Prognostic value of apoptosis in rectal cancer patients of the Dutch Total Mesorectal Excision trial: Radiotherapy is redundant in intrinsically high-apoptotic tumors

Purpose: The combination of radiotherapy and good quality surgery reduces local recurrence rate for rectal cancer patients. This study assesses the prognostic value of both intrinsic and radiotherapy-induced apoptosis and evaluates the relevance of radiotherapy for outcome of rectal cancer patients. Experimental Design: Tumor samples (1,198) were available from the DutchTotal Mesorectal Excision trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term radiotherapy or not. Tumor samples were obtained at time of surgery. Tissue microarrays were constructed and stained with the active caspase-specific M 30 antibody to determine the amount of apoptotic epithelial tumor cells. Results: Nonirradiated patients with a negative circumferential margin displaying lower than median levels of apoptosis developed more local recurrences (10.5% versus 6.1%; P = 0.06) and more rapidly after surgery than patients with high intrinsic apoptosis in their tumors (median time to recurrence, 13.0 versus 21.3 months; P = 0.04). In multivariate analysis, intrinsic apoptosis was an independent predictor for the development of local recurrences (hazard ratio, 2.0; P = 0.05). Radiotherapy increased apoptosis level (11 versus 23 apoptotic cells/mm(2) tumor epithelium; P < 0.001), but this apoptosis did not influence patients' prognosis. Conclusions: Rectal cancer patients with low intrinsic apoptosis will benefit from radiotherapy with respect to the development of local recurrences. Because apoptosis is an inherent characteristic of tumors, patients who do not need radiotherapy may be selected based on the apoptotic index of the primary tumor.