Hormone Therapy May Harm Some but Aids Many with Localized Prostate Cancer

The prostate is one of the tiniest and most obscure of organs, though it may suddenly seem the largest and most obtrusive to a man just diagnosed with prostate cancer. Despite its remote location—tucked among the bladder, rectum, and urethra—the prostate gland is controlled by the brain, which sends life-giving testosterone by way of the testes. Like healthy prostate cells, cancerous ones need the hormone to survive. In the 1940s, a pair of researchers tried cutting off the supply of testosterone, through castration and other means, in men who had advanced cancer, with apparently miraculous effects.

“These men would have bone metastases, be in pain, and they would undergo treatment and, within days, they were much better,” said Philip Kantoff, HMS professor of medicine at Dana–Farber Cancer Institute (DFCI).

Though the patients’ tumors often came back, Charles Huggins and Clarence Hodges would win the Nobel Prize for their strategy of depriving prostate cancer cells of testosterone—an approach that would be refined over the next half century. In the 1980s, two researchers independently characterized luteinizing hormone–releasing hormone (LHRH), the brain signal that controls the testosterone-producing pathway. The discovery, which also won the Nobel Prize, opened the door to an array of testosterone-suppressing drugs. Today, such hormone-suppressing drugs, administered in conjunction with radiation, provide a powerful tool for treating not just men with metastatic prostate cancer but those with more localized though still serious forms of the disease.

A new study by Anthony D’Amico, Kantoff, and colleagues in the Jan. 23 issue of The Journal of the American Medical Association suggests that in these nonmetastatic cases, adding hormone therapy to radiation can have a double-edged effect: it enhances the survival of otherwise relatively healthy patients, but it can hasten fatal heart attacks in those with a history of cardiovascular disease.

“We may be doing more harm than good in these patients by adding hormone therapy because it can accentuate the rate of fatal myocardial infarction,” said D’Amico, HMS professor of radiation oncology at Brigham and Women’s Hospital. He, Kantoff and colleagues studied the fates of 206 men randomly assigned to receive either radiation therapy or radiation combined with androgen-suppressing therapy. They found that among men with few or no other health concerns, those who received radiation alone had a death rate that was four times higher than those who had the combined treatment. But the reverse was true for men with a recent history of heart disease: those who received the combined therapy had a death rate that was twice as high as those who had radiation only.

The findings, while dramatic, are not a complete surprise. Over the past few years, reports linking testosterone-suppressing therapy to a host of side effects such as obesity, insulin resistance, and cardiac disease have been popping up. In 2006, HMS researchers Matthew Smith, Nancy Keating, and colleagues, in a massive review of 73,196 Medicare patients, found that men taking LHRH agonists were more likely to develop diabetes, coronary heart disease, and heart attacks (see Focus Sept. 29, 2006).

Despite the emerging news, it appears that even men with early, low-risk prostate cancer are being given hormone therapy. A recent study by researchers at the University of California, San Francisco, found a striking increase in the number of such cases.

“A lot of doctors are just giving it out without primary evidence that it actually benefits patients,” said Kantoff. “Certainly it makes one think more broadly that before you institute hormone-deprivation therapy, make sure the person has a clear indication for getting it.”

Part of the problem—one substantiated by the recent findings—is that hormone therapy, in the right patient, is a powerful tumor-suppressing agent. “Herein lies the dilemma,” said D’Amico, who is also in the radiation oncology departments at DFCI and Children’s Hospital. “You want to give someone the hormone therapy because it improves their cureability but, in fact, you may decrease their life expectancy because you’re accentuating an underlying non–prostate cancer health issue, i.e., cardiovascular disease.”

Ironically, D’Amico, Kantoff, and colleagues are partly responsible for putting combined therapy on the treatment map of many physicians and patients. Until the mid-1990s, it was reserved primarily for men with advanced prostate cancer. “In 1995, Anthony and I got together and said, what about guys who don’t have those big bad tumors, but who have smaller tumors that are potentially operable but you want to treat them with radiation rather than surgery? Does it add anything to give them hormone therapy?” Kantoff said.

Over the next six years they and their colleagues would enroll men with localized, though high-risk prostate cancer (determined by prostate-specific antigen level, Gleason score, and whether or not the cancer had invaded the wall of the prostate gland). All the men received two months of radiation therapy but half received the radiation during the middle of a six-month course of testosterone-suppressive therapy.

The men were followed closely for the first few years and then annually. After four and a half years of follow-up, the results seemed clear—men receiving the combined treatment had higher overall survival rates. In 2005, Kantoff, D’Amico, and colleagues published a report saying as much. But studies like those of Keating, Smith, and others began surfacing. The researchers decided to see how the men in their study were faring, but this time they went back and reconstructed the men’s health when they began treatment.

“What Anthony did, his brainchild, was to go back retrospectively to our patients and ask the very important question: can we predict who will get into trouble?” said Kantoff. “And the answer was, yes. Comorbidity appeared to not only nullify the effect of androgen-deprivation therapy, it may have made it worse.”

What was striking was how many of the moderate- to high-comorbidity, testosterone-deprived patients died from heart attacks. More than 50 percent of the 19 deaths in this group were due to myocardial infarction. Only two out of the 11 deaths in the no- or minimal-comorbidity testosterone-blocked group were due to heart attacks.

How exactly the suppression of testosterone is working to bring about the fatal attacks is not clear. One possibility is that it is a consequence of the more immediate side effects of hormone therapy. “In people who have a critical underlying coronary lesion, it may be that all that needs to happen is for them to gain five to 10 percent of their body weight—that could be enough of a stress to have a coronary event,” Kantoff said. “It could be that simple, though rarely are things that simple.”

There is a more complex, if speculative, explanation, said D’Amico. It turns out, the inner lining of the coronary arteries is coated with androgen receptors, which upregulate when testosterone levels are low. In the complete absence of the hormone, the receptors begin degrading. In mice, androgen receptor degradation sets up an inflammatory response that can exacerbate an already existing lesion in the artery, and it might do the same in the arteries of an androgen-suppressed person. “Of course, it’s all theory,” he said.

At least the solution to the problem appears straightforward. “If you have somebody who has prostate cancer indices that suggest they could benefit from combined therapy, and they also have a personal history of coronary heart disease or known cardiovascular risk factors, send them to a cardiologist first,” D’Amico said. “Have the cardiologist address the issue and then consider the hormone therapy or do not use the hormone therapy at all.”