title: Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab.
abstract: OBJECTIVE
  Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status.
  
  
  METHODS
  Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS).
  
  
  RESULTS
  In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio [HR] = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006).
  
  
  CONCLUSIONS
  ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.
authors.affiliation: Hubert Piessevaux, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels; Marc Buyse, International Drug Development Institute, Louvain-la-Neuve; Eric Van Cutsem and Sabine Tejpar, University Hospital Gasthuisberg, Leuven, Belgium; Michael Schlichting and Steffen Heeger, Merck KGaA, Darmstadt; and Carsten Bokemeyer, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Piessevaux
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Michael
authors.initials: M
authors.lastname: Schlichting
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeger
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012372:ROC Curve; D012680:Sensitivity and Specificity; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab