Molecular Prognostic Factors in Locally Irresectable Rectal Cancer Treated Preoperatively by Chemo-radiotherapy

Purpose: The aim of this study was to determine the relationship between survival and value of molecular markers in the primary tumour in a group of patients with irresectable rectal cancer, treated with preoperative chemo- radiotherapy. Materials and Methods: Immunohistochemistry for p53, p21, bcl-2 and Ki-67 was performed on pre-treatment biopsy specimens of 34 patients with irresectable rectal cancer. Preoperative treatment consisted of pelvic irradiation of 45-56 Gy, combined with 5FU and leucovorin (350/20 mg/m 2 x 5 d; in weeks 1 and 5 during radiotherapy). The median follow-up was 38 months. Endpoints were pathological T-stage and survival after surgery. Results: Expression of p21 correlated significantly with survival (p=0.005). Survival and p21 expression also correlated significantly, when adjusted for tumour response (p=0.005, RR=4.8 (1.6-14.7)). Conclusion: Expression of p21 predicts a worse survival in irresectable rectal cancer treated with preoperative chemo-radiotherapy. No relationship was found between tumour response in chemo- radiotherapy and p53, bcl-2 or Ki-67. Colorectal cancer is a major public health problem in the Western world and ranks as the third leading cause of death in both males and females. In 1997, 8,600 new colorectal cancer patients were registered in the Netherlands, of whom 25% had rectal cancer (1). In early stages a surgical resection is the only curative treatment. Following potentially curative resection, however, local recurrence rates vary between 5 and 40% (2-5) . Moreover, the majority of patients present at an advanced stage. At the time of diagnosis 38% of patients will have regional spread of disease and 25% will already have distant spread (6). (Neo-)adjuvant therapies like pelvic irradiation and chemotherapy, either alone or in combination, have an additional role in these subsets of patients. At present, conventional clinico-pathological parameters cannot entirely identify aggressive tumours that would benefit from (neo-) adjuvant therapy. As for other human malignancies, the development of rectal adenocarcinoma is associated with a series of inherited and/or acquired gene abnormalities that disregulate cell growth and cell death. These genes or their protein products can be measured in tumour tissue. The aim of this study was to determine the relationship between survival after chemo-radiotherapy and the value of molecular markers, in the primary tumour, in a group of patients with locally irresectable rectal cancer treated with preoperative chemo-radiotherapy.