期刊
LANCET ONCOLOGY
卷 11, 期 5, 页码 459-464出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S1470-2045(10)70058-9
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资金
- Merck Co, Inc
- Norwegian Cancer Society
- Norwegian Health and Rehabilitation Foundation
Background Histone deacetylase (HDAC) inhibitors have shown radiosensitising activity in preclinical tumour models. This phase 1 study assessed the use of vorinostat combined with pelvic palliative radiotherapy for gastrointestinal carcinoma. Methods Between Feb 14, 2007, and May 18, 2009, eligible patients with histologically confirmed carcinoma, scheduled to receive pelvic palliative radiation to 30 Gy in 3 Gy daily fractions over 2 weeks, were enrolled into cohorts of escalating vorinostat dose. Vorinostat was administered orally once daily, 3 h before each radiotherapy fraction, at the following dose levels: 100 mg (n=1), 200 mg (n=4), 300 mg (n=6), and 400 mg (n=6). Endpoints included safety, tolerability, and biological activity (tumour histone acetylation). This study is registered with ClinicalTrials.gov, number NCT00455351. Findings One patient withdrew consent after one treatment day, leaving 16 patients evaluable for tolerability. Most recorded adverse events were grade land 2, among which fatigue (all patients) and gastrointestinal events (all patients) were most common. Grade 3 adverse events included fatigue (n=5), anorexia (n=3), diarrhoea (n=2), hyponatraemia (n=1), hypokalaemia (n=1), and acneiform rash (n=1). Of these, treatment-related grade 3 events (ie, dose-limiting toxicities) were observed in one of six patients at vorinostat 300 mg once daily (fatigue and anorexia), and in two of six patients at vorinostat 400 mg once daily (two events of diarrhoea and one each of fatigue, anorexia, hyponatraemia, and hypokalaemia). The maximum-tolerated dose of vorinostat in combination with palliative radiotherapy was thus determined to be 300 mg once daily. Histone hyperacetylation was detected, indicating biological activity of vorinostat. Interpretation Vorinostat can be safely combined with short-term pelvic palliative radiotherapy. This study highlights the potential use of HDAC inhibitors with radiation, and suggests investigation of vorinostat in long-term curative pelvic radiotherapy-eg, as a component of preoperative chemoradiotherapy for rectal cancer.
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