title: Pharmacokinetics of isolated lung perfusion with melphalan for resectable pulmonary metastases, a phase I and extension trial.
abstract: BACKGROUND
  Isolated lung perfusion (ILuP) with melphalan was performed under normo- and hyperthermic conditions combined with pulmonary metastasectomy for patients with resectable lung metastases. We present the results of pharmacokinetic analysis of a phase I and extension trial.
  
  
  METHODS
  Twenty-one procedures of ILuP with melphalan were performed in the phase I trial according to a dose-escalation schedule under normothermic and hyperthermic conditions followed by surgical resection of pulmonary metastases. In an extension trial 8 additional procedures with 15 and 45 mg melphalan were performed under hyperthermic conditions. Samples of serum, perfusate, lung, and tumor tissue were obtained.
  
  
  RESULTS
  High perfusate concentrations of melphalan were recorded in contrast to low systemic concentrations. Marked interindividual variability was observed in melphalan concentrations in perfusate, tumor, and lung tissue. Statistically significant correlation between melphalan dose, and perfusate area under the concentration-time curve (R(2) = 0.578, P = 0.001) and lung tissue concentrations (R(2) = 0.459, P = 0.028) were noted. No significant correlation between melphalan dose and tumor tissue concentrations could be established.
  
  
  CONCLUSIONS
  Isolated lung perfusion effectively delivers high doses of melphalan to the lung and tumor tissues with minimal systemic levels. Significant correlation between perfused melphalan dose, perfusate area under the concentration-time curve and lung tissue melphalan concentrations were observed.
authors.affiliation: Department of Pulmonary Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands. marcogrootenboers@hetnet.nl
authors.forename: Marco Jj H
authors.initials: MJ
authors.lastname: Grootenboers
authors.forename: Jeroen M H
authors.initials: JM
authors.lastname: Hendriks
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Boven
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.forename: Bart
authors.initials: B
authors.lastname: van Putte
authors.forename: Bernard
authors.initials: B
authors.lastname: Stockman
authors.forename: Ernst
authors.initials: E
authors.lastname: De Bruijn
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: Paul E Y
authors.initials: PE
authors.lastname: Van Schil
authors.forename: Franz Mnh
authors.initials: FM
authors.lastname: Schramel
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008875:Middle Aged
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan