Is postoperative adjuvant chemotherapy necessary in locally advanced rectal cancers after preoperative chemoradiation

Abstract

To evaluate the impact of postoperative adjuvant chemotherapy in patients with locally advanced rectal cancers who have received preoperative chemoradiation, and to determine which post-chemoradiation TNM stages will benefit from postoperative chemotherapy. Between 1986 and 2000, 209 patients with tethered or fixed rectal cancers were treated with preoperative chemoradiation according to 3 different schedules. In schedule I, 54 patients were treated with 40 Gy RT plus concurrent 5FU infusion and mitomycin C. In schedule II, 27 patients were treated with “sandwich” chemoradiation: 40 Gy preoperative RT with concurrent 5FU infusion, leucovorin and mitomycin C, and 18 Gy postoperative RT with similar concurrent chemotherapy. The design of both schedules I and II did not include any postoperative adjuvant chemotherapy. In schedule III, 128 patients were treated with 50 Gy preoperative RT concurrent with 5FU infusion, leucovorin and mitomycin C, followed by 5 cycles of postoperative bolus 5FU/leucovorin chemotherapy. After excluding patients with M1 disease and patients in schedules I and II who have received some postoperative chemotherapy off-protocol, 184 patients were available for the analysis. There were 134 males and 50 females. The median age was 62 years (range: 30–82 years). There were 141 tethered and 43 fixed rectal cancers. There were 91 low- (3–5 cm from the anus), 82 mid- (6–10 cm) and 11 high- (> 10 cm) rectal cancers. 97 patients had an abdominoperineal resection, 84 patients had an anterior resection, 2 patients had a Hartman’s resection and one patient had an exenteration. The post-chemoradiation TNM stage distribution was as follow: 36 stage 0 (T0N0M0), 52 stage I, 58 stage II, and 38 stage III. 99 patients (in schedule III) received postoperative bolus 5FU/leucovorin chemotherapy and 85 patients did not. 65% (55/88) of stages 0 and I, and 46% (44/96) of stages II and III had received postoperative adjuvant chemotherapy. As of January 1, 2004, 100 patients are alive, 78 patients were dead and 6 patients were lost to follow-up. 120 patients (65%) were free of relapse, 9 patients (5%) had local recurrence alone, 44 patients (24%) had distant metastases, and 11 patients (6%) had both local and distant failures. The 5-year overall survival was 65% for all 184 patients, 77% for those who received postoperative chemotherapy versus 52% for those who did not (logrank p = 0.0001). The 5-year relapse-free survival was 65%, 76% for the chemotherapy group and 57% for the no-chemotherapy group (p = 0.00017). The 5-year actuarial distant failure rate was 23% for those who received postoperative chemotherapy and 42% for those who did not. For stages 0-I, the 5-year overall survival was 85% for the chemotherapy group and 78% for the no-chemotherapy group (p = 0.34), and the 5-year relapse-free survival was 87% for the chemotherapy group and 77% for the no-chemotherapy group (p = 0.18). For stages II and III, there were statistically significant differences in the outcome with the addition of postoperative chemotherapy. The 5-year overall survival was 66% for those who received chemotherapy and 37% for those who did not (p = 0.00079), and the respective 5-year relapse-free survival was 62% versus 35% (p = 0.0033). The 5-year actuarial distant failure rate was 38% for the chemotherapy group and 58% for the no-chemotherapy group (p = 0.02). In the multivariate analysis of prognostic factors (post-chemoradiation stage, postoperative bolus chemotherapy, fixed versus tethered tumors, different treatment schedules, lymphovascular/ perineural invasion, pT4 and positive nodal disease), postoperative chemotherapy was an independent prognosticator for the relapse-free survival (hazard ratio = 0.4, p = 0.01). For locally advanced rectal cancer, the administration of postoperative adjuvant 5FU/leucovorin chemotherapy after preoperative chemoradiation appeared to reduce recurrences, and improve the overall survival and the relapse-free survival, especially in high risk groups with post-chemoradiation stages II and III disease