title: Increased local cytostatic drug exposure by isolated hepatic perfusion: a phase I clinical and pharmacologic evaluation of treatment with high dose melphalan in patients with colorectal cancer confined to the liver.
abstract: A phase I dose-escalation study was performed to determine whether isolated hepatic perfusion (IHP) with melphalan (L-PAM) allows exposure of the liver to much higher drug concentrations than clinically achievable after systemic administration and leads to higher tumour concentrations of L-PAM. Twenty-four patients with colorectal cancer confined to the liver were treated with L-PAM dosages escalating from 0.5 to 4.0 mg kg(-1). During all IHP procedures, leakage of perfusate was monitored. Duration of IHP was aimed at 60 min, but was shortened in eight cases as a result of leakage from the isolated circuit. From these, three patients developed WHO grade 3-4 leukopenia and two patients died due to sepsis. A reversible elevation of liver enzymes and bilirubin was seen in the majority of patients. Only one patient was treated with 4.0 mg kg(-1) L-PAM, who died 8 days after IHP as a result of multiple-organ failure. A statistically significant correlation was found between the dose of L-PAM, peak L-PAM concentrations in perfusate (R = 0.86, P< or =0.001), perfusate area under the concentration-time curve (AUC; R = 0.82, P<0.001), tumour tissue concentrations of L-PAM (R = 0.83, P = 0.011) and patient survival (R = 0.52, P = 0.02). The peak L-PAM concentration and AUC of L-PAM in perfusate at dose level 3.0 mg kg(-1) (n = 5) were respectively 35- and 13-fold higher than in the systemic circulation, and respectively 30- and 5-fold higher than reported for high dose oral L-PAM (80-157 mg m(-2)) and autologous bone marrow transplantation. Median survival after IHP (n = 21) was 19 months and the overall response rate was 29% (17 assessable patients; one complete and four partial remissions). Thus, the maximally tolerated dose of L-PAM delivered via IHP is approximately 3.0 mg kg(-1), leading to high L-PAM concentrations at the target side. Because of the complexity of this treatment modality, IHP has at present no place in routine clinical practice.
authors.affiliation: Department of Surgery, Leiden University Medical Center, The Netherlands.
authors.forename: A L
authors.initials: AL
authors.lastname: Vahrmeijer
authors.forename: J H
authors.initials: JH
authors.lastname: van Dierendonck
authors.forename: H J
authors.initials: HJ
authors.lastname: Keizer
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: R A
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: M E
authors.initials: ME
authors.lastname: Pijl
authors.forename: A
authors.initials: A
authors.lastname: Marinelli
authors.forename: P J
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: J H
authors.initials: JH
authors.lastname: van Bockel
authors.forename: G J
authors.initials: GJ
authors.lastname: Mulder
authors.forename: C J
authors.initials: CJ
authors.lastname: van de Velde
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D010478:Chemotherapy, Cancer, Regional Perfusion; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan