The sequence of hormonal therapy and radiation affects outcomes in men treated for prostate cancer

A common treatment for men with intermediate-risk prostate cancer is to combine radiation with drugs that block testosterone — a hormone that makes the tumors grow faster. (This type of treatment is also called androgen deprivation therapy, or ADT).

New research is suggesting the sequence of these treatments may be crucially important.

Dr. Dan Spratt, a professor of radiation oncology at the University of Michigan, led the research. He and his colleagues pooled data from two previously published clinical trials (here and here). Taken together, the studies enrolled just over 1,000 men who had been randomly assigned to one of two groups:

• hormonal therapy given before radiation (followed in all cases by both treatments given together), or
• hormonal therapy that started either concurrently with radiation and then continued after it was finished, or that started only after the radiation treatments were completed.

By themselves, the individual studies didn’t show a significant difference in outcomes after an average follow-up of nearly 15 years. But by pooling the data, Spratt’s team produced a dataset with enough statistical power to show that men who started on hormonal therapy either during or after radiation did significantly better in all respects: compared to the men who were treated with hormone therapy first, they had lesser odds of experiencing a rise in prostate-specific antigen levels (suggesting the cancer might be returning); they lived longer without a progression of their disease; and they were less likely to have cancer spread to other parts of the body. The results also suggested they had a lower risk of actually dying from prostate cancer, although this particular finding wasn’t statistically significant.

Researchers have already devoted a lot of attention to how long hormonal therapy should last when it’s given with radiation. This is now the first study to show that sequence also matters.

Why would that be the case? Possible explanations center on testosterone’s capacity to fix genetic damage in irradiated cancer cells. Just how sequencing plays into this repair mechanism isn’t known, but Dr. Spratt says the new results point to avenues for further study.

Importantly, the results apply specifically to men with unfavorable intermediate-risk prostate cancer who typically get four to six months of hormonal therapy. According to Spratt, sequencing may not be as relevant to men with high-risk tumors who can get hormonal treatments for several years.

Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, editor of the Harvard Health Publishing Annual Report on Prostate Diseases, and editor in chief of HarvardProstateKnowledge.org, says there are circumstances in which some men will need hormonal therapy before radiation. Describing the new results as compelling, he adds “Efforts to investigate sequencing prospectively (i.e., forward in time) should become an important component of future research.”