Vorinostat, a new oral anti-cancer drug, shows promising antitumour activity and is well tolerated when combined with short-term palliative radiotherapy in patients with advanced pelvic cancer. This new type of therapy, which is believed to stop tumour growth by altering the expression of several genes necessary for cancer cell growth, might enhance the effect of palliative radiotherapy and could become an important component of long-term curative pelvic radiotherapy including preoperative chemoradiotherapy for rectal cancer. These are the conclusions of an Article published Online First in The Lancet Oncology.
Radiotherapy is an effective palliative treatment to control pain and bleeding in patients with advanced pelvic cancer who are not suitable for curative radiotherapy or surgery. Previous studies have shown that vorinostat, a type of histone deacetylase (HDAC) inhibitor, has direct tumour-killing ability. Additionally, research suggests that HDAC inhibitors might improve radiation efficacy—giving an HDAC inhibitor before radiotherapy (which causes DNA damage) might prevent tumour cells from being able to repair the DNA damage from the radiation treatments resulting in tumour cell death.
To further evaluate this new therapeutic strategy, Professor Anne H. Ree from the Norwegian Radium Hospital and Norwegian colleagues did the Pelvic Radiation and Vorinostat (PRAVO) phase 1 escalating dose-study to examine the safety and effects of four different doses of vorinostat on tumour response in 16 patients receiving standard palliative radiotherapy for advanced pelvic cancer.
The study was designed to determine the safety, tolerability, and biological activity of the combined regimen defined by dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Vorinostat was administered daily in 100 mg (n=1), 200 mg (n=3), 300 mg (n=6), and 400 mg (n=6) doses 3 hours before pelvic palliative radiation to 30 Gy in 3 Gy daily fractions over 2 weeks.
Vorinostat was generally well tolerated and most adverse events were grade 1 and 2. The most common side effects experienced by all patients were fatigue and gastrointestinal symptoms (nausea, vomiting, diarrhoea, and anorexia). Seven out of sixteen patients experienced grade 3 adverse events. Of these, treatment related grade 3 events (DLT events) were reported in one of six patients at a dose of 300 mg, and in two of six patients at 400 mg. No grade 4 toxic events were reported. The authors conclude that 300 mg of vorinostat daily in combination with palliative radiotherapy for two weeks is the MTD.
Biological activity of vorinostat, as shown by the presence of histone hyperacetylation in tumour biopsies, were detected in patients treated at the lowest and highest doses, indicating that lower doses than the suggested MTD might be sufficient. Additionally, most patients had an overall decrease in tumour volume 6 weeks after completion of treatment.
The authors say: "These observations show that vorinostat can be safely combined with a standard palliative radiotherapy regimen to treat advanced pelvic cancer".
They conclude: "This study adds to mounting evidence supporting the use of HDAC inhibition in cancer therapy. These data encourage further examination of this class of molecularly targeted agents in clinical radiotherapy".
Professor Anne Hansen Ree, Norwegian Radium Hospital, Oslo, Norway. T) +47 482 57 968 (mobile) E) a.h.ree@medisin.uio.no
For full Article, see: http://press.thelancet.com/tloree.pdf
Journal
The Lancet Oncology