Abstract: We included four trials with a total of 4663 participants. All four trials reported short PRT courses, with three trials using 25 Gy in five fractions, and one trial using 20 Gy in four fractions. Only one study specifically required TME surgery for inclusion, whereas in another study 90% of participants received TME surgery. Preoperative radiotherapy probably reduces overall mortality at 4 to 12 years' follow-up (4 trials, 4663 participants; Peto OR 0.90, 95% CI 0.83 to 0.98; moderate-quality evidence). For every 1000 people who undergo surgery alone, 454 would die compared with 45 fewer (the true effect may lie between 77 fewer to 9 fewer) in the PRT group. There was some evidence from subgroup analyses that in trials using TME no or little effect of PRT on survival (P = 0.03 for the difference between subgroups). Preoperative radiotherapy may have little or no effect in reducing cause-specific mortality for rectal cancer (2 trials, 2145 participants; Peto OR 0.89, 95% CI 0.77 to 1.03; low-quality evidence). We found moderate-quality evidence that PRT reduces local recurrence (4 trials, 4663 participants; Peto OR 0.48, 95% CI 0.40 to 0.57). In absolute terms, 161 out of 1000 patients receiving surgery alone would experience local recurrence compared with 83 fewer with PRT. The results were consistent in TME and non-TME studies. There may be little or no difference in curative resection (4 trials, 4673 participants; RR 1.00, 95% CI 0.97 to 1.02; low-quality evidence) or in the need for sphincter-sparing surgery (3 trials, 4379 participants; RR 0.99, 95% CI 0.94 to 1.04; I2 = 0%; low-quality evidence) between PRT and surgery alone. Low-quality evidence suggests that PRT may increase the risk of sepsis from 13% to 16% (2 trials, 2698 participants; RR 1.25, 95% CI 1.04 to 1.52) and surgical complications from 25% to 30% (2 trials, 2698 participants; RR 1.20, 95% CI 1.01 to 1.42) compared to surgery alone. Two trials evaluated quality of life using different scales. Both studies concluded that sexual dysfunction occurred more in the PRT group. Mixed results were found for faecal incontinence, and irradiated participants tended to resume work later than non-irradiated participants between 6 and 12 months, but this effect had attenuated after 18 months (low-quality evidence). We found moderate-quality evidence that PRT reduces overall mortality. Subgroup analysis did not confirm this effect in people undergoing TME surgery. We found consistent evidence that PRT reduces local recurrence. Risk of sepsis and postsurgical complications may be higher with PRT. The main limitation of the findings of the present review concerns their applicability. The included trials only assessed short-course radiotherapy and did not use chemotherapy, which is widely used in the contemporary management of rectal cancer disease. The differences between the trials regarding the criteria used to define rectal cancer, staging, radiotherapy delivered, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy did not appear to influence the size of effect across the studies. Future trials should focus on identifying participants that are most likely to benefit from PRT especially in terms of improving local control, sphincter preservation, and overall survival while reducing acute and late toxicities (especially rectal and sexual function), as well as determining the effect of radiotherapy when chemotherapy is used and the optimal timing of surgery following radiotherapy.

Plain-language summary: We searched medical databases on 4 June 2018 for randomised trials (experimental studies where people are randomly allocated to one of two or more treatment groups) to determine whether there is any benefit to radiotherapy before surgical treatment for people with rectal cancer in terms of reducing the risk of dying from any cause, the risk of dying from cancer, and the risk of cancer recurring in the pelvis. We considered high-dose regimen of radiotherapy followed by any type of surgical treatment to remove cancer of the rectum. We found four trials involving 4663 people with operable rectal cancer. Our results suggest that administering short-course radiotherapy before surgery probably reduces mortality. However, when our analysis was limited to a contemporary type of surgery (total mesorectal excision), there was no evidence of a difference between the group receiving radiotherapy before surgery and the group receiving surgery alone. There may be little or no difference between groups in cancer-related death when short-course radiotherapy is used. We found moderate quality evidence that using preoperative radiotherapy compared to surgery alone may provide substantial benefit in terms of reduction of local recurrence of the cancer. There was little or no effect of preoperative radiotherapy on curative resection and sphincter-sparing surgery. We found higher rates of sepsis, surgical complications, and sexual complications in participants treated with radiotherapy compared to those who received only surgery. Overall the studies were well-designed. We judged the quality of the evidence as moderate for cancer recurrence and overall mortality, as there were serious concerns regarding the applicability of the findings to the contemporary management of rectal cancer. We further downgraded the quality of the evidence for the remaining outcomes due to imprecise results and/or variations between the trials regarding the criteria used to define rectal cancer, the stage of participants, preoperative imaging used for assessing stage, the type of surgery performed, the radiation dose and fractioning, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy.