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in some cases, together. More information on each of these minimal treatment options follows.
OPTION 1 Active Observation/Surveillance
Some men with a low PSA, or a PSA that takes a long time to double in number (prolonged PSA doubling time), and no signs or symptoms of metastatic disease are potential candidates for undertaking no additional treatment for a certain period of time, as long as most of these men remain on ADT and are monitored regularly by a doctor.
OPTION 2 Low-Dose Anti-Androgen Pill
Please note that this is also considered a form of secondary hormonal treatment by some physicians, especially when taking higher doses of these medications. For more information on use of a higher dose anti-androgen pill, see chapter three.
One way to remove 90 to 95 percent of male testosterone is to get an LHRH injection or an orchiectomy (surgical removal of the testicles). However, another 5 to 10 percent of testosterone is produced by the adrenal glands. One way to block the impact of that extra testosterone is to add a drug that blocks the androgen receptor (AR), simply known as an anti-androgen. There are three anti-androgens used in this situation, namely bicalutamide, flutamide, and nilutamide.
Therapy using LHRH treatment (or orchiectomy) plus an anti-androgen pill is known by several names, including combined androgen blockade (CAB), combined androgen deprivation treatment, maximum androgen blockade (MAB), and complete androgen suppression. Regardless of the name, such therapy is a simple approach to use to determine whether the PSA can be stabilized or even reduced.
In a review over a decade ago of twenty-seven randomized clinical trials for locally advanced or metastatic disease studying the benefits of ADT (LHRH) alone as compared to combined ADT (LHRH plus a low-dose anti-androgen), researchers found only a small benefit (approximately 2 or 3 percent over five years) in survival for some patients receiving the combined therapy. Thus, most anti-androgens are used when the PSA increases on ADT; using them can lower side effects and cost.
Dosage A range of low-dose anti-androgen options exists.
Advantages These drugs are simple to take. There are now some generic options, so check availability and price, please. They can have some effectiveness when given in higher doses for HRPC patients, especially when used in the early stages of HRPC (see also secondary hormonal options in chapter three). If a patient responds quickly to one non-steroidal anti-androgen, he is likely to respond to the other two after that one anti-androgen loses effectiveness.
The catch These pills are not inexpensive. Also, if the AR is blocked, the small amount of estrogen in a man’s body may become more potent, so breast pain (mastalgia) and breast enlargement (gynecomastia) are not uncommon. Also, these drugs can cause sexual dysfunction and increase the risk of gastrointestinal problems, hot flashes, and liver toxicity.
What else do I need to know? It should be kept in mind that the amount of cancer is generally inversely related to the impact of the anti-androgen pill. So, men with asymptomatic, non-metastatic disease have a much greater chance of responding favorably as compared to men with symptoms and metastatic disease.
Remember, patients who respond to one anti-androgen are more likely to respond to the other two anti-androgens. Also, please keep in mind that each anti-androgen comes with some unique side effects and other concerns.
Bicalutamide is the easiest to take and the most effective at the lowest doses, but is known for having a higher rate of breast discomfort.
Flutamide is inexpensive, but it needs to be taken 2 to 3 times a day. It causes a higher rate of diarrhea and liver toxicity as compared to the other anti-androgens.
Nilutamide can, in rare situations, cause impaired night vision or lung inflammation (pneumonitis).
All of the above anti-androgens can be taken one after another, or in high doses (see chapter three), or not at all after your PSA rises on LHRH injections, or after surgery to remove the testicles.
OPTION 3 Anti-Androgen Withdrawal
Cancers can develop resistance to many medications in a somewhat similar way to how bacteria develop resistance to an antibiotic. This was acknowledged in 1992 when the concept of anti-androgen withdrawal (AAWD) syndrome was first recognized. It was found that, after a period of time on treatment with an anti-androgen pill, a tumor could actually use the drug to stimulate its own growth! Simply removing the anti-androgen when the PSA increase occurs has become a form of treatment (or non-treatment, really). Because the tumor can no longer use this specific anti-androgen as fuel, the PSA goes down. A PSA drop of 50 percent when an anti-androgen is removed is classified as a true AAWD. Only about 20 percent of men see a PSA benefit when going off the anti-androgen pill, but it still seems to be worth it for those who do respond.
Dosage No dosage needed; just remove the anti-androgen pill for several weeks. In the case of bicalutamide, the pill should be discontinued for longer (4 to 6 weeks).
Advantages A patient can get a treatment effect or a PSA reduction without doing anything except removing a pill from his daily regimen. It can usually be determined whether the patient is getting a benefit from AAWD within 6 weeks.
The catch You will need more frequent PSA testing and visits to the doctor after seeing a PSA increase (while you were on an anti-androgen).
What else do I need to know? AAWD can potentially be undertaken with any anti-androgen drug.
Although these minimal treatments may work for selected patients for a time, at some point additional therapies will likely be needed to manage the HRPC. Chapter three will discuss a variety of options that are generally referred to as secondary hormonal treatments.
Notes
After diagnosis with HRPC, you begin to consider a number of options with your physician. Several options exist in addition to the FDA-approved treatments for HRPC. Some of the most widely used medications for HRPC are the so-called “secondary hormonal treatments,” which work in a variety of ways. Some may even work by reducing testosterone below the accepted castrate level (to nearly 0 ng/dL). Regardless of how they act, you should be aware of these options.
Many doctors and patients like these secondary hormonal options, but interestingly they have never been approved for the specific purpose of prostate cancer treatment for men with HRPC. Why? It is probably because the drugs themselves were available for years for other purposes before doctors started to try them for HRPC. When the drugs were found to be effective for prostate cancer as well as the other purposes, there was no desire to recruit patients for an official clinical trial to exactly quantify their effectiveness, although it would have been better for patients to have such an official clinical trial completed.
Each secondary hormonal therapy has its own cost considerations. Some are inexpensive (estrogen, for example), and some are more costly (such as anti-androgen pills). Because doctors will use some of these options, we’ll discuss the advantages and drawbacks of each therapy. Keep in mind that a true response to a secondary hormone therapy is determined using a variety of tests, including one for PSA reduction, in the first few months of treatment (usually 3 months). The larger the response the better, for some patients. A 50 percent or more drop in PSA is outstanding, but a smaller response is also