Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial
Mené sur 12 patients atteints d'un cancer du poumon non à petites cellules avec métastases cérébrales, cet essai multicentrique de phase I évalue la dose maximale tolérée du vorinostat (un inhibiteur d'histone désacétylase) délivré de façon concomitante à une radiochirurgie stéréotaxique ciblant les métastases
Purpose : We sought to determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure (LF), distant intracranial failure (DF), and overall survival (OS) rates. Methods and Materials : In this multicenter study, patients with 1-4 NSCLC brain metastases, each <2 cm, were enrolled in a phase 1, 3+3 dose-escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any CTCAE v3.0 grade 3-5 acute non-hematologic adverse event (AE) related to vorinostat or SRS occurring within 30 days. Results : From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. As no DLTs were observed, the MTD was established as 400 mg. Acute AEs were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n = 2), nausea (n = 1), and fatigue (n = 2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier OS was 13 months. There were no local failures. One (8%) patient at the 400 mg dose level with a 2.0 cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months following SRS. Conclusions : The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew prior to completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.