Synergistic antitumor effects of histamine plus melphalan in isolated hepatic perfusion for liver metastases.
BACKGROUND
Nonresectable primary and metastatic liver tumors remain an important clinical problem. Melphalan-based isolated hepatic perfusion (M-IHP) leads to more than 70% objective responses in selective groups of patients with nonresectable metastases confined to the liver. Complete responses are rare and progression-free survival is limited. Tumor necrosis factor (TNF), a very active agent in isolated limb perfusion, is linked to serious hepatotoxicity, restricting its use in IHP. Because of its vasoactive properties, histamine (Hi) is an alternative to TNF. In this article we evaluate its potential synergistic effect in M-IHP, improving response rates.


METHODS
Our experimental rat IHP model is used for the treatment of soft tissue sarcoma liver metastases. Blood samples are collected for monitoring liver enzymes. Livers are excised 72 h and 7 days after treatment for histologic evaluation.


RESULTS
After sham-IHP and Hi-IHP, tumor progression was observed in 100% of treated animals, while after M-IHP this number fell to 62% and after Hi + M-IHP it fell to only 22% (P = 0.006). Overall response rates were of 55% for Hi + M-IHP vs. 25% for M-IHP, and, more importantly, complete responses (CR) were observed only after Hi + M-IHP (22%) (P = 0.009). Hepatotoxicity peaked within 24 h after IHP, independent of the treatment administered, recovered in 48 h, and was related mainly to the elevation of transaminases (grade 3 ASAT and grade 1 ALAT for control group and grades 3 and 4, respectively, for all other treatments). No serious systemic toxicity was observed. Histology of the liver showed no serious damage.


CONCLUSIONS
Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity.
Brunstein
Flavia
F
Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands. flis_br@yahoo.com
Eggermont
Alexander M M
AM
de Wiel-Ambagtsheer
Gisela aan
Ga
van Tiel
Sandra T
ST
Rens
Joost
J
ten Hagen
Timo L M
TL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D010478:Chemotherapy, Cancer, Regional Perfusion; D004195:Disease Models, Animal; D004357:Drug Synergism; D006632:Histamine / Q000008:administration & dosage*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D009368:Neoplasm Transplantation; D051381:Rats; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary
D006632:Histamine; D008558:Melphalan