Radiotherapy for rectal cancer: Short course versus long course – When and how

Abstract

Prior to the introduction of improved surgical techniques such as total mesorectal excision, local recurrence rates after resection were unacceptably high with surgery alone. Phase III trials were designed to determine the benefit of the addition of radiotherapy to radical surgery, and these have reported significant reductions in local recurrence. Two different strategies were evaluated in the preoperative setting. Initially in Scandinavia the approach of a hypo-fractionated 1-week course of radiotherapy performed prior to radical surgery was evaluated in a series of phase III trials. In contrast, the strategy of integrating fluoropyrimidine chemotherapy with long-course fractionated radiotherapy in the postoperative setting was then evaluated preoperatively. Two key trials determined that the addition of fluoropyrimidine to neoadjuvant radiotherapy compared with radiotherapy alone significantly reduced the risk of local recurrence. Following the increasing use of total mesorectal excision and the associated lower rates of local recurrence, in the Netherlands and in the United Kingdom (UK) two phase III trials were conducted. The Dutch TME and MRC CR07 trials showed a reduction in local recurrence from the addition of short-course preoperative radiotherapy but without any impact on overall survival. The two strategies (short-course and long-course treatment) have developed in parallel. This leads to a number of questions: • When preoperative radiotherapy is combined with radical surgery to reduce the risk of local recurrence, is there any difference in the efficacy of the two approaches? • Is there any difference in the acute toxicity of the two approaches? • Is there any difference in the late toxicity between the two approaches? Two phase III trials have directly compared short-course preoperative radiotherapy followed by immediate surgery versus long-course concurrent chemoradiotherapy followed by a delay in surgery. The Polish trial was designed to determine whether long-course chemoradiotherapy would increase the chance of sphincter preservation, whereas the TROG trial was designed to compare local recurrence rates between the two approaches. Given the relatively low rates of local recurrence seen in routine clinical practice and within the trials, both studies are underpowered for a formal comparison of efficacy. However, neither trial has reported a significant difference in local recurrence between the two approaches. With respect to acute toxicity, long-course chemoradiotherapy is associated with the concomitant administration of fluoropyrimidine chemotherapy. The acute toxicity is higher with this approach compared with short-course hypo-fractionated radiotherapy. In terms of long-term toxicity, neither the Polish nor the TROG trials have reported any evidence of any significant difference in late toxicity between the two approaches. The trials that have compared these two approaches have focused on the neoadjuvant use of radiotherapy combined with radical surgery. The current evidence does not suggest any major differences in efficacy and long-term outcome in patients with resectable disease. However, where the margin of excision is threatened or involved, current consensus is that long-course chemoradiotherapy is the preferred approach. There are limited non-randomised studies that have reported the use of short-course preoperative radiotherapy followed by an elective delay to surgery from both Sweden and Leeds. There are also comparative interim data from the Stockholm III trial. Short-course preoperative radiotherapy followed by an elective delay to surgery is a treatment option that could be considered in patients who are considered unsuitable for concurrent chemoradiotherapy. The use of these two radiotherapy strategies needs to be considered within the changing landscape of rectal cancer management. There is increasing interest in organ-preserving approaches where surgery is deferred or avoided. In this context dose escalation of the radiation dose is likely to increase the complete response rates. This approach is more easily and safely obtained by dose-escalating long-course concurrent chemoradiotherapy. Dose escalation of short-course radiotherapy should be approached with caution and within the context of a clinical trial. The efficacy of short-course radiotherapy and delay in early rectal cancer is the subject of an ongoing study within the UK (TREC). The Dutch CARTS study has evaluated chemoradiotherapy followed by local excision. A further area of interest is the use of neoadjuvant chemotherapy that is integrated closely with neoadjuvant radiotherapy. In this context the use of short-course radiotherapy may have some advantages and needs to be tested in clinical trials. This will be illustrated by discussion of both the European RAPIDO and the North American PROSPECT trials.