metastatic prostate cancer

Locally advanced prostate cancer involves spread beyond the capsule without the presence of distant metastases, and metastases to regional lymph nodes. Metastatic prostate cancer indicates metastases in the lymph nodes, bone metastasis or metastatic soft tissue
Primary treatment for patients with locally advanced or metastatic prostate cancer - hormonal treatment.
Hormone therapy for prostate cancer

For the first time the effectiveness of hormonal treatment (operative castration and estrogen appointment) in patients with metastatic prostate cancer is shown in 1941.
Since then hormone therapy is one of the main methods of treatment for patients with advanced forms of prostate cancer. Currently the use of hormone replacement therapy is not limited to a group of patients with metastatic disease, its use as a single agent or discuss multimodalyyugo treatment for non-metastatic prostate cancer
Molecular basis of the hormonal control of the prostate

Growth, functional activity and cell proliferation in the prostate may be adequate stimulation androgens. The main androgen, circulating in the blood, testosterone. Not having oncogenic properties, it is necessary for the growth of tumor cells.
The main source of androgens in the male testes, about 5-10% of adrenal androgens are synthesized. More than half of testosterone in the blood is associated with sex hormone, 40% albumin. Functionally active. unbound form of testosterone is only 3%.
After passive diffusion across the cell membrane testosterone be converted into dihydrotestosterone by the enzyme 5-a reductase. Although the physiological effects of testosterone and dihydrotestosterone are similar, the latter has 13 times more active. The biological effect of the two substances is realized by binding to androgen receptors located in the cell cytoplasm. Later complex "ligand-receptor" moves to the nucleus, where attached to specific areas promouternym genes.
Testosterone secretion is under the regulatory influence of the hypothalamic-pituitary-gonadal axis. Secreted by the hypothalamus stimulates LHRH secretion of LH and FSH in the anterior pituitary. The action is aimed at the stimulation of LH release of testosterone by interstitial Leydig cells in the testes.
Negative feedback to the hypothalamus provide circulating in the blood androgens and estrogens derived from androgens by biotransformation.
Regulation of androgen synthesis in the adrenal axis is' hypothalamus (corticotropin-releasing factor), pituitary (adrenocorticotropic hormone) - adrenal glands (androgens) "feedback mechanism. Virtually all of androgens secreted by adrenal glands, are in a state bound to albumin, their functional activity in comparison with testosterone and DHT is extremely low. Androgen levels. allocated by the adrenal glands, at the maintenance level after bilateral orchiectomy.
ADT prostate cells completing their apoptosis (programmed cell death).
Create androgen blockade

Now to create androgen deprivation use two basic principles:
suppression of androgen secretion by the testes due to medical or operative castration;
inhibition of the action of circulating androgens at receptor interaction in prostate cells (anti-androgens).
The combination of these two principles is reflected in the concept of "maximum (or total) androgen blockade"
Reducing the concentration of testosterone (castration)

Bilateral orchiectomy

Bilateral orchiectomy in a short time leads to a decrease in testosterone levels less than 50 ng / dL (based on the results of operations that level considered castration). 24 hours after the operative castration testosterone is reduced by 90%. Given this, bilateral orchiectomy considered the "gold" standard for building androgen deprivation therapy, the effectiveness of all the other methods evaluated in comparison with the operation.
Possible to perform this operation on an outpatient basis under local anesthesia by one of two methods: complete subcapsular orchiectomy or orchiectomy with preservation of the epididymis and visceral leaf tunica vaginalis. Subcapsular orchiectomy allows patients to avoid the negative psychological impact of the "empty" scrotum, but must account for the complete removal urologist intratesticular tissue containing Leydig cells. When technically true of the operation results of propene and subcapsular orchiectomy identical.
Recently mentioned the decreasing prevalence operative castration associated with diatonic disease at an early steel, as well as the use of pharmacological treatments are equivalent in effectiveness of castration.
Estrogens

Estrogens have a multicomponent mechanism of action:
decreased secretion of LHRH by a feedback mechanism:
Inactivation of androgens;
direct suppression of Leydig cell function:
direct cytotoxic effect on prostatic epithelium (shown only in vitro).
The most common estrogen diethylstilbestrol. The use of estrogens is limited due to high risk of cardiac and vascular complications (thrombogenic properties of estrogen metabolites), even at a low dose (1 mg), although comparable to the operational effectiveness of castration.
At present, interest in the estrogen therapy is based on the three positions.
Compared with LHRH agonists estrogens have lower costs and lead to dangerous side effects (osteoporosis, cognitive disorders).
Estrogens are highly effective in patients with advanced prostate cancer androgenrefrakternym.
Currently, the discovery of new classes of estrogen receptor beta. allegedly involved in oncogenesis in the prostate.
To prevent cardiovascular toxicity of estrogens proposed the use of parenteral routes of administration (to prevent the formation of toxic metabolites, due to the effect of the first passage through the liver), as well as cardioprotective drugs. However studies have shown that the use of anticoagulants and antiplatelet agents for their calculation angioprotektivnoe action actually reduces the risk of embolic complications tromoo.
Inhibitor-releasing hormone

Agonists-releasing hormone (LHRH) (buserelin, goserelin, leuprorelin, triptorelmn) - synthetic analogs of LHRH. The mechanism of action lies in the initial stimulation of the pituitary LHRH receptors and the allocation of LH and FSH, which increases testosterone production of Leydig cells. 2-4 weeks for the feedback mechanism is suppression of the synthesis of pituitary LH and FSH, which reduces the blood level of testosterone to castration. However the use of LHRH agonists can not achieve this in about 10% of cases.
Meta-analysis of 24 major studies involving about 6,600 patients, showed that the life expectancy of patients with prostate cancer in LHRH agonists alone did not differ from that of patients who underwent bilateral orchiectomy.
An initial "flash" LH, and therefore of testosterone begins 2 3 days after injection of these drugs and lasts for up to 10-20 days. This "flash" can lead to a life-threatening exacerbation of symptoms, particularly in patients with advanced forms of it. Among these symptoms should list bone pain, acute urinary retention, renal failure due to ureteral obstruction, spinal cord compression, severe complications of the vascular system seodechno the tendency to hypercoagulability. There are differences between the phenomena of "clinical flare" and "biochemical flare" (increase in PSA). Most susceptible to the phenomenon of "clinical flare" patients with large lesions of bone occurring symptomatically (about 4-10% of patients with advanced disease Ml).
When using LHRH-receptor agonist, simultaneously assign antnandrogennye drugs, which prevents unwanted effects described elevated levels of testosterone. Antiandrogens used for 21-28 days.
For patients at high risk of spinal cord compression should be a means, leading to a rapid decrease in testosterone levels in the blood (operational castration, LHRH antagonists).
Receptor antagonists releasing hormone

Appointment of LHRH-receptor antagonist (cetrorelix) leads to a rapid decrease in testosterone levels by blocking LHRH receptors in the pituitary gland: within 24 hours after the appointment of a decrease in LH concentrations to 84%. Given this, there is no need to appoint anti-androgen drugs in the absence of the phenomenon of "flash."
LHRH antagonist monotherapy is comparable to that in the appointment of LHRH agonists in combination with anti-androgens.
The possibility of widespread use of drugs of this group complicates a number of facts. Most of the LHRH-receptor antagonists can cause severe allergic reactions mediated by histamine, including after a previous successful applications. Taking this into account. these drugs are used in patients who have waived their operative castration for which other medications hormonal treatment options are not possible.
Medical staff monitor patients for 30 minutes after administration of the drug due to the high risk of allergic reactions.
Inhibitors of androgen synthesis

Ketoconazole is an oral antifungal drug that inhibits the synthesis of adrenal androgens and testosterone Leydig cells. Effect after the drug comes very quickly, sometimes within 4 hours after administration: effect of ketoconazole and quickly reversible, therefore, a constant (400 mg every 8 hours) dosing regimen to maintain a low level of testosterone.
Ketoconazole - quite well-tolerated and effective drug, it is administered to patients who have first-line hormonal treatment was not effective.
Despite the fast-paced, duration of treatment with ketoconazole in patients without concomitant hormonal modulation (operational, medical castration) leads to a gradual increase of testosterone in the blood to normal within 5 months.
At present, the use of ketoconazole limited group of patients with prostate cancer androgenrefrakternym.
Side effects of ketoconazole: gynecomastia, lethargy, weakness, liver dysfunction, blurred vision, nausea.
Given the suppression of adrenal function, Ketoconazole is usually prescribed in combination with hydrocortisone (20 mg 2 times a day).
Antiandrogen treatment

Antiandrogens block the intracellular receptors, having a greater affinity than testosterone, causing apoptosis of prostate cells.
Orally administered androgens attributed to two main groups:
antiandrogens with steroid structure (cyproterone, medroxyprogesterone);
nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide).
Steroidal anti-androgens also have suppressive effect on the pituitary gland, through which there is a decrease in testosterone levels, whereas during treatment with non-steroidal drugs testosterone levels remained normal or slightly elevated.
Steroidal antiandrogens

Cyproterone one of the first and most well-known drug in the group antiandrogens direct blocking action on androgen receptors also reduces testosterone levels in the blood by the central suppression (progestogen properties). Cyproterone is taken orally, the recommended dose -100 mg 2-3 times a day.
In monotherapy efficacy cyproterone compared with flutamide.
The side effects caused by cyproterone gipogonadnzmom (decreased libido, impotence, fatigue), to 10% of patients may experience severe complications of the cardiovascular system, which limits the use of this drug. Gynecomastia - a side effect, less than 20% of men taking cyproterone. The literature rarely mentioned observations of fulminant hepatic toxicity.
Non-steroidal anti-androgens ("pure" antiandrogens)

Blocking androgen receptor antiandrogen leads to increased concentrations of LH and testosterone levels about 1.5 times due to the mechanism of positive feedback to the hypothalamus. The lack of decline in testosterone levels to avoid a number of side effects due gipogonadnzmom: loss of libido, poor health, osteoporosis.
Although a direct comparison of the three drugs used (bicalutamide, flutamide, nilutamide) monotherapy did not spend, they do not differ in the severity of the pharmacological side effects of gynecomastia, mastodynia, hot flashes. However bnkalutamil somewhat safe versus nilutamide and flutamide.
Gynecomastia, mastodynia, hot flashes due to peripheral aromatization is in excess of testosterone to zstradiola.
Toxicity to the gastrointestinal tract (mainly diarrhea) is more common in patients taking flutamil. Hepatotoxicity (from mild to fulminant forms) in varying degrees, all antiandrogens, in this regard, requires periodic monitoring of liver function.
Although the mechanism of action of the "pure" antiandrogens is not intended to reduce testosterone levels, long-term preservation of erectile function is possible only in every fifth patient.
Nilutamide. At the moment, there are no studies on the use of the drug as monotherapy for prostate cancer in comparison with other antiandrogens or castration.
Recent studies using nilutamide as a second-line treatment for patients with prostate cancer androgenrefrakternym showed a good response to therapy.
Nonpharmacologic nilutamide side effects include blurred vision (long-term adaptation to darkness after the bright light - about 25% of patients), and 1% of patients can be interstitial pneumonia (up to lung fibrosis), hepatotoxicity, nausea, sensitization to alcohol.
The half-life is 56 hours nilutamide elimination occurs with the participation of cytochrome P450 liver. Recommended dosage - 300 mg once a day for 1 month, then a maintenance dose of 150 mg once a day.
Flutamide - the first drug in the family of "pure" anti-androgens. Flutamide - prodrug. The half-life of the active metabolite, 2-gidroksiflutamida is 5-6 hours, it makes it necessary to 3x daily dosing (250 mg 3 times daily). Derivation 2 gidroksiflutamida perform kidney. Unlike steroidal anti-androgen, side effects due to fluid retention or thromboembolic complications are absent
The use of flutamide as monotherapy versus orchiectomy and maximal androgen blockade does not affect the life expectancy of patients with advanced forms of prostate cancer.
Pharmacological side effects - diarrhea, hepatotoxicity (rare - fulminant form).
Bicalutamide - nonsteroidal antiandrogen with a long half-life (6 days). Bicalutamide take 1 time a day, it had a large compliance.
Bicalutamide has the most active and best safety profile of the "pure" anti-androgens. On the pharmacokinetics of the drug did not affect age, renal and hepatic disease of mild to moderate severity.
In most patients, the level of testosterone in the blood remains constant. The use of bicalutamide 150 mg in patients with locally advanced or metastatic disease is comparable to the performance of operational or medical castration. However, he has a much better side from the position of sexual and physical activity. However, the incidence of gynecomastia (66.2%) and mastodynia (72.8%) in this group of patients is high.
The use of bicalutamide is not recommended for patients with limited forms of the disease, as it is associated with a decrease in life expectancy. Response to hormonal treatment
Following the appointment of drugs that cause androgen deprivation. effect to some extent evident in most patients. Given that the target for the hormonal treatment - androgenchuvstvitelnye prostate cells, incomplete or blurred effect indicates the presence of a population of androgen-refractory cells.

Side effects of hormone treatment of patients with cancer poostaty known for a long time (see Table 33-19). Some of them Kozin adversely affect the quality of life of patients, especially the young while others can significantly increase the risk of health problems associated with aging.

Side effects of hormone treatment

Castration

Side Effects

Treatment / Prevention

Decreased libido

No

Impotence

Phosphodiesterase-5, intracavernous injection therapy using local negative pressure

Hot flashes (55-80% of patients)

Cyproterone, clonidine. venlafaxine

Gynecomastia, mastodynia (50% of maximum androgen blockade, 10-20% of castration)

Prophylactic radiotherapy mammektomiya tamoxifen, aromatase angibitory

Weight gain

Exercise

Muscular weakness

Exercise

Anemia (severe in 13% of patients with maximal androgen blockade)

Erythropoietic drugs

Osteopenia

Exercise, calcium and vitamin D, bisphosphonate

No cognitive impairment

The pathology of the cardiovascular system (heart attack, heart failure, stroke, deep vein thrombosis, pulmonary embolism), Parenteral, anticoagulants

Antiandrogens

Steroid

Pharmacological side effects: loss of libido, impotence, gynecomastia rarely

Nonpharmacological

Nonsteroidal

Pharmacological side effects: mastodynia (40-72%), hot flushes (9-13%), gynecomastia (49-66%) Prophylactic radiotherapy mammektomiya tamoxifen, aromatase angibitory

Nonpharmacological

Osteoporosis

Likelihood of bone fractures in patients receiving hormonal treatment for prostate cancer, significantly higher than that in the population. Hormone therapy for 5 years increases the risk of fracture by 1.5 times over 15 years - more than 2 times.

Oeteoporoza diagnosis is to perform rentgenabsorbtsiometrii to determine bone mineral density of the femur, performed all the men who are planning to hormonal treatment.

Improve mineral density allow regular exercise, not smoking, the use of calcium and vitamin D. For the prevention of osteoporosis, use drugs from the group of bisphosphonates Bisphosphonates (preferably zoledronic acid) should be administered to all men with confirmed osteoporosis.

Hot flashes

Hot flashes subjective sensation of heat in the upper body and head. objectively followed by excessive sweating.

Presumably the reason for this complication toning adrenergic centers in the hypothalamus, abnormalities in the concentration of beta-endorphin, the effect of peptides, calcitonin gene-related, the thermoregulatory centers of the hypothalamus.

Treatment of hot flashes should be done only in patients who are not tolerant to this side effect of hormonal treatment.

Cyproterone (initial dose of 50 mg / day. Subsequently titrated to 300 mg / day) due to his actions progestagen greatly reduces the frequency of hot flashes.

The use of estrogen (diethylstilbestrol in the minimum dose or estradiol transdermal form) is most effective (90% efficiency). However pronounced mastodynia and thromboembolic complications due to use of estrogen generally limit their use.

Antidepressants (especially selective serotonin reuptake inhibitors, venlafaxine) reduce the frequency of hot flashes by 50%.

Sexual function

About 20% of patients receiving hormonal treatment, in some way preserve sexual function. Libido is being negatively influenced to a greater extent. Only about 5% of patients maintain a high level of sexual interest.

In appropriate patients, the effectiveness of oral phosphodiesterase type 5, intracavernous injections of alprostadil.

Gynecomastia

Gynecomastia is caused by an excess of estrogen in the body (estrogen therapy, peripheral transformation of androgens to estrogens in the treatment of antiandrogen medication) to 66% of patients receiving bicalutamide 150 mg. detect gynecomastia, including up to 72% reported pain in the breast.

For the prevention or elimination of painful gynecomastia explored the possibility of radiotherapy (10 Gy), which is ineffective if gynecomastia is emerging. For the treatment of this complication also use liposuction and mastectomy. To reduce the severity of mastodynia using tamoxifen.

Anemia

Normochromic, normocytic anemia is diagnosed in 90% of patients receiving hormone therapy for prostate cancer. Usually note a decline in hemoglobin of 10%. The hemoglobin concentration decreased after 1 month. the majority of men (87%) returned to baseline values ​​after 24 months because of compensatory mechanisms.

For the treatment of anemia, regardless of etiology, use of recombinant erythropoietin products. Anemia is reversible after discontinuation of hormone replacement therapy for a year.

Combined hormonal treatment

Minimal androgen blockade (peripheral androgen blockade)

Involves the simultaneous use of an inhibitor of 5-a-reductase inhibitors and non-steroidal anti-androgenic drug. The advantages of this treatment regimen - maintaining the quality of life and sexual function at an acceptable level

Before final results of clinical studies, the use of this regimen is not recommended.

Maximum androgen blockade

Given that after operational or medical castration in the blood to maintain certain low androgen levels allocated to the adrenal glands, the concept of maximal androgen blockade (the combination of castration and anti-androgens) is interesting.

However the clinical benefit of this treatment regimen is questionable in daily clinical practice.

Systematic reviews and meta-analyzes recently completed large-scale studies have shown that 5-year survival rate of patients on background maximal androgen blockade higher than that in patients treated with monotherapy (castration) of less than 5%.

The use of maximal androgen blockade in patients with advanced forms of prostate cancer associated with a high frequency and severity of side effects, and the significant increase in the cost of treatment.

Continuous or intermittent hormonal therapy

Some time after the start of treatment to androgen deprivation, the cancer cells in the prostate are androgenrefrakterny Status: no longer serves androgens trigger apoptosis of certain cell lines.

The concept of intermittent hormonal therapy is based on the assumption. the abolition of the hormone therapy further tumor growth is due to differentiation androgenchuvstvitelnoy cell line. thereby allowing the re-use of androgen withdrawal phenomenon. That's why to be delayed in time the transition of prostate cancer androgenrefrakterny.

In addition, intermittent hormone treatment allows for improved quality of life in the intervals between treatment cycles, and reduce treatment costs.

Equivalence of intermittent and continuous approaches to the treatment of patients with metastatic prostate cancer and recurrence after radical treatment confirmed by a number of clinical studies.

In one study, PSA nadir, reached after 9 months of hormonal induction treatment, served as an independent prognostic factor in the length of life. Decline in PSA levels after induction treatment cycle of less than 0.2 ng / ml, less than 4 ng / ml, more than 4 ng / ml corresponded to the average life expectancy of patients with advanced forms of prostate cancer 75 months, 44 months and 13 months, respectively.

Immediate or delayed hormonal therapy

At present there is no clear opinion concerning the start of hormonal treatment. Previously proposed modes include the possibility of therapy, directly after the failure of radical treatment, and after the appearance of clinical signs of metastasis.

This situation is the lack of possibility to extrapolate the results of clinical trials because of their limitations in practice.

During prostate cancer and the use of hormonal treatment characterizes a number of facts.

First, even in men, intact in the hormonal level, the progression of prostate cancer takes a long time. Studies show that after a recurrence of prostate cancer to metastatic disease is 8 years old. 5 years from the date of metastasis to the patient's death.

Secondly, 20% of men in the background of the hormonal treatment for prostate cancer cause of death will not be linked with the disease, while the remaining cause of death - cancer in the transition of hormone form. One prospective randomized study shows. that 10 years after the start of hormone therapy in a group of patients were still alive, only 7%. The average life expectancy after the start of hormone therapy is 4.4 years, after 8 years of living are about 4.5% of patients.

Third, hormonal therapy is not harmless. Without taking into account the side effects of treatment, men receiving hormone therapy for prostate cancer, age faster, which leads to an early death from causes related to age.

In this regard, needs-based approach to the choice of the start of hormonal therapy in patients with prostate cancer.

Currently, there is a definite position regarding the hormonal treatment for patients with localized prostate cancer. Life expectancy in this group of patients in terms of hormone replacement therapy significantly lower than that in the delayed treatment strategy. This is so. that the appointment of the hormonal treatment leads to rapid aging of the patients in whom the risk of death from prostate cancer, and so low.

In this situation, the appointment of hormonal treatment should be thoroughly discussed with the patient himself.

Prostate cancer with metastases to regional lymph nodes

Results of immediate and delayed treatment with hormonal therapy in patients with advanced disease pNl-Z (histological examination after RP) evaluated a group of researchers Grour Eastern Cooperative Oncology (ECOG) and the European Organization for Research and Treatment of bladder cancer.

The first study showed that after 7.1 years of follow deaths in patients with delayed treatment exceeded that in the group of patients with immediate hormonal therapy. Subsequent updates of this study showed that the average duration of life with immediate treatment is 13.9 years versus 11.3 years in patients with delayed treatment of the disease. Despite the high mortality rate from unrelated causes of prostate cancer (55 vs. 11% in the delayed treatment), immediate use of hormonal treatment has been unequivocal clinical benefit.

However a clear interpretation and the objectivity of the results of this study are limited due to the small group of patients studied (100 men), lack of correlation calculation of life expectancy and the degree of differentiation of tumor cells, the lack of patients treated with hormonal therapy.

Study performed by a group of the European Organization for Research and Treatment of bladder cancer (302 patients with advanced disease pN1-W. M0 without first treating the underlying source) showed that the average life expectancy of patients receiving hormonal treatment immediately after diagnosis was 7.8 years compared to 6.2 years in patients with delayed treatment.

Locally advanced and asymptomatic metastatic prostate cancer

In one study, Medical Research Council Prostate Cancer Working Party Investigators Group (934 patients), launched in 1997 (the results are evaluated in 2004) it was shown that, for this group of patients immediate appointment of hormonal treatment has a positive effect on both cancer- specific survival, and on the severity of symptoms associated with prostate cancer. However, on the background of long-term observation of patients, overall survival, depending on the time of the beginning of hormonal treatment was not significantly changed.

Findings

Hormone therapy should not be used in men with localized prostate cancer, as it does not lead to an increase in overall survival, only worsening the mortality due to other causes.

For patients with locally advanced, metastatic asymptomatic and symptomatic, but not prostate cancer using stalirovannym immediate hormonal treatment leads to a significant increase in cancer-specific life expectancy, without affecting overall survival.

In patients with prostate cancer with stage N + after RP, life expectancy is much higher with immediate hormonal treatment for patients without primary treatment increased life expectancy is not significant.

Up of patients with prostate cancer receiving hormone treatment

Patients were examined at 3 and 6 months after treatment. The minimum volume of the survey: PSA, digital rectal examination and careful assessment of symptoms, aimed at obtaining evidence of the effectiveness of treatment and its side effects.

Observation of the patient is carried out on an individual basis, taking into account symptoms, prognostic factors and treatment assignment.

Patients with stage M0 disease with a good response to treatment, examine (assessment of symptoms, digital rectal examination, PSA determination) every 6 months.

Patients with stage M1 disease with a good response to treatment, are examined (assessment of symptoms, digital rectal examination, determination of PSA, clinical blood count, creatinine, alkaline phosphatase) every 3-6 months.

In cases where there is evidence of disease progression or poor response to treatment, an individual approach to monitoring.

Routine use of instrumental methods of examination (ultrasound, MRI, CT scan, bone scan) with stable patients is not recommended.