Hormone therapy for prostate cancer

Hormone therapy for prostate cancer is prescribed in the early stages of the disease, in case of relapses, and also to young patients both as part of a combination treatment and as an independent method.

As early as 1941, the hormonal nature of prostate cancer (PCa) was established, since castration and the introduction of estrogens slowed the progression of metastatic tumors. Since then, antiandrogen therapy has been considered the basis for treating late stages of PCa. However, the treatment regimens and schemes are not clearly defined.

Although hormone therapy for prostate cancer has good symptomatic effects, it has not been proven to affect survival.

The growth and functioning of the prostate gland requires stimulation by androgens. Testosterone, not being a carcinogen, enhances the proliferation of tumor cells. Most of the androgens are produced by the testicles and only 5-10% of androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate) are produced by the adrenal glands. The secretion of androgens is regulated by the hypothalamic-pituitary-gonadal system. Gonadotropin-releasing hormone secreted by the hypothalamus stimulates the release of luteinizing and follicle-stimulating hormone by the anterior pituitary gland. Under the influence of luteinizing hormone, Leydig cells of the testicles synthesize testosterone. In the cells of the prostate gland, under the influence of 5α-reductase, it is transformed into dihydrotestosterone, which exceeds testosterone in androgenic activity by 10 times. In peripheral tissues, aromatase catalyzes the conversion of testosterone to estradiol, and both provide negative feedback, inhibiting the secretion of luteinizing hormone. In the absence of androgens, prostate cells undergo apoptosis (programmed death). Antiandrogen therapy refers to any treatment that interferes with the action of androgens.

The action of androgens can be disrupted by suppressing their secretion in the testicles (using surgical or medicinal castration) or by blocking androgen receptors in the prostate gland (using antiandrogens). A combination of these methods is possible.

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Indications for Hormonal Therapy for Prostate Cancer

Indication	Justification
Castration
Distant metastases; there are symptoms	Reduction of symptoms and reduction of the risk of severe complications (spinal cord compression, pathological fractures, urinary tract obstruction, extraosseous metastases)
Distant metastases; no symptoms	Slowing down progression and preventing associated symptoms and complications
Metastasis to the lymph nodes	Prolongation of survival and relapse-free period
Locally advanced tumors	Slowing down progression
Antiandrogens
Short course	Reducing the risk of exacerbation at the onset of treatment with gonadotropin-releasing hormone analogues
Monotherapy (for nonsteroidal antiandrogens)	An alternative to castration for locally advanced tumors

With distant metastases, the median survival is 28-53 months, only 7% of patients survive for 10 years. The prognosis depends on the initial PSA level, Gleason index, the number of metastases and the presence of bone pain. With T _3-4 M ₀ M ₀ tumors, the median survival often exceeds 10 years.

In long-term hormone therapy for prostate cancer, especially in relatively young patients who are sexually active, tolerability of treatment is of crucial importance. In this regard, increasing attention is being paid to monotherapy with non-steroidal androgens (bicalutamide), which allows maintaining normal testosterone levels and has moderate side effects.

The side effects of long-term antiandrogen therapy have been known for a long time. Some of them reduce the quality of life (especially in young patients), and worsen the course of concomitant diseases in old age.

Orchiectomy

Surgical castration is still considered the "gold standard" to which other types of hormone therapy for prostate cancer are compared. Bilateral orchiectomy reduces testosterone levels by 95%>, but not to zero. Orchiectomy - regular or subcapsular (with preservation of the tunica albuginea and epididymis) - is a simple operation, virtually devoid of complications and easily performed under local anesthesia. The main disadvantage of orchiectomy is the psychological trauma, due to which some men are not ready to agree to such an operation. In recent years, orchiectomy has been used less frequently, which is due to early diagnosis and the development of no less effective drug castration.

Estrogens in prostate cancer

Estrogens suppress the secretion of gonadotropin-releasing hormone, accelerate the inactivation of androgens and, according to experimental data, have a direct cytotoxic effect on the epithelium of the prostate gland. Diethylstilbestrol is usually used. Previously, it was recommended to prescribe it at 5 mg / day orally, but due to the formation of metabolites during the first pass through the liver, causing thrombosis, cardiovascular complications often occurred (the main cause of high mortality). There were attempts to prescribe diethylstilbestrol at 3 and 1 mg / day. In terms of effectiveness, it was comparable to orchiectomy, but the risk of complications was still significantly higher. In this regard, after the discovery of antiandrogens and gonadotropin-releasing hormone analogues, diethylstilbestrol lost its popularity.

Three factors have played a role in the renewed interest in estrogens:

• estrogens do not cause osteoporosis and cognitive impairment (unlike gonadotropin-releasing hormone analogues);
• the frequency of remissions (decrease in the level of PSL) against the background of the use of diethylstilbestrol and diethylstilbestrol diphosphate reaches 86%;
• Estrogen receptors involved in the pathogenesis of tumors have been discovered.

To reduce the side effects of estrogens on the cardiovascular system, it is recommended to administer them parenterally (bypassing the liver) and combine them with cardioprotectors. In a Scandinavian trial that included 917 patients and compared the effectiveness of intramuscular administration of polyestradiol phosphate and flutamide with orchiectomy or triptorelin therapy, survival and the risk of death from cardiovascular diseases were the same, although polyestradiol phosphate caused cardiovascular complications much more often. When adding low doses of warfarin (1 mg/day) or acetylsalicylic acid (75-100 mg/day) to diethylstilbestrol (1-3 mg/day), the risk of cardiovascular diseases and pulmonary embolism remained high.

Meta-analysis confirmed the equal efficacy of diethylstilbestrol and orchiectomy, but side effects that occur even when prescribing low doses of the drug prevent its widespread use. In conclusion, it can be said that further studies are needed for the further use of estrogens as first-line hormone therapy for prostate cancer.

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Gonadotropin-releasing hormone analogues in prostate cancer

Long-acting GnRH analogues (buserelin, goserelin, leuprorelin and triptorelin) have been used for about 25 years and are currently the main form of hormone therapy for prostate cancer.

These drugs are administered once every 1, 2 or 3 months. They stimulate pituitary gonadotropin-releasing hormone receptors and cause a short burst of secretion of luteinizing hormone, follicle-stimulating hormone and testosterone (2-3 days after the first injection; duration of action - until the end of the first week). Long-term treatment reduces the number of gonadotropin-releasing hormone receptors and ultimately suppresses the production of the above hormones. Testosterone levels drop to post-castrate levels after 2-4 weeks, but this effect is absent in 10% of patients.

According to the meta-analysis, GnRH analogues are equivalent in effectiveness to orchiectomy and diethylstilbestrol. Indirect comparisons show that all drugs in this group are equivalent.

Currently, GnRH analogues are the standard type of hormone therapy for prostate cancer, as they do not have the disadvantages of orchiectomy (surgery, psychological trauma) and diethyl esterol (cardiotoxicity). Their major disadvantage is the risk of exacerbation due to a short testosterone release: increased bone pain, spinal cord compression, urethral obstruction (up to renal failure), infarction, pulmonary embolism (due to increased blood clotting). However, the vast majority of exacerbations occur in a small group of patients (4-10%) with M1 tumors _that have massive, clinically expressed bone metastases. Much more often, only an asymptomatic increase in PSA levels or pathology in bone scintigraphy is noted. Simultaneous administration of antiandrogens significantly reduces the risk of exacerbation, but does not exclude it completely. Antiandrogens are prescribed from the day of administration of the gonadotropin-releasing hormone analogue and are discontinued after 2 weeks. If there is a risk of spinal cord compression, immediate testosterone reduction is performed using orchiectomy or gonadotropin-releasing hormone antagonists.

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Gonadotropin-releasing hormone antagonists in prostate cancer

These drugs compete with gonadotropin-releasing hormone for its receptors in the pituitary gland and immediately reduce the level of luteinizing hormone, follicle-stimulating hormone and testosterone. Along with this important advantage, antagonists are not without their drawbacks; many of them cause life-threatening allergic reactions, and long-acting drugs have not been developed.

Comparison of the GnRH antagonist abarelix with leuprorelin and a combination of leuprorelin and bicalutamide showed similar decreases in testosterone and PSA levels (without a transient increase). Side effects (including allergic reactions) are comparable with all drugs. Long-term results of their use have not yet been obtained. Abarelix has recently been approved for use in the United States, but only in cases where metastatic disorders make other treatments impossible.

Antiandrogens for prostate cancer

Antiandrogens compete with testosterone and dihydrotestosterone for binding to androgen receptors, which leads to apoptosis of tumor cells. There are non-steroidal, or pure (nilutamide, flutamide, bicalutamide), and steroidal antiandrogens (diproterone, megestrol, medroxyprogesterone). If the former only block androgen receptors and do not reduce testosterone levels (sometimes it even increases slightly), the latter also have a progestogenic effect, suppressing the secretory activity of the pituitary gland.

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Steroidal antiandrogens

Steroid antiandrogens are synthetic analogues of hydroxyprogestin, androgen receptor blockers. In addition, having a progestogenic effect, they suppress the release of luteinizing and follicle-stimulating hormones and inhibit adrenal function. Megestrol in high doses has a cytotoxic effect.

The decrease in testosterone levels that occurs when taking steroid antiandrogens leads to impotence, decreased libido, and sometimes gynecomastia. In addition, liver and cardiovascular dysfunctions are possible (the risk of this is as high as 40% when taking cyproterone).

Cyproterone is the first widely used drug in this group. In the only trial comparing it with medical castration, survival was significantly lower with cyproterone than with goserelin.

A study comparing monotherapy with different antiandrogens (EOCTC-30892) included 310 patients and showed similar survival with cyproterone and flutamide with a median follow-up of 8.6 years.

Nonsteroidal antiandrogens

Antiandrogen therapy is possible in monotherapy mode, as patients tolerate it better than castration. Angioandrogens do not reduce testosterone levels, which prevents weakness, osteoporosis and loss of sexual desire in patients.

Gynecomastia, nipple pain, and hot flashes occur with equal frequency with bicalutamide and flutamide, but other side effects are less common with bicalutamide than with flutamide.

Flutamide monotherapy has been studied for over twenty years, but no studies have been conducted to determine the most effective dose of the drug. The active metabolites of flutamide have a half-life of 5-6 hours, and to maintain therapeutic concentrations, the drug is prescribed 3 times a day (daily dose - 750 mg).

The main advantage of flutamide is the preservation of erection in 80% of patients. However, after 7 years from the start of treatment, no more than 20% of patients can lead a sexual life.

Survival with flutamide monotherapy is similar to that with orchiectomy or combination hormonal therapy for prostate cancer. Specific side effects of flutamide include diarrhea and increased liver enzymes; deaths from liver failure have been reported.

Bicalutamide was initially given as monotherapy at 50 mg/cyr (often in combination with GnRH analogues), which reduced survival by 3 months compared with castration. At a dose of 150 mg/day, bicalutamide leads to a decrease in PSA levels to the same extent as castration, without worsening tolerability. Bicalutamide monotherapy (150 mg/day) was compared with surgical and medical castration in two large studies involving 1435 patients.

In metastatic tumors, bicalutamide was inferior to castration, but the median survival differed by only 6 weeks. Additional analysis showed that castration was more effective only in patients with very high baseline PSA levels (more than 400 ng/ml). In locally advanced tumors, survival did not change significantly.

According to a large trial (Early Prostate Cancer Programme), which included 8113 patients without distant metastases, the addition of bicalugamide at a dose of 150 mg/day to standard treatment (prostatectomy, radiotherapy or dynamic observation) reduced the risk of progression or relapse by 42% (median follow-up time - 3 years). When the median reached 5.4 years, the effect of bicalugamide in locally advanced tumors became even more pronounced, but in patients with localized tumors, survival with bicalugamide was lower than with placebo

Thus, bicalutamide in high doses serves as an alternative to castration in locally advanced tumors and in some cases in metastatic tumors, but it is not prescribed for localized processes.

Combination hormonal therapy for prostate cancer

Castration reduces testosterone levels by 95%, but there are adrenal androgens that are converted to dihydrotestosterone in the prostate gland. The addition of antiandrogens (combination hormone therapy or maximum androgen blockade) can eliminate this effect.

Compared with castration, combination hormone therapy for prostate cancer increases 5-year survival by less than 5%.

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Combination of antiandrogens with finasteride

Finasteride (5α-reductase inhibitor) reduces the level of dihydrotestosterone in the prostate gland, and antiandrogens block the binding of the latter to receptors. The level of testosterone in the blood remains normal, which improves the tolerability of treatment (potency is maintained). The combination of finasteride and androgens is especially suitable for those patients who attach primary importance to quality of life. However, there are no long-term results or data from randomized trials yet, so this treatment is experimental.

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Intermittent hormone therapy for prostate cancer

Antiandrogen therapy is unable to eliminate all tumor cells, and sooner or later (after about two years) the tumor develops resistance to hormonal therapy. According to experimental data, resistance can develop very early due to adaptation of tumor stem cells. Theoretically, if hormonal therapy is stopped before resistant cells develop, further tumor growth will be supported only by hormone-dependent stem cells, and resumption of hormonal therapy will again cause remission; thus, interruptions in hormonal therapy can slow down the development of resistance. In addition, such treatment will be better tolerated by patients. In preliminary trials, intermittent hormonal therapy for prostate cancer had a symptomatic effect and reduced PSA levels to the same extent as continuous combination hormonal therapy, but randomized trials have not yet been completed. Thus, although this method is widely used in different groups of patients, it should still be considered experimental.

Delayed hormone therapy for prostate cancer

To date, the optimal time to initiate hormone therapy, as well as the impact of delaying it (until symptoms of progression) on quality of life and survival in inoperable tumors, have not been established.

According to the report of the Office for Health Care Quality Improvement (USA), early hormonal therapy increases survival only in some cases where it was the main treatment method, but overall there are no reliable differences. Immediate hormonal therapy for prostate cancer significantly reduced the risk of progression and associated complications, but had little effect on survival. 5-year survival and the risk of death from the tumor did not differ significantly, and the 10-year survival was higher by only 5.5%. Given these data, the American Society of Clinical Oncology does not make recommendations on the time of initiation of hormonal therapy. According to a number of trials, simultaneous and adjuvant hormonal therapy against the background of radiation significantly prolongs the time to progression and survival compared with radiation and delayed hormonal therapy in case of disease progression.

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Side effects of antiandrogen therapy

Description	Prevention and treatment
Castration
Loss of sexual desire, erectile dysfunction	Phosphodiesterase type 5 inhibitors (sildenafil), intracavernous injections, vacuum devices
Hot flashes (in 55-80% of patients)	Diethylstilbestrol, cyproterone, venlafaxine, clonidine
Gynecomastia and nipple pain (digestive stilbestrol - 49-80% of patients; castration - 10-20% of patients; castration + antiandrogens - 50% of patients)	Prophylactic radiation, mastectomy, tamoxifen, aromatase inhibitors
Obesity	Physical activity
Muscle atrophy	Physical activity
Anemia (severe - in 13% of patients with combined hormone therapy)	Epoetin-ß
Osteoporosis (except diethylstilbestrol)	Physical activity calcium, vitamin D, diphosphonates
Decreased intelligence (except diethylstilbestrol)	Physical activity, calcium, vitamin D, diphosphonates
Estrogens
Cardiovascular disorders (myocardial infarction, heart failure, stroke, deep vein thrombosis, pulmonary embolism)	Parenteral administration of anticoagulants
Antiandrogens
Steroids decreased libido erectile dysfunction, gynecomastia (rare)	Phosphodiesterase type 5 inhibitors (sildenafil), intracavernous injections, vacuum devices Prophylactic radiation mastectomy, tamoxifen, aromatase inhibitors
Nonsteroidal: gynecomastia (49-66% of patients), nipple pain (40-72%), hot flashes (9-13%)	Prophylactic radiation, mastectomy, tamoxifen aromatase inhibitors, diethylstilbestrol, cyproterone, venlafaxine, clonidine

Quality of life during hormone therapy for prostate cancer has not been sufficiently studied. The first attempt to obtain a subjective assessment of the patient's physical condition was made by D.A. Karnovsky (1947), who proposed an index for assessing the quality of life in patients with prostate cancer. This is a summary indicator of the function of the patient's organs and systems, which allows for an objective assessment of the effectiveness and safety of treatment, and also serves as a prognostic criterion for the course of prostate cancer. The gradation range is from 100% (normal condition, no signs or symptoms of the disease) to 0 (death).

The combination of orchiectomy and flutamide worsens quality of life compared with orchiectomy and placebo, which is associated with the occurrence of emotional disturbances and diarrhea.

Immediate hormonal therapy for prostate cancer (orchiectomy, gonadotropin-releasing hormone analogues or combination therapy) worsens quality of life compared to delayed therapy due to the development of weakness, emotional disturbances and decreased performance.

When treated with gonadotropin-releasing hormone analogues (regardless of stage), patients more often report poor health, anxiety, and are less likely to experience a positive effect from treatment than after orchiectomy.

When comparing hormone therapy for prostate cancer (leuprorelin, goserelin, or cyproterone) and dynamic observation in the late stages of the disease, treatment more often caused impotence and decreased intelligence, but emotional disturbances were usually noted against the background of taking cyprogeron®.

In a randomized trial comparing the efficacy of bicalutamide and castration, quality of life was assessed. Ten parameters were assessed: sexual desire, erection, performance, mood, energy, communication, activity limitation, pain, duration of bed rest, and general well-being. The observation period was one year. In both distant metastases and locally advanced tumors, bicalutamide reduced performance and sexual desire less than castration. Additional analysis showed that patients who were sexually active before the study more often maintained sexual desire and a sense of their attractiveness while taking bicalutamide. It is known that motor therapy with bicalutamide (unlike drug castration) helps to avoid the development of osteoporosis. The most common side effects of antiandrogens are gynecomastia and nipple pain (in 66 and 73% of patients while taking bicalutamide). Their occurrence is associated with a violation of the balance between androgens and estrogens in the mammary glands. Patients tolerate these symptoms quite easily and rarely require discontinuation of treatment. They are usually stopped by radiation therapy of the mammary gland area, sometimes it is carried out immediately before the appointment of antiandrogens.

In terms of cost-effectiveness, orchiectomy is superior to other methods (especially if it is performed when symptoms associated with metastasis occur). It provides the longest period of relatively full life. The least advantageous method is combined hormone therapy, which increases survival when prescribed and is very expensive economically.

In the late stages of the disease, hormone therapy for prostate cancer slows the progression of prostate cancer, prevents complications and has a symptomatic effect; an increase in survival has not been proven. Orchiectomy and various types of drug castration (gonadotropin-releasing hormone analogues, diethylstilbestrol) are equally effective in this case.

In locally advanced tumors, nonsteroidal antiandrogens as monotherapy are as effective as castration.

The combination of castration and non-steroidal antiandrogens (combination hormone therapy for prostate cancer) slightly increases survival, but is difficult for patients to tolerate.

The effectiveness of intermittent hormone therapy for prostate cancer and the combined use of antiandrogens with finasteride has not been proven.

In later stages, immediate initiation of hormone therapy reduces the risk of progression and associated complications (compared to delayed hormone therapy).

Monitoring during hormone therapy

The main indications for hormone therapy are locally advanced and metastatic tumors.

Observation is carried out to assess the effectiveness of treatment, the correctness of compliance with prescriptions, the detection of side effects and the prescription of symptomatic treatment in case of progression of the process. It is necessary to clearly define the indications for additional studies, since in many cases their implementation is not justified. Regular examination is necessary in case of continuation of treatment in case of progression of the disease. The observation scheme for hormone therapy of prostate cancer is not regulated.

The PSA level is a convenient marker for assessing the course of metastatic tumors, more reliable than acid phosphatase activity. Many studies are devoted to the prognostic value of the initial level and the rate of decrease in PSA content. The initial level reflects the prevalence of the process, but with low differentiation, the tumor sometimes does not produce PSA. The duration of remission should not be assessed based on this indicator.

Monitoring the dynamics of changes in the PSA level (absolute values after 3 and 6 months, the rate of decrease and the minimum level) allows us to evaluate the effectiveness of hormone therapy for prostate cancer. The PSA level after 3 and 6 months reflects the prognosis, although it is not considered an absolute criterion. Patients with a zero PSA level have the greatest chance of stable remission against the background of hormone therapy.

After achieving remission, regular monitoring is indicated to detect symptoms of progression: in the case of distant metastases, they occur on average after 12-18 months. Systematic determination of PSA concentration allows us to detect early signs of progression of the process: the PSA level usually increases several months before the symptoms appear. However, the PSA content does not fully reflect the state of the tumor. In 15-34% of patients, obvious progression is observed with a normal PSA level. This can be explained by the fact that the decrease in PSA levels during treatment is not always proportional to the decrease in tumor mass. In addition, hormone therapy for prostate cancer increases the proportion of poorly differentiated cells that produce less PSA.

Determining the creatinine level allows detecting urinary tract obstruction, which requires nephrostomy or stent placement. A decrease in hemoglobin concentration and an increase in liver enzyme activity may indicate progression of the process or the occurrence of side effects, which will require a break in treatment (liver damage is caused by non-steroidal antiandrogen drugs).

It should be taken into account that hormone therapy for prostate cancer leads to a decrease in hemoglobin levels by an average of 20%.

The study of the activity of alkaline phosphatase and its bone isoenzyme can be used to detect bone metastases, since hormone therapy does not affect these indicators. It should be taken into account that an increase in the activity of alkaline phosphatase may be associated with osteoporosis against the background of androgen deficiency. In such cases, it is necessary to determine the activity of bone alkaline phosphatase.

Bone scintigraphy is not indicated if the PSA level is unchanged and there are no symptoms of bone damage, since an increase in PSA is a more reliable sign of progression. In addition, interpretation of scintigraphy results can be difficult, and the appearance of new foci or an increase in old ones in the absence of symptoms cannot be a basis for changing treatment.

If clinical or laboratory data indicate disease progression, chest X-ray, ultrasound of the liver, kidneys and TRUS are recommended. In the absence of symptoms, these studies are not performed. In case of resistance to hormone therapy of prostate cancer, the examination scheme is selected individually.

The examination is carried out 3 and 6 months after the start of hormone therapy:

• in the absence or presence of distant metastases;
• resistance to hormone therapy for prostate cancer.

If the treatment is effective (reduction of symptoms, satisfactory emotional state, good tolerability of treatment and a drop in PSA levels to less than 4 ng/md), examinations are performed every 3-6 months.

In the case of monotherapy with antiandrogen drugs, more frequent examination is justified, since with the progression of the process, their cancellation can improve the patient's condition.

If the disease progresses and there is no effect from the therapy, it is necessary to draw up an individual examination plan.

Clinical guidelines for monitoring during hormone therapy

A follow-up examination is performed 3 and 6 months after the start of hormone therapy for prostate cancer. It includes measuring the PSA level, DRE, and a thorough analysis of symptoms to determine the effectiveness and side effects of treatment. The examination can be supplemented by determining the level of hemoglobin, creatinine, and alkaline phosphatase activity.

The examination plan is specified individually (taking into account the symptoms, prognosis and type of treatment).

If there are no metastases and the treatment is effective, examination is carried out every 6 months.

Disease progression and lack of effect require an individual examination plan.

X-ray examination is not indicated in the absence of symptoms of process progression.

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