Rosenthal David I, Yom Sue S, Liu Li, Machtay Mitchell, Algazy Kenneth, Weber Randal S, Weinstein Gregory S, Chalian Ara A, Mille Linda K, Rockwell Kenneth, Tonda Margaret, Schnipper Edward, Hershock Diane
Department of Radiation Oncology, Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia 19104, USA.
Invest New Drugs. 2002 Aug;20(3):343-9. doi: 10.1023/a:1016201732368.
Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC).
Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design.
Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m2 in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade I (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response.
Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.
与游离顺铂相比，脂质体顺铂制剂在与放射治疗（RT）联合使用时具有两个潜在优势：1）肿瘤选择性定位，提高治疗比率；2）半衰期延长，可实现更多的放射增敏作用。我们开展了一项针对头颈部鳞状细胞癌（HNSCC）的Ⅰ期研究，将隐形脂质体顺铂（SPI-077）与RT联合使用。
Ⅳa/b期HNSCC患者接受SPI-077治疗，静脉注射，每两周一次，共两次，同时接受RT（6-7周内给予60-72 Gy）。SPI-077剂量按照标准的Ⅰ期设计进行递增。
20例患者接受了38剂SPI-077治疗，剂量从20-200 mg/m²分为六个剂量水平递增。其中两名患者因可逆性3级肝毒性或皮疹仅接受了一剂治疗。三名患者出现1级，一名患者出现2级输注反应。四名患者转氨酶短暂升高：1级（n = 1）、2级（n = 1）和3级（n = 2）。一名患者出现3级中性粒细胞减少。未出现耳毒性、神经毒性或肾毒性。靶区放射皮肤和黏膜毒性似乎未加重。完成治疗的17例患者中有10例（59%）达到初始完全缓解。
SPI-077的全身和靶区放射毒性极小。通过更缓慢、更稀释的初始输注可将输注反应降至最低。在没有剂量限制毒性的情况下，停止了进一步的剂量递增，以处理脂质体结合顺铂的重新配方问题。尽管如此，本研究表明高剂量的SPI-077可以安全给药。潜在的有益治疗比率表明脂质体放射增敏剂制剂值得进一步研究。
