SAN FRANCISCO—A year-long treatment with a common statin drug appears to reduce the risk of rectal injury in prostate cancer patients treated with high-dose radiation therapy, researchers reported here at the 2016 Genitourinary Cancers Symposium (Abstract 120).
In a Phase II study, radiation-caused injury to the rectum occurred in about 13 percent of patients, meeting the primary endpoint of the study—a 50 percent reduction of the expected 30 percent historical adverse event rate, said Mitchell Anscher, MD, Professor of Radiation Oncology at the Massey Cancer Center at Virginia Commonwealth University in Richmond.
Late rectal toxicity of Grade 2 was observed in seven of the 53 patients. Unresolved rectal toxicity was mild, with only 4 percent—or two of 53 patients—experiencing a Grade 2 adverse event, the researchers reported.
“Lovastatin as utilized in this study may reduce the incidence of late rectal toxicity of Grade 2 or greater,” Anscher said.
“It looks like lovastatin helps,” he told OT at his poster presentation. “There is pre-clinical data in mice that suggest the effects of radiation can be ameliorated by statins, but nobody has really tried a prospective clinical trial. The role of statins in preventing or ameliorating late radiation injury deserves further study.”
He and his colleagues recruited 53 patients for the study. “We followed them all for a minimum of two years,” Anscher said. “Most rectal toxicity manifests within two years after radiation therapy. Overall, 15 percent of patients experienced Grade 2 or greater rectal toxicity, so we hit our estimate of 50 percent of the 30 percent of rectal toxicity in historical controls.”
The researchers are also assessing the patients for urinary function, bowel function, and sexual function. “At this point we have just analyzed the rectal toxicity,” he explained at his poster presentation.
Questions to be Answered
In commenting on the study, Sumanta Pal, MD, Assistant Professor of Medical Oncology at the City of Hope, told OT, “The big question that is lurking in the context of statin therapy in prostate cancer is mechanism of action. We know from other studies that statins may augment the effect of conventional systemic treatments. Here, we see it may have a protective effect in the context of radiotherapy.
“What is warranted now is an investment in laboratory-based efforts to characterize how this happens,” Pal said. “Once we pinpoint the mechanism of action, perhaps we can use more focused strategies to improve outcomes.”
“Lovastatin has a long-standing history of its toxicity profile,” Anscher said. “People tolerated it pretty well. It is very low cost; you can get three months' supply at Walmart for $4. Statins are known to reduce cholesterol levels, but also are known to have other properties, including anti-inflammatory effects.
“We would like to see if we could move this forward in a Phase III trial. Lovastatin is a relatively weak anti-inflammatory agent so we might want to see if we could get better results with atorvastatin or one of the other drugs,” he said.
“If a person comes to me with prostate cancer, I would talk to him about whether to take a statin,” Anscher said. “I would be comfortable prescribing him a statin on what I have seen here if the person agreed to be monitored in case of side effects. However, this is a very preliminary study, with small numbers of patients, and needs to be confirmed in a Phase III trial.
“Even if the patient had no cholesterol to start with, I would still be okay with giving them a statin because they are not going to be on it forever. We only put them on the statin for a year,” he said.
Study Details, Participants
For the trial, the research team recruited men with histologically—proven adenocarcinoma of prostate who were planning to undergo curative radiation treatment, with a planned dose of 60 Gray or greater. No prior radiation therapy was allowed to be entered in the trial, but androgen deprivation therapy was permitted. Patients were followed for two years—one-year after lovastatin treatment was terminated. Patients were seen at 1, 2, 4, 6, 9, 12, 15, 18, 21, and 24 months after end of radiation therapy.
Patients were treated with external beam radiation or with brachytherapy. External beam radiation was delivered in fractions ranging from 1.8 Gray to 2 Gray. The total dose to the prostate was 78 Gray to 79 Gray. A brachytherapy boost of 90 Gray was delivered when the patients were receiving palladium103 or a boost of 100 Gray was given when using iodine125 after external beam radiation. For patients treated with monotherapy brachytherapy, the dose was 124 Gray with palladium103 or 144 Gray with iodine125.
If the patient was not on a statin at the time of the definitive radiation treatment, he was prescribed a lovastatin dose of 20 mg per day. If he was already on a statin, the patient was converted to lovastatin, 20 mg to 80 mg a day. Statin therapy was begun on the first day of radiation therapy and continued for one year. If needed for management of hyperlipidemia, lovastatin was continued beyond 12 months, or the patient was converted back to his original statin therapy.
Lovastatin was discontinued if liver enzyme tests exceeded three times the upper limit of normal or if levels of creatine kinase were elevated—an indication of muscle damage that can occur with statin therapy. Anscher said that for other adverse events of Grade 2 or less thought to be caused by lovastatin therapy, the dose was lowered to 10 mg a day. If there were Grade 3 adverse events due to lovastatin, the statin was discontinued and the patient was removed from the study.
The median age of the men in the study was 63 years; the median follow-up was 26 months. About 31 percent of the men in the study identified as white; 22 percent were African-American. Anscher said 45 men were treated with external beam radiation alone; two men were treated with external beam radiation plus brachytherapy; and six men were treated with brachytherapy monotherapy.
The study was supported by grants from Virginia Commonwealth University and the Massey Cancer Center.