title: Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest.
abstract: BACKGROUND
  Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev.
  
  
  METHODS
  A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index.
  
  
  RESULTS
  A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response.
  
  
  CONCLUSIONS
  FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa.
authors.forename: C
authors.initials: C
authors.lastname: Antoniotti
authors.affiliation: Unit of Medical Oncology 1, Istituto Oncologico Veneto, IRCSS, Padova.
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa.
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa.
authors.forename: L
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Department of Medical Oncology, University of Rome La Sapienza, Rome.
authors.forename: E
authors.initials: E
authors.lastname: Cortesi
authors.affiliation: Division of Medicine and Medical Oncology, Azienda Istituti Ospitalieri, Cremona.
authors.forename: G
authors.initials: G
authors.lastname: Tomasello
authors.affiliation: Azienda Ospedaliero-Universitaria Città Della Salute e Della Scienza, Turin.
authors.forename: R
authors.initials: R
authors.lastname: Spadi
authors.affiliation: Department of Medical Oncology, Fondazione Poliambulanza, Brescia.
authors.forename: A
authors.initials: A
authors.lastname: Zaniboni
authors.affiliation: Department of Medical Oncology, University Campus Biomedico, Rome.
authors.forename: G
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Unit of Medical Oncology, Università Cattolica del Sacro Cuore, Rome.
authors.forename: C
authors.initials: C
authors.lastname: Barone
authors.affiliation: Unit of Oncology, Sant'Elia Hospital, Caltanissetta.
authors.forename: S
authors.initials: S
authors.lastname: Vitello
authors.affiliation: Unit of Medical Oncology, San Gerardo Hospital, Monza.
authors.forename: R
authors.initials: R
authors.lastname: Longarini
authors.affiliation: Unit of Medical Oncology, Mater Salutis Hospital, Legnago.
authors.forename: A
authors.initials: A
authors.lastname: Bonetti
authors.affiliation: Unit of Medical Oncology, Galliera Hospital, Genoa.
authors.forename: M
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Medical Oncology Sandro Pitigliani, Prato Hospital, Istituto Toscano Tumori, Prato.
authors.forename: S
authors.initials: S
authors.lastname: Di Donato
authors.affiliation: Unit of Medical Oncology, Azienda Sanitaria Ospedaliera Santa Croce e Carle, Cuneo.
authors.forename: C
authors.initials: C
authors.lastname: Granetto
authors.affiliation: Clinical Trials Coordinating Center, Istituto Toscano Tumori, Firenze.
authors.forename: L
authors.initials: L
authors.lastname: Boni
authors.affiliation: Unit of Medical Oncology 2, Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa; Unit of Medical Oncology 2, University of Pisa, Pisa. Electronic address: alfredo.falcone@med.unipi.it.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: FOLFOXIRI; bevacizumab; depth of response; early tumor shrinkage