We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- 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.
- Authors
Vahrmeijer, A L; van Dierendonck, J H; Keizer, H J; Beijnen, J H; Tollenaar, R A E M; Pijl, M E J; Marinelli, A; Kuppen, P J K; van Bockel, J H; Mulder, G J; Velde, C J H van de
- 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[SUP-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[SUP-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 ≤ 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[SUP-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[SUP-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[SUP-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.
- Subjects
COLON cancer; LIVER metastasis
- Publication
British Journal of Cancer, 2000, Vol 82, Issue 9, p1539
- ISSN
0007-0920
- Publication type
Article