Tumor Regression Grading in Rectal Cancer: Is It Time to Move Forward?
Authors: Vincenzo Valentini, Bruce D. Minsky
Journal: Journal of Clinical Oncology (2014)

In contrast with adjuvant colon cancer trials where 2-year results are adequate, patients with rectal cancer receiving preoperative chemoradiotherapy can experience late failures. Long-term follow-up of the German CAO/ARO/AIO (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the German Cancer Society)-94 Rectal Cancer Trial reveals a continuous increase in local recurrence up to 10 years. Therefore, there is substantial interest in short-term surrogate end points. Many preoperative chemoradiotherapy trials have explored the use of pathologic complete response rate (pCR) and/or tumor regression grading (TRG) as primary end points. The lack of standard definitions of TRG, various intervals between the end of chemoradiotherapy, and the lack of pathology quality control have made the data challenging to interpret. In the article that accompanies this editorial, Fokas et al present a well designed and robust analysis of the prognostic impact of TRG in patients with rectal adenocarcinoma treated by preoperative chemoradiotherapy and total mesorectal excision. The study includes patients enrolled on the German CAO/ARO/AIO-94 randomized phase III trial of preoperative versus postoperative chemoradiotherapy. The authors report that, by multivariable analysis, TRG is a significant, independent prognostic factor for metastasis-free and disease-free survival (DFS). Previously published studies from other groups have reported similar results, including a significant impact of TRG on local control, incidence of metastasis, DFS, and overall survival (OS). This study, however, differs from others reported in the literature because of the homogeneity of the surgical and adjuvant treatments performed, large number of prospectively enrolled patients, and long follow-up (median, 132 months). Is response a reasonable surrogate end point? The analysis conducted by Bonnetain et al showed that pCR predicted local recurrence, progression-free survival (PFS) or OS poorly. They suggested that pCR could be used as primary end point for phase II rectal cancer trials or as an intermediate end point in futility stopping rules for phase III trials when OS or PFS is the final end point. If new phase III trials need earlier end points than OS, they recommended using PFS, otherwise they discourage its use as definitive end points. Similarly Valentini et al pooled data from five large European randomized clinical trials for locally advanced rectal cancer (N 2,795). The ad hoc comparison between OS according to pCR and 2-year DFS showed that the latter had a stronger prognostic impact. They suggested that 2-year DFS could be considered as an intermediate end point in future trials. The evaluation of prognostic relevance of TRG score is also affected by the method of pathological evaluation. In the present trial, the standardized five-point TRG was used based on the work of Dworak et al. This is one of several TRG methods, and there is no consensus for a universally approved regression classification. The macroscopic examination of the specimen to evaluate TRG score is critical and could affect its prognostic significance. A protocol to assess and to classify a tumor according to a TRG score has been recommended from Quirke et al. The Guidelines of the Royal College of Pathologists in the United Kingdom have gained widespread acceptance as the minimum standard for reporting. There are a number of suggested methods for assessing tumor regression after preoperative therapy. The College of American Pathologists Guidelines recently suggest that tumor response should be graded on a scale of 0 (complete response; no viable cancer cells) to 3 (poor response; minimal or no regression, extensive residual cancer). The various classification systems proposed for rectal cancer need to be cross-validated for their predictive value and reproducibility in a broader setting. It should be emphasized that TRG scores have not accounted for the possible involvement of lymph nodes. The correlation among the different values of TRG and the incidence of positive nodes is an area of active investigation. A detailed description of the method of pathological assessment and the selected TRG scoring system should be clearly identified. The presence of a favorable TRG after radical surgery, especially an abdominal perineal resection which requires a permanent stoma, challenges us to consider alternatives for our patients. New clinical trials are exploring the option of more conservative surgery such as local excision or forgoing surgery completely using the watch-andwait approach in patients who achieve a favorable response to preoperative therapy. For example, the 2013 series by Habr-Gama et al reported the results of this approach in 70 patients with tumors located at a maximum of 7 cm from the anal verge who underwent highresolution magnetic resonance imaging (MRI) or three-dimensional transrectal ultrasound and had cT2-4 or N1-2 disease. If there was no residual abnormality by proctoscopy and restaging was negative 10 weeks after chemoradiotherapy, patients were staged as initial clinical complete response (cCR) and placed on the watch-and-wait strategy JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 15 MAY 2