The key evidence supporting the use of this protocol comes from the following phase III trials: the German CAO/ARO/AIO-949 trial and the Australian TROG 01.04 trial.rr
Pre-operative chemoradiotherapy vs post-operative chemoradiotherapy
The German CAO/ARO/AIO-94 trial was a multicentre phase III randomised trial involving 823 patients comparing pre-operative chemoradiotherapy (CRT) with post-operative CRT in patients with stage II to III rectal cancer.r In this study 421 patients were randomised to receive pre-operative CRT (with surgery completed 6 weeks after CRT) and 402 patients were randomised to post-operative CRT. In both arms patients received CRT of 50.4Gy in 28 fractions, 5 days per week, a 120 hour fluorouracil infusion on weeks 1 and 5 and one month after surgery patients received four 5-day cycles of fluorouracil. In the post-operative treatment group patients also received a 5.4Gy boost to the tumour bed. The primary endpoint was overall survival (OS) and the secondary endpoints were disease free survival (DFS) and cumulative incidences of local (LR) and distant (DR) recurrences.
When compared to post-operative CRT, pre-operative CRT improved local control (10 year cumulative incidence of LR was 7.1% in the pre-op cohort vs 10.1% post-op cohort) and was associated with lower grade toxicity. It did not improve overall survival (10 year OS 59.6% in the pre-op cohort vs 59.9% in the post-op cohort [p=0.85]). There was also no significant difference in 10 year DR rates (29.8% in pre-operative vs 29.6% in the post-operative arm) or 10 year DFS (68.1% in pre-op arm vs 67.8% in post-op arm). An earlier publication on the trial reported that in patients that required abdominoperineal excision there was also a statistically significant improvement in sphincter preservation rate in the pre-op CRT arm compared to the post-op arm, 39% vs 19% respectively (p=0.004).r
Figure 1: Cumulative incidence of LR among the 799 patients randomly assigned to pre-operative or post-operative CRT, according to an intention-to-treat analysis.r
© JCO 2004
Similar conclusions were reached by a 2017 meta-analysis which included 1,273 patients across three randomised controlled trials comparing pre-operative and post-operative CRT.r Pre-operative CRT was found to improve locoregional control with reduced acute toxicity. No significant differences were observed in overall survival, relapse free survival, distant recurrence rates, sphincter preservation rates and chronic toxicity.
Although the German trial established the standard for preoperative CRT in rectal carcinomas, the chemotherapy regimen used in that trial has been superseded. Link to ID 73 Rectal locally advanced fluorouracil (protracted infusion) chemoradiation and ID 84 Rectal locally advanced capecitabine chemoradiation.
Long course vs short course pre-operative chemoradiotherapy
The Australian TROG 01.04 trial was a phase III multicentre randomised trial involving 326 patients comparing pre-operative long course (LC) CRT and pre-operative short course radiotherapy (SC) in patients with T3 rectal cancers.r Between 2001 and 2006 163 patients were randomised to LC CRT (50.4Gy in 28 fractions, 5 days per week, with continuous infusion fluorouracil, surgery was completed 4-6 weeks after CRT), and 163 patients were randomised to SC CRT (25Gy in 5 fractions, 5 days per week, with early surgery). Surgery was followed by four monthly cycles of fluorouracil and folinic acid given daily for 5 days, 4-6 weeks after surgery. Although three year LR recurrence rates between SC and LC were not statistically significant different, the CI for the difference is consistent with either no clinically important difference or differences in favour of long course (7.5% for SC and 4.4% for LC [difference 3.1%; 95% CI: -2.1 to 8.3; P = 0.24]). There were no statistically significant differences in 5 year DR (27% SC vs 30% LC) or 5 year OS (74% SC vs 70% LC).
In a comparison of short course pre-operative RT (n= 155) to long course pre-operative CRT (n=157), Bjuko et al. 2004 reported no significant difference in sphincter preservation rates, 61% vs 58%, respectively (p=0.57).r
Watch and wait
For patients who achieve a clinical complete response to neoadjuvant CRT, there are a number of observational studies suggesting a watch and wait strategy is a feasible option, although not standard of care. Given the absence of level I or II evidence, this approach would typically be reserved for patients in whom surgery carries significant risks and should be accompanied by a robust surveillance program to permit early salvage of local tumour regrowth.r
Timing of surgery post-chemoradiotherapy
The optimal timing of surgery following neoadjuvant CRT is unclear. While some studies suggest longer waits beyond the standard 6-8 weeks can result in high rates of pCR, they may also result in increased post-operative morbidity and more difficult surgical resection.rr