title: Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA).
abstract: BACKGROUND
  Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients.
  
  
  METHODS
  The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM(®) program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses.
  
  
  RESULTS
  A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS.
  
  
  CONCLUSIONS
  This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment.
authors.affiliation: EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France. benoit.you@chu-lyon.fr.|Service d'Oncologie Médicale, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France. benoit.you@chu-lyon.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: You
authors.affiliation: Service d'hématologie, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Centre Hospitalier Lyon-Sud, Pierre-Benite, France.|Université Lyon 1, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Service d'hématologie, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Centre Hospitalier Lyon-Sud, Pierre-Benite, France.|Université Lyon 1, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bachy
authors.affiliation: Service d'hématologie, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Centre Hospitalier Universitaire de Dijon, 21034, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: Centre Henri Becquerel, 76038, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Institut Gustave Roussy, 94805, Villejuif, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Centre Léon Bérard, 69008, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sebban
authors.affiliation: EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France.|Service d'Oncologie Médicale, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.affiliation: EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France.|Service d'Oncologie Médicale, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France.
authors.forename: Jéome
authors.initials: J
authors.lastname: Guitton
authors.affiliation: EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France.|Service d'Oncologie Médicale, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.affiliation: EMR UCBL/HCL 3738, Faculté de médecine Lyon Sud, Université Lyon 1, Lyon, France.|Service d'Oncologie Médicale, Centre d'Investigation de Thérapeutiques en Oncologie et Hématologie de Lyon (CITOHL), Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Chemin du Grand Revoyet, 69495, Pierre-Benite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001663:Bilirubin / Q000097:blood; D002330:Carmustine / Q000008:administration & dosage; D003404:Creatinine / Q000097:blood; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000628:therapy; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012709:Serum Albumin / Q000032:analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D012709:Serum Albumin; D003561:Cytarabine; D005047:Etoposide; D003404:Creatinine; D008558:Melphalan; D001663:Bilirubin; D002330:Carmustine
keywords: Etoposide; Lymphoma; Non-Hodgkin; Pharmacokinetics; Stem cell transplantations; Survival