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
Al. Vahrmeijer et al., 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, BR J CANC, 82(9), 2000, pp. 1539-1546
A phase I dose-escalation study was performed to determine whether isolated
hepatic perfusion (IHP) with melphalan (L-PAM) allows exposure of the live
r to much higher drug concentrations than clinically achievable after syste
mic administration and leads to higher tumour concentrations of L-PAM. Twen
ty-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 pro
cedures, leakage of perfusate was monitored. Duration of IHP was aimed at 6
0 min, but was shortened in eight cases as a result of leakage from the iso
lated circuit. From these, three patients developed WHO grade 3-4 leukopeni
a and two patients died due to sepsis. A reversible elevation of liver enzy
mes and bilirubin was seen in the majority of patients. Only one patient wa
s treated with 4.0 mg kg(-1) L-PAM, who died 8 days after IHP as a result o
f multiple-organ failure. A statistically significant correlation was found
between the dose of L-PAM, peak L-PAM concentrations in perfusate (R = 0.8
6, P less than or equal to 0.001), perfusate area under the concentration-t
ime 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 ci
rculation, and respectively 30- and 5-fold higher than reported for high do
se 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 remissi
ons). Thus, the maximally tolerated dose of L-PAM delivered via IHP is appr
oximately 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 pre
sent no place in routine clinical practice. (C) 2000 Cancer Research Campai
gn.