title: Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.
abstract: BACKGROUND
  In the PARAMOUNT ("A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL.
  
  
  METHODS
  Patients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m(2), day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed.
  
  
  RESULTS
  A median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms.
  
  
  CONCLUSIONS
  PARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.
authors.affiliation: Montpellier University Hospital, Montpellier, France. Electronic address: jl-pujol@chu-montpellier.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pujol
authors.affiliation: Instituto de Biomedicina de Sevilla - IBIS (Hospital Universitario Virgen del Rocío, Universidad de Sevilla and Consejo Superior de Investigaciones Científicas), Seville, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: San Camillo, High Specialization Hospital, Rome, Italy; Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Marinis
authors.affiliation: Institute of Oncology Bucharest, Bucharest, Romania.
authors.forename: Mircea
authors.initials: M
authors.lastname: Dediu
authors.affiliation: Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Az Ospedale S. Gerardo, Monza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bidoli
authors.affiliation: Instituto de Biomedicina de Sevilla - IBIS (Hospital Universitario Virgen del Rocío, Universidad de Sevilla and Consejo Superior de Investigaciones Científicas), Seville, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Corral
authors.affiliation: Eli Lilly and Company, Madrid, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: San Antonio
authors.affiliation: Eli Lilly and Company, Neuilly sur Seine, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Chouaki
authors.affiliation: Eli Lilly and Company, Indianapolis.
authors.forename: William
authors.initials: W
authors.lastname: John
authors.affiliation: Eli Lilly and Company, Indianapolis.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Eli Lilly Oncology Europe, Houten, The Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Visseren-Grul
authors.affiliation: Division of Medical Oncology, S. G. Moscati Hospital, Avellino, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
mesh_terms: D000740:Anemia / Q000209:etiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D018450:Disease Progression; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D060828:Induction Chemotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011788:Quality of Life; D016019:Survival Analysis; D016896:Treatment Outcome; D028761:Withholding Treatment
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin
keywords: ALIMTA; LY231514; Low-grade toxicities; NS-NSCLC; Post-induction maintenance therapy