Short-Course Radiation Versus Long-Course Chemoradiation for Rectal Cancer: Making Progress

There are two broad approaches to preoperative pelvic radiation therapy for resectable rectal cancer: short-course radiation and longcourse chemoradiotherapy. Although the radiation techniques are similar, the fractionation and timing of surgery differ. In general, short-course radiation delivers 25 Gy (5 Gy in five fractions) of radiation followed by surgery 1 week later. Long-course chemoradiotherapy delivers 50.4 Gy (1.8 Gy in 28 fractions) of radiation concurrently with chemotherapy, followed by surgery 4 to 8 weeks later. These competing approaches evolved in parallel; short-course radiation developed in northern Europe and Scandinavia and long-course chemoradiotherapy in the United States and selected European countries. Advocates for each approach base their unwavering enthusiasm on the results of three large randomized trials that were published during the last 15 years. Two landmark trials support the use of short-course preoperative radiation. The Swedish Rectal Cancer Trial randomly assigned patients with cT1-3 disease to short-course radiation versus surgery alone. This was the first (and only) trial that revealed a significant improvement in survival with preoperative radiation. However, the high local recurrence rate in the preoperative arm (46%) prompted the Dutch group to perform the Commissie Klinisch Vergelijkend Onderzoek (CKVO) 95-04 trial, which used the same design but mandated the use of total mesorectal excision (TME). Both the initial and long-term reports revealed a significant improvement in local control with preoperative radiation, although no difference in overall survival was observed. Three years later, the results of the German Rectal Cancer trial were reported. Both the initial and long-term follow-up reports confirmed significant improvements in local control, acute and long-term toxicity, and sphincter preservation with preoperative chemoradiotherapy. However, there was no difference in overall survival. This trial changed the standard of care for patients with cT3-4 and/or node-positive disease to preoperative longcourse chemoradiotherapy. There is an ongoing and at times heated controversy as to the ideal preoperative approach. The first randomized trial comparing these two approaches in patients with resectable cT3 disease was reported by Bujko et al. TME was performed for distal tumors only, postoperative chemotherapy was optional, and there was no central radiation review. Although the long-course chemoradiotherapy arm had a lower incidence of positive radial margins (4% v 13%; P .017), there were no significant differences in crude local recurrence or 4-year survival. Advocates of short-course radiation have quoted patient convenience and lower cost. Supporters of long-course chemoradiotherapy have emphasized the lower surgical morbidity, increased sphincter preservation, and the ability to safely combine radiation with concurrent systemic chemotherapy. Cross-trial comparisons were not helpful. Phase III trials of short-course radiation versus surgery alone included patients with cT1-3Nx disease, whereas trials of long-course chemoradiotherapy were limited to patients with cT3 and/or nodepositive disease. The lines were drawn, alliances formed, and we sat at different dinner tables at the American Society of Clinical Oncology GI Cancers Symposium. Then our brave friends in Australia and New Zealand challenged us and successfully completed a randomized trial. In the article that accompanies this editorial, the Trans-Tasman Radiation Oncology Group (TROG) report the results of their welldesigned, carefully performed, multicenter randomized trial. In brief, patients with ultrasoundor magnetic resonance imaging–staged cT3Nany adenocarcinoma located in the lower two thirds of the rectum were randomly assigned to short-course radiation versus longcourse chemoradiotherapy. Patients in both arms received 6 months of postoperative adjuvant chemotherapy. The primary end point was 3-year local recurrence. Compared with short-course radiation, patients who received long-course chemoradiotherapy had a 3% lower cumulative local recurrence rate at 3 years (4.4% v 7.5%) and a 2% lower cumulative local recurrence rate at 5 years (5.7% v 7.5%). Neither were statistically significant. Likewise, there were no significant differences in distant failure, overall survival, or late radiation toxicity. A subset analysis of the 79 patients with distal tumors revealed a cumulative incidence of local recurrence of 12.5% for short-course radiation and 0% for longcourse chemoradiotherapy. There are two shortcomings of the trial. First is the relatively small number of patients (n 326) who were randomly assigned. The trial was not powered to show equivalence. It was designed to have an 80% power to detect a difference in the projected 3-year local recurrence rate of 15% for short-course radiation compared with 5% for longcourse chemoradiotherapy. If it was powered for a smaller difference (or ideally, equivalent local recurrence), the statistics would have been more robust. This point is illustrated by the limitations of the CIs. Although the 3% lower incidence of local recurrence with long-course JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 31 NOVEMBER 1 2012