Читать книгу Promoting Wellness Beyond Hormone Therapy, Second Edition - Mark A. Moyad - Страница 9
ОглавлениеAfter 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 beneficial. A response to a secondary hormone treatment also may be determined using an imaging test, and even at times by considering a symptom reduction (less pain, for example). You can review with your doctor to determine whether a particular treatment is working for you.
Question: Why are adrenal glands so important to HRPC and the secondary hormonal treatments?
Answer: Other than the testicles, the human body makes androgens or male hormones in the adrenal glands (one of which sits on top of each kidney). The actual metabolic products that come from the adrenal gland hormones are known as “adrenal androgens,” or “androgen building blocks,” or “precursors” because they are used to make testosterone. Adrenal gland androgens include dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione. They all have the potential to continue to stimulate prostate cancer growth. Even if a patient has castrate levels of testosterone, it is known that adrenal gland androgens can at least weakly stimulate the androgen receptor (AR).
Thus, dietary supplements that should NOT be used when taking a secondary hormonal therapy include DHEA, DHEA-S, Tribulus Terrestis (which may have some DHEA-resembling compound in it), androstenedione, or any other supplement that claims to increase male hormone (testosterone) levels. Androstenedione is no longer sold over the counter, but there are still ways it can be obtained.
The problem with these supplements or compounds is that they can offset the impact of some of the secondary hormonal therapies as the treatments work better when the body has lower levels of these compounds. For example, new studies have shown better responses to anti-androgen drugs in individuals with lower DHEA blood levels. Therefore, be watchful for those compounds in supplements, and be sure always to check with your physician before taking a supplement.
CORTICOSTEROIDS
Corticosteroids are not considered to be true “secondary hormonal treatments” like the other drugs listed in this chapter. However, they are often given in conjunction with these drugs as well as a number of other HRPC treatments, so some information is being offered on them here.
Also known as glucocorticoids (generally); examples include: dexamethasone, hydrocortisone, prednisone, prednisolone, and methylprednisolone.
How is it taken? Usually as a pill, but can also be given by injection or intravenously (IV).
Dosage There is a variety of drugs and doses. It is not unusual to see patients taking 30 to 40 mg of hydrocortisone, or 10 mg or less of prednisone, or less than 1 mg of dexamethasone. Doctors are careful about the potency of these drugs.
Steroid Medication Review
Hydrocortisone—least potent
Prednisone—4 times more potent than hydrocortisone
Prednisolone—5 times more potent than hydrocortisone
Methylprednisolone—5 times more potent than hydrocortisone
Dexamethasone—most potent, 30 times more than hydrocortisone
Advantages These drugs are simple to take and have a good safety record.
The catch These drugs serve largely to reduce the side effects of some secondary hormonal drugs (ketoconazole or abiraterone) and chemotherapy drugs. They also suppress the immune system.
What else do I need to know? These medications have at least some anti-prostate cancer effect, probably by lowering adrenal androgen production. They have not received a lot of attention compared to the other secondary hormone therapies because they do not appear to be as effective or have an impact that lasts as long as the other therapies. Regardless, it is important to know that they at least have some impact. There does not seem to be an advantage to using one specific corticosteroid drug or dosage as compared to another, but check with your doctor on the latest research.
ESTROGEN
Also known as DES, estradiol, or by multiple generic names.
How is it taken? pill, patch, or injection.
Dosage Various doses based on the drug and situation.
Advantage Usually inexpensive, and it also has a role in reducing hot flashes and preventing bone loss in very small dosages.
The catch It increases the risk of several cardiovascular problems, particularly blood clots, so the drug is usually given with a prescription blood thinner. It also can cause breast pain and enlargement and fluid retention. The higher the dosage, the higher the risk of serious side effects.
What else do I need to know? The “female” hormone estrogen has been used for more than 50 years to treat prostate cancer. In some countries, it is still used to lower testosterone levels and function as an androgen deprivation treatment (ADT) instead of LHRH therapy. However, in most countries, LHRH drugs replaced estrogen many years ago because estrogen has serious cardiovascular toxicity (blood clots, edema, high blood pressure) in higher doses, especially as an oral drug.
Some doctors still use estrogen for two purposes in treating prostate cancer. First, as mentioned above, it can be used to treat side effects of ADT, such as hot flashes, bone loss, and perhaps even cognitive changes. Secondly, research has shown that estrogen can reduce adrenal androgens, and it also may directly kill some HRPC cells. Lower doses of estrogen seem to cause fewer side effects, and there are now several drugs to reduce these side effects if they still occur. For example, there are blood pressure medications, diuretic drugs, and blood thinners that can reduce the risk of most of estrogen’s side effects.
Newer delivery systems make it easier for some patients to use estrogen, and they may also reduce side effects. For example, some patients use an estrogen patch (estradiol transdermal patch) to reduce hot flashes. The patch appears to reduce the risk of blood clots by bypassing the liver’s ability to increase the clotting production that usually occurs when exposed to oral estrogen.
However, overall, the oral form of estrogen is still very popular as a secondary hormone treatment. One of the most popular is diethylstilbestrol or DES. This drug is quite inexpensive and is prescribed in a range of doses (less than 1 mg to 2 or 3 mg/day). Most doctors prefer patients to be on a prescription blood thinner, such as Coumadin (warfarin), to counteract the blood clotting concerns.
Other notable side effects of estrogen are breast pain (mastalgia) and breast enlargement (gynecomastia). These conditions can mostly be prevented by taking an oral (pill) dose of tamoxifen daily, or more simply by getting a dose of radiation to each breast (just once, taking seconds). Some studies suggest that oral tamoxifen daily is a little more effective at preventing breast pain and enlargement as compared to radiation, but radiation works with just a single treatment. Regardless, there are many issues to consider if you and your doctor decide that estrogen is an option for you in preventing ADT side effects or as a secondary hormonal treatment.
There are also other estrogen-derived treatments that you may hear about, and they are just as effective as DES for cancer treatment or for treating side effects. Several common ones are listed below:
• EMCYT (pill, also known as estramustine phosphate)
• Ethinyl estradiol (pill)
• Estradurin (injectable, also known as polyestradiol phosphate)
• Fosfestrol (pill)
• Vivelle-Dot and others (patch)
FIVE-ALPHA REDUCTASE INHIBITORS (5AR INHIBITORS)
Also known as 5AR inhibitors, finasteride, and dutasteride (brand name Avodart).
How is it taken? pill.
Dosage A single pill, taken daily. There are two options, namely finasteride (dosage 5 mg per day) and dutasteride (dosage 0.5 mg per day).
Advantages Easy to take, with minimal side effects. Finasteride now has a generic option, but dutasteride remains in your body for a longer time (a 5-week half-life) as compared to finasteride (an 8-hour half-life). Therefore, it is possible to take dutasteride just once a week (or simply not daily), save money, and still potentially get the same benefit.
The catch With these drugs, reductions in sex drive and overall sexual function are possible, as are breast tenderness and enlargement. Hot flashes and liver toxicity are also potential side effects. A recent large study of prostate cancer prevention regimes found that dutasteride slightly, but significantly, increased the risk of heart failure as compared to a placebo. This possible side effect needs to be further investigated to be sure that it is an actual concern.
What else do I need to know? These medications, particularly dutasteride, are receiving a lot of attention in the area of prostate cancer prevention and beyond. The drugs have been shown to reduce the risk of non-aggressive prostate cancer, but could rarely increase the risk of an aggressive tumor. Still, these drugs (especially dutasteride) have been tested for men on active surveillance (REDEEM clinical trial) and for men with a rising PSA after localized treatment (ARTS clinical trial), with beneficial results and some controversies. Discuss those results with your doctor.
Over the past several years, a small study of men with a rising PSA after localized prostate cancer treatment showed interesting results. These men did not have HRPC, but they were hormone sensitive and did not go on LHRH injections. Men took twice the daily dose of finasteride (10 mg total daily) and an anti-androgen (flutamide at 125 mg twice a day). They were compared to a group of men taking just flutamide. The researchers found greater PSA reductions and a lower chance of disease progression in the combination group (finasteride and flutamide) as compared to those taking flutamide alone. The side effects experienced by the groups were similar. This suggests that a combination approach using the 5-alpha reductase inhibitor may be a potential option in the future, even for some men with HRPC.
HIGH DOSE ANTI-ANDROGEN REPLACEMENT
Also known as Non-steroidal anti-androgens, including bicalutamide, flutamide, and nilutamide. Steroidal anti-androgens include megestrol acetate (Megace) and cyproterone acetate (Androcur).
How is it taken? pill.
Dosage Dosages vary by drug and situation. Commonly used are bicalutamide in low to high doses (50 to 150 mg/day), flutamide (a range of doses), nilutamide (150 to 300 mg/day), and cyproterone acetate (in some countries such as Canada, 100 to 200 mg a day).
Advantages Simple to take. There are now some generic options, so check the price, please. Can have some effectiveness when given in higher doses for HRPC patients, especially when used in the early stages of HRPC. If someone responds quickly to one non-steroidal anti-androgen, he is more than likely to respond to the other two after that one anti-androgen is no longer effective.
The catch Non-steroidal anti-androgens are used for treatment of the cancer itself (in high doses) or along with other medications (LHRH), but steroidal anti-androgens are really just used today for treating side effects of ADT, such as hot flashes, and not commonly used to treat HRPC.
What else do I need to know? These drugs directly bind to and block the androgen receptor (AR).
Steroidal anti-androgens (cyproterone acetate and megestrol acetate) are known for having progesterone-like (female hormone-like) activity, which is why they are more commonly used to treat hot flashes from ADT (LHRH). They also have side-effect issues such as impact on sexual function, weight gain, fluid retention (edema), nausea, and a slight risk of blood clots. Cyproterone acetate has also been found to potentially increase the risk of heart disease.
Non-steroidal anti-androgens (bicalutamide, flutamide, and nilutamide) are more specific and selective for the AR, so there is a lower incidence of side effects. Research suggests that there is a good chance a patient will respond to an anti-androgen if he has already responded well to ADT or a previous anti-androgen.
KETOCONAZOLE
Also known as Nizoral.
How is it taken? pill.
Dosage 200 to 400 mg three times a day (a total of 600 to 1200 mg per day).
Advantages Arguably, the most popular currently available second-line hormonal treatment, and one of the most effective. Ketoconazole is also one of the least expensive drugs used to treat prostate cancer.
The catch Side effects are a concern. There have been many noted because this is also one of the best-studied secondary hormonal therapies. Side effects include: sticky skin, easy bruising, dry skin, liver toxicity, nausea and vomiting, breast enlargement and tenderness, fatigue, swelling (edema), and rash. Zytiga may soon replace this drug (see chapter six).
Question: How should I take my ketoconazole to make it the most effective?
Answer: Ketoconazole is absorbed much better in an acidic environment, so individuals taking antacids or any acid-suppressive over-the-counter or prescription medicine (H2 blockers or proton pump inhibitors, for example) will have trouble absorbing these pills.
Thus it is advised to take the pills with something acidic regardless of whether or not you are on an acid-inhibiting medication. For example, soda pop (regular or diet cola) is acidic and works well. The more popular recommendation is to take between 250 and 500 mg of ascorbic acid, also known as vitamin C, with each dosage. One word of caution is to avoid “pH neutral” or “buffered” vitamin C, as these have been formulated to be non-acidic and won’t assist in absorbing ketoconazole. Please make sure you buy inexpensive “ascorbic acid” or plain old vitamin C when taking it with ketoconazole. It should say only ascorbic acid on the ingredient label.
Also, do NOT take ketoconazole with grapefruit or grapefruit juice. Avoid other citrus and exotic fruit juices as well. Grapefruit particularly has the ability to block a protein in the gut (P-glycoprotein) and liver (CYP3A4), where approximately half of all prescription medications are metabolized. What does this mean? Consuming grapefruit (and possibly some other juices) may actually raise the level of exposure to ketoconazole in the body and cause more side effects. In addition, ketoconazole itself is similar to grapefruit in that it blocks the ability of the liver enzymes (CYP3A4) to metabolize a variety of drugs (cholesterol-lowering drugs or statins and some antibiotics, for example). This means that ketoconazole can increase your level of exposure to some other drugs (almost half of those on the market), and thereby increase your chance of side effects from them. For example, it can increase the risk of liver toxicity and muscle or joint discomfort from taking a cholesterol-lowering drug (statins). Generally speaking, you have to be careful what you eat and drink with ketoconazole. Also, you need to be mindful of what effect ketoconazole can have on other prescription medications you are currently taking.
This drug enzymatically inhibits the production of adrenal androgens, but it is not specific for adrenal androgens only, so it usually requires corticosteroid replacement to prevent adrenal problems. Often prescribed is 20 to 30 milligrams of hydrocortisone in the morning and 10 milligrams in the evening, or some variation of this regimen.
Higher androstenedione levels are predictive of a less-than-adequate response to ketoconazole, which further shows that this drug works by inhibiting adrenal androgen synthesis. Some doctors may want to measure androstenedione levels and, if they are high, consider a higher dosage, another treatment method, or another secondary hormonal treatment.
Working closely with your doctor is critical in avoiding any issues as you begin to take ketoconazole.
What else do I need to know? Ketoconazole has been used medically for a variety of purposes. It is a well-known synthetic anti-fungal drug, used to prevent skin and fungal infections (athlete’s foot and ringworm) and is even effective in individuals with suppressed immune systems. It is also sold over the counter and as a simple prescription in very low doses (1 to 2 percent) as an anti-dandruff shampoo. It is sold as a topical cream and even an oral tablet.
This drug is very effective at reducing male hormone production and other hormones in the adrenal glands. It can reduce testosterone levels and thus has even been used in the past to prevent post-operative erections. Clinical research suggests that this drug is effective at killing some HRPC. Previous clinical research has suggested as many as 50 percent of men get some kind of response to this drug.
Ketoconazole accumulates or is absorbed by fatty tissue, which is one of the reasons it has more side effects as compared to newer anti-fungal medicines (fluconazole and itraconazole). However, this absorption also explains why it is more effective with cancer: because it can penetrate a lot of barriers.
The average dosage is 400 mg every 8 hours (1200 mg total for the day). However, this dosage causes a number of the side effects listed above. Other studies have demonstrated that by starting with 200 mg every 8 hours (600 mg total for the day) you can reduce the side effects, but the drug is still almost as effective.
Question: Why does it have to be taken every 8 hours?
Answer: The drug is rapidly destroyed by the liver and, therefore, does not remain at an effective dosage in the blood for a long period of time. It is said to have a short half-life. For this reason, it must be taken at least every 8 hours to give optimal results.
SANDOSTATIN
Also known as Somatostatin or somatostatin analogues (octreotide acetate or lanreotide).
How is it taken? Injection or IV.
Dosage Given as an injection or intravenously (IV) in a variety of dosages.
Advantages This is a new potential secondary hormonal treatment. Sandostatin is known for its lack of side effects. The only short-term notable side effects are some fatigue and diarrhea, especially during the first month of the treatment.
The catch Since it is new as a secondary hormonal treatment, the true positives and negatives of using these drugs for HRPC are not yet clear. Researchers are not sure whether it is even effective against HRPC.
What else do I need to know? This is a drug that inhibits growth hormone (GH) production. It is best known for treating children and adults who produce too much GH (known as gigantism in children and acromegaly in adults). GH itself is a drug that has been given in some anti-aging clinics, but the research supporting this hormone for anti-aging is weak. There are also possible serious long-term toxicity issues. In fact, GH is a troubling medication because it causes the release of another hormone known as insulin-like growth factor 1 (IGF1). Some research studies appear to show that higher levels of IGF1 may promote tumor growth. The fact that Sandostatin may help some with HRPC provides some support for this argument.
Some preliminary research suggests that, when a drug like Sandostatin is combined with a steroid medication (such as dexamethasone), it may allow hormone therapy to be slightly effective again for a time, or it may block IGF1 or another factor that allows a prostate cancer cell to survive. Using Sandostatin as a treatment is a new concept so, as always, talk to your doctor for the latest information on it.
Question: Is combining secondary hormonal treatments an option?
Answer: Yes. There is now some preliminary research to suggest that secondary hormonal therapies may be better when they are given in combination. This seems to make sense, because each medication targets a separate anti-cancer pathway. Estrogen kills cells directly; high-dose anti-androgens block a receptor; ketoconazole reduces adrenal hormones and self-hormone production in tumors; and Sandostatin reduces the amount of a type of fuel that could promote tumor growth. Thus, it is not surprising that a few studies have shown a higher response rate in men with HRPC when the drugs are combined. There are even some new studies using secondary hormone therapies with medications such as dutasteride (5-alpha-reductase inhibitor) with ketoconazole, for example, or a bone maintenance drug (bisphosphonate) with multiple therapies. However, other studies have shown mixed results, so talk to your doctor to determine the best course of treatment for your situation.
The next chapters in the book will consider HRPC treatments approved by the U.S. Food and Drug Administration (FDA). As was mentioned earlier, there are exciting new drug therapies being researched currently. Since this book was started, several new drugs have been added to the following section, demonstrating that research in HRPC is in an exciting period with many breakthroughs happening. Remember, each new drug being tested offers the promise of a new treatment option for HRPC patients.
