EPIDEMIOLOGY
Prostate cancer (PCa) is considered one of the most serious medical problems among the male population today. In Europe, it is the most common solid cancer, with an incidence of 214 cases per 100 thousand men, ahead of lung and colorectal cancer. In addition, prostate cancer currently ranks 2nd among cancer diseases in terms of mortality in men. Moreover, since 1985 there has been a slight increase in deaths from prostate cancer in most countries, including regions where it is not common.
PCa is more common in older men. Because of this, it is a greater problem in developed countries, where the percentage of older men is higher. Thus, in developed countries, prostate cancer accounts for about 15% of cancer cases in men, while in developing countries it is 4%.
It should be noted that the incidence of prostate cancer varies significantly depending on the region. For example, in Sweden, which has 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 proceeds almost unnoticed until the malignant tumor extends beyond the prostate gland and begins to spread to other organs (metastasize).
Cancer is an alarming word. Many men fear that their prostate problems are caused by cancer. In most cases, this is an unfounded fear, however, prostate cancer, like most other types of cancer, can be asymptomatic for a long time or manifest itself with lower urinary tract symptoms, which are usually associated with chronic prostatitis or prostatic hyperplasia.
ETIOLOGY (REASONS FOR DEVELOPMENT) OF THE DISEASE:
Not fully understood. The development of prostate cancer is associated with hormonal changes in older men, in particular with high levels of testosterone, the male sex hormone. Prostate cancer is a hormone-dependent tumor, that is, tumor growth is stimulated by testosterone. Therefore, in men who have higher levels of testosterone in the blood, prostate cancer is more likely to occur and its course will be more malignant.
Risk factors in the development of prostate cancer:
Factors that determine the risk of developing clinical prostate cancer have not yet been sufficiently studied, but some of them have already been identified. There are 3 well-established risk factors for prostate cancer: age, ethnicity and heredity.
AGE.
Most often, the age of sick men is over 60-70 years. According to autopsy data, in 30-40% of cases, cancer cells in the prostate gland are found in patients aged 60 years, and by the age of 80 they are found in 60-70% of cases.
FAMILY HISTORY.
The presence of a genetic component is supported by the observation that the hereditary form of the disease is detected in approximately 10% of all men with prostate cancer. Men whose closest relatives suffer from prostate cancer develop this disease 2 times more often than men who do not have relatives with this disease.
Why prostate cancer is so common is not known. In most cases there is no clear family history, but there is a form of the disease that runs in families. Don’t worry if you have a relative with prostate disease. However, if you have two close relatives with prostate cancer, especially if they developed the disease at a young age, you should be examined yourself after 40 years of age and periodically carry out routine examinations.
There are differences in prostate cancer susceptibility between races and in different parts of the world, and this may be a consequence of differences in diet and environmental factors. For example, prostate cancer is low in Japan, but Japanese people living in America are at high risk of developing the disease. This is a result of differences in nutrition. Certain types of fatty foods may predispose a person to prostate cancer, while other foods, such as those containing soy, are protective. It is too early to give definitive advice, but as we understand the significance of these differences, we will be able to make recommendations about foods that will reduce the risk of developing prostate cancer.
SYMPTOMS OF PROSTATE CANCER:
Prostate cancer has a slow and malignant course. This means that the tumor grows slowly (compared to, say, liver cancer) and may not appear for many years. On the other hand, prostate cancer gives early metastases, that is, a small tumor can already begin to spread to other organs. Most often, the spread goes to the bones (pelvis, hips, spine), lungs, liver, adrenal glands. This is the biggest danger of cancer.
Before metastases appear, the tumor can be removed, and this will stop the disease. But if metastases appear, no surgeon can remove them all, and it will no longer be possible to completely cure the person. This is precisely the biggest problem with cancer – the disease begins to bother a person only when it has already gone very far and the chances of a cure have significantly decreased. Prostate cancer can manifest itself as increased frequency of urination, pain in the perineum, and blood in the urine and semen. But you may not experience any of these symptoms.
Then the first manifestation of the disease will be metastases of the cancerous tumor. This may be pain in the bones (pelvis, hips, spine), pain in the chest. There is an increased urge to urinate, especially at night, difficulty starting urination, blood in the urine, and pain. In advanced cases, acute urinary retention may develop, as well as symptoms of cancer intoxication – sudden weight loss, weakness, pale skin with an earthy tint
THE ARE FOUR STAGES OF PROSTATE CANCER:
Stage I: with DRE, the tumor is not detected and is not visualized on ultrasound. The tumor was discovered by chance during prostate surgery and does not extend beyond the prostate. No regional or distant metastases were detected (T1,N0,M0, Gleason ≤ 6, PSA level < 10); or a tumor was detected by X-ray or TRUS in one half or on one side (right or left) of the prostate. The cancer is located within the prostate, there are no metastases (T2a, N0, M0, Gleason ≤ 6, PSA level < 10).
Stage II: Stage 2A of prostate cancer – the tumor is not detected by palpation and is not visible on ultrasound, the cancer was discovered by chance during surgery or biopsy due to a high PSA level. The cancer has not spread to nearby lymph nodes or other organs (T1,N0,M0, Gleason 7, PSA level <20); or the same readings T1,N0,M0, Gleason ≤ 6, PSA level from 10 to 20; or cancer can be palpated and detected by TRUS, the tumor is located in only one lobe of the prostate, cancer is not detected in other places (T2a or T2b, N0, M0, Gleason ≤ 7, PSA < 20).
2B stage of prostate cancer – the tumor is palpable and visualized on ultrasound, has spread to both sides of the prostate gland. No metastasis (T2c, N0, M0, has any Gleason value and any PSA); or the cancer is located within the prostate gland, it is palpable and can be visualized with TRUS. No cancer was detected in regional lymph nodes and distant organs and systems (T1 or T2, N0, M0, any Gleason value, PSA ≥ 20); the same as in the previous T1 or T2,N0,M0, only Gleason ≥ 8, any PSA level.
Stage III – the cancer has spread beyond the prostate, may also have spread to the seminal vesicles, but has not spread to nearby lymph nodes or elsewhere in the body (T3,N0,M0, any Gleason score , any PSA value).
Stage IV – the cancer has spread to nearby organs and tissues (bladder, rectum, urethral sphincter and/or pelvic wall), except for the seminal vesicles. The cancer has not spread to the nearest lymph nodes, and there are no distant metastases (T4, N0, M0, any Gleason value, any PSA level); or the tumor may be located within the prostate, may spread to nearby organs and tissues, while cancer cells have metastasized to regional lymph nodes, but are not present in other organs (any T, N1, M0 parameter, any Gleason value, any PSA level); or there are distant metastases (any T value, any N value, M1, any Gleason value, any PSA value).
SCREENING AND EARLY DIAGNOSIS OF PROSTATE CANCER
Population or mass screening refers to the examination of men at risk without symptoms of the disease. In contrast, early diagnosis, or unscheduled examination, is carried out in individual clinical cases, and is initiated by the person (patient) undergoing examination and/or his attending physician. Both types of surveys have 2 main goals:
- 1. Reducing mortality from prostate cancer.
- 2. Improving the quality of life, which is of great importance.
It is recommended to carry out an initial determination of the level of specific prostate antigen (PSA) at the age of 40 years, on the basis of which the frequency of examinations can be established. For men with an initial PSA level ≤1 ng/ml, an 8-year interval between examinations seems sufficient. Men over 75 years of age with a baseline PSA level ≤ 3 ng/mL do not need to undergo further PSA testing, as the risk of death from PCa in this group is very low.
DIAGNOSTICS.
The main methods for diagnosing prostate cancer include digital rectal examination (DRE), PSA level determination and transrectal ultrasound (TRUS). The final diagnosis is made when adenocarcinoma (malignant prostate tumor) is detected in biopsy or postoperative material. Pathological studies also make it possible to stage the tumor and determine its extent.
DIGITAL RECTAL EXAMINATION (DRE)
Most prostate tumors are localized in the peripheral zone of the prostate and can be detected by DRE if their volume reaches 0.2 cm3 or more. Identification of a nodule or area of consolidation using DRE is an absolute indication for prostate biopsy. In approximately 18% of all patients, prostate cancer is detected only by DRE, regardless of PSA level. Detection of a tumor during DRE in patients with a PSA level < 2 ng/ml has a positive predictive value in 5–30% of cases.
PROSTATIC SPECIFIC ANTIGEN (PSA)
The diagnosis of prostate cancer has improved dramatically with the introduction of PSA testing. PSA is a serum kallikrein-like protease that is produced primarily by pancreatic epithelial cells. For practical purposes it can be said to be organ specific, but is not considered cancer specific. Therefore, its level may be elevated in benign prostatic hyperplasia (BPH), prostatitis and other non-cancerous conditions.
The PSA level as an independent indicator is a more reliable prognostic factor for cancer than detection of abnormalities by DRE and TRUS. There are many commercial diagnostic systems for measuring PSA levels, but no uniform international standards have been established for this indicator. The PSA level is considered a “continuous” parameter, i.e., the higher its value, the greater the likelihood of having prostate cancer. This means that there is no generally accepted threshold or boundary value for this indicator. A generally accepted normal PSA reading is 0 to 4 ng\ml.
The level of total PSA tends to increase with age.
Therefore, the upper limit of normal for different age groups is different:
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
The results of a recent study on prostate cancer prevention conducted in the United States confirmed that many men may have prostate cancer despite low blood PSA levels.
Table. presents the relationship between prostate cancer detection rate and PSA level in men with normal PSA levels in the placebo group.
TABLE. RISK OF PCa WITH LOW PSA LEVELS
| PSA level, ng/ml | Risk of prostate cancer, % |
| 0–0.5
0.6–1 1.1–2 2.1–3 3.1–4 |
6.6
10.1 17.0 23.9 26.9 |
To date, no long-term results have been obtained on the basis of which it would be possible to determine the optimal PSA threshold value for identifying non-palpable but clinically significant PCa. Thus, according to various authors, the probability of developing prostate cancer within 7 years is 34% with a PSA of 3-6 ng/ml; 6-10 ng/ml – 44%; > 10 ng\ml – 71%.
A false increase in PSA lasting about 10 days can occur after a digital rectal examination or prostate massage performed the day before, after ejaculation, rectal ultrasound examination and in patients suffering from constipation.
Some modifications of the PSA value have been proposed that may increase the specificity of this indicator for the early diagnosis of prostate cancer, namely: PSA density, transition zone PSA density, age norms and molecular forms of PSA. However, these derivatives and some isoforms of PSA (cPSA, proPSA, BPSA, iPSA) are of little value in clinical practice.
FREE TO TOTAL PSA RATIO (F/T PSA)
The s/o PSA ratio is the most studied and widely used criterion in clinical practice for the differential diagnosis of benign prostatic hyperplasia (BPH) and PCa. This indicator allows you to determine the risk categories of prostate cancer in men with a total PSA level of 4 to 10 ng/ml and a negative DRE result. PCa is detected by biopsy in 56% of men with c/o PSA < 0.1 and only in 8% of men with s/o PSA > 0.25. C/o PSA has no clinical significance when the total PSA level is > 10 ng/ml and when monitoring patients with previously diagnosed prostate cancer.
PSA GROWTH RATE, PSA LEVELS DOUBLE TIME
There are 2 ways to measure changes in PSA levels over time:
—the rate of rise of PSA, which is defined as the absolute annual increase in PSA (ng/ml/year);
—the doubling time of the PSA level, which expresses the exponential increase in PSA over time, reflecting relative changes.
These 2 criteria may have prognostic value in patients treated for prostate cancer.
PSA-3 MARKER
In contrast to 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 PSA-3 assessment over that of PSA is its slightly higher sensitivity and specificity. PSA-3 levels reflect small but significant increases in the rate of positive biopsy results, but are not affected by pancreatic volume or prostatitis.
Information about whether PSA-3 levels are associated with tumor aggressiveness is controversial. Although this indicator has potential prognostic value for detecting PCa in men with elevated PSA levels in whom the initial biopsy was negative, the method of determining PSA-3 remains experimental. In the near future, perhaps not only in laboratories but also in clinical practice, several molecular diagnostic tests will be used, for example to detect the prostate cancer-specific TMPRSS2-erg gene fusion in urine sediment after massage.
TRANSECTAL ULTRASOUND STUDY (TRUS).
When sonography with a rectal probe, in 75% of cases, prostate cancer is visualized in the peripheral zone. The typical picture of prostate cancer is a node of reduced echogenicity with unclear, uneven contours, but the node can also be isoechoic and hyperechoic, and in some cases the tumor is not visualized at all. TRUS in the grey-scale mode does not allow detecting prostate cancer with sufficient reliability. Therefore, TRUS-guided targeted biopsy of suspicious areas does not seem to be an effective replacement for multifocal biopsy. However, additional TRUS-guided biopsy of suspicious areas may be useful.
ELASTROGRAPHY OF THE PROSTATE IN THE DETECTION OF PROSTATE CANCER
The sensitivity and specificity of elastography imaging require further study in conjunction with the current standard technique of ultrasound-guided multifocal prostate biopsies. The experience available to date allows us to draw some conclusions:
- A negative prostate elastography result is not an indication to cancel a prostate biopsy.
- It is unlikely that the specificity will be high enough to make an absolute diagnosis. Biopsies will still be necessary to confirm diagnostic results and determine Gleason grading.
Elastography can be used in the following cases:
- 3.1. In patients with elevated serum PSA concentrations and negative results of several biopsies. In such cases, there is a possibility that the tumor was not detected, because has an unusual location (for example, in the front of the gland). An alternative to a 20-point biopsy (which is quite traumatic) may be to search for a tumor using elastography. If a tumor is detected, it can be biopsied with a much smaller number of punctures under local anesthesia.
- 3.2. If elastography and conventional sonography visualize a prostate tumor, then during a biopsy it is possible to reduce the number of biopsies.
- 3.3. The combination of multifocal prostate biopsy with additional sections from affected areas of the prostate (based on elastography results) will increase the number of positive results.
- 3.4. Perhaps elastography will allow us to assess the size of tumors and the likelihood of spreading beyond the prostate. Because ultrasound images in black and white are not suitable for this purpose.
- 3.5. The most aggressive tumors may show a different appearance on elastography images than less aggressive tumors, which is very important information when evaluating treatment options.
TRUS of the prostate in the gray scale (Fig. 3.1a) did not reveal any pathological nodes. Elastography showed loss of elasticity in the left peripheral zone lateral to the mid-gland and normal elasticity at the base (Fig. 3.2b). According to the biopsy, a tumor of 6 points on the Gleason scale was detected in the area of reduced elasticity.
In Fig. Figures 3.1c and 3.1d show the elasticity measurements of the abnormal area and the corresponding area on the normal side. The difference in the graphs is obvious.
PROSTATE BIOPSY
Primary biopsy
Indications for performing a pancreatic biopsy are the PSA level and/or changes identified by the DRE method. Also, when performing a biopsy, the patient’s age, possible concomitant diseases and complications should be taken into account.
Currently, TRUS-guided pancreatic biopsy is a standard diagnostic method. TRUS-guided transperineal biopsy appears to be a useful alternative in special cases, such as after rectal resection.
REPEATED BIOPSY
Indications for repeat biopsy:
- increasing or persistently high PSA level, changes detected during DRE
- atypical small acinar proliferation
The optimal timing for repeat biopsy has not been established. It is determined based on the results of a pathomorphological examination of the primary biopsy, taking into account the risk of detecting prostate cancer (high or rapidly growing PSA level, changes in DRE data, family history). The later the repeat biopsy is performed, the higher the detection rate of PCa.
If clinical suspicion of PCa remains despite negative biopsy results, MRI can be performed to identify PCa in the anterior parts of the gland, followed by TRUS- or MRI-guided biopsy of suspicious areas.
ZONES FOR BIOPSY AND NUMBER OF COLUMS
During the initial biopsy, tissue sampling should be performed in the peripheral parts of the pancreas as laterally and posteriorly as possible. Additional columns should be taken from areas in which changes were detected based on the results of PRUS/TRUS and which are determined in each case individually.
Sextant biopsy is no longer considered effective. When the pancreas volume is 30–40 cm3, it is necessary to perform a biopsy from at least 8 points. As the number of points increases to more than 12, the accuracy of the analysis does not change significantly. Based on the results of the British Study on the Diagnosis and Treatment of PCa, a 10-core biopsy was recommended.
DIAGNOSTIC TOUR OF THE PROSTATE GLAND (TURP)
Carrying out a diagnostic TURP instead of repeated biopsies is not advisable. The detection rate of prostate cancer using this method does not exceed 8%, which indicates its ineffectiveness for diagnosing cancer.
Biopsy of seminal vesicles.
Clear indications for biopsy of the seminal vesicles have not yet been determined. It is not recommended as a first-line test, but it may be useful in patients at high risk for seminal vesicle invasion in whom a positive biopsy may lead to a change in management. If the PSA level is >15–20 ng/ml, a biopsy is indicated only if its results will influence treatment tactics, i.e., if invasion into the seminal vesicles is detected, radical prostatectomy will not be performed. At PSA level > 15–20 ng/ml the probability of invasion into the seminal vesicles is 20–25%. For a more accurate preoperative diagnosis, a biopsy of the seminal vesicles can be used.
BIOPSY OF THE TRANSITION ZONE
Primary biopsy with tissue sampling from the transition zone is characterized by a very low detection rate of PCa, but 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 be carried out during the initial biopsy.
Antibiotics.
The use of oral or intravenous antibiotics appears to be the most modern method of treatment. The optimal dosage and duration of treatment are determined individually. Quinolones are preferable among drugs, while ciprofloxacin is more effective than ofloxacin.
Complications.
The incidence of complications after biopsy is low (table). Minor complications include macrohematuria and hematospermia. Serious infection after biopsy occurs in less than 1% of cases. The recently observed increase in the number of cores during biopsy has not led to an increase in serious complications requiring treatment. Taking low-dose aspirin is no longer considered an absolute contraindication to biopsy.
TABLE 5. PERCENTAGE OF BIOPSY COMPLICATIONS, INDEPENDENT OF THE NUMBER OF COLUMN*
| Complications | Biopsy percentage |
| Hematospermia | 37.4 |
| Hematuria (> 1 day) | 14.5 |
| Rectal bleeding < 2 days | 2.2 |
| Prostatitis | 1.0 |
| Febrile fever (> 38.5 °C) | 0.8 |
| Epididymitis | 0.7 |
| Rectal bleeding > 2 days ± need for its surgical stop | 0.7 |
| Acute urinary retention | 0.2 |
| Other complications requiring hospitalization | 0.3 |
*Based on the NCCN Consensus Guidelines, ed. 1st, 2007
PATHOMORPHOLOGICAL STUDY OF PUNCTURE BIOPTS OF THE PAN.
Diagnosis of prostate cancer is based on pathomorphological examination. However, immunohistochemical (IHC) analysis may also be useful.
Prostate biopsy should be reported using clear, concise terminology and terms such as “atypia”, “atypical glands” and “possible” should be avoided malignant neoplasm.”
Diagnostic terms used in the conclusion based on the results of a pancreatic biopsy:
• Benign neoplasm/absence of cancer. If appropriate, a description should be included (eg, atrophy). Chronic inflammation may also be specified (optional)
• Acute inflammation, negative for malignancy
• Atypical adenomatous hyperplasia/adenosis, no malignancy detected
• Granulomatous inflammation, negative for malignancy neoplasms
• High-grade prostatic intraepithelial neoplasia (PIN), negative for adenocarcinoma
• High-grade PIN with atypical glands, suspicious for adenocarcinoma
• Locate of atypical glands/nodule suspicious for adenocarcinoma
• Adenocarcinoma
* From: van der Kwast, 2003 [36].
For each biopsy site, the percentage of positive carcinoma bars and Gleason score should be reported based on the 2005 system.
Radioisotope testing,more commonly called a radionuclide bone scan, is performed to detect the spread of a tumor into bone tissue.
Before the test, a small amount of a radioisotope is injected into the body. Where the bone is affected, a special scanner detects increased accumulation of radionuclide. This test is not a specific test for detecting cancer. Radionuclide accumulation can occur as a result of other conditions such as arthritis, the site of an old fracture, and benign bone diseases. Further X-ray examination of pathologically changed areas of bone tissue may be helpful. Sometimes an orthopedic surgeon may take a bone sample from the area where pathological changes were detected during a radioisotope scan for microscopic examination to identify the factor causing the pathological changes.
PROSTATE CANCER TREATMENT:
Until recently, surgical treatment was the only method used to remove most malignant tumors. And if the tumor spread (metastasized), there was no treatment. Many treatments are now available to kill or suppress the growth of cancer that has metastasized to other organs. And prostate cancer was one of the first types of cancer for which this type of treatment was developed.
At the same time, the choice of treatment for prostate cancer, even for a clinically localized tumor, has become much more complicated due to the fact that different methods have equal oncological results , but significantly differ in their complications.
Because the tumor is often not an acute problem, some patients are told that they do not need urgent treatment. This strategy is called“watchful waiting” or “active surveillance.”This does not mean that the presence of a tumor is neglected. The main thing is that the patient is regularly monitored – to confirm the absence of tumor growth, appropriate tests and studies are carried out. The concept of watchful waiting is dictated by the fact that prostate cancer, as a rule, progresses slowly and is diagnosed in older men with a high risk of death from concomitant diseases. It may be chosen to treat patients with localized PCa and short life expectancy, or older patients with less aggressive tumors. It is impossible to accurately predict the growth of a cancerous tumor, but its assessment can be determined by the histological structure of the tumor (material obtained during a biopsy), which is examined under a microscope. Sometimes studies show that the tumor is growing so slowly that the patient can be excused from visiting the clinic, although they will be advised to keep in contact with their GP. Because early prostate cancer is unlikely to get out of control quickly, some urologists recommend several months of monitoring and measuring your PSA level (how quickly it rises) to ensure you don’t miss the stage of cancer that requires treatment.
SURGICAL TREATMENT.
Surgical treatment methods are used only when the tumor is limited to the prostate capsule and there are no metastases yet. In this case, radical removal of the prostate gland is performed. If the operation is performed successfully, it practically guarantees a complete cure for prostate cancer without any health consequences. Surgical treatment of prostate cancer consists of radical prostatectomy (RP), in which the prostate from the urethra to the bladder is removed en bloc with the seminal vesicles and paraprostatic tissue. This operation is often accompanied by a bilateral pelvic lymphadenectomy (BPL). In men with localized prostate cancer and a life expectancy of ≥ 10 years, the goal of RP, regardless of approach, is to remove the tumor while preserving urinary continence and, if possible, erectile function. There is no age limit for RP, and a patient should not be denied surgery based solely on their age. Rather, a greater number of comorbidities greatly increases the risk of death from causes unrelated to prostate cancer.
RADICAL RADIATION THERAPY (RT)
Radiation therapy is the irradiation of the prostate gland with radioactive radiation. This allows you to reduce the rate of tumor growth and reduce the likelihood of metastases. Radiation therapy does not cure cancer, but it improves the patient’s condition, making it easier and prolonging his life. Irradiation is also used in individuals who wish to maintain sexual activity. According to the US National Institutes of Health, established in 1988: RT gives the same life expectancy as surgical treatment; in addition, the quality of life after RT is at least no worse than after RP. Three-dimensional conformal radiation therapy (3D-CRT) is the “gold standard” of treatment, but at the beginning of the 3rd millennium, intensity modulated radiation therapy (IMRT), as an improved form of 3D-CRT, is gradually gaining its position in high-tech centers.
TECHNICAL ASPECTS: 3D CRT AND IMRT
Anatomical information obtained by scanning the patient in the treatment position is transferred to a 3-dimensional planning program that allows you to visualize the clinical volume of treatment and then add a safety margin around it. Real-time monitoring of the irradiation field using beam imaging allows comparison of the irradiated and simulated fields and correction of deviations if they exceed 5 mm. 3D-CRT increases the effectiveness of local treatment due to dose escalation without increasing the risk of complications.
Sometimes short-term hormonal treatment is used to shrink the prostate gland before radical prostatectomy or radiation therapy. Hormone therapy is believed to increase the effectiveness of primary treatment, so it is often given before radiation therapy. During hormonal treatment, which is usually carried out for three months or longer, side effects are observed, but once the courses of hormonal and radiation therapy are completed, the side effects disappear. In some cases (when the prostate tumor is very large), a combination of radiation and hormonal therapy is recommended, which continues until the end of radiation therapy.
Both radical prostatectomy and radiation therapy are the main treatments with possible serious side effects. It is important to understand that these two methods do not differ much in the degree of risk, discomfort and time required to return to normal. Given the approximately equal effectiveness of various types of treatment, it is necessary to inform the patient with prostate cancer about alternative treatment methods.
Transperineal brachytherapy (contact radiation) is a safe and effective treatment method that generally requires no more than 2 days of hospitalization. Patients with low-risk prostate cancer are best suited for low-dose brachytherapy. The 5- and 10-year relapse-free survival rates range from 71 to 93% and 65 to 85%, respectively.
In addition to RP, EBRT, and/or brachytherapy, alternative treatments for clinically localized PCa, such as cryosurgical ablation and high-intensity focused ultrasound (HIFU) therapy, are also being developed. Cryoablation is recognized as one of the alternative treatment methods, in accordance with the recommendations of the American Urological Association. Both methods were developed as minimally invasive treatments that potentially have the same effectiveness as proven surgical and non-surgical methods, but with fewer complications.
CRYOABLATION OF THE RV
The method is based on freezing, which causes cell death due to:
- dehydration leading to protein denaturation
- direct rupture of cell membranes by ice crystals
- vascular stasis and formation of microthrombi, which leads to disruption of microcirculation with the development of ischemia
- apoptosis
To freeze the pancreas, 12–15 cryoprobes of size 17G are installed in it under TRUS control, thermosensors are inserted into the area of the external sphincter and bladder neck and a urethral heater. Under TRUS control, 2 freeze-thaw cycles are carried out, due to which the temperature in the middle of the pancreas and at the level of the spinal cord is reduced to -40 °C.
HIFU THERAPY FOR PCa
High Intensity Focused Ultrasound (HIFU) is focused ultrasound waves emitted by a transducer that cause tissue damage through mechanical, thermal, and cavitation effects. The goal of HIFU therapy is to increase the temperature of the tumor tissue above 65 °C so that it is destroyed by achieving coagulative necrosis. The predicted 5-year biochemical recurrence-free survival (BFS) rate is 66%.
Hormonal therapy
In 1941, Huggins and Hodges demonstrated the effectiveness of surgical castration and estrogen therapy in the progression of metastatic prostate cancer. They were the first to establish the sensitivity of prostate cancer to androgen deprivation. Since the pioneering studies by Huggins and Hodges, androgen suppression strategies have become central to the treatment of advanced prostate cancer.
Basics of hormonal control of the pancreas
Pancreatic cells are physiologically dependent on androgens, which stimulate their growth, function and proliferation. Testosterone, although not considered carcinogenic, plays a significant role in regulating the mechanism of growth and development of tumor cells. The main organ producing the majority of androgens in men is the testes, and only 5-10% of androgens (androstenedione, dihydroepiandrosterone and dihydroepiandrosterone sulfate) are synthesized by the adrenal glands.
Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis. Hypothalamic luteinizing hormone releasing factor (LHRH) stimulates the synthesis of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the anterior pituitary cells. LH stimulates the synthesis of testosterone by Leydig cells located in the testicles. In pancreatic cells, testosterone is converted by the enzyme 5-α-reductase into 5-α-dihydrotestosterone (DHT), which is 10 times more active than testosterone. In peripheral cells, circulating testosterone is aromatized and converted into estrogens, which, together with circulating androgens, have a negative feedback effect on the secretion of LHRH by the hypothalamus.
The lack of androgen stimulation of pancreatic cells leads to their apoptosis (programmed cell death). Any type of treatment that causes suppression of androgen activity is referred to as androgen deprivation.
Groups of drugs used for hormonal treatment of prostate cancer:
Estrogen
Estrogen has several mechanisms of action:
- decrease in LHRH secretion via a negative feedback mechanism
- androgen inactivation
- direct suppression of Leydig cell function
- direct cytotoxic effect on pancreatic epithelial cells (only in in vitro studies)
THERE ARE 3 MAIN REASONS FOR THE RENEWING INTEREST IN THE USE OF ESTROGENS FOR THE TREATMENT OF PCa.
- LHRH analogues have a large number of severe side effects and their long-term mass use is expensive, while estrogens reduce testosterone levels and do not cause a decrease in bone mineral density (BMD) and cognitive impairment (level of evidence 3)
- In phase II studies in which patients diagnosed with hormone-refractory prostate cancer (HRPC) received estrogen drugs (DES, DES-bisphosphonate), the PSA reduction rate was 86%
- A new estrogen receptor-β (ER-β) has recently been discovered and is thought to play an important role in PCa tumorigenesis
ANALOGUES OF LHRH
Long-acting LHRH analogues (buserelin, goserelin, leuprorelin and triporelin) have been used for more than 15 years in advanced prostate cancer and are currently the main form of hormonal therapy. These drugs are synthetic analogues of LHRH, mainly administered as depot injections once every 1, 2, 3 or 6 months. They initially stimulate LHRH receptors, causing a transient increase in the release of LH and FSH. This, in turn, causes an increase in testosterone synthesis (“waves” of testosterone or a “flare” effect), which begins 2-3 days after the first injection and continues for approximately the first week from the start of therapy.
LHRH antagonists
In contrast to LHRH analogues, antagonists competitively bind to LHRH receptors in the pituitary gland. As a result, the levels of LH, FSH and testosterone quickly decrease without the development of “flares”. Given the more desirable mechanism of action, LHRH antagonist therapy was considered very promising. However, for practical reasons, almost no clinical studies have been conducted. Many LHRH antagonists also cause serious histamine-mediated allergic reactions, and until recently there were no depot forms of these drugs.
ANTIANDROGENS
Antiandrogens competitively inhibit testosterone and DHT receptors in the nuclei of prostate cells, which causes apoptosis and inhibition of prostate cancer growth. These oral drugs are classified according to their chemical structure into steroidal, such as cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate, and non-steroidal or pure (nilutamide, flutamide and bicalutamide). Both classes bind competitively to androgen receptors. This is the only mechanism of action of non-steroidal antiandrogens, but in addition to this, steroidal antiandrogens also have gestagenic properties due to central inhibition of pituitary function. As a result, nonsteroidal antiandrogens do not reduce testosterone levels, which remain at normal or even slightly elevated levels.
STEROID ANTIANDROGENS
These drugs have gestagenic properties and reduce the release of gonadotropins (LH and FSH), and also suppress the activity of the adrenal cortex. At high levels they have a cytotoxic effect. Because steroidal antiandrogens cause a decrease in testosterone levels, the main pharmacological side effects are loss of libido and erectile dysfunction, although gynecomastia is quite rare. Non-pharmacological side effects include cardiovascular complications (4-40% for CPA) and hepatotoxicity.
NON-STEROID ANTIANDROGENS
Due to the higher quality of life and compliance compared to castration, the use of non-steroidal antiandrogens in monotherapy is increasing. They do not suppress testosterone secretion, therefore, during antiandrogen therapy, libido, general physical well-being and bone mineral density BMD are preserved. All drugs have a hepatotoxic effect, so it is necessary to regularly monitor the level of liver enzymes.
Unfortunately, all hormonal drugs have a number of unpleasant side effects – increased blood pressure, decreased potency, gynecomastia and others. If you are prescribed hormonal therapy, be sure to consult with your doctor about what to do if such phenomena occur. The course of treatment is long, many months. The administration of these hormones increases survival and at the same time (when taken in high doses and long-term use) causes an increase in the incidence of cardiovascular complications (stroke, myocardial infarction, thromboembolism, circulatory failure).
SUBCAPSULE BILATERAL ORCHIECTOMY.
This operation involves cutting the tunica albuginea of each testicle and removing active tissue from the inside, causing the testicles to no longer produce testosterone. Sometimes removal of the entire testicle may be recommended. Orchiectomy is a fairly simple operation. But it involves staying in a hospital and usually requires general anesthesia. There is pain for several days. Minor complications such as trauma, swelling or infection of the wound occur. The results of the operation are observed immediately, and sometimes the symptoms of the disease regress within the next few days after surgery.
CHOICE OF TREATMENT
The effect of various treatment methods on the tumor is the same. The choice between them is made based on what possible side effects they cause. If one type of treatment does not satisfy the patient, it can be replaced with another. When choosing between surgery and radiation therapy for early cancer, the patient’s opinion can be asked, so in this case it would be useful to give more information about the treatment options.
At the patient’s disposal:
— RPE is an operation that leads to a cure, and he no longer has to worry about further treatment;
—a course of radiation therapy;
—injections once a month or every three months
— taking pills.
PROTATE CANCER
Although anti-cancer therapy is increasingly improved, the ability to prevent cancer would be a better alternative. The best example of cancer prevention is stopping smoking, which reduces the risk of lung cancer. It is possible that ways to prevent prostate cancer will also soon be found. Japanese people are less likely to get 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 nutrition. A diet high in animal fats may increase the risk of prostate cancer, while some vitamins and minerals are protective. More importantly, soy products in Japanese cuisine can act like a mild female sex hormone (phytoestrogen).
Finasteride is a drug that is commonly used to treat benign prostate hyperplasia. It reduces the action of the male sex hormone within the prostate and thereby affects the development of cancer. The results of a study were recently published in which 18,000 men took finasteride or a placebo for seven years. In the group taking finasteride, the number of men who developed prostate cancer was a quarter less than in the control group. However, early tumors were detected in patients’ prostate biopsies, and it is not at all clear how much the drug would reduce the number of men who will develop symptoms or die from prostate cancer in the future. It was noted that although the overall number of prostate cancers fell, the number of so-called high-grade tumors, which are the most dangerous, increased slightly in those taking finasteride.
The significance of these results is not clear and it is too early to recommend finasteride as a preventive treatment. Research is currently ongoing using other active substances that could prevent the occurrence of prostate cancer.
In the diagnostic and treatment center New Life the appointment is conducted by a urologist, Ph.D. (Doctor of Philosophy) Fedorishin Rodion, who has been dealing with the problems of early diagnosis of prostate cancer for more than 15 years, as well as minimally invasive therapeutic and diagnostic interventions on the prostate gland.
In all doubtful cases, patients undergo ultrasound examination of the prostate gland and seminal vesicles (TRUS) using expert-class devices. If a tumor is suspected, the urologist performs a transrectal multifocal automatic biopsy of the prostate gland under sonographic guidance. Thanks to clinical experience (more than 5,000 biopsies performed), the manipulation is performed on an outpatient basis, painlessly and with high quality.
In economically developed countries, public awareness about prostate cancer is at a high level, and most men independently consult a doctor to determine their PSA level. The American and European Urological Associations recommend that all men over 50 years of age undergo a digital rectal examination, a PSA blood test, and consult a urologist about the test results once a year.
