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.
Intermittent Androgen Deprivation Revealed
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.
Theories Behind Intermittent Androgen Deprivation
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.
Outcomes of Intermittent Androgen Deprivation
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.
Guidelines for Intermittent Androgen Deprivation
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.
a. Initial PSA less than 50
b. Initial PSA doubling time of greater than 12 months
c. For those men with an initial PSA greater than 10, a decrease of PSA to less than 4 following the first cycle of hormonal therapy
d. For those men with an initial PSA of less than 10, a decrease of PSA to less than 0.2-0.5 following the first cycle of hormonal therapy
e. Men without bulky tumors, numerous positive lymph nodes, or extensive bone metastases.
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.
