A Rose, Is a Rose, Is a Rose...or Not

Refinements in colorectal cancer staging systems have evolved from the Dukes’ classification to the most recent subgroup stratification of patients as reflected in the sixth edition of the tumor-node-metastasis system Cancer Staging Manual. Modifications of the staging system have proceeded in recognition that neither all stage II nor all stage III colon or rectal cancer patients can be aggregated for prognostic purposes within a single stage. Patients are truly not all alike, and most certainly are not in terms of the likelihood of surviving their cancer. In the future, it is possible that subset characteristics within a stage may also serve to predict likelihood of treatment benefit. This edition of the Journal of Clinical Oncology includes three large retrospective analyses of colon cancer and rectal cancer patients, that evaluate stage and additional potential prognostic factors to assess risk of relapse, survival, and benefit of therapy. The articles by Gill et al, Gunderson et al, and Greene et al provide valuable data describing nuances of staging for colorectal cancers. These authors have demonstrated that both T and N stage classifications are critical in defining risk, both in terms of recurrence and in overall survival. They build on recently published intergroup subset analyses confirming that more accurate staging and improved survival is achieved for colon and rectal cancer patients based on the number of lymph nodes that are analyzed by the pathologist. Whether one focuses on the more stratified and refined American Joint Committee on Cancer (AJCC), Sixth Edition, staging, for example, in the substrata of stage III, or whether one adopts the risk classifications of Gunderson et al for rectal cancer—in particular, distinguishing between the moderately highand high-risk categories—it is clear that important prognostic information is already available to help guide clinicians and patients as they consider current therapy options. What the risk classifications imply about the underlying biology of the disease and its associated implications for directing patients to individualized therapy is a separate, but related, issue. The integration of stage and other pathologic and molecular determinants is essential to the design of the next generation of colorectal adjuvant studies. We have learned that the three stage III subclassifications provide statistically important prognostic information. What we have not been able to understand is whether these subgroups are predictive in general. In the context of the present three studies, the goal of defining robust predictive characteristics remains elusive, for a variety of particular reasons clearly described by the authors. For example, Gill et al state that their prognostic and predictive model is limited, since many studies might have adjusted prognostic factors for stage, but other factors, such as extent of lymph node involvement and grade, are not uniformly evaluated. Therefore, the Gill model is confined to just a few prognostic factors. The Gunderson article, as a second example, is limited by the use of descriptive data to evaluate treatment outcome relative to treatment method since the treatment varied from trial to trial, making it difficult to compare the same regimen in different trials. In addition, the studies included in the rectal cancer pooled analysis accrued patients over a 13-year period, introducing a variety of surgical techniques and treatment methods. If the current staging system is to have as much value in guiding clinical research as it does in defining risk, it is critical that robust predictive factors must also be identified and integrated into prospective clinical trial design. It seems that an outstanding fundamental question remains: Do the refinements of categories within stage via T and N (and T within N, and vice versa) reflect different underlying biology or do they more simply our ability to statistically characterize the natural history of the disease at the time of presentation? The latter would imply that it is possible to direct therapy to those subgroups numerically most likely to benefit from current adjuvant treatments; JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 10 MAY 15 2004