The role of targeted agents in preoperative chemoradiation for rectal cancer

Abstract

In the United States, randomized trials have established preoperative chemoradiation as the standard of care for patients with locally advanced rectal cancer. Pathologic complete response (pCR) rates occur in 10% to 16% of patients and have been shown to be correlated with both disease-free and overall survival. Therefore, recent efforts incorporating newer cytotoxic and molecularly targeted agents into chemoradiotherapy regimens have reported the pCR rate to be a surrogate marker of clinical outcomes. Substitution of oral fluoropyrimidines, including capecitabine, for infusional 5-fluorouracil reportedly generated pCR rates of up to 32% in phase 2 studies, but definitive evaluation awaits results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial. Similarly, regimens incorporating irinotecan generated pCR rates as high as 38%, but to the authors' knowledge have not been evaluated in randomized trials. In contrast, 2 large randomized trials reported that the addition of weekly oxaliplatin to fluoropyrimidine-based chemoradiation led to an increase in grade 3/4 toxicity but no difference in pCR rates. Early phase trials evaluating the anti-epidermal growth factor receptor (EGFR) antibody cetuximab in combination with chemoradiation reported modest pCR rates of 5% to 12%, and efforts have focused on identifying biomarkers of response including EGFR copy number, k-ras mutational status, and both serum and tumor-specific expression of EGFR ligands. Finally, incorporation of the anti-vascular endothelial growth factor antibody bevacizumab into chemoradiation appears to be safe and feasible, with initial studies reporting a beneficial effect on vascular normalization and correlations between circulating biomarkers of angiogenesis and pathologic response. Future efforts should include prospective studies of these agents in biomarker-defined subpopulations, as well as studies of novel agents that target angiogenesis, tumor-stromal interaction, and the cell signaling pathways implicated in colorectal cancer.