Brunstein Flavia, Eggermont Alexander M M, de Wiel-Ambagtsheer Gisela aan, van Tiel Sandra T, Rens Joost, ten Hagen Timo L M
Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
Ann Surg Oncol. 2007 Feb;14(2):795-801. doi: 10.1245/s10434-006-9208-4. Epub 2006 Nov 10.
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.
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.
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.
Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity.
不可切除的原发性和转移性肝肿瘤仍然是一个重要的临床问题。基于美法仑的孤立肝灌注（M-IHP）在局限于肝脏的不可切除转移瘤的特定患者群体中可产生超过70%的客观缓解率。完全缓解罕见，无进展生存期有限。肿瘤坏死因子（TNF）是孤立肢体灌注中一种非常有效的药物，但与严重的肝毒性相关，限制了其在IHP中的应用。由于其血管活性特性，组胺（Hi）是TNF的一种替代物。在本文中，我们评估其在M-IHP中的潜在协同作用，以提高缓解率。
我们的实验大鼠IHP模型用于治疗软组织肉瘤肝转移。采集血样监测肝酶。治疗后72小时和7天切除肝脏进行组织学评估。
假IHP和Hi-IHP治疗后，100%的治疗动物出现肿瘤进展，而M-IHP治疗后这一比例降至62%，Hi + M-IHP治疗后仅降至22%（P = 0.006）。Hi + M-IHP的总体缓解率为55%，而M-IHP为25%，更重要的是，仅在Hi + M-IHP治疗后观察到完全缓解（CR）（22%）（P = 0.009）。IHP后24小时内肝毒性达到峰值，与所给予的治疗无关，48小时内恢复，主要与转氨酶升高有关（对照组为3级谷草转氨酶和1级谷丙转氨酶，其他所有治疗组分别为3级和4级）。未观察到严重的全身毒性。肝脏组织学检查未显示严重损伤。
Hi + M-IHP具有协同抗肿瘤作用，且局部或全身毒性均未增加。
