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 E. Fietkau R. Hartmann A. et al.Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.Ann Oncol. 2018; 29: 1521-1527Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] 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.George Jr., T.J. Allegra C.J. Yothers G. Neoadjuvant rectal (NAR) score: a new surrogate endpoint in rectal cancer clinical trials.Curr Colorectal Cancer Rep. 2015; 11: 275-280Crossref PubMed Scopus (89) Google Scholar] and subsequently validated by Roselló et al. in a large retrospective series [3.Roselló S. Frasson M. García-Granero E. et al.Integrating downstaging in the risk assessment of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: validation of Valentini's nomograms and the neoadjuvant rectal score.Clin Colorectal Cancer. 2018; 17: 104-112Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. 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.Valentini V. van Stiphout R.G. Lammering G. et al.Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials.J Clin Oncol. 2011; 29: 3163-3172Crossref PubMed Scopus (369) Google Scholar] 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.National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology (NCCN guidelines). Rectal Cancer. Version 3.2018.https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf (11 August 2018, date last accessed).Google Scholar] 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, high-risk, LARC [6.Sclafani F. Brown G. Cunningham D. et al.PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer.Ann Oncol. 2016; 27: 1557-1565Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. 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.Fokas E. Fietkau R. Hartmann A. et al.Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.Ann Oncol. 2018; 29: 1521-1527Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,2.George Jr., T.J. Allegra C.J. Yothers G. Neoadjuvant rectal (NAR) score: a new surrogate endpoint in rectal cancer clinical trials.Curr Colorectal Cancer Rep. 2015; 11: 275-280Crossref PubMed Scopus (89) Google Scholar], 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);P = 0.003] compared with those with low NAR score (5-year PFS: 92.3%, overallP < 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);P = 0.04] in patients with intermediate NAR score and 93.8% in those with low NAR score (overallP < 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. This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. The EXPERT study was supported by a fellowship grant from the Pelican Cancer Foundation and by an education grant from Sanofi-Aventis which also provided the study drug. The EXPERT-C trial was endorsed by Cancer Research UK and was supported by a research grant from Merck & Co. Sanofi-Aventis and Merck & Co. provided the study drugs. Neither company was involved in study design, data analysis, or manuscript preparation or had access to study data (no grant number is applicable).

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