It may seem counterintuitive, but doctors sometimes ask patients to periodically skip doses of critical medications on purpose. Among other benefits, these so-called “drug holidays” can offer a break from a drug’s side effects. And for some diseases like prostate cancer, an on-off treatment cycle may be used to boost a patient’s response to a drug whose effectiveness has begun to wane.
This strategy is sometimes used to give prostate cancer patients who are undergoing hormone therapy extended breaks in their treatment regimens. Known as intermittent androgen deprivation (or intermittent androgen suppression), this treatment approach offers the prospect of a better quality of life, and though it is not curative, the hope of prolonged survival.
As a consequence, intermittent androgen deprivation has become increasingly popular since it was first described nearly 30 years ago. Despite its growing use, however, important questions remain. Can taking breaks from therapy truly extend a man’s life, or might it actually cut his life short?
The limits of androgen deprivation
To better appreciate the rationale for intermittent therapy, it helps to understand the role of androgens in prostate cancer development and the shortcomings of continuous androgen deprivation.
The growth of prostate tumors is stimulated by androgens, or male hormones. The two most common androgens are testosterone and dihydrotestosterone (DHT). Since the Nobel Prize-winning discovery that prostate tumors depend on these hormones to grow, reducing androgen levels or blocking the action of androgen has become the standard of care for men with cancer that has spread beyond the prostate to the bones and other organs.
There has also been increasing interest in using it in men whose prostate-specific antigen (PSA) level has begun to rise after treatment with surgery or radiation (biochemical recurrence). Biochemical recurrence is an early sign that the cancer has not been eradicated.
Today, androgen deprivation is usually achieved with drugs that block the signals for androgen production by the testicles (luteinizing hormone-releasing hormone agonists, LHRHa) or block their action (receptor blockers and antiandrogens), or drugs that directly block the synthesis of androgens. Therapy is typically administered on a daily basis, and initially it is very effective.
Unfortunately, however, its effects fade over a period of months or years as prostate cancer cells become capable of growing on their own without exposure to male hormones.
Furthermore, men on androgen deprivation therapy may experience a variety of adverse effects on their physical and mental health and quality of life, including hot flashes, erectile dysfunction, osteoporosis, muscle loss, weight gain, and depression.
Why intermittent therapy?
Interrupting treatment causes a man’s testosterone level to rise, re-exposing the prostate tumor to androgens. Some research has suggested that this may trigger cellular changes that make the cancer vulnerable to hormone therapy for a longer time.
Although intermittent androgen deprivation regimens vary, a typical cycle might be six to nine months on medication, then an equal period off treatment. A patient will be monitored closely during his break from therapy, however, and any signs that his cancer is worsening (such as rising PSA levels) would indicate the need to resume treatment.
To learn more about on-and-off hormonal treatment, doctors in Canada launched an international study comparing 690 men who underwent intermittent androgen deprivation with another 696 men who received standard continuous hormone treatment.
The men selected to participate had undergone radiation therapy for cancer that was localized—that is, confined to the prostate—but had experienced a biochemical recurrence. (Some of the men initially had surgery to remove their prostates, but required follow-up radiation therapy.)
None of the men reported having prostate cancer symptoms. For the study, most of the participants received injections of an LHRHa, plus an antiandrogen drug. Men in the intermittent group received therapy for eight months at a time before taking breaks.
The results of this study were published in 2012 in The New England Journal of Medicine. On the pressing question of survival time, the investigators found the two groups to be similar: The typical man receiving intermittent therapy lived 8.8 years, compared with 9.1 years in the continuous-therapy group, a small difference that may have occurred by chance.
A little more than a half year after publication of the Canadian study’s findings, The New England Journal of Medicine published the results of another large trial comparing intermittent androgen deprivation and continuous therapy in prostate cancer patients. This study was overseen by doctors in the United States, but like the Canadian-led study it also involved a large number of men from clinics in several countries.
Included were 770 men who received intermittent therapy and 765 men who had continuous hormone treatment. However, in contrast to the Canadian investigation, the men in this study had more advanced cancer that had begun to metastasize, or spread, to the bones and other organs.
In the U.S.-led study, men who received continuous therapy lived longer than their counterparts in the intermittent therapy group: 5.8 years, compared to 5.1 years, a modest but significant difference. Further, the authors estimated that men in the intermittent therapy group were about 10 percent more likely to die than the continuously treated men, though they argue that the actual risk might really be twice that.
The authors of this study speculated that if the Canadian trial had lasted longer, it might also have found that men in the continuous therapy group lived longer. On the other hand, a 2013 review of nine trials found no overall difference in survival rates between men receiving intermittent or continuous androgen deprivation for localized, advanced or metastatic prostate cancer.
Interestingly, data from this review show that while men who opt for intermittent therapy are more likely to die of prostate cancer, those numbers are offset by equally high rates of deaths from other causes in men who have continuous hormone treatment.
A better life?
A perhaps less vexing question about intermittent therapy: Does it improve a man’s quality of life? For clarification, both the Canadian and U.S. New England Journal studies examined this question.
In the Canadian study, which looked at men with prostate-confined cancer, those who received intermittent therapy reported significantly fewer problems associated with hormone treatments, such as hot flashes, erectile dysfunction, low libido (or desire for sexual activity), and fatigue.
In the study of men with metastatic prostate cancer, those who received intermittent therapy reported better erectile function and mental health at first, but after three months there was little difference between the two groups.
Many other studies also show that patients have fewer side effects and enjoy better quality of life during the off-treatment phase of intermittent androgen deprivation. Some research suggests that men may derive certain long-term benefits from scheduled breaks in hormone treatments.
For instance, a few studies offer clues that intermittent therapy might reduce a man’s risk for developing conditions such as heart disease and osteoporosis. However, data to support those claims are limited.
The bottom line
There will undoubtedly be further debate over the benefits of intermittent androgen deprivation. Future research is likely to examine strategies involving different timing and different drugs from those investigated in the New England Journal studies.
For now, however, it’s probably safe to say that this treatment strategy doesn’t prolong survival. For most men with advanced metastatic prostate cancer, continuous therapy is likely to remain the standard of care.
It’s worth noting that there is no consensus regarding the use of androgen deprivation—continuous or intermittent—in men who have had a biochemical recurrence following surgery or radiation.
Studies have shown that it is not uncommon for some men in this situation to live metastasis-free for a decade or more. Thus for men who are at low risk of developing metastatic disease (PSA doubling time after treatment greater than 12 months and a PSA at diagnosis below 10 ng/mL), the risks of hormonal treatment before signs of metastasis may outweigh the benefits.
But for men at high risk of developing metastatic disease (PSADT after treatment less than 9 months and a PSA above 20 ng/mL at diagnosis), androgen deprivation—even intermittent suppression—may be a reasonable option; the latter appears to minimize the side effects of hormone treatment without compromising a man’s chances for survival.
Learn more about The Best Treatment for Every Prostate Cancer Risk Group and Prostate Cancer Clinical Trials.