title: Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation.
abstract: Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3 mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: L B J
authors.initials: LB
authors.lastname: van Iersel
authors.forename: M R
authors.initials: MR
authors.lastname: Verlaan
authors.forename: A L
authors.initials: AL
authors.lastname: Vahrmeijer
authors.forename: E L
authors.initials: EL
authors.lastname: van Persijn van Meerten
authors.forename: F G J
authors.initials: FG
authors.lastname: Tijl
authors.forename: R W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.forename: P J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: R A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: C J H
authors.initials: CJ
authors.lastname: van de Velde
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006499:Hepatic Artery; D006801:Humans; D007260:Infusion Pumps; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010477:Perfusion / Q000379:methods*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan