Glossary
Hormonal Therapy - Systemic Therapy
Systemic therapies are medicines that circulate via the bloodstream throughout the whole body. The term systemic therapy encompasses various types of treatments including hormone treatment, immune treatments, chemotherapy, medicines to block angiogenesis, and injected radiation treatments like Samarium and Strontium.
Testosterone Inactivating Pharmaceuticals (TIP) for Prostate Cancer
Blocking testosterone is proven to prolong life in randomized prospective trials. Testosterone Inactivating Pharmaceuticals (TIP), otherwise known as androgen deprivation or hormone blockade are FDA approved medicines used either alone or with radiation to treat various stages of prostate cancer. Despite widespread experience, there are many controversies about the optimal way to use TIP. Probably the biggest issue is side effects. TIP impacts quality of life. So there is an art to picking the right amount of TIP for each individual. The goal is to administer enough TIP to get the job done, without going overboard. The optimal methodology for using TIP varies from situation to situation because prostate cancer comes in a spectrum of "stages" ranging from low-risk which can be safely monitored, to metastatic castrate-resistant disease.
Testosterone
Testosterone is manufactured intracellularly from cholesterol and progesterone, mainly in the testicles. Dihydrotestosterone (DHT), a substantially more potent form of testosterone, is converted from testosterone by the enzyme 5-alpha reductase which is located in the prostate and the liver. Dehydroepiandosterone (DHEA) and androstenedione (ANDRO), weaker androgens, are synthesized in the adrenal glands, located above each kidney. The adrenal glands are where other common hormones such as cortisone and adrenaline are created. DHEA and ANDRO are synthesized from cholesterol and progesterone just like testosterone.
Prostate cancer cannot survive without testosterone. Prior to puberty the prostate gland is only a vestigial nubbin, but when the time comes it blossoms into a walnut sized gland to manufacture semen. After puberty, if testosterone is removed, the gland involutes and atrophies. Prostate cancer cells (which are derived from the prostate gland) also need testosterone to survive. Prostate cancer cells grow and proliferate when testosterone is present; they shrivel and die when testosterone is absent. When testosterone levels in the blood drop, the cancer cells "commit suicide" through a process called apoptosis.
Testosterone Inactivating Pharmaceuticals
There are different varieties of Testosterone Inactivating Pharmaceuticals (TIP). However, they fall into three main categories. In the first category are the LHRH agonists such as Lupron, Zoladex, Eilgard, and Vantas. These medicines are administered by injection on a monthly, quarterly, semi-annual or yearly basis. They work by suppressing the pituitary gland (at the base of the brain) which in turn sends a suppressive hormonal signal to the testicles.
In the second category are the anti-androgens such as Casodex, Eulexin and Nilutamide. These pills work at the molecular level to block testosterone from activating the androgen receptor (the switch in the cell that enhances cell growth when it's turned on).
In the third category are the 5-alpha-reductase inhibitors such as Proscar and Avodart. They work by blocking the conversion of testosterone into its more potent analogue, DHT.
Combinations
These medications can be used in combination to attain more complete testosterone suppression and thus increase the anti-cancer effect. However, urologists throughout the world more commonly employ single-drug therapy with LHRH agonists alone. This policy is rooted in studies done back in the 1990s that showed that anti-androgens added to LHRH agonists only enhanced survival by a couple months. Also many urologists at that time were concerned about the high cost of Casodex. Unfortunately, this policy of using LHRH agonists without Casodex persists, even though these days Casodex is generic and much more affordable.
Adding medicines from the third category, the 5-alpha reductase inhibitors like Proscar or Avodart, is often justified with the rationale that, "It can't hurt, and it might help." While using drugs from all three categories is popular in some circles, clinical studies are lacking. There are a number of studies, however, confirming that Proscar and Avodart have an anti-cancer effect.
TIP Added to Radiation Improves Survival
The most convincing proof that TIP enhances survival is from studies of men who are undergoing radiation. In the studies, little or no TIP is compared with TIP administered for a more prolonged period. The two groups are monitored over time to determine if one group has superior survival. Men receiving longer periods of TIP show consistently better survival. However, the optimal duration of TIP is still unknown. Treatment periods between 8 and 24 months are under consideration. In our practice we often recommend 12-18 months depending on how well treatment is tolerated.
Even without radiation, TIP as sole treatment effectively controls prostate cancer for many years. In a prospective trial in men with proven lymph node spread (stage D1), better long-term survival was seen when TIP was started immediately as compared to TIP initiated at the time of cancer progression. However, in another prospective trial with locally advanced prostate cancer (seminal vesicle invasion or stage T3b), better survival occurred when radiation was added to TIP, compared to men who were treated with TIP alone.
To summarize - when the disease is aggressive, TIP and radiation together appear best, but only up to a point. Once the disease becomes metastatic, TIP alone is considered standard. At the other end of the spectrum are the men with intermediate-risk disease. For the more "favorable type" of intermediate-risk disease, combination treatment is overkill. These men should be treated with one treatment or the other, not both. Men with the more "unfavorable type" of intermediate-risk disease should consider combination treatment, but only with short-term TIP for three or four months.
Anti-Androgen Monotherapy
Traditionally, anti-androgen medications have been used in combination with LHRH agonists to block testosterone. When anti-androgens are used alone, as so-called anti-androgen monotherapy, it causes in a milder degree of testosterone blockade. There are three anti-androgens - Casodex, Flutamide, and Nilutamide. They work by keeping testosterone away from the androgen receptor, an enzymatic "switch" inside the prostate cancer cell. This switch stimulates cell growth when it's turned "on". Anti-androgens keep the switch "off." Because anti-androgens do not eliminate testosterone altogether, they have fewer side effects than the LHRH agonists such as Lupron, Trelstar, Eligard and Zoladex.
Clinicians with experience using Casodex as a single agent, estimate that: "Casodex monotherapy is about 70% as effective as the LHRH agonists but with only 30% of the toxicity." Anti-androgens have been studied in prospective randomized trials as stand-alone therapy and combined with radiation. Overall, compared to LHRH agonists, side effects are certainly less. And compared to placebo, they clearly retard prostate cancer growth. The only caveat is a higher risk of breast growth. This can be partially or completely prevented with prophylactic breast radiation or an estrogen blocking pill called Femara.
Quality of Life
Whenever the action of testosterone is inhibited, side effects ensue--hot flashes, osteoporosis, loss of muscle and loss of libido are typical. Many other side effects can also occur. Anti-androgen monotherapy (AAM) is less likely to induce muscle loss and less likely to reduce libido than the LHRH agonists. For example, only about 50% of younger men on AAM lose their libido whereas about 80% of men lose their libido with LHRH agonists.
There is one side effect that is more common with AAM than with LHRH agonists - breast enlargement. The medical term is gynecomastia. Gynecomastia occurs in 10% to 20% of men treated with LHRH agonists and in 50% to 60% of men on AAM. Gynecomastia can be prevented with radiation or an estrogen blocking pill called Femara. However, once breast tissue develops, it can only be removed with liposuction or surgery. To be effectively prevented, the radiation or the Femara must be started prior to AAM.
Length of Life
The attraction of AAM is fewer side effects. But to what degree do we sacrifice anti-cancer effectiveness and long-term survival? Studies performed to answer to this question have various flaws. For example, low-dose Casodex (50 mg daily) has been compared with LHRH agonists in men with advanced metastatic prostate cancer. Survival was shorter in men treated with low-dose Casodex compared to men who received Lupron or Zoladex.
Higher doses of Casodex (150 mg daily) have been compared with Zoladex, a LHRH agonist, in men with fairly advanced cancer that had not quite yet spread to the bones. After six years, men treated with Zoladex lived an average of six months longer than the men treated with Casodex 150 mg daily. However, the statisticians were concerned that there were an insufficient number of participants for the trial to be conclusive. The trial was statistically underpowered. Similar conclusions have been drawn from another study in men with advanced metastatic disease.
Practical Considerations
The side effects of AAM are less than with LHRH agonists. However, in regards to anti-cancer effectiveness, it is possible, even likely, that AAM is somewhat less effective in controlling cancer than the LHRH agonists. LHRH agonists should be considered standard when cure is the goal. For example, when testosterone blockade is given in conjunction with surgery or radiation or when younger patients relapse soon after surgery or radiation with fast PSA doubling times. On the other hand, anti-androgen monotherapy is a good choice for older patients or men who are less tolerant of side effects and need milder treatment to maintain quality of life.
5-Alpha-Reductase Inhibitors
"Hormonal therapy" can be targeted to block testosterone activity inside the prostate while sparing the rest of the body from negative side effects. Proscar and Avodart, both FDA-approved medications to shrink the prostate gland, function by this very mechanism. They block a special form of testosterone called dihydrotestosterone (DHT) that only occurs inside the gland. The general public is familiar with these medications due to their ability to reduce the size of the prostate gland and ameliorate a common problem familiar to aging men: the need to get up frequently at night to urinate. Yet thanks to their lowering effect on DHT, these drugs also have anti-cancer effects.
The Benefits of Proscar and Avodart for Fighting Prostate Cancer
Proscar and Avodart have been evaluated in several double blind placebo controlled trials. In one trial, 10,000 men were treated with Proscar or placebo for seven years and then underwent a prostate biopsy. The men treated with Proscar were 25% less likely to be diagnosed with prostate cancer, compared to the men treated with placebo. In two other double blind placebo controlled trials, Avodart was also shown to reduce the risk of a prostate cancer diagnosis by about 22%.
More recently, an abstract presented at the American Society of Clinical Oncology in March 2011 reported on 302 men on active surveillance who were given either Avodart or placebo for three years. As is typically the case with men on active surveillance, repeat prostate biopsies were performed 18 and 36 months after the initial diagnosis to determine if the cancer was progressing. Men who received Avodart had a progression rate that was 38% less than the men on placebo.
Another study published in European Urology retrospectively evaluated 288 men on active surveillance who received Avodart or Proscar that were compared to men who received neither. After three years of observation, the biopsy progression rate was 50% lower - 18% for the men on treatment versus 36% for the men on no treatment.
Is There a Downside Risk?
Given that Avodart and Proscar lower PSA by about 50%, the question becomes: "Are they masking the capacity of PSA to detect cancer progression?" The answer is no. PSA still rises in men with progressive disease. In fact, studies show that Avodart and Proscar improve the accuracy of the PSA monitoring process, enhancing the likelihood of detecting High-Risk cancer. The most common side effect is a reduction in libido that occurs in about one out of five men. This reduction in libido may fade away after a few months with continued treatment. Questions have also been raised as to whether Avodart and Proscar cause a shift toward high-grade when they are used for prolonged periods. In our estimation, research published so far indicates that these medications do not cause higher-grade disease. They may, however, lead to the earlier diagnosis of high-grade disease.
Preventing the Side Effects of TIP
The selection of treatment intensity has little meaning if the patient is not familiar with the advantages of the treatment and a good understanding of all the potential side effects. Many of the side effects of TIP are reversible or preventable with simple measures. Side effects that are not completely reversible should receive much more attention than those that are reversible. Side effects of minor consequence (i.e. dry skin or loss of body hair) are not going to be addressed.
Loss of Libido
Libido, a passionate attraction to the opposite sex, needs to be contrasted with potency, which is the ability to get an erection. Libido can exist without potency and potency can exist without libido. This latter reality was studied at Prostate Oncology Specialists by using Viagra in 20 men who were potent prior to starting TIP. Nineteen of the 20 men on TIP who were administered Viagra were able to get an adequate erection.
However, Viagra is underused while on TIP because of low desire. On average, libido is completely lost in 90% of men over age 70. Men between age 60 and 70 retain libido 15% of the time. Men less than age 50 retain libido as much as half the time. Generally libido returns to normal levels when testosterone recovers. However even after testosterone recovery about 25% of men over age 65 describe their libido as diminished compared to before TIP.
About 25% of men over age 70 who are treated with more than two years of TIP will not recover testosterone production. This risk is much less common in younger men and in men treated for shorter periods. The implications of testosterone production failure are not irretrievable because testosterone replacement can be conveniently administered by the daily application of a testosterone gel to the skin.
The loss of libido and the subsequent temporary cessation of sexual activity have wide ranging ramifications far beyond the intended scope of this booklet. Briefly, healthy men have an average of three to five erections while sleeping every night. The cessation of this "exercise" can cause permanent penile atrophy. So whether or not couples continue to have sexual intercourse during TIP, we counsel our patients to induce erections two to three times a week with Viagra, a pump, or with injections.
Loss of Muscle Mass
TIP causes tiredness and weakness. This side effect is much more common when the TIP is administered for more than 6 months. The degree of tiredness and weakness vary from nonexistent to incapacitating. Most commonly this side effect is described by patients as being noticeable, unpleasant, but tolerable. Examples of this effect would be a loss of 20-30 yards on the distance of a golf drive or a less powerful serve in tennis. Some men start requiring a short nap in the afternoon.
The tiredness results from a loss of muscle mass. The muscle loss problem can be reversed with a strength training program. Unfortunately typical aerobic exercise programs are not sufficient to sustain muscle mass during the TIP treatment. Walking, aerobics, and stretching are healthy things to do, but they accomplish little toward building muscle mass.
The basis of strength training is lifting weights to the point of muscle failure. A professional trainer is highly desirable if you can afford it. Typically, strength training can be accomplished in a one-hour session twice a week. Strength training exercises are intense, so a day or two of rest is needed after each session. During each one-hour session all the major muscle groups are exercised: Pectorals, deltoids, biceps, triceps, latissimus dorsi, upper and lower back muscles, abdominals, gluteus, quadriceps, hamstrings, and calf muscles. Usually three sets of 10-12 repetitions are done with weights selected to result in muscle failure toward the end of the third set (once the break-in period is completed so no injury occurs).
Strength training is so effective that men on TIP can actually increase their muscle mass. We find that the secondary side effect of tiredness and weakness is greatly minimized.
Hot Flashes
Hot flashes from TIP are irritating but are usually tolerable. They occur in about two-thirds of men treated with TIP. Ten to twenty percent of men on TIP are really bothered by them. Several measures are available. The most effective are progesterone or estrogen. Eighty percent of men treated with progesterone or estrogen have a dramatic reduction in the incidence and intensity of the hot flashes.
One convenient mode of administration is a long-acting shot called Depo-Provera. Usually a single injection is sufficient. The side effects of progesterone are possible increased appetite and some vague questions regarding its effect on prostate cancer. In one study of progesterone administered to men with prostate cancer, of the 40 patients evaluated, the cancer improved in three and became worse in one.
Estrogen patches are also effective. However, there is some risk of breast enlargement and in some cases prophylactic breast radiation may be required (see below).
Effexor, a medication approved for the treatment of depression, seems to reduce hot flashes in about 50% of men treated. Neurontin, which is used in high doses to suppress seizures, seems to reduce hot flashes when used in low doses. Both of these drugs seem to have a fairly low incidence of side effects.
Weight Gain
The loss of testosterone, as well as the loss of muscle mass, slow the rate of body metabolism. Without careful discipline in regard to diet, TIP will result in weight gain. The time to take note of this problem is before the weight has accumulated. Following a diet to keep a stable weight is easier to accomplish than initiating a diet to lose weight. It is wise to evaluate your diet for evidence of excess fat and sugar intake at the time of starting TIP.
Breast Growth
Breast growth occurs in more that 50% of men on anti-androgen monotherapy. It occurs to a milder degree in about one-third of men treated with other forms of TIP. Men on anti-androgen monotherapy typically have to be treated with preventative radiation therapy to the breast area or with estrogen blocking pills such as Femara.
Osteoporosis
Accelerated calcium loss from the bones occurs in men deprived of testosterone just as with post-menopausal women deprived of estrogen. Untreated bone loss can result in hip and spine fractures. Men who fracture their hips have a 50% mortality rate. Fortunately osteoporosis is reversible or preventable with common medications from a class of medications termed bisphosphonates. Common trade names are Fosamax, Boniva, Actonel and Zometa. These medications are administered as a pill once a week, once a month, or in the case of Zometa, intravenously.
Some men already have osteoporosis before starting TIP. Therefore, prior to starting TIP, men should obtain a baseline bone density test. We recommend starting a bisphosphonate at the same time TIP is initiated as a preventative measure. Men who have preexisting osteoporosis or who continue to have bone loss while on oral bisphosphonates are usually treated with an intravenous bisphosphonates such Zometa. Vitamin D and calcium supplementation is also required.
Memory Changes
Some men on TIP complain about problems with "word finding" and remembering names. Perhaps 10% of men treated with TIP will mention a problem remembering words. The problem reverses when the TIP is stopped. A good memory is directly related to one's overall strength and conditioning. Some of the difficulties with memory may occur because of "just feeling tired out." Complaints of memory problems occur less frequently with regular strength training.
Anemia
Blood is a mixture of red cells and "serum" (water). When the proportion of red cells in the blood is diminished this is called "anemia." Red cells carry oxygen so when anemia becomes severe the most common side effect is shortness of breath. A milder degree of anemia can contribute to a feeling of tiredness. As discussed above, tiredness can also result from loss of muscle mass. Therefore it is important to monitor for the development of anemia with a simple blood test called a CBC. Normally men have a blood hematocrit of about 42% (the hematocrit is part of the CBC blood test). Treatment with TIP on the average reduces the hematocrit to around 36% which is usually well tolerated.
About 10% of men develop a more severe degree of anemia with hematocrits less than 32%. This is significant for several reasons. First, if your doctor is unaware of this phenomenon he may conclude that you need evaluation with a bone marrow biopsy, a somewhat unpleasant and unnecessary procedure. Second, the anemia is easily correctable with low doses of hormone such as Procrit or Aranesp. This type of anemia does not respond to iron replacement.
Arthritis
Joint pains, particularly in the hands but sometimes in other joints, are fairly common with TIP. Actual joint swelling or visually arthritic changes are extremely uncommon if they occur at all. The pain may respond to Glucosamine, MSM, Motrin, Celebrex and Aleve. There is some soft evidence that Chondroiten, another popular over the counter preparation for treatment of the joint, is not a good idea for men with prostate cancer. It is possible (but not proven) that chondroiten may accelerate the growth of prostate cancer.
Liver Changes
Casodex and Flutamide can occasionally cause irritation of the liver. This is easily detected at an early stage with simple blood tests. When the problem occurs, whichever agent is being used must be stopped because the irritation" can progress to severe liver damage if allowed to proceed unchecked. The problem is easily reversible if the process is detected and the offending agent stopped in a timely fashion. Once the liver tests revert to normal we have had good luck by switching from one type of anti-androgen to the other. In other words, if the liver problem was incited by Casodex we have found that Eulexin is usually safe and visa versa.
Mood Swings
Emotional changes as a result of hormonal treatment for cancer are not at all unexpected. How much of the emotional impact comes from medicines and how much is related to the overall situation (having cancer that requires treatment) is difficult to measure. Nevertheless men on TIP treatment do comment about being more closely in touch with their feelings and crying more easily. Some men find this effect of TIP unpleasant whereas others see it as a positive development. For men in the former situation low doses of common antidepressant medications (such as Zoloft, Celexa or Paxil) easily reverse the unpleasant feelings.
Blood Pressure and Cholesterol Changes
We have observed both upward and downward movement of blood pressure and cholesterol after the initiation of TIP. Standard management with the addition or removal of blood pressure or cholesterol medications is effective in a manner similar to people who are not on TIP.
Final Thoughts
TIP affects many aspects of a man's life. Our general impression after many years of experience delivering this form of treatment is that it is tolerable if the side effects are expertly managed. Preventative measures such as weight lifting and diet make a huge difference in how men feel while they are on the treatment. Careful monitoring of blood tests, bone density is essential. The management of side effects like joint pains, hot flashes, reduced libido and impotence is imperfect but expert medical care by knowledgeable physicians and care givers can go accomplish much toward reducing the impact of these problems.
