title: Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.
abstract: OBJECTIVE
  We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan.
  
  
  METHODS
  The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response.
  
  
  RESULTS
  A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses.
  
  
  CONCLUSIONS
  Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.
authors.affiliation: Surgical Metabolism Section, Surgery Branch, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892-1502, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Pingpank
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.forename: Richard
authors.initials: R
authors.lastname: Chang
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
authors.forename: Ziv
authors.initials: Z
authors.lastname: Neeman
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Kam
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Souping
authors.initials: S
authors.lastname: Zhai
authors.forename: Tatiana
authors.initials: T
authors.lastname: Beresneva
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Seidel
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
mesh_terms: D000328:Adult; D000368:Aged; D002404:Catheterization; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006440:Hemofiltration / Q000379:methods*; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D009367:Neoplasm Staging; D010166:Palliative Care / Q000379:methods; D011336:Probability; D018570:Risk Assessment; D016019:Survival Analysis; D019452:Terminally Ill; D016896:Treatment Outcome
chemical_list: D008558:Melphalan