Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer
Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer
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DOI：
10.1097/jto.0b013e3180cc2587
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发表时间：
2007-08-01
影响因子：
20.4
通讯作者：
Leof, Edward B.
中科院分区：
文献类型：
--
作者：
Sarkaria, Jann N.;Schwingler, Paul;Leof, Edward B.
目的：评价西罗莫司联合胸部放疗和顺铂治疗肺癌的安全性和耐受性。在平行，西罗莫司的影响进行了研究，在小鼠模型的放射性pneumonia.Materials和方法：第一阶段的试验评估标准的三维适形胸部放射治疗（60戈伊）和每周顺铂（25毫克/m2）IV）与口服西罗莫司剂量递增相结合。在血液中评估西罗莫司药物水平和对mTOR信号传导至核糖体S6蛋白的抑制。西罗莫司给药期间和C57 BL 65小鼠全胸部放射治疗后的影响进行了评估，通过监测小鼠呼吸频率和survival.Results：7例III期肺癌患者累计的临床研究。4例接受2 mg/天西罗莫司治疗的患者均未出现剂量限制性毒性。3例患者接受5 mg/天西罗莫司治疗，1例患者在该剂量水平出现3级吞咽困难的剂量限制性毒性。然而，由于该研究因资金损失而提前终止，因此未定义该方案中sirolumus的最大耐受剂量。在小鼠实验中，伴随西罗莫司治疗与放射相关的发病率或mortals.Conclusions：西罗莫司，放射和顺铂联合治疗的患者耐受性良好。
Purpose: The safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in patients with lung cancer. In parallel, the effects of sirolimus were studied in a murine model of radiation pneumonitis.Materials and Methods: The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 Mg/m(2) IV) in combination with escalating doses of oral sirolimus. Sirolimus drug levels and inhibition of mTOR signaling to ribosomal S6 protein were assessed in blood. The effects of sirolimus administered during and after whole thoracic radiation of C57BL65 mice were evaluated by monitoring mouse breathing rates and survival.Results: Seven patients with stage III lung cancer were accrued to the clinical study. None of the four patients treated with 2 mg/day sirolimus developed dose-limiting toxicities. Three patients were treated with 5 mg/day sirolimus, and one patient at this dose level had dose-limiting toxicity of grade 3 dysphagia. However, the maximally tolerated dose of sirolumus in this regimen was not defined because the study was terminated prematurely because of loss of funding. In the mouse experiments, concomitant sirolimus treatment was not associated with an increase in radiation-associated morbidity or mortality.Conclusions: Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.