Neoadjuvant rectal score: run with the hare and hunt with the hounds.

In a retrospective analysis of the CAO/ARO/AIO-04 trial [1] Fokas et al. have confirmed the prognostic value of the neoadjuvant rectal (NAR) score as originally proposed by the investigators of the NSABP R-04 trial [2] and subsequently validated by Rosell o et al. in a large retrospective series [3]. The results of their analysis lend further support to the use of this composite score as a prognostic tool for routine practice and stratification factor for future trials of adjuvant therapy. It should be borne in mind, however, that validation of the NAR score (as well as the development of the prognostic nomograms on which the NAR score is based) [4] has been carried out using data from patients who were treated with neoadjuvant (chemo)radiotherapy. In locally advanced rectal cancer (LARC), neoadjuvant systemic chemotherapy, either before or after standard (chemo)radiotherapy, has been increasingly investigated and ultimately endorsed by international guidelines [5] while the potential of the NAR score to act as a surrogate for long-term outcomes in this treatment setting is unknown. Therefore, we sought to fill this gap by using PAN-EX, a pooled analysis of individual patient data from two phase II trials (EXPERT and EXPERT-C) of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, highrisk, LARC [6]. In our study, 240 of 269 patients (89.2%) underwent curative surgery and were therefore assessable for this analysis which was conducted after a median follow-up of 6 years. The cT category of the NAR score formula was obtained from the baseline staging (i.e. before neoadjuvant chemotherapy) and assessed in all cases by high-resolution MRI. Using the same cut-off values as previously reported [1, 2], the NAR score was low (i.e. <8) in 66 patients (27.5%), intermediate (i.e. 8–16) in 114 (47.5%) and high (i.e. >16) in 60 (25.0%). Progression-free survival (PFS) was significantly worse in patients with high NAR score [5-year PFS: 50.0%, HR 6.1 (95% CI: 3.0–12.5); P< 0.001] and intermediate NAR score [5-year PFS: 72.3%, HR 2.9 (95% CI: 1.44–5.87); P1⁄4 0.003] compared with those with low NAR score (5-year PFS: 92.3%, overall P< 0.001). Similar results were observed for overall survival (OS) which, at 5 years, was 61.5% [HR 4.3 (95% CI: 2.0–9.0); P< 0.001] in patients with high NAR score, 81.0% [HR 2.2 (95% CI: 1.0–4.6); P1⁄4 0.04] in patients with intermediate NAR score and 93.8% in those with low NAR score (overall P< 0.001) (Figure 1). The results of our analysis are in line with those reported by Fokas et al. and provide further independent validation of the NAR score. Furthermore, they show that the prognostic ability of this composite score is maintained irrespective of the treatment delivered in the neoadjuvant setting. Nevertheless, we would like to point out that, in addition to the accurate definition of T stage at baseline, the NAR score entirely relies on the availability of pathological data from surgical specimens and, as such, it falls short of what would be required to assist physicians in the decision-making during the pre-operative treatment phase. The future management of rectal cancer will likely be characterised by the increased use of personalised, adaptive treatment strategies and more informative, early indicators of tumour downstaging/response to neoadjuvant treatment and prognosis are urgently needed.