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Why do we need another tumor regression grading system for rectal cancer after neoadjuvant therapy?

Diseases of the Colon & ReCtum Volume 58: 1 (2015) the exposure of primary rectal cancer to radiation with or without chemotherapy may result in significant tumor cell death leading to tumor size reduction (downsizing) and a shift toward earlier disease staging through sterilization of deeper layers of the tumor and metastatic perirectal nodes (downstaging). ultimately, the population of tumor cells within the cancer may be reduced and replaced by fibrosis or scarring of the rectal wall. in this setting, attempts have been made to quantify this reduction in cancer population and replacement by normal tissue. Various grading systems have been proposed, mostly derived from experience with other solid cancers treated by radiation therapy, to provide a relevant and clinically useful prognostic feature. Common between all grading systems is the percentage of tumor cells relative to fibrosis as the primary parameter used for classification. therefore, on 1 end of the spectrum is the absence (0%) of residual cancer cells (complete pathological response – pCR), whereas the other end represents tumors with little or no tumor cell death, resulting in nearly 100% residual cancer cells. however logical they may seem, these classification systems have suffered from significant limitations to be fully implemented into clinical practice. the 2 different ends of the spectrum have obvious contrasting differences in all major oncological outcomes, because patients with pCR are associated with excellent results in terms of local disease control and survival. the problems reside in the intermediate groups between complete and no response to therapy. these intermediate groups have been subdivided in 1, 2, and even 3 subgroups based on subjective patterns of response to therapy. the lack of standardization of these grading systems has also contributed to difficulties in their widespread implementation. in addition, the actual grading by pathologists of tumor regression may be quite challenging because of the subjective nature of the histological interpretation of response. this could potentially lead to nonreproducible findings. in fact, a recent study resulted in poor concordance among different experienced pathologists regardless of the tumor regression grading (tRG) system used. finally, many of these grading systems failed to demonstrate independent correlation with oncological outcomes, particularly within intermediate responses, in patients with rectal cancer after chemoradiation (CRt) and surgery, seriously questioning the usefulness of this information in clinical practice. so perhaps we do need another tRG system. in the current edition of Diseases of the Colon & Rectum, Kalady and colleagues have elegantly reviewed the outcomes of patients with rectal cancer following neoadjuvant CRt with respect to a “new” tRG system. in fact, at a first glance, the grading system proposed by the american Joint Committee on Cancer/College of american Pathologists seems to solve all the issues because it provides clinically relevant prognostic information to these patients and a proposition for the standardization of tRG nationwide. in addition, the authors were able to demonstrate for the first time, for this particular grading system, that it works across the board to all subcategories of response. therefore, not only pCR is different from no response to CRt, but also, intermediate categories have distinct oncological outcomes statistically different from each other. finally, oncological outcomes were independent from other prognostic features frequently not tested in many studies for alternative tumor regression grading systems. however promising this american Joint Committee on Cancer/College of american Pathologists tRG system may be, there are a few challenges that need to be addressed. in this first study to demonstrate its clinical relevance, inherent limitations may suggest the next steps required for its widespread implementation. first, this hypothesis needs to be validated in a prospective study, preferably by more than one institution to avoid all potential biases. this is reflected by the variety of different treatment regimens, including Why Do We Need Another Tumor Regression Grading System for Rectal Cancer After Neoadjuvant Therapy?