Integration of novel agents into combined-modality treatment for rectal cancer patients.
With optimized local treatment--achieved through preoperative radiochemotherapy (RCT) and total mesorectal excision (TME) surgery--distant metastases are by far the predominate sites of tumor failure in rectal cancer today. The challenge is to integrate more effective systemic therapy into combined-modality programs. Capecitabine, oxaliplatin, irinotecan as well as targeted therapies improved results for colorectal cancer patients when treated in the metastatic and adjuvant setting. These agents have now been incorporated into phase I-II studies for rectal cancer. Phase I/II studies with combination chemotherapy suggest higher pathologic complete response (pCR) rates in the range of 15-25% and improved tumor regression compared with 5-fluorouracil (5-FU) RCT alone. However, the pCR rate is an early surrogate endpoint that may not necessarily translate into improved long-term outcomes. For some studies, this increased pCR rate is associated with an increase in acute toxicity--and data on long-term toxic sequelae are not yet available. Further challenges are to define the best sequence of combinations, including neoadjuvant combination chemotherapy prior to RCT, the role of postoperative chemotherapy, and the best sequence of targeted therapies. Phase III trials are needed to determine, if these novel combination regimens offer an advantage compared with 5-FU-based combined modality. These studies have now been started in Germany (CAO/ARO/AIO-04), Europe (PETACC 6), and the USA (NSAPB-R04, E5204 Intergroup Trial).