Glossary
2° Hormonal Therapy
Prostate cancer resistant to LHRH agonists like Lupron, Trelstar, Eligard and Zoladex is termed castration resistant. Previously this state of affairs was called hormone resistant or androgen dependent. The name was changed because resistance to an LHRH agonist does not necessarily mean that other hormonally active medications won't work. In fact, PSA often drops when medications like Casodex, Nilutamide, Estrogen, Ketoconazole and Zytiga are initiated in the setting of a rising PSA with low testosterone levels in the blood.
Given that castration resistance creates such a dire situation, what are the signs of its presence? The most obvious sign is a rising PSA despite treatment. Since Testosterone Inactivating Pharmaceuticals (TIP) function by lowering testosterone in the blood, resistance must be confirmed by checking testosterone in the blood. A rising PSA with a low testosterone confirms that resistance to TIP is present.
An even earlier sign of TIP resistance is a high PSA nadir. The PSA nadir is defined as the lowest PSA attained while on TIP. After starting TIP the PSA starts declining. Once it stabilizes at a lower level that is the nadir. A PSA nadir level of more than 0.1 while on Lupron and Casodex is the earliest indication of castration resistance.
Nilutamide
Nilutamide is a once-daily pill with a mechanism of action similar to Casodex; it works by blocking testosterone from activating the androgen receptor. Apparently Nilutamide is more potent because about 50% of men with a PSA that is rising on Casodex will respond to Nilutamide. Nilutamide has a couple side effects that don't occur with Casodex. First, Nilutamide slows the speed of adjustment of the eyes to changes in light. For example, when you go into a movie theater it takes a minute or two for your eyes to adjust. With Nilutamide it may take 3 or 4 minutes. This effect goes away when Nilutamide is stopped. The other side effect to be aware of is pulmonary. About 1% of men treated with Nilutamide develop shortness of breath, cough or wheezing. If this occurs, the Nilutamide needs to be stopped immediately because the symptoms can be progressive and ultimately life-threatening.
Ketoconazole
Ketoconazole, also known as Nizoral is an FDA approved antibiotic that has an additional effect of blocking testosterone synthesis inside the cancer cell. In the 1980s, when not used for antibiotic purposes, the drug was primarily administered to men with hormone sensitive prostate cancer, that is cancer responsive to testosterone deprivation. Subsequently it was discovered that high dose Ketoconazole (HDK) is effective against prostate cancer even after the development of hormone resistance. It is HDK's activity against hormone resistant disease that is of particular interest and the main topic of this article.
The question of HDK's mechanism of action was addressed in an article published in the Journal of Clinical Oncology March of 2004 by Eric Small, MD. In this study, Dr. Small showed that two of testosterone-like hormones coming from the adrenal glands, DHEA and Androstendione (Andro), were in the blood at higher levels in men with hormone resistant disease that responded to HDK therapy. Andro is the same chemical Mark McGwire took to hit all those home runs. These same researchers also reported that resistance to HDK in men that were previously responding was signaled by rising levels of DHEA and Andro. This connection between the levels of these hormones and HDK effectiveness appears to confirm a long suspected relationship between HDK's potent hormone blocking ability and its anti-cancer activity.
When it appears that HDK is not working the possibility that the ketoconazole is not being absorbed from the stomach into the blood must be considered. This can be evaluated by measuring the amount of HDK in the blood. If the level of ketoconazole is below 1, poor absorption is the most likely explanation. HDK is absorbed best when taken without food and in combination with an acidic agent, like vitamin C (ascorbic acid). The typical dose of ketoconazole is one 200 mg pill every 8 hours increased to two pills every 8 hours if there are no side effects. Once HDK has been started, the PSA should be checked every 2 to 4 weeks to determine whether or not it is effective. A rising PSA after 30 days does not invariably mean that HDK will prove to be ineffective with further treatment. We generally recommend waiting 60 days before concluding that HDK is ineffective.
It has been argued that in men showing early signs of hormone resistance, HDK therapy should be delayed until the results of stopping Casodex or Flutamide can be ascertained. This is accomplished by looking for what has been termed the "anti-androgen withdrawal response." It is true that 10-15% of men experience a transient PSA decline lasting an average of 3 months with this maneuver (the Lupron or Zoladex is continued). In our experience these responses are too infrequent and too brief to justify delaying the initiation of a more effective treatment such as HDK.
The number of potential drug interactions with ketoconazole is very extensive and includes most diabetes medications, many allergy medications, blood thinners, as well as some types of sleeping pills and certain antibiotics. Careful review of all potential drug interactions is essential for anyone starting ketoconazole. The most prominent direct side effect of HDK is fatigue. The degree of fatigue varies from individual to individual. The best method to minimize fatigue is to maintain muscle strength with a weight lifting program for at least one hour twice a week. We have also seen some benefit with the use of a medication call Provigil, a drug that is FDA approved for the treatment of narcolepsy.
Other common side effects from HDK include stomach and liver problems. Initially, blood tests to check liver function must be done monthly. If any abnormalities are detected the drug must be stopped immediately. Usually HDK must also be stopped if stomach problems like heartburn develop, since taking antacids blocks its absorption into the blood stream making HDK ineffective.
Hydrocortisone is blocked by HDK. Hydrocortisone replacement (20 mg with breakfast and 10 mg with lunch) is routinely administered. Men taking hydrocortisone should wear a bracelet so that if they are knocked unconscious, emergency personal know to administer intramuscular hydrocortisone.
The most encouraging aspect of high dose ketoconazole treatment is the possibility of extended remissions lasting for years. If the medication is well tolerated over the first few months it usually continues to be well tolerated throughout the course of treatment.
Estrogens
Estrogens have been utilized for decades to treat prostate cancer. They are generally well-tolerated. Oral estrogens increase clotting factors in the liver and must be used with an oral anticoagulant such as Coumadin. Estrogens cause breast enlargement which can usually be prevented with a brief course of radiation to the breast area. Radiation cannot eliminate existing breasts so it is important to start radiation before estrogen is implemented. Transdermal estrogen patches do not seem to be associated with an increased risk of blood clots and in our experience anticoagulation is unnecessary.
