title: 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.
abstract: OBJECTIVE
  To compare 5 x 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 x 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).
  
  
  CONCLUSIONS
  N-positive disease after chemoradiotherapy indicates radiochemoresistance. N-positive disease after 5 x 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.
authors.affiliation: Department of Radiotherapy, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. bujko@coi.waw.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bujko
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michalski
authors.forename: Lucyna
authors.initials: L
authors.lastname: Kepka
authors.forename: Marek P
authors.initials: MP
authors.lastname: Nowacki
authors.forename: Anna
authors.initials: A
authors.lastname: Nasierowska-Guttmejer
authors.forename: Piotr
authors.initials: P
authors.lastname: Tokar
authors.forename: Dariusz
authors.initials: D
authors.lastname: Dymecki
authors.forename: Mariusz
authors.initials: M
authors.lastname: Pawlak
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Lesniak
authors.forename: Piotr
authors.initials: P
authors.lastname: Richter
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wojnar
authors.forename: Ewa
authors.initials: E
authors.lastname: Chmielik
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D016001:Confidence Intervals; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil