Should a minimum 8-week interval between preoperative radiotherapy and surgery become the standard of care? No, it shouldn't

Editor We read with interest the meta-analysis by Ryan et al.1 which explored the utility of extending the interval between chemoradiotherapy and surgery. The meta-analysis showed superior recurrence-free survival (RFS) and reduced distant metastasis with an extended interval. The authors concluded: ‘The findings support a minimum 8-week interval as the standard of care…’. However, irreparable DNA damage which ceases clonogenic division, occurs only at the time of irradiation and not during the interval to surgery. With the adoption of a minimum 8-week interval, resectable tumours could become unresectable and distant metastasis may develop if the interval is too long. The reduced distant metastasis rates with the longer interval shown in the meta-analysis1 are likely to result from selection bias, as most of the studies were retrospective. Thus, patients might not undergo surgery because of distant metastasis occurring within the longer interval. Consequently, these patients could have been excluded from the analysis, artificially diminishing the distant metastasis rate and improving RFS. Moreover, better RFS should be associated with at least a tendency towards better overall survival, which was not observed1. To exclude selection bias, we performed a meta-analysis of randomized trials comparing long versus short interval to surgery2–4. No difference was found for RFS (Fig. 1), either in randomized trials that meet the inclusion criteria for the meta-analysis by Ryan et al.2,3 (odds ratio (OR) 1·17, 95 per cent c.i. 0·72–1·89; P = 0·52) or when all randomized trials with relevant data were analysed2–4 (OR 0·96, 95 per cent c.i. 0·74–1·24; P = 0·74). A minimum 8-week interval should not be considered the standard of care for every patient. For example, delaying surgery beyond 8 weeks is beneficial for those patients with excellent tumour response, because some will achieve a complete pathological response allowing for watch-and-wait. For those with a persistent tumour, delaying surgery beyond 8 weeks may not be considered safe because radioresistant cancers behave more aggressively than radiosensitive ones5. Forest plot comparing recurrence-free survival for short and long wait intervals a Randomized trials that meet inclusion criteria for the meta-analysis by Ryan et al.1. b All randomized trials with relevant data.