Send to

Choose Destination
See comment in PubMed Commons below
Br J Cancer. 2000 May;82(9):1539-46.

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.

Author information

  • 1Department of Surgery, Leiden University Medical Center, The Netherlands.


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.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center