The key evidence supporting the use of this protocol comes from the updated Dutch trial, the MRC-CR07 trial, TROG 0104, and the Polish study by Bjuko et al.rrrr
Neoadjuvant short course versus surgery alone
The Dutch Colorectal Cancer Group trial randomised 1861 patients with resectable rectal cancer (tumours not further than 15cm from the anal verge and below the level of S1-2) to receive either pre-operative radiotherapy (25Gy in 5 fractions) followed by TME (n=924) or TME alone (n=937).r 85 patients received post-operative radiotherapy.
Long-term data (with a median follow up of 12 years) was published in 2011.
- The 10 year rates of local recurrence were 11% and 5% for the two groups respectively (p < 0.0001), but no significant difference in overall survival was detected.
- For patients with stage III cancer with a negative circumferential resection margin, 10 year survival was 50% in the pre-operative radiotherapy group vs 40% in the surgery alone group (p=0.032).
- Subgroup analysis demonstrated that increasing distance from the anal verge was associated with greater radiotherapy effect; this was analysed as a continuous variable rather than the arbitrary cut offs of 5 and 10cm in the previous analysis.
- At 12 year follow up, the cumulative incidence of cancer specific death at 10 years was 17% for RT+TME group and 22% for TME alone, (p=0.04).
Figure 1: Local recurrence in the 1748 eligible patients who underwent a macroscopically complete local resection. RT = radiotherapy, TME = total mesorectal excision.
© Lancet Oncol 2011r
The MRC CR-07 trial randomised 1350 patients to preoperative RT (25Gy in 5 fractions) or selective postoperative CRT in patients with positive margins (45Gy in 25 fractions with concurrent fluorouracil).r TME resections were performed in 92% of patients. 53 patients received postoperative chemoradiotherapy and 7 received postoperative radiotherapy only. At 4 years follow-up, results show both local control and disease-free survival were improved by pre-operative radiotherapy when compared to selective postoperative CRT.
- A 61% reduction in the relative risk of local recurrence in patients receiving pre-operative RT, and an absolute difference in 3-year disease free survival at 3 years of 6% was reported.
- Subgroup analyses suggested a small down staging effect on T stage (p= 0.0001) in the pre-operative group, however, no difference in overall survival was noted between the treatment groups.
Short course RT vs long course chemoradiation
In 2012, the Trans Tasman Radiation Oncology Group (TROG) published the results of a randomised trial comparing neoadjuvant short course RT and long course CRT for patients with T3 rectal cancer.r With a median follow up of more than 5 years, rates of acute and late toxicity were similar in the two groups. No statistically significant differences were seen in 3-year rates of local recurrence, DFS and OS. A trend towards improved down staging was noted in the long-course group, although a reduction in APR rates for distal tumours was not observed. The authors commented that for bulky or distal tumours, long-course CRT may be preferable to short-course RT.
The Polish study by Bujko et al 2004 randomised 316 patients to preoperative 5x 5Gy short course irradiation with TME or CRT of 50.4Gy with 2 courses of bolus fluorouracil followed by TME.r This study found that despite significant down staging, CRT did not result in increased sphincter preservation rate. There was no difference seen in disease free survival, local control or late toxicity, however this trial was powered specifically to look at sphincter preservation.
Timing of surgery
Recommended timing of surgery is within 10 days of starting radiotherapy.rr
The timing of surgery after short course RT has been reported in the Stockholm III trial.r In this randomised, non-blinded, phase 3, non-inferiority trial patients were randomised to either 5 x5 Gy short course with surgery within a week, or after 4-8 weeks. Acute radiation induced toxicity was recorded in 1 (<1%) patients in the immediate surgery group and 23 (7%) in the delayed surgery arm. In a pooled analysis of the two short course radiotherapy regimens, the risk of postoperative complications was significantly lower after short course radiotherapy with delay to surgery 53% vs 41% , OR 0.61 P =0.001. Therefore short course radiotherapy with 4-8 weeks delay to surgery is a valid alternative to conventional short course radiotherapy with immediate surgery. The feasibility of this approach has also been demonstrated in retrospective studies.rr This increase in post-operative complications was not seen in patients treated with the first fraction of radiotherapy within 10 days.r