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Prognostic Value of Apoptosis in Rectal Cancer Patients of the Dutch Total Mesorectal Excision Trial: Radiotherapy Is Redundant in Intrinsically High-Apoptotic Tumors

Authors' Affiliations: Departments of ¹ Clinical Oncology and ² Surgery, Leiden University Medical Center, Leiden, the Netherlands; ³ Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center; ⁴ Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁵ Department of Pathology, University Medical Center St. Radboud, Nijmegen, the Netherlands

Requests for reprints: Corrie A.M. Marijnen, Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. Phone: 31-71-526-3464; Fax: 31-71-526-6760; E-mail: C.A.M.Marijnen{at}lumc.nl.

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 Dutch Total 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 M30 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/mm² 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.

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