Androgens, the family of male sex hormones that includes testosterone, trigger sexual development, the growth of facial hair, a deepening voice, and increased muscle and bone mass. But when prostate cancer begins to develop, androgens seemingly turn traitor by fueling tumor growth. In the 1940s, Dr. Charles Huggins, a researcher at the University of Chicago, demonstrated in Nobel Prize–winning experiments that shutting down androgen production could rein in prostate cancer. Since then, androgen deprivation, commonly called hormone therapy, has been the mainstay of treatment for metastatic prostate cancer.
Given that the testicles pump out 90% to 95% of androgens (the adrenal glands churn out the balance), early therapies involved surgical removal of the testicles or the administration of a female hormone called diethylstilbestrol (DES) to block androgen production. Today, physicians generally prescribe drugs, such as a luteinizing hormone–releasing hormone (LHRH) agonist, to achieve the same benefit without the cardiovascular side effects that accompany DES or the psychological impact of castration.
Although the drugs can hold the cancer in check, patients often experience profound side effects: fatigue, hot flashes, loss of libido, impotence, weight gain, loss of muscle and bone, anemia, cognitive decline, and depression. Worse still, the cancer becomes resistant to androgen deprivation, a state called androgen-independent prostate cancer, in 24 months on average. (Some patients, however, take hormone therapy for more than a decade, so the side effects aren’t trivial.) The median survival time for patients with metastatic androgen-independent prostate cancer is about 18 months.
Seeking to delay androgen independence and improve quality of life, researchers began testing intermittent hormone therapy (IHT). Also called intermittent androgen suppression or intermittent androgen deprivation, IHT involves periods of treatment lasting several months that alternate with “drug holidays,” or off-treatment periods. Several Phase II clinical trials* have shown both the feasibility of IHT and improvements in quality of life. Although the studies were small and patients weren’t followed for long periods of time, preliminary data indicated that patients on IHT seem to live as long as patients who take hormone therapy continuously.
|*Note: Phase II clinical trials typically include less than 300 people. They test whether a treatment is effective and further evaluate its safety. They also help determine whether a larger, Phase III trial should be undertaken.
Despite the promise of IHT, its use remains controversial because so many questions about it have not been definitively answered. Among them: Which patients are most likely to benefit? To what extent does it improve quality of life? Do the drug holidays delay androgen independence? How long should patients stay on hormone therapy before temporarily stopping it? At what point should hormone therapy be restarted? What is the effect on overall survival?
In clinical practice, patients have responded so well to IHT that many physicians now recommend it in certain cases. Yet many highly respected organizations, including the American Society of Clinical Oncology, still consider it investigational, a therapy that patients should consider only if they can enroll in a clinical trial. This article will review the research to date on IHT, explain why some physicians routinely prescribe it, note which patients are good candidates for therapy, and highlight what men should know before starting it.
The beginnings of IHT
In the absence of androgens, normal prostate cells cannot grow. But in Darwinian fashion, wily prostate cancer cells can mutate and multiply unchecked. In fact, when taken continuously, hormone therapy may fuel progression of the disease it once held in check, usually within two to three years.
The theory behind taking hormone therapy intermittently is that if treatment stops before tumor cells reach an androgen-independent state, they may regain characteristics of normal cells, such as programmed cell death, as androgen levels rise. And because the cells have not yet become resistant to hormone therapy, they may be kept in check when hormones are later reintroduced. Stated another way, periodically changing the cells’ environment might extend the amount of time it takes for them to adapt and mutate, prolonging survival.
Studies in male mice in the 1990s gave credence to the theory. Two groups of researchers found that the time it took to reach an androgen-independent state was, on average, three times longer with IHT than with continuous androgen suppression. Buoyed by the results, other researchers began testing IHT in humans, using changes in PSA to determine when to stop and restart therapy. In one study, 47 patients with recurrent localized or metastatic disease were treated with combined androgen blockade for 24 to 32 weeks until their PSA was 4 ng/ml or less and at its lowest point, or nadir. (See “Combined androgen blockade” below.) Therapy was then stopped until the PSA level rose to between 10 ng/ml and 20 ng/ml. On average, patients were able to stay off hormone therapy for about 10 months before starting treatment again. During that time, their testosterone levels returned to normal, and they reported an increased sense of well-being and recovery of libido and potency.
Combined androgen blockade
Combined androgen blockade — also known as maximum androgen blockade or total androgen blockade — involves the concomitant use of a drug that acts centrally on the brain (an LHRH agonist or GnRH agonist) and another that acts peripherally at the prostate cell level (an anti-androgen). In that way, all androgen activity is blocked — not only the production of testosterone, but also its action in the prostate itself.
Several more small studies followed. (See “Early IHT studies,” below.) Most included patients who took LHRH agonists with or without an anti-androgen until their PSA reached its nadir and was 4 ng/ml or lower, typically six to nine months. Therapy then stopped. (Patients whose PSA did not drop below 4 ng/ml had to stick with continuous hormone therapy and were excluded from the study.) When the PSA reached an arbitrary, predefined level — often in the range of 10 ng/ml to 20 ng/ml, although lower for men who had had a radical prostatectomy — therapy began again. The first treatment cycle, defined as the time from the start of therapy to the end of the drug holiday, lasted for seven to 16 months on average, with six to nine months of that time typically spent off therapy. Time off therapy varied widely, however: some patients experienced rapid disease progression while others enjoyed treatment holidays as long as 48 months.
Early IHT studies
Klotz LH, Herr HW, Morse MJ, Whitmore WF Jr. Intermittent Endocrine Therapy for Advanced Prostate Cancer. Cancer 1986;58:2546–50. PMID: 2429759.
Goldenberg SL, Bruchovsky N, Gleave ME, et al. Intermittent Androgen Suppression in the Treatment of Prostate Cancer: A Preliminary Report. Urology 1995;45:839–45. PMID: 7538246.
Higano CS, Ellis W, Russell K, Lange PH. Intermittent Androgen Suppression with Leuprolide and Flutamide for Prostate Cancer: A Pilot Study. Urology 1996;48:800–4. PMID: 8911533.
Oliver RT, Williams G, Paris AM, Blandy JP. Intermittent Androgen Deprivation After PSA-Complete Response as a Strategy to Reduce Induction of Hormone-Resistant Prostate Cancer. Urology 1997;49:79–82. PMID: 9000190.
Bruchovsky N, Klotz LH, Sadar M, et al. Intermittent Androgen Suppression for Prostate Cancer: Canadian Prospective Trial and Related Observations. Molecular Urology 2000;4:191–99. PMID: 11062374.
Grossfeld GD, Small EJ, Lubeck DP, et al. Androgen Deprivation Therapy for Patients with Clinically Localized (Stages T1 to T3) Prostate Cancer and for Patients with Biochemical Recurrence After Radical Prostatectomy. Urology 2001;58:56–64. PMID: 11502450.
Researchers made several other observations about IHT and the patients most likely to benefit from it:
- Patients undergoing treatment for localized disease, or for PSA-only relapse after definitive therapy, were more likely to enjoy longer treatment holidays.
- Off-treatment periods got progressively shorter with successive cycles of IHT in most studies. However, a 2007 Canadian study found that the duration of off-treatment periods was consistent across cycles relative to the duration of the first off-treatment period.
- One study reported that younger patients and those with short off-treatment times in the first treatment cycle saw their disease progress more rapidly than older patients and those with longer off-treatment times.
- The same study found that patients whose PSA decline was prompt and continuous during each treatment phase generally had a better prognosis than patients whose decline in PSA slowed and plateaued in subsequent cycles.
- IHT did not appear to shorten the time to androgen independence or death in a European study that randomly assigned 201 patients with a rising PSA after a radical prostatectomy to receive either IHT or continuous hormone therapy. Similar numbers of patients in the two groups progressed to androgen-independent prostate cancer in about the same amount of time. A second study showed no differences in overall survival between the two regimens.
Researchers also documented improvements in quality of life. Study participants consistently reported that they recovered their libido and sexual function when they weren’t taking hormone therapy. One study specifically evaluated health-related quality of life in 10 patients on IHT. All of them experienced clinically significant improvements in vitality, sexual function, and general health during the off-therapy phase. Patients over age 71 said that their urinary function improved, too. Similarly, a Japanese study of 49 patients with either locally advanced or metastatic disease who completed quality-of-life questionnaires found that energy levels rose significantly during the off-treatment phase. These patients also reported fewer side effects and an improved sense of well-being soon after they temporarily stopped hormone therapy. (See “How researchers measure quality of life,” below.)
How researchers measure quality of life
How we each define quality of life is, admittedly, rather subjective. But researchers have developed several questionnaires for use in clinical trials to try to assess quality of life. Some of the tools, such as the RAND 36-Item Health Survey, the Functional Assessment of Cancer Therapy–General (FACT–G), and the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, pose about 30 to 40 general questions related to physical health and emotional well-being, or ask respondents to indicate the degree to which they agree with various statements. For example:
During the past week, have you had trouble sleeping?
___ Not at all
___ A little
___ Quite a bit
___ Very much
During the past week, did pain interfere with your daily activities?
___ Not at all
___ A little
___ Quite a bit
___ Very much
Compared to a year ago, how would you rate your health in general now?
___ Much better than one year ago
___ Somewhat better now than one year ago
___ About the same
___ Somewhat worse now than one year ago
___ Much worse now than one year ago
In prostate cancer–related studies, researchers may ask participants additional questions about their urinary habits, and about their ability to get and maintain an erection, whether they were able to have sexual intercourse, and whether sexual activity during the past month was satisfying. Participants may complete the same survey every few weeks or months, allowing researchers to gauge the response to treatment, on average, of the entire group.
Another possible benefit: IHT may slow bone loss. Men undergoing hormone therapy experience a loss in bone mineral density of 3% to 5% during their first year on the drugs, increasing their risk of a fracture. A 2002 study showed that changes in bone mineral density paralleled the on- and off-therapy periods, with the greatest loss in bone mineral density during the first treatment period. Bone loss slowed during off-treatment periods.
Several larger, randomized controlled trials currently under way in North America and Europe should provide better guidance on the risks and benefits of IHT. (For a summary of these trials and information on how to participate at a medical center in your area, see “Phase III clinical trials of IHT,” below.) Mature results from these studies probably won’t be published for a few years, but in my opinion, that shouldn’t discourage men from pursuing IHT if they stand to benefit from its start-and-stop regimen.
Phase III clinical trials of IHT
Randomized, controlled Phase III trials currently under way in North America and Europe aim to tease out differences in survival and quality of life between patients who take hormone therapy continuously and those who do so intermittently. Phase III trials include relatively large groups of people (1,000 or more) to confirm effectiveness of a drug or procedure, monitor side effects, compare it to commonly prescribed treatments, and collect information that will allow the drug or treatment to be used safely.
- The National Cancer Institute of Canada/Southwest Oncology Group JPR7 study includes 1,386 patients at multiple sites who experienced biochemical recurrence after radiation therapy. Although researchers stopped recruiting participants in 2005, they continue to follow the patients’ progress.
- The Southwest Oncology Group 9346/National Cancer Institute of Canada PR8 Study includes men with metastatic, stage IV prostate cancer. Researchers aim to enroll 1,512 men. For more information about this study, details on how to enroll, and a list of participating sites in the United States, Canada, and Europe, log on to www.cancer.gov/clinicaltrials.
- The South European Uro-oncological Group 9901 trial is recruiting 900 patients in England newly diagnosed with stage III or stage IV prostate cancer.
When cancer returns
Based on the information that we do have, as well as my own experience with IHT in treating patients, I think it’s a suitable option for many men. For example, men who are too old to have surgery, aren’t candidates for radiation therapy due to other conditions (inflammatory bowel disease, for example), or have medical conditions that pose a greater threat to their survival than prostate cancer might opt for IHT. Men suffering from metastatic prostate cancer can also consider IHT.
In my practice, however, about 80% of the men I talk to about IHT have recently learned that their cancer is no longer in remission. Sometimes they have symptoms, or I can tell by looking at a bone scan that their cancer is making a comeback. But generally, these patients experience what’s called biochemical recurrence — an increase in PSA after supposedly curative treatment for prostate cancer. The PSA threshold for determining biochemical recurrence depends on what type of therapy the patient had initially. (See Table 1 below.) If you experience a biochemical recurrence of prostate cancer, keep in mind that you are not alone. About 15% to 35% of patients who were initially “cured” with localized therapy, such as radiation, experience biochemical recurrence, usually within five to six years.
Table 1: Guidelines for determining biochemical recurrence
||0.2 ng/ml on at least two successive tests.
||Some physicians use a higher threshold of 0.4 ng/ml or greater.
|Radiation therapy (external beam or brachytherapy)
||Three successive elevations in PSA compared to nadir (low point), regardless of actual reading, according to the American Society for Therapeutic Radiology and Oncology.
||Many oncologists use a different threshold — PSA nadir plus 2 ng/ml — because it is more closely associated with clinical progression.
Ideally, post-treatment PSA levels should be less than 0.5 ng/ml, but this is rare; levels of 0.6–1.4 ng/ml are more common.
|Neoadjuvant hormone therapy and radiation therapy
||Same as for radiation therapy.
||Same as for radiation therapy.
When a patient opts for IHT, I generally start with a nine-month treatment phase; studies have shown that it may take that long for the PSA to reach its nadir. Interestingly, these numbers can hint at the length of treatment holidays. A 2007 study of patients with biochemical recurrence following radiation therapy showed that those with an initial, or baseline, PSA less than 10 ng/ml spent an average of 91 weeks off treatment after the first “on-therapy” phase; those with a baseline PSA greater than 20 ng/ml averaged less than 40 weeks off treatment. PSA nadir also seemed to determine how long the off-treatment phase would last; men with nadir values of 0.2 ng/ml or less spent the most time off treatment. (For details on this study and other recent findings, see “The latest thinking on IHT,” below.)
Deciding when to restart therapy, however, requires as much art as science. We want patients off therapy long enough to allow their testosterone to rise and prompt any surviving tumor cells to regain certain characteristics, such as the ability to commit suicide when they no longer function normally. Allowing testosterone to recover between treatment cycles is also necessary for the restoration of sexual function, libido, and sense of well-being. Waiting too long to restart therapy, however, may allow cancer to regain its footing and further advance.
During the off-treatment phase, my patients have their PSA and blood testosterone levels checked every one to three months, depending on whether the biochemical recurrence followed radiation therapy or surgery. I use these values to set trigger points for restarting therapy, while also taking into consideration the patient’s pretreatment PSA, the initial tumor stage and Gleason score, PSA velocity and doubling time, any symptoms, tolerance for therapy, and other factors. In a patient with metastatic disease and a high pretreatment PSA, I might suggest restarting therapy when the PSA increases by several points; in a patient with local disease and a moderately elevated pretreatment PSA, the trigger point might be a little lower. (For a patient with recurrence after a radical prostatectomy, the PSA trigger would be much lower — 0.4 ng/ml to 0.5 ng/ml.) As with the initial cycle, the patient then starts hormone therapy, sticking with it for nine months and until the PSA reaches its nadir, which should be less than 4 ng/ml (though much lower for patients who have had a radical prostatectomy). The cycles continue until the cancer becomes androgen independent.
I was recently asked if my patients worry about using a treatment that is still being evaluated, and I can tell you that they don’t feel anxious about not having all of the answers yet. What they do worry about is whether their PSA will drop low enough during each treatment cycle to allow them to have another drug holiday. They also worry when an off-treatment period is shorter than the one before it. They know that eventually their cancer will progress to the point where it no longer responds to hormone therapy. That’s what provokes anxiety.
The latest thinking on IHT
Boccon-Gibod L, Hammerer P, Madersbacher S, et al. The Role of Intermittent Androgen Deprivation in Prostate Cancer. BJU International 2007;100:738–43. PMID: 17662079.
Bruchovsky N, Klotz L, Crook J, Goldenberg SL. Locally Advanced Prostate Cancer: Biochemical Results from a Prospective Phase II Study of Intermittent Androgen Suppression for Men with Evidence of Prostate-Specific Antigen Recurrence After Radiotherapy. Cancer 2007;110:858–67. PMID: 17265527.
Malone S, Perry G, Eapen L, et al. Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome. International Journal of Radiation Oncology, Biology, and Physics 2007;68:699–706. PMID: 17379438.
Shaw GL, Wilson P, Cuzick J, et al. International Study Into the Use of Intermittent Hormone Therapy in the Treatment of Carcinoma of the Prostate: A Meta-Analysis of 1,446 Patients. BJU International 2007;99:1056–65. PMID: 17346277.
Tunn U. The Current Status of Intermittent Androgen Deprivation (IAD) Therapy for Prostate Cancer: Putting IAD Under the Spotlight. BJU International 2007;99(Suppl 1):19–22. PMID: 17229164.
On the horizon
Once the results of the Phase III studies are released, we’ll have much more solid information about survival and quality of life for patients on IHT. Then I think we’ll look at expanding the use of IHT to a larger pool of patients and finding ways to increase the length of each cycle as well as the number of cycles of hormone therapy. We may even find ways to reduce or counter the side effects of hormone therapy and further boost quality of life. And if we find that effectiveness and safety favor IHT, we may be able to trim the costs associated with continuous therapy. (See “The cost of hormone therapy,” below.) We’ll also need to look for signs of advancing disease other than PSA, as prostate cancer can progress without a dramatic impact on PSA. Until then, I think that appropriately chosen patients who are well informed about IHT and who are monitored closely might want to consider trying it.
The cost of hormone therapy
Androgen deprivation therapy (ADT) not only erodes quality of life in many patients, but it can also tap savings. Two recent studies examined the cost of ADT, with one noting that prostate cancer patients on ADT cost the health care system almost twice as much as patients who weren’t. That study, which drew upon data from Medicare, reported that the cost of ADT alone was $25,796 per person over three years. A second study, published in Cancer in February 2007, found that the average annual cost of ADT was higher than for other prostate cancer treatments — $12,590. That study used data from the Cancer of the Prostate Strategic Urologic Research Endeavor disease registry, which includes more than 12,000 patients. If intermittent hormone therapy is proven to be as safe and effective as continuous ADT, the economic burden of continual treatment might lessen.
Krupski TL et al. Health Care Cost Associated with Prostate Cancer, Androgen Deprivation Therapy, and Bone Complications. Journal of Urology 2007;178(4 Pt 1):1423–28. PMID: 17706711.
Wilson LS et al. Cumulative Cost Pattern Comparison of Prostate Cancer Treatments. Cancer 2007;109:518–27. PMID: 17186528.
Originally published Jan. 1, 2008; last reviewed March 31, 2011.
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