Preoperative chemoradiation for locally advanced rectal cancer: emerging treatment strategies.

Over the past decade, patients with locally advanced rectal cancer at The University of Texas M. D. Anderson Cancer Center have been managed with preoperative chemoradiation. Patients achieving a complete clinical response to preoperative chemoradiation have had better pelvic tumor control, sphincterpreservation, and overall survival than those with gross residual disease. Some patients achieving a complete clinical response have even had rectal-preserving surgery (full-thickness local excision). These results emphasize the importance of maximizing tumor response. Further improvement in response and survival could be achieved by using novel chemotherapeutic agents or through tumor-selective molecular targeting strategies that enhance the effects of chemotherapy, radiotherapy, or both. Irinotecan (CPT-11, Camptosar) is a novel chemotherapy agent being evaluated clinically as a radiosensitizing agent in rectal cancer. Inhibition of several molecular targets-such as epidermal growth factor receptor, ras oncogene activation, the cyclooxygenase-2 (COX-2) enzyme, and neoangiogenesis-appears to be tumor-selective in preclinical models. COX-2 expression has been shown to enhance cytotoxic therapy in preclinical models. In vitro and in vivo studies show that selective COX-2 inhibition enhances the effects of radiotherapy as well as chemotherapy. COX-2 is also markedly upregulated in human colorectal cancer and appears to be associated with adverse patient prognosis. Thus, integration of molecular targeting, such as COX-2 selective inhibition with existing chemoradiation approaches, may provide selective tumor radiosensitization and chemosensitization, resulting in improved pelvic control, sphincter preservation, and overall survival.