Prostate Cancer: a New Life Urologist's Perspective

PROSTATE CANCER. EPIDEMIOLOGY

Prostate cancer (PCa) is considered today one of the most serious medical problems among the male population. In Europe, it is the most common solid cancer, with an incidence of 214 cases per 100,000 men, surpassing lung cancer and colorectal cancer. Moreover, prostate cancer currently ranks second among oncological diseases in terms of mortality in men. Furthermore, since 1985, there has been a slight increase in the number of deaths from PCa in most countries, including regions where it is not widespread.

Prostate cancer occurs more frequently in elderly men. Therefore, it represents a significant problem in developed countries, where the proportion of elderly men is higher. In developed countries, prostate cancer accounts for about 15% of cancer cases in men, whereas in developing countries it accounts for 4%.

It should be noted that the incidence of PCa varies significantly by region. For example, in Sweden, which is characterized by a high life expectancy and relatively low mortality from smoking-related diseases, prostate cancer is the most common malignant tumor in men, accounting for 37% of all new cancer cases in 2004.

The danger lies in the fact that the disease progresses almost unnoticed until the malignant tumor extends beyond the prostate and begins to spread to other organs (metastasize).

Cancer is an alarming word. Many men fear that the problems they experience with their prostate are caused by cancer. In most cases, this fear is unfounded; however, prostate cancer, like most other types of cancer, can remain asymptomatic for a long time or manifest with lower urinary tract symptoms, which are usually attributed to chronic prostatitis or prostate hyperplasia.

PROSTATE CANCER. ETIOLOGY (CAUSES OF DEVELOPMENT):

Not fully understood. The development of prostate cancer is associated with hormonal changes in elderly men, in particular with high levels of testosterone — the male sex hormone. Prostate cancer is a hormone-dependent tumor, meaning that tumor growth is stimulated by testosterone. Therefore, in men with higher blood testosterone levels, the occurrence of prostate cancer is more likely, and its course will be more malignant.

Risk factors in the development of prostate cancer:

The factors determining the risk of developing clinical PCa are not yet well studied, although some have already been identified. Three risk factors for PCa have been firmly established: age, ethnic background, and heredity.

AGE.

Most often, affected men are over 60-70 years old. According to autopsy data, in 30-40% of cases, cancer cells are detected in the prostate of patients aged 60, and by the age of 80, they are found in 60-70% of cases.

FAMILY HISTORY.

The presence of a genetic component is confirmed by observations showing that the hereditary form of the disease is found in approximately 10% of all men suffering from prostate cancer. In men whose close relatives have prostate cancer, this disease develops twice as often as in men with no relatives affected by it.

Why prostate cancer is so widespread is unknown. In most cases, there is no obvious family history, but there is a form of the disease that runs in families. Do not worry if a relative of yours has prostate disease. However, if you have two close relatives with prostate cancer, especially if the disease occurred in them at a young age, you should start screening after the age of 40 and undergo periodic planned examinations.

There are differences in susceptibility to prostate cancer among races and in different parts of the world, which may result from differences in diet and environmental exposures. For example, prostate cancer is rare in Japan, but among Japanese living in America, the risk of developing this disease is high. This is due to differences in diet. Certain types of fatty foods may predispose a person to prostate cancer, while other foods, such as those containing soy, are protective. It is still too early to give definitive advice, but as we better understand the significance of these differences, we will be able to provide recommendations on foods that reduce the risk of developing prostate cancer.

SYMPTOMS OF PROSTATE CANCER:

Prostate cancer is characterized by a slow and malignant course. This means that the tumor grows slowly (compared, for example, with liver cancer), and it may remain asymptomatic for many years. On the other hand, prostate cancer can produce early metastases, meaning that even a small tumor can start spreading to other organs. Most commonly, the spread occurs to the bones (pelvis, hips, spine), lungs, liver, and adrenal glands. This is the greatest danger of the cancer.

Before metastases appear, the tumor can be removed, which will stop the disease. But if metastases have appeared, no surgeon can remove them all, and a complete cure becomes impossible. This is the greatest problem of cancer — the disease begins to trouble a person only when it has already progressed significantly and the chances of recovery are greatly reduced. Prostate cancer may manifest as increased urination, pain in the perineum, blood in the urine and semen. However, it may not present any of these symptoms.

Then the first manifestation of the disease will be metastases of the cancerous tumor. These can be bone pains (in the pelvis, hips, spine), chest pain. Increased urinary urgency, especially at night, difficulty starting urination, blood in the urine, and pain may be noted. In advanced cases, acute urinary retention may develop, as well as symptoms of cancer intoxication — rapid weight loss, weakness, pale skin with an ashen hue.

FOUR STAGES OF PROSTATE CANCER ARE DISTINGUISHED:

Stage I: in DRE the tumor is not detected and is not visualized on ultrasound. The tumor is found incidentally during prostate surgery and does not extend beyond the prostate. No regional or distant metastases are detected (T1,N0,M0, Gleason ≤ 6, PSA level < 10); or the tumor is detected during DRE or TRUS in one lobe or on one side (right or left) of the prostate. The cancer is confined to the prostate, with no metastases (T2a,N0,M0, Gleason ≤ 6, PSA level < 10).

Stage II: Stage 2A prostate cancer — the tumor is not detectable on palpation and is not visible on ultrasound, cancer is found incidentally during surgery or biopsy due to elevated PSA levels. The cancer has not spread to nearby lymph nodes or other organs (T1,N0,M0, Gleason 7, PSA level < 20); or the same indicators T1,N0,M0, Gleason ≤ 6, PSA level from 10 to 20; or the cancer can be palpated and detected on TRUS, the tumor is only in one lobe of the prostate, and cancer is not found elsewhere (T2a or T2b,N0,M0, Gleason ≤ 7, PSA < 20).

Stage 2B prostate cancer — the tumor is palpable and visualized on ultrasound, spreading to both sides of the prostate. No metastases are present (T2c,N0,M0, any Gleason score and any PSA); or the cancer is confined to the prostate, is palpable, and may be visualized on TRUS. No cancer is detected in regional lymph nodes or distant organs and systems (T1 or T2,N0,M0, any Gleason score, PSA ≥ 20); the same as the previous T1 or T2,N0,M0, only Gleason ≥ 8, PSA level any.

Stage III — the cancerous tumor has begun to spread beyond the prostate and may also involve the seminal vesicles, but has not penetrated the nearby lymph nodes or other parts of the body (T3,N0,M0, any Gleason score, any PSA level).

Stage IV – the cancerous tumor has spread to nearby organs and tissues (bladder, rectum, urethral sphincter, and/or pelvic walls), excluding the seminal vesicles. Cancer has not invaded nearby lymph nodes, and there are no distant metastases (T4,N0,M0, any Gleason score, PSA level any); or the tumor may be confined to the prostate, may spread to nearby organs and tissues, with cancer cells metastasizing to regional lymph nodes, but not to other organs (any T,N1,M0, any Gleason score, PSA level any); or distant metastases are present (any T, any N, M1, any Gleason score, any PSA level).

SCREENING AND EARLY DIAGNOSIS OF PROSTATE CANCER

Population or mass screening refers to examining men in the risk group without symptoms of the disease. In contrast, early diagnosis, or opportunistic examination, is conducted in individual clinical cases and is initiated by the person undergoing the examination (the patient) and/or their attending physician. Both types of examinations pursue two main goals:

• 1. Reduction of mortality from prostate cancer.
• 2. Improvement of quality of life, which is of great importance.

It is recommended to perform the initial determination of prostate-specific antigen (PSA) levels at the age of 40, based on which the frequency of examinations can be established. For men with an initial PSA level ≤1 ng/ml, an 8-year interval between examinations appears sufficient. Men over 75 years old with an initial PSA level ≤ 3 ng/ml do not need further PSA testing, as the risk of death from prostate cancer in this group is very low.

DIAGNOSTICS.

The main methods for diagnosing PCa include digital rectal examination (DRE), PSA determination, and transrectal ultrasound (TRUS). A definitive diagnosis is made upon detection of adenocarcinoma (malignant tumor of the prostate) in biopsy or postoperative material. Pathomorphological studies also allow tumor staging and determination of its extent.

DIGITAL RECTAL EXAMINATION (DRE)

Most prostate neoplasms (PN) are located in the peripheral zone of the prostate and can be detected by DRE if their volume reaches 0.2 cm3 or more. Detection of a nodule or area of induration via DRE is an absolute indication for performing a prostate biopsy. In approximately 18% of all patients, prostate cancer is detected solely through DRE, regardless of PSA level. Detection of a tumor by DRE in patients with PSA levels < 2 ng/ml has a positive predictive value in 5–30% of cases.

PROSTATE-SPECIFIC ANTIGEN (PSA)

The diagnosis of PCa has been radically improved with the introduction of PSA testing. PSA is a kallikrein-like serine protease in blood serum, predominantly produced by prostate epithelial cells. For practical purposes, it can be considered organ-specific, but it is not considered cancer-specific. Therefore, its level may be elevated in benign prostatic hyperplasia (BPH), prostatitis, and other non-malignant conditions.

The PSA level as an independent indicator serves as a more reliable prognostic factor for cancer than detecting abnormalities via DRE and TRUS. There are many commercial diagnostic systems for measuring PSA levels, but there are no unified international standards for this indicator. PSA is considered a “continuous” parameter, meaning that the higher its value, the greater the likelihood of prostate cancer. This implies that there is no universally accepted threshold or borderline value for this indicator. The commonly accepted normal PSA level is from 0 to 4 ng/ml.

The total PSA level tends to increase with age.
Therefore, the upper limit of normal differs for various age groups:
40 — 49 years — 2.5 ng/ml
50 — 59 years — 3.5 ng/ml
60 — 69 years — 4.5 ng/ml
70 — 79 years — 6.5 ng/ml

Results from a recent prostate cancer prevention study conducted in the USA confirmed that many men may have prostate cancer despite having a low blood PSA level.
The table shows the relationship between the detection rate of prostate cancer and PSA levels in men with normal PSA in the placebo group.

TABLE. RISK OF PROSTATE CANCER WITH LOW PSA LEVEL

So far, no long-term results have been obtained that would allow determination of the optimal PSA threshold for detecting non-palpable but clinically significant prostate cancer. According to various authors, the probability of developing PCa within 7 years is: for PSA 3–6 ng/ml — 34%; 6–10 ng/ml — 44%; > 10 ng/ml — 71%.
Transient PSA elevation lasting about 10 days may occur after a recent digital rectal exam or prostate massage, after ejaculation, during rectal ultrasound, and in patients with constipation.

Some modifications of PSA values have been proposed to improve the specificity of this indicator for early diagnosis of PCa, namely: PSA density, transition zone PSA density, age-adjusted norms, and molecular forms of PSA. However, these derivatives and some PSA isoforms (cPSA, proPSA, BPSA, iPSA) are of limited clinical value.

RATIO OF FREE TO TOTAL PSA (F/T PSA)

The F/T PSA ratio is the most studied and widely used clinical criterion for differentiating benign prostatic hyperplasia (BPH) from PCa. This indicator allows identification of risk categories for prostate cancer in men with total PSA levels from 4 to 10 ng/ml and a negative DRE result. Prostate cancer is detected on biopsy in 56% of men with F/T PSA < 0.1 and in only 8% of men with F/T PSA > 0.25. F/T PSA has no clinical significance when total PSA > 10 ng/ml and in patients with previously diagnosed PCa.

PSA VELOCITY, PSA DOUBLING TIME

There are two ways to measure changes in PSA levels over time:

— PSA velocity, defined as the absolute annual increase in PSA (ng/ml/year);
— PSA doubling time, which represents the exponential increase in PSA over time, reflecting relative changes.

These two criteria may have prognostic value in patients who have undergone treatment for prostate cancer.

PSA-3 MARKER

Unlike the serum markers described above, PSA-3 — a prostate-specific non-coding mRNA — is measured in urine sediment obtained after prostate massage. The advantage of assessing PSA-3 over PSA lies in its slightly higher sensitivity and specificity. PSA-3 levels reflect small but significant increases in the likelihood of a positive biopsy, yet are not dependent on prostate volume or prostatitis.

Information on whether PSA-3 levels are associated with tumor aggressiveness is conflicting. Although this marker potentially has prognostic value for detecting PCa in men with elevated PSA whose initial biopsy was negative, the PSA-3 determination method remains experimental. In the near future, several molecular diagnostic tests may be used not only in laboratories but also in clinical practice, for example, to detect TMPRSS2-ERG gene fusion, specific to PCa, in urine sediment after prostate massage.

TRANSRECTAL ULTRASOUND (TRUS)

During sonography with a rectal probe, 75% of prostate cancers are visualized in the peripheral zone. The typical appearance of prostate cancer is a hypoechoic nodule with unclear, irregular contours; however, the nodule may also be isoechoic or hyperechoic, and in some cases, the tumor is not visualized at all. TRUS in grayscale mode does not allow prostate cancer to be determined with sufficient reliability. Therefore, targeted biopsy of suspicious areas under TRUS guidance is not an effective substitute for multifocal biopsy. However, additional biopsy of suspicious zones under TRUS guidance may be useful.

PROSTATE ELASTOGRAPHY IN DETECTING PROSTATE CANCER

The sensitivity and specificity of elastography visualization require further study alongside the modern standard method of multifocal prostate biopsies under ultrasound guidance. Current experience allows for some conclusions:

1. A negative result on prostate elastography is not an indication to cancel a prostate biopsy.
2. It is unlikely that specificity will be high enough to make an absolute diagnosis. Biopsies will still be necessary to confirm diagnostic results and determine the Gleason grade.

Elastography can be used in the following cases:

• 3.1. In patients with elevated serum PSA and negative results from multiple biopsies. In such cases, there is a possibility that the tumor was not detected because of its unusual location (e.g., in the anterior part of the gland). As an alternative to a 20-core biopsy (which is quite traumatic), elastography may be used to locate the tumor. If the tumor is detected, a biopsy can be performed with far fewer punctures under local anesthesia.
• 3.2. If a prostate tumor is visualized on elastography and conventional sonography, the number of biopsy cores can potentially be reduced.
• 3.3. Combining multifocal prostate biopsy with additional cores from affected areas identified by elastography may increase the number of positive results.
• 3.4. Elastography may allow assessment of tumor size and the likelihood of spread beyond the prostate, since grayscale ultrasound images are not suitable for this purpose.
• 3.5. The most aggressive tumors may produce distinct elastography images compared to less aggressive tumors, which is important information for evaluating treatment options.

Grayscale TRUS of the prostate (Fig. 3.1a) revealed no pathological nodules. Elastography showed loss of elasticity in the left peripheral zone lateral to the mid-gland and normal elasticity at the base (Fig. 3.2b). Biopsy revealed a Gleason score 6 tumor in the area of reduced elasticity.

Figures 3.1c and 3.1d show elasticity measurements of the abnormal area and the corresponding area on the normal side. The difference between the graphs is evident.

PROSTATE BIOPSY

Primary biopsy

Indications for performing a prostate biopsy include PSA level and/or changes detected by DRE. Age, comorbidities, and potential complications should also be considered when performing a biopsy.

Currently, performing a TRUS-guided prostate biopsy is the standard diagnostic method. Transperineal TRUS-guided biopsy is a useful alternative in special cases, such as after rectal resection.

REPEAT BIOPSY

Indications for repeat biopsy:

• rising or persistently high PSA levels, changes detected by DRE
• atypical small acinar proliferation

The optimal timing for a repeat biopsy is not established. It is determined based on the results of the primary biopsy’s histopathology, taking into account the risk of detecting prostate cancer (high or rapidly rising PSA, DRE findings, family history). The later the repeat biopsy is performed, the higher the detection rate of prostate cancer.

If clinical suspicion of prostate cancer persists despite negative biopsy results, MRI can be performed to detect prostate cancer in the anterior gland, followed by biopsy of suspicious zones under TRUS or MRI guidance.

BIOPSY ZONES AND NUMBER OF CORES

During the primary biopsy, tissue should be sampled from the peripheral zones of the prostate as laterally and posteriorly as possible. Additional cores should be taken from zones with changes detected by DRE/TRUS, determined individually in each case.

Sextant biopsy is no longer considered effective. For a prostate volume of 30–40 cm3, biopsy should be performed from at least 8 points. Increasing the number of points beyond 12 does not significantly improve accuracy. Based on the results of the British study on the diagnosis and treatment of prostate cancer, a 10-core biopsy is recommended.

DIAGNOSTIC TRANSURETHRAL RESECTION OF THE PROSTATE (TURP)

Performing a diagnostic TURP instead of repeat biopsies is not advisable. The detection rate of prostate cancer with this method does not exceed 8%, indicating its ineffectiveness for cancer diagnosis.

Seminal vesicle biopsy.

Clear indications for seminal vesicle biopsy have not yet been established. It is not recommended as a first-line examination method, but it is appropriate for patients at high risk of seminal vesicle invasion, where a positive biopsy result would help change the treatment strategy. At PSA levels >15–20 ng/mL, biopsy is indicated only if the results will influence treatment, i.e., if radical prostatectomy will not be performed when invasion of the seminal vesicles is detected. At PSA levels >15–20 ng/mL, the probability of invasion into the seminal vesicles is 20–25%. For more accurate preoperative diagnosis, seminal vesicle biopsy can be used.

TRANSITION ZONE BIOPSY

Primary biopsy sampling from the transition zone has a very low detection rate of prostate cancer; however, our clinical experience shows that in 10% of cases, tumor cells are localized in the transition zone. Therefore, tissue sampling from the transition zone should always be performed during primary biopsy.

Antibiotics.

The use of oral or intravenous antibiotics is considered the most modern treatment method. Optimal dosage and duration are determined individually. Quinolones are preferred, with ciprofloxacin being more effective than ofloxacin.

Complications.

The frequency of complications after biopsy is low (see table). Minor complications include macroscopic hematuria and hematospermia. Severe infection after biopsy occurs in less than 1% of cases. The recent increase in the number of biopsy cores has not led to a rise in serious complications requiring treatment. Low-dose aspirin is no longer considered an absolute contraindication for biopsy.

TABLE 5. PERCENTAGE OF BIOPSY COMPLICATIONS REGARDLESS OF THE NUMBER OF CORES*

*Compiled based on the Consensus Guidelines of the National Comprehensive Cancer Network (NCCN), 1st edition, 2007.

HISTOPATHOLOGICAL EXAMINATION OF PROSTATE BIOPSY SPECIMENS

Prostate cancer diagnosis is based on histopathological examination. Immunohistochemistry (IHC) may also be effective.
Biopsy reports should be written using clear, precise terminology, avoiding terms such as “atypia,” “atypical glands,” and “possible malignancy.”
Diagnostic terms used in prostate biopsy reports:
• Benign lesion/absence of cancer. Include a description if necessary (e.g., atrophy). Chronic inflammation may also be noted (optional)
• Acute inflammation, negative for malignancy
• Atypical adenomatous hyperplasia/adenosis, malignancy not detected
• Granulomatous inflammation, negative for malignancy
• High-grade prostatic intraepithelial neoplasia (PIN), negative for adenocarcinoma
• High-grade PIN with atypical glands, suspicious for adenocarcinoma
• Focus of atypical glands/nodule suspicious for adenocarcinoma
• Adenocarcinoma
* From: van der Kwast, 2003 [36].

For each biopsy location, indicate the percentage of cores positive for carcinoma and the Gleason score based on the 2005 system.

Radioisotope study, commonly referred to as radionuclide bone scanning, is performed to detect tumor spread to bone tissue.

Before the study, a small amount of radioisotope is administered. Areas of bone involvement show increased radioisotope uptake, detected by a special scanner. This study is not a specific test for detecting cancer. Uptake may occur due to other conditions such as arthritis, old fracture sites, or benign bone disease. Further radiographic examination of pathologically altered bone areas may be helpful. Occasionally, an orthopedic surgeon may take a bone tissue sample from areas with abnormal radioisotope uptake for microscopic examination to identify the cause of the pathological changes.

TREATMENT OF PROSTATE CANCER:

Until recently, surgical treatment was the only method used to remove most malignant tumors. In cases of tumor spread (metastasis), no effective treatment existed. Nowadays, many treatment options are available to destroy or suppress the growth of cancer that metastasizes to other organs. Prostate cancer has become one of the first types of cancer for which such treatments have been developed.
At the same time, choosing a treatment method for prostate cancer, even for clinically localized tumors, has become more complex because different methods have similar oncological outcomes but differ significantly in terms of complications.

Since the tumor often does not behave aggressively, some patients are informed that urgent treatment is not necessary. This approach is called “watchful waiting” or “active surveillance.” This does not mean that the tumor is ignored. The key is regular monitoring — with appropriate tests and examinations to confirm that the tumor is not growing. The rationale for this approach is that prostate cancer generally progresses slowly and is diagnosed in older men with a high risk of death from comorbidities. It can be chosen for patients with localized prostate cancer and limited life expectancy or elderly patients with less aggressive tumors. The growth of the tumor cannot be predicted with absolute certainty, but its assessment can be guided by the histological structure of the tumor (from biopsy material) examined under a microscope. Sometimes studies show that the tumor grows so slowly that the patient can be temporarily released from clinic visits, although maintaining contact with their primary physician is advised. Because early-stage prostate cancer is unlikely to progress rapidly, some urologists recommend monitoring for several months with PSA measurements (to track its rate of increase) to avoid missing the stage at which treatment becomes necessary.

SURGICAL TREATMENT.

Surgical methods are used only when the tumor is confined within the prostate capsule and there are no metastases. In this case, radical prostate removal is performed. If the surgery is successful, it practically guarantees complete cure of prostate cancer without significant health consequences. Surgical treatment of prostate cancer involves radical prostatectomy (RPE), in which the prostate is removed as a single block from the urethra to the bladder, along with the seminal vesicles and periprostatic tissue. This procedure is often accompanied by bilateral pelvic lymphadenectomy (PLND). For men with localized prostate cancer and an expected life expectancy of ≥ 10 years, the goal of RPE — regardless of the surgical approach — is to remove the tumor while preserving urinary continence and, if possible, erectile function. There are no strict age limitations for RPE, and a patient should not be denied surgery based solely on age. However, a greater number of comorbidities significantly increases the risk of death from causes unrelated to prostate cancer.

RADICAL RADIATION THERAPY (RT)

Radiation therapy involves exposing the prostate area to radioactive radiation. This reduces tumor growth, lowers the risk of metastasis, and improves the patient’s condition, relieving symptoms and prolonging life. Radiation therapy can also be used in patients wishing to preserve sexual function. According to the US National Institutes of Health (established in 1988), RT provides a similar life expectancy to surgical treatment; in addition, quality of life after RT is at least not worse than after RPE. Three-dimensional conformal radiation therapy (3D-CRT) is considered the “gold standard” treatment, but at the beginning of the 21st century, intensity-modulated radiation therapy (IMRT), an advanced form of 3D-CRT, gradually gained ground in high-tech centers.

TECHNICAL ASPECTS: 3D-CRT AND IMRT

Anatomical information obtained during patient scanning in the treatment position is fed into 3D planning software, which allows visualization of the clinical target volume and the addition of a safety margin around it. Real-time field control using radiation imaging enables comparison of the treated and planned fields and correction of deviations if they exceed 5 mm. 3D-CRT improves the effectiveness of local treatment by allowing dose escalation without increasing the risk of complications.

Sometimes short-term hormone therapy is used to reduce prostate size before radical prostatectomy or radiation therapy. Hormone therapy is thought to increase the effectiveness of the main treatment and is therefore more often administered prior to radiation therapy. During hormone therapy, which usually lasts for three months or slightly longer, side effects may occur, but these disappear once hormone and radiation therapy courses are completed. In some cases (when the prostate tumor is very large), a combination of radiation and hormone therapy is recommended, continuing until the end of radiation therapy.

Both radical prostatectomy and radiation therapy are the main treatment methods with potential serious side effects. It is important to understand that these two methods do not differ significantly in terms of risk, discomfort, or recovery time. Given the roughly equal effectiveness of different treatment options, patients with prostate cancer should be informed about alternative treatment methods.

Transperineal brachytherapy (contact radiation) is a safe and effective treatment method, usually requiring no more than 2 days of hospitalization. Low-dose brachytherapy is best suited for patients with low-risk prostate cancer. The 5- and 10-year recurrence-free survival rates range from 71% to 93% and 65% to 85%, respectively.

Alongside radical prostatectomy, external beam radiation therapy (EBRT), and/or brachytherapy, alternative treatments for clinically localized prostate cancer are also being developed, such as cryosurgical ablation and high-intensity focused ultrasound (HIFU) therapy. Cryoablation is recognized as an alternative treatment method according to the American Urological Association guidelines. Both methods were developed as minimally invasive treatments that potentially offer the same effectiveness as established surgical and non-surgical methods, but with fewer complications.

CRYOABLATION OF THE PROSTATE

This method is based on freezing, which induces cell death through:

• dehydration leading to protein denaturation
• direct rupture of cell membranes by ice crystals
• vascular stasis and microthrombosis, causing microcirculation disruption and ischemia
• apoptosis

To freeze the prostate, 12–15 cryoprobes of 17G size are inserted under TRUS guidance, thermosensors are placed near the external sphincter and bladder neck, and a urethral warmer is used. Under TRUS control, two freeze-thaw cycles are performed, reducing the temperature in the prostate and at the bladder neck to −40 °C.

HIFU THERAPY FOR PROSTATE CANCER

High-intensity focused ultrasound (HIFU) uses focused ultrasound waves emitted by a transducer, which cause tissue damage through mechanical, thermal, and cavitation effects. The goal of HIFU therapy is to raise the tumor tissue temperature above 65 °C, causing destruction via coagulative necrosis. The predicted 5-year biochemical recurrence-free survival rate (BCRFS) is 66%.

Hormonal therapy

In 1941, Huggins and Hodges demonstrated the effectiveness of surgical castration and estrogen therapy in metastatic prostate cancer progression. They were the first to establish prostate cancer sensitivity to androgen deprivation. Following these initial studies, androgen suppression strategies became the mainstay of treatment for advanced prostate cancer.

Principles of hormonal control of the prostate

Prostate cells physiologically depend on androgens, which stimulate their growth, function, and proliferation. Testosterone, although not considered carcinogenic, plays a significant role in regulating the growth and development of tumor cells. The testes produce most of the androgens in men, with only 5–10% synthesized by the adrenal glands (androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate).

Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis. Hypothalamic luteinizing hormone-releasing factor (LHRF) stimulates the anterior pituitary to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates Leydig cells in the testes to synthesize testosterone. In prostate cells, testosterone is converted by 5-α-reductase into 5-α-dihydrotestosterone (DHT), which is ten times more potent than testosterone. In peripheral cells, circulating testosterone is aromatized into estrogens, which, along with circulating androgens, exert negative feedback on hypothalamic LHRF secretion.

Lack of androgen stimulation of prostate cells leads to apoptosis (programmed cell death). Any treatment that suppresses androgen activity is considered androgen deprivation therapy.

Drug classes used in hormonal treatment of prostate cancer:

Estrogens

Estrogens have several mechanisms of action:

• reducing LHRF secretion via negative feedback
• inactivating androgens
• direct suppression of Leydig cell function
• direct cytotoxic effect on prostate epithelial cells (only observed in in vitro studies)

THERE ARE 3 MAIN REASONS FOR THE RENEWED INTEREST IN USING ESTROGENS FOR PROSTATE CANCER TREATMENT.

1. LHRH analogs cause a large number of severe side effects, and their long-term widespread use is costly, whereas estrogens lower testosterone levels without reducing bone mineral density (BMD) or impairing cognitive function (level of evidence 3).
2. In phase II studies, in which patients with hormone-refractory prostate cancer (HRPC) received estrogen preparations (DES, DES-diphosphonate), the PSA reduction rate was 86%.
3. Recently, a new estrogen receptor-β (ER-β) was discovered, which is believed to play an important role in prostate cancer oncogenesis.

LHRH ANALOGS

For more than 15 years, long-acting LHRH analogs (buserelin, goserelin, leuprorelin, and triptorelin) have been used in advanced prostate cancer, and today they represent the main form of hormonal therapy. These drugs are synthetic analogs of LHRH, mainly administered as depot injections every 1, 2, 3, or 6 months. Initially, they stimulate LHRH receptors, causing a transient increase in LH and FSH release. This in turn triggers increased testosterone production (“testosterone surge” or “flare effect”), which begins 2–3 days after the first injection and lasts for about the first week of therapy.

LHRH Antagonists

In contrast to LHRH analogs, antagonists competitively bind to LHRH receptors in the pituitary gland. As a result, LH, FSH, and testosterone levels rapidly decline without inducing a “flare.” Given this more favorable mechanism of action, LHRH antagonist therapy was considered highly promising. However, for practical reasons, clinical trials have been limited. Many LHRH antagonists also caused severe histamine-mediated allergic reactions, and until recently, depot formulations of these drugs were not available.

ANTIANDROGENS

Antiandrogens competitively inhibit testosterone and DHT receptors in the nuclei of prostate cells, leading to apoptosis and inhibition of prostate cancer growth. These oral drugs are classified by chemical structure as steroidal (e.g., cyproterone acetate (CPA), megestrol acetate, and medroxyprogesterone acetate) and non-steroidal or “pure” (nilutamide, flutamide, and bicalutamide). Both classes competitively bind to androgen receptors. This is the only mechanism of action of non-steroidal antiandrogens, while steroidal antiandrogens also have progestogenic properties through central inhibition of pituitary function. As a result, non-steroidal antiandrogens do not lower testosterone levels, which remain normal or slightly elevated.

STEROIDAL ANTIANDROGENS

These drugs have progestogenic properties and reduce gonadotropin (LH and FSH) secretion, as well as suppress adrenal cortex activity. At high doses, they exert cytotoxic effects. Because steroidal antiandrogens lower testosterone levels, their main pharmacological side effects include loss of libido and erectile dysfunction, while gynecomastia is relatively rare. Non-pharmacological side effects include cardiovascular complications (4–40% for CPA) and hepatotoxicity.

NON-STEROIDAL ANTIANDROGENS

Due to better quality of life and compliance compared to castration, the use of non-steroidal antiandrogens as monotherapy is increasing. They do not suppress testosterone secretion, so libido, overall physical well-being, and bone mineral density (BMD) are preserved during therapy. All drugs, however, exert hepatotoxic effects, and regular monitoring of liver enzyme levels is required.

Unfortunately, all hormonal drugs have a number of unpleasant side effects — hypertension, reduced potency, gynecomastia, among others. If you are prescribed hormonal therapy, be sure to consult your physician about what to do if such effects occur. Treatment is long-term, often lasting many months. The use of these hormones increases survival but, at high doses and with prolonged administration, also leads to a higher incidence of cardiovascular complications (stroke, myocardial infarction, thromboembolism, circulatory failure).

SUBCAPSULAR BILATERAL ORCHIECTOMY

This procedure involves incising the tunica albuginea of each testis and removing the active tissue from the inside, after which the testes no longer produce testosterone. In some cases, complete removal of the testis may be recommended. Orchiectomy is a relatively simple procedure, but it requires hospitalization and usually general anesthesia. Postoperative pain lasts for several days. Minor complications such as trauma, swelling, or wound infection may occur. The effects of the procedure are immediate, and sometimes disease symptoms regress within days following surgery.

TREATMENT CHOICE

The therapeutic impact of different treatment methods on the tumor is equivalent. The choice between them is made based on their potential side effects. If one type of treatment does not suit the patient, it can be replaced by another. In choosing between surgery and radiation therapy for early prostate cancer, the patient’s opinion may be considered; therefore, it is useful to provide more information about treatment options in this case.

Patient options include:

— Radical prostatectomy — a surgery that leads to a cure, eliminating the need for further treatment;
— a course of radiation therapy;
— injections once a month or once every three months;
— oral medications.

PROSTATE CANCER PREVENTION

Although anticancer therapies are becoming increasingly advanced, the ability to prevent cancer would be the best alternative. The best example of cancer prevention is smoking cessation, which reduces the risk of lung cancer. It is possible that preventive measures for prostate cancer will also be identified in the near future. The Japanese are less prone to prostate cancer than people in Western countries, but if they move from Japan to the United States, their risk of developing the disease increases. This is believed to be related to diet. A diet high in animal fats may increase the risk of prostate cancer, whereas certain vitamins and trace elements may have protective effects. More importantly, soy products in Japanese cuisine may act similarly to mild female sex hormones (phytoestrogens).

Finasteride is a drug commonly used to treat benign prostatic hyperplasia. It reduces the action of male sex hormones within the prostate and thereby influences cancer development. Recently, results were published from a study in which 18,000 men received either finasteride or placebo for seven years. In the finasteride group, the number of men who developed prostate cancer was one quarter lower compared to the control group. However, early tumors were detected on prostate biopsies, and it remains unclear to what extent the drug would reduce the number of men who will eventually develop symptoms or die from prostate cancer. It was noted that although the overall number of prostate cancers was reduced, the incidence of so-called high-grade tumors, which are the most dangerous, was somewhat higher in those taking finasteride.
The significance of these findings remains uncertain, and it is too early to recommend finasteride as preventive therapy. Studies are currently ongoing with other active substances that may help prevent the development of prostate cancer.

In all doubtful cases, patients undergo ultrasound examination of the prostate and seminal vesicles (TRUS) using expert-class equipment. If a tumor is suspected, the urologist performs transrectal multifocal automated prostate biopsy under sonographic guidance. Thanks to extensive clinical experience (over 5,000 biopsies performed), the procedure is carried out on an outpatient basis, painlessly and with high quality.

In economically developed countries, public awareness of prostate cancer is at a high level, and most men independently visit a doctor to check their PSA levels. The American and European Urological Associations recommend that all men over 50 undergo annual digital rectal examination, have a blood test for PSA, and consult a urologist regarding the results.