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Can quantified pathologic response assessed as residual tumor burden be a promising staging system for patients with rectal cancer treated with chemoradiation followed by surgery?

Recently, the most common criteria adopted to assess chemoradiation response are tumor regression grade (TRG), modified TRG, and ypTNM stage, each of which predicts the oncologic outcome for patients with rectal cancer who are treated with chemoradiation followed by surgery. Agarwal et al recently reported on a new staging system according to residual tumor burden, which interested us greatly. We would like to make some comments regarding this interesting article. As can be noted in the article, Agarwal et al assessed the response to chemoradiation by quantifying the percentage of residual cancer cells in relation to the tumor bed and dividing the entire group into 4 subgroups according to cutoff values of 5% and 50%. However, as expected, survival curves for the subgroups were not distinct enough between each group, especially between the major and minor response groups. The reason why the authors chose the present cutoff values rather than others was unclear. Perhaps it is possible to determine a better cutoff value through receiver operating characteristic curves or other methods with which to stratify the entire group. In addition, the number of cases in each subgroup was unbalanced, with the sample size in the major pathologic response group being nearly twice that in near-complete pathologic response group, thus having a negative effect on the recurrence-free survival results. With regard to the multivariable analysis, we do not think it was appropriate to include the clinical T and N classifications in the Cox proportional hazards regression model. Clinical stage is not considered to be a predictor of oncologic outcome compared with pathologic stage. If these were included in the multivariable analysis at the same time, it would influence the correctness of the results because colinearity existed between the 2 stages. Studies have suggested that the interval between the completion of chemoradiation and surgery could affect the pathologic response, thus influencing the outcome. It was reported that an interval of greater than 7 weeks resulted in a higher pathologic complete response rate. Therefore, it may be essential to consider the effect of the interval on the response to chemoradiation. It would be interesting for Agarwal et al to reassess the chemoradiation response according to TRG criteria and ypTNM stage and then compare different staging methods in predicting outcome among patients with rectal cancer who received chemoradiation and radical surgical resection. Thus, we could determine whether the staging method using residual tumor burden should be preferred. In the assessment of the chemoradiation response and oncologic outcome for patients with locally advanced rectal cancer who receive chemoradiotherapy according to different stages of disease, it will always result in a dilemma. For example, in a patient with rectal cancer who has only a few tumor cells remaining in the outer layer of the rectal wall, should the disease be staged as ypT3 in contrast to TRG1 according to the TRG staging system? Would this patient experience a poorer survival compared with patients with stage ypT2 disease but many tumor cells existing in the muscular layer, when other significant prognostic factors were controlled for? It is essential to create a new pathologic staging system that adopts all the important prognostic factors such as ypT classification, ypN classification, and the residual tumor burden in predicting the oncologic outcome for patients with rectal cancer who are treated with chemoradiation.