Randomized multicentre phase III study of short course radiation therapy followed by prolonged pre-operative chemotherapy and surgery in patients with high risk primary rectal cancer compared to standard preoperative chemoradiotherapy, surgery and optional adjuvant chemotherapy.

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 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. We 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.
We will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and adjuvant chemotherapy.

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. We 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.
We will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.

The primary endpoint will be analyzed two years after the last patient was included. At this time point median follow up is three years.

Duration of the study: Four year inclusion, two year follow up after inclusion of the last patient. Estimated duration of the study is six year.

Patients will be randomized between an experimental group in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery and a control group with long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy is allowed in the control group.