ABSTRACT: 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.
The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 i.v.) 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 C57BL6/J mice were evaluated by monitoring mouse breathing rates and survival.
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 sirolimus 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.
Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2007; 2(8):751-7. · 4.55 Impact Factor