Improved Patient and Regimen Selection in Locally Advanced Rectal Cancer: Who, How, and What Next?

Before the advent of neoadjuvant chemoradiation therapy (NCRT) for locally advanced rectal cancer, local failure represented half of treatment failures. The German Rectal Cancer Study Group trial demonstrated that NCRT along with total mesorectal excision can improve local control and the rate of sphincter-preserving surgery. Thus, the National Comprehensive Cancer Network now recommends NCRT as the standard of care for stage III and IV rectal cancer. Recent trials and analysis have questioned accepted wisdom regarding patient selection for NCRT and methods of administration. EORTC 22921 demonstrated that the addition of chemotherapy to radiation therapy, regardless of timing, improved local control but not overall survival, and subgroup analysis from this study generated the hypothesis that the subgroup of patients with good pathologic response to NCRT would benefit the most from additional chemotherapy following surgery. The prognosis of rectal cancer is stage dependent, and 2 major analyses question whether T1/2 N1 and T3 N0 patients benefit from NCRT. Application of the results from these studies is hindered by imperfections in staging. Future improvement in patient selection might result from biologic analysis of tumor sensitivity. NCRT might be improved with the use of oral fluoropyrimidines and perhaps the addition of a second agent such as oxaliplatin, irinotecan, or cetuximab. Improvements in radiation, such as the use of more conformal techniques, might decrease the toxicity of therapy. Given the success of NCRT in improving local control, distant metastasis now predominates as the cause of treatment failure, and larger gains will likely be made from improvements in adjuvant chemotherapy.