title: Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).
abstract: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure.
  
  
  
  Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS).
  
  
  
  Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682).
  
  
  
  PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC.
  
  
  
  NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
authors: Department of Medical Oncology, Cantonal Hospital, St Gallen, Switzerland markus.joerger@kssg.ch.
authors: M
authors: M
authors: Joerger
authors: Pneumology Clinic, Asklepios Fachkliniken, Gauting.
authors: J
authors: J
authors: von Pawel
authors: Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn.
authors: S
authors: S
authors: Kraff
authors: Department of Medical Oncology, Klinik Löwenstein, Löwenstein.
authors: J R
authors: JR
authors: Fischer
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen.
authors: W
authors: W
authors: Eberhardt
authors: Department of Medical Oncology (Cancer Research), West German Cancer Center, University Hospital Essen of University Duisburg-Essen, Essen.
authors: T C
authors: TC
authors: Gauler
authors: Oncological Practice, Praxis Leer, Leer.
authors: L
authors: L
authors: Mueller
authors: Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf.
authors: N
authors: N
authors: Reinmuth
authors: Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf.
authors: M
authors: M
authors: Reck
authors: Pulmonology and Oncology, Klinik Schillerhöhe, Gerlingen.
authors: M
authors: M
authors: Kimmich
authors: Department of Oncology and Hematology, University Hospital, Medical Center II, Tübingen.
authors: F
authors: F
authors: Mayer
authors: Department of Oncology and Hematology, Eberhard Karls University Medical Center, Tübingen.
authors: H-G
authors: HG
authors: Kopp
authors: Medical Oncology, Augusta-Kranken-Anstalt, Bochum.
authors: D M
authors: DM
authors: Behringer
authors: Medical Oncology, Johanniter-Krankenhaus Bonn, Bonn.
authors: Y-D
authors: YD
authors: Ko
authors: Cancer Research, University Hospital Essen, Essen, Germany.
authors: R A
authors: RA
authors: Hilger
authors: CESAR Central Office (CCO), Vienna CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.
authors: M
authors: M
authors: Roessler
authors: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Free University Berlin, Berlin, Germany.
authors: C
authors: C
authors: Kloft
authors: Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Free University Berlin, Berlin, Germany.
authors: A
authors: A
authors: Henrich
authors: CESAR Central Office (CCO), Vienna CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.
authors: B
authors: B
authors: Moritz
authors: Saladax Biomedical, Inc., Bethlehem, USA.
authors: M C
authors: MC
authors: Miller
authors: Saladax Biomedical, Inc., Bethlehem, USA.
authors: S J
authors: SJ
authors: Salamone
authors: Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn.
authors: U
authors: U
authors: Jaehde
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin
keywords: neuropathy; non-small-cell lung cancer; paclitaxel; pharmacokinetics; therapeutic drug monitoring