Prognostic Factor after Multimodality Treatment in Patients Circumferential Margin Involvement Is the Crucial

Purpose: After preoperative (radio)chemotherapy, histologic determinants for prognostification have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival. Experimental Design: A series of 201patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (<2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival. Results: Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P < 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P < 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively). Conclusions: Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapyinduced regression. For patients with locally advanced rectum carcinoma (LARC), surgery alone is often not curative. In case of cT4 tumors or a threatened circumferential margin (CRM; <2 mm on preoperative imaging) in cT3 tumors, long-term neoadjuvant radio(chemo)therapy is required. This will result in downstaging and increased local control (1–4). The histopathology of specimens obtained after this kind of preoperative therapy is markedly different compared with untreated cases. Various stages of histologic tumor regression may be present, often resulting in changed morphology. Histologic changes after the radiochemotherapy regimen range from absence of any treatment effect to a complete response with no residual tumor identified. One of the first systems for grading histologic regression focused on patients with esophageal carcinoma who were treated with radiochemotherapy (5). Their results showed that, after multivariate analysis, only grading of tumor regression was a significant predictor for disease-free survival (5). Subsequently, this system was modified by Dworak et al. (6) for grading regression in the rectum. Currently, several different methodologies for measuring the degree of histologic tumor regression after radiochemotherapy in rectal cancer have been described (6–10) but none has become universally accepted. Reproducibility seems to be a key factor. The objective of our study is to evaluate which factors determine outcome in patients with LARC after radiochemotherapy, focusing on the contribution of histologic tumor regression grading and the CRM. Tumor regression after radiochemotherapy was measured using four different methodologies and evaluated for prognostic effect with respect to overall survival and local recurrence. CRM was evaluated according to Quirke et al. (11, 12). Additionally, prognostic implications of clinicopathologic and histologic variables were determined. Materials andMethods Patient selection. The patient population consisted of a consecutive series of patients with LARC with biopsy-proven adenocarcinoma. All Imaging, Diagnosis, Prognosis Authors’Affiliations: Departments of Surgery and Radiotherapy, Catharina Hospital; Department of Pathology, PAMM Laboratories, Eindhoven, the Netherlands; Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; and Department of Surgery, Medical Centre Rijnmond-South, Rotterdam, the Netherlands Received 5/15/07; revised 8/3/07; accepted 8/23/07. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: Iris D. Nagtegaal, Department of Pathology 437 PA, Radboud University, P.O. Box 9101, Nijmegen, the Netherlands. Phone: 31243614314; E-mail: i.nagtegaal@pathol.umcn.nl. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1197 www.aacrjournals.org Clin Cancer Res 2007;13(22) November15, 2007 6617 American Association for Cancer Research Copyright © 2007 on November 12, 2012 clincancerres.aacrjournals.org Downloaded from DOI:10.1158/1078-0432.CCR-07-1197