PHASE II EVALUATION OF IV MELPHALAN (L PAM) AND WBH FOR MALIGNANT MELANOMA

热疗对各种形式的化疗的增强作用在临床前已经得到了很好的证实。烷基化剂是一类细胞毒性随温度升高而线性增加的基因毒性药物。在这方面，我们证明了使用melphalan （L-PAM）和41摄氏度(C)高温处理L929细胞时，剂量（或热）增强比为3.6。值得注意的是，这种热/L-PAM相互作用也可以在动物研究的背景下推断出治疗增益。从临床角度来看，涉及肢体热灌注和L-PAM治疗局部/区域性疾病的研究在涉及黑色素瘤患者的随机和非随机试验中均显示出延长生存期和无病生存期。罗马雷吉娜埃琳娜研究所（Instituto Regina Elena）的卡瓦列尔的研究小组观察到，如果在~41.8摄氏度的温度下进行肢体灌注，完全缓解率会增加两倍，而两剂美法兰的温度为41C。他们的数据显示，随着温度的升高，L-PAM的临床疗效显著改善（P=0.02），这与我们的体外实验结果一致。转移性恶性黑色素瘤患者通常难以接受标准治疗。因此，为了将上述实验室和临床结果扩展到癌症患者的全身治疗，威斯康星大学启动了41.8℃全身热疗（WBH）联合增加剂量L-PAM的I期研究。一种新的输送系统，即Aquatherm，被用于WBH的管理。本研究结果表明，L-PAM的药代动力学不受白白醇的影响（即清除率、消除半衰期和体积或分布）。L-PAM + WBH的II期剂量为17.5 mg/m2。在这项研究的背景下，5名恶性黑色素瘤患者接受了治疗。观察到的反应包括：2例患者部分缓解；2例好转；还有一名患者病情恶化。这些数据共同有力地支持了WBH和L-PAM用于转移性恶性黑色素瘤患者的II期试验的启动。

The potentiating effects of hyperthermia on various forms of chemotherapy is well established preclinically. Alkylating agents are one class of genotoxic drugs in which cytotoxicity appears to increase linearly with increasing temperature. In this regard, we demonstrated a dose (or thermal) enhancement ratio of 3.6 when L929 cells were treated with melphalan (L-PAM) and 41-degree-celsius (C) hyperthermia. It is noteworthy that such heat/L-PAM interactions can also extrapolate to a therapeutic gain in the context of animal studies. From a clinical standpoint, studies involving hyperthermic limb perfusion and L-PAM for local/regional disease have shown prolonged survival and disease free survival both in randomized and non-randomized trials involving melanoma patients. Cavaliere's group at the Instituto Regina Elena in Rome observed a two-fold increase in the complete response rate if limb perfusions were performed at ~41.8C, as opposed to 41C, at two doses of melphalan. Their data suggested a significant (P=0.02) improvement in clinical response due to L-PAM with increasing temperature, which is concordant with our in vitro results. Patients with metastatic malignant melanoma are generally refractory to standard therapy. Thus, in order to extend the aforementioned laboratory and clinical results to systemic treatment of cancer patients, a phase I study of 41.8C whole body hyperthermia (WBH) coupled with increasing doses of L-PAM was initiated at the University of Wisconsin. A new delivery system, i.e., the Aquatherm, was used for administration of WBH. The results of this study demonstrated that the pharmacokinetics of L-PAM were not altered by WBH (i.e., clearance, elimination half life and volume or distribution). The phase II dose of L-PAM plus WBH was established at 17.5 mg/m2. In the context of the study five patients with malignant melanoma were treated. Responses observed included: two patients with partial remission; two patients with improvement; and one patient with progressive disease. These data taken collectively strongly support the initiation of a phase II trial of WBH and L-PAM for patients with metastatic malignant melanoma.