Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 920
- 试验地点
- 64
- 主要终点
- Disease related Treatment Failure (DrTF)
研究概览
简要总结
Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.
详细描述
Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/ 5-fluorouracil and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.
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 (Outcomes Assessor)
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
- •Primary tumour characteristics:
- •Histological proof of newly diagnosed primary adenocarcinoma of the rectum
- •Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (clinical T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to tumor node metastasis (TNM-Classification version 5)), clinical T4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive Mesorectal Fascia (MRF+), i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes (LN), > 1 cm (lat LN+)
排除标准
- •Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen
- •Presence of metastatic disease or recurrent rectal tumour
- •Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis
- •Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years
- •Known Dihydro-Pyrimidine Dehydrogenase (DPD) deficiency
- •Any contraindications to MRI (e.g. patients with pacemakers)
- •Medical or psychiatric conditions that compromise the patient's ability to give informed consent
- •Concurrent uncontrolled medical conditions
- •Any investigational treatment for rectal cancer within the past month
- •Pregnancy or breast feeding
- •Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract
- •Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months
- •Patients with symptoms or history of peripheral neuropathy
研究组 & 干预措施
B: 5x5Gy -> CAPOX -> surgery
experimental group (arm B) M1 scheme: 5 fractions of 5 Gy external beam radiation (5x5Gy) followed by CAPOX followed by TME surgery
干预措施: M1 scheme (Other)
A: 5 weeks chemoradiation -> surgery
control group (arm A) standard long course chemoradiotherapy followed by TME surgery
干预措施: standard long course chemoradiotherapy (Other)
结局指标
主要结局
Disease related Treatment Failure (DrTF)
时间窗: 3 year follow-up after surgery
DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait \& watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.
Number of Patients With Disease Related Treatment Failure (DrTF)
时间窗: 3 years follow-up after surgery
DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait \& watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.
次要结局
- Surgical complications(3 year follow-up)
- Quality of life QLQ-CIPN20(3 year after surgery)
- CRM negative rate(within 30 days)
- Quality of life QLQ-CR-29+(3 year after surgery)
- Overall survival(10 year)
- Short and long-term toxicity(3 year follow-up)
- Quality of life QLQ-C30(3 year after surgery)
- pCR rate(within 30 days)
- Quality of life LARS(3 year after surgery)
- Number of Patients Completing the Prescribe Neo-adjuvant Treatment Dose(30 days after neoadjuvant treatment)
- Number of Patients With Negative CRM Negative(30 days after surgery)
- Number of Patients With a Pathological Complete Response (pCR)(30 days after surgery)
- Number of Patients With Surgical Complications(30 days after surgery)
- Quality of Life QLQ-C30 Scores(3 year after surgery)
- Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20)(3 year after surgery)
- Quality of Life LARS Scores(3 year after surgery)
- Number of Patients With a Locoregional Recurrence(5 years after surgery)
- Overall Survival(10 year)
研究者
B. van Etten, MD, PhD
Dr. B. van Etten, surgical oncologist
University Medical Center Groningen