Optimal wait between long‐course neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer: a dilemma

Long-course neoadjuvant chemoradiotherapy (NACRT) prior to surgical management of locally advanced, non-metastatic rectal cancer is a well-established management protocol worldwide. Its effect on tumour downsizing is well known (Fig. 1). However, the optimal time period between completion of radiotherapy and surgery for maximal downstaging remains debatable. The Lyon R90-01 randomized trial concluded that a long waiting period of 6–8 weeks between NACRT and TME (total mesorectal excision) surgery increased tumour downstaging, with no adverse effects on toxicity or outcome. Hereafter, this waiting period was arbitrarily designated as 6 weeks and followed as such by the surgical fraternity. Subsequent studies by Glehen et al., de Campos-Lobato et al. and Evans et al. in stage II and stage III rectal cancers go on to state that a longer time interval between NACRT and surgery correlated with better pathological response. In a comprehensive study, Wolthius et al. tried to assess the role of different time intervals between NACRT and radical surgery for locally advanced, non-metastatic rectal cancer as well as their effect on pathological response, post-operative morbidity and oncological outcome. They dichotomized patients into two groups based on the waiting period as short interval (<7 weeks) and long interval (>7 weeks). Their study proved that a waiting period of more than 7 weeks correlated with better overall survival (84% versus 77%) as well as statistically significant improvement in recurrence-free survival (P = 0.0261) and cancer-specific survival (P = 0.0457). O’Neill et al., Dhadda et al. and Habr-Gama et al. have advocated a waiting period of 10–14 weeks prior to TME surgery, with no compromise on the oncological outcomes. The possibility of further enhancing the downsizing of the tumour has been considered, although another area of interest is the alleviation of patient anxiety during this waiting period. In their study published in 2009, Habr-Gama et al. proposed additional chemotherapy (three cycles of 5-fluorouracil/leucovorin) in this resting period. The longer waiting time did not have an impact on postoperative morbidity, more radical surgeries or anastomotic leaks after low anterior resection. The questions that still remain unanswered are the optimization of this waiting interval, regularity of assessment in order to determine the best period for surgical intervention and the need for re-staging. Additionally, which tumours are more likely to respond to this additional chemotherapy, if advocated in the waiting period, still remains food for thought. Caution also needs to be exercised as regards the widening of this wait, as some patients may even experience tumour re-growth and spread. Multi-centre randomized trials are thus mandatory to bridge the gap in this hiatus of knowledge. However, it can be safely said that a minimum duration of 8 weeks should be maintained between NACRT and surgery. Any inadvertent delay due to scheduling/demographic issues is unlikely to lead to any significant adverse impact until 10–14 weeks of waiting interval. Fig. 1. Top: Pre-neoadjuvant chemoradiotherapy (NACRT) tumour. Bottom: Post-NACRT downsized tumour. PERSPECTIVES