title: Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: results from a large patient cohort.
abstract: OBJECTIVE
  A number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome.
  
  
  METHODS
  Patients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS)--defined as the time from start of first-line to progression on third-line treatment--were estimated using the Kaplan-Meier method and curves were compared with log-rank test.
  
  
  RESULTS
  A total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)-VEGFi-mTORi compared with those receiving VEGFi-mTORi-VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively).
  
  
  CONCLUSIONS
  Few patients received three lines of TTs. The sequence VEGFi-VEGFi-mTORi was associated with improved survival with respect to VEGFi-mTORi-VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.
authors.affiliation: Sapienza University of Rome, Department of Radiology, Oncology and Human Pathology, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacovelli
authors.affiliation: Oncology Unit, A. Cardarelli Hospital, Naples, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cartenì
authors.affiliation: Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Department of Medical Oncology, Polytechnic University of the Marche Region, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: Medical Oncology, Genitourinary Cancer Section, University Federico II, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Lorenzo
authors.affiliation: Fondazione del Piemonte per l'Oncologia IRCC, Candiolo, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ortega
authors.affiliation: Oncology Division, Department of Oncology and Hematology, University of Modena e Reggio Emilia, Modena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sabbatini
authors.affiliation: The Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ricotta
authors.affiliation: Oncology Division, Ospedali Riuniti, Bergamo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Messina
authors.affiliation: National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II' Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lorusso
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliero Universitaria of Cagliari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Atzori
authors.affiliation: Oncology and Hematology Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: De Vincenzo
authors.affiliation: Oncology Unit, St. Maria della Misericordia Hospital, Udine, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Sacco
authors.affiliation: University and IRCCS AOU-San Martino-IST, National Cancer Research Institute, Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boccardo
authors.affiliation: Medical Oncology, St. Chiara Hospital, Trento, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Valduga
authors.affiliation: Medical Oncology, 'G.B. Rossi' Academic Hospital, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Massari
authors.affiliation: Department of Medical Oncology, Santa Maria Annunziata Hospital, Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Baldazzi
authors.affiliation: Medical Oncology & Breast Unit Department, Sen A. Perrino Hospital, Brindisi, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinieri
authors.affiliation: Medical Oncology, Maggiore della Carità University Hospital, Novara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mosca
authors.affiliation: Oncology Unit, Belcolle Hospital, Viterbo, Italy.
authors.forename: Enzo Maria
authors.initials: EM
authors.lastname: Ruggeri
authors.affiliation: Medical Oncology, University of Brescia, Brescia, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.affiliation: Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Cerbone
authors.affiliation: Medical Oncology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: giuseppe.procopio@istitutotumori.mi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procopio
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases