Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial


      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, distant intracranial failure, and overall survival rates.

      Materials and Methods

      In this multicenter study, patients with 1 to 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 Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.


      From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events 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 overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.


      The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before 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.
      To read this article in full you will need to make a payment
      ASTRO Member Login
      ASTRO Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kaal E.C.
        • Niel C.G.
        • Vecht C.J.
        Therapeutic management of brain metastasis.
        Lancet Neurol. 2005; 4: 289-298
        • Lassman A.B.
        • DeAngelis L.M.
        Brain metastases.
        Neurol Clin. 2003; 21 (vii): 1-23
        • Seiwert T.Y.
        • Salama J.K.
        • Vokes E.E.
        The concurrent chemoradiation paradigm–general principles.
        Nat Clin Pract Oncol. 2004; 4: 86-100
        • Chang E.L.
        • Wefel J.S.
        • Hess K.R.
        • et al.
        Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial.
        Lancet Oncol. 2009; 10: 1037-1044
        • West A.C.
        • Johnstone R.W.
        New and emerging HDAC inhibitors for cancer treatment.
        J Clin Invest. 2014; 124: 30-39
        • Emanuele S.
        • Lauricella M.
        • Tesoriere G.
        Histone deacetylase inhibitors: Apoptotic effects and clinical implications (review).
        Int J Oncol. 2008; 33: 637-646
        • Siegel D.
        • Hussein M.
        • Belani C.
        • et al.
        Vorinostat in solid and hematologic malignancies.
        J Hematol Oncol. 2009; 2: 31
        • Zhang Y.
        • Jung M.
        • Dritschilo A.
        • et al.
        Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors.
        Radiat Res. 2004; 161: 667-674
        • Chinnaiyan P.
        • Vallabhaneni G.
        • Armstrong E.
        • et al.
        Modulation of radiation response by histone deacetylase inhibition.
        Int J Radiat Oncol Biol Phys. 2005; 62: 223-229
        • Munshi A.
        • Kurland J.F.
        • Nishikawa T.
        • et al.
        Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity.
        Clin Cancer Res. 2005; 11: 4912-4922
        • Munshi A.
        • Tanaka T.
        • Hobbs M.L.
        • et al.
        Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci.
        Mol Cancer Ther. 2006; 5: 1967-1974
        • Sonnemann J.
        • Kumar K.S.
        • Heesch S.
        • et al.
        Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells.
        Int J Oncol. 2006; 28: 755-766
        • Palmieri D.
        • Lockman P.R.
        • Thomas F.C.
        • et al.
        Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks.
        Clin Cancer Res. 2009; 15: 6148-6157
        • Ree A.H.
        • Dueland S.
        • Folkvord S.
        • et al.
        Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: The Pelvic Radiation and Vorinostat (PRAVO) phase 1 study.
        Lancet Oncol. 2010; 11: 459-464
        • Gondi V.
        • Pugh S.L.
        • Tome W.A.
        • et al.
        Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multi-institutional trial.
        J Clin Oncol. 2014; 32: 3810-3816
        • Kim H.T.
        Cumulative incidence in competing risks data and competing risks regression analysis.
        Clin Cancer Res. 2007; 13: 559-565
        • Kaplan E.
        • Meier P.
        Nonparametric estimation for incomplete observation.
        J Am Stat Assoc. 1958; 53: 457-481
        • Drzymala R.E.
        • Wasserman T.H.
        • Won M.
        • et al.
        A phase I-B trial of the radiosensitizer: Etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG study 95-02).
        Radiother Oncol. 2008; 87: 89-92
        • Yamazaki H.
        • Nakamura S.
        • Nishimura T.
        • et al.
        Hypofractionated stereotactic radiotherapy with the hypoxic sensitizer AK-2123 (sanazole) for reirradiation of brain metastases: A preliminary feasibility report.
        Anticancer Res. 2013; 33: 1773-1776
        • Chan E.
        • Arlinghaus L.R.
        • Cardin D.B.
        • et al.
        Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer.
        Radiother Oncol. 2016; 119: 312-318
        • Olsen E.A.
        • Kim Y.H.
        • Kuzel T.M.
        • et al.
        Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.
        J Clin Oncol. 2007; 25: 3109-3115
        • Mann B.S.
        • Johnson J.R.
        • Cohen M.H.
        • et al.
        FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.
        Oncologist. 2007; 12: 1247-1252
        • Shaw E.
        • Scott C.
        • Souhami L.
        • et al.
        Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90-05.
        Int J Radiat Oncol Biol Phys. 2000; 47: 291-298


      Commenting Guidelines

      To submit a comment for a journal article, please use the space above and note the following:

      • We will review submitted comments as soon as possible, striving for within two business days.
      • This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
      • We require that commenters identify themselves with names and affiliations.
      • Comments must be in compliance with our Terms & Conditions.
      • Comments are not peer-reviewed.