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We hypothesized that anemia could represent one of the major factors influencing the outcome of patients undergoing neo-adjuvant treatment of rectal cancer.This analysis included all the consecutive patients who underwent neo-adjuvant treatment (chemotherapy and/or radiotherapy) before surgery for rectal cancer in three oncology/radiotherapy departments from June 1996 to December 2003.Three hundred and seventeen patients were eligible for our analysis. Median age at diagnosis was 64 years (range 26–88 years); male/female ratio was 184/133. Two hundred and eighty-five patients (89.9%) were diagnosed with adenocarcinoma, while 32/317 (10.1%) with mucinous adenocarcinoma. Neo-adjuvant treatments carried out were as follows: radiotherapy alone in 75/317 patients (23.7%), radiotherapy plus chemotherapy in 242/317 patients (76.3%). At univariate and multivariate analysis, only the hemoglobin (Hb) level (group 1: ≤12 g/dl versus group 2: >12 g/dl) resulted in a significant factor for disease-free survival. The role of the Hb level seemed to be confirmed further by the clinical downstaging obtained in ∼55% of patients in group 2, in comparison with 35% of the patients achieving a significant downstaging in group 1.Our results indicated that anemia could represent an important parameter able to influence the outcome in patients receiving neo-adjuvant treatment of rectal cancer.