Phase I Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy
Mené sur 18 patients atteints d'un cancer de la prostate avec récidive biochimique après une prostatectomie radicale, cet essai de phase I évalue la dose limitante toxique et la tolérabilité de l'évérolimus en combinaison avec une radiothérapie fractionnée dans le cadre d'un traitement de sauvetage
Background : Up to half of patients treated with salvage radiation therapy (SRT) for rising PSA ultimately develop a second biochemical recurrence (sBCR). Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin (mTOR) pathway can lead to tumor hypoxia and radioresistance. Everolimus is an mTOR inhibitor with both anti-tumor and radiosensitizing effects. Methods : We performed a phase I study using a modified 3+3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of BCR following prostatectomy. After a two-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam CT localization in 37 fractions of 1.8 Gy each (total dose 66.6 Gy). Patients were monitored for both acute (≤ 90 days) and chronic (> 90 days) treatment-related toxicities. Results : 18 patients received everolimus at dose levels of 5 mg (N = 6), 7.5 mg (N = 6), or 10 mg (N = 6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment related toxicities included: grade 1/2 mucositis (55.6%), grade 1/2 fatigue (38.9%), grade 1/2 rash (61.1%), and grade 1 urinary symptoms (61.1%). Four patients (22.2%) experienced a grade 3 acute toxicity (N = 1 for rash, anemia, lymphopenia, and neutropenia), and no patients experienced grade ≥ 3 chronic toxicity. After a median follow-up time of 17.8 months (range 1.2 – 46.0 months), 9 patients (56.3%) achieved an undetectable PSA nadir, and 5 patients (31.3%) have developed sBCR. Discussion : Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy RT.