Adding antiandrogen to radiation therapy improves survival in recurrent prostate cancer
A nearly two-decades-long clinical trial has demonstrated that adding antiandrogen therapy to radiation therapy can improve the survival of prostate cancer patients who have evidence of disease recurrence after radical prostatectomy. The study conducted by the NRG Oncology Radiation Therapy Oncology Group appears in the February 2 New England Journal of Medicine.
"Surgery is a very common treatment for men with localized prostate cancer, but more than 30 percent of them will have recurrent disease; so we specialists in genitourinary oncology have been working to address this problem for a long time," says William U. Shipley, MD, of the Massachusetts General Hospital (MGH) Department of Radiation Oncology, corresponding author of the NEJM report. "This study's findings – that adding antiandrogen therapy to the radiation typically used against recurrence reduces the incidence of metastasis, death from prostate cancer and overall deaths – will change the standard of care for patients experiencing a postoperative recurrence."
Initiated in 1998, the study enrolled 760 patients who, after removal of the prostate gland for localized cancer, developed what is called biochemical recurrence, signified by an increase in prostate-specific antigen (PSA) levels. Participants were randomly assigned to receive either bicalutamide – which at the time was the most common antiandrogen drug in use – or a placebo for 24 months, along with six and a half weeks of radiation therapy. Enrolled from 150 sites in North America, participants were evaluated at the beginning and end of their radiation treatment and then at intervals ranging from every three months to annually for an average of around 13 years.
In 2010 the team published an interim analysis (ascopubs.org/doi/abs/10.1200/jco.2011.29.7_suppl.1), showing that bicalutamide treatment was associated with a reduction in both biochemical recurrence and the development of metastasis. But since prostate cancer can be a slowly progressing disease, longer-term follow up was required to determine whether or not participants could be considered cured of their disease.
The current paper reports that, at an average of 12 years after entering the trial, 21 or 5.8 percent of patients in the bicalutamide group had died from prostate cancer versus 46 or 13.4 percent of those in the placebo group. While 14.5 percent of those in the bicalutamide group developed distant metastases, 23 percent of those in the placebo group had metastatic spread. A second biochemical recurrence was observed in 44 percent of those in the bicalutamide group, compared with almost 68 percent of those in the placebo group.
The overall survival rate among the bicalutamide group was 76.3 percent, compared with 71.3 percent survival in the placebo group, a difference that can be accounted by the reduction in prostate cancer death. There were no significant differences in long-term adverse effects, including effects on the heart and liver, which other investigators have associated with therapies that interfere with either the production or the action of testosterone.
In recent years, bicalutamide has largely been replaced by GnRH agonist drugs like leuprolide, which, Shipley notes, are being investigated together with radiation to treat similar patients in two major clinical trials. "Those trials started about five years ago, so it will take some time to get their results. But since both approaches act by lowering the supply of testosterone to the tumor itself, there isn't any reason to expect the results to be different," he says.
Shipley is the Andreas Soriano Distinguished Professor of Radiation Oncology at Harvard Medical School. The co-authors of the NEJM paper include Niall Heney, MD, of MGH Urology and Anthony Zietman, MD, of MGH Radiation Oncology. The study was supported by National Cancer Institute grants U10 CA21661, U10 CA180868, U10 CA180822 and UG 1CA189867, and by Astra Zeneca.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute (http://www.massgeneral.org/research/about/RI-welcome.aspx) conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."