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.