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Hormonal therapy is a vital tool in fighting advanced prostate cancer.  Although it is not a cure, hormonal therapy can keep prostate cancer in a state of suspended animation, at least for a while.  By slowing the growth of the prostate cancer, hormonal therapy can provide men with locally advanced, metastatic, or recurrent disease many years of life that is free of the effects of prostate cancer. For some men, however, the side effects of the hormonal therapy can be almost as unbearable as the prostate cancer itself.  Symptoms like hot flashes, weakness, weight gain, and sexual dysfunction can ruin quality of life and make men yearn to stop the therapy.  Out of this dilemma has come a controversial, EXPERIMENTAL approach to hormonal therapy called intermittent androgen deprivation (IAD).  In this post, I will describe the theoretical basis for IAD, describe the ideal candidates for this therapy, and report the outcomes of studies that have evaluated it.

Before we can dive into the details of IAD we first need to explain what IAD actually involves and how it is different from traditional hormonal therapy or continuous androgen deprivation (CAD).  Intermittent androgen deprivation involves giving the same class of drugs as traditional hormonal therapy.  In contrast to CAD, however, IAD gives these medicines in a more sporadic fashion.  For example, rather than receiving Depot Lupron continually every 3 months  (as with traditional hormonal therapy), men undergoing IAD may receive the medication every 3 months for 2-3 doses, but then do not receive it again for over a year.  In so doing, IAD allows for breaks in treatment, which provides time for the testosterone level (and PSA) to climb.  While this may seem counterproductive, allowing the PSA and testosterone to rise may provide IAD with advantages in terms of cancer survival and limitation of side effects.

Intermittent androgen deprivation has been postulated to provide two very different, theoretical advantages over traditional hormonal therapy. 

    1) Cancer Control: numerous studies have demonstrated that when prostate cancer is exposed to long-term androgen deprivation, it eventually develops ways to outsmart the treatment and become castration resistant. As a result, the prostate cancer can live and thrive despite the absence or significant limitation of testosterone.  The theory behind this adaptation is that a few “androgen independent” cells within a prostate cancer cell population thrive and rapidly replicate once the remaining “androgen dependent” cells are suppressed in a low testosterone environment.  By intermittently re-introducing testosterone to the environment of prostate cancer cells, IAD was thought to theoretically delay the overgrowth of “androgen independent” cells by allowing some more docile,  “androgen dependent” cells to remain and compete for resources with their more aggressive counterparts. Thus, researchers have argued that IAD may successfully treat advanced prostate cancer for a longer period of time than traditional hormonal therapy by staving off the emergence of castration resistant prostate cancer.

    2) Limitation of Side Effects : The other theoretical advantage of IAD is the limitation of the most common side effects of traditional hormonal therapy.  By allowing testosterone to intermittently return to normal levels, IAD can provide a reprieve from the side effects commonly experienced with low testosterone such as hot flashes, fatigue, and sexual dysfunction, if only on a short term basis.

Numerous studies have been performed to try to determine whether the theoretical advantages of IAD actually pan out in a clinical setting.  Although differing in study design and the details of the IAD regimen, these investigations have demonstrated similar results.  First, most studies have demonstrated that while IAD is not superior to continuous androgen deprivation, it is, at least, not inferior.  The previously largest study to date was carried out in Europe and randomized over 600 men to either undergo IAD or traditional hormonal therapy.  After 8 years of follow up, the study demonstrated equivalent overall mortality (54% vs 54%).  Interestingly, the study did report that men undergoing IAD were more likely to die from prostate cancer than those men undergoing CAD (34 vs 27%).  However, this difference was counteracted by the fact that men undergoing traditional hormonal therapy were more likely to die from heart disease than those men undergoing IAD (17% vs 13%).  

The results of this study were confirmed in June of 2011 when the preliminary results of Southwestern Oncology Group (SWOG) JPR7 study were released at the meeting of the American Society of Clinical Oncology.  This very large study randomized over 1400 men to undergo either continuous or intermittent androgen deprivation.  After following these men for an average of 6 years, the investigators found that IAD was at least equivalent to traditional hormonal therapy in terms of overall survival.  While those men on IAD did demonstrate a longer period of time until they progressed to hormone refractory disease, they demonstrated a higher rate of deaths from prostate cancer.  However, as in the European study, this higher risk of death from prostate cancer was mitigated by a lower rate of death from other causes as compared to those men undergoing CAD.

While IAD has not been demonstrated to be superior (but also not inferior) to traditional hormonal therapy in terms of survival, numerous studies have reported significant advantages of IAD in relation to side effects.  The European study previously discussed, for example, demonstrated significantly lower rates of hot flashes and breast tenderness in men undergoing IAD.  The SWOG study presented this year also reported fewer hot flashes.  Phase II studies have reported that men undergoing IAD also demonstrated significant improvement in sexual function during the off-treatment phase of the regimen (when their testosterone and PSA levels were allowed to rise).  These off treatment-phases can be lengthy.  In the large European study previously mentioned, for example, the average time off-therapy was approximately 1 year while 29% of men were able to stay off-therapy for more than 3 years.  Hence, IAD can potentially allow for up to 3 years of recovered sexual function without jeopardizing cancer control!  Unfortunately, the first off-treatment cycle is usually the longest with subsequent off-treatment cycles lasting for shorter periods of time.  Also, older men tended to regain their testosterone levels more slowly in off-treatment cycles and, thus, also reported lower sexual function and quality of life during these periods of time as compared to their younger peers.  Nonetheless, the ability of IAD to provide a respite from sexual dysfunction, hot flashes and other destroyers of quality of life while not impacting overall survival is compelling.

Because IAD is still experimental, no hard and fast rules exist as to who are the optimal candidates for the therapy and how the treatment regimen should be carried out.  Nonetheless, using the data generated from the studies completed to date, numerous recommendations have been published.

The criteria about the PSA nadir after the first cycle of hormonal therapy are particularly important. Studies have demonstrated that men without significant declines in PSA in response to hormonal therapy were much more likely to progress to hormone resistant disease and eventual death as compared to men with the optimal PSA responses mentioned above.

Recommendations have also been made about treatment protocols for IAD.  Typically, men are initially treated with 6-9 months of continuous androgen deprivation.  If an appropriate PSA nadir is reached, hormonal therapy is then stopped and PSA levels are monitored.  Androgen deprivation is not reinstituted until a threshold PSA level is reached.  This level has been a PSA of 10 in many studies although this is an arbitrary number not really substantiated by any specific data.  Such a regimen is repeated until a hormone refractory state is reached during which PSA is found to rise despite androgen deprivation.  At that point, alternative therapies are employed.

Why is Androgen Deprivation Therapy Still Considered Experimental

As I mentioned previously, IAD is still considered an experimental therapy for prostate cancer.  The reason for this status is that not enough long-term data is available to recommend it as a mainstream strategy.  In addition, the numerous short-term studies conducted to date were all carried out using somewhat different inclusion criteria and treatment protocols, making comparisons difficult.  As a result, while we await more long term data from studies such as the Phase III SWOG trial previously mentioned, IAD has to be considered investigational and approached very carefully.  Nonetheless, for those men facing long-term androgen deprivation and worried about associated side effects, IAD should be at least considered and discussed with their urologist or oncologist.

A question that I have repeatedly heard from readers has been about the length of time hormonal therapy needs to be given in conjunction with radiation to treat prostate cancer.  As I replied to these readers, the answer, like most aspects of prostate cancer treatment, is not very straightforward and remains somewhat controversial.  In this post I will attempt to clarify which men actually need hormonal therapy in addition to radiation, the benefits of this additional hormonal therapy, and the ideal duration of the therapy.

The benefits of adding hormones to radiation therapy for prostate cancer were first demonstrated through animal experiments.  These studies evaluated the added efficacy of androgen deprivation (hormonal therapy) when combined with radiation therapy in treating prostate tumors in mice.  The studies scientifically demonstrated that the hormonal therapy reduced the amount of radiation necessary to destroy and control the growth of the tumors.  These and other studies have proposed that radiation and hormonal therapy work synergistically to destroy prostate cancer cells and keep them from spreading locally and into the bloodstream. 

The added benefits of hormonal therapy were then tested in the clinical setting on real patients.  One of the seminal studies testing the theory was conducted in Europe over a decade ago. The study compared the outcomes of men with locally advanced prostate cancer who underwent either radiation therapy alone or radiation therapy combined with a 36 month course of hormonal therapy.  The study demonstrated that, 10 years after treatment,  men undergoing combination therapy enjoyed superior overall survival (58% vs 39%) and a much lower chance of dying specifically from prostate cancer ( 11% vs 31%) when compared with those men undergoing radiation alone.  Studies such as this ushered in the wave of hormonal therapy that has been becoming more and more popular in the treatment of localized prostate cancer.     

As more and more patients were placed on hormonal therapy, it soon became apparent that this additional treatment does not represent a free lunch.  As I described in my previous post, hormonal therapy comes with significant risks to your heart while increasing your chance of developing diabetes.  In addition, hot flashes and sexual dysfunction can have a dramatic impact on quality of life for men on the therapy.  As such, many began to wonder if 3 years of hormonal therapy is really worth the benefits.  Studies have been conducted comparing the combination of radiation plus short term hormonal therapy (4-6 months) with radiation alone.  One such study demonstrated a superior 8 year overall survival for men undergoing the combination therapy (74% vs 61%) as compared to men undergoing radiation therapy alone.  The presence of this new data subsequently begged the question of whether long term hormonal therapy yielded any benefits above and beyond those achieved with short term hormonal therapy.  Excellent, randomized studies were conducted to answer just this question. 

Two large, randomized trials have been carried out comparing short term with long term hormonal therapy in combination with radiation therapy.  These studies were carried out specifically in men with HIGH RISK prostate cancer.  Only men with either locally advanced prostate cancer (T2c-T4) or positive lymph nodes were evaluated.  I emphasize this point because, as I shall explain later, the results and conclusions can not and should not be applied to treatment decisions for ALL men with prostate cancer. 

The first trial, known as Radiation Therapy Oncology Group 92-02 studied over 1500 men with T2c-T4 prostate cancer (cancer which took over both lobes of the prostate and/or extended out of the prostate to varying extents) with or without positive lymph nodes.  Men in the study were randomly enrolled into one of two treatment protocols:

1)      Radiation plus 4 months of hormonal therapy (starting 2 months prior to radiation)

2)      Radiation plus 28 months of hormonal therapy(starting 2 months prior to radiation)

The study demonstrated that, after 10 years, men undergoing long term hormonal  therapy enjoyed better cancer specific survival (89% vs 84%), lower chance of metastatic disease (15% vs 29%), and a lower chance of further local spread ( 12% vs 22%) than those undergoing short term hormonal therapy .  What the study did not demonstrate, however, was a significantly improved overall survival rate for men undergoing the long term versus the short term hormonal therapy.  The study then analyzed a particularly high risk subset of men with Gleason 8-10 prostate cancer.  In this subset of patients, in contrast, a significantly superior overall survival rate (45% vs 32%) was seen in men undergoing long term hormonal therapy.

The second study was conducted by the European Organization for Research and Treatment of Cancer.  This trial evaluated 970 men with either locally advanced prostate cancer (T2c to T4) or men with positive lymph nodes and any local stage.  The study divided the patients randomly into two treatment groups:

1)      Radiation therapy plus 6 months of hormonal therapy (starting the first day of radiation).

2)      Radiation therapy plus 36 months of hormonal therapy (starting the first day of radiation).

After about 6 years of follow up, the study demonstrated a small but significant overall survival advantage for men on long term versus short term hormonal therapy (85% vs 81%).  The difference in death rates (19% vs 15%) represented a 42% higher chance of death for men undergoing short term versus long term hormonal therapy. 

While demonstrating slightly different impacts, both studies concluded that men with HIGH RISK prostate cancer should be considered for long term hormonal therapy.

While the above mentioned studies argue for adding long term hormonal therapy to radiation for treatment of HIGH RISK prostate cancer, they DO NOT conclude that all men undergoing radiation therapy for prostate cancer need hormonal therapy.  Before discussing the suggested regimens for men without high risk disease, we should review the accepted “risk” categories for prostate cancer:

1)      High Risk: Prostate cancer that is locally advanced (T2C-T4) and/or Gleason score 8-10 and/or associated with a PSA greater than 20

2)      Intermediate Risk: Prostate cancer with moderate local stage (T2b) and/or Gleason score 7 and/or PSA 10-20.

3)      Low Risk: Prostate cancer with low local stage (T1b-T2a) and Gleason score 2-6 and PSA less than 10.

These risk categories are very important to understand, particularly in context of prostate cancer studies.  In relation to adding hormonal therapy to radiation for prostate cancer, the utility of the additional hormonal therapy depends on what risk group you are looking at.  As I mentioned above, the added benefits of hormonal therapy, particularly long term hormonal therapy were demonstrated only in HIGH RISK prostate cancer patients.  In contrast, no study has ever demonstrated any benefit of adding hormonal therapy to radiation of LOW RISK prostate cancer.  The data for INTERMEDIATE RISK is more mixed.  While no studies have specifically evaluated the added benefit of combining hormonal therapy with radiation therapy for INTERMEDIATE RISK prostate cancer, numerous patients with INTERMEDIATE RISK disease were included in the studies evaluating HIGH RISK patients.  These studies did demonstrate a benefit of adding hormonal therapy to a radiation therapy regimen for patients with INTERMEDIATE RISK disease.  No study, however, has demonstrated any significant additional benefit of long term over short term hormonal therapy for INTERMEDIATE RISK disease.  As a result, many of the radiation oncologists performing these studies recommend a combination of short term hormonal therapy and radiation for men with INTERMEDIATE RISK prostate cancer.  This recommendation, of course, is only valid  if the risks of the additional hormonal therapy (heart risk, diabetes, osteoporosis) do not outweigh the benefits for a given patient.  In addition, because no randomized studies have been carried out looking to answer this question in men with INTERMEDIATE RISK disease, the data and recommendations I have just mentioned for INTERMEDIATE RISK disease can be considered fairly trustworthy but not definitive.

The controversy over the optimal duration of hormonal therapy to give in combination with radiation for prostate cancer again demonstrates the recurrent theme we hear about repeatedly in relation to prostate cancer therapy: prostate cancer treatment cannot be carried out with a “one size fits all” approach.  While studies seem to demonstrate a modest although significant advantage to long term ( > 2 years) hormonal therapy in addition to radiation for HIGH RISK prostate cancer, there has been NO evidence demonstrating that hormonal therapy for LOW RISK prostate cancer is of any benefit at all.  INTERMEDIATE RISK prostate cancer, in turn, may be optimally managed with a combination of radiation and short term hormonal therapy although we still await definitive studies to confirm this.  In addition, even when keeping these risk groups in mind, the final decision of whether or not to add hormonal therapy to radiation (and, if so, for how long ) really rests on weighing the risks and benefits for each individual patient. In some men with HIGH RISK prostate cancer, cardiac and metabolic risk factors may make the risks of heart attack and diabetes posed by hormonal therapy far outweigh the benefits of the treatment.  In contrast, some otherwise healthy men with HIGH RISK prostate cancer may derive significant benefits from the additional hormone therapy with minimal additional risks.  The key to answering this question is to really understand your situation.  Make sure that you understand your particular prostate cancer risk group.  Also, make sure that you discuss your cardiac and metabolic risk factors with both your urologist/radiation oncologist and your primary doctor (who is more familiar with your overall health).  Finally, make sure that your doctor weighs these competing factors with you so that you can be assured that, no matter what your given situation, the treatment course you chose truly provides you with more benefits than risks.

If you have been diagnosed with prostate cancer, chances are you have been told about hormonal therapy.  Nearly 70 years ago, the management of prostate cancer was revolutionized by the discovery that prostate cancer is fueled by the male hormone testosterone.  Prior to this discovery, numerous men languished in hospital beds suffering from the pain of advanced prostate cancer.  After the discovery, men with advanced prostate cancer started undergoing orchiectomy (surgical removal of the testicles).  Because the testicles naturally produce most of the testosterone in men, removing them effectively removes most of the testosterone from the body.  With the “food” gone, the prostate cancer moves much more slowly and sometimes decreases in size.  While not a cure, such hormonal manipulation has led to significantly decreased symptoms for men with advanced prostate cancer.

Hormonal therapy was further advanced about 30 years ago with the development of “medical castration.”  Rather than removing the testicles, doctors could give medicine which would effectively prevent the body from producing testosterone.  This approach was significantly more appealing for most men as it avoided the psychological trauma of castration.  Initially, medical castration or hormonal therapy was used just for men with prostate cancer which had spread to the bones and other distant organs.  Studies demonstrated that the treatment, although not a cure, could allow men with metastatic prostate cancer to live symptom free for many years.  More recently, the use of hormonal therapy has been further expanded to men with localized disease.  Numerous studies demonstrated that hormonal therapy given in combination with radiation therapy for men with locally advanced prostate cancer is superior to radiation alone.  As a result many doctors now give at least a short course of hormonal therapy at the start of radiation therapy while others give hormonal therapy up to 2 years following radiation therapy for men with localized disease.  Other doctors also give early hormonal therapy for men with a PSA recurrence after radical prostatectomy.  With these expanded indications, more and more men are currently treated with hormonal therapy. 

The problem with such widespread use of hormonal therapy is that this treatment modality, like all medicines, is no free lunch.  As more and more men have been treated with hormonal therapy, more and more risks have been discovered.  The risk of osteoporosis, for example, is very well known to urologists and patients alike and is often very carefully monitored and treated.  Recently, however, the very real impact of hormonal therapy on the heart has been demonstrated.  Studies have demonstrated that treatment with hormonal therapy often leads to metabolic changes such as increases in blood sugar and cholesterol.  As a result, a very real increase in heart attacks and heart related deaths have been attributed to the use of hormonal therapy.  While radiation oncologists and urologists are very well trained to evaluate and treat prostate cancer, they are generally not as great at looking at the big picture.  As a result, the treatment of prostate cancer often takes priority over heart health, particularly when a primary care doctor is not part of the decision making process.  The goal of this post is to review the real metabolic consequences of hormonal therapy and the subsequent heart risks that they then create.

With the metabolic changes mentioned above, it probably does not seem surprising that studies have demonstrated that taking hormonal therapy may pose a substantial risk to the heart.  Large studies ( 37,000- 73,000 men) have demonstrated that hormonal therapy results in a 16-19% increased risk of coronary artery disease, an 11-28% increased risk of heart attack, and a 16-35% increased risk of sudden death when compared with men not undergoing the treatment.  Another study demonstrated a 20% increased risk of heart complications within 1 year of starting hormonal therapy.  Not surprisingly, higher risk was seen in older men, with one study demonstrating that men over age 65 undergoing hormonal therapy have over 2 times the risk of heart related death within 5 years of starting therapy (5.5% vs 2%) as compared with those that do not undergo the therapy.

The impact of hormonal therapy for men with preexisting heart disease is even more dramatic.  A recent study published in the Journal of the American Medical Association studied men with localized prostate cancer undergoing 4 months of hormonal therapy in combination with radiation therapy.  The study specifically looked at men with a prior history of a heart attack or heart failure.  In this group, the study found that 26% of men undergoing hormonal therapy died within an average of 5 years as compared to 11% of men who did not undergo the therapy.  That represents TWICE the risk of death for men with prior heart disease who underwent hormonal therapy plus radiation therapy as compared to the men that underwent radiation therapy alone.  Interestingly, the authors of the study did not demonstrate an increased risk of death for those men undergoing hormonal therapy who did not have significant underlying heart disease or risk factors for heart disease. 

So what do we conclude from this worrisome information?  Should hormonal therapy no longer be offered to men with prostate cancer?  Should men already on hormonal therapy stop the treatment?  Of course not.  Hormonal therapy has been vital in the fight against prostate cancer, particularly for men with advanced disease.  Instead, this data should make us rethink who should receive hormonal therapy and what precautions should be taken when the therapy is administered.  The problem with many urologists and radiation oncologists is that they often get caught up with prostate cancer and, sometimes, miss the big picture.  While they see the potential benefits of hormonal therapy in terms of prostate cancer, they don’t pay enough attention to the impacts of this treatment on other vital aspects of a patient’s health.  As a result, as the patient, you need to make sure that a few steps get taken prior to proceeding with hormonal therapy:

As with many other aspects of prostate cancer treatment I have discussed on this blog, hormonal therapy, again, proves that there is no such thing as a free lunch.  While hormonal therapy has been shown to be beneficial for many patients with varying extents of prostate cancer, this benefit does not come without risk.  The development of significant heart disease can negate any prostate cancer benefits in SOME men.  As a result, before agreeing to hormonal therapy, make sure that your doctor weighs the relative risks and benefits in YOUR case.  If you and your doctor conclude that hormonal therapy is right for you, make sure that you put together the right team and plan to manage the potential risks.  As a urologist, I am committed to battling prostate cancer with all the medical and surgical tools available to me.  As a patient, you need to make sure that your doctors keep your overall health in mind while fighting this battle.