The key evidence supporting the use of this protocol comes from the updated Dutch trial,r the MRC-CR07 trial,r TROG 0104,r the Polish study by Bjukor and the meta-analysis by Camma.r
Neoadjuvant short course versus surgery alone
The meta-analysis by Cammar concluded that, compared to surgery alone, the combination of pre-operative radiotherapy and surgery significantly improved overall survival and cancer specific survival. Surgical technique is a key factor in the success of tumour control, and significant improvements in local control have been seen with the use of total mesorectal excision (TME).rr
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 preoperative radiotherapy (25Gy in 5 fractions) followed by total mesorectal excision (TME) (n=924) or TME surgery alone (n=937).
Long-term data (with a median follow up of 12 years) was published in 2011.r
- 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 2: Local recurrence in the 1748 eligible patients who underwent a macroscopically complete local resection. RT = radiotherapy, TME = total mesorectal excision.
© Lancet Oncol Van Gijn, 2011r
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 cancer1. 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 2004r randomised 316 patients to preoperative 5x5Gy short course irradiation with TME or CRT of 50.4Gy with 2 courses of bolus fluorouracil followed by TME. This study found that despite significant downstaging, 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.
The MRC CR-07 trialr 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). TME resections were performed in 92% of patients. 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-op group, however, no difference in overall survival was noted between the treatment groups.
Timing of surgery
Recommended timing of surgery is within 10 days of starting radiotherapy.rr
The timing of surgery after short course RT is under investigation in the Stockholm III trial. An interim analysis of 303 patients showed decreased complications in the delayed surgery group (4-8 weeks) compared to the immediate surgery group.r The feasibility of the approach has also been demonstrated in retrospective studies.rr