Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: An analysis of outcomes in a randomized trial

Purpose: To compare 5 × 5 Gy preoperative radiotherapy with immediate surgery vs. preoperative chemoradiotherapy (50.4 Gy, 5-fluorouracil, leucovorin) with delayed surgery in a randomized trial for cT3-T4 low-lying rectal cancer. Despite the downstaging effect of chemoradiotherapy, similar long-term outcomes were observed in both groups. Methods: The Cox model was used to evaluate the prognostic value of ypTN (“yp” denotes that pathologic classification was performed after initial multimodality therapy) categories and the surgical margin status in 291 patients. Results: Disease-free survival (DFS) (hazard ratio [HR] 1.05, 95% confidence interval [CI], 0.73–1.51), distant metastases (HR, 1.17; 95% CI, 0.77–1.78), and local control (HR, 1.45; 95% CI, 0.74–2.84) were similar in both arms. The ypN status was the only independent prognostic factor for DFS ( p < 0.001). An interaction ( p = 0.016) between N stage and the assigned treatment was demonstrated. For ypN-negative patients, DFS was similar in both arms (HR, 0.83, 95% CI, 0.47–1.48); however, for ypN-positive patients, DFS was worse in the chemoradiotherapy arm (HR, 1.73; 95% CI, 1.07–2.77). The 4-year (median follow-up) DFS rate in N-positive patients was 51% in the 5 × 5-Gy arm vs. 25% in the chemoradiotherapy arm. The corresponding 4-year rates for the incidence of local recurrence and distant metastases were 14% vs. 27% (HR, 1.95; 95% CI, 0.78–4.86) and 38% vs. 68% (HR, 2.05; 95% CI, 1.21–3.48). Conclusion: N-positive disease after chemoradiotherapy indicates radiochemoresistance. N-positive disease after 5 × 5 Gy RT includes both radiosensitive and radioresistant tumors, because the interval between radiotherapy and surgery was too short for radiosensitive cancer to undergo necrosis. Thus, the greater risk of distant metastases recorded in the chemoradiotherapy arm suggests that radiochemoresistance of nodal metastases from rectal cancer is associated with a high potential for developing distant metastases.