title: Rationale and design of MILES-3 and MILES-4 studies: two randomized phase 3 trials comparing single-agent chemotherapy versus cisplatin-based doublets in elderly patients with advanced non--small-cell lung cancer.
abstract: BACKGROUND
  Platinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer (NSCLC) patients, but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospective phase III trials dedicated to elderly patients. Furthermore, the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospectively. We present the rationale and design of two open-label, multicenter, randomized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4. The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy (both trials) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors (MILES-4).
  
  
  METHODS
  Both trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC, ECOG performance status 0-1. In the MILES-3 trial, patients are randomized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine. In the MILES-4 study patients with non-squamous histology are randomized, in a factorial design with 1∶1∶1∶1 ratio, to four arms: gemcitabine (A), cisplatin/gemcitabine (B), pemetrexed (C), cisplatin/pemetrexed (D). Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin; A+B vs C+D to test the role of pemetrexed. Primary endpoint of both trials is overall survival. Secondary and exploratory endpoints include progression-free survival, response rate, toxicity, and quality of life.
  
  
  CONCLUSIONS
  MILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC.
authors.affiliation: Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
authors.affiliation: Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Clinical Trials Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Napoli, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.affiliation: Medical Oncology, Vito Fazzi Hospital, Lecce, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Leo
authors.affiliation: Medical Oncology, Sacco Hospital, Milano, Italy.
authors.forename: Virginio
authors.initials: V
authors.lastname: Filipazzi
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Favaretto
authors.affiliation: Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRCCS, Meldola (FO), Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Burgio
authors.affiliation: Medical Oncology, A.Perrino Hospital, Brindisi, Italy; IEO Istituto Europeo di Oncologia-IRCCS, Milano, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinieri
authors.affiliation: Medical Oncology, Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Napoli, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.affiliation: Medical Oncology, Second University, Napoli, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Medical Oncology, Guglielmo da Saliceto Hospital, Piacenza, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cavanna
authors.affiliation: Medical Oncology, Garibaldi Nesima Hospital, Catania, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bordonaro
authors.affiliation: Thoraco-pulmonary Medical Oncology, Istituto Nazionale Tumori-Fondazione Pascale IRCCS, Napoli, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Costanzo
authors.affiliation: Thoraco-pulmonary Medical Oncology, Istituto Nazionale Tumori-Fondazione Pascale IRCCS, Napoli, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sandomenico
authors.affiliation: Medical Statistics, Department of Mental Health and Preventive Medicine, Second University, Napoli, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Clinical Trials Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Napoli, Italy. Electronic address: francesco.perrone@usc-intnapoli.net.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Thoraco-pulmonary Medical Oncology, Istituto Nazionale Tumori-Fondazione Pascale IRCCS, Napoli, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morabito
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011379:Prognosis; D011446:Prospective Studies; D011788:Quality of Life; D012107:Research Design; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D002945:Cisplatin; D000093542:Gemcitabine
keywords: Advanced NSCLC; Cisplatin; Elderly; Gemcitabine; Pemetrexed; Randomized trial