Prostate cancer hormone therapy

Prostate cancer hormone therapy is prescribed in the early stages of the disease, with relapses, and also in young patients both as part of a combination treatment and as an independent method.

In 1941, the hormonal nature of prostate cancer (PCa) was established, since castration and the administration of estrogens slowed the course of metastatic tumors. Since this time, antiandrogen therapy is considered the basis of treatment of advanced stages of prostate cancer. However, regimens and regimens of therapy are not clearly defined.

Although prostate cancer hormone therapy brings a good symptomatic effect, it is not proven that it affects life expectancy.

The growth and function of the prostate gland requires androgen stimulation. Testosterone, not being a carcinogen, enhances the proliferation of tumor cells. Most of the androgens produce testes and only 5-10% of androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate) produce adrenals. The secretion of gsgoherope is regulated by the hypothalamic-pituitary-gonadal system. Gnadoliberin, secreted by the hypothalamus, stimulates the release of luteinizing and follicle-stimulating hormone by the anterior pituitary gland. Under the influence of the luteinizing hormone, the Leydig cells of the testicles synthesize testosterone. In cells of the prostate gland under the action of 5α-relutase, it is transformed into dihydrotestosterone, which exceeds testosterone in androgenic activity by a factor of 10. 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 are apoptotic (programmed death). By anti-androgen therapy is understood any treatment that violates the action of androgens.

Disrupt the effect of androgens can be by suppressing their secretion in the testes (with the help of surgical or drug castration) or blockade of androgen receptors in the prostate (with the help of antiandrogens). A combined application of these methods is possible.

[1], [2], [3], [4], [5], [6]

Indications for hormone therapy for prostate cancer

Indication	Justification
Castration
Distant metastases; there are symptoms	Reducing symptoms and reducing the risk of severe complications (compression of the spinal cord, pathological fractures, obstruction of the urinary tract, extraosteal metastases)
Distant metastases; no symptoms	Slowing down of progression and prevention of associated symptoms and complications
Metastases in the lymph nodes	Prolonged survival and disease-free period
Locally dispersed tumors	Deceleration of progression
Antiandrogens
Short course	Reduction of the risk of exacerbation at the beginning of baking with analogues of gonadoliberin
Monotherapy (for non-steroidal antiandrogens)	Alternative 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 baseline PSA level, the Gleason index, the number of metastases and the presence of bone pain. In tumors T _3-4 M ₀ M _{0, the} median survival is often more than 10 years.

With prolonged hormonotherapy of prostate cancer, especially in relatively young patients who have sex life, the tolerability of treatment becomes crucial. In this regard, more and more attention is paid to monotherapy with nonsteroidal androgens (bicalutamide), which allows to maintain a normal level of testosterone and has moderate side effects.

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

Orchiectomy

Surgical castration is still considered a "gold standard", with which other types of hormone therapy for prostate cancer are compared. Bilateral orchiectomy lowers testosterone levels by 95%>, but not to zero. Orchiectomy - normal or subcapsular (with the preservation of the belly and epididymis) is a simple operation, practically devoid of complications and easily performed under local anesthesia. The main drawback of orchiectomy is a psychological trauma, in connection with which some men are not ready to agree to such an operation. In recent years, orchiectomy is resorted to less often, which is associated with early diagnosis and development of no less effective drug castration.

Estrogens for prostate cancer

Estrogens inhibit the secretion of gonadoliberin, 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 inwards, but due to the formation of metabolites causing thrombosis through the liver, cardiovascular complications often occurred (the main cause of high mortality). There were attempts to prescribe diethylstilbestrol a at 3 and 1 mg / day. It was comparable in effectiveness to orchiectomy, but the risk of complications was still much higher. In this regard, after the discovery of antiandrogens and gonadoliberin analogues, diethylstilbestrol lost its popularity.

In the renewed interest in estrogen, three factors played a role: 

• estrogens do not cause osteoporosis and cognitive impairment (unlike gonadoliberin analogues); 
• the frequency of remission (decrease in the level of PSL) against the background of the use of diethylstilbestrol and diethylstilbasgrol diphosphate reaches 86%; 
• Estrogen receptors are involved in the pathogenesis of tumors.

To reduce the side effect of estrogens on the cardiovascular system, it is recommended to administer them parenterally (bypassing the liver) and combine with taking cardioprotectors. In the Scandinavian test, which included 917 patients and compared the effectiveness of intramuscular injection of polyestradiol phosphate and flutamide with orchiectomy or tryptorelin therapy, survival and risk of death from cardiovascular diseases were the same, although polyestradiol phosphate was much more likely to cause cardiovascular complications. When low doses of warfarin (1 mg / day) or acetylsalicylic acid (75-100 mg / day) were added to diethylstilbestrol (1-3 mg / day), the risk of cardiovascular disease and thromboembolism of the pulmonary artery remained high.

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

[7], [8], [9]

Analogues of gonadoliberin in prostate cancer

Analogues of long-acting gonadoliberin (buserelin, goserelin, leuprorelin and triptorelin) have been used for about 25 years, currently it is the main type of hormone therapy for prostate cancer.

These drugs are administered once every 1, 2 or 3 months. They stimulate the receptors of gonadoliberin of the pituitary gland and cause a short splash in the secretion of luteinizing, follicle-stimulating hormones and testosterone (2-3 days after the first injection, the duration of action is until the end of the first week). Long-term treatment reduces the number of receptors of gonaloliberin and eventually suppresses the production of the above hormones. The level of testosterone drops to postastraciopion in 2-4 weeks, but in 10% of patients this effect is absent.

According to meta-analysis, analogues of gonadoliberia in efficiency correspond to orchiectomy and diethylstilbestrol. Indirect comparisons show that all preparations of this group are equivalent.

Currently, gonadoliberia analogues serve as a standard form of prostate cancer hormone therapy, as they lack the drawbacks of orchiectomy (surgery, trauma) and diethylgylbestrol (cardiotoxicity). Their important drawback is the risk of exacerbation due to a short release of testosterone: increased pain in the bones, compression of the spinal cord, obstruction of the urethra (up to renal failure), heart attack, thromboembolism of the pulmonary artery (due to increased blood coagulability). However, the overwhelming majority of exacerbations occur in a small group of patients (4-10%) with M ₁ tumors with massive, clinically pronounced metastases in the bones. Much more often mark only an asymptomatic increase in the level of PSA or pathology in bone scintigraphy. Simultaneous administration of antiandrogens significantly reduces the risk of exacerbation, but does not exclude it completely. Antiandrogens are prescribed from the day of introduction of the analogue of gonadoliberin and cancellation after 2 weeks. When the threat of compression of the spinal cord is resorted to an immediate decrease in the level of testosterone with the help of orchiectomy or antagonists gonadoliberii.

[10], [11], [12], [13], [14], [15]

Gonadoliberin antagonists in prostate cancer

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

A comparison of the antagonist gonadoliberin abarelix with leuprorelin and a combination of leuprorelin and bicalutamide showed an identical decrease in testosterone and PSA levels (without its transient increase). Side effects (including allergic reactions) are comparable when using all drugs. Remote results of their application have not yet been received. Abarelix was recently approved for use in the United States, but only in cases where metastatic disorders make it impossible to use other treatments.

Antiandrogens in prostate cancer

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

[16], [17], [18]

Steroidal antiandrogens

Steroidal antiandrogens are synthetic analogues of hydroxyprogesgerone, androgen receptor blockers. In addition, by providing progestagenic action, 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, which occurs when taking steroid antiandrogens, leads to impotence, weakening of libido and sometimes to gynecomastia. In addition, there may be violations of the liver and cardiovascular system (against the background of cyproterone therapy, their risk reaches 40%).

Ciproterone is the first widely used drug from this group. In a single trial comparing it with drug castration, survival with cyproterone was significantly lower than with goserelin.

The study, in which monotherapy with different antiandrogens was compared (EOKTS-30892), covered 310 patients. It showed the same survival rate against the use of cyproterone and flutamide with a median follow-up time of 8.6 years.

Non-steroidal antiandrogens

Possible therapy with antiandrogens in monotherapy, as patients suffer it better than castration. Angiandrogens do not reduce the level of testosterone, which prevents weakness, osteoporosis and loss of sexual desire in patients.

Gynecomastia, pain in the nipples and flushes on the background of taking bicalutamide and flutamide occur with equal frequency, but other side effects of bicalutamide are less frequent than flutamide.

Monotherapy with flutamide has been studied for more than twenty years, but studies to determine the most effective dose of the drug have not been carried out. Active metabolites of flutamide have a half-life of 5-6 hours and for maintenance of therapeutic concentration 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, sexual activity can not be conducted by more than 20% of patients.

Survival in monotherapy with flutamide is the same as with orchiectomy or combined hormone therapy for prostate cancer. Particular side effects of flutamide - diarrhea and increased activity of hepatic enzymes; cases of death from liver failure are described.

Initially, bicalutamide was administered as monotherapy at 50 mg / cyr (often in combination with gonadoliberin analogs), which reduced survival by 3 months compared to castration. At a dose of 150 mg / day bicalutamide leads to a decrease in the level of PSA to the same extent as castration, and without worsening portability. Monotherapy with bicalutamide (150 mg / day) was compared with surgical and drug castration in two large studies, covering 1,435 patients.

With metastatic tumors, bicalutamide was inferior to castration, but the median survival was only 6 weeks apart. Additional analysis showed that castration was more effective only in patients with a very high baseline PSA level (> 400 ng / ml). With locally advanced tumors, survival did not change reliably.

In a large trial (the Early Prostate Cancer Program), which included 8113 patients without distant metastases, the addition of bicalgamide 150 mg / day to standard treatment (prostatectomy, radiation therapy or dynamic observation) reduces 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 with disseminated tumors became even more pronounced, but in patients with localized tumors, survival with bicalugamide was lower than that in placebo

Thus, bicalutamide in high doses serves as an alternative to castration in locally advanced tumors and in a number of cases with metastatic tumors, but in a localized process it is not prescribed.

Combined prostate cancer hormone therapy

Castration lowers testosterone levels by 95%, but there are adrenal androgens that turn into dihydrotestosterone in the prostate gland. Adding anti-androgens (combined hormone therapy or maximal androgen blockade) can eliminate this effect.

Compared with castration, combined prostate cancer hormone therapy improves 5-year survival by less than 5%.

[19], [20], [21], [22], [23], [24]

Combination of antiandrogens with finasteride

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

[25], [26], [27], [28], [29], [30]

Intermittent hormone therapy for prostate cancer

Antiandrogen therapy is not capable of eliminating all tumor cells, and sooner or later (approximately two years later) the tumor develops resistance to hormone therapy. According to experimental data, resistance can occur very early in connection with the adaptation of tumor stem cells. Theoretically, in the case of cessation of hormone therapy before the emergence of resistant cells, further growth of the tumor will be supported only by hormone-dependent stem cells, and the resumption of hormone therapy will again lead to remission; Thus, breaks in hormone therapy can slow the emergence of resistance In addition, such treatment patients will be better tolerated. In preliminary trials, intermittent hormone therapy for prostate cancer had symptomatic effects and reduced PSA levels to the same extent as constant combined hormone therapy, however, randomized studies have not yet been completed. Thus, although this method is widely used in different groups of patients, it should still be considered experimental.

Delayed prostate cancer hormone therapy

Until now, the optimal time for the onset of hormone therapy has not been established, as well as the effect of delaying (before the onset of symptoms of progression) on quality of life and survival in inoperable tumors.

According to the report of the Office of Quality of Medical Care (USA), early hormone therapy improves survival only in selected cases, where it was the main method of treatment, but on the whole there are no reliable differences. Immediate prostate cancer hormone therapy significantly reduced the risk of progression and associated complications, but had little effect on survival. The 5-year survival and risk of dying from the tumor did not differ significantly, and the 10-year survival was only 5.5% higher. Given these findings, the American Society for Clinical Oncology does not give recommendations on the timing of the onset of hormone therapy. According to a number of tests, simultaneous and adjuvant hormone therapy against the background of radiation significantly prolongs the time to progression and survival compared with irradiation and delayed hormone therapy in the course of disease progression.

[31], [32], [33], [34], [35]

Side effects of antiandrogen therapy

Description	Prevention and treatment
Castration
Loss of sexual desire, erectile dysfunction	Inhibitors of phosphodiesterase type 5 (sildenafil), intracavernous injection, vacuum devices
Tides (in 55-80% of patients)	Diethylstilbestrol, cyproterone, venlafaxine, clonidine
Gynecomastia and pain in the nipples (dizgilstilbestrol - 49 80% of patients, castration - 10 -20% of patients, castration + antiandrogens - 50% of bug	Prophylactic radiation, mastectomy, tamoxifen, aromatase inhibitors
Obesity	Exercise stress
Atrophy of muscles	Exercise stress
Anemia (severe - in 13% of patients with combined hormone therapy)	Epoetin-ß
Osteoporosis (except diethylstilbestrol)	Physical load of 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
Steroidal depression of sexual desire erectile dysfunction, gynecomastia (rarely)	Inhibitors of phosphodiesterase type 5 (sildenafil), intracavernous injections, vacuum devices Prophylactic irradiation mastectomy, tamoxifen, aromatase inhibitors
Non-steroidal: gynecomastia (49-66% of patients), pain in the nipples (40-72%), hot flashes (9-13%)	Prophylactic irradiation, mastectomy, tamoxifen aromatase inhibitors, Diethylstilbestrol, cyproterone, venlafaxine, clonidine

The quality of life against the background of hormone replacement therapy for prostate cancer has not been adequately studied. The first attempt to obtain a subjective assessment of the physical condition of the patient was undertaken by D.A. Karnovsky (1947), who proposed an index for assessing the quality of life in patients with PCa. This is a summary of the function of the patient's organs and systems, which allows an objective assessment of the efficacy and safety of treatment, and also serves as a prognostic criterion for the progression of prostate cancer. The gradation range is from 100% (normal state, absence of signs and symptoms of the disease) to 0 (death).

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

Immediate prostate cancer hormone therapy (orchiectomy, gonadoterin analogues or combined treatment) worsens the quality of life compared to delayed due to weakness, emotional disturbances and decreased efficiency.

When treating gonadoliberin analogues (regardless of the stage), patients often note poor health, anxiety and less often experience a positive effect of treatment than after an orchiectomy.

When comparing hormone therapy for prostate cancer (leuprorelin, goserelin, or cyproterone) and dynamic follow-up in the late stages of the disease, treatment often caused impotence and decreased intelligence, but emotional disorders were usually noted when taking cyprogerone.

In a randomized trial comparing the efficacy of bicallaamid and castration, the quality of life was assessed. Ten parameters were assessed: sexual desire, erection, working capacity, mood, energy, communication, activity limitation, pain, duration of bed rest and overall health. The observation period is one year. As with distant metastases, and with locally distributed tumors, bicalutamide less reduced efficiency and sexual attraction than castration. Additional analysis showed that in patients who were sexually active prior to the study, sexual attraction and a sense of attractiveness were more common with bicalutamide. It is known that motor therapy with bicalutamide (in contrast to drug castration) allows to avoid the development of osteoporosis. The most frequent side effects of antiandrogens are gynecomastia and pain in the nipples (in 66 and 73% of patients on the background of bicalutamide). Their occurrence is associated with a disbalance between androgens and estrogens in the mammary glands. These symptoms can be easily tolerated and rarely require treatment cancellation. They are usually stopped by radiotherapy zone of the mammary glands, sometimes it is carried out immediately before the appointment of antiandrogens.

In terms of the ratio of cost and effectiveness, orchiectomy is superior to other methods (especially if it is carried out in the presence of symptoms associated with metastasis). It provides the longest period of relatively full life. The least profitable method is combined hormone therapy, an increase in survival rate at its appointment and is economically very costly.

In advanced stages of the disease, prostate cancer hormone therapy slows the progression of prostate cancer, prevents complications and has symptomatic effect; an increase in survival is not proven. Orchiectomy and various variants of drug castration (analogues of gonadoliberin, diethylstilbestrol) in this case are equally effective.

With locally advanced tumors, non-steroidal anti-androgens, in the form of monotherapy, are not inferior to castration in effectiveness.

The combination of castration and the administration of non-steroidal antiandrogens (combined hormone therapy for prostate cancer) somewhat increases survival, but is severely tolerated by patients.

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

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

Observation with hormone therapy

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

Observation is conducted to assess the effectiveness of treatment, the correctness of the prescriptions, the detection of side effects and the appointment of symptomatic treatment in the process of progression. It should be clearly defined indications for additional studies, as in many cases, their conduct is not justified. Regular examination is necessary in case of continuation of treatment with progression of the disease. The monitoring scheme for hormone therapy for prostate cancer is not regulated.

The level of PSA is a convenient marker for evaluating the course of metastatic tumors, more reliable than the activity of acidic phosphatase. A lot of works are devoted to the prognostic value of the initial level and the rate of decrease in the PSA content. The baseline reflects the prevalence of the process, but with low differentiation, the tumor sometimes does not produce PSA. To estimate the duration of remission on the basis of this indicator should not be.

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

After remission has been achieved, regular observation is shown to detect symptoms of progression: with distant metastases, they occur an average of 12-18 months. A systematic determination of PSA concentration reveals early signs of progression of the process: PSA growth usually occurs a few months before the onset of symptoms. However, the PSA content does not fully reflect the condition of the tumor. In 15-34% of patients, obvious progression is observed at a normal PSA level. This can be explained by the fact that a decrease in the PSA level against the background of treatment is not always proportional to a decrease in the tumor mass. In addition, prostate cancer hormone therapy increases the proportion of low-grade cells that produce less PSA.

Determination of the level of creatinine allows detecting obstruction of the urinary tract, in which nephrostomy or stent placement is necessary. Decreased hemoglobin concentration and increased activity of liver enzymes 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 antiandrogenic drugs).

It should be borne in mind that hormone therapy for prostate cancer leads to a decrease in hemoglobin level by an average of 20%.

The study of the activity of AP and its bone isoenzyme can be used to detect metastases in the bone, since hormone therapy does not affect these parameters. It should be taken into account that an increase in the activity of AP may be associated with osteoporosis in 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, as an increase in PSA content is a more reliable sign of progression. In addition, the interpretation of the results of scintigraphy is difficult, and the emergence of new foci or the increase of old ones in the absence of symptoms can not be the basis for changing treatment.

If clinical or laboratory data indicate a progression of the disease, chest radiographs, ultrasound of the liver, kidneys and TRUS are recommended. In the absence of symptoms, these studies do not. With resistance to hormone therapy for prostate cancer, the examination schedule is selected individually.

Examination is carried out at 3 and 6 months after the start of hormone therapy:

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

With a good effect of treatment (reduction in symptoms, satisfactory emotional state, good tolerability of treatment and a decrease in the PSA level of less than 4 ng / md), the examination is performed every 3-6 months.

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

With the progression of the disease and the absence of the effect of the therapy, it is necessary to compile an individual examination schedule.

Clinical recommendations for monitoring hormone therapy

Follow-up examinations are performed at 3 and 6 months after the onset of hormone replacement therapy for prostate cancer. It includes measuring the level of PSA, PRI, and a thorough analysis of the symptoms to determine the effectiveness and side effect of treatment. The examination can be supplemented by determining the level of hemoglobin, creatinine and activity of alkaline phosphatase.

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

In the absence of metastases and a good effect of treatment, the examination is performed every 6 months.

Progression of the disease and lack of effect require an individual examination schedule.

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

[36], [37], [38], [39], [40], [41],