title: Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial.
abstract: BACKGROUND
  Carboplatin plus paclitaxel administered every 3 weeks is standard first-line chemotherapy for patients with advanced ovarian cancer. A weekly paclitaxel schedule combined with carboplatin every 3 weeks prolonged progression-free survival and overall survival in a Japanese phase 3 trial. The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more effective than the same drugs given every 3 weeks.
  
  
  METHODS
  We did a multicentre, randomised, phase 3 study at 67 institutions in Italy and France. Women with FIGO stage IC-IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy were randomly allocated in a 1:1 ratio to receive either carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m(2)) every 3 weeks for six cycles or carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m(2)) every week for 18 weeks. Randomisation was done by computer-based minimisation, stratified by centre, residual disease after surgery, and ECOG performance status. The study was not blinded. Coprimary endpoints were progression-free survival and quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index [FACT-O/TOI] score), and analysis was by modified intention to treat. This report presents the final analysis. The study is registered with ClinicalTrials.gov, number NCT00660842.
  
  
  RESULTS
  822 patients were enrolled into the study between Nov 20, 2008, and March 1, 2012; 12 withdrew their consent immediately after randomisation and were excluded, and 810 were eligible for analysis. 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule. After median follow-up of 22·3 months (IQR 16·2-30·9), 449 progression-free survival events were recorded. Median progression-free survival was 17·3 months (95% CI 15·2-20·2) in patients assigned to treatment every 3 weeks, versus 18·3 months (16·8-20·9) in women allocated to the weekly schedule (hazard ratio 0·96, 95% CI 0·80-1·16; p=0·66). FACT-O/TOI scores differed significantly between the two schedules (treatment-by-time interaction p<0·0001); with treatment every 3 weeks, FACT-O/TOI scores worsened at every cycle (weeks 1, 4, and 7), whereas for the weekly schedule, after transient worsening at week 1, FACT-O/TOI scores remained stable. Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3-4 neutropenia (167 [42%] of 399 patients vs 200 [50%] of 400 patients), febrile neutropenia (two [0·5%] vs 11 [3%]), grade 3-4 thrombocytopenia (four [1%] vs 27 [7%]), and grade 2 or worse neuropathy (24 [6%] vs 68 [17%]). Three deaths during the study were attributed to chemotherapy; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen.
  
  
  CONCLUSIONS
  A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer.
  
  
  BACKGROUND
  None.
authors.affiliation: Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy. Electronic address: s.pignata@istitutotumori.na.it.
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.affiliation: Dipartimento per la Tutela della Salute della Donna, della Vita Nascente, del Bambino e dell' Adolescente, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Ginecologia Oncologica, Azienda Ospedaliera Città della Salute e della Scienza, Presidio S Anna e Università, Torino, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: Statistica Medica, Seconda Università di Napoli, Napoli, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Hôpital Hôtel-Dieu, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.affiliation: Oncologia Medica, Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bologna
authors.affiliation: Centre Alexis Vautrin, Vandoeuvre-Les-Nancy, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Weber
authors.affiliation: Unità di Ginecologia Oncologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raspagliesi
authors.affiliation: Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Università La Sapienza, Roma, Italy.
authors.forename: Pierluigi Benedetti
authors.initials: PB
authors.lastname: Panici
authors.affiliation: Ginecologia ed Ostetricia, Policlinico, Bari, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Cormio
authors.affiliation: Oncologia Medica C, Centro di Riferimento Oncologico, Aviano-PN, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorio
authors.affiliation: Oncologia ed Ematologia, AO Carlo Poma, Mantova, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Cavazzini
authors.affiliation: Ginecologia Oncologica, Centro di Ricerca e Formazione ad Alta Tecnologia nelle Scienze Biomediche, Università Cattolica del Sacro Cuore, Campobasso, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ferrandina
authors.affiliation: Oncologia Medica Ospedale S Giovanni Calibita Fatebenefratelli, Roma, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Breda
authors.affiliation: Oncologia Medica Ospedale S Chiara, Trento, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Murgia
authors.affiliation: Dipartimento di Oncologia AO S Maria della Misericordia, Udine, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Sacco
authors.affiliation: Oncologia Medica, Ospedale Antonio Perrino, Brindisi, and Istituto Europeo di Oncologia, Milano, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinieri
authors.affiliation: Dipartimento per la Tutela della Salute della Donna, della Vita Nascente, del Bambino e dell' Adolescente, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Vanda
authors.initials: V
authors.lastname: Salutari
authors.affiliation: Dipartimento per la Tutela della Salute della Donna, della Vita Nascente, del Bambino e dell' Adolescente, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ricci
authors.affiliation: Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Pisano
authors.affiliation: Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Greggi
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Lauria
authors.affiliation: Unità di Ginecologia Oncologica, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS, Milano, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Lorusso
authors.affiliation: Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Università La Sapienza, Roma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: Ginecologia ed Ostetricia, Policlinico, Bari, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Selvaggi
authors.affiliation: Statistica Medica, Seconda Università di Napoli, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Signoriello
authors.affiliation: Unità Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Piccirillo
authors.affiliation: Unità Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.affiliation: Unità Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011788:Quality of Life; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016190:Carboplatin; D017239:Paclitaxel