An embarrassment of riches: neoadjuvant therapy of rectal cancer.

Two decades ago, therapy for locally advanced rectal cancer included surgery followed by additional radiation therapy or fluorouracil (FU) chemotherapy. The principles of surgery for rectal cancer included the freeing of the rectum from the surrounding mesorectal tissues via blunt dissection with a low anterior, sphincter-sparing resection whenever possible. Sphincter preservation was rarely accomplished for tumors within reach of the examining finger on rectal examination. With the exception of the introduction of mechanical stapling devices permitting low anterior resections for low-lying lesions, surgical techniques remained static for decades. Single-agent FU was delivered in a bolus technique, as it had been since the 1960s, and radiation therapy, although technically improved, was similar to that used in the 1950s. Adjuvant therapy was embraced by many in the 1980s; in the early 1990s the results of randomized trials led a National Cancer Institute Consensus Conference to endorse the use of postoperative radiation therapy and chemotherapy for patients with T3 or node-positive disease. In contrast, the last decade has brought enormous advances. Surgical techniques have improved so that a total mesorectal excision (TME), in which the perirectal fascia (the mesorectum) is sharply dissected, permitting en bloc removal of an intact tumor with its vascular, lymphatic, and supporting structures, is now endorsed by virtually all surgeons. The methods of delivery of FU now include biochemical modulation with leucovorin, long-term continuous infusion, and capecitabine or other oral fluoropyrimidine formulations such as UFT (a combination of uracil and tegafur), or S1 (a fluoropyrimidine derivative combined with inhibitors of degradation). For metastatic colon and rectal cancer, two major new cytotoxic drugs, irinotecan and oxaliplatin, have demonstrated efficacy, whereas biologics such as the epidermal growth factor receptor (EGFR) inhibitor cetuximab and the antiangiogenesis agent bevacizumab have also been shown to be of benefit. Multiple new EGFR and angiogenesis inhibitors are actively being developed for clinical application in colorectal cancer. Until recently, gastrointestinal oncologists had only one drug in their armamentarium, so they spent the 1960s through 1990s testing minor variations of agents and modulations of timing while staying with the same basic approaches. What did we learn from the investigations of that era? First, continuous infusion FU as an adjuvant with radiation is superior to bolus FU in reducing both local and distant recurrences, but it does not appear that additional intensification of continuous-infusion FU is of much benefit. Second, TME improves outcomes compared with conventional blunt dissections, but the application of this technique by US surgeons is uneven. The expertise of the surgeon as an important prognostic factor in determining outcome has been well documented. Third, although TME is superior to conventional or inadequate surgery, it does not produce a high enough level of local tumor control to be adequate sole local therapy for many patients, and adjuvant radiation therapy and chemotherapy further reduces local recurrence rates. Fourth, recent data from Sauer et al show that preoperative radiochemotherapy is superior to postoperative therapy, when appropriate high-risk patients can be defined. Fifth, the results obtained in adjuvant treatment of cancer of the colon cannot easily be extrapolated to treatment of rectal cancer. With respect to chemotherapy and biologic agents to combine with radiation therapy, we have gone from one choice to a plethora of options. The challenge to the academic gastrointestinal oncology community is to find ways to rapidly test in definitive clinical trials the most promising new treatment approaches from a wide variety of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 7 MARCH 1 2005