Marinelli A, Vahrmeijer A L, van de Velde C J
Department of Surgery, Leiden University Medical Center, The Netherlands.
Recent Results Cancer Res. 1998;147:83-94. doi: 10.1007/978-3-642-80460-1_9.
In an attempt to improve tumor response and survival among patients with colorectal cancer metastases confined to the liver, we developed an experimental (rats and pigs) and clinical isolated hepatic perfusion (IHP) technique to exploit maximally the steep dose-response relation of may anticancer drugs. In this overview we present our experimental and clinical results with mitomycin C (MMC) and melphalan (L-Pam). In rats, treatment with a four times higher maximally tolerated dose (MTD) of MMC during IHP compared to hepatic artery infusion (HAI) resulted in higher, more effective intratumoral concentrations of MMC. As a result, only in the IHP-treated rats were complete remissions observed and long-term survival achieved. Hepatotoxic side effects were minimal and transient in all animals. In the clinical phase I/II study with MMC 30 mg/m2 administered as a bolus in the isolated circuit, two of nine patients had a complete remission, with a median survival of 17 months. Four patients developed venoocclusive disease (VOD) of the liver, and as a result one patient died. Therefore we consider MMC unsuitable for further IHP studies. Meanwhile experiments in rats showed that IHP with the L-PAM MTD of 12 mg/kg was even more effective than MMC and did not cause hepatotoxic side effects. In the phase I/II dose-findings study with L-PAM in IHP, the MTD in humans was approximately 3.0 mg/kg. As in the rats, systemic toxicity was dose-limiting. The median survival of the whole group was 18 months. We have started a phase II study of L-PAM in IHP with a fixed dose of 200 mg L-PAM to determine if IHP can significantly increase the median survival and complete remission rate compared to other treatment modalities. Results from this study are expected by the end of 1997.
为提高局限于肝脏的结直肠癌转移患者的肿瘤反应率和生存率，我们研发了一种实验性（大鼠和猪）及临床孤立肝灌注（IHP）技术，以最大程度利用多种抗癌药物陡峭的剂量反应关系。在本综述中，我们展示了使用丝裂霉素C（MMC）和美法仑（L-Pam）的实验及临床结果。在大鼠中，与肝动脉灌注（HAI）相比，IHP期间使用四倍于最大耐受剂量（MTD）的MMC进行治疗，导致肿瘤内MMC浓度更高、更有效。结果，仅在接受IHP治疗的大鼠中观察到完全缓解并实现了长期生存。所有动物的肝毒性副作用均轻微且短暂。在临床I/II期研究中，以30 mg/m²的MMC在孤立循环中推注给药，9名患者中有2名完全缓解，中位生存期为17个月。4名患者发生了肝静脉闭塞性疾病（VOD），1名患者因此死亡。因此，我们认为MMC不适合进一步的IHP研究。同时，大鼠实验表明，使用12 mg/kg的L-Pam MTD进行IHP甚至比MMC更有效，且未引起肝毒性副作用。在IHP中使用L-Pam的I/II期剂量探索研究中，人类的MTD约为3.0 mg/kg。与大鼠一样，全身毒性是剂量限制因素。整个组的中位生存期为18个月。我们已启动一项使用固定剂量200 mg L-Pam进行IHP的L-Pam II期研究，以确定与其他治疗方式相比，IHP是否能显著提高中位生存期和完全缓解率。预计该研究结果将于1997年底得出。
