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

高温对各种形式的化疗的增效作用在临床前已得到充分证实。 烷化剂是一类遗传毒性药物，其细胞毒性似乎随温度升高而线性增加。 在这方面，我们证明了当用美法仑（L-PAM）和41 ° 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相互作用也可以外推到动物研究背景下的治疗增益。 从临床角度来看，涉及局部/区域疾病的高温肢体灌注和L-PAM的研究已经在涉及黑色素瘤患者的随机和非随机试验中显示了延长的生存期和无病生存期。 罗马里贾纳埃琳娜研究所的Cavaliere小组观察到，在两种剂量的美法仑下，如果在约41.8 ℃而不是41 ℃进行肢体灌注，完全反应率会增加两倍。 他们的数据表明，随着温度的升高，由于L-PAM，临床反应显著改善（P=0.02），这与我们的体外结果一致。患有转移性恶性黑色素瘤的患者通常对标准疗法难治。 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，在威斯康星州大学开始了41.8 ℃全身热疗（WBH）结合增加剂量的L-PAM的I期研究。 一种新的输送系统，即，Aquatherm用于施用WBH。 该研究的结果表明，L-PAM的药代动力学不被WBH改变（即，清除率、消除半衰期和体积或分布）。 L-PAM + WBH的II期剂量确定为17.5 mg/m2。 在研究的背景下，治疗了5名恶性黑色素瘤患者。 观察到的缓解包括：2例患者部分缓解; 2例患者改善; 1例患者疾病进展。 这些数据共同有力地支持了WBH和L-PAM治疗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.