Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer
Rolf Sauer, M.D.,  for the German Rectal Cancer Study Group NEJM 2004;351:1731
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  PreOp PostOp
number of patients 421 402
survival/5y 76% 74%
local relapse/5y 6% 13%
short term side effects 27% 40%
long term side effects 14% 24%
sphincter saving (as a change) 39% 13%
We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival.

Results Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01).

After preoperative chemoradiotherapy, there was a significant shift toward earlier TNM stages (P<0.001): 8 percent of the patients in this group had a complete response, according to histopathological examination of the tumor specimen, and only 25 percent (as compared with 40 percent in the postoperative-treatment group) had positive lymph nodes (TNM stage III). Eighteen percent of the patients in the postoperative-treatment group had TNM stage I disease on histopathological examination of their resected specimen; all 18 percent had previously been found to have stage T3 or T4 or node-positive disease on endorectal ultrasonography.

The rates of complete resection and sphincter-sparing surgery did not differ between the groups when the 799 patients in the full analysis population were considered. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiotherapy

Postoperative Morbidity and Toxicity of Chemoradiotherapy

In-hospital mortality was 0.7 percent in the preoperative chemoradiotherapy group (3 of the 415 treated patients died while hospitalized) and 1.3 percent in the postoperative-treatment group (5 of the 384 treated patients died while hospitalized; P=0.41). The overall rate of postoperative complications was 36 percent in the preoperative-treatment group and 34 percent in the postoperative-treatment group (P=0.68). The rate of anastomotic leakage of any grade was 11 percent in the preoperative-treatment group and 12 percent in the postoperative-treatment group (P=0.77). The rates of delayed sacral-wound healing (10 percent in the preoperative-treatment group vs. 8 percent in the postoperative-treatment group, P=0.10), postoperative bleeding (3 percent vs. 2 percent, respectively; P=0.50), and ileus (2 percent vs. 1 percent, respectively; P=0.26) did not differ significantly between the groups.

Grade 3 or 4 acute and long-term toxic effects that occurred among patients who received preoperative or postoperative radiotherapy are summarized in the table below. The overall rates of acute and long-term side effects were lower with the preoperative approach than with the postoperative approach, especially with respect to acute and chronic diarrhea and the development of strictures at the anastomotic site. When the toxicity analyses were performed for all patients, including the 110 patients in the postoperative-treatment group who, for various reasons, received no radiotherapy, no significant differences between the two groups were noted (overall rate of acute toxic effects, 25 percent in the preoperative-treatment group vs. 24 percent in the postoperative-treatment group; P=0.78; overall rate of long-term toxic effects, 14 percent vs. 15 percent, respectively; P=0.85).

Conclusions Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.