title: Pathologic complete response and disease-free survival are not surrogate endpoints for 5-year survival in rectal cancer: an analysis of 22 randomized trials.
abstract: BACKGROUND
  We performed a literature-based analysis of randomized clinical trials to assess the pathologic complete response (pCR) (ypT0N0 after neoadjuvant therapy) and 3-year disease-free survival (DFS) as potential surrogate endpoints for 5-year overall survival (OS) in rectal cancer treated with neoadjuvant (chemo)radiotherapy (CT)RT.
  
  
  METHODS
  A systematic literature search of PubMed, EMBASE, the Web of Science, SCOPUS, CINAHL, and the Cochrane Library was performed. Treatment effects on 3-year DFS and 5-year OS were expressed as rates of patients alive (%), and those on pCR as differences in pCR rates (∆pCR%). A weighted regression analysis was performed at individual- and trial-level to test the association between treatment effects on surrogate (∆pCR%and ∆3yDFS) and the main clinical outcome (∆5yOS).
  
  
  RESULTS
  Twenty-two trials involving 10,050 patients, were included in the analysis. The individual level surrogacy showed that the pCR% and 3-year DFS were poorly correlated with 5-year OS (R=0.52; 95% CI, 0.31-0.91; P=0.002; and R=0.60; 95% CI, 0.36-1; P=0.002). The trial-level surrogacy analysis confirmed that the two treatment effects on surrogates (∆pCR%and ∆3yDFS) are not strong surrogates for treatment effects on 5-year OS % (R=0.2; 95% CI, -0.29-0.78; P=0.5 and R=0.64; 95% CI, 0.29-1; P=0.06). These findings were confirmed in neoadjuvant CTRT studies but not in phase III trials were 3-year DFS could still represent a valid surrogate.
  
  
  CONCLUSIONS
  This analysis does not support the use of pCR and 3-year DFS% as appropriate surrogate endpoints for 5-year OS% in patients with rectal cancer treated with neoadjuvant therapy.
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Petrelli
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Karen
authors.initials: K
authors.lastname: Borgonovo
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Mary
authors.initials: M
authors.lastname: Cabiddu
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Ghilardi
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Lonati
authors.affiliation: Oncology Department, UO Oncologia, ASST Bergamo Ovest, 24047 Treviglio, BG, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Barni
keywords: Rectal cancer; disease-free survival (DFS); overall survival (OS); pathologic complete response (pCR); surrogate endpoints