The D prefix: toward a reproducible validated alternative end point in rectal cancer.

613 Diseases of the Colon & ReCtum Volume 58: 6 (2015) fluoropyrimidine-based preoperative chemoradiotherapy (CRt) followed by total mesorectal excision is considered the current standard in the management of patients with clinically defined locally advanced rectal cancer. Current national Comprehensive Cancer network guidelines recommend chemoradiation for all patients who are at clinical stage ct3/t4. the recent publication of the early surgical end points in the national surgical adjuvant Breast and Bowel Project (nsaBP) R-04 trial comparing preoperative radiation therapy and capecitabine with or without oxaliplatin with preoperative radiation therapy and continuous intravenous infusion of 5-fluorouracil (5-fu) with or without oxaliplatin and presentations of preliminary data raise important points regarding the difficulty of finding an early end point to gauge the efficacy of CRt when evaluating different or novel regimens. the criterion standard end point in clinical trials of chemotherapy and radiotherapy in rectal cancer remains overall survival (os). although reliable and easy to measure, this end point takes years to observe. however, an alternative early end point, which would provide an earlier accurate assessment of treatment effects, would be useful. neoadjuvant CRt achieves significant tumor downstaging/downsizing with pathologic complete response (pCR) in ≤30% of patients in some series where early cancers have been included. after completion of CRt, individual series, population studies, and a meta-analysis have all shown that longer intervals up to a maximum of 12 to15 weeks appear associated with an increased chance of achieving a pCR at surgical resection, and, counterintuitively, outcomes may also improve in terms of a significant reduction in 3-year local recurrence rate (1.2% vs 10.5%; p = 0.04). however, further extensions of this interval do not appear to benefit the patient. Patients with rectal cancer who achieve a pCR or near pCR consistently fare better than the patients who fail to do so. in contrast, patients with no evidence of response fare badly. however, how to best define this response/lack of response and which method to use in terms of clinical measurement, imaging, or pathology to measure size, volume, tumor cell density, t-stage and n-stage downstaging, regression, or residual functional activity remain controversial issues. alternative early study end points are important because rapid methods to define and quantify the clinical use of novel strategies, such as dose escalation of radiotherapy or the integration of new drugs, along with comparing different strategies within clinical trials using CRt would be a major advantage. these end points should be objective, measurable, sensitive, easy to interpret, and clinically relevant, reflecting a tangible benefit to the patient. in contrast, the currently accepted late end points demand a long period from the end of recruitment to primary efficacy analysis for end points, such as 5-year local recurrence or disease-free survival (Dfs) or os. long-term follow-up has the advantage of capturing long-term late toxic effects and second malignancies, which may differ between treatments when a large proportion of patients are cured. however, this protracted period may also allow patients who fail later in the trial to receive potentially more effective treatments and survive longer. the outcome could therefore relate to the intensity of preoperative radiotherapy or chemoradiation, the use of varying postoperative adjuvant chemotherapy, or the eventual availability of more effective palliative treatments. also, interpatient heterogeneity with diversity in the phenotypic, epigenetic, and gene The D Prefix: Toward a Reproducible Validated Alternative End Point in Rectal Cancer