Neoadjuvant score in locally advanced rectal cancer: integrating downstaging in risk assessment and looking for new valuable end points
Authors: S. Roselló, A. Cervantes
Journal: Annals of Oncology (2018)

Current standard of care for locally advanced rectal cancer consists on neoadjuvant treatment [chemoradiation (ChRT) or short-course radiotherapy] followed by surgery [1.Glynne-Jones R. Wyrwicz L. Tiret E. et al.Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv22-iv40Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar, 2.Roselló S. Papaccio F. Roda D. et al.The role of chemotherapy in localized and locally advanced rectal cancer: a systematic revision.Cancer Treat Rev. 2018; 63: 156-171Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. Patients should be clinically staged with pelvic Magnetic Resonance Imaging, which defines high-risk features in some of them and justifies therefore the use of preoperative treatment. After surgery, prognosis is mainly based upon pathological assessment of the surgical specimen according to tumor–node–metastasis. Patients who achieve a pathological complete response (pCR) after neoadjuvant ChRT have a much better prognosis than those with a partial response or no response at all [3.Maas M. Nelemans P.J. Valentini V. et al.Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.Lancet Oncol. 2010; 11: 835-844Abstract Full Text Full Text PDF PubMed Scopus (1285) Google Scholar]. However, downstaging is not usually considered when establishing prognosis of rectal tumors after neoadjuvant treatment. Individual variables such as ypT and ypN stages, T downstaging, circumferential margin status and tumor regression grade (TRG) were not found to be surrogates for OS or locoregional recurrence in the FFCD 9203 trial [4.Methy N. Bedenne L. Conroy T. et al.Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial.Ann Oncol. 2010; 21: 518-524Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. However, integrating different prognostic variables may add some extra value to better estimate the risk of relapse or death of an individual patient. Valentini et al. [5.Valentini V. Van Stiphout R. 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] developed three nomograms based on data from five European clinical trials of neoadjuvant treatment in localized rectal cancer. These nomograms, which included clinical and pathological variables as well as some related with the applied treatments, were able to predict the risk of locoregional or distant relapse, as well as the risk of death. Based on the nomogram for overall survival (OS), a simplified formula, the Neoadjuvant Rectal (NAR) score, was further developed, including the variables with the greatest weight on the nomogram: clinical T stage, and pathological T and N, reflecting not only the pathological stage, but also the effect of the neoadjuvant treatment and downstaging [6.George T. Allegra C. 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]. NAR was validated in the NSABP R-04 trial as well as by other institutions [7.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. 2017; https://doi.org/10.1016/j.clcc.2017.10.014PubMed Google Scholar, 8.Shen L. van Soest J. Wang J. et al.Validation of a rectal cancer outcome prediction model with a cohort of Chinese patients.Oncotarget. 2015; 6: 38327-38335Crossref PubMed Scopus (13) Google Scholar, 9.Armstrong D.E. Raissouni S. Price Hiller J.A. et al.External validation of the neoadjuvant rectal (NAR) score and Valentini prediction nomogram (VPN): a multicenter study.J Clin Oncol. 2014; 32: 397Crossref Google Scholar]. NAR is a useful tool to better estimate prognosis and could be of value for stratifying patients for further adjuvant chemotherapy trials. In an elegant paper published by Fokas et al. in this issue of Annals of Oncology, investigators of the German Rectal Cancer Study Group explore the potential role of NAR as individual level surrogate for long-term end points such as disease-free survival (DFS) and OS [10.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]. They have also studied some other early variables such as TRG or pCR. Both may reflect tumor biology, treatment efficacy and prognosis of localized rectal cancer patients after neoadjuvant treatment, but may have important limitations. TRG may be defined by different classifications currently on use, and there is a wide variability on the results between pathologists [11.Fokas E. Ströbel P. Fietkau R. et al.Tumor regression grading after preoperative chemoradiotherapy as a prognostic factor and individual-level surrogate for disease-free survival in rectal cancer.J Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (81) Google Scholar]. On the other hand, pCR lacks standardization across trials and its role remains controversial. pCR may depend on the chemotherapy backbone, the dose and schedule of radiotherapy used and the elapsed time from the end of RT to surgery. Moreover, the pCR rate reported in most randomized trials ranges from 12% to 16%. These numbers are far below the rates observed after neoadjuvant therapy in breast cancer, where pCR is well accepted as a surrogate for OS. Establishing surrogate end points requires a rigorous statistical validation, including confirmation in large trial datasets. Fokas et al. explored the role of the NAR score as a surrogate of DFS in the CAO/ARO/AIO-04 phase III trial in a post hoc analysis, looking if changes in mean NAR score among different neoadjuvant treatment interventions should translate into changes in DFS or OS. A surrogate end point is defined as an end point used in clinical trials as a substitute for a direct measure [12.Robb M.A. McInnes P.M. Califf R.M. Biomarkers and surrogate endpoints: developing common terminology and definitions.JAMA. 2016; 315: 1107-1108Crossref PubMed Scopus (82) Google Scholar]. Some end points require large samples or long follow-up time, so that the final results of a clinical trial can take many years during which a treatment may become outdated [13.Buyse M. Molenberghs G. Paoletti X. et al.Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.Biom J. 2016; 58: 104-132Crossref PubMed Scopus (65) Google Scholar]. Surrogate end points aim to predict an outcome earlier, less costly and more conveniently than the true clinical end point of interest. However, effects on surrogate end points do not provide direct evidence of a clinical benefit of a therapy [14.FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource. Silver Spring (MD): Food and Drug Administration (US); 2016. https://www.ncbi.nlm.nih.gov/books/NBK326791/. Co-published by National Institutes of Health (US), Bethesda (MD).Google Scholar]. To validate a surrogate end point, a clear mechanistic rationale is required, as well as data from randomized clinical trials, showing that the effect on the surrogate end point strongly predicts the clinical outcome of interest. In the CAO/ARO/AIO-0 trial, the addition of oxaliplatin to neoadjuvant ChRT was associated with lower NAR scores, and in the multivariable analysis NAR was shown to be an independent prognostic factor predicting not only DFS, but also local recurrence, distant relapse and OS. To assess individual-level surrogacy of NAR for DFS, the four Prentice criteria (PC) were applied, confirming a significant treatment effect on DFS, a significant impact of treatment arm on the NAR score and a significant association between NAR score and DFS. More restrictively, the fourth PC aims at demonstrating that there is a biological mechanism through which the surrogate fully captures the effect of treatment on the true end point [13.Buyse M. Molenberghs G. Paoletti X. et al.Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.Biom J. 2016; 58: 104-132Crossref PubMed Scopus (65) Google Scholar]. A good surrogate ideally lies on the causal pathway of the treatment effect on the true end point, but there is often a complex relationship between a potential surrogate and the true end point. In this article, the treatment effect on DFS was captured by the NAR score, confirming the value of the NAR score as a surrogate for DFS. One of the strengths of NAR is that it incorporates clinical and pathological variables reflecting the initial tumor extent and the response to neoadjuvant treatment, and it is easily calculated. However, it has important limitations, which are extensively detailed in the discussion by Fokas et al. In addition, this formula does not include other relevant variables associated with an increased risk of relapse or death, such as involvement of the circumferential margin, the macroscopic assessment of the surgical mesorectal plane or the presence of lymphovascular or perineural involvement [7.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. 2017; https://doi.org/10.1016/j.clcc.2017.10.014PubMed Google Scholar]. It should be also noted that NAR was developed after Valentini’s nomogram for OS. However, Valentini’s nomograms were not developed to predict DFS [13.Buyse M. Molenberghs G. Paoletti X. et al.Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.Biom J. 2016; 58: 104-132Crossref PubMed Scopus (65) Google Scholar]. The authors chose DFS instead of OS, because DFS was the primary end point in the CAO/ARO/AIO-04 trial. This study strongly suggests a role of the NAR score as a surrogate of DFS. NAR can predict the outcome of rectal cancer patients treated with neoadjuvant ChRT and surgery. Those patients with an increased risk of relapse may be offered to participate in clinical trials exploring further adjuvant treatment strategies. On the other hand, it remains to be seen if the NAR score will be able to select those patients who are most likely to benefit from adjuvant treatment. This work was supported in part by grants from the Spanish Government, the Ministerio de Economía y Competitividad (FIS PI12/02767 and PI15/02180 to AC) and Generalitat Valenciana (PROMETEO 2013-005 to AC).