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

Abstract

Purpose: 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. Results: 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.more » 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. Conclusions: 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.« less

Authors:
 [1];  [2]; ;  [3];  [4];  [5]; ;  [6];  [1];  [6];  [1]
  1. Department of Radiation Oncology, Stanford University, Stanford, California (United States)
  2. (United States)
  3. Division of Oncology, Department of Medicine, Stanford University, Stanford, California (United States)
  4. Oncology, GlaxoSmithKline, Collegeville, Pennsylvania (United States)
  5. Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida (United States)
  6. Department of Neurosurgery, Stanford University, Stanford, California (United States)
Publication Date:
OSTI Identifier:
22723005
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 99; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BRAIN; LUNGS; NEOPLASMS; PATIENTS; RADIATION DOSES; RADIOTHERAPY; SURGERY; TOXICITY

Citation Formats

Choi, Clara Y.H., Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose, California, Wakelee, Heather A., Neal, Joel W., Pinder-Schenck, Mary C., Yu, Hsiang-Hsuan Michael, Chang, Steven D., Adler, John R., Modlin, Leslie A., Harsh, Griffith R., and Soltys, Scott G., E-mail: sgsoltys@stanford.edu. Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.04.041.
Choi, Clara Y.H., Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose, California, Wakelee, Heather A., Neal, Joel W., Pinder-Schenck, Mary C., Yu, Hsiang-Hsuan Michael, Chang, Steven D., Adler, John R., Modlin, Leslie A., Harsh, Griffith R., & Soltys, Scott G., E-mail: sgsoltys@stanford.edu. Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial. United States. doi:10.1016/J.IJROBP.2017.04.041.
Choi, Clara Y.H., Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose, California, Wakelee, Heather A., Neal, Joel W., Pinder-Schenck, Mary C., Yu, Hsiang-Hsuan Michael, Chang, Steven D., Adler, John R., Modlin, Leslie A., Harsh, Griffith R., and Soltys, Scott G., E-mail: sgsoltys@stanford.edu. Fri . "Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial". United States. doi:10.1016/J.IJROBP.2017.04.041.
@article{osti_22723005,
title = {Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial},
author = {Choi, Clara Y.H. and Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose, California and Wakelee, Heather A. and Neal, Joel W. and Pinder-Schenck, Mary C. and Yu, Hsiang-Hsuan Michael and Chang, Steven D. and Adler, John R. and Modlin, Leslie A. and Harsh, Griffith R. and Soltys, Scott G., E-mail: sgsoltys@stanford.edu},
abstractNote = {Purpose: 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. Results: 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. Conclusions: 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.},
doi = {10.1016/J.IJROBP.2017.04.041},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 1,
volume = 99,
place = {United States},
year = {2017},
month = {9}
}