 14 days in a 21 days cycle for 4 cycles (12 weeks), starting 1 week after radiotherapy ended;
干预措施: 5FU (Drug)
结局指标
主要结局
Decision to Watch and Wait due to clinical complete response
时间窗: 18 weeks from last date of radiation
Decision to Watch and Wait due to clinical complete response achieved at 18 weeks from last date of radiation using clinical (DRE), endoscopic and radiological criteria (mrTRG grade) or near-complete clinical response (no progressive disease clinically, endoscopically or radiologically)
次要结局
- Local regrowth-free survival at 3 years(3 years from last date of radiation)
- Surgery-free survival at 3 years(3 years from last date of radiation)
- Total Mesorectal Excision-free survival at 3 years(3 years from last date of radiation)
- Distant metastases free survival at 3 years(3 years from last date of radiation)
- Colostomy-free survival at 3 years(3 years from last date of radiation)
研究者
Rodrigo Oliva Perez
Principal Investigator
Hospital Alemão Oswaldo Cruz