Prostate Cancer: Clinical Guidelines

List of Abbreviations

ADT – androgen deprivation therapy

BT – brachytherapy

DT – doubling time

G-CSF – granulocyte colony-stimulating factor

mHSPC – metastatic hormone-sensitive prostate cancer

BPH – benign prostatic hyperplasia

CI – confidence interval

EBRT – external beam radiotherapy

IHT – intermittent hormone therapy

CRPC – castration-resistant prostate cancer

CT – computed tomography

LHRH – luteinizing hormone-releasing hormone

RT – radiotherapy

LNs – lymph nodes

PT – physical therapy

MAB – maximal androgen blockade

IAEA – International Atomic Energy Agency

ICD-10 – International Classification of Diseases 10th Revision

mpMRI – multiparametric magnetic resonance imaging

MRI – magnetic resonance imaging

NSAA – non-steroidal antiandrogens

AUR – acute urinary retention

tPSA – total prostate-specific antigen

CHT – continuous hormone therapy

PSA – prostate-specific antigen

PET/CT – positron emission tomography combined with computed tomography

RARP – robot-assisted radical prostatectomy

PCa – prostate cancer

RP – radical prostatectomy

fPSA – free prostate-specific antigen

SLN – sentinel lymph node

TFD – total focal dose

PLA – pelvic lymphadenectomy

DRE – digital rectal examination

TRUS – transrectal ultrasound

TURP – transurethral resection of the prostate

LE – level of evidence

US – ultrasound examination

CT – chemotherapy

ERAS (early rehabilitation after surgery)

IGRT – Image Guided Radiation Therapy

IMRT – Intensity-Modulated Radiation Therapy

PCPT – Prostate Cancer Prevention Trial

PHI – Prostate Health Index

Terms and Definitions

Brachytherapy (interstitial radiation therapy) is the implantation of radioactive seeds into the prostate tissue.

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

International Prostate Symptom Score (IPSS) is a questionnaire used to assess the severity of urinary symptoms.

Metastasis-directed therapy is treatment targeting tumor metastases (surgery involving the surgical removal of a metastasis, or radiation therapy).

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

Prehabilitation is rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

Prostate-specific antigen (PSA) is a protein tumor marker that indicates the potential presence of a malignant prostate neoplasm.

Transurethral resection of the prostate (TURP) is an endoscopic procedure involving the removal of prostate tissue using an instrument passed through the urethra.

Third stage of rehabilitation – rehabilitation during the early and late rehabilitation periods, and the period of residual disease symptoms in departments (offices) of rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, and speech therapy (defectology offices) providing outpatient medical care, in day hospitals, as well as by mobile home-visiting teams (including in sanatorium-resort organizations).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Prostate cancer (PCa) is a malignant neoplasm originating from the epithelium of the prostate glands.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology and pathogenesis of this disease remain poorly understood. Many studies focus on investigating diet, food products, hormonal influences, and infections in the etiology of PCa. The prevalence of PCa depends on ethnic and geographical characteristics. The highest incidence is observed in African Americans living in the USA (60% higher than in white Americans), and the lowest in Chinese living in China [1]. In addition to racial characteristics, risk factors for the development of PCa include genetic predisposition, male age, and dietary habits. The probability of developing a prostate tumor in a man who has a first-degree relative (father or brother) with PCa is 1.8 times higher than in the general population. If two or more relatives were affected (father and brother or both brothers), the risk of developing PCa increases by 5.51 and 7.71 times, respectively [2, 3]. African Americans have an increased risk of PCa detection, as well as a higher probability of aggressive PCa [4]. Furthermore, the risk of developing PCa increases in men consuming large amounts of animal fats [5].

Many studies are devoted to analyzing the association of PCa with dietary factors and medications, as well as occupational and other environmental factors (smoking, surgeries, infections, etc.) (Table 1).

Table 1. Impact of dietary factors and medications on the risk of PCa development

Table 2. Impact of other factors on the risk of PCa development

Thus, the issue of PCa etiology and potential prevention methods remains controversial. The results of numerous studies on the role of factors that may influence the risk of PCa development are contradictory and often raise more doubts and questions than they provide affirmative and unambiguous answers. Conducting further prospective genetic, molecular-biological, and epidemiological studies in carefully selected groups may allow a more detailed determination of the risk factors for PCa development, as well as ways to prevent this disease.

1.3 Epidemiology of the Disease or Condition

PCa is one of the most common malignant diseases in men. Worldwide, approximately 1.6 million cases of PCa are diagnosed annually, and 366,000 men die from this pathology each year [30]. This is precisely why increasing attention has recently been paid to the diagnosis and treatment of this pathology both abroad and in the Russian Federation. The highest incidence rates of PCa are registered in the USA, Canada, and a number of European countries, where it ranks first in the structure of oncological diseases in men. Thus, according to the US National Cancer Institute, from 1986 to 1992, the incidence rate of PCa among the white population increased by 108% and by 102% for black Americans. In the Russian Federation, the incidence of PCa is also steadily increasing. In the structure of malignant neoplasms among the male population of Russia, PCa ranks second, accounting for 14.5% of all diagnosed neoplasms in men after tracheal, bronchial, and lung tumors (17.4%) [31]. Thus, in 2017, 40,785 new cases of PCa were newly diagnosed, and the standardized rate was 40.47 per 100,000 population. The increase in incidence from 2007 to 2017 was 70.61%, with an average annual growth rate of 5.09% for 2017. Mortality from PCa in Russia has increased over the past 10 years. In 2017, 12,565 men died from PCa in Russia. Over 10 years (from 2007 to 2017), the increase in the mortality rate was 13.85%, with an average annual growth rate of 1.29%. Despite the improvement of PCa diagnostic methods and the introduction of PSA monitoring, the incidence of advanced forms of PCa in Russia remains high. According to 2018 data, stage IV metastatic PCa, for which radical treatment of patients is no longer possible, was verified in 18.9% of patients. Locally advanced PCa without regional and distant metastases (stage III PCa) was diagnosed in 21.5% of patients, and localized stage I–II PCa was detected in 58.5% of patients [32].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10), prostate cancer has the code

C61 – Malignant neoplasm of prostate.

1.5 Classification of the disease or condition

1.5.1. International Histological Classification:

8148/2 – Prostatic intraepithelial neoplasia, grade III;

8140/3 – Adenocarcinoma;

8141/3 – Scirrhous adenocarcinoma;

8550/3 – Acinar adenocarcinoma;

8201/3 – Cribriform carcinoma.

Morphological classification of PCa

Adenocarcinoma:

• microacinar;
• large acinar;
• cribriform;
• papillary;
• solid-trabecular;
• endometrioid;
• glandular-cystic;
• mucinous.

Transitional cell carcinoma.

Squamous cell carcinoma.

1.5.2. Staging

Staging of prostate cancer (PCa) is carried out in accordance with the TNM (tumor-node-metastasis) classification (UICC [Union for International Cancer Control], 8th edition, 2017).

The T category describes the extent of the primary tumor.

T - primary tumor:

• Tx - primary tumor cannot be assessed;
• T0 - no evidence of primary tumor;
• T1 - clinically inapparent tumor (not palpable and not visible by imaging):

- T1a - tumor incidental histological finding in 5% or less of tissue resected during transurethral resection of the prostate (TURP);

- T1b - tumor incidental histological finding in more than 5% of tissue resected during TURP;

- T1c - tumor identified by needle biopsy (performed due to elevated PSA);

T2 - tumor is confined within the prostate¹:

• T2a - tumor involves one lobe and accounts for <50% of that lobe;
• T2b - tumor involves one lobe and accounts for >50% of that lobe;
• T2c - tumor involves both lobes;

T3 - tumor extends through the prostatic capsule²:

• T3a - extracapsular extension (unilateral or bilateral);
• T3b - tumor invades seminal vesicle(s);

T4 - tumor is fixed or invades adjacent structures other than seminal vesicles (bladder neck, external sphincter, rectum, levator muscles, and/or anterior abdominal wall).

The N category indicates the presence or absence of regional lymph node metastases.

N - regional lymph nodes³:

• Nx - regional lymph nodes cannot be assessed;
• N0 - no regional lymph node metastasis;
• N1 - regional lymph node metastasis.

The M category characterizes the presence or absence of distant metastases.

M - distant metastases⁴:

• Mx - distant metastasis cannot be assessed;
• M0 - no distant metastasis;
• M1 - distant metastasis;

• M1a - non-regional lymph node(s);
• M1b - bone(s);
• M1c - other site(s).

pT - pathohistological evaluation of the primary tumor:

• pT2 - organ-confined tumor;
• pT3 - extracapsular extension:

- pT3a - extracapsular extension (unilateral or bilateral), including microscopic invasion to the bladder neck;

- pT3b - seminal vesicle invasion;

• pT4 - tumor invades adjacent structures or tissues (involves rectum, bladder neck, levators, pelvic wall, or external anal sphincter).

Footnote comments are presented in accordance with the numerical designation in the text above:

¹A tumor identified in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c.

²Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2, not T3 (thus, tumor involvement of the capsule without invasion of periprostatic fat should be staged as T2).

³Regional lymph nodes - pelvic lymph nodes below the bifurcation of the common iliac arteries. The side of the lesion does not affect the N descriptor.

⁴When more than one metastatic site is present, the most advanced category is used (e.g., if a PCa patient has both bone and liver metastases, the M1c category should be specified).

1.5.3. Morphological classification according to the Gleason score

To assess the degree of PCa differentiation, the Gleason grading system, proposed by the Canadian pathologist Donald F. Gleason, is most widely used. According to the Gleason system, tumor differentiation is evaluated on a 5-point scale: score 1 represents the most well-differentiated tumor, and score 5 represents the most poorly differentiated tumor. Since PCa typically exhibits a heterogeneous morphological structure, it is standard practice to designate the most prevalent histological grade (primary score) and the second most common differentiation grade (secondary score). The primary and secondary scores are added together to obtain the Gleason score (ranging from 2 to 10). The Gleason classification has special prognostic significance for evaluating PCa treatment outcomes.

In 2014, a consensus conference of the International Society of Urological Pathology (ISUP) was held regarding PCa grading [33]. Based on prognostic data of tumor differentiation according to the Gleason scale, a classification comprising five prognostic groups was developed to align grading with tumors of other localizations. The group of prostate tumors with a Gleason score of 7 (3 + 4 and 4 + 3) was divided into two distinct groups due to significant differences in clinical prognosis (Table 3).

Table 3. Histological prognostic classification of prostate cancer by the International Society of Urological Pathology (ISUP)

Thus, the new ISUP classification provides a more accurate stratification of prostate tumors. The authors of this staging system expect that changing the numerical designation of prognostic subgroups (from 1 to 5 instead of 6 to 10 as in the standard Gleason stratification) will help reduce the frequency of active radical treatment in patients with clinically insignificant PCa. Currently, ISUP prostate cancer grading is used alongside the standard Gleason grading. For example, prostate acinar adenocarcinoma with a Gleason score of 6 (3 + 3) is ISUP Grade 1, a score of 7 (3 + 4) is ISUP Grade 2, and so on. In 2016, the World Health Organization approved the use of this classification.

1.6 Clinical presentation of the disease or condition

In the early stages, PCa is typically asymptomatic. Symptoms in non-metastatic PCa are most often associated with concomitant benign prostatic hyperplasia (BPH). Patients with localized PCa most commonly present with bladder outlet obstruction symptoms related to BPH, such as urinary frequency, hesitancy, weak urinary stream, urgency, and nocturia. Locally advanced PCa may be characterized by urinary obstruction symptoms caused by both concomitant BPH and large tumor volume. Tumor invasion into the bladder neck and/or urethra may cause hematuria and urinary incontinence. Extensive tumor involvement of the bladder neck can lead to compression of the ureteral orifices, pain, ureteropyelectasis, hydronephrosis, and renal failure. Extension of the tumor into the cavernous neurovascular bundles leads to erectile dysfunction. Symptoms of tumor invasion or compression of the rectal wall include defecation disorders, blood in the stool, and pain in the rectum and perineum. Spread of the tumor to the pelvic floor muscles may cause discomfort while sitting and perineal pain. Massive tumor involvement of pelvic lymph nodes leads to lymphostasis, edema of the external genitalia and lower extremities.

In metastatic PCa, clinical symptoms (paraneoplastic syndrome: general malaise, weakness, progressive weight loss, fever, anemia, cachexia) are associated with both the overall extent of the tumor process and the localization of metastases. These frequently include bone pain corresponding to the site of metastases. Severe pain occurs with pathological bone fractures. The development of neurological disorders due to spinal involvement and the severity of neurological symptoms depend on the degree of spinal cord compression and the level of the lesion.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

• anamnestic data,
• physical examination findings,
• laboratory test results,

4) instrumental examination findings,

5) pathologo-anatomic examination findings of prostate tissue.

The clinical diagnosis is based on the results of the following analyses:

• physical examination (digital rectal examination (DRE)) makes it possible to detect a suspicious prostatic lesion;
• laboratory tests may reveal elevated levels of serum tumor markers (prostate-specific antigen (PSA), prostate health index, etc.);
• pathologo-anatomic examination report of biopsy material (prostate biopsy);
• diagnostic imaging findings allow for accurate disease staging.

Determination of the extent of the tumor process (staging)

To assess the extent of the primary tumor (localized or extracapsular process), digital rectal examination (showing a positive correlation with the disease stage in less than 50% of cases), diagnostic imaging methods, and prognostic factors are used.

The main prognostic factors determining the stage of the tumor process:

• PSA level;
• tumor differentiation grade according to the Gleason score;
• clinical stage according to digital rectal examination and diagnostic imaging data.

Based on a combination of prognostic factor data, tables and nomograms have been developed that predict the probability of the pathomorphological tumor stage with high accuracy. The Partin tables and Kattan nomograms have gained the greatest popularity [34–36].

In addition to the main factors, additional prognostic factors are used:

• perineural tumor invasion;
• number of positive biopsy cores;
• percentage of cancer in biopsy cores;
• length of cancer in biopsy cores.

2.1 Complaints and Anamnesis

As a rule, in early-stage prostate cancer, symptoms are absent, since the peripheral zones of the prostate gland are most commonly affected. With a prostate neoplasm, symptoms appear that can be divided into three groups:

• symptoms of bladder outlet obstruction: weak and interrupted urinary stream, sensation of incomplete bladder emptying, frequent urination, urgency, stress urinary incontinence;
• symptoms associated with local tumor progression: hemospermia, hematuria, urinary incontinence, erectile dysfunction, pain in the suprapubic region and perineum;
• symptoms associated with distant metastases: bone pain, lower back pain (due to ureteral obstruction), lower extremity edema (lymphedema), paraplegia (spinal cord compression), weight loss, anemia, uremia, cachexia.

2.2 Physical Examination

Comments: DRE allows the detection of PCa in the peripheral zones with a nodule volume of at least 0.2 ml. Performing this examination for screening in asymptomatic men leads to the detection of PCa in only 0.1–4% of cases [39, 40]. DRE entails a clinically significant increase in PSA levels [41].

2.3 Laboratory Diagnostics

In men with suspected PCa (men with lower urinary tract symptoms, men older than 50 years, men older than 45 years with a family history), it is recommended to determine the total blood PSA level to establish the prognostic group, diagnostic methods, and treatment strategy [42–47].

GCR ALEL 2Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) - A (level of evidence – 2).

Comments: PSA is a kallikrein-like serine protease secreted by prostate epithelial cells. It is an organ-specific, not a tumor-specific marker; therefore, serum PSA levels may be elevated not only in PCa, but also in benign prostatic hyperplasia (BPH) and chronic prostatitis. Acute urinary retention (AUR), prostate biopsy, and surgical interventions (transurethral resection (TUR), prostatectomy) also lead to an increase in PSA levels within several weeks, which must be taken into account when interpreting data.

The average normal PSA level is considered to be 2.5 ng/ml. In addition, age-specific norms for the marker level should be taken into account: age 40–49 years - 0–2.5 ng/ml, 50–59 years - 0–3.5 ng/ml, 60–69 years - 0–4.5 ng/ml, 70–79 years - 0–6.5 ng/ml [48]. Finasteride^** therapy in patients with BPH leads to a decrease in PSA concentration, while a level of 2 ng/ml should be considered normal [49]. However, there is no discriminative blood PSA level that completely rules out the risk of detecting PCa. According to literature data, the risk of detecting PCa in men with a PSA level less than or equal to 4 ng/ml varies depending on the PSA value [50] (Table 4).

Table 4. Detection rate of PCa on biopsy according to PSA level (results of the Prostate Cancer Prevention Trial [PCPT])

With a PSA level of 2.5–10.0 ng/ml, the majority of patients (75%) are diagnosed with BPH, while with a PSA level above 10 ng/ml, PCa is most likely [42]. At the same time, 13.2% of men aged 50–66 years with a serum PSA concentration of 3–4 ng/ml are diagnosed with clinically significant PCa upon biopsy [51].

In 2006, based on the results of a large study involving 9,459 men, it was demonstrated that the discriminative PSA level of 4 ng/ml is not adequate, and age-specific norms were introduced (Table 5) [52]. It was also shown that lowering the discriminative PSA level leads to "unnecessary" biopsies and an increase in the diagnosis of clinically insignificant cancer. Thus, in men older than 60 years, the universally accepted discriminative PSA level is 2.5 ng/ml. Table 5 shows the mean normal value, whereas the threshold value for deciding to perform a biopsy is 2.5.

Table 5. Mean PSA values based on the results of the Prostate Cancer Prevention Trial (PCPT)

• density - the ratio of the PSA level to the prostate volume (in cm³) calculated from transrectal ultrasound (TRUS) data. A density of >0.15 is more characteristic of PCa [53, 54];
• transition zone density - the ratio of the PSA level to the volume of the prostate transition zones (in cm³) calculated from TRUS data. A transition zone density of >0.35 is characteristic of PCa [55, 56];
• molecular forms (fractions) - the ratio of free prostate-specific antigen (fPSA) to total prostate-specific antigen (tPSA). A ratio of <0.1 is more characteristic of PCa. Thus, in men with a PSA level of 4–10 ng/ml and a PSA density of <0.1, PCa was verified in 56% of cases, and in men with a PSA density of >0.25 [57];
• PSA velocity - the increase in PSA level over a period of time. An increase in PSA concentration by more than 0.35 ng/ml per year increases the probability of PCa [58].

GCR BLEL 3Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) - B (level of evidence – 3).

Comments: modifications that increase the specificity of PSA diagnostics for early PCa are used not only for primary diagnosis, but also to determine indications for a repeat prostate biopsy in men with no evidence of PCa on the initial biopsy [59].

In addition to the primary test for early diagnosis of PCa, blood PSA testing is also recommended for tumor staging and monitoring of patients after local treatment or during systemic treatment [60–65].

GCR CLEL 3Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) - C (level of evidence – 3).

Comments: PCA3 is a non-coding microRNA that is detected in urine after digital rectal examination/massage of the prostate gland. Determination of PCA3 can improve the accuracy of PCa diagnosis compared with the determination of PSA and its fractions (total, free, ratio) [66-69]. The PCA3 level reflects small but significant increases in the frequency of a positive biopsy result. The PCA3 index can be used together with PSA and other clinical risk factors in nomograms or other risk stratification systems to decide on performing an initial or repeat biopsy. The PCA3 level increases with increasing PCa volume. Urinary PCA3 content increases in proportion to tumor tissue volume, but does not depend on tumor differentiation [71]. The use of PCA3 as a monitoring tool during active surveillance has not been confirmed. The cost-effectiveness of this method requires further evaluation.

Use of the Prostate Health Index

Comments: determining the PHI is successfully used in clinical practice to optimize clinical sensitivity and specificity when assessing the probability of prostate cancer in the tPSA range of 2 to 10 ng/ml and with a negative ("normal") digital rectal examination result. The PHI index - is a calculated parameter whose formula combines the values of three serum tests: tPSA, fPSA, and -2proPSA. -2proPSA is an isoform of fPSA and is concentrated in the tissue of the peripheral zone of the prostate gland. A multicenter prospective study showed that using the PHI helps avoid up to 20% of so-called "unnecessary" biopsies. A correlation between the PHI value and the Gleason score (tumor grade/aggressiveness) has been demonstrated.

A multicenter prospective-retrospective study determined the clinical sensitivity and specificity of PHI at various cut-off values (Table 6).

Table 6. Clinical sensitivity and specificity of prostate cancer detection for various cut-off values of the Prostate Health Index (PHI) in men with negative digital rectal examination results^*

^*Hybritech and WHO calibrators were used for tPSA and fPSA determination.

A correlation between the PHI index and the probability of prostate cancer has also been demonstrated: the higher the PHI value, the higher the risk of prostate cancer (Table 7).

Table 7. Probability (risk assessment) of prostate cancer according to the Prostate Health Index (PHI) in patients with tPSA levels of 2 to 10 ng/ml and 1.6 to 7.8 ng/ml^*

Note. CI – confidence interval. ^*Hybritech and WHO calibrations were used to measure PSA and fPSA.

It is also advisable to use the PHI index in combination with other parameters in nomograms and prostate cancer risk calculators.

Comments: additional laboratory testing involves evaluating the following serum parameters: free prostate-specific antigen, [2]proPSA, and human kallikrein-2. When examining 161 prostate cancer patients who underwent radical prostatectomy (RP), kallikrein-2 levels differed significantly between patients with localized versus locally advanced prostate cancer [77]. Several studies indicate that measuring kallikrein-2 helps avoid a large number of "unnecessary" biopsies while not missing a significant amount of poorly differentiated prostate cancer [76].

Comments: elevated serum alkaline phosphatase activity is detected in 70% of patients with generalized disease.

2.4 Instrumental Diagnostics

In all patients with suspected prostate cancer (presence of a suspicious lesion in the prostate during DRE or elevated PSA level), it is recommended to perform transrectal ultrasonography (TRUS) to identify pathological areas in the prostate and improve the accuracy of transrectal prostate biopsy [79–82].

GOL CLOE 1Grade of Recommendation – C (Level of Evidence – 1).

Comments: the echographic appearance of prostate cancer is heterogeneous. Classic ultrasound semiotics of prostate cancer describe hypoechoic focal zones in the peripheral regions of the prostate gland [79, 83]. As tumor foci increase in size, they may contain both hypoechoic and hyperechoic areas. 37.6% of prostate tumors diagnosed on biopsy present as isoechoic areas on TRUS [84].

Comments: the feasibility of using the aforementioned novel ultrasound diagnostic methods is currently being investigated.

In patients with a Gleason score of ≥7, it is recommended to perform multiparametric magnetic resonance imaging (mpMRI) using the PI-RADS scoring system to diagnose prostate cancer, particularly to detect anterior prostate tumors that are inaccessible during standard biopsy [47, 88–91].

GOL ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

2.4.1. Diagnostic imaging methods for extracapsular extension of prostate tumor

Comments: the differential diagnostic accuracy of T2 and T3 stages based on transrectal ultrasound alone is quite low. TRUS does not provide greater accuracy in determining extracapsular tumor extension compared to DRE [92]. 3D-TRUS and color Doppler mapping do not improve diagnostic accuracy and are not recommended for local staging of prostate cancer [80, 93, 94].

Comments: MRI is a more sensitive diagnostic method for extraprostatic tumor extension, and the use of dynamic contrast-enhanced magnetic resonance prostatovesiculography with an endorectal magnetic coil increases staging accuracy by another 16%. The sensitivity and specificity of MRI for detecting extracapsular tumor extension and seminal vesicle involvement were 0.57 (95% CI: 0.49–0.64) and 0.91 (95% CI: 0.88–0.93), and 0.58 (95% CI: 0.47–0.68) and 0.96 (95% CI: 0.95–0.97), respectively – MRI has high specificity, but poor and heterogeneous sensitivity. Multiparametric MRI has low diagnostic performance for determining microscopic extracapsular tumor extension; however, as the length of the tumor extension into the periprostatic tissue increases, the detection rate of the latter rises. Thus, the detection rate of prostate cancer extracapsular extension less than 1 mm in length does not exceed 14%. At the same time, in the presence of extracapsular tumor spread greater than 3 mm in length, this indicator increases to 100%.

Comments: CT of the prostate is less informative than MRI for the differential diagnosis of localized and extraprostatic disease, but CT is more frequently prescribed for planning external beam radiotherapy (EBRT).

In all patients with a confirmed diagnosis of intermediate- or high-risk prostate cancer (according to the classification), evaluation of intrapelvic lymph nodes by pelvic CT or MRI is recommended [99, 100].

GCR BLEL 1Grade of Recommendation – B (Level of Evidence – 1).

The status of lymph nodes (LNs) (N stage) using pelvic MRI, abdominal and retroperitoneal ultrasound/CT is recommended to be assessed when planning radical treatment. In patients with T2 stage or lower, PSA level <20 ng/ml, and Gleason score <6, the probability of LN metastases does not exceed 10%, therefore they are not recommended to undergo LN staging [101].

GCR BLEL 2Grade of Recommendation - B (Level of Evidence – 2).

Comments: the status of lymph nodes (LNs) (N stage) should be assessed when planning radical treatment.

The use of whole-body positron emission tomography combined with whole-body bone computed tomography (PET-CT) with 11C-choline is not recommended for routine primary staging in prostate cancer patients and for determining lymph node metastases due to comparable sensitivity compared to mpMRI [102, 103].

GCR BLEL 2Grade of Recommendation - B (Level of Evidence – 2).

Comment: PSMA PET-CT (68Ga or 18F) has higher sensitivity compared to mpMRI and choline PET-CT, although small-sized lymph node metastases may remain undiagnosed [104].

2.4.2. Diagnostic methods for distant metastases

The following methods are used to diagnose distant metastases:

• bone scintigraphy,
• ultrasound, CT, MRI of the abdominal cavity,
• radiography, CT of the chest. Recommendations for the use of these methods are presented below.

In case of adverse factors, such as PSA greater than 20 ng/ml, presence of tumor with Gleason pattern 4 or 5 (ISUP 2–5) in biopsy material, as well as in patients with clinical signs of bone metastasis, whole-body bone scintigraphy (bone scan) is recommended to detect bone metastases (M stage) [105].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: the study can be omitted in patients without clinical symptoms from the skeletal system and with a PSA level <10 ng/ml. In the presence of symptoms (bone pain), it is recommended to perform skeletal bone scintigraphy regardless of the PSA level and tumor differentiation [106].

In doubtful cases based on bone scan results, it is recommended to perform PET-CT with 11C-choline, 18F-sodium fluoride, or whole-body MRI, which also allow for the diagnosis of visceral metastases [107].

GCR BLEL 2level of recommendation validity – B (level of evidence validity – 2).

2.5 Other Procedures

If the probability of prostate cancer persists based on the results of any of the three baseline diagnostic methods (digital rectal examination, serum PSA level determination, and TRUS), it is recommended to perform transrectal ultrasound-guided multifocal prostate biopsy to verify the diagnosis of prostate cancer [70, 81, 108, 109].

GCR ALEL 1level of recommendation validity – A (level of evidence validity – 1).

Comments: the standard technique for prostate biopsy is transrectal ultrasound-guided multifocal prostate biopsy [110, 111].

For TRUS, a 5.0–8.5 MHz rectal transducer is most commonly used. A standard biopsy needle has a diameter of 18 G and allows for obtaining a tissue core 15–20 mm in length. The standard biopsy technique involves bilateral sampling from the apex to the base of the gland. Performing a sextant biopsy is no longer considered acceptable. For a prostate volume of 30–40 ml, sampling from 8 or more sites is feasible. In all other cases, a 12-core biopsy must be performed. Biopsy of the transitional zone of the prostate has low sensitivity for tumor verification and may be recommended when performing a repeat biopsy

Patient preparation for biopsy, recommendations for the procedure

In patients with suspected prostate cancer, before performing a prostate biopsy to reduce the risk of infectious complications, it is recommended to administer a cleansing enema and treat the rectum with a povidone-iodine solution [112–114].

GCR BLEL 3level of recommendation validity – B (level of evidence validity – 3).

Comments: due to the increasing rate of microbial resistance to quinolones, as well as in the presence of risk factors for infectious complications, it is preferable to pre-culture rectal flora with antibiotic susceptibility testing (risk factors for infectious complications: prostate volume ≥ 75 cm³, diabetes mellitus, presence of a cystostomy or indwelling urinary catheter, long-term corticosteroid therapy, immunodeficiency states, voiding dysfunction) [115] to reduce the risk of infectious complications [81, 114, 116–118, 120]. To perform transperineal biopsy, which avoids contact with rectal flora, a single intravenous injection of #cefazolin 2 g under anesthesia is recommended [119].

Performing a repeat biopsy is recommended in case of negative initial biopsy results and persistent indications for the procedure [123].

GOL CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: repeat biopsy detects prostate cancer in 20% of men when no tumor was found on initial histological examination.

Indications for repeat biopsy:

• changes in PIN (5–30% risk of cancer) [123, 124];
• presence of atypical acinar proliferation (i.e., atypical glands suspicious for prostate cancer — 31–40% risk of cancer) [125, 126];
• persistently elevated or increasing PSA level;
• high-grade prostatic intraepithelial neoplasia (if multiple (three or more) cores of high-grade neoplasia are present in biopsy samples, the probability of detecting invasive prostate cancer upon repeat biopsy is 50–100%) [127–129];
• presence of a solitary microfocus of intraductal carcinoma (>90% risk of verifying poorly differentiated prostate cancer) [130];
• presence of a suspicious lesion in the prostate gland according to mpMRI.

The presence of high-grade prostatic intraepithelial neoplasia in one or two biopsy cores is no longer an indication for repeat biopsy.

Comments: the rate of prostate cancer detected by repeat saturation biopsy (>20 cores) ranges from 30 to 43% and depends on the number of prostate tissue cores obtained during the biopsy. In special cases, saturation biopsy can be performed transperineally. This allows diagnosing prostate cancer additionally in 38% of cases. It should be noted that acute urinary retention develops in 10% of patients after this procedure.

Comments: indications for seminal vesicle biopsy are currently not clearly defined. The decision to perform a seminal vesicle biopsy should be made individually, taking into account that the probability of tumor invasion into the seminal vesicles with a PSA value greater than 15 ng/mL is 20–25%. Seminal vesicle biopsy is useful only if it influences the choice of treatment strategy (choice between radiation therapy and radical surgery).

In cases where local treatment for prostate cancer is planned, to detect metastases in regional lymph nodes, it is recommended to perform bilateral pelvic lymph node dissection (PLND) via supra-pubic (open) or laparoscopic approaches in order to stratify patients who may be recommended for adjuvant therapy [101, 137–139].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: staging (T) of localized prostate cancer can be based on MRI results. Additional information is obtained from the number and localization of positive biopsy cores, the degree of tumor malignancy, and the serum PSA level.

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Genetic testing for germline mutations in genes involved in DNA repair via homologous recombination (HRR) (e.g., BRCA1, BRCA2, ATM, etc.) is recommended for all patients with locally advanced prostate cancer and regional lymph node metastases (N1). Testing for somatic HRR gene mutations potentially provides more comprehensive results compared to testing for germline mutations alone. Tumor testing for somatic mutations in HRR genes using NGS is recommended for all patients with metastatic prostate cancer [141].

GCR CLEL 5level of recommendation validity – C (level of evidence validity – 5).

Comments: as shown by the diagnostic part of the PROfound study involving 4,425 patients with mCRPC, HRR gene mutations occur in 27.9% of cases. The study identified both germline and somatic mutations in the following 15 HRR genes: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. These mutations were detected by genetic testing of DNA from tumor tissue using next-generation sequencing (NGS) [142]. The detection of HRR gene mutations may influence patient management tactics (e.g., the prescription of the PARP (poly(ADP-ribose)polymerase) inhibitor olaparib^**) [141].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The prescription and use of medicinal products indicated in the clinical guideline are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition.

3.1. Watchful waiting (delayed treatment)

Indications for watchful waiting:

• localized prostate cancer (T1a–T2cN0M0);
• expected life expectancy of the patient less than 10 years (less than 15 years for TaG1–G2);
• well-differentiated tumor;
• severe concomitant diseases.

When analyzing the results of the delayed treatment strategy, it was noted that the 10-year cancer-specific survival of patients with well- and moderately differentiated tumors is 87%, and of patients with poorly differentiated tumors is 34% [143]. Other studies have demonstrated that in patients with T1–2 prostate cancer and tumor differentiation of ISUP ≤2, cancer-specific survival rates were 82–87% and 80–95%, respectively [144]. The risk of death from prostate cancer during watchful waiting in various age groups with a tumor differentiation of Gleason score 2–4 is 4–7%, score 5 is 6–11%, score 6 is 18–30%, score 7 is 42–70%, score 8–10 is 67–80% (level of recommendation – C, level of evidence – 3) [145]. The PIVOT study demonstrated no benefit of active surgical treatment in low-risk prostate cancer patients compared with watchful waiting at a median follow-up of 12.7 years [146].

For patients with severe comorbid pathology and an expected life expectancy of less than 10 years, watchful waiting (delayed treatment) strategy is recommended [134, 145].

GOL ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: the watchful waiting (delayed treatment) strategy implies refraining from immediate treatment upon detection of prostate cancer, with dynamic monitoring and initiation of therapy upon signs of disease progression. This tactical option avoids complications and adverse reactions of radical treatments

Upon the appearance of signs of disease progression and the motivation or desire of the patient under watchful waiting for active treatment, hormone therapy is recommended [147, 148].

GCR ALEL 1level of recommendation validity – A (level of evidence validity – 1).

Comments: the patient should be informed that immediate initiation of hormone therapy for prostate cancer leads to longer cancer-specific survival than delayed initiation of treatment.

In presumably localized prostate cancer (N0, M0)

For young patients with a moderately differentiated tumor (stages T1a, T1b, T1c) undergoing watchful waiting with an expected life expectancy >10 years, periodic repeat PSA testing, TRUS, and biopsy are recommended to detect signs of disease progression [98, 149].

GCR CLEL 5level of recommendation validity – C (level of evidence validity – 5).

Comments: the frequency of repeat examinations is not currently defined, but should not be less than 3 months and more than 12 months.

For patients with a well- and moderately differentiated tumor of stage T1b–T2b without clinical manifestations, with an expected life expectancy <10 years, undergoing watchful waiting, it is recommended to perform repeat PSA testing, TRUS, and biopsy to detect signs of disease progression [98].

GCR CLEL 5level of recommendation validity – C (level of evidence validity – 5).

Comments: the frequency of repeat examinations is not currently defined, but should not be less than 3 months and more than 12 months.

3.2. Active surveillance

Comments: the term "active surveillance", also known as "active monitoring", reflects conservative management of prostate cancer. The term was adopted in the past decade and implies that immediate treatment is not necessary for the patient. The patient is closely monitored and receives treatment at predefined progression milestones determined by parameters such as a short PSA doubling time and worsening pathomorphological findings on repeat biopsy. The treatment strategy in this case aims at a complete cure of the patient.

Active surveillance was proposed to reduce the rate of overtreatment in patients with clinically localized prostate cancer in the very low progression risk group without abandoning radical treatment, unlike the watchful waiting approach [153]. A number of additional studies on active surveillance in clinically localized prostate cancer have been conducted (Tables 8, 9). These studies have confirmed that strictly selected patients with very low-risk prostate cancer exhibit very slow progression and low cancer-specific mortality, and only a limited number of patients require delayed radical treatment.

Table 8. Clinical trials on active surveillance in patients with localized prostate cancer, inclusion criteria

Table 9. Clinical studies on active surveillance in patients with localized prostate cancer (main results)

Note. RP – radical retropubic prostatectomy; PSA DT – PSA doubling time.

Criteria for initiating treatment after active surveillance are less clearly defined, but the following are recommended for most cohorts:

• PSA doubling time with a threshold of 2 to 4 years. This criterion is questioned due to the weak correlation between PSA doubling time and the degree of tumor progression on repeat biopsy;
• an increase in the Gleason score >7 during systematic follow-up biopsies performed at intervals of 1–4 years.

Table 10 demonstrates the main criteria for active surveillance and delayed treatment.

Table 10. Definition of active surveillance and delayed treatment [154]

Note. DRE — digital rectal examination; PSA — prostate-specific antigen; mpMRI — multiparametric magnetic resonance imaging.

3.3. Surgical treatment

3.3.1. Radical prostatectomy

As one of the primary treatment methods for patients with localized PCa, RPE is recommended [134, 155–157].

GCR ALOE 1Grade of Recommendation — A (Level of Evidence — 1).

Comments: surgical treatment (radical prostatectomy) involves the removal of the prostate gland with its capsule, seminal vesicles, and a segment of the urethra, followed by the formation of a vesicourethral anastomosis. The goal of surgery for localized and locally advanced non-metastatic prostate cancer is complete cure of the patient.

Radical surgical treatment is typically performed in PCa patients with a life expectancy of more than 10 years.

Table 11 presents long-term outcomes of surgical treatment in patients with PCa.

Table 11. Long-term outcomes of surgical treatment in patients with PCa

Surgical access options for radical prostatectomy:

• • • • retropubic;
      • perineal;
      • laparoscopic/robotic.

A phase III randomized trial demonstrated that robot-assisted RPE reduces hospitalization time and intraoperative blood loss, and provides earlier recovery of continence [158]. However, updated data following a 24-month follow-up analysis of patients with PCa after surgical treatment revealed no significant differences in functional outcomes depending on the surgical approach (retropubic, laparoscopic, or robot-assisted) [159]. A statistically significant impact on the functional and oncological outcomes of surgical treatment in PCa patients was exerted by the experience of the operating surgeon [160–162]. Furthermore, highly experienced surgeons exhibit a lower rate of positive surgical margins [163, 164]. Thus, none of the surgical approaches can be recommended as superior.

3.3.2. Pelvic lymphadenectomy

Comment: PLND is the most accurate method for assessing the status of pelvic lymph nodes in patients with PCa. Based on the extent of lymphadenectomy performed, there are 3 main types of PLND: limited, standard, and extended. Standard PLND involves the removal of fatty tissue containing LNs between the external and internal iliac arteries from the bifurcation of the common iliac artery to the pubic bone-encircling artery (Cooper's ligament). The lateral boundary of the lymphadenectomy is the medial border of the external iliac artery, the medial boundary is the obturator nerve, and the posterior boundary is the obturator muscle. During standard lymphadenectomy, the obturator and external iliac LNs are removed. Limited PLND involves the removal of only the obturator group LNs. Extended PLND implies the additional removal of tissue with lymph nodes along the internal and common iliac vessels. According to literature data, removing these LN groups allows for accurate PCa staging in 94% of cases [139]. According to some authors, performing PLND during RPE does not affect oncological outcomes, including post-surgical survival [138]. Nevertheless, it is crucial to emphasize the importance of extended PLND for accurate disease staging, as none of the current diagnostic methods possess sufficient sensitivity and specificity to assess regional lymph node status [138]. To determine the risk of lymphogenous metastases, a number of nomograms based on preoperative prognostic factors have been developed. The most well-known are the Briganti nomograms [165, 166], the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram [167], and the Roach formula [168]. If the risk of lymphogenous metastases exceeds 5 %, performing an extended pelvic lymphadenectomy is mandatory [169, 170].

3.3.3. Pelvic lymphadenectomy with sentinel lymph node mapping

Recently, sentinel lymph node (SLN) mapping has been introduced into the clinical practice for patients with PCa. PLND with SLN assessment in patients with PCa is a relatively new diagnostic method for staging lymphogenous metastases. The method is based on radioisotope lymphoscintigraphy using a lymphotropic radiopharmaceutical (RFP) capable of selective accumulation in LN tissue. This procedure requires special hardware and software: a radioisotope laboratory facility, a gamma camera, a gamma radiation detector, and the radiopharmaceutical itself.

It should be noted that the primary goal of PLND with SLN mapping is the detection and removal of all SLNs, including those located outside the boundaries of standard PLND, with sensitivity reaching 95.2% according to world literature [171]. Thus, the detection of SLNs in patients with PCa is an important diagnostic step during PLND and significantly improves its diagnostic yield. However, this technique is not standard, and controversies persist regarding technical aspects of the procedure (radiopharmaceutical dosage, radiopharmaceutical uptake index for sentinel lymph node biopsy, etc.). Randomized prospective studies are required to include this technique in treatment standards [172].

3.3.4. Nerve-sparing radical prostatectomy

Comments: nerve-sparing RPE can be recommended for the majority of men with low-risk localized PCa. A relative contraindication to this surgical technique is a high risk of extracapsular extension (cT2c stage, biopsy Gleason grade/ ISUP score >3). The use of validated nomograms to calculate the risk of extracapsular tumor extension helps in deciding whether to use or omit the nerve-sparing technique during RPE [175, 176]. In addition to nomograms, mpMRI evaluating the neurovascular bundles is recommended to guide the decision on nerve-sparing surgery [177].

3.3.5. Radical prostatectomy in patients with PCa with lymph node metastases

Comments: data from several prospective studies comparing survival rates in PCa patients with lymph node metastases (pN1) demonstrate a survival benefit of RPE in the management of this patient cohort [178].

3.3.6. Neoadjuvant antiandrogen therapy

In patients with stage T1–T2 PCa, it is not recommended to administer short (3-month) or long (9-month) courses of neoadjuvant therapy with gonadotropin-releasing hormone agonists [179].

GCR ALOE 1Grade of Recommendation — A (Level of Evidence — 1).

Comments: according to several studies, neoadjuvant hormone therapy reduced the detection rate of locally advanced tumors, lowered the rate of positive surgical margins, and decreased the probability of pelvic lymph node metastases; however, it had no impact on survival rates (recurrence-free, cancer-specific) [179]. Therefore, neoadjuvant hormone therapy prior to surgery is not recommended in routine clinical practice.

3.3.7. Complications of surgical treatment in patients with PCa

Intraoperative and postoperative complications of RPE stratified by access type are presented in Table 12 [181].

Table 12. Intraoperative and postoperative complications of RPE and RARP

Note. RARP – robot-assisted radical prostatectomy; RPE – radical prostatectomy; RRP – radical retropubic prostatectomy.

Erectile dysfunction occurs in all patients following radical prostatectomy performed without a nerve-sparing technique.

The most frequent complications of extended PLND include lymphocele formation (10.3–19.8%) and deep vein thrombosis of the lower extremities (less than 1%) [182–184].

3.3.8. Salvage prostatectomy

For patients with local recurrence after external beam radiotherapy and minimal comorbidities, it is recommended to perform salvage RPE in medical institutions with sufficient surgical expertise, with the goal of local tumor control [185].

GCR ALEL 2Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) - A (level of evidence – 2).

Comments: salvage RPE for local recurrences after radiotherapy is an optimal method to achieve satisfactory outcomes and local tumor control. However, it should be noted that the risk of complications and side effects with salvage RPE is significantly higher than with primary surgery due to fibrosis and slower regeneration of irradiated tissues.

A literature review by Chade et al. demonstrated that salvage radical prostatectomy achieves the following outcomes: 5- and 10-year biochemical recurrence-free survival rates ranging from 47-82% and 28-53%, respectively, while 10-year cancer-specific survival and overall survival rates varied within 70-83% and 54-89%, respectively. The most significant predictors of localized recurrence, disease progression, and cancer-specific survival were the pre-salvage radical prostatectomy PSA level and tumor differentiation grade on biopsy [186].

Salvage radical prostatectomy should be performed only in selected patients with minimal comorbidities, a life expectancy of at least 10 years, a pre-operative PSA level of less than 10 ng/mL, an ISUP tumor differentiation grade <2/3, no pre-operative distant metastases, and clinical stage ≤T2 [186]. According to meta-analyses, salvage radical prostatectomy is associated with less favorable incontinence outcomes compared to non-surgical treatment modalities [185].

3.4. Radiation therapy

Radiotherapy (RT) is one of the primary treatment modalities for prostate cancer (PCa) and can be used either as a monotherapy or as a component of combined and multimodal treatment. Advances in imaging over recent decades, the development of information technologies, the improvement and widespread clinical implementation of modern radiotherapy equipment, and the refinement of radiotherapy planning and dose delivery methods enable precise tumor irradiation with minimal impact on surrounding healthy organs.

Radiotherapy Options

• By the method of delivering ionizing radiation to the tumor:

a) external beam radiotherapy;

b) brachytherapy;

c) combined radiotherapy.

• By the type of ionizing radiation:

a) photon (electromagnetic);

b) corpuscular (particles).

Various RT options are used in the treatment of prostate cancer.

• External Beam Radiotherapy:

• photon:

- standard (2D, conventional);

- conformal (3D);

- intensity-modulated radiotherapy;

• corpuscular:

- proton (high-energy protons);

- neutron (fast neutrons).

• Interstitial Radiotherapy (Brachytherapy):

a) high-dose-rate brachytherapy (temporary);

b) low-dose-rate brachytherapy (permanent, continuous).

• Combined Radiotherapy: a combination of two dose delivery methods – external beam radiotherapy and brachytherapy.

As a radical treatment method for localized PCa, it is recommended to use RT in combination with hormone therapy (both neoadjuvant and adjuvant) to improve patient survival [179, 187].

GCR ALOE 1Grade of Recommendation — A (Level of Evidence — 1).

3.4.1. External beam radiation therapy (EBRT)

The most common method of radiotherapy for PCa is external beam radiotherapy (EBRT).

Indications for EBRT in PCa:

• localized PCa (T1–T2N0M0);
• locally advanced PCa (T3–T4N0M0), in combination with hormone therapy.

Contraindications to EBRT in PCa:

• presence of concomitant infectious and inflammatory diseases of the urogenital system, bowel, or fistulas;
• prior pelvic irradiation;
• indwelling urethral catheter;
• infravesical obstruction;
• "microcystis";
• decompensated somatic comorbidities;
• mental disorders;
• cachexia.

Advantages of EBRT:

• potential for complete cure;
• accessibility;
• fewer restrictions on use (age, concomitant somatic diseases, etc.);
• absence of perioperative complications;
• outpatient treatment capability.

Disadvantages of EBRT:

• treatment duration (radical courses in conventional fractionation regimens take up to 1.5–2.0 months);
• inability to precisely stage the tumor process;
• inability to cure concomitant benign prostatic hyperplasia.

Conventional EBRT in PCa

For patients with localized PCa (T1–T2N0M0) in combination with hormone therapy, and patients with locally advanced PCa (T3–T4N0M0), it is recommended to perform external beam radiotherapy [179, 187].

LoE CGoE 5Level of Evidence - C (Level of Evidence – 5).

If conformal (3D) EBRT is not feasible, it is recommended to perform EBRT using 2D planning (conventional), in which the prostate gland and seminal vesicles are identified based on the anatomical structure of surrounding organs (bone structures, contrast-enhanced bladder, rectum) [187–189].

GCR ALOE 1Grade of Recommendation — A (Level of Evidence — 1).

Comments: when performing conventional EBRT, a conventional fractionation regimen is used with a fractional dose (FD) of 1.8–2.0 Gy daily, once a day, five days a week, up to a total dose (TD) of 65–70 Gy. If irradiation of regional lymph nodes is necessary, the TD to the pelvic region is 45-50 Gy [190].

Conformal EBRT in PCa

Conformal EBRT (external beam radiotherapy using medical electron accelerators) for PCa is delivered using bremsstrahlung radiation from high-energy linear electron accelerators (LEAs) equipped with a multileaf collimator, following volumetric (3D) dosimetric planning.

The conformal radiotherapy technique involves a sequence of successive procedures:

• X-ray topometric patient preparation using a computed tomograph, with the patient in a position identical to the treatment position, mandatory use of immobilization devices ensuring patient fixation in a comfortable and functional position;
• determination of target volumes (based on a series of computed tomography scans obtained during CT topometry). All information obtained from diagnostic studies, as well as clinical, constitutional, and pathomorphological factors, must be taken into account;
• 3D dosimetric treatment planning (EBRT);
• verification of patient positioning;
• delivery of EBRT sessions.

The choice of treatment tactics for prostate cancer is determined by the patient's affiliation with a particular prognostic group [191].

• Low risk of progression – conformal radiation therapy at a total dose (TD) of 74–78 Gy. The irradiation volume includes the prostate gland (± seminal vesicles). Irradiation of the pelvic lymph nodes and/or hormone therapy is not indicated.
• Intermediate risk – conformal radiation therapy at a TD of 74–78 Gy¹ combined with neoadjuvant², concurrent, and adjuvant hormone therapy (for 4–6 months). The irradiation volume includes the prostate gland and seminal vesicles³ [98].
• High risk – conformal radiation therapy at a TD of 74–81 Gy¹ combined with neoadjuvant², concurrent, and adjuvant hormone therapy (for 24–36 months). The irradiation volume includes the prostate gland and seminal vesicles³ [98, 200–211].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments:

¹Escalation of TD ≥74 Gy contributes to improved survival in patients with prostate cancer at intermediate and high risk of disease progression. To reduce the risk of radiation-induced complications during TD escalation, the use of image-guided intensity-modulated radiation therapy (IG-IMRT) is recommended.

²The administration of neoadjuvant hormone therapy prior to EBRT in patients with prostate cancer at intermediate and high risk of disease progression helps reduce prostate volume, alleviate local disease symptoms, and lower the incidence of radiation-induced complications.

³In patients with prostate cancer at intermediate and high risk of disease progression in the presence of additional adverse prognostic factors, the feasibility of including regional lymph nodes in the irradiation volume may be considered [98].

In patients with a very high risk of progression, wide-field radiation therapy is recommended – a combination of irradiation of the lesser pelvis lymphatic drainage areas and additional local irradiation of the seminal vesicles and prostate gland (with sequential reduction of the volume of irradiated tissues) [200].

If irradiation of regional lymph nodes is necessary, the irradiation volumes are defined in accordance with RTOG recommendations [201, 202].

Radiation dose constraints for critical organs [203, 204]

Critical structures (organs at risk) during prostate cancer radiation therapy include the rectum, urinary bladder, penile bulb, intestines, and femoral heads. Contouring of organs at risk is performed in accordance with RTOG recommendations [205].

Toxicity assessment

Acute and late treatment toxicity is assessed in accordance with RTOG/EORTC classifications [206].

Hypofractionation

In recent years, interest has justifiably grown in the use of hypofractionation regimens for prostate cancer radiation therapy, which involve increasing the fractional dose (FD), reducing the number of fractions, and shortening treatment time. In randomized trials involving radiation therapy (IMRT, IGRT) moderate hypofractionation regimens have been studied (at an FD of 2.4–4.0 Gy per fraction over 4-6 weeks); data have been obtained showing that these regimens have efficacy and toxicity quite comparable to those of traditional dose fractionation [207–211]. Moderate hypofractionation regimens can be used in conformal irradiation for prostate cancer as an alternative to the traditional regimen, provided that high-precision targeting is achieved through the use of technologiesIGRT, IMRT.

The implementation of extreme hypofractionation regimens used in IG-IMRT (SBRT) and involving the delivery of an FD ≥6.5 Gy over several fractions is possible only in specialized centers with the appropriate level of technical equipment, trained personnel, and clinical experience in performing this technology [98].

Palliative radiation therapy

In patients with advanced forms of the disease, in order to improve quality of life (reduction of dysuric symptoms, pain syndrome, hematuria) and achieve the maximum possible therapeutic effect on the prostate tumor in such cases, the use of palliative radiation therapy is recommended [212].

GCR ALEL 1Grade of Recommendation - A (Level of Evidence – 1).

Comments: fractionation regimen: FD 2-3 Gy, daily, once a day, 5 days a week, up to a TD equivalent to 50 Gy. If a therapeutic effect is achieved after palliative treatment and the patient's general somatic condition improves, the possibility of continuing treatment with a radical program should be considered.

Symptomatic radiation therapy

In patients with prostate cancer, to relieve or reduce disease manifestations (pain syndrome in bone metastases) in order to improve quality of life (reduction or relief of pain), the use of symptomatic radiation therapy is recommended [212–214].

GCR ALEL 1Grade of Recommendation - A (Level of Evidence – 1).

Comments: the fractionation regimen is determined by the specific clinical situation and the patient's somatic condition.

Several irradiation regimens can be used:

• FD 8 Gy, single dose;
• FD 5 Gy, every other day, 5 fractions, up to a TD of 25 Gy;
• FD 4 Gy, daily, 5 times a week, 5-6 fractions, up to a TD of 20-24 Gy;
• FD 3 Gy, daily, 5 times a week, 10 fractions, up to a TD of 30 Gy.

3.4.2. Brachytherapy (interstitial radiation therapy)

Brachytherapy (BT) consists of the introduction (implantation) of radioactive sources directly into the prostate tissue. In prostate cancer, both low-dose-rate (radiation source permanently remains in tissues) and high-dose-rate (radiation source temporarily remains in tissues) BT are used. Brachytherapy is based on the temporary or permanent insertion of radiation sources into the affected organ.

Currently, brachytherapy in the low- and intermediate-risk patient subgroup, along with radical prostatectomy and external beam radiation therapy, is an effective treatment method for prostate cancer [215–217].

Low-dose-rate brachytherapy

Indications for low-dose-rate brachytherapy in prostate cancer:

• PSA level ≤10 ng/mL;
• Gleason score 6 (3 + 3) or 7 (3 + 4) in less than 33% of core biopsies;
• clinical T1c–T2a, N0, M0;
• prostate volume ≤50 cm³.

Contraindications:

• absolute:

- presence of metastases;

- expected patient life expectancy less than 5 years;

• relative:

- presence of prostatitis;

- large prostate size;

- rectal diseases (ulcerative colitis, proctitis, etc.);

- patient age;

- pronounced dysuric symptoms (high IPSS score, presence of a large amount of residual urine).

In localized prostate cancer, it is recommended to use permanent BT, in which radioactive sources of I-125 (half-life 60 days) or Pd-103 (half-life 17 days) are introduced into the prostate gland [216, 218].

LoE CGoE 5Level of Evidence - C (Level of Evidence – 5).

Comments: due to the more homogeneous distribution of ionizing radiation, BT makes it possible to deliver a higher TD to the prostate gland with less radiation impact on surrounding tissues compared to EBRT. Radioactive sources are implanted through the perineum under transrectal ultrasound guidance. Recommended doses for monotherapy BT with I-125 implantation are 140–160 Gy and 110-125 Gy with Pd-103 implantation.

When using various modern implantation techniques, a history of TURP and prostate volume are not contraindications for BT [215, 216]. Studies have also shown that the presence of prostatitis does not affect urination quality after implantation [217], and inflammatory bowel disease does not lead to increased gastrointestinal toxicity [219]. Patient age is also not a limiting factor for BT: procedure tolerability is practically comparable across different age groups, and good recurrence-free survival results among younger patients expand the applicability of the technique [220].

High-dose-rate brachytherapy

High-dose-rate brachytherapy involves the use of temporary radiation sources with an activity of 1,200 cGy/hour and higher. The most commonly used source in practice is iridium-192 (Ir 192), which has a half-life of approximately 72 days.

The use of high-dose-rate brachytherapy (temporary implantation technique), which involves the removal of radionuclides after radiation completion, has also found wide application in clinical practice compared to permanent implantation. This is due to the fact that this technology allows for a more precise and uniform dose distribution throughout the irradiated volume, enabling radical treatment both as a monotherapy and in various combinations with EBRT.

Indications for high-dose-rate brachytherapy in PCa:

• PSA level without an upper limit, but without distant metastases^x;
• Gleason score up to 10^x;
• clinical T1–T3, N0, M0^x;
• prostate volume ≤50 cm³ (a larger volume is not a contraindication).

Note. ^X – refers to the possibility of use in a combined regimen (DLT + BT).

Contraindications:

• absolute:

- presence of metastases;

- inability to undergo anesthesia or maintain the supine position;

- presence of a rectourethral fistula;

• relative:

- history of TURP (brachytherapy performed no earlier than 6 months after TURP);

- urodynamic indications (except for severe obstructive symptoms, IPSS >20, Qmax <10 ml/s).

Unlike low-dose-rate brachytherapy, due to its specific features and advantages, this treatment method allows for treatment in virtually all patients with localized and locally advanced prostate cancer. From the standpoint of modern radiobiology, when performing radiation therapy for PCa, the use of hypofractionation regimens and, consequently, high-dose-rate brachytherapy is preferable, as it has the potential to be a more effective technique compared to traditional radiation treatment technologies even with dose escalation, as well as compared to low-dose-rate brachytherapy.

Advantages of high-dose-rate brachytherapy

When comparing high- and low-dose-rate brachytherapy techniques in the treatment of PCa, according to International Atomic Energy Agency (IAEA) recommendations [221], high-dose-rate interstitial radiation therapy has several of the following advantages:

• elimination of radiation doses to staff and visitors;
• elimination of source preparation and transport for each patient;
• less discomfort and lower risks of thromboembolism due to the short duration of the patient staying in the lithotomy position;
• optimization of dose distribution;
• ability to integrate external beam radiation therapy and high-dose-rate brachytherapy, leading to a shorter total treatment duration and potentially better tumor control;
• higher patient throughput in large specialized centers;
• shorter staff training period compared to the implementation of low-dose-rate brachytherapy;
• absence of source migration relative to the target volume throughout the entire radiation treatment course;
• more effective dose-volume optimization potential associated with source-stepping technology;
• lower toxicity due to improved sparing of organs at risk: urethra, rectum, urinary bladder, and penile bulb.

Disadvantages of high-dose-rate brachytherapy

According to the same IAEA recommendations [221], high-dose-rate brachytherapy also has a number of disadvantages:

• the necessity of ensuring a high level of quality assurance before each high-dose-rate brachytherapy application, associated with the use of multiple fractions in the treatment scheme requiring repeated insertion of intracats;
• the lack of comparative and prospective randomized studies on quality of life;
• unclear economic benefit compared to low-dose-rate brachytherapy. However, with a high center throughput, ¹⁹²Ir monotherapy has an economic advantage.

Regimens for high-dose-rate brachytherapy

High-dose-rate BT can be performed both as an independent treatment method for patients with low- and intermediate-risk prostate cancer, and in combination with EBRT for the treatment of patients with high-risk localized prostate cancer.

In clinical practice, when performing high-dose-rate BT as monotherapy, the following dose delivery regimens are most frequently used:

1 implantation – 1 fraction of 19 Gy, 2 fractions of 12–15 Gy, 3 fractions of 10–11.5 Gy, 4 fractions of 8.5–9.5 Gy, 6 fractions of 6.5–7 Gy;

2 implantations – 2 fractions of 12–15 Gy, 6 fractions of 6.5–7 Gy;

3 implantations – 3 fractions of 10–11.5 Gy.

High-dose-rate BT using 2 or more implantations is characterized by high efficacy and good tolerability. When implementing this technology, the standard interval between implantations ranges from 1 to 3 weeks.

Currently, the delivery of 19 Gy in 1 fraction can be recommended only within the framework of research protocols.

When performing high-dose-rate BT as a component of combined radiation therapy for patients with intermediate- and high-risk prostate cancer, the following dose delivery regimens are often used: 16 Gy in 3 fractions, 11–22 Gy in 2 fractions, and 12–15 Gy in a single fraction. There is evidence of equivalent efficacy and comparable low toxicity of high-dose-rate BT in the following regimens: 1 fraction of 15 Gy and 2 fractions of 10 Gy.

The recommended dose delivery regimens for high-dose-rate BT as monotherapy are: 2 fractions (2 implantations) of 10–15 Gy each; 3 fractions (3 implantations) of 10–11.5 Gy each. In all cases, the total dose to the prostate gland (λ/β = 1.5–3) must be at least the dose equivalent to 100 Gy in standard (2 Gy) fractionation [218].

LoE CGoE 5Level of Evidence - C (Level of Evidence – 5).

When using high-dose-rate BT as a stage of combined radiation therapy, the recommended regimen is 1 fraction of 15 Gy [218].

GCR CLEL 5Grade of recommendation – C (Level of evidence – 5).

For patients with prostate cancer recurrence after external beam radiation therapy or brachytherapy, as well as for patients after non-radical prostatectomy, salvage low-dose-rate or high-dose-rate brachytherapy is recommended [218, 222, 223].

GCR CLEL 4Grade of recommendation - C (Level of evidence – 4).

Comments: when using salvage high-dose-rate Ir-192 brachytherapy, the following advantages can be highlighted: firstly, the total target dose is reduced from 60–70 Gy with traditional salvage external beam radiation therapy to 15–18 Gy with salvage high-dose-rate brachytherapy, without loss of the lethal radiobiological effect on recurrent prostate cancer cells, which in turn significantly reduces radiation loads on critical organs and thereby decreases the risk of radiation-induced injuries; secondly, unlike hormone therapy, salvage high-dose-rate brachytherapy is a radical method for treating prostate cancer recurrence.

It should be noted that salvage brachytherapy must be performed in specialized centers with extensive experience in brachytherapy procedures.

3.5. Pharmacotherapy

The choice of drug therapy is determined in a specific clinical situation in accordance with the instructions for medical use of specific drugs, the presence of indications for use, and contraindications in the patient.

3.5.1. Prognostic factors for survival in patients with newly diagnosed metastatic PCa

The median survival of patients with newly diagnosed metastatic prostate cancer is approximately 42 months [224]. However, this patient population is heterogeneous. A number of prognostic survival factors have been proposed, including the number and localization of bone metastases, the presence of visceral metastases, the ISUP grade, disease extent (low or high disease volume), and PSA level at 7 months from the start of therapy [225–228].

Table 13. Prognostic factors based on the SWOG 9346 study [229]

3.5.2. First-line hormonal therapy

Primary ADT has been the standard of care for over 50 years [230]. There is a lack of Level 1 evidence confirming the superiority of a specific type of HT: orchiectomy, GnRH agonists, or GnRH antagonists. The exception is patients with impending spinal cord compression, for whom bilateral orchiectomy or GnRH antagonists are the preferred options.

According to modern diagnostic methods, testosterone levels after surgical castration are 15 ng/dL. Several studies have shown that treatment outcomes are consistently better at lower testosterone levels than at the traditional level of <50 ng/dL (1.7 nmol/L). Therefore, the modern castrate testosterone level is considered to be <20 ng/dL (0.7 nmol/L). At the same time, the castrate level considered by regulatory authorities and used in clinical trials of ADT for prostate cancer remains <50 ng/dL (1.7 mmol/L).

Gonadotropin-releasing hormone agonists

Comments: the mechanism of action of GnRH agonists is based on the desensitization of GnRH receptors, leading to a decrease in pituitary luteinizing hormone production and subsequently to a reduction in testosterone production by Leydig cells in the testes. Following the administration of GnRH agonists, a transient increase in testosterone concentration by 3–5 days is observed (flare-up phenomenon), followed by its decrease to post-castration levels by days 21–28. To prevent the flare-up phenomenon in patients with metastatic prostate cancer, antiandrogens should be prescribed prior to GnRH agonist administration and during the 1st week of therapy.

Side effects and complications of therapy with GnRH agonists are similar to those of surgical castration.

Indications for GnRH agonists:

• localized prostate cancer (T1–2N0M0) – when radical treatment is impossible or refused by the patient (both in the presence and absence of symptoms, with a PSA doubling time of less than 12 months and a total PSA level of more than 50 ng/mL, as well as in the presence of a poorly differentiated tumor) or as neoadjuvant therapy before radical radiation therapy;
• locally advanced prostate cancer (T3–4N0M0) – as monotherapy or as neoadjuvant and adjuvant therapy in combination with surgical or radiation treatment;
• metastatic prostate cancer (T1–4N1M0, N1–4N0M1).

For the treatment of prostate cancer, it is recommended to use GnRH agonists [231, 232].

GGR ALOCE 1Grading of Recommendations Assessment, Development, and Evaluation – A (Level of Evidence – 1).

Comments:

The following treatment regimens are used:

Goserelin** 3.6 mg subcutaneously into the anterior abdominal wall once every 28 days or 10.8 mg subcutaneously into the anterior abdominal wall once every 3 months; the medicinal product is in a depot form in a preloaded syringe, ready for use.

Leuprorelin** 3.75 mg, or 7.5 mg, or 11.25 mg, or 22.5 mg, or 45 mg depending on the duration of action and dosage form (manufacturer).

Triptorelin** 3.75 mg intramuscularly once every 28 days or Triptorelin** 11.25 mg intramuscularly or subcutaneously once every 3 months; the medicinal product is dissolved immediately before injection and administered as a suspension.

Buserelin** 3.75 mg intramuscularly once every 28 days; the medicinal product is dissolved immediately before injection and administered as a suspension.

Large randomized placebo-controlled trials with buserelin have not been conducted.

Treatment with GnRH agonists is carried out long-term, until the development of resistance to hormonal therapy. Some authors recommend the use of GnRH agonists in an intermittent therapy regimen, but the efficacy of intermittent blockade remains debatable.

Gonadotropin-releasing hormone antagonists

Unlike GnRH agonists, antagonists competitively bind to GnRH receptors in the pituitary gland without inducing a "flare" effect.

Degarelix** is the most studied GnRH antagonist for subcutaneous administration once a month.

Based on the results of a large randomized trial (n = 610), the standard dose of degarelix** should be 240 mg in the first month, followed by 80 mg monthly injections. The main specific side effect of degarelix** is injection site pain (moderate or mild), identified in 40% of patients, predominantly after the first injection.

Combined data from six prospective phase III randomized trials involving 2,328 men between 2005 and 2012, evaluating the comparative efficacy of GnRH agonists versus antagonists, were analyzed to determine potential differences in the development of cardiovascular events after initiating gonadotropin-releasing hormone agonists compared to GnRH antagonists (degarelix**). Compared with GnRH agonists, the use of the GnRH antagonist degarelix** resulted in a 56% reduction in cardiovascular events in prostate cancer patients with a history of cardiovascular disease [233].

This hypothesis was confirmed by data from a prospective randomized phase II trial comparing GnRH agonists and antagonists in patients with advanced prostate cancer and a history of heart disease. Patients receiving GnRH antagonists had a significantly lower number of cardiac events over one year of therapy compared to GnRH agonists [234]. The phase III PRONOUNCE trial [235] is currently ongoing to provide further confirmation of the data obtained in this study.

As part of the CS21 study, an additional analysis of treatment efficacy regarding alkaline phosphatase concentrations was performed. Baseline bone-specific alkaline phosphatase (BSAP) levels were high in patients with metastatic disease. In patients with metastatic disease or with a baseline PSA level ≥50 ng/mL, a pronounced decrease in BSAP levels was observed with degarelix compared to the GnRH agonist group. Unlike patients in the GnRH agonist group, patients in the degarelix therapy group maintained low BSAP levels throughout the entire study period [236].

In patients with early signs of spinal cord compression or infravesical obstruction, it is recommended to use GnRH antagonists (degarelix**) [236, 237].

GGR BLOCE 1Grading of Recommendations Assessment, Development, and Evaluation – B (Level of Evidence – 1).

ADT with non-steroidal antiandrogens

Based on a Cochrane systematic review, non-steroidal antiandrogen (NSAA) monotherapy compared to castration (medical or surgical) proved to be a less effective therapy in terms of overall survival, clinical progression, treatment failure, and discontinuation due to adverse events [232].

In patients with M1 stage receiving GnRH agonist therapy, initial short-term antiandrogen therapy (ATC G03HB Antiandrogens and estrogens) is recommended to reduce the risk of the "flare" effect [232, 238–241].

GOL ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

In patients with M1 stage disease, antiandrogen monotherapy is not recommended [232].

GOL ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comparison of intermittent and continuous antiandrogen therapy

The clinical efficacy of intermittent hormonal therapy (IHT) was evaluated in three independent reviews [242–244] and two meta-analyses [245, 246]. All of these reviews included data from eight randomized clinical trials, of which only three were conducted exclusively in patients with distant metastases (M1). The remaining five studies included various patient groups, predominantly with locally advanced tumors or disease recurrence.

The SWOG 9346 trial is the largest study evaluating the efficacy of intermittent androgen deprivation (IAD) in patients with M1b stage 247. Of 3,040 patients screened, only 1,535 ultimately met the inclusion criteria. This highlights that only about 50% of M1b stage patients with the best PSA response to the induction course of ADT will be candidates for an intermittent regimen. The study was designed to demonstrate comparable results between IAD and continuous androgen deprivation therapy, which was achieved as the primary endpoint; however, it is not entirely possible to rule out a lower survival rate with IAD based on the results of this study.

Other trials have shown no difference in survival, with an overall hazard ratio for OS of 1.02 (0.94–1.11) 242. Based on these reviews and meta-analyses, it was concluded that a difference in OS or PFS between IAD and continuous hormone therapy (CHT) is unlikely. A recent review of available phase III trial data highlights limitations in most studies and suggests interpreting non-inferiority analysis results with caution 248. None of the studies comparing IAD and CHT in M1 patients showed a survival benefit, although a trend toward improved OS and PFS (progression-free survival) was noted with CHT. Most of these studies, however, were non-inferiority trials, i.e., designed to show comparable outcomes. In individual cohorts, the negative impact on sexual function was less pronounced with IAD. There is a trend in favor of IAD regarding quality of life, particularly concerning therapy-related side effects such as hot flashes [249, 250].

Thus, the lack of any survival benefit in M1 patients demonstrates that IAD should be considered as an option for a well-informed patient concerned about significant side effects of therapy.

The threshold PSA level at which ADT should be discontinued or continued as intermittent androgen suppression (IAS) remains to be determined in prospective studies [243, 251]. Nevertheless, there is a consensus among a large number of authors on the following statements:

IAD is based on intermittent castration; therefore, only agents that lead to castration are acceptable for use.

The use of GnRH antagonists may be an alternative to agonists.

The induction ADT cycle should not exceed 9 months; otherwise, testosterone recovery is unlikely.

Androgen deprivation therapy should be discontinued only when all of the following criteria are met:

- the patient is well-informed and compliant with treatment;

- there is no clinical progression;

- there is a clear PSA response to therapy, with an empirically established PSA level of less than 4 ng/mL in metastatic disease.

Close follow-up is mandatory and should include clinical examination every 3–6 months. Follow-up should be more frequent as the disease progresses.

PSA measurement must always be performed by the same laboratory.

Therapy is re-initiated upon clinical progression in the patient or when a pre-determined (empirically established) PSA threshold is exceeded: typically at 10–20 ng/mL in M1 stage patients.

The duration of ADT courses is at least 3–6 months.

Subsequent treatment cycles are based on the same principles until the first signs of castration resistance appear.

The patient group that derives the maximum benefit from IAD has yet to be defined, but the most important factor is likely the response to the first IAD cycle, such as the PSA response to treatment 243.

Intermittent treatment should be offered only to well-motivated M1 stage patients with a marked PSA response following the induction period.

Immediate versus delayed androgen deprivation therapy

In symptomatic patients, immediate therapy is mandatory. However, due to the lack of high-quality studies, controversy still exists regarding asymptomatic metastatic prostate cancer patients. According to several studies, immediate ADT did not improve overall survival (OS), although it significantly reduced the risk of disease progression [232, 252, 253].

In symptomatic M1 stage patients, immediate systemic androgen deprivation therapy is recommended to relieve symptoms and reduce the risk of potential serious complications from progressive disease (spinal cord compression, pathological fractures, ureteral obstruction) [352, 253].

GCR ALEL 1Level of recommendation grading – A (level of evidence – 1).

In asymptomatic M1 stage tumor patients, immediate systemic androgen deprivation therapy is recommended to improve survival, delay progression to symptomatic disease, and prevent serious complications associated with disease progression [252, 253].

GCR ALEL 1Level of recommendation grading – A (level of evidence – 1).

3.5.3. Combination therapy

Complete androgen blockade (maximal androgen blockade – MAB)

A large randomized trial involving 1,286 M1b patients found no difference between surgical castration with or without flutamide 254. However, results varied when other antiandrogens or castration methods were used, and systematic reviews showed that MAB using non-steroidal antiandrogens provides a small survival benefit (<5%) compared to monotherapy (surgical castration or GnRH agonist use) [255, 256] after five years of therapy [257]. At the same time, this minimal benefit in a small subgroup of patients must be weighed against the increased incidence of side effects associated with long-term use of non-steroidal antiandrogens.

Androgen deprivation therapy in combination with other agents

Combination with abiraterone acetate**#

Two large randomized trials (STAMPEDE, LATITUDE) investigated the addition of #abiraterone** (see Appendix A3) (1000 mg daily) with prednisone (5 mg daily) to ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) [258]. The primary objective of these studies was to improve OS. Both trials demonstrated a significant improvement in OS, although in the LATITUDE trial with an HR of 0.62 (0.51–0.76) only in the subgroup of patients with high-volume metastatic disease. HR values in the STAMPEDE trial were very similar at 0.63 (0.52–0.76) in the overall patient population 258. All secondary endpoints, such as PFS, time to radiological progression, time to pain, or time to chemotherapy, were positive with an advantage for the combination therapy arm. There were no statistically significant differences in treatment-related deaths with the combination of ADT plus #abiraterone** and prednisone compared to ADT [HR: 1.37 (0.82–2.29)]. Nevertheless, twice as many patients discontinued therapy prematurely due to toxicity in the combination arms in the STAMPEDE trial (20%) compared to LATITUDE (12%). Based on these data, #abiraterone** combined with prednisone plus ADT should be considered a first-line standard of care in patients with metastatic hormone-sensitive prostate cancer 259.

In M1 stage prostate cancer patients who can tolerate this regimen, ADT in combination with #abiraterone** 1000 mg once daily on an empty stomach daily until disease progression or unacceptable toxicity, combined with prednisone 5 mg daily, is proposed [241].

GCR ALEL 1Level of recommendation grading – A (level of evidence – 1).

Comments: currently, this indication for #abiraterone** is in the process of registration in the Russian Federation.

Androgen deprivation therapy in combination with chemotherapy

Three large randomized trials have been conducted [228, 260, 261]. All of them compared castration alone as standard therapy with a subgroup of patients receiving ADT in combination with docetaxel** (75 mg/m² every three weeks, chemotherapy started no later than three months from the start of HT, treatment duration – 6 cycles, concomitant prednisolone use was not mandatory). The primary objective in all three trials was to assess OS.

The GETUG 15 trial included patients with metastatic prostate cancer diagnosed initially or at disease progression after prior radical treatment [261]. Patients were stratified based on prior treatment and risk groups [225]. The CHAARTED trial used the same inclusion criteria, and patients were stratified by metastatic tumor volume; high volume was defined by the presence of visceral metastases or four or more bone metastases with at least one lesion outside the spine or pelvic bones [228].

STAMPEDE is a multi-stage, multi-arm trial in which the reference arm (androgen deprivation monotherapy) included 1,184 patients. One experimental arm was a subgroup receiving docetaxel** combined with ADT (n = 593), and another was a subgroup receiving docetaxel** combined with zoledronic acid** (n = 593). The trial enrolled patients with either M1, N1, or two of the following three criteria: T3/4, PSA >40 ng/mL, or ISUP grade 4–5. Also included were patients with relapse after local treatment if they met one of the following criteria: PSA >4 ng/mL with PSA doubling time <6 months or PSA >20 ng/mL, N1, or M1. Stratification regarding metastatic volume (high/low volume) was not applied [260].

Hematological toxicity was one of the most frequent adverse events of docetaxel therapy across all these studies. Grade 3–4 neutropenia was observed in 12–15% of patients, and grade 3–4 febrile neutropenia in 6–12%. The use of granulocyte colony-stimulating factor (G-CSF) statistically significantly reduced the risk of febrile neutropenia. Primary and secondary prophylactic treatment with G-CSF should be performed in accordance with available guidelines [259, 262].

Based on these data, docetaxel** in combination with castration-based ADT should be considered as standard of care in patients with newly diagnosed metastatic prostate cancer, provided they meet the eligibility criteria for the drug [259]. Docetaxel** is administered at a standard dose of 75 mg/m² in combination with steroids as premedication. Continuous corticosteroid therapy is not mandatory. A total of 6 cycles of docetaxel** chemotherapy at a dose of 75 mg/m² in combination with ADT is recommended.

Thus, the standard of care for patients with newly diagnosed metastatic or recurrent hormone-sensitive prostate cancer is combination therapy using castration and abiraterone acetate** combined with prednisone, or docetaxel**. The survival benefit for both drugs was similar [263]. Furthermore, no significant overall survival advantage was noted for either of the drugs in a recently published meta-analysis [264]. Both methods have distinct and drug-specific side effects, which requires careful monitoring of adverse events during treatment. Therefore, the choice of therapy will depend on patient preference, characteristic side effects, drug availability, and cost.

For patients presenting with M1 prostate cancer who have no contraindications to docetaxel** therapy, castration in combination with chemotherapy (docetaxel**) is recommended—6 cycles of therapy at a dose of 75 mg/m² in combination with ADT. This is followed by ADT alone [263–265].

Level of Recommendation: BLevel of Evidence: 1Level of recommendations – B (level of evidence – 1).

Combination with apalutamide**

In the large randomized phase III TITAN trial [266], progression-free survival (PFS) and overall survival (OS) were evaluated as primary endpoints in patients with metastatic hormone-sensitive prostate cancer (mHSPC) receiving apalutamide** combined with ADT versus placebo with ADT. The trial demonstrated a significant improvement in PFS (median PFS was not reached in the apalutamide** group compared with 22.1 months in the placebo group [HR for progression or death 0.48; 95% CI: 0.39–0.60, p <0.0001]) and OS (median OS was not reached in either group [HR for death 0.67, 95% CI: 0.51–0.89, p <0.0053]). Toxicity of the new class of drugs was minimal.

In patients with M1 prostate cancer who can tolerate this treatment regimen, ADT in combination with apalutamide** 240 mg orally once daily until disease progression or unacceptable toxicity is recommended [266].

Level of Recommendation: ALevel of Evidence: 2Level of recommendations – A (level of evidence – 2).

Combination with enzalutamide**

Two large randomized trials (ENZAMET, ARCHES) investigated the addition of enzalutamide** (160 mg daily) to ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) [267, 268]. The randomized phase 3 ENZAMET trial compared enzalutamide** plus ADT with ADT monotherapy in 1,125 patients with mHSPC. Patients were stratified by metastatic volume, early docetaxel use, bone-modifying agents, and comorbidity score. At the first interim analysis with a median follow-up of 34 months, the primary endpoint of the ENZAMET trial—improved OS in mHSPC patients—was met in the early enzalutamide** plus ADT group (HR = 0.67; 95% CI: 0.52–0.86; p = 0.002). All secondary endpoints, such as PSA-based and clinical progression-free survival, were favorable, favoring the enzalutamide combination therapy group. The randomized phase 3 ARCHES trial included 1,150 mHSPC patients regardless of disease prognosis factors. Patients were randomized 1:1 to ADT plus enzalutamide** or ADT plus placebo. Patients were stratified by prior docetaxel chemotherapy (none, 1–5 cycles, and 6 cycles) and metastatic volume (high and low volume). At a median follow-up of 14.4 months, the primary endpoint of the ARCHES trial—improved radiographic progression-free survival (rPFS) in mHSPC patients in the enzalutamide** plus ADT group—was achieved, with a 61% reduction in the risk of progression or death (HR = 0.39; 95% CI: 0.30–0.50; p <0.001). The safety profile of enzalutamide** was consistent with previous data from studies involving patients with mCRPC. Adverse events associated with enzalutamide** in these trials included fatigue, seizures, and hypertension.

Based on these data, enzalutamide** (see Appendix A3) combined with ADT should be considered as a first-line standard of care in patients with metastatic hormone-sensitive prostate cancer.

In patients with M1 prostate cancer who can tolerate this treatment regimen, ADT in combination with enzalutamide** is recommended [267, 268]. Treatment is administered at the standard dosage of 160 mg/day until disease progression or unacceptable toxicity.

Level of Recommendation: ALevel of Evidence: 2Level of recommendations – A (level of evidence – 2).

3.5.4. Local treatment of the primary tumor in newly diagnosed metastatic disease

The role of local treatment, specifically local radiotherapy to the prostate gland, in patients with metastatic hormone-sensitive disease was first demonstrated in the HORRAD trial. The trial included 432 patients with metastatic prostate cancer randomized to ADT alone or ADT combined with external beam radiotherapy (EBRT) to the prostate. Overall survival did not differ significantly between the subgroups (HR: 0.9 [0.7–1.14]); the median time to biochemical progression (PSA rise) was significantly longer in the radiotherapy + ADT group (HR: 0.78 [0.63–0.97]) [269]. The STAMPEDE trial enrolled 2,061 patients with hormone-sensitive prostate cancer randomized to ADT alone or ADT combined with EBRT to the prostate. This trial confirmed that radiotherapy did not improve OS in the overall study population. However, following the results of the CHAARTED trial, patients were categorized by tumor volume. The low-volume subgroup included 819 patients, and the high-volume subgroup included 1,120 patients. The low-volume subgroup showed a significant benefit from combination treatment (hormone therapy + prostate EBRT) in terms of improved OS. Therefore, prostate radiotherapy should be considered in patients with low-volume metastatic disease. It remains unclear whether these data can be extrapolated to radical prostatectomy as a local treatment modality in patients with low-volume metastatic disease.

3.5.5. Metastasis-directed therapy

In patients with relapses after local treatment, targeted therapy of metastases has been proposed to delay systemic treatment. One phase II randomized trial has been conducted in patients with oligometastatic prostate cancer (presence of $\le 3$ metastatic lesions). The study included 62 patients; about half of them had lymph node-only metastases. The study showed that ADT-free survival was higher in the subgroup of patients receiving local treatment for oligometastases compared to the observation subgroup [270]. Currently, there are no data confirming an improvement in OS. A systematic review emphasizes that this approach should currently still be considered experimental [271].

3.5.6. Recommendations for first-line therapy in patients with metastatic hormone-sensitive prostate cancer

In symptomatic M1 patients, immediate systemic therapy is recommended to relieve symptoms and reduce the risk of potential serious complications of progressive disease (spinal cord compression, pathological fractures, ureteral obstruction) [252, 253].

LeveL of Evidence AGrade of Recommendation 3Level of evidence – A (grade of recommendation – 3).

Particularly in patients with early signs of spinal cord compression or infravesical obstruction, the use of luteinizing hormone-releasing hormone (LHRH) antagonists is recommended [233–236].

LeveL of Evidence BGrade of Recommendation 2Level of evidence – B (grade of recommendation – 2).

In patients with M1 stage and early signs of developing complications, such as spinal cord compression or pathological fractures, surgical intervention and/or local radiation therapy is recommended to eliminate disease symptoms [272].

LeveL of Evidence BGrade of Recommendation 3Level of evidence – B (grade of recommendation – 3).

In patients with M1 stage and symptoms of the disease, immediate systemic therapy is recommended aimed at symptom relief, improved survival, delayed progression to the symptomatic stage, and prevention of serious complications associated with disease progression. In M1 patients without tumor symptoms, immediate systemic therapy is recommended to improve survival, delay progression to the symptomatic stage, and prevent serious complications associated with disease progression [252, 253].

LeveL of Evidence AGrade of Recommendation 1Level of evidence – A (grade of recommendation – 1).

Comments: in well-informed M1 patients without tumor symptoms, delayed ADT is an option since it reduces treatment side effects, provided that the patient is under close monitoring [232, 252, 253].

Patients with M1 stage receiving LHRH agonists are offered initial short-term antiandrogen therapy to reduce the risk of the "flare-up" effect [238–241, 254, 257].

LeveL of Evidence AGrade of Recommendation 1Level of evidence – A (grade of recommendation – 1).

In patients with M1 disease stage, antiandrogen monotherapy is not recommended [257].

LeveL of Evidence AGrade of Recommendation 2Level of evidence – A (grade of recommendation – 2).

Patients with M1 prostate cancer who have no contraindications to docetaxel therapy** are offered ADT in combination with chemotherapy (docetaxel 75 mg/m², 1 day in a 21-day cycle, up to 6 cycles of docetaxel**) [225, 228, 260, 261].

LeveL of Evidence AGrade of Recommendation 1Level of evidence – A (grade of recommendation – 1).

Patients with M1 prostate cancer who can tolerate this treatment regimen are offered ADT in combination with one of the following drugs, in alphabetical order: #abiraterone** in combination with prednisone, apalutamide, or enzalutamide** [266–268].

LeveL of Evidence AGrade of Recommendation 1Level of evidence – A (grade of recommendation – 1).

In patients with M1 prostate cancer who have a low volume of metastatic disease defined by CHAARTED criteria, ADT in combination with prostate radiation therapy is recommended [273].

LeveL of Evidence BGrade of Recommendation 2Level of evidence – B (grade of recommendation – 2).

The use of ADT in combination with any local treatment (radiation therapy/surgery) outside of clinical trials (except for symptom control) is not recommended in patients with M1 stage and high-volume metastatic disease [273, 274].

LeveL of Evidence CGrade of Recommendation 4Level of evidence – C (grade of recommendation – 4).

Patients who do not wish to consider ADT combined with docetaxel** therapy, abiraterone acetate**# combined with prednisolone, apalutamide**, enzalutamide**, or prostate radiation therapy, or who are not eligible for the aforementioned treatments, should be offered ADT alone with or without antiandrogen therapy [98, 81, 257].

LeveL of Evidence CGrade of Recommendation 5Level of evidence – C (grade of recommendation – 5).

In patients with M1 stage who show a good treatment response, follow-up should be performed every 3–6 months. This should include at least a disease history taking, DRE, PSA level determination, often supplemented by hemoglobin, creatinine, and alkaline phosphatase levels. Testosterone levels must also be determined, especially during the first year [98, 81, 257].

LeveL of Evidence CGrade of Recommendation 5Level of evidence – C (grade of recommendation – 5).

Intermittent therapy should be offered only to well-motivated M1 patients with a pronounced PSA response after the induction period [245, 246].

LeveL of Evidence AGrade of Recommendation 1Level of evidence – A (grade of recommendation – 1).

3.5.7. Treatment of castration-resistant prostate cancer (CRPC)

Definition of castration-resistant prostate cancer

Serum testosterone level < 50 ng/dL or 1.7 nmol/L combined with:

• biochemical progression: 3 consecutive rises in PSA 1 week apart, resulting in a 50% increase over the nadir with a PSA level > 2.0 ng/mL, or
• radiological progression: appearance of new lesions: two or more new bone lesions or a soft tissue lesion according to RECIST (Response Evaluation Criteria in Solid Tumors) [275]. Symptomatic progression alone should be questioned and further investigated. This is not sufficient to diagnose CRPC.

Non-metastatic castration-resistant prostate cancer

Frequent PSA testing in prostate cancer patients undergoing ADT treatment has led to earlier detection of biochemical progression. Approximately one-third of these patients will develop bone metastases within two years, diagnosed by bone scan [276].

In patients who develop CRPC and have distant metastases undetectable by bone scan and CT, baseline PSA value, PSA velocity, and PSA doubling time (DT) were associated with time to first bone metastasis and OS [276, 277]. These factors can be used in deciding which patients should receive therapy to prevent the development of metastatic disease.

Two large phase III randomized trials, PROSPER [278] and SPARTAN [279], evaluated metastasis-free survival (MFS – survival until the appearance of distant metastases) as the primary endpoint in patients with non-metastatic castration-resistant prostate cancer (CRPC, M0) who were treated with enzalutamide** (PROSPER) vs. placebo or apalutamide** (SPARTAN) vs. placebo, respectively. M0 status was established using CT and bone scans. Only high-risk patients with a short PSA doubling time ($\le 10$ months) were included in the studies. Both studies demonstrated a significant improvement in MFS (PROSPER: median MFS was 36.6 months in the enzalutamide** group vs. 14.7 months in the placebo group [HR for metastasis or death 0.29; 95% CI: 0.24–0.35, p < 0.001]; SPARTAN: median MFS was 40.5 months in the apalutamide** group vs. 16.2 months in the placebo group [HR for metastasis or death 0.28, 95% CI: 0.23–0.35, p < 0.001]). Time to symptomatic progression was significantly longer with enzalutamide** (HR 0.58; 95% CI: 0.46–0.72, p < 0.0001) and apalutamide** compared to placebo (HR 0.45; 95% CI: 0.32–0.63, p < 0.001). Toxicity of the new class of drugs was minimal.

PSA monitoring every 3 months in men undergoing ADT is recommended to detect biochemical progression before the development of metastatic disease [276, 277, 280].

GOL CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

PSA doubling time is recommended to be used when making treatment decisions for patients with nmCRPC [276, 277, 280].

GOL CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: in patients with nmCRPC and no detectable metastases, PSA DT is a factor influencing the risk of distant metastases and overall survival. A PSA DT ≤10 months correlates with a higher risk of bone metastases and mortality.

In patients with high-risk nmCRPC (PSA DT ≤10 months), it is recommended to prescribe apalutamide** or enzalutamide** in combination with ADT [278, 279].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: two large phase III randomized controlled trials involving patients with high-risk nmCRPC (PSA DT ≤10 months) demonstrated a significant reduction in the risk of metastasis development when apalutamide** or enzalutamide** was prescribed in combination with ADT compared to placebo and HT. Both studies showed that the addition of androgen receptor inhibitors to ADT does not lead to increased toxicity; the incidence of grade 3–4 AEs was low in both studies.

For a PSA DT ≤10 months, prescribe at the following dosages:

apalutamide** 240 mg once daily orally in combination with ADT until disease progression or unacceptable toxicity;

enzalutamide** 160 mg once daily orally in combination with ADT until disease progression, unacceptable toxicity, or a change in hormone therapy.

For a PSA DT >10 months, continuation of ADT and active surveillance or a change in hormone therapy is recommended [276, 277, 280].

Metastatic castration-resistant PCa

Standard androgen deprivation therapy in patients with castration-resistant PCa

Ultimately, despite castration, patients with PCa will show signs of disease progression. Two studies have shown only a minimal survival benefit in patients who continued LHRH analogues during second- and third-line therapy [281, 282]. However, in the absence of prospective data, the minor potential benefit of continuing ADT outweighs the minimal treatment risk. Furthermore, all randomized trials maintained androgen suppression in all subsequent treatment lines; therefore, castration therapy aimed at reducing endogenous testosterone levels should be continued in all patients with CRPC.

First-line therapy for metastatic castration-resistant PCa

Abiraterone acetate**

Abiraterone** is one of the recommended first-line drugs for the treatment of patients with metastatic mCRPC (prior to docetaxel**) [283].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: the evaluation of the efficacy of abiraterone acetate** therapy was conducted in the phase III COU-AA-302 trial involving 1088 patients with metastatic CRPC with asymptomatic or mildly symptomatic disease who had not previously received chemotherapy. Patients were randomized to abiraterone acetate** and placebo groups, both in combination with prednisone [283]. Patients with visceral metastases were excluded. The main stratification factors were ECOG performance status of 0 or 1. Overall survival and radiographic PFS (rPFS) were the primary co-primary endpoints. At a median follow-up of 22.2 months, a significant improvement in rPFS was observed (median 16.5 vs 8.2 months, HR: 0.52, p <0.001) with abiraterone acetate** therapy. At the final data analysis with a median follow-up of 49.2 months, the OS endpoint was statistically significantly better in the drug group (34.7 vs 30.3 months, HR: 0.81, 95% CI: 0.70–0.93; p = 0.0033) [284]. Adverse events (AEs) associated with mineralocorticoid excess and hepatic dysfunction were more common in the abiraterone acetate** group, but grade 1–2 toxicity predominated among them. Subgroup analysis of the trial showed that the drug is equally effective in elderly patients (>75 years) [285].

Enzalutamide**

Enzalutamide** is one of the recommended first-line drugs for the treatment of patients with metastatic mCRPC (prior to docetaxel**) [286, 287].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: a randomized phase III study (PREVAIL) [288] included similar patient populations comparing enzalutamide** with placebo. Patients with visceral metastases were included in the study, but their number was small. Corticosteroid use was permitted but not mandatory. The PREVAIL study enrolled 1,717 chemotherapy-naive mCRPC patients and demonstrated a significant improvement in rPFS (HR: 0.186; CI: 0.15–0.23, p <0.0001) and OS (HR: 0.706; CI: 0.6–0.84, p <0.001). A >50% decrease in PSA levels was observed in 78% of patients. The most common clinically significant adverse events were fatigue and arterial hypertension. Enzalutamide** was similarly effective and well tolerated in patients aged >75 years [289], as well as in patients with or without visceral metastases [290].

Enzalutamide** was also compared with bicalutamide at a dose of 50 mg once daily in a randomized double-blind phase II study (TERRAIN) [286], showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44, p <0.0001) in favor of enzalutamide**. Based on long-term follow-up and final analysis, the advantage in OS and rPFS was also confirmed [287].

Docetaxel**

Docetaxel** is one of the recommended first-line drugs for the treatment of patients with metastatic mCRPC, particularly in the subgroup of patients with visceral metastases, a short duration of initial ADT response, and pronounced pain syndrome [291, 292].

GOL ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: docetaxel**-based chemotherapy showed a significant increase in median survival by 2–2.9 months compared to mitoxantrone plus prednisone therapy [291, 293]. The standard first-line chemotherapy regimen is docetaxel** at a dose of 75 mg/m² as an intravenous infusion once every three weeks in combination with prednisone 5 mg twice daily (BID), up to 10 cycles. Prednisone may be omitted if there are contraindications or absence of prominent symptoms. The following independent prognostic factors: visceral metastases, pain, anemia (Hb <13 g/dL), worsening bone scan findings, and prior estramustine use can help stratify response to docetaxel**. Patients were divided into three risk groups: low risk (0 or 1 factor), intermediate (2 factors), and high risk (3 or 4 factors)—and demonstrated assessments of three significantly different median OS values of 25.7, 18.7, and 12.8 months, respectively [294].

Note: age per se is not a contraindication to docetaxel** [295], however, careful monitoring and comorbidities should be addressed due to the high risk of neutropenic complications in this patient cohort [296]. In mCRPC patients unable to tolerate the standard regimen and dose, docetaxel** 50 mg/m² as an intravenous infusion once every 2 weeks is permitted, given the lower toxicity of this regimen [292].

Second-line therapy in mCRPC

All patients receiving therapy for mCRPC eventually experience disease progression due to the development of resistance to the administered treatment. When switching to a new line of therapy, it is recommended to use medications with a different mechanism of action and no cross-resistance.

Cabazitaxel**

Cabazitaxel** is one of the recommended second-line drugs for the treatment of patients with metastatic mCRPC upon disease progression after docetaxel therapy, especially in the subgroup of patients with visceral metastases, a short period of effective docetaxel** therapy, and pronounced pain syndrome [297–301].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: Cabazitaxel** is a second-generation taxane with activity in malignant neoplasms resistant to docetaxel. A large prospective, randomized phase III trial (TROPIC study) compared the efficacy of cabazitaxel** plus prednisone versus mitoxantrone plus prednisone in 755 patients with mCRPC who experienced disease progression after docetaxel** therapy [297]. Patients received a maximum of ten cycles of cabazitaxel** (25 mg/m² as an intravenous infusion every 3 weeks) or mitoxantrone (12 mg/m²) combined with prednisone (10 mg/day). The primary endpoint was OS, which was significantly higher with cabazitaxel** (median OS: 15.1 vs. 12.7 months, p <0.0001). There was also a significant improvement in PFS (median PFS: 2.8 vs. 1.4 months, p <0.0001), objective response rate per RECIST criteria (14.4% vs. 4.4%, p <0.005), and PSA response rate (39.2% vs. 17.8%, p <0.0002). Treatment-related WHO grade 3–4 adverse events occurred significantly more often in the cabazitaxel** group, particularly hematologic toxicity (68.2% vs. 47.3%, p <0.0002) and non-hematologic toxicity (57.4% vs. 39.8%, p <0.0002) [298]. Two post-marketing phase III studies showed that cabazitaxel** is not superior to docetaxel** when used as first-line therapy. When used as second-line therapy, cabazitaxel** at a dose of 20 mg/m² was non-inferior in efficacy to 25 mg/m², but less toxic. Therefore, the lower dose should be preferred, especially in the patient subgroup at high risk of neutropenic complications [299, 300]. Preferably, cabazitaxel** should be administered with prophylactic G-CSF, and the drug should be used by physicians experienced in managing neutropenia and sepsis [301].

Radium-223**

Radium-223 dichloride** is one of the recommended agents for second-line therapy in patients with metastatic CRPC upon disease progression after first-line therapy, including patient subgroups with or without pain (regardless of pain intensity), bone lesions, and without visceral metastases [302–305].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: the only bone-specific agent demonstrated to confer a survival benefit is the alpha-emitting radiopharmaceutical radium-223 dichloride [223 Ra]**. In a large phase III trial (ALSYMPCA) involving 921 patients with symptomatic mCRPC randomized to receive radium-223 dichloride [223 Ra]** or placebo plus standard of care. Overall survival (OS) was the primary endpoint. In the radium-223 dichloride [223 Ra]** group, a significant improvement in median OS of 3.6 months was observed (HR: 0.70; p <0.001), and the efficacy of radionuclide therapy with radium-223 dichloride [223 Ra]** was also shown to be independent of prior docetaxel therapy** [302, 303]. The drug also prolonged the time to the first skeletal-related event (pathological fracture, spinal cord compression), reduced pain severity, and improved quality of life. Toxicity associated with radium-223 dichloride [223 Ra]** was minor and, except for a slightly higher rate of hematological toxicity and diarrhea, did not significantly differ from the placebo group [302]. Early administration of radium-223 dichloride [223 Ra]** does not preclude subsequent chemotherapy. Following the completion of therapy within the ALSYMPCA trial, 23% of patients in the radionuclide therapy group and 21% of patients in the placebo group received docetaxel**.

In the international multicenter phase IIIb trial (iEAP), 839 patients with mCRPC with 2 or more bone metastatic lesions, without visceral metastases, were enrolled. The inclusion criteria allowed radionuclide therapy with radium chloride [223 Ra]** in patients without pain syndrome who had metastatic lymph node involvement, had previously received docetaxel**, androgen signaling inhibitors, or denosumab**, as well as patients who received androgen signaling inhibitors or denosumab** during treatment with radium chloride [223 Ra]**. The results of the iEAP trial were consistent with the data from the ALSYMPCA trial. Median OS in the radium chloride [223 Ra]** group was 16 months, time to progression of the main bone resorption marker ALP was 8 months, and time to PSA progression was 4 months [304].

The use of radium-223 dichloride [223 Ra]** in combination with abiraterone acetate** and prednisolone is not recommended due to a higher risk of fractures and an increased number of deaths in the abiraterone acetate plus radium-223 dichloride [223 Ra]** combination group. This was particularly evident in patients not receiving concurrent bone-modifying agents [305].

Use of abiraterone** following prior docetaxel**

Abiraterone** is one of the recommended agents for second-line therapy in patients with metastatic CRPC upon disease progression after docetaxel** therapy in the patient subgroup without visceral metastases and with minimally expressed pain [306, 307].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: positive results from the large phase III COU-AA-301 trial with a median follow-up of 12.8 months [306] were reported and subsequently confirmed in the final analysis [307]. A total of 1195 patients with mCRPC were randomized 2:1 to receive abiraterone acetate** plus prednisone or placebo plus prednisone. All patients had disease progression following docetaxel** therapy. The primary endpoint was OS. At a median follow-up of 20.2 months, median survival in the abiraterone acetate** group was 15.8 months compared with 11.2 months in the placebo group (HR: 0.74, p <0.0001). The benefit was observed across all patient subgroups. Therapy toxicity was low, and grade 3–4 adverse events were extremely rare; however, mineralocorticoid-related side effects, predominantly grade 1–2 (fluid retention, edema, and hypokalemia), were more frequent in the abiraterone acetate** group.

Use of enzalutamide** following docetaxel**

Enzalutamide** is one of the recommended agents for second-line therapy in patients with metastatic CRPC upon disease progression after docetaxel** therapy [287, 308].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Comments: the planned interim analysis of the AFFIRM trial was published in 2012 [308]. The trial enrolled 1199 patients with mCRPC randomized 2:1 to receive enzalutamide** or placebo, respectively. All patients had disease progression following docetaxel** therapy. Corticosteroids were optional but permitted and received by approximately 30% of patients. The primary endpoint was OS. At a median follow-up of 14.4 months, median survival in the enzalutamide** group was 18.4 months compared with 13.6 months in the placebo group (HR: 0.63; p <0.001). The survival benefit was observed regardless of age, baseline pain intensity, and type of progression. The final analysis with longer follow-up confirmed these results [287]. Enzalutamide** was also active in patients with visceral metastases. Therapy toxicity was low, with the incidence of grade 3–4 adverse events being lower in the enzalutamide** group than in the placebo group. An adverse event of special interest in the enzalutamide** group was seizures, which were observed in 0.6% of patients.

Enzalutamide** may also be used in patients progressing on docetaxel** therapy who have visceral metastases.

Management of mCRPC after docetaxel** and first-line hormonal therapy

The choice of subsequent treatment after docetaxel** and first-line hormonal therapy (abiraterone** or enzalutamide**) in mCRPC remains open [309]. Acceptable options include radium-223 dichloride** or second-line chemotherapy (cabazitaxel**). In general, subsequent treatment courses in unselected patient populations are expected to provide less benefit than earlier application [310, 311], and there is also evidence of cross-resistance between enzalutamide** and abiraterone** [312, 313].

Olaparib**

Olaparib** is recommended as monotherapy for mCRPC with germline or somatic mutations in genes involved in DNA repair via homologous recombination in patients with disease progression following therapy with novel hormonal agents (abiraterone** or enzalutamide**) [314].

GSI BLEL 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: the Phase III PROfound study evaluating the efficacy and safety of olaparib** compared with enzalutamide** or abiraterone** in patients with mCRPC and homologous recombination repair (HRR) gene mutations enrolled patients with disease progression after prior treatment with novel hormonal agents. The study included two patient cohorts. Cohort A: patients with BRCA1, BRCA2, or ATM gene mutations. Cohort B: patients with mutations in BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L genes. In cohort A, treatment with olaparib** resulted in a statistically and clinically significant improvement in rPFS (7.39 months) compared with enzalutamide** or abiraterone** (3.55 months) (HR 0.34; 95% CI, 0.25–0.47; p <0.0001). In the overall patient population (cohorts A + B) with mCRPC harboring alterations in genes directly or indirectly involved in HRR, the use of olaparib** also led to a statistically significant and clinically meaningful improvement in rPFS (5.82 months) compared with enzalutamide**/abiraterone** (3.52 months) (HR 0.49; 95% CI, 0.38–0.63; p <0.0001) [314]. According to mature data analysis, overall survival (OS) in cohort A was 19.09 months for olaparib** versus 14.69 months for enzalutamide**/abiraterone** (HR, 0.69; 95% CI, 0.50–0.97; p = 0.0175) [315]. According to the interim analysis, OS in cohorts A + B was 17.51 months for olaparib** versus 14.26 months for enzalutamide**/abiraterone** (HR, 0.67; 95% CI, 0.49–0.93; p = 0.0063). Of the patients who received enzalutamide**/abiraterone**, 80.6% of patients in cohort A and 84.6% of patients in cohort B crossed over to olaparib** upon disease progression. The most frequent adverse events (AEs) (of any grade) reported with olaparib** were anemia (46.5%), nausea (41.4%), fatigue and asthenia (41.0%), and decreased appetite (30.1%) [314].

Thus, olaparib** is a promising treatment option following mCRPC treatment with docetaxel** and abiraterone** or enzalutamide** and disease progression on these drugs in patients with mutations in genes involved in DNA repair via homologous recombination. In the phase III PROfound study, all patients had previously received enzalutamide** and/or abiraterone**, with a subset of patients also having previously received taxanes. Subgroup analyses demonstrated the superiority of olaparib (in terms of rPFS and OS) over enzalutamide**/abiraterone** in mCRPC patients regardless of whether they had previously received taxanes [316].

#Pembrolizumab** is recommended for use in patients with mismatch repair deficiency, regardless of tumor origin, including prostate cancer, at the following dosage regimen: 200 mg IV as an infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity [317].

GOL CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: for this indication in the Russian Federation, the drug #pembrolizumab** is under the registration process.

Treatment Monitoring

Baseline assessments should include medical history and clinical examination, as well as baseline blood tests (PSA, CBC, renal function tests, liver function tests, ALP), bone scintigraphy, and CT of the chest, abdomen, and pelvis [318]. The use of choline or PSMA PET/CT in the progression of CRPC is not fully studied and most likely provides no significant benefit, similar to patients with biochemical recurrence or hormone-naive patients. Using PSA levels alone to monitor disease in mCRPC patients is insufficiently reliable [319, 320], as visceral metastases may develop in men without a rise in PSA level [321]. Instead, a combination of bone scintigraphy and CT scanning, PSA measurement, and assessment of the patient's clinical status is recommended for evaluating disease progression [293]. More recently, the majority of experts at a consensus meeting suggested regularly reviewing and repeating blood tests every two to three months, and bone scintigraphy and CT scanning at least once every six months, even in the absence of clinical indications [318]. This reflects the fact that all therapies with proven OS benefit carry potential toxicity and significant cost, and in the absence of objective benefit, patient treatment should be adjusted. Most experts emphasize that therapy should not be discontinued based solely on biochemical progression (PSA rise). Instead, at least two of the three criteria should be met to discontinue therapy (biochemical progression [PSA rise], radiologic progression, and clinical deterioration). For research purposes, updated PCWG3 recommendations place greater emphasis on the importance of documenting progression in existing lesions and introduce the concept of "no longer clinically meaningful benefit" to emphasize the distinction between the first evidence of progression and the clinical need to stop or change therapy [322]. These recommendations are likely also applicable to clinical practice outside of clinical trials.

Treatment Sequence and Duration

The timing of treatment modification in mCRPC remains a subject of debate, although there are clear recommendations to promptly initiate or change treatment in patients with symptomatic progression of metastatic disease. Despite the increasing number of effective therapies, direct comparative data and evaluations of the sequence of available drugs are still lacking. Therefore, it remains unclear how to select "second-line" therapy. In the absence of other data, inclusion criteria from registration trials have been used as a priority for treatment sequencing.

The ECOG performance status scale was used for patient stratification. Overall, patients with an ECOG score of 0–1 tolerate treatment better and derive greater benefit than patients with an ECOG score of ≥2. Nevertheless, it is important that treatment decisions are made individually. This is particularly true when symptoms related to disease progression are determined by the ECOG status. In such cases, it may be appropriate to use active life-prolonging drugs to determine whether treatment will improve the patient's functional status [318, 323].

Symptomatic Treatment in Metastatic Castration-Resistant Prostate Cancer

CRPC is generally a disabling disease, frequently affecting elderly men. A multidisciplinary approach involving urologists, medical oncologists, radiation oncologists, nurses, psychologists, and social workers is essential [324]. When considering additional systemic treatments, including management of pain, constipation, anorexia, nausea, fatigue, and depression, critical palliative care issues must be taken into account.

The use of radiopharmaceuticals based on beta-emitting radionuclides (samarium-153 Sm oxabifor, strontium chloride [89Sr]) can be recommended as a means of long-term and sustained pain relief, reducing the need for analgesics, and improving quality of life [325–330]. The effect of these drugs on progression-free survival and overall survival has not been studied in randomized trials. The methodology for radionuclide therapy in painful bone metastases is outlined in guidelines [325]. National principles for radionuclide therapy of bone metastases with beta-emitting radiopharmaceuticals comply with international recommendations [326].

GGR CLeveled Evidence 5Level of evidence and recommendation grade – C (level of confidence of data – 5).

Complications due to bone metastases

In most patients with mCRPC, bone metastases are accompanied by severe pain syndrome. EBRT is highly effective [331] even as a single fraction [332]. A single infusion of a third-generation bisphosphonate may be considered if RT is unavailable [333]. Common complications resulting from bone metastases include spinal fractures with spinal cord compression and pathological fractures. Vertebroplasty can be an effective method for treating spinal fractures, regardless of their etiology, having a positive impact on both pain and quality of life [334]. Nevertheless, it remains important to recommend standard palliative surgical interventions, which can be effective in treating osteoblastic metastases [335, 336]. Spinal cord compression is a medical emergency. It must be diagnosed as early as possible, and patients should be trained to recognize its characteristic signs. If this condition is suspected, high-dose corticosteroids must be prescribed as soon as possible and spinal MRI performed. A consultation with a neurosurgeon or orthopedic trauma surgeon should be scheduled, and the possibility of decompression followed by EBRT discussed [337]. Otherwise, EBRT with or without systemic therapy is the method of choice.

Prevention of adverse events

associated with bone metastases

Use of bisphosphonates

The use of zoledronic acid** in mCRPC for the prevention of skeletal-related events was studied during a period when effective systemic anti-cancer therapy was lacking, but docetaxel** administration was available. The study included 643 patients with CRPC [338] with bone metastases who were randomized to receive zoledronic acid** at a dose of 4 mg or 8 mg once every three weeks for the subsequent fifteen months, or placebo. The 8 mg dose showed no clear benefits and, due to poor tolerability, was reduced to 4 mg. At 15 and 24 months of follow-up, patients receiving 4 mg of zoledronic acid**, compared to the placebo group, showed fewer skeletal-related events (44% vs. 33%, p = 0.021) and, in particular, fewer pathological fractures (13.1% vs. 22.1%, p = 0.015). Furthermore, the zoledronic acid** group demonstrated a prolongation in time to the first skeletal-related event. None of the prospective studies with bisphosphonates demonstrated an overall survival benefit.

RANK ligand inhibitors

Denosumab** is a fully human monoclonal antibody against RANK ligand (receptor activator of nuclear factor kappa-B ligand), a key mediator of osteoclast formation, function, and survival. In non-metastatic CRPC patients, therapy with this drug at a dosage of 60 mg demonstrated an increase in bone metastasis-free survival compared to the placebo group (median benefit: 4.2 months, HR: 0.85, p = 0.028) [337]. However, this benefit did not translate into a difference in OS (43.9 vs. 44.8 months, respectively), and denosumab** was not approved by either the FDA or EMA for this indication [339]. Nevertheless, denosumab** 60 mg showed a benefit in treating bone mineral density loss associated with androgen deprivation therapy compared to placebo, significantly reducing the risk of vertebral fractures [340], and is registered for this indication in the Russian Federation, EMA, and FDA.

A phase III study evaluated the efficacy and safety of denosumab 120 mg** (n = 950) versus zoledronic acid** (n = 951) in patients with mCRPC. Denosumab** is superior to zoledronic acid** in delaying or preventing skeletal-related events, defined as the time to the first event (pathological fracture, radiation therapy or surgery to bone, or spinal cord compression), at 20.7 versus 17.1 months, respectively (HR: 0.82, p = 0.008). However, these results did not translate into a survival benefit in a recent retrospective re-evaluation of endpoints, although denosumab** demonstrated similar superiority over zoledronic acid when comparing the incidence of both first and subsequent symptomatic skeletal events [341].

To prevent skeletal-related events in mCRPC patients with bone metastases, the use of bone-modifying agents (zoledronic acid** or denosumab**) is recommended [337–339, 341].

Level of recommendation ALevel of evidence 2Grade of recommendation – A (level of evidence – 2).

Note: The potential toxicity of bisphosphonates and RANK ligand inhibitors (e.g., osteonecrosis of the jaw) must be continuously considered (up to 5% in M0 CRPC and up to 8.2% in mCRPC, respectively) [331, 337, 341, 342]. Prior to initiating therapy, patients must undergo a dental examination; the risk of jaw necrosis increases with certain risk factors, including a history of trauma, dental surgery, or odontogenic infection [343]. Additionally, the risk of osteonecrosis of the jaw increases with the duration of drug use [344].

3.6. Symptomatic therapy: pain management

The principles of analgesia and the optimal selection of pain management therapy in prostate cancer patients with chronic pain syndrome comply with the principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Care".

In addition to symptomatic drug therapy, palliative radiation therapy to metastatic bone lesions can be used for pain relief [345].

GGR BLeveled Evidence 3Level of evidence and recommendation grade – B (level of confidence of data – 3).

3.7. Supportive care in patients with prostate cancer

Principles of treatment and prevention of nausea and vomiting in prostate cancer patients comply with the principles outlined in the guidelines "Prevention and Treatment of Nausea and Vomiting" (authors: Vladimirova L.Yu., Gladkov O.A., Kogonia L.M., Koroleva I.A., Semiglazova T.Yu. DOI: 10.18027/2224–5057–2018–8–3s2–502–511).

 https://rosoncoweb.ru/standarts/RUS-SCO/2018/2018-35.pdf

Principles of treatment and prevention of bone complications in prostate cancer patients comply with the principles outlined in the guidelines "Use of Bone-Modifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" (authors: Manzyuk L.V., Bagrova S.G., Kopp M.V., Kutukova S.I., Semiglazova T.Yu. DOI: 10.18027/2224–5057–2018–8–3s2–512–520).

https://rosoncoweb.ru/stan-darts/RUSSCO/2018/2018-36.pdf

Principles of prevention and treatment of infectious complications and febrile neutropenia in prostate cancer patients comply with the principles outlined in the guidelines "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M. DOI: 10.18027/2224–5057–2018–8–3s2–521–530).

https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-37.pdf

Principles of prevention and treatment of hepatotoxicity in prostate cancer patients comply with the principles outlined in the guidelines "Management of Hepatotoxicity" (authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. DOI: 10.18027/2224–5057–2018–8–3s2–531–544).

https://rosoncoweb.ru/stan-darts/RUSSCO/2018/2018-38.pdf

Principles of prevention and treatment of cardiovascular complications in prostate cancer patients comply with the principles outlined in the guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Anti-Cancer Drug Therapy" (authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G., Sycheva E.A. DOI: 10.18027/2224–5057–2018–8–3s2–545–563).

https://rosoncoweb.ru/stan-darts/RUSSCO/2018/2018-39.pdf

Principles of prevention and treatment of skin complications in prostate cancer patients comply with the principles outlined in the guidelines "Practical Guidelines for the Drug Treatment of Dermatological Reactions in Patients Receiving Anti-Cancer Drug Therapy" (authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kruglova L.S., Manzyuk L.V., Orlova R.V. DOI: 10.18027/2224–5057–2018–8–3s2–564–574).

https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-40.pdf

Principles of nutritional support in prostate cancer patients comply with the principles outlined in the guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" (authors: Sytov A.V., Leyderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh. DOI: 10.18027/2224–5057–2018–8–3s2–575–583).

https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf

The principles of prevention and treatment of nephrotoxicity in patients with prostate cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" (authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. DOI: 10.18027/2224–5057–2018–8–3s2–591–6030).

https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf

The principles of prevention and treatment of thromboembolic events in patients with prostate cancer comply with the guidelines set forth in the methodological recommendations "Practical Guidelines for the Prevention and Treatment of Thromboembolic Events in Cancer Patients" (authors: Somonova O.V., Antukh E.A., Elizarova A.L., Matveeva I.I., Selchuk V.Yu., Cherkasov V.A., DOI: 10.18027/2224–5057–2018–8–3s2–604–609).

https://rosoncoweb.ru/stan-darts/RUSSCO/2018/2018-45.pdf

The principles of prevention and management of drug extravasation sequelae in patients with prostate cancer comply with the guidelines set forth in the methodological recommendations "Guidelines for the Management of Antineoplastic Drug Extravasation Sequelae" (Buydenok Yu.V. DOI: 10.18027/2224–5057–2018–8–3s2–610–616).

https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf

3.8. Nutritional therapy

Dietary characteristics are a risk factor for prostate cancer: the risk of developing the disease increases in men consuming large amounts of animal fats [5]. Numerous studies focus on analyzing the association of prostate cancer with dietary factors and medications (see Table 1).

Any changes in the patients' usual diet are impractical unless dictated by the need to correct comorbid conditions or to relieve or prevent complications of ongoing treatment (surgical, medical, or radiation) [346].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Any of the radical treatment methods for patients with prostate cancer may lead to adverse events. Radical prostatectomy (RPE) is more frequently associated with urinary incontinence and erectile dysfunction, whereas radiation therapy is more commonly associated with cystitis and bowel complications. However, as the time elapsed after radical treatment increases, the difference in the incidence of side effects becomes statistically insignificant regardless of the treatment method [347, 348].

Comments: the clinical efficacy of pelvic floor muscle training (with or without biofeedback) and extracorporeal magnetic innervation for the management of urinary incontinence has not been proven [351]. Surgical interventions, including the placement of slings and artificial sphincters, improve quality of life. The overall cure rate is approximately 60%, leading to an improvement in urinary incontinence [352]. To date, the optimal use of phosphodiesterase type 5 inhibitors after nerve-sparing RPE remains controversial. Given the conflicting data from studies investigating the efficacy of various dosing regimens of phosphodiesterase type 5 inhibitors following nerve-sparing RPE, there are no specific recommendations for their use [353, 354].

In prostate cancer patients undergoing systemic therapy, it is recommended to adopt a lifestyle change with moderate aerobic exercise, weight control, and psychological counseling [355, 356].

GOM CLOE 2Grade of Recommendation – C (Level of Evidence – 2).

4.1. Prehabilitation

Comments: in particular, psychological support as part of pre-rehabilitation improves mood and reduces anxiety and depression levels. Patients who undergo a psychological pre-rehabilitation course adapt better to daily life following surgical treatment.

4.2. Stage I rehabilitation in surgical treatment

Comments: fast track rehabilitation tactics and ERAS (early rehabilitation after surgery), which include multimodal analgesia, early enteral nutrition, avoidance of routine use of tubes and drains, early mobilization (activation and verticalization) of patients as early as 1–2 days after surgery, do not increase the risk of early postoperative complications or the rate of hospital readmissions. Fast track rehabilitation tactics reduce the length of hospital stay and the rate of postoperative complications. Fast track tactics are effective and safe in urological patients.

Comments: the use of the fast track technique in patients after laparoscopic prostatectomy significantly reduces the length of hospital stay.

Comments: performing 20-minute medical massage sessions starting from the 2nd day after surgery reduces pain intensity, anxiety, and tension, while improving the quality of life.

4.3. Stage II of rehabilitation in surgical treatment

4.4. Stage III of rehabilitation in surgical treatment

4.5. Rehabilitation during radiation therapy

5. Prevention and Dispensary Observation

Prevention of Prostate Cancer

Effective methods for the primary prevention of prostate cancer are currently unavailable.

The incidence of prostate cancer in men increases annually, occurring significantly more often in men over 60 years of age. The aggressiveness of prostate cancer may be driven by specific genetic markers, but large randomized clinical trials are required to develop screening programs for detecting genetic mutations associated with aggressive prostate cancer. According to literature data, a number of exogenous factors influence the risk of prostate cancer in men, as detailed in the section «Etiology of Prostate Cancer». To date, there is no evidence supporting the benefit of vitamins, antioxidants, or other pharmacologic agents for the prevention of prostate cancer.

Dispensary follow-up (Active surveillance)

Dispensary follow-up aims at the timely detection of disease recurrence; therefore, when symptoms of recurrence or metastasis occur, diagnostics are performed to the extent necessary to achieve the goals of follow-up, in accordance with the recommendations presented in the section «Diagnostics of the disease, condition (group of diseases, conditions)». The minimum diagnostic workup includes a digital rectal examination (DRE), PSA level monitoring, hemoglobin, creatinine, alkaline phosphatase, and testosterone levels.

Following radical prostatectomy, PSA level determination is recommended every 3 months for 1 year, every 6 months for the 2nd and 3rd years, and annually thereafter [349, 375–378].

GCR CLEL 5level of recommendation validity – C (level of evidence validity – 5).

Comments: a rise in PSA level after radical prostatectomy >0.2 ng/mL indicates disease recurrence [375–377]. Three consecutive rises in PSA level above the nadir value achieved after radiation therapy define disease recurrence [379]. A palpable tumor nodule and an elevated PSA level indicate the development of a local recurrence. It should be noted that a local recurrence may occur without an elevation in PSA level [380]. Routine use of diagnostic imaging (CT, bone scintigraphy) is not recommended in the absence of biochemical recurrence.

TRUS-guided biopsy of the recurrent tumor is recommended when planning a second line of radical treatment [379–381].

GOL CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

In patients with prostate cancer with distant metastases, it is recommended to perform follow-up examinations every 3–6 months [81, 98].

GCP CLOE 5Level of Evidence – C (Grade of Recommendation – 5).

Comments: the minimum diagnostic workup includes DRE, monitoring of PSA, hemoglobin, creatinine, alkaline phosphatase, and testosterone levels. If necessary, it is recommended to perform CT of the abdomen and retroperitoneum, bone scintigraphy, and PET-CT.

The follow-up strategy may be modified individually for each patient depending on the extent of the tumor process and clinical manifestations of the disease.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection in the Russian Federation", is organized and delivered:

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;
2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;
3. based on these clinical guidelines;
4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

When prostate cancer is suspected or diagnosed, general practitioners, district general practitioners, family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an ambulatory oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive primary specialized health care.

Consultation at the ambulatory oncological care center, primary oncological office, or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral. The oncologist at the ambulatory oncological care center (or the oncologist at the primary oncological office/department in the absence of such a center) shall organize the acquisition of biopsy (surgical) material and arrange for other diagnostic examinations necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic examinations within the medical organization that includes the ambulatory oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing care to prostate cancer patients.

The timeframe for pathomorphological examinations required for the histological verification of prostate cancer shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material at the pathology bureau (department).

When prostate cancer is suspected and/or detected during the provision of emergency medical care, such patients shall be transferred or referred to medical organizations providing care to prostate cancer patients to determine management tactics and the need for additional specialized antitumor treatment methods.

The oncologist at the ambulatory oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing care to prostate cancer patients to clarify the diagnosis (if the diagnosis, including tumor spread and disease stage, cannot be established by the oncologist at the ambulatory center, office, or department) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized (excluding high-tech) medical care for prostate cancer patients at a specialized medical organization shall not exceed 14 calendar days from the date of histological verification of prostate cancer or 14 calendar days from the date of establishing a preliminary diagnosis of prostate cancer (in the absence of medical indications for outpatient pathological studies).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or medical organizations providing care to prostate cancer patients that possess the necessary license, material and technical base, and certified specialists, in inpatient and day-care settings, and includes the prevention, diagnosis, and treatment of prostate cancer requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing care to prostate cancer patients, the tactics of medical examination and treatment are determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical records.

Indications for hospitalization in a round-the-clock or day hospital of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a multidisciplinary team of oncologists and radiotherapists, with the involvement of other specialist physicians as necessary.

Indications for emergency or urgent hospitalization in a medical organization are:

1. presence of prostate cancer complications requiring emergency or urgent specialized medical care (e.g., acute urinary retention, gross hematuria, etc.);
2. presence of complications from prostate cancer treatment (surgery, radiation therapy, drug therapy, etc.).

Indications for elective hospitalization in a medical organization are:

1. need to perform complex interventional diagnostic medical procedures requiring subsequent inpatient or day-care monitoring (prostate biopsy);
2. presence of indications for specialized antitumor treatment (radical prostatectomy, radiation therapy – brachytherapy, external beam and other types of radiation therapy, chemotherapy, focal treatment modalities) requiring inpatient or day-care monitoring.

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment or a stage of specialized (including high-tech) medical care in an inpatient or day-care setting in the absence of treatment complications requiring drug correction and/or inpatient medical interventions;
2. refusal by the patient or their legal representative of specialized, including high-tech, medical care in an inpatient or day-inpatient setting, as established by a concilium of a medical organization providing oncological care, provided there are no complications of the underlying disease and/or treatment that require drug correction and/or inpatient medical interventions;
3. need to transfer the patient to another medical organization in the relevant medical specialty.

The conclusion regarding the feasibility of transferring a patient to a specialized medical organization is made after a preliminary consultation based on submitted medical documents and/or a preliminary examination of the patient by medical specialists of the target organization.

7. Additional Information

The prognosis is determined by the stage at which prostate cancer is detected, as well as the tumor differentiation grade and PSA level. The 5-year recurrence-free survival rate for patients with stage I–II disease after radical treatment (radical prostatectomy and radiation therapy) is 70–90%, and overall survival is 85–97%. When prostate cancer is diagnosed at the metastatic stage, the median time to disease progression during treatment is 24–36 months.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kaprin Andrey Dmitrievich, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, General Director of the National Medical Research Radiological Center of the Ministry of Health of Russia, Head of the Department of Urology and Operative Nephrology with a Course in Oncourology at the Medical Institute of the Peoples' Friendship University of Russia (Moscow, Russia).
2. Alekseev Boris Yakovlevich, Doctor of Medical Sciences, Professor, Deputy Director for Science at the National Medical Research Radiological Center of the Russian Ministry of Health.
3. Matveev Vsevolod Borisovich, Corresponding Member of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Deputy Director for Scientific and Innovative Work and Head of the Urological Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, President of the Russian Society of Oncourologists.
4. Pushkar Dmitry Yuryevich, Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Urology at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health (Moscow, Russia), Chief Urologist of the Russian Ministry of Health, Russian Society of Urology.
5. Govorov Alexander Viktorovich, Doctor of Medical Sciences, Professor at the Department of Urology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health (Moscow, Russia), Russian Society of Urology.
6. Gorban Nina Andreevna, Candidate of Medical Sciences, Head of the Center for Pathomorphology and Molecular Genetic Diagnostics at the Central Clinical Hospital with Policlinic of the Executive Directorate of the President of the Russian Federation, Russian Society of Oncopathologists.
7. Kirichek Andrey Andreevich, Assistant at the Department of Surgical Diseases with a Course in Oncology at the F.P. Haаз Moscow Medical and Social Institute, Oncologist at Moscow Clinical Oncology Hospital No. 62 (Moscow, Russia), Russian Society of Oncourologists.
8. Biryukov Vitaly Alexandrovich, Candidate of Medical Sciences, Senior Researcher at the Department of Radiation and Surgical Treatment of Urological Diseases with the Prostate Brachytherapy Group, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
9. Volkova Maria Igorevna, Doctor of Medical Sciences, Leading Researcher at the Urological Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
10. Gulidov Igor Alexandrovich, Head of the Department of Proton and Photon Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
11. Gumenetskaya Yulia Vasilyevna, Doctor of Medical Sciences, Head of the Radiotherapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
12. Krylov Valery Vasilyevich, Doctor of Medical Sciences, Head of the Department of Radionuclide Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
13. Karyakin Oleg Borisovich, Doctor of Medical Sciences, Head of the Department of Radiation and Surgical Treatment of Urological Diseases with the Prostate Brachytherapy Group, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Russian Society of Clinical Oncology.
14. Krasheninnikov Alexey Arturovich, Junior Researcher at the Department of Tumors of the Reproductive and Urinary Systems, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
15. Mardynsky Yury Stanislavovich, Corresponding Member of the Russian Academy of Sciences, Head of the Radiotherapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
16. Nyushko Kirill Mikhailovich, Candidate of Medical Sciences, Leading Researcher at the Department of Tumors of the Reproductive and Urinary Systems, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
17. Zakharova Tatyana Ivanovna, Candidate of Medical Sciences, Pathomorphologist, Department of Pathology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
18. Kostin Andrey Alexandrovich, Deputy Director General for Science, National Medical Research Radiological Center of the Russian Ministry of Health.
19. Khmelevsky Evgeny Vitalievich, Head of the Radiotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
20. Fedenko Alexander Alexandrovich, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
21. Bolotina Larisa Vladimirovna, Head of the Chemotherapy Department within the Tumour Drug Therapy Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
22. Falaleeva Natalya Alexandrovna, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
23. Filonenko Elena Vyacheslavovna, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Medical Care Organization Section

1. Nevolskikh Alexey Alekseevich, Doctor of Medical Sciences, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
2. Ivanov Sergey Anatolyevich, Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
3. Khaylova Zhanna Vladimirovna, Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
4. Gevorkyan Tigran Gagikovich, Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines – specialists with higher medical education in the following specialties:

• • oncology;
  • urology;
  • internal medicine;
  • general medical practice (family medicine);
  • surgery;
  • anesthesiology and intensive care medicine

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Methods used for evidence collection/selection: searching electronic databases, analysis of current scientific developments on the problem of germ cell tumors in Russia and abroad, synthesis of the practical experience of Russian and foreign specialists.

Methods used to formulate recommendations: expert consensus.

Appendix Table Error! Bookmark not defined.. Scale for evaluating levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Appendix Table Error! Bookmark not defined.. Scale for evaluating levels of evidence (LoE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table P3. Scale for evaluating grades of recommendation (GR) for methods of prevention, diagnostics, treatment, and rehabilitation (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. European Association of Urology Guidelines.
2. Order of the Russian Ministry of Health No. 907n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Urology'."
3. Order of the Russian Ministry of Health No. 915n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Oncology'."
4. Instructions for registered medicinal products (in the appendix in separate files).
5. Current instructions for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

The patient is informed about the clinical presentation of prostate cancer, introduced to various treatment methods, their potential outcomes and complications.

The patient should be informed about the symptoms and various complications of prostate cancer. It is especially important to warn prostate cancer patients with metastatic vertebral lesions about potential spinal cord compression for prompt medical attention if this complication occurs.

Recommendations for chemotherapy complications - contact your oncologist.

1. If body temperature rises to 38 ^°C or higher: start taking antibiotics (as prescribed by the oncologist).

2. For stomatitis:

• diet with mechanical and thermal sparing of the mucosa;
• frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoctions, lubricate the oral cavity with sea buckthorn (peach) oil;
• treat the oral cavity (as recommended by the oncologist).

3. In case of diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice water are permitted. Drink plenty of fluids;
• take medications (as prescribed by the oncologist).

4. For nausea: take medications (as prescribed by the oncologist)

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. IPSS questionnaire

Russian title: IPSS Questionnaire (International Prostate Symptom Score).

Original title: International Prostate Symptom Score Action Algorithms.

Source (official website of developers, validation publication) [382, 383].

Type (underline):

• rating scale,
• index,
• questionnaire,
• other.

Purpose: allows assessing symptom severity in patients with voiding dysfunction. Based on the score, the physician determines the severity of the patient's symptoms and selects a particular type of treatment.

Content:

International Prostate Symptom Score (1-PSS)

Interpretation: to obtain the IPSS score, the points obtained from the answers to the questions must be summed. A score of 0 to 7 indicates mild symptoms, 8–19 moderate symptoms, and 20–35 severe symptoms.

Appendix G2. WHO/ECOG performance status scale

Russian name: WHO/ECOG performance status scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official website of developers, validation publication): https://ecogacrin.org/resources/ecog-performance-status

Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982,5(6):649–655.

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Scoring key (interpretation): provided within the scale itself.

Appendix G3. Karnofsky performance scale

Russian name: Karnofsky scale.

Original title (if any): KARNOFSKY PERFORMANCE STATUS.

Source (official website of developers, validation publication): Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. edn. Edited by MacLeod C. New York: Columbia University Press; 1949: 191–205.

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Scoring key (interpretation): provided within the scale itself.

Appendix G4. Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Russian title: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Original title (if any): Response Evaluation Criteria in Solid Tumors 1.1.

Source (official website of developers, validation publication).

Original publication: Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228–247.

Type: rating scale.

Purpose: evaluation of response to chemotherapy. The content, key, and template in Russian are presented in methodological recommendations No. 46 of the State Budgetary Healthcare Institution "Scientific and Practical Center of Medical Radiology" of the Moscow Healthcare Department and are available on the website

http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf

This document is the property of the Moscow Healthcare Department, and may not be reproduced or distributed without appropriate permission.