Recommendations of the European Association of Urology
On March 15-19, 2019, the 34th annual congress of the European Association of Urology (EAU) was held in Barcelona, which was attended by doctors from more than 120 countries.
The EAU Congress is the largest event in the field of medicine, which is held annually to exchange experience between urologists from Europe and around the world. Every year, urologists present original data, exchange ideas on urological innovations, and spread knowledge of evidence-based medicine about the most clinically and socially significant diseases of the urogenital area. And the beginning of this was laid 45 years ago. The first EAU congress was held in Padua (Italy) in 1974, where only 100 doctors took part. About 15,000 doctors from all over the world took part in the Congress in Barcelona in 2019, about 4,500 abstracts were sent, about 1,200 of which were approved in the form of reports.
Leading specialists and employees of the City Center for Endoscopic Urology and New Technologies attended this significant event. Head of the Center, Chief Physician of St. Petersburg State Budgetary Institution of Health Clinical Hospital of St. Luke, MD Popov Sergey Valerievich made a video presentation “Laparoscopic resection of intraparenchymal kidney neoplasm in condition of warm ischemia”.
This text is based on the full text version of the European Association of Urology (EAU) 2014 guidelines.
The EAU group developed evidence-based guidelines for the treatment of RCC to assist urologists in evaluating approaches to the treatment of this pathology and implementing these recommendations into clinical practice. Publications concerning RCC are mostly retrospective and include some of the largest multicenter studies and other qualitative control trials. IN last years a large number of randomized trials have been conducted, mainly on the medical treatment of metastatic RCC, which made it possible to formulate recommendations based on data with a high level of certainty.
Where possible, information was assigned an appropriate level of evidence (LE) and grade of recommendation (SR) (Tables 1, 2).
Epidemiology and etiology
RCC accounts for 2-3% of all high-incidence tumors in Western countries. Over the past 2 decades, there has been an annual increase in the incidence of RCC by an average of 2% both in Europe and worldwide. In 2012 in European Union there were 84,400 new cases of RCC and 34,700 deaths associated with this disease. Europe until the early 1990s. there was an increase in the overall mortality rate from RCC, then it stabilized or began to decline.
RCC accounts for about 90% of all malignant kidney tumors with specific pathohistological and genetic characteristics. The incidence rate among men is 1.5 times higher than among the female population. The peak incidence falls on the age range of 60-70 years. Etiological factors include smoking, obesity and high blood pressure. A history of kidney cancer (RC) in first-degree relatives is also associated with an increased risk of developing RCC. The role of diet and exposure to carcinogens in the development of RP has not been proven. Moderate alcohol consumption for as yet unknown reasons may have a preventive effect.
Widespread adoption of imaging techniques such as ultrasonography(ultrasound) and computed tomography (CT), has led to an increase in the number of incidentally detected tumors, which are mostly smaller and lower stage.
Studies have shown that smoking, obesity and arterial hypertension are confirmed risk factors (LE: 2a). Smoking cessation and obesity should be considered primary prevention of RCC (SR B).
Diagnosis and staging
Clinic
Many kidney masses remain asymptomatic until the later stages of the disease. Currently, >50% of all cases of RCC are discovered incidentally during evaluation of patients for other abdominal diseases (LE: 3). The classic triad of clinical symptoms (flank pain, gross hematuria, and a palpable abdominal mass) is now rare (6–10%) and correlates with aggressive histology and advanced disease (LE: 3). Paraneoplastic syndromes such as hypertension, cachexia, weight loss, fever, neuromyopathy, amyloidosis, elevated erythrocyte sedimentation rate (ESR), anemia, abnormal liver function, polycythemia, and hypercalcemia may be present in up to 30% of patients with clinical signs of RCC (LE 4). Some patients also present with symptoms of metastatic disease, such as bone pain or persistent cough, along with clinical signs (LE: 3).
In the presence of a palpable tumor in the abdominal cavity, palpable cervical lymph nodes, persistent varicocele and bilateral edema lower extremities patients are shown a more detailed radiation examination.
Laboratory diagnostics
The most frequently measured laboratory parameters are serum creatinine, glomerular filtration rate (GFR), complete blood count, ESR, liver function tests, corrected alkaline phosphatase, lactate dehydrogenase (LDH), and corrected serum calcium, coagulogram, and urinalysis (LE: 4) . If there are central renal masses adjacent to or opening into the lumen of the collecting system of the kidney, urine cytology and possibly upper tract endoscopic examination should be performed to rule out urothelial cancer (LE: 4).
Separately, bilateral renal function should be assessed using nephroscintigraphy in the following situations (LE: 2b): if renal function is impaired, as evidenced by an increase in serum creatinine concentration or a significantly reduced GFR; if there is a risk of a significant decrease in renal function during treatment (a tumor of a single kidney, a tumor lesion of both kidneys in hereditary forms of cancer).
Nephroscintigraphy is also important in patients at risk of future decline in kidney function due to comorbidities such as diabetes, severe arterial hypertension, chronic pyelonephritis, renovascular disease, nephrolithiasis or polycystic kidney disease.
Radiation diagnostics
The majority of renal tumors are detected by ultrasound or CT performed for another reason (LE: 3). Imaging can be used to distinguish between solid and cystic kidney masses. For solid renal masses, the most important differential criterion for malignant neoplasms is the presence of contrast enhancement (LE: 3). Traditionally, ultrasound, CT, or magnetic resonance imaging (MRI) have been used to identify and characterize kidney masses. Contrast-enhanced ultrasound may be useful in patients with chronic renal failure and relative contraindications to the use of contrast agents, with complex cystic tumors, and in the differential diagnosis of vascular diseases in the periphery of the kidney, such as infarction and renal cortical necrosis (LE: 3).
Imaging with CT or MRI
CT or MRI is used to characterize renal masses, and images must be obtained both before and after intravenous administration. contrast agent to detect contrast. On CT images, contrast in renal neoplasms is determined by comparing the contrast on the Housefield scale (in units of the scale HU) before and after contrast injection. A 15 HU change in contrast is strong evidence of enhancement (LE: 3). It can be extremely difficult to distinguish oncocytoma and non-fat angiomyolipoma (AML) from malignancy on CT or MRI (LE: 3).
Abdominal CT can diagnose RCC and provide information on the structure and function of the contralateral kidney (LE: 3), extension of the primary tumor beyond the kidney, involvement of the venous system, enlargement of regional lymph nodes, and the state of the adrenal glands and liver (LE: 3). Contrast-enhanced CT angiography of the abdominal vessels is used to assess the blood supply to the kidneys (especially when planning a kidney resection).
If the CT data is uncertain, you can resort to performing an MRI and get Additional information regarding the detection of contrast enhancement, local spread of malignancy and the degree of involvement of the venous system (LE: 3). MRI is also indicated in patients allergic to contrast media and in pregnant women without renal impairment (LE: 3).
Renal arteriography and cavography have limited indications and are used as additional diagnostic tools in selected patients with RCC (LE: 3). In patients with the slightest sign of decreased renal function, isotope renography and a complete assessment of renal function should be considered (LE: 2a). Currently, positron emission tomography (PET) is not the standard imaging modality (LE: 3).
CT of organs chest is the most accurate method for detecting lung metastases (LE: 3). If CT is not available to detect lung metastases, a chest x-ray should be performed. Most bone and brain metastases have some form of clinical manifestation at the time of diagnosis, so routine skeletal scans and brain CT are usually not indicated (LE: 3).
Bosniak classification of cystic neoplasms in the kidneys
The Bosniak classification is used to evaluate cystic neoplasms in the kidneys based on their appearance on CT images to predict the risk of malignancy (Table 3) (LE: 3).
Kidney biopsy
Percutaneous biopsy of kidney tumors is more commonly used for histological confirmation of radiologically indeterminate kidney tumors, selection of patients for follow-up, verification of the diagnosis before ablative treatment, and systemic therapy in patients with metastatic RC (LE: 3). Percutaneous biopsy of a kidney tumor can be performed either by punch biopsy or fine needle biopsy. Due to the high percentage of kidney tumors detected by CT or MRI (subject to contrast agent accumulation), preoperative kidney biopsy is not indicated in patients with a high life expectancy (LE: 4).
Most kidney tumor biopsies are performed under local anesthesia (LE: 3). Depending on the location of the tumor, a biopsy is performed under ultrasound or CT guidance (LE: 2b). For biopsy, a 18-gauge needle is used to provide sufficient material for histological examination (LE: 2b). In order to prevent dissemination of tumor cells during biopsy, the latter should be performed through a special cannula (coaxial biopsy method) (LE: 3). At least 2 tissue fragments (complete, >10 mm in length) must be obtained. Obtaining necrotic tissue should also be avoided to increase the diagnostic value of the method (LE: 4), for which the biopsy should be taken from the peripheral zone (LE: 2b).
Percutaneous biopsy of a kidney tumor has a low morbidity. The most common complications are hematuria and subcapsular or pararenal hematomas. In general, bleeding is not clinically significant (0.0-1.4%) and is most often limited to the kidney. Needle biopsy of a kidney tumor is of greater diagnostic value, since it allows to determine its histological structure and grade of malignancy compared to fine needle biopsy (LE: 2b). Large tumor size and a solid component are predictors of needle biopsy (LE: 2b). The diagnostic value of a kidney biopsy is 78-97%, specificity is 98-100%, and sensitivity is 86-100% (LE: 2b). If the biopsy is negative, but if malignancy is suspected on x-ray, repeat biopsy or surgery should be considered (LE: 4). Assessment of the degree of tumor differentiation based on biopsy data is a difficult task. Furman's classification is limited (43-75%) but can be improved using a simplified two-tier system (high versus low grade) (LE: 2b). Biopsy is of low diagnostic value for cystic renal tumors and cannot be recommended in these cases in the absence of sites with a solid component (Bosniak classification of cysts - IV) (LE: 2b). A combination of fine needle biopsy and needle biopsy is appropriate for complex cystic lesions (LE: 3).
Histological diagnosis
Renal neoplasms include a wide range of histological forms described in 2004 by the WHO and modified by The International Society of Urological Pathology (ISUP) Vancouver Classification. From a clinical point of view, 3 main histological subtypes of RCC are important: clear cell, papillary (types I and II), and chromophobe (Table 4).
In all histological subtypes of RCC, the prognosis worsens depending on the stage and histological grade (Tables 5, 6).
An improvement in 5-year overall survival (OS) for each RCC histological subtype of 49% has occurred since 2006, which seems to be related to the early detection of RCC and the administration of tyrosine kinase inhibitors. Sarcoma-like changes are characteristic of all histological subtypes of RCC and are equivalent to a high degree of malignancy and aggressiveness of the tumor.
Clear cell RCC
Macroscopically, the capsule is usually absent. A large tumor may be with infiltrative growth. The cut surface is golden yellow with hemorrhages and necrosis. The Furman classification is usually used. It is determined by a specific deletion of chromosome 3p and a mutation in the von Hippel-Lindau (VHL) gene located on chromosome 3p25. Patients with clear cell RCC have a worse prognosis than those with papillary and chromophobe RCC. Five-year cancer-specific survival (RSV) is 91%, 74%, 67%, and 32% for patients with clinical stage T1, T2, T3, and T4, respectively (patients treated between 1987 and 1998). The indolent variant of clear cell RCC has a multilocular cystic structure and accounts for 4% of all clear cell RCC variants.
Papillary RCC
Papillary RCC macroscopically consists of pseudocapsules of yellow or Brown with soft texture. The most persistent genetic changes are trisomy of chromosomes 7 and 17 and loss of the Y chromosome. Papillary RCC is heterogeneous and consists of 3 subtypes: 2 main (1 and 2) and the third - oncocytic carcinoma. Compared to clear cell, papillary RCC has more high level organ-limited tumors - clinical stage pT1-2N0M0 (74.9% versus 62.9%) and a high level of 5-year RSV (85.1% versus 76.9%). The prognosis of type 2 papillary RCC is worse than type 1 (2.16 vs 3.28). Exophytic growth, pseudonecrotic changes, and pseudocapsules are typical features of type 1 papillary RCC. Pseudocapsules and extensive necrotic changes lead to the appearance of a spherical tumor in the extrarenal region. Tumors with massive necrosis are fragile and vulnerable to spontaneous rupture and rupture with minimal trauma, followed by development of retroperitoneal bleeding. The well-developed pseudocapsule of type 1 papillary RCC does not rupture despite the presence of necrosis. On post-contrast CT scans, necrosis foci appear echo-negative in the central part of the tumor, surrounded by its tissue, which accumulates a contrast agent on CT.
Chromophobic RCC
Macroscopically, chromophobic RCC is a pale brown, relatively uniform and tough, limited mass lacking a capsule. In 2010, instead of Fuhrman's classification, a G.P. Paner et al. Genetically characterized by the loss of 2, 10, 13, 17 and 21 chromosomes. This type of RCC is characterized by a relatively favorable prognosis, 5-year relapse-free survival (RFS) (89.3%) and RSV (93.0%), as well as 10-year RSV (88.9%).
Conclusion
Many patients with RCC still present with clinical symptoms such as palpable masses, hematuria, paraneoplastic and metastatic syndromes (LE: 3). Accurate staging of RCC with abdominal and thoracic CT or MRI is mandatory (LE: 3). CT is the most sensitive method used to detect lung metastases. In the absence of CT, a chest x-ray should be performed. Scanning of the bones of the skeleton and CT of the brain in the absence of specific clinical indications are not justified.
Increasingly, percutaneous biopsy of a kidney tumor is used in the diagnosis: for histological confirmation of radiographically indeterminate kidney tumors, in the selection of patients for follow-up and ablative treatments, for systemic therapy of patients with metastatic RCC (mRCC).
Abdominal CT and MRI with contrast are recommended for monitoring patients with RCC and are equivalent methods for staging and diagnosis (SR B). Abdominal CT and MRI with contrast are the most appropriate imaging modalities for RP characterization and preoperative staging (SR C). Chest CT is recommended to determine lung and mediastinal involvement (SR C). Bone scintigraphy is not usually recommended (CP C). Kidney biopsy is recommended before ablative therapies and systemic therapy in patients without comorbidities (SR C). Percutaneous renal biopsy is recommended in patients who require active surveillance (CP C) and should be performed by coaxial technique (CP C).
Classification and prognostic factors
Classification
The generally accepted staging system for RCC is the TNM classification, which is recommended for use in clinical and scientific work. The latest TNM classification was published in 2010 (Table 7). The predictive value of the TNM classification has been confirmed by single and multicenter studies. However, some uncertainties remain: in the subset of T1 tumors, resection (4 cm) may not be the best option for localized cancer; the significance of the size of clinical stage T2 tumors has been questioned; the 2002 version of the TNM classification assigned tumors with invasion into the tissue of the renal sinus to the clinical stage pT3a. However, based on accumulated data, it can be assumed that the prognosis for tumor invasion into the renal sinus is worse than for invasion into the perirenal adipose tissue, and, therefore, such tumors should not be included in the pT3a staging group (LE: 3); some subdivisions of the TNM classification (pT2b, pT3a, pT3c and pT4) may overlap; the accuracy of the N1-N2 subsection was questioned (LE: 3); To determine category M in patients with RP, a thorough preoperative instrumental examination, including CT scan of the chest and abdomen, should be performed (LE: 4).
Prognostic factors include anatomical, histological, clinical and molecular factors.
Anatomical factors include tumor size, venous invasion, renal capsule invasion, adrenal involvement, lymph node involvement, and presence of distant metastases. These factors are combined in the generally accepted TNM classification (Tables 7, 8).
The use of an anatomical classification system for renal tumors allows an objective prediction of the potential morbidity of organ-conserving surgery (CA) and ablative therapies, provides information on treatment planning, for patient counseling and proper comparison of tumor resection and ablative therapies. However, when choosing best method treatment anatomical features should always be considered in conjunction with the patient and the experience of the surgeon.
Histologic factors include Furman's degree of cellular differentiation, RCC subtype, sarcomatoid features, small vessel invasion, tumor necrosis, and collecting system invasion. Furman's grade is the accepted histological classification system for RCC. Recently, it has been suggested that a simplified 2- or 3-level Furman classification can be as accurate as a classical 4-level scheme (LE: 3).
According to the WHO classification, there are 3 main histological subtypes of RCC, confirmed at the molecular level using genetic and cytogenetic studies (LE: 2b): clear cell - 80-90%; papillary - 10-15%; chromophobic - 4-5%.
Univariate analysis shows that patients with chromophobe cancer tend to have a better prognosis than those with papillary or clear cell RCC (LE: 3).
Among patients with papillary cancer, 2 prognostically different groups were distinguished: type 1 - tumor with low malignant potential, cells with chromophilic cytoplasm, favorable prognosis and type 2 - tumor with high malignant potential, cells with eosinophilic cytoplasm, high predisposition to metastasis (LE: 3) . RP associated with the 11.2 Xp translocation is associated with poor prognosis. With a low incidence, this type of cancer should be suspected in young patients.
Clinical factors include the patient's general condition, local symptoms, degree of cachexia, severity of anemia, and platelet count (LE: 3).
A large number of molecular markers are currently being investigated, including carbonic anhydrase IX (CaIX), vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF), Ki 67 (proliferation), p53, PNEN (phosphatase and tensin homologue), E -cadherin, C-reactive protein (CRP), osteopontin and CD 44 (cell adhesion) (LE: 3). Before today none of these markers has been able to demonstrate improvements in the accuracy of current prediction systems, so their use is not recommended in regular practice.
In recent years, postoperative prognostic systems and nomograms, including combinations of independent prognostic factors, have been developed and tested on patients from other medical centers. These systems may be more accurate than TNM classification or Furman grading alone for predicting survival (LE: 3). An important advantage of nomograms is their ability to measure the accuracy of the forecast, which makes it possible to objectively evaluate all new prognostic parameters. Several new preoperative nomograms have been developed with high predictive accuracy. The most common predictive systems are shown in Table 9.
Conclusion
In patients with RCC, the following parameters should be defined to provide important prognostic information: TNM stage, Fuhrman grade, and WHO (2004) histological subtype (LE: 2).
It is recommended to use the modern classification of TNM (SR B), as well as the division of RCC into histological variants (SR B). In metastatic RCC, the use of prognostic systems (SR B) is recommended. The use of integrated prognostic systems or nomograms for localized disease is not recommended, although these systems may be useful when enrolling patients in clinical trials (SR C). The use of molecular prognostic markers (CP C) in everyday practice is not recommended.
Other kidney tumors
Based on the results of detailed morphological studies, the current classification of neoplasms in the renal epithelium was established, outlined in a monograph prepared by WHO in 2004. A revised histopathological classification was published in 2013 by the ISUP Vancouver classification of renal neoplasms. This classification appears to constitute the new WHO classification. Approximately 85-90% of all malignant neoplasms of the kidneys are common clear cell, papillary and chromophobe types of cancer. The remaining 10-15% of renal tumors include a variety of rare sporadic and familial carcinomas and a group of unclassified carcinomas.
Bellini collecting system carcinoma- a very rare type of RCC, often detected at a late stage in the development of the disease. Up to 40% of patients have metastases at first presentation, and most die within 1-3 years of initial diagnosis. The hazard ratio of RSV versus clear cell RCC is 4.49. Currently, the largest series shows that metastases in regional lymph nodes at the time of diagnosis were present in 44% of patients, and distant metastases were found in 32%. The survival rate was 48% at 5 years and 14% at 10 years. The median survival was 30%, the response to targeted therapy was unsatisfactory.
Medullary carcinoma of the kidney- a devastating malignancy primarily affecting young black people who are heterozygous for sickle cell anemia. However, in recent years there have been cases of detection of this disease in white patients, as well as in Hispanics. The disease is a subtype of carcinoma of the collecting system, is very rare and accounts for approximately 2% of all primary kidney tumors in young people aged 10 to 20 years. In 95% of patients at the time of treatment, the presence of metastases is observed. Median survival is 5 months. A single surgical intervention is not enough, systemic therapy is not defined, various chemotherapy regimens are used, the tumor is radiosensitive.
Sarcomatoid RCC- this is RCC different type, which has transformed into a cancer of a high degree of differentiation, but in itself it is not distinguished into a separate histological variety. In the presence of sarcomatoid changes in RCC, the prognosis worsens. Metastases from sarcomatoid RCC are associated with poor response to systemic therapy. Treatment with sunitinib resulted in a small number of positive responses to treatment. The combination of gemcitabine and doxorubicin may be an option (LE: 3, RG C).
Unclassified RCC is a diagnostic category used to define a type of RCC that cannot be assigned to any other categories specific to RCC-type carcinomas.
Multilocular cystic RCC- well-differentiated clear cell RCC, which accounts for up to 4% of kidney tumors removed surgically. To date, no description of metastases for this tumor has been given. According to the Bosniak classification, multilocular clear cell RCC is a type II or III cystic neoplasm. However, the same types of neoplasms according to Bosniak are characteristic of a mixed epithelial-stromal tumor of the kidney, cystic nephroma, or multilocular cyst (all of them are benign tumors). In many cases, preoperative biopsy and intraoperative frozen section examination do not provide a correct diagnosis. Fortunately, the same organ-sparing operative strategy exists for all of these tumors (LE: 3, RG B).
Hybrid oncocytoma(chromophobe RCC) has a mixture of cells of chromophobe RCC of renal oncocytoma. It can occur in 3 different clinical and pathological situations: sporadic, associated with renal oncocytosis or oncocytomatosis, or in patients with Burt-Hogg-Dubet syndrome (characterized by the presence of hematomas on the skin and several kidney tumors). No data were obtained for malignancy. However, patients should be monitored in the same way as for chromophobic RCC.
Translocation carcinomas of the kidneys rare tumors that occur in young people and only in 25% over the age of 40 years. This type The tumor consists of 2 subgroups involving chromosome 6p21 or Xp11.2. Both types have a high malignant potential. Several VEGF-targeted drugs have been shown to be effective in clinical practice against 2 subgroups of translocation carcinoma.
Tubulocystic RCC characteristic of men at any age. There is a possible association with papillary RCC, which often leads to the development of a cystic component (Bosnjak III or IV). The tumor has a certain malignancy potential, but in most cases (90%) it has a sluggish character.
Mucinous tubular and spindle cell carcinomas associated with the loop of Henle. Most mucinous tubular and spindle cell carcinomas behave in the same way as low-grade tumors.
Carcinoma associated with end-stage kidney disease and acquired cystic disease associated with RCC. Degenerative cystic changes (acquired kidney cysts) and a higher incidence of RCC are typical features of end-stage kidney disease. Acquired kidney cysts occur in almost 50% of cases in patients undergoing dialysis, but the frequency of occurrence also depends on the duration of dialysis, gender (in men - 3 times more often) and diagnostic criteria adopted in the method of assessing the condition. In the case of the presence of end-stage diseases of the own kidneys, RCC is found in 4% of patients. The lifetime risk of developing RCC for these patients is at least 10 times higher than in the general population. Compared to sporadic RCC, cancer associated with end-stage kidney disease and acquired renal cystosis is multicentric, bilateral, and less aggressive, and occurs in younger patients (more often males). RCC developing in patients undergoing transplantation is manifested by more favorable clinical, pathological and functional outcomes than in patients undergoing dialysis. Despite the fact that the histological spectrum of tumors in acquired renal cysts is similar to that in sporadic RCC, in most of these cancer cases, the papillary form prevails: in tumors associated with acquired cysts, it is 41-71%, while in sporadic cancer - 10%. The remaining tumors are represented mainly by clear cell carcinoma. RCC associated with end-stage kidney disease and acquired cysts has been described under the name RCC-associated cystic disease. Patients with end-stage kidney disease should have an annual kidney assessment. Such patients can undergo radical nephrectomy (RNE).
Clear cell (tubulo) papillary RCC, renal angiomyomatous tumor. This type of tumor occurs in patients with end-stage renal disease. However, most of the reported cases were sporadic. The published data indicate a sluggish process. No cases of metastasis were noted. A tumor of similar morphology and immunophenotype, but with visible smooth muscle stroma, was termed angiomyomatous tumor of the kidney.
RCC associated with the presence neuroblastoma,- a rare type of tumor that occurs in people who have had neuroblastoma in childhood. This group of patients has a 329-fold risk of RP. The tumor is heterogeneous and is characterized by oncocytoid features. Its development is possible in children of both sexes.
papillary adenomas- tumors of papillary or tubular structure with a low degree of differentiation and a diameter of ≤5 mm. Due to their small size, they are usually found incidentally in sections of the kidney tissue during nephrectomy.
Metanephric tumors subdivided into metanephric adenoma, adenofibroma and metanephric stromal tumors. These are rare benign tumors that require surgical removal.
Epithelial and stromal tumors of the kidneys- these are 2 types of benign mixed mesenchymal and epithelial tumors (combined according to a new concept): cystic nephroma and mixed epithelial-stromal tumors. Imaging shows that most of the cystic neoplasms representing this type of tumor can be classified according to Bosniak as belonging to III, less often - to II or IV classes. Both types of neoplasms are generally considered benign and must be removed.
Oncocytomas of the kidneys- benign tumors, accounting for 3 to 7% of all kidney tumors. The standard diagnostic method is histopathological examination. Although a preoperative diagnosis can only be made by performing a percutaneous biopsy, this method is not specific for oncocytoma, since its cells are also found in clear cell RCC, granular cell RCC, eosinophilic and oncocytic variants of papillary RCC (type 2). In some cases, you can resort to expectant tactics of observation. Alternative Methods are nephrectomy and minimally invasive therapies (LE: 3, RG C).
Hereditary kidney tumors can occur in von Hippel-Lindau syndrome, hereditary papillary RCC, Burt-Hogg-Dube syndrome, congenital leiomyomatosis and RCC, tuberous sclerosis, intrauterine succinate dehydrogenase mutation, non-polypous colorectal cancer syndrome, hyperparathyroidism, constitutional translocation of the 3rd chromosome, and familial Syndromic-free clear cell RCC. Renal medullary carcinoma may also be included in this list due to its association with hereditary hemoglobinopathies.
Mesenchymal tumors include various types of sarcomas. With the exception of AML, they are relatively rare.
AML is a benign mesenchymal tumor composed of varying degrees of adipose tissue, fusiform and epithelioid smooth muscle cells, and abnormally thickened blood vessels. Such tumors can occur sporadically, and in women it happens 4 times more often. They also occur in tuberous sclerosis and in this case have a multiple character, more large size are bilateral and can cause profuse bleeding. AML accounts for about 1% of tumors that are surgically removed. It is often diagnosed by ultrasound, CT or MRI due to the presence of adipose tissue. Performing a biopsy is rarely successful. Before surgery, it is often difficult to distinguish between AML and tumors containing mostly smooth muscle cells, and between AML and epithelial tumors. AML can be found in the lymph nodes of tuberous sclerosis, however this is not considered a metastasis. AML is characterized by vascular growth involving the IVC and renal vein. AML involving lymph nodes and tumor thrombus is benign. Epithelioid AML is a potentially malignant variant of this tumor. AML is characterized by slow and gradual growth (0.088 cm/year) and low morbidity. The main complication of AML is retroperitoneal bleeding or bleeding into the collecting system of the kidneys, which can be life threatening. Bleeding is associated with the presence of an angiogenic component in the tumor, characterized by unevenly growing and aneurysmal blood vessels. The main risk factors for bleeding are the size of the tumor, the severity of the angiogenic component in it, and the presence of tuberous sclerosis in the patient. The primary indications for intervention are symptoms such as pain, bleeding, or suspicion of a malignant tumor.
In general, AML can be treated with organ-sparing approaches, but in some situations, complete removal of the kidney may be required (LE: 3). Selective arterial embolization (SAE) and radiofrequency ablation (RFA) can also be used. While SAE is effective in stopping bleeding in the acute setting, its usefulness for the long-term management of AML is limited. Clinical trials of mTOR inhibitors as well as sirolimus in combination with delayed surgery are ongoing.
Further studies are required in order to determine the nature and course of new histological varieties of tumors: a rare thyroid-like follicular tumor that mimics follicular thyroid cancer; RCC associated with succinate dehydrogenase B mutation; RCC associated with anaplastic lymphoma kinase translocation.
An overview of other renal tumours, indicating the possibility of malignancy and recommendations for treatment, is presented in Table 10.
Conclusion
With the exception of AML, most of these less common kidney tumors cannot be distinguished from RCC based on imaging findings and should therefore be treated in the same way as for RCC (LE: 3). For proven oncocytoma, observation is preferred (LE: 3). There is no standardized approach to the treatment of rare types of RCC (LE: 3).
Cysts with Bosniak type >III should be considered as a variant of RCC and treated accordingly (SR C). If AML is identified, surgery, thermal ablation, and SAE may be considered if: the tumor is large (the previously recommended threshold of >(3) 4 cm is disputed); the tumor occurs in a woman of childbearing age; observation is insufficient in this patient. CCA (CP C) is preferred.
Treatment of localized RCC
Surgery. Organ-sparing surgery and nephrectomy
Studies have shown that the RSV rates of open nephrectomy and open nephrectomy are comparable. For example, with a median follow-up of 9.3 years, the survival rate in the group of patients who underwent RNE was 72.5%, and in the group of patients who underwent kidney resection - 64.4%. Local recurrence was recorded in 1 patient who underwent RNE and in 6 patients who underwent kidney resection.
A number of studies have shown that RNE is associated with high mortality. There were no differences between kidney resection and RNE in patients with SCC 4-7 cm. There were also no differences in OS, RSV, and DFS in patients undergoing laparoscopic nephrectomy and laparoscopic nephrectomy with RP >4 cm. There were no differences in hospital stay, mean blood loss, or blood transfusion rates. The quality of life in patients who underwent kidney resection was better than in patients who underwent RNE. When comparing RFA, RNE and kidney resection, RSV in each of the 3 treatments was 100%.
NCA is preferable for localized RCC, however, in some patients with localized RCC, CCA is not possible for a number of reasons. These reasons include: locally advanced tumor growth; the impossibility of performing resection due to the unfavorable location of the tumor; significant deterioration in the general condition of the patient. In these situations, the only treatment option is RNE, which is the "gold standard" of treatment.
There were no differences in 5- and 10-year OS between patients who underwent adrenalectomy and those who did not undergo it. Adrenalectomy is justified in the presence of radiographic and intraoperative data confirming the expediency of its implementation.
CT and MRI do not detect metastases in normal-sized lymph nodes. Extended dissection of lymph nodes is the main method for assessing their condition. Retrospective studies show that lymph node dissection is warranted in patients high risk(tumor size >10 cm, clinical stage T3-4, high Fuhrman differentiation, presence of sarcomatoid features, or coagulative tumor necrosis). Survival is higher in patients with fewer positive lymph nodes (<4) и отсутствием экстранодального расширения. Была предложена предоперационная номограмма оценки степени поражения лимфоузлов.
There are no advantages to performing embolization over conventional nephrectomy. For patients who cannot tolerate surgery or who have pain due to metastases, embolization can reduce symptoms such as hematuria, flank pain, or bone pain. The implementation of embolization prior to the resection of hypervascular metastases in the bones or spine helps to reduce blood loss during the operation.
Conclusion
The oncological outcomes of kidney resection are comparable to those of RNE (LE: 1b). Ipsilateral adrenalectomy during radical kidney resection does not increase OS (LE: 3). RNE combined with lymph node dissection in patients with localized RP and no clinical evidence of lymph node metastasis does not improve survival (LE: 1b). Performing lymph node dissection in patients with localized RP and enlarged lymph nodes may be considered for staging purposes (LE: 3). Embolization may be considered as a palliative option in certain patients (LE: 3).
Surgical treatment should be recommended for patients with localized RP (SR B). CCA is recommended for patients with clinical stage T1a (CP A). In patients with clinical stage T1b and where technically feasible, CCA should be performed (SR B). Adrenalectomy is not recommended in the absence of clinical signs of adrenal disease (SR B). Lymph node dissection is not recommended in the absence of clinical signs of lymph node involvement (SR A). In patients with enlarged lymph nodes, according to studies, lymph node dissection can be performed for the purpose of staging and local control (SR C).
radical nephrectomy
The oncological outcomes of laparoscopic and open RNE are similar. However, laparoscopic nephrectomy is associated with less blood loss, shorter hospital stay, and a shorter recovery time. There were no differences in the frequency of transfusion of blood components and the development of complications. The duration of the operation was shorter with open RNE. Oncological results with transabdominal and retroperitoneal approaches are comparable. Also, there were no differences in 5-year survival, RSV and DFS in the groups of patients who underwent standard laparoscopic nephrectomy and laparoscopic hand-assisted nephrectomy. The duration of the operation was significantly shorter in group 2, while the hospital stay was shorter in the group of patients who underwent standard laparoscopic nephrectomy. Comparison between robotic nephrectomy and laparoscopic nephrectomy was performed in 1 prospective cohort study. With a median follow-up of less than 1 year, there were no differences in the occurrence of local recurrences and distant metastases.
Kidney resection
There were no differences between DFS, OS, and postoperative mortality in the group of patients who underwent laparoscopic and open nephrectomy. The average volume of blood loss was less, and the duration of the operation was longer with laparoscopic nephrectomy. GFR was higher with laparoscopic kidney resection. Similar data were obtained when comparing transabdominal and retroperitoneal approaches for laparoscopic kidney resection. Currently, there are no studies comparing robotic and laparoscopic nephrectomy. It was shown that during robotic kidney resection, the volume of blood loss was less, and the period of ischemia was shorter.
Conclusion
Laparoscopic RNE has a low morbidity compared to open surgery (LE: 1b). Oncological outcomes in the treatment of patients with clinical stage T1-2 are comparable with open and laparoscopic RNE (LE: 2a). Kidney resection can be performed by open, laparoscopic, or robotic approaches (LE: 2b).
For patients with clinical stage T2 and those who are unable to undergo CCA, laparoscopic RNE (SR B) is recommended. Patients with clinical stage T1 who are indicated for kidney resection are not recommended to undergo laparoscopic RNE (SR A).
Therapeutic approaches as an alternative to surgical treatment
Studies evaluating the possibility of active surveillance have shown that RCC with slow growth and metastasis occurs in a limited number of patients (1-2%). Short- and medium-term oncological results suggest that this strategy is appropriate for initial monitoring of small renal neoplasms, which can then be treated as they progress. Active surveillance involves MRI, CT, or contrast-enhanced ultrasound; most indicated for elderly and somatically aggravated patients, with low life expectancy and high-risk patients.
Alternative treatments include RFA, cryoablation, microwave therapy, and high-intensity focused ultrasound (HIFU) therapy. Significant advantages of these methods: low morbidity, the possibility of outpatient treatment, as well as the treatment of high-risk patients who cannot be treated with standard surgical treatment. It is also possible to carry out these interventions in elderly and somatically burdened patients.
Among the available ablative techniques, RFA and cryoablation have been the most extensively studied in terms of their practicality, complication rates, and oncological safety. However, studies show that the frequency of relapses in these groups is higher compared with the frequency after CCA.
Cryoablation, like RFA, can be performed by percutaneous or laparoscopic approaches. There are no significant differences in complication rates, OS, RSV, and DFS when these treatments are compared. The duration of hospital stay for percutaneous cryoablation was 2.1 days, for laparoscopic cryoablation - 3.5 days (p<0,01). При сравнении лапароскопической криоаблации и лапароскопической резекции почки также не было отмечено различий в частоте осложнений, последующем восстановлении и послеоперационном уровне креатинина сыворотки крови. Лапароскопическая резекция почки была больше ассоциирована с кровопотерей. Ни в одной из групп не было отмечено местных рецидивов или метастазирования. При сравнении роботической резекции почки и лапароскопической криоаблации обнаружены существенные различия в местном рецидивировании (0% против 11%) и метастазировании (0,5% против 5,6%). Осложнения после РЧА определяются как незначительные и составляют около 29%. При сравнении РЧА и резекции почки различий в ОВ и РСВ отмечено не было (медиана наблюдения составила 6,3 года). Тем не менее резекция почки была ассоциирована с большим числом осложнений и частотой переливания крови. При сравнении РЧА и РНЭ РСВ в обеих группах составила 100%, тогда как ОВ в группе больных, перенесших РЧА, была ниже (75% против 100%).
Minimally invasive treatments for RCC, such as HIFU, microwave and laser ablation, are currently considered experimental.
Conclusion
Mortality rates in patients treated with surgery are lower compared to those in patients without surgery. However, the analysis of indicators in elderly patients (>75 years) did not reveal this pattern (LE: 3). Small kidney tumors grow slowly and disease progression is rare (LE: 3). Available data do not allow definitive conclusions regarding the morbidity and oncological outcomes of cryoablation and RFA (LE: 3). There was a higher rate of local recurrence with minimally invasive treatments than with kidney resection (LE: 3).
The paucity of available data precludes recommendations for cryoablation and RFA (SR C). Active surveillance, cryoablation, and RFA (SR C) may be recommended for elderly, medically compromised patients, and patients with limited life expectancy.
Treatment of RCC with tumor thrombi
The formation of a thrombus in the IVC in patients with RCC is an unfavorable prognostic factor. In patients with non-metastatic RCC, removal (resection) of the kidney and tumor thrombus is indicated (LE: 3, RG C). There is also a strategy: preoperative filter placement or embolization, the effectiveness of which is currently not determined (LE: 3). The surgical approach depends on the level of the thrombus and the degree of IVC occlusion. It has been proven that the level of location of the tumor thrombus does not reflect the degree of tumor spread to the lymph nodes, invasion of pararenal tissue, or the presence of distant metastases.
Existing evidence suggests that adjuvant vaccination with self-tumor antigens may reduce the risk of recurrence after nephrectomy in a subgroup of patients with stage T3 RP, but further studies of the effect of this therapy on OS are needed (LE: 1b). III phase clinical research The efficacy of sunitinib, sorafenib, pazopanib, and everolimus is ongoing, so there is no evidence of concomitant use with VEGF-R inhibitors or the mammalian target of rapamycin (mTOR). Therefore, outside the scope of clinical trials, adjuvant therapy after the implementation of radical surgical treatment of RP is not indicated (SR A).
Surgical treatment of mRCC (palliative nephrectomy)
Surgical treatment leads to a cure only if all detectable tumor foci are removed. In most patients with RCC metastases, nephrectomy is palliative and therefore requires further systemic treatment. The analysis showed that in patients who underwent removal of the affected kidney tumor, long-term survival was better. There is currently only limited data on the value of using cytoreductive nephrectomy in combination with targeted therapies (sunitinib and sorafenib).
Conclusion
Nephrectomy in combination with the appointment of interferon-α (IFN-α) improves survival rates in patients with metastatic RCC who are in a satisfactory general condition (LE: 1a). Palliative nephrectomy may improve OS and delay systemic therapy (LE: 3).
Literature analysis showed that complete kidney removal or radiotherapy in the presence of RCC metastases (in the lungs, pancreas, liver, brain, etc.) leads to an increase in OS and RSV compared with drug therapy. Radiation therapy for metastatic RP may be used in selected patients with unresectable symptomatic lesions of the brain or bones that do not respond to systemic therapy.
Complete removal of metastases, except for the brain and bones, is the most appropriate treatment (LE: 3), increases OS, RSV, and delays systemic therapy (LE: 3). Radiation therapy for brain and bone metastases can reduce pain symptoms (LE: 3).
The decision to remove metastases must be made on a case-by-case basis (SR C). In some cases, with metastasis to the brain and bones, stereotactic radiation therapy and stereotactic radiation surgery (SR S) can be used to relieve pain symptoms.
Use of systemic therapy in mRCC
Chemotherapy
Due to the fact that RCC develops from the proximal tubules of the collecting system, the cells of this tumor have a high level of expression of glycoprotein P, which is the cause of resistance to most chemotherapy drugs. The only moderately effective therapy regimen is a combination of fluorouracil with immunodrugs. However, in a prospective randomized study of IFN-α, the combination of IFN-α, interleukin (IL) -2 and fluorouracil has been shown to be equally effective. Thus, the combination of fluorouracil with immunotherapy is equivalent in efficacy to IFN-α monotherapy (LE: 1b). In patients with clear cell mRCC, chemotherapy alone is not effective (SR B).
Immunotherapy
In the course of randomized trials in mRCC, a higher efficiency of using IFN-α than hormone therapy was noted. The response rate to IFN-α treatment was 6-15%, with a 25% reduction in the risk of progression and a slight improvement in specific survival at 3-5 months. compared with these indicators obtained using placebo. Achieving a positive effect of treatment with IFN-α is of great importance for patients with metastatic clear cell carcinoma, low risk criteria according to Motzer (Table 11) and the presence of only lung metastases. A recent study demonstrated that first-line use of IFN-α plus bevacizumab increased response rates and time to progression compared with IFN-α alone. All recent randomized trials of targeted drugs (sunitinib, IFN-α in combination with bevacizumab, temsirolimus) used as first-line therapy demonstrated their advantage over IFN-α alone.
IL-2 has been used to treat mRCC since 1985, with response rates ranging from 7% to 27%. The optimal treatment regimen for IL-2 has not yet been established, but the use of high doses of the drug in a bolus regimen contributes to the achievement of long-term (≥10 years) complete responses in some patients with metastatic RP (LE: 1b). Response to immunotherapy is observed only in patients with clear cell RCC. Research on vaccination continues. Vaccination with the 5T4 tumor antigen has not been shown to improve survival compared with standard first-line therapy (LE: 1b).
Conclusion
IFN-α monotherapy is inferior to targeted therapy for metastatic RCC (LE: 1b). IL-2 monotherapy may be used in selected cases (clear cell RCC, lung metastases) (LE: 2). Side effects with IL-2 therapy are significantly more pronounced than with IFN-α treatment (LE: 2-3). The combination of bevacizumab and IFN-α is more effective than IFN-α in the treatment of low- and intermediate-risk patients (LE: 1b). The combination of cytokines with or without additional chemotherapy does not improve OS compared with monotherapy (LE: 1b). IFN-α monotherapy or high-dose IL-2 should not be recommended as first-line therapy for metastatic RCC (SR A).
Angiogenesis inhibitors
Recent advances in molecular biology have led to several new drugs being used to treat mRCC (Table 12). During carcinogenesis in sporadic RCC, HIF accumulates due to inactivation of the VHL gene, leading to overexpression of VEGF and PDGF (platelet growth factor), each of which is involved in the stimulation of neoangiogenesis. This process plays an important role in the development and progression of RCC. To date, both in the US and in Europe, the following targeted drugs are approved for the treatment of metastatic RCC: sorafenib, sunitinib, bevacizumab in combination with IFN-α, pazopanib, temsirolimus, everolimus, axitinib. Research continues on the effectiveness of other new anti-angiogenic drugs, as well as their combinations with each other and with cytokines. Tivozanib and dovitinib are in Phase III trials and are not currently approved.
Sorafenib is an oral multikinase inhibitor that inhibits the activity of serine / threonine kinase Raf-1, B-Raf, VEGF-2 receptors (VEGFR-2) and PDGF (PDGFR), FMS-like tyrosine kinase-3 (FLT-3) and c-KIT .
Sunitinib is an oral tyrosine kinase inhibitor. This drug selectively inhibits PDGFR, VEGFR, c-KIT and FLT-3 and has antitumor and antiangiogenic activity.
Pazopanib is an oral angiogenesis inhibitor that targets VEGFR, PDGFR, and c-KIT.
Axitinib is a 2nd generation oral selective inhibitor that targets VEGFR-1, -2, and -3 with minimal effect on other targets.
Currently, other tyrosine kinase inhibitors (tivozanib and dovitinib) are not approved for the treatment of metastatic RP.
Bevacizumab is a humanized antibody that binds isoforms of VEGF-A. The use of bevacizumab in the regimen of 10 mg / kg every 2 weeks. in patients refractory to immunotherapy, contributed to an increase in the total number of responses (10%) and indicators of DFS compared with those when using placebo. The use of bevacizumab in the regimen of 10 mg / kg every 2 weeks. in patients + IFN-α in the mode of 9 million units subcutaneously 3 r./week. contributed to an increase in DFS indicators compared with IFN-α monotherapy in the regimen of 9 million units subcutaneously 3 r./week.
Temsirolimus is a specific mTOR inhibitor. In one study, patients with high-risk metastatic RCC were randomized into 3 groups depending on the drug they were taking: temsirolimus, IFN-α, or a combination of both. In the group of patients treated with temsirolimus, OS was 10.9 months. compared with 7.3 months. in the IFN-α group (p<0,0069). У пациентов, получавших темсиролимус в сочетании с ИФН-α, существенного увеличения ОВ не зарегистрировано. Темсиролимус не рекомендуется пациентам, имеющим устойчивость к рецепторам VEFG TKI.
Everolimus is an oral mTOR kinase inhibitor used for VEFG TKI receptor resistance. The median progression-free survival was 4 months. in the everolimus group and 1.9 months. in the placebo group (p<0,001).
Phase III clinical trials have demonstrated that sunitinib and bevacizumab in combination with IFN-α are indicated as first-line therapy in untreated patients with clear cell metastatic RCC and at low to intermediate risk. The COMPARZ study showed that pazopanib can also be recommended as first-line therapy. Axitinib and tivozanib are not approved for the treatment of untreated patients with metastatic RCC.
Conclusion
Tyrosine kinase inhibitors increase progression-free survival and/or OS as first- or second-line therapy in clear cell RCC (LE: 1b). Axitinib has been shown to be effective in terms of progression-free survival as second-line therapy after cytokine and VEGF-targeted therapy compared with sorafenib (LE: 1b). Sunitinib is more effective than IFN-α in untreated patients (LE: 1b). The combination of bevacizumab and IFN-α is more effective than IFN-α in untreated low-to-intermediate risk patients (LE: 1b). Pazopanib is superior to placebo in patients with metastatic RCC and after cytokine therapy (LE: 1b). Pazopanib is not inferior to sunitinib in patients with clear cell mRCC (LE: 1b). Temsirolimus monotherapy prolongs OS compared with IFN-α therapy in patients with high-risk mRCC (LE: 1b). Everolimus prolongs progression-free survival in patients after treatment failure or intolerance to VEGF inhibitors. Sorafenib is recommended in patients with clear cell RCC after cytokine or targeted therapy (LE: 4). mTOR inhibitors (everolimus and temsirolimus) and VEFG-targeted therapy (sunitinib or sorafenib) can be used for non-clear cell RCC (LE: 3). The efficacy of drug combinations compared with the efficacy of monotherapy has not been proven (LE: 1a).
Systemic therapy of patients with mRCC should be based on the use of targeted drugs (SR A). Sunitinib and pazopanib are recommended as first-line treatment for advanced clear cell/mRCC (SR A). Bevacizumab + IFN-α is recommended as first-line treatment for advanced clear cell/mRCC in patients at low or intermediate risk (SR A). Temsirolimus is recommended as first-line therapy in patients with high-risk RCC (SR A). Axitinib is recommended as second-line therapy for mRCC after prior VEGFR or cytokine therapy (SR A). Everolimus is recommended for patients with clear cell RCC after targeted therapy with VEGF inhibitors (SR A). Pazopanib and sorafenib are recommended after cytokine failure as alternatives to axitinib (SR B). Sequential use of targeted drugs is recommended (SR A).
Follow-up after nephrectomy, nephrectomy, or ablative therapy for RCC
Dynamic follow-up after surgical treatment allows assessing postoperative complications, kidney function, detecting the presence of local recurrences after kidney resection or ablative treatment, relapses in the contralateral or ipsilateral kidney, and also analyze the possibility of distant metastases, which is of great importance during cryotherapy or RFA.
Currently, there is no consensus on the need for dynamic monitoring of patients after their treatment for RCC. Evaluation of postoperative complications and renal excretory function is carried out on the basis of anamnesis, physical examination and determination of serum creatinine and GFR. Regular monitoring of EGFR levels over a long period of time allows you to see if kidney function has worsened after surgery or if it worsened even before surgery. Kidney function and cancer-free survival can be optimized by performing a CCA (LE: 3). The incidence of local relapses is low (2.9%). Recurrence in the contralateral kidney is also rare (1.2%). Although the rate of local recurrence is higher with ablative techniques than with conventional surgery, the patient can still be cured by repeat ablative therapy or nephrectomy (LE: 3). Early diagnosis of relapse can improve the effectiveness of systemic therapy, including in clinical trials.
Intensive radiological examination is not necessary for all patients. Depending on the risk of recurrence and metastasis, it is advisable to implement a differentiated monitoring regimen. The results of studies of prognostic factors with a long follow-up period of patients allow us to draw some conclusions: chest x-ray is insensitive to small metastases, and ultrasound has limitations; for low-risk tumors, CT scan intervals should be determined, taking into account the side effect of radiation (in this case, MRI may be recommended); with an average or high risk of recurrence, CT of the chest and abdominal cavity is the method of choice; follow-up should also include clinical assessment of renal function and cardiovascular risks; PET, PET-CT and bone scintigraphy are not standard methods of dynamic control, given the limited specificity and sensitivity; Depending on the availability of new effective treatments, more stringent postoperative monitoring and surveillance may be required (LE: 4).
Some authors have developed scoring systems and nomograms to quantify the likelihood of recurrence, metastases and subsequent death of the patient. These systems were compared and validated (LE: 2). More recently, a preoperative prognostic model based on age, symptoms, and TNM staging has been published and validated (LE: 3). The dynamic monitoring algorithm, which takes into account the risk of recurrence or the appearance of metastases, as well as the effectiveness of the treatment, are presented in Table 13.
Conclusion
The goal of surveillance is to detect local recurrence or metastasis at a stage where the patient can be cured by surgery. Renal function should be assessed (LE: 4). Risk stratification should be based on existing classification systems (LE: 4).
Patient monitoring should be carried out taking into account risk factors and the type of treatment performed (SR C). For low risk, CT/MRI may be used (SR C). In the intermediate risk group, follow-up includes CT/MRI at regular intervals according to risk stratification based on nomograms (SR C). In high-risk patients, follow-up should include CT/MRI (SR C). Follow-up of patients undergoing CCA for large RP (>7 cm) should be intensified (SR C).
The European Association of Urology (EAU) 2018 Pocket Guidelines app is the #1 resource for practicing urologists. Based on the most widely read clinical guidelines in urology, the app gives you access to comprehensive information on the management, investigation, diagnosis and follow-up of a wide range of urological conditions on your mobile device.The development of clinical guidelines is one of the main activities of the EAU. The 2018 recommendations cover most of the urological field. More than 350 physicians are involved in the development of the EAU Guidelines, which are updated based on the latest systematic reviews of available clinical data.
The EAU Pocket Guidelines 2018 app provides a quick and easy way to access the information provided in the 2018 Guidelines.
The EAU Pocket Guidelines 2018 app covers the following topics:
Non-muscle invasive cancer Bladder
- Urothelial cancer of the upper urinary tract
- Muscle-invasive and metastatic bladder cancer
- Prostate cancer
- Renal cell carcinoma
- testicular cancer
- Cancer of the penis
- Neurogenic male LUTS, including benign prostatic obstruction (BPO)
- Urinary incontinence
- Neurourology
- Male sexual dysfunction: erectile dysfunction and premature ejaculation
- Priapism
- Curvature of the penis
- Male infertility
- Male hypogonadism
- Urological infections
- Urolithiasis disease
- Pediatric urology
- Urological trauma
- Chronic pelvic pain
- Kidney transplant
- Thromboprophylaxis in urological surgery
In addition to providing on-the-go access to the information contained in Pocket Guidelines 2018, the app also includes 5 time-saving interactive tools to help Urolo Essence treat their patients. This:
1. EORTC risk calculator for non-muscle invasive bladder cancer;
2. Algorithm for assessing LUTS in men aged 40 years and older;
3. A tool for assessing blunt trauma to the kidney in adults;
4. G8 Geriatric Screening Tool for Prostate Cancer and Muscle-Invasive Bladder Cancer Health Status;
5. Diagnostic and therapeutic algorithm for calcium oxalate stones.
Matthias Oelke a, Alexander Bachmann b, Orëlien Descazeaud c, Mark Emberton d, Stavros Gravas e, Martin C. Michel f,
James N "Dow g, Jorgen Nordling h, Jean J. De la Rosette"
a Department of Urology, Hannover Medical School, Hannover, Germany; b Department of Urology, University Hospital Basel, Basel, Switzerland: c Department of Urology, Dupuytren Hospital, University of Limoges, Limoges, France; d Division of Surgical and Interventional Science, University College London, London, UK; e Department of Urology, University of Thessaly, Larissa, Greece; f Department of Pharmacology, Johannes-Gutenberg-University, Mainz, Germany; g Academic Urology Unit, University of Aberdeen, Aberdeen, UK; h Department of Urology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; i Department of Urology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
TREATMENT AND FOLLOW-UP FOR MEN
WITH SYMPTOMS OF THE LOWER URINARY TRACT WITH BENIGN PROSTATE HYPERPLASIA
MANAGEMENT
Keywords: 5α-reductase inhibitors, α-adrenergic receptor antagonists, benign prostatic hyperplasia, bipolar transurethral resection of the prostate, botulinum toxin injections, Desmopressin, ethanol injections, laser prostatectomy, lower urinary tract symptoms, muscarinic receptor antagonists, open prostatectomy , phosphodiesterase inhibitors, prostatic stent, transurethral incision of the prostate, transurethral resection of the prostate, transurethral microwave therapy, transurethral needle ablation
Data collection: We searched the literature in computer databases to find relevant articles published between 1966 and 10/31/2012. The Oxford classification system (2001) was used to determine the level of evidence for each article and to assign a grade of recommendation for each treatment regimen.
Generalization: For men with mild symptoms, expectant management is appropriate. All men with troubling LUTS should be offered advice on lifestyle changes prior to or concomitantly with therapy. Men with bothersome moderate to severe LUTS quickly respond to agblockers. For men with an enlarged prostate, especially those >40 ml, 5a-reductase inhibitors (5-ARIs) are effective and gradually reduce
Notes: 1. Adapted by the staff of the Department of Urology, Moscow State Medical University. A.I. Evdokimov. 2. The article is available on the website www.sciencedirect.com. Journal homepage: www.europeanuroLogy.com.
LUTS and the possibility of urinary retention or the need for surgery. For patients in whom bladder symptoms predominate, antimuscarinic therapy should be considered. The phosphodiesterase type 5 inhibitor tadalafil can quickly reduce LUTS, and its effectiveness is comparable to α1-blockers; in addition, tadalafil improves erectile function. In men with nocturia due to nocturnal polyuria, Desmopressin can be used. Therapy with a1-blockers and 5-AI (in men with an enlarged prostate) or antimuscarinics (with persistent accumulation symptoms) combines the positive effects of both classes of drugs and provides greater efficacy. Surgical treatment is prescribed for men with absolute indications or treatment-resistant LUTS due to benign prostatic obstruction. Currently, the standard of care for men with a prostate volume of 30-80 ml is transurethral resection of the prostate (TURP), while open surgery or transurethral enucleation with a holmium laser is suitable for men with a prostate > 80 ml. Alternatives to monopolar TURP include bipolar TURP and transurethral incision of the prostate (for< 30 мл), а также лазерную терапию. Трансуретральная микроволновая терапия и трансуретральная игольчатая абляция представляют собой эффективные виды терапии с минимальной инвазивностью, для которых частота проведения повторных процедур выше, чем для ТУРП. Простатические стенты являются альтернативой катетеризации для мужчин, которым противопоказано оперативное лечение. Инъекции этанола или ботулинового токсина в предстательную железу пока являются экспериментальными видами терапии.
Conclusions: This symptom-oriented guideline provides practical guidance for the treatment of men with LUTS. The full version is available online (www.uroweb.org/^/rbg/12_Ma!e_LUTS_KSh).
1. Introduction
The onset of lower urinary tract symptoms (LUTS) in men is traditionally thought to be associated with prostate enlargement. The process involves one or all of the following mechanisms: histologically detectable benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), or benign prostatic obstruction (BPO). However, during the last decade, the causal relationship between the prostate and the pathogenesis of LUTS has been questioned. Despite the fact that the increased prostate may affect the occurrence of LUTS in some men over 40, other factors are equally important. Figure 1 lists the many causes of LUTS. Any person who complains of LUTS often has several of these factors. The multifactorial approach to the etiology of LUTS has led many experts to consider the entire urinary tract as a single functional department. This broader comprehensive approach to the pathogenesis of LUTS has led to a change in the title of the guideline (to reflect a change in attitude) from "EAU (European Association of Urology) Guidelines for the Treatment of LUTS Indicative of BPO (BPH)" to the more modern and accurate title "European Association of Urology Guidelines urologists (EAU) for the treatment and follow-up of men with lower urinary tract symptoms for benign prostatic hyperplasia.
Since patients present to their doctor with complaints of LUTS rather than underlying prostate-related causes such as BPH, this updated guideline has been written with a focus on men who complain of a variety of symptoms related to bladder filling, emptying, and/or symptoms after a bowel movement. The recommendations in the guide are based on the best available evidence. Such recommendations apply to men > 40 years of age who seek professional care for various forms of non-neurogenic benign LUTS, such as LUTS/BPO, detrusor overactivity/overactive bladder (OAB) or nocturnal polyuria. EAU guidelines for the treatment of LUTS due to neurological disease, urinary incontinence, urogenital infections, ureteral stones, or lower urinary tract malignancies have been published elsewhere.
2. Data collection
Recommendations in this guideline are based on literature searches using English-language articles published in PubMed/Medline, Web of Science, and Cochrane from 1966 to 10/31/2012, including the following search terms: symptoms from the lower urinary tract, benign prostatic hyperplasia, detrusor overactivity, overactive bladder, nocturia and nocturnal polyuria in combination with various regimens - and the following search restrictions: human, adult male, review, randomized clinical trials, clinical trials and meta-analysis (Table 1). Each selected article was analyzed separately, classified and assigned a Level of Evidence (LE) according to a classification system modified based on the Oxford Center for Evidence-Based Medicine classification in 2001 (Table 2a). Subsections for various types conservative therapy, drug and surgical therapy are presented in the form of a homogeneous list: 1) mechanism of action, 2) available drugs with a table of the main pharmacokinetic characteristics (for this article they are presented in table 3), 3) efficacy with a table of studies with the largest LE, 4 ) transfer-
Detrusor underactivity
Bladder tumor
neurogenic bladder
urinary tract infection
Narrowing of the urethra
Prostatitis
foreign body
The European Association of Urology (EAU) guidelines on non-neurogenic LUTS in men are mainly concerned with LUTS due to benign prostatic enlargement (BPE) or benign prostatic obstruction (BPO), detrusor overactivity or overactive bladder (OAB), and nocturia due to nocturnal polyuria. Other causes of LUTS in men are described in a separate EAU guideline.
Table 1. Literature search methodology
Databases: PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) Web of Science (http://apps.webofknowledge.com) Cochrane (http://www.cochrane.org/ )
English language
and safety, 5) practical aspects, and 6) recommendations derived from relevant articles using recommendations (GR) according to a classification system modified from the Oxford Center for Evidence-Based Medicine classification (Table 2b). A complete literature review with all tables, recommendations and findings is available online at the EAU homepage (www.uroweb.org/gls/pdf/12_Male_LUTS-pdf); this article presents short review such analyzes and a list of all LE and GR for the analyzed therapies in one table (Table 4).
The team behind the guidelines included urologists, a pharmacologist, and an epidemiologist and statistician who have been working on the guidelines for the past 6 years. The guide is written primarily for urologists, but it can also be used by therapists, patients, or other interested parties. The working group intends to update the content and recommendations in accordance with the given structure and classification system every 2 years.
3. Generalization of data
3.1. Conservative tactics
Many men with LUTS are not bothered enough by symptoms to start drug therapy or
surgical operation. For most of these men, a conservative approach known as watchful waiting is appropriate. All men with LUTS should be evaluated before starting any therapy. The purpose of such an examination is to determine the severity of LUTS and to identify men with the so-called. uncomplicated LUTS that do not pose a threat to life expectancy from men with less frequent presentation of complicated LUTS that can affect life expectancy. For men with mild to moderate uncomplicated LUTS who are not bothered by symptoms, follow-up is appropriate. Such a method usually includes the following components: education, persuasion, lifestyle recommendations and periodic monitoring, which in turn include:
■ reducing fluid intake at certain times to reduce the frequency of urination in inappropriate situations (for example, at night or at in public places);
■ avoiding or reducing consumption of caffeine or alcohol, which can be diuretic and irritant, thus increasing fluid excretion and urinary frequency and urgency, as well as nocturia;
■ application of relaxation techniques and double urination;
■ massaging the urethra to prevent leakage after urination;
■ distraction techniques such as penile pressure, breathing exercises, perineal pressure, and psychological techniques to distract thoughts from the bladder and toilet can help control filling symptoms;
Table 2(a). Evidence level and (b) grade of recommendation, modified based on the Oxford Center for Evidence-Based Medicine classification
Level of justification Type of justification
1a Evidence from meta-analysis of randomized trials
1b Evidence from at least 1 randomized trial
2a Evidence from 1 well-designed controlled trial without randomization
2b Evidence obtained from at least 1 appropriately designed other type of “quasi-experimental” study
3 Evidence from well-designed non-experimental studies, such as comparative or correlation studies and descriptions of clinical series
4 Evidence obtained from reports or decisions of expert commissions or from the experience of relevant recognized experts
A Based on clinical trials of good quality and stability that examined specific recommendations, including at least 1 randomized trial
B Based on well-conducted clinical trials, but not including randomized clinical trials
■ bladder training, which encourages men to hold back on sensory urges to increase bladder capacity and time between urination;
■ revision of accepted medicines and optimizing the time of administration or replacing some drugs with others that have less impact on the urinary system. In particular, these recommendations apply to diuretics;
■ provision necessary assistance with a decrease in mobility or a violation of mental status;
■ constipation therapy.
3.2. Drug therapy
3.2.1. Antagonists of a-adrenergic receptors (a1-blockers)
3.2.1.1. Mechanism of action. Contraction of the human prostate is mediated primarily, if not exclusively, by α1A-adrenergic receptors. a1-adrenergic receptors in blood vessels, other non-prostatic smooth muscle cells and the central nervous system are considered mediators of adverse events during therapy with a1-blockers, and, apparently, all 3 subtypes of receptors (a1A, a1B and ash) are involved in their development. In this concept, preference is given to a1A-selective blockers.
3.2.1.2. Available drugs. Five types of a1-blockers are currently widely used: alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin (Table 3). Indoramin and naftopidil are also available in some countries but are not covered in this guideline.
3.2.1.3. Efficiency. Indirect comparisons between α1-blockers and limited direct comparisons indicate that all α1-blockers have similar efficacy at appropriate doses. Although such improvements take several weeks to fully manifest, the drugs showed significantly greater efficacy compared to placebo already within hours or several days after the start of therapy. α1-blockers have similar efficacy as a percentage improvement in International Prostate Symptom Score (IPSS) scores in patients with mild, moderate, or severe LUTS. In controlled trials, α1-blockers have generally been shown to reduce IPSS score after placebo induction regimen by approximately 30-40% and increase maximum urinary flow rate (max) by approximately 20-25%. In open studies (no run-in period), an improvement in IPSS score of up to 50% and an increase in Qmax of up to 40% were reported. α1-blockers are able to reduce both storage symptoms and emptying symptoms. Prostate size did not affect the efficacy of α1-blockers in follow-up studies< 1 года, однако в долгосрочных исследованиях эффективность была выше у пациентов с небольшой предстательной железой (<40 мл) по сравнению с пациентами с большим размером железы . Эффективность а1-блокаторов
similar in all age groups. α1-blockers do not reduce the size of the prostate gland and do not prevent acute urinary retention in long-term studies, so some patients require surgical treatment. However, the decrease in the IPSS score and the improvement
Table 3. Main pharmacokinetic characteristics
ristics and standard doses of medicinal preparations
rats registered in Europe for therapy
lower urinary tract symptoms
Agonists
signs or symptoms of BPH
Alfuzosin HB 1.5 4-6 3 x 2.5 mg
Alfuzosin 3V 3 8 2 x 5 mg
Alfuzosin XL 9 11 1 x 10 mg
Doxazosin HB 2-3 20 1 x 2-8 mg
Doxazosin GITS 8-12 20 1 x 4-8 mg
Silodosin 2.5 11-18 1 x 4-8 mg
Tamsulosin MB 6 10-13 1 x 0.4 mg
Tamsulosin OCAS 4-6 14-15 1 x 0.4 mg
Terazosin 1-2 8-14 1 x 5-10 mg
5a-reductase inhibitors (for the treatment of benign
prostatic enlargement against the background of BPH)
Dutasteride 1-3 3-5 weeks 1 x 0.5 mg
Finasteride 2 6-8 1 x 5 mg
Antimuscarinics (for the treatment of OAB/filling symptoms)
Darifenacin 7 12 1 x 7.5-15 mg
Fesoterodine 5 7 1 x 4-8 mg
Oxybutynin HB 0.5-1 2-4 3-4 x 2.5-5 mg
Oxybutynin PV 5 16 2-3x5 mg
Propiverine 2.5 13 2-3 x 15 mg
Propiverine PV 10 20 1 x 30 mg
Solifenacin 3-8 45-68 1 x 5-10 mg
Tolterodine HB 1-3 2-10 2 x 1-2 mg
Tolterodine PV 4 6-10 1 x 4 mg
Trospium HB 5 18 2 x 20 mg
Trospium PV 5 36 1 x 60 mg
Vasopressin analogues (for the treatment of nocturnal polyuria)
Desmopressin tablets 1-2 3 1 x 0.1-0.4 mg orally at bedtime
Desmopressin, lyo- 0.5-2 2.8 1 x 60-240 mcg*
filizat for pen-under the tongue before
oral intake (resorption) at bedtime
Type 5 phosphodiesterase inhibitors (for the treatment of
signs or symptoms of BPH with erectile dysfunction
or without erectile dysfunction)
Tadalafil 2 (0.5-12) 17.5 1 x 5 mg
Note. BPH - benign prostatic hyperplasia; PV - extended release; GITS - gastrointestinal therapeutic system; HB - immediate release; LUTS - symptoms from the lower urinary tract; MW = modified release; OAB - overactive bladder; OCAS, Oral Absorption Controlled System; SR - sustained release; tmax - time to reach maximum plasma concentration;
t^2 - half-life. * Equivalent to 0.1-0.4 mg when dosed in tablets.
Table 4 Level of evidence and grade of recommendation for different treatments for lower urinary tract symptoms in men and follow-up
Conservative therapy: waiting tactics
For men with mild symptoms, watchful waiting is appropriate.
Drug therapy
1. Men with moderate or severe LUTS can be offered α-blocker therapy
2. Men with moderate to severe LUTS and an enlarged prostate (>40 mL) may be offered 5α-reductase inhibitor therapy. 5α-reductase inhibitors may prevent disease progression to acute urinary retention and the need for surgery
3. Muscarinic receptor antagonists may be used in men with moderate to severe LUTS and predominant storage symptoms.
In men with IVO - with caution
4. Phosphodiesterase type 5 inhibitors reduce moderate to severe LUTS (storage and voiding) in men with or without erectile dysfunction. In Europe, only tadalafil (5 mg once daily) is registered for the treatment of men with LUTS.
5. Vasopressin analogs can be used to treat nocturia against the background of nocturnal polyuria.
6. For men with bothersome moderate or severe LUTS, an enlarged prostate, and a decreased Qmax (men who are likely to have disease progression), combination therapy with an α-blocker and a 5α-reductase inhibitor may be offered.
7. In patients with troublesome moderate or severe LUTS, combination therapy with an α-blocker and a muscarinic antagonist can be used if relief of filling symptoms is insufficient with either drug alone
Caution should be exercised when prescribing combination therapy to men with OI
Surgery
1. M-TURP is currently the standard surgical procedure for men with a prostate size of 30-80 ml and bothersome moderate to severe LUTS due to BPH. M-TURP provides subjective and objective improvement that is superior to that of drug or minimally invasive therapies Complication rates are higher with M-TURP than with drugs or other minimally invasive procedures
B-TURP results are comparable in the short to medium term to M-TURP B-TURP has a more favorable perioperative safety profile compared to M-TURP Preferred therapy for men with prostate size<30 мл без средней доли и с беспокоящими умеренными или тяжелыми СНМП на фоне ДГПЖ является ТУИП
2. The preferred therapy for men with a prostate size >80 ml and bothersome moderate to severe LUTS due to BPH who require surgical treatment is open prostatectomy or holmium laser enucleation
Open prostatectomy is the most invasive surgical technique with a significant complication rate.
3. With TUMT and TUIA, symptom improvement is comparable to that with TURP, but these methods are associated with lower morbidity and less improvement in urinary flow characteristics Duration of effect is longer with TURP, which has a lower retreatment rate than TUMT or TUIA
4. HoLEP and 532nm laser vaporization of the prostate are alternatives to TURP for men with moderate to severe LUTS associated with BPH, leading to immediate objective and subjective improvement compared to TURP
Mid-term functional outcomes with 532nm laser vaporization of the prostate are comparable to TURP
Long-term functional results in HoLEP comparable to TURP/open prostatectomy Diode laser surgery results in short-term objective and subjective improvement
Diode and thulium lasers are considered safe in terms of intraoperative safety and hemostatic properties.
In terms of intraoperative safety, 532 nm laser vaporization is superior to TURP For patients receiving anticoagulants or those at high risk of cardiovascular complications, 532 nm laser vaporization should be considered
5. Prostatic stents are an alternative to catheterization in men who are contraindicated in surgery
6. Ethanol injections into the prostate for men with moderate to severe LUTS due to BPH are currently an experimental therapy and should only be used in clinical trials
7. BTX injections into the prostate for men with bothersome moderate to severe LUTS due to BPH or men with urinary retention are currently an experimental therapy and should only be used in clinical trials
Follow-up
Follow-up for all conservative, medical or operative therapies is based on empirical data or theoretical considerations and not evidence-based studies
Note. IVO - infravesical obstruction; BPO - benign prostatic obstruction; B-TURP - bipolar transurethral resection of the prostate; BTX - botulinum toxin; GR - class of recommendations; HoLEP - holmium laser enucleation; LE - level of justification; LUTS - symptoms from the lower urinary tract; M-TURP - monopolar transurethral resection of the prostate; Qmzx - maximum flow rate; TYUER - laser vapoenucleation based on thulium-yttrium-aluminum-garnet; TUIP - transurethral dissection of the prostate; TUMT - transurethral microwave therapy; TUIA - transurethral needle ablation; TURP - transurethral resection of the prostate.
The decrease in Qmax during therapy with agblockers is maintained for at least 4 years.
3.2.1.4. portability and safety. The tolerability profile of certain drugs can be influenced by distribution in the tissues of the lower urinary tract, subtype selectivity and pharmacokinetic profile of certain substances. The most common adverse events with agblocker therapy are asthenia, dizziness, and (orthostatic) hypotension. In particular, patients with comorbid cardiovascular disease and/or receiving drugs that affect the vessels may be prone to agblocker-mediated vasodilation. In contrast, the incidence of hypotension with the α1A-selective blocker silodosin is comparable to that with placebo. The intraoperative "flabby iris syndrome" was only discovered in 2005 in the context of cataract surgery; when using tamsulosin, its risk is highest. According to the results of a systematic review, a1-blockers do not have an undesirable effect on libido. They have a small positive effect on erectile function, but sometimes cause changes in ejaculation (i.e., reduced volume or absence of seminal fluid at orgasm). When using silodosin, the frequency of ejaculation disorders is highest; however, the efficacy of LUTS therapy is thought to be increased in patients with impaired ejaculation.
3.2.1.5. Practical recommendations. α1-blockers are often considered first-line therapy for men with LUTS because of their rapid onset of effect, high efficacy, and low incidence and severity of adverse events. Before cataract surgery, the ophthalmologist should be informed about previous therapy with a1-blockers.
3.2.2. 5a-reductase inhibitors
3.2.2.1. Mechanism of action. 5a-reductase inhibitors (5-ARI) block the conversion of testosterone to dihydrotestosterone in the cells of the prostate stroma by inhibiting the enzyme 5a-reductase and initiating apoptosis in prostate epithelial cells, which leads to a decrease in prostate size by about 18 28% and a decrease in the concentration of circulating prostate-specific antigen (PSA) by 50% after 6-12 months. therapy.
3.2.2.2. Available drugs. Dutasteride and finasteride are available for clinical use (Table 3). Finasteride only inhibits type 2 5a-reductase, while dutasteride inhibits both type 1 and 5a-reductase with similar efficacy (dual 5-ARI). However, the clinical benefit of dual inhibition is not yet clear.
3.2.2.3. Efficiency. Clinical efficacy compared with placebo is observed with a minimum duration of therapy> 6-12 months. After 2-4 years of therapy, 5-ARI reduces LUTS (IPSS) by 15-30%, reduces prostate volume by 18-28% and increases Qmax by 1.5-2.0 ml/s in patients with LUTS due to BPH . In an indirect comparison of individual studies and one direct comparison
In a comprehensive study, dutasteride and finasteride have been shown to have similar efficacy in the treatment of LUTS. Symptom reduction depends on baseline prostate size and may not differ in efficacy from placebo in patients with prostate<40 мл . В сравнительных исследованиях с применением а1-блокаторов и в ходе проведенного недавно метаанализа было показано, что 5-АМ снижают СНМП медленнее и что финастерид менее эффективен, чем доксазозин или теразозин, но обладает одинаковой эффективностью с тамсулозином . Долгосрочное исследование с применением дутастерида у мужчин с проявлением симптомов, объемом предстательной железы >30 ml and an increased risk of disease progression showed that dutasteride reduced LUTS in these patients no less effectively than the a1-blocker tamsulosin. The larger the initial prostate volume (or serum PSA concentration), the faster and more pronounced the benefit of dutasteride in reducing symptoms. 5-AM, but not a1-blockers, reduce the long-term risk (>1 year) of acute urinary retention or the need for surgery. In a study of the long-term efficacy and safety of Proscar, after 4 years of finasteride therapy, the relative risk of acute urinary retention (AUR) was reduced by 57%, and the risk of surgery by 55% compared with placebo. In the Prostate Symptom Drug Therapy Study (MTOPS), the finasteride group showed a significant reduction in the risk of AUR and surgery compared with placebo (68% vs. 64%, respectively). Data from a pooled analysis of randomized trials and 2-year follow-up showed that finasteride therapy significantly reduced the incidence of AUR by 57% and surgery by 34% compared with placebo in patients with moderate symptomatic BPH.
In addition, dutasteride has been shown to be effective in reducing the risk of AUR and surgery for BPH. Pooled data from phase 3 trials showed a reduction in the relative risk of AUR (57%) and surgery (48%) compared with placebo at 2 years. In addition, this decline was maintained up to 4 years during the open-label phase of the study.
3.2.2.4. portability and safety. The most significant adverse effects are associated with sexual function and include decreased libido, erectile dysfunction and, less commonly, ejaculatory disorders. The frequency of sexual dysfunction and other adverse events is low and decreases with increasing study duration. Gynecomastia (breast enlargement accompanied by sore breasts or nipples) develops in approximately 1-2% of patients.
Based on data from 2 important trials of prostate cancer chemoprevention (the PCRT Prostate Cancer Prevention Trial and the
decrease in prostate cancer detection with REDUCE dutasteride), 5-ARI groups have a higher incidence of poorly differentiated cancer compared to placebo groups. Although there is no evidence of a causal relationship between 5-ARI use and low-grade prostate cancer, PSA should be regularly monitored in men receiving 5-ARI. Any confirmed increase in PSA during 5-ARI therapy should be evaluated.
3.2.2.5. Practical recommendations. 5-ARI therapy should only be recommended for men with bothersome moderate to severe LUTS and an enlarged prostate (prostate volume > 40 mL) or elevated PSA (> 1.4 ng/mL). Due to the slow onset of effect, 5-ARIs are only suitable for long-term therapy.
3.2.3. Muscarinic receptor antagonists
3.2.3.1. Mechanism of action. Muscarinic receptors are highly expressed on detrusor smooth muscle cells and other cell types such as salivary and prostate epithelial cells, bladder urothelial cells, or nerve cells of the peripheral or central nervous system. Inhibition of muscarinic receptors reduces smooth muscle contractions and bladder threshold. Antimuscarinic effects may also be induced or modulated by the urothelium and/or the central nervous system.
3.2.3.2. Available drugs. The following muscarinic receptor antagonists have been registered for the treatment of OAB/filling symptoms in men and women: darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride (Table 3).
3.2.3.3. Efficiency. Muscarinic receptor antagonists have previously been tested mainly in women because it was believed that LUTS in women is caused by bladder disorders and therefore should be treated with bladder-specific drugs. There were 4 retrospective analyzes (2 analyzes with tolterodine extended release, 1 analysis with solifenacin 5 mg, and 1 analysis with fesoterodine 4 and 8 mg) of data from large randomized controlled trials (RCTs) of OAB therapy in women and men without suspected infravesical obstruction (IVO); the analysis concerned only the group of men. It has been shown that tolterodine can significantly reduce urge incontinence, daytime or 24-hour urinary frequency, and urgency-related urination, and improve patient satisfaction with therapy compared with placebo. Solifenacin significantly improved GPA Questionnaire for patient perceptions of bladder function, mean OAB-q score, and overall perception of bladder problems, and fesoterodine significantly increased the median percentage improvement in urinary frequency, episodes
urgency and urgency incontinence (UUI), while a significantly higher percentage of cases showed a response to therapy, in contrast to placebo. In open studies with tolterodine, daytime urinary frequency, nocturia, urge incontinence, and IPSS scores were significantly reduced after 12–25 weeks, compared with baseline.
Several studies have examined the efficacy of antimuscarinic monotherapy in men with symptoms of OI and OAB, with poor results. In the study "Use of tolterodine and tamsulosin in men with LUTS including OAB: Efficacy and Safety Evaluation" in patients who received tolterodine as monotherapy, there was a significant improvement only in relation to urge incontinence, but no significant improvement was shown in terms of urgency, IPSS score (total vs. filling subscale), and the overall percentage of patients who reported a benefit to therapy compared to placebo. Further analysis showed that men with PSA concentrations< 1,3 нг/мл (меньший размер предстательной железы) могут получить пользу при применении антимускариновых препаратов . В 2 других исследованиях был зарегистрирован положительный эффект антимускариновых препаратов у пациентов с ГАМП и сопутствующей ИВО. В небольшом рандомизированном исследовании без плацебо у пациентов в группе пропиверина гидрохлорида наблюдалось улучшение частоты мочеиспускания и эпизодов неотложных позывов по сравнению с исходным уровнем . В открытом исследовании толтеродин снижал среднюю частоту мочеиспусканий за 24 ч и ноктурии, а балл Индекса симптомов Американской ассоциации урологов значимо улучшался .
3.2.3.4. portability and safety. Muscarinic receptor antagonists are generally well tolerated. Compared with placebo, the following drug-related adverse events are more common: dry mouth (<16%), запор (<4%), затруднения при мочеиспускании (<2%), назофарингит (<3%) и головокружение (<5%). Увеличение объема остаточной мочи (PVR) у мужчин без ИВО является минимальным и не отличается значимо от плацебо (0-5 мл по сравнению с изменением от -3,6 до 0 мл). Частота задержки мочи у мужчин без ВРО была сравнима с частотой при приеме плацебо в исследованиях толтеродина (0-1,3% по сравнению с 0-1,4%). Краткосрочная терапия антимускари-новыми препаратами (толтеродин) у мужчин с ИВО считается безопасной .
3.2.3.5. Practical recommendations. Although not all antimuscarinic drugs have been tested in older men with LUTS and symptoms of OAB, it is likely that all of them will have similar efficacy and cause similar adverse events. Data on long-term studies of the effectiveness of muscarinic receptor antagonists in men with LUTS are not yet available; therefore, these drugs should be used with caution, and regular evaluation of IPSS and residual urine volume (PVR) is recommended.
3.2.4. Phosphodiesterase type 5 inhibitors
3.2.4.1. Mechanism of action. Phosphodiesterase type 5 inhibitors (PDE5) increase the concentration and prolong the period of activity of intracellular cyclic guanosine monophosphate, thus reducing the tone of the smooth muscles of the detrusor, prostate and urethra. The dominant enzymes in the lower urinary tract are PDE4 and PDE5. In addition, nitric oxide and PDE5 may also be involved in the urination cycle by inhibiting reflex pathways in the spinal cord and nerve impulse transmission in the urethra, prostate, or bladder. In addition, a hypothesis has been proposed that PDE5 inhibitors increase blood supply and oxygen saturation in the lower urinary tract, but the exact mechanism of action of PDE5 inhibitors has not yet been elucidated.
3.2.4.2. Available drugs. Although 3 selective oral PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) have been registered in Europe for the treatment of erectile dysfunction and have undergone clinical trials in men with LUTS, only tadalafil (5 mg once daily) is registered for use in men with LUTS in Europe (Table 3).
3.2.4.3. Efficiency. Over the past few years, the results of randomized clinical trials of the efficacy of all 3 available oral PDE5 inhibitors have been published. A recent meta-analysis (3,214 men with a median follow-up of 12 weeks) showed that monotherapy with a PDE5 inhibitor resulted in a significant improvement in the International Index of Erectile Function (IIEF) score (+5.5) and IPSS (-2.8), but did not significantly improve Qmax (0.00) compared to placebo.
Tadalafil 5 mg was shown to significantly reduce IPSS after a run-in period of 22-37% (4.7-6.6 IPSS scores; IPSS scores versus placebo: 2.14.4). A significant reduction in LUTS (IPSS) when taking tadalafil was noted after 1 week. therapy. In recent randomized trials, which are not included in the meta-analysis mentioned above, for the first time a statistically significant increase in Qmax was observed when taking tadalafil compared with placebo (+2.4 ml / s) . Tadalafil had no significant effect on PVR.
In addition, a combination of α-blockers and PDE5 inhibitors was investigated. Meta-analysis of 5 randomized trials with a limited number of patients and a short follow-up period, which studied the combination of α-blockers and PDE5 inhibitors (2 studies with tadalafil 20 mg, 2 studies with sildenafil 25 mg and 1 study with vardenafil 20 mg), compared with monotherapy with a1-adrenergic receptor blockers showed that this combination significantly improved Qmax (+1.5 ml/s), IPSS (-1.8) and IIEF (+3.6) compared with monotherapy with a-blockers. However, since only tadalafil 5 mg is registered, data on the combination of PDE5 inhibitors and other drugs for the treatment of LUTS are considered insufficient.
3.2.4.4. portability and safety. PDE5 inhibitors most commonly cause headache, back pain,
dizziness and dyspepsia. PDE5 inhibitors are contraindicated in patients receiving nitrates, potassium channel activators, nicorandil or agblockers, doxazosin or terazosin. In addition, they are contraindicated in patients with unstable angina, patients who have recently had a myocardial infarction (<3 мес. назад) или инсульт (<6 мес. назад), пациентам с миокардиальной недостаточностью (стадия >2 by the New York Heart Association), hypotension, poor blood pressure control, significant hepatic or renal insufficiency, or if anterior ischemic optic neuropathy with sudden loss of vision has been observed with previous use of PDE5 inhibitors.
H.2.4.5. practical considerations. To date, only tadalafil 5 mg once daily has been approved for the treatment of LUTS in men with or without erectile dysfunction. Thus, in clinical practice, only tadalafil should be used for the treatment of men with LUTS. A meta-analysis of the effectiveness of PDE5 inhibitors showed that younger men with a low body mass index and more severe LUTS experience the greatest benefit with the use of PDE5 inhibitors. The experience of long-term use of tadalafil in patients with LUTS is limited to one study, therefore, it is not possible to evaluate the effectiveness or tolerability of the drug over a period of more than 1 year. Currently, there is limited information on prostate reduction and no evidence to slow the progression of the disease.
H.2.5. Herbal preparations: herbal medicine
Herbal preparations are obtained from the roots, seeds, pollen, bark or fruits of one plant (single preparations); other preparations combine extracts of 2 or more plants in one tablet (combination preparations). The most widely used plants are: Cucurbita pepo (pumpkin seeds), Hypoxis rooperi (African potato greens), Pygeum africanum (African plum bark), Secale cereale (rye pollen), Serenoa repens (synonyms: Sabal serrulata; dwarf palm berries, gray palm). -noa) and Urtica dioica (nettle roots).
Different manufacturers use different extraction methods, give the active ingredients different qualitative and quantitative characteristics, or combine 2 or more herbal ingredients in one tablet. Extracts of the same plant produced by different companies do not necessarily have identical biological or clinical effects; therefore, the effects of one brand cannot be extended to other products. In addition, even 2 different series of the same manufacturer may contain different concentrations of active ingredients and have different biological effects. Thus, the pharmacokinetic properties of various herbal extracts can vary significantly.
The available results from a Cochrane meta-analysis show that (1) men who take Pygeum africanum are more likely to
symptoms were twice as likely to improve (however, validated questionnaires such as IPSS were not used in the studies analyzed), (2) men who took Secale cereale were twice as likely to improve with the drug compared with placebo, (3) Serenoa repens did not outperform placebo, finasteride, or tamsulosin as measured by improvement in IPSS score (similar improvement in IPSS score in studies with finasteride or tamsulosin could be interpreted as treatment equivalence).
The guideline panel is unable to make definitive recommendations on herbal medicine for the treatment of LUTS in men due to the heterogeneity of these drugs, insufficient regulatory frameworks, and significant methodological issues associated with published studies and meta-analyses.
3.2.6. Vasopressin analogue: Desmopressin
3.2.6.1. Mechanism of action. The antidiuretic hormone arginine vasopressin (AVP) plays a key role in maintaining body water homeostasis and controlling urine production by binding to the V2 receptor in the renal collecting ducts. AVP increases water reabsorption as well as urinary osmolality and decreases water excretion as well as total urine volume. AVP can be used to measure the volume of urine excreted; however, AVP also exhibits V1 receptor-mediated vasoconstrictive/hypertensive effects and has a very short serum half-life, making it unsuitable for the treatment of nocturia/polyuria nocturnus.
3.2.6.2. Available drugs. Desmopressin is a synthetic AVP analog with high affinity for the V2 receptor and antidiuretic properties, but no significant affinity for the V1 receptor and no hypertensive effects. Desmopressin has been approved in most European countries for the treatment of nocturia associated with nocturnal polyuria in adult patients (Table 3). Clinical effects, namely a decrease in urine volume and an increase in urine osmolality, last approximately 8-12 hours.
3.2.6.3. Efficiency. In pivotal clinical studies, Desmopressin significantly reduced nighttime urine output by approximately 0.6-0.8 ml/min (-40%), reduced the number of urination per night by approximately 0.8-1.3 (-40%) and increased the time to first urination at night by about 1.6-2.1 hours. Desmopressin significantly reduced the volume of urine excreted at night and the percentage of urine excreted at night.
A meta-analysis of available RCTs showed that desmopressin significantly reduced total nighttime urination and increased restful sleep compared with placebo. However, these RCTs were conducted in a heterogeneous population at different dosages.
3.2.6.4. portability and safety. The most common adverse events in the short term (< 3 нед.) и долгосрочных (12 мес.) исследованиях были: головная боль, тошнота, диарея, боль в животе, головокружение, сухость во рту и гипонатриемия (концентрация натрия в сыворотке
< 130 ммоль/л). В долгосрочном исследовании наблюдались периферические отеки (2%) и гипертензия (5%) .
Hyponatremia of any severity, not necessarily associated with symptoms, is observed in 5-7.6% of patients shortly after the start of therapy. The risk of developing hyponatremia is significantly lower in males and increases significantly with age, with low serum sodium at baseline and with higher 24-hour urine volume at baseline, adjusted for body weight. Risk of hyponatremia in patients< 65 лет составляет < 1%, тогда как риск у пациентов старшего возраста увеличивается до 8% при нормальной концентрации натрия и до 75% у пациентов с низкой концентрацией натрия на исходном уровне . Опубликованный недавно дополнительный анализ показывает, что прием Десмопрессина перорально в дозе 50-100 мкг (рассасывание) у мужчин является безопасным .
3.2.6.5. practical considerations. Desmopressin is prescribed for patients with nocturia due to nocturnal polyuria, the drug should be taken once a day at bedtime. Since the optimal dose varies from patient to patient, Desmopressin therapy should be started at a low dose (0.1 mg/day) and gradually increased weekly until maximum benefit is achieved. The maximum recommended oral daily dose is 0.4 mg/day. Patients should avoid fluid intake for at least 1 hour before taking Desmopressin and for 8 hours after dosing. Serum sodium concentration should be monitored on days 3 and 7 after initiation of therapy and at regular intervals thereafter.
3.2.7. Combination therapy
3.2.7.1. agblockers in combination with 5a-reductase inhibitors. The use of an α1-blocker in combination with 5-ARI aims to combine the differing effects of both drug classes in improving symptoms and preventing disease progression. Analyzes of 4-year data from the MTOPS study were obtained, as well as 2- and 4-year results from the Avodart and Tamsulosin Combination Therapy (CombAT) studies. The latter study only included older men with enlarged prostates and higher serum PSA concentrations and therefore represents men at higher risk of disease progression. In contrast to earlier studies with only 6-12 months of follow-up, long-term data have shown that combination therapy is superior to monotherapy in terms of symptom reduction and Qmax improvement. The MTOPS study found that the risk of long-term clinical progression (mostly as measured by IPSS increase) was reduced by 66% with combination therapy (compared to placebo) and even more with finasteride or doxazosin monotherapy (34 and 39%, respectively). In addition, finasteride alone or in combination with other drugs, but not doxazosin, significantly reduced the risk of AUR and the need for surgery for BPH in a 4-year study. In the CombAT study, combination therapy reduced the risk of AUR by 67.8%,
a 70.6% risk of BPH-related surgery and a 41.3% risk of worsening symptoms compared with tamsulosin at 4 years.
Cancellation of a1-blocker after 6-9 months. combination therapy was investigated in an RCT and in an open multicentre study. However, the main limitation of these studies was the short duration of follow-up after discontinuation of therapy.
In combination therapy, adverse events were observed that are characteristic of both classes of drugs. α1-blockers in combination with 5-ARI should be used primarily in men with moderate or severe LUTS who are at risk of disease progression (eg, larger prostate, higher PSA, older age), or if the patient agrees to long-term therapy (> 12 months).
3.27.2. a1-blockers in combination with muscarinic receptor antagonists. Therapy with an α1-blocker in combination with a muscarinic receptor antagonist aims to inhibit both α1-adrenergic receptors and M2 and M3 receptors in the lower urinary tract and thus exploits the action of both classes of drugs to achieve a synergistic effect.
Several RCTs and prospective studies have evaluated the efficacy of combination therapy with α1-blockers and muscarinic receptor antagonists both as initial therapy in men with OAB and suspected VRO and as follow-up therapy in men with persistent filling symptoms despite α1-blocker therapy. . Combination therapy was more effective in reducing urinary frequency, nocturia, or IPSS score than α1-blocker monotherapy or placebo. Combination therapy significantly reduced the number of urge incontinence and urgency episodes and improved quality of life (Qol). Persistent LUTS with α1-blocker therapy can be significantly reduced by the additional use of a muscarinic receptor antagonist, especially with detrusor overactivity. Two systematic reviews (statistical analysis not shown) of studies on the efficacy and safety of antimuscarinic drugs (including tolterodine, oxybutynin, propiverine, solifenacin, trospium, and fesoterodine) for the treatment of LUTS, including OAB in men, confirmed that combination therapy offers significant benefit for this male populations.
In combination therapy with a1-blockers and muscarinic receptor antagonists, adverse events were observed that are characteristic of both classes of drugs. Some side effects (eg, dry mouth or lack of ejaculation) may occur at an increased frequency and cannot be explained simply by adding the frequencies of both drugs. Combination studies of α1-blockers and antimuscarinics that measured PVR showed an increase (but not clinically significant) in PVR, and the risk of AUR was low. A recent RCT examined the safety of
relation to maximum detrusor pressure and Qmax for combined therapy with solifenacin (6 and 9 mg) and tamsulosin in men with LUTS and OI compared with placebo. At the end of therapy, the main urodynamic parameters with the combined use of drugs were no worse than with placebo; Qmax increased compared to placebo.
The increase in efficacy and quality of life in patients receiving therapy with α1-blockers and muscarinic receptor antagonists is most likely due to class effects. The studies primarily used filling symptoms as endpoints, were of short duration, and included only men with low residual urine volume at baseline. Thus, in combination therapy, the measurement of residual urine is recommended to assess the increase in its volume or the risk of urinary retention.
3.3■ Surgical treatment
3.3.1. Transurethral resection and transurethral incision of the prostate
3.3.1.1. Mechanism of action. Transurethral resection of the prostate (TURP) is aimed at resection of tissue in the transitional zone of the prostate for the treatment of LUTS associated with VRO. TURP is still considered the standard surgical procedure for the treatment of LUTS associated with VRO and prostate size.< 80 мл. Трансуретральное рассечение предстательной железы (ТУИП) снижает ВРО за счет рассечения ткани простаты в зоне шейки мочевого пузыря без удаления тканей.
3.3.1.2. Efficiency. In 1999, a meta-analysis of 29 RCTs was conducted, which revealed a mean decrease in LUTS by 70.6% and a mean increase in Qmax by 125% after TURP. In a recent analysis of 20 modern RCTs published between 2005 and 2009 with a maximum follow-up of 5 years, TURP resulted in a significant improvement in mean Qmax (+162%) and a significant decrease in mean IPSS score (-70%), mean quality of life score (-69%) and mean residual urine volume (-77%). In addition, TURP provides a long-term clinical outcome. One study with a median follow-up of 13 years showed a significant and sustained improvement in most symptoms and improvement in urodynamic parameters after TURP; subjective and objective failures were associated with detrusor underactivity rather than with the recurrence of VRO.
A meta-analysis of 10 short-term and long-term RCTs comparing TURP and TUIP showed similar improvement in LUTS and less pronounced but non-significant improvement in Qmax in TUIP patients with a small prostate but no enlargement of the median prostate lobe.
A meta-analysis of 6 studies showed that the need for reoperation is more common after TUIP (18.4%) than after TURP (7.2%) (relative risk 2.40).
3.3.1.3. portability and safety. Perioperative complications include mortality within the first 30 days (0.1% after TURP), water intoxication syndrome (<1,1% после ТУРП и 0% после ТУИП) и переливание крови (8,6% после ТУРП и незначительная частота после ТУИП) . Сходные результаты по осложнениям ТУРП были выявлены в ходе анализа современных РКИ, в которых ТУРП применяли в качестве терапии сравнения: кровотечение с необходимостью переливания крови 2% (диапазон 0-9%), синдром водной интоксикации 0,8% (диапазон 0-5%), ОЗМ (диапазон 0-13,3%), задержка свертывания 4,9% (диапазон 0-39%) и инфекция мочевыводящих путей (ИМП) 4,1% (диапазон 0-22%) .
Long-term complications include urinary incontinence (ranging from 1.8% after TUIP to 2.2% after TURP), urinary retention and UTI, bladder neck stenosis (4.7% after TURP), narrowing of the urethra (3.8% after TURP and 4.1% after TUIP), retrograde ejaculation (65.4% after TURP and 18.2% after TUIP), and erectile dysfunction (6.5% after TURP).
3.3.1.4- Practical considerations. TURP and TUIP are effective as primary therapy in men with moderate to severe LUTS associated with VR. The choice between TURP and TUIP should be based primarily on prostate volume: with prostate volume<30 мл пациентам подходит ТУИП, при объеме предстательной железы 30-80 мл пациентам подходит ТУРП. Перед проведением ТУРП или ТУИП необходимо вылечить ИМП . Исследования оптимального порогового значения не проводились, но частота осложнений возрастает с увеличением размера простаты . Верхняя граница зависит от опыта хирурга, и чаще всего рекомендуется ограничение 80 мл.
3-3-2. Modifications of transurethral resection of the prostate: bipolar resection of the prostate
3.3.2.1. Mechanism of action. Bipolar TURP (B-TURP) does not have the main disadvantage of monopolar TURP (M-TURP), i.e., it allows the operation to be performed using saline solution (SW1 0.9%). Unlike M-TURP systems, B-TURP systems do not require energy to travel through the patient's body to reach the skin electrode. The bipolar circuit is closed at the resection site between an active and passive electrode connected to a single attachment on the resectoscope.
3.3.2.2. Efficiency and safety. B-TURP is the most actively and extensively researched alternative to M-TURP. A meta-analysis based on 17 RCTs showed that there is no clinically significant difference in short-term (up to 12 months) efficacy, incidence of urethral narrowing and bladder neck narrowing, but B-TURP is preferred due to a more favorable perioperative safety profile (elimination of TURP syndrome; less bleeding ie less clotting delay and transfusion frequency, shorter duration of infusion, catheterization and possibly hospitalization). Two subsequent meta-analyses based on RCTs support these conclusions, which, despite the relatively low quality of the study, seem to be quite reliable and reflect the most reliable data so far. Modern update
The meta-analysis identified 16 additional RCTs published within the last 3 years (33 RCTs; 3601 randomized patients). An update of the pooled results is not yet ready, but none of the RCTs individually support M-TURP. The frequency of medium-term, short-term and perioperative complications did not differ significantly between groups. The effect on overall sexual function, efficacy, and all other secondary measures were comparable throughout the follow-up. Seven RCTs published to date have had >12 months of follow-up. (range 18-60 months) and showed no difference in IPSS and Qmax between B-TURP and M-TURP at interim.
3.3.2.3. practical considerations. B-TURP is an attractive alternative to M-TURP for patients with moderate or severe LUTS associated with VRO, the efficacy of the two therapies is similar, and perioperative complications are lower for B-TURP. Duration of improvement in B-TURP has been reported in some RCTs with >12 months of follow-up. Intermediate results (up to 5 years) for the safety/efficacy of B-TURP are comparable to those for M-TURP. At this point, the choice of B-TURP should be based on the availability of equipment for bipolar surgery, the experience of the surgeon, and patient preference.
3.3.3. Open prostatectomy
3.3.3.1. Mechanism of action. Open prostatectomy is the oldest surgical treatment for moderate to severe LUTS secondary to VRO. Removal of prostate tissue eliminates BPO and thereby reduces LUTS.
3.3.3.2. Efficiency. Open prostatectomy results in a 63-86% reduction in LUTS (12.5-23.3 points, IPSS-QoL score improvement of 60-87%, mean Qmax increase of 375% (range: 88-677%; absolute values +16 .5-20.2 ml/s) and an 86-98% reduction in residual urine.Effectiveness is maintained after long-term follow-up > 5 years.
3.3.3.3. portability and safety. Perioperative complications include mortality (< 0,25% в современных обзорах) и переливание крови (7-14%) . Долгосрочные осложнения включают недержание мочи (< 10%) и стеноз шейки мочевого пузыря или стриктуру уретры (приблизительно 6%) .
3.3.3.4. practical considerations. Open prostatectomy is the most invasive, but also the most effective and reliable treatment for LUTS/VRO. Only holmium enucleation shows similar results, but with a lower complication rate. In the absence of endourological equipment and a holmium laser, open prostatectomy is the surgical procedure of choice for men with a prostate volume >80 ml with an absolute indication for surgery or with moderate/severe LUTS associated with BRO for whom drug therapy has failed.
3.3.4. Transurethral Microwave Therapy
3.3.4.1. Mechanism of action. Microwave thermotherapy works by microwave radiation through an intraurethral antenna to heat the prostate gland, which leads to tissue destruction, apoptosis, and a-receptor denervation, thus reducing BPO and LUTS.
3.3.4.2. Efficiency. Although 1 RCT showed comparable clinical results 5 years after transurethral microwave therapy (TUMT) or TURP, a systematic review found that TUMT was slightly less effective than TURP in reducing LUTS. The pooled total symptom score for TUMT was reduced by 65% at 12 months, compared with 77% for TURP, a weighted mean difference of -1.0 in favor of TURP. TURP showed a greater improvement in Qmax (119%) than TUMT (70%) with a weighted mean difference of 5.08 ml/s in favor of TURP. In addition, TUMT was associated with an increased risk of retreatment for BPH symptoms After TUMT, IPSS symptom score (weighted mean difference -4.20) and maximum flow rate (2.30 ml/s) according to 1 also improved compared with α-blockers .
3.3.4.3. portability and safety. The therapy is well tolerated, although most patients experience perineal discomfort and urinary urgency and require pain medication before or during therapy. A Cochrane systematic review of RCTs comparing TURP and TUMT found that catheterization time, dysuria/urgency, and urinary retention were significantly lower with TURP, while hospitalization, hematuria, clotting delay, transfusions, water intoxication syndrome, and urethral constriction was significantly lower in TUMT. The incidence of sexual dysfunction and the need for retreatment for narrowing of the urethra or bladder neck was higher after TURP than after TUMT.
3.3.4.4. practical considerations. Before TUMT, a cystoscopy should be performed to determine the presence of a middle lobe of the prostate gland or insufficiency of the length of the prostatic urethra. With a low peri- and postoperative complication rate and no need for anesthesia, TUMT is a true outpatient procedure and represents an alternative for elderly patients with comorbidities and for patients for whom anesthesia is a risk and for whom invasive therapy is not suitable. Independent baseline variables predictive of poor outcome include small prostate size, moderate to severe HVO, and low intra-procedural energy. Predictive factors for individual devices cannot always be applied to devices from other manufacturers.
3.3.5. Transurethral needle ablation of the prostate
3.3.5.1. Mechanism of action. The transurethral needle ablation machine (TUIA) uses low radio
frequencies on the prostate through needles inserted into the parenchyma of the prostate through the urethra. The energy induces coagulative necrosis in the prostate transition zone, which results in a reduction in prostate volume and a decrease/resolution of BPO.
3.3.5.2. Efficiency. A meta-analysis of 2 randomized trials, 2 non-randomized protocols and 10 studies with 1st group conducted using TUIA showed that at 1 year after the procedure there was a 50% reduction in the mean IPSS score and a 70% improvement in Qmax compared with baseline. level. A more recent meta-analysis of 35 studies (9 comparative, 26 non-comparative) confirmed these findings. TUIA significantly improved IPSS score and Qmax from baseline, but compared to TURP, this improvement after 12 months was significantly lower. The mean difference between TURP and TUIA was -4.72 and 5.9 ml/s for the IPSS score and Qmax, respectively.
The retreatment rate for TUIA is higher than for TURP (odds ratio (OR): 7.44 (2.47-2.43) The overall retreatment rate after TUIA was 19.1% (95% confidence interval (CI): 18 .7-39.7) based on 17 non-comparative studies.
3.3.5.3. portability and safety. Postoperative urinary retention with an average duration of 1-3 days is observed in 13-42% of patients; after 1 week 90-95% of patients do not require catheterization. Bladder filling symptoms are often observed during the first 4-6 weeks. after operation . TUIA is associated with fewer adverse events compared with TURP, including mild hematuria, urinary tract infections, stenoses, urinary incontinence, erectile dysfunction, and ejaculation disorders (RR: 0.14; 95% CI: 0.05–0.41).
3.3.5.4. practical considerations. The TUIA procedure can be performed as a one-day intervention under local anesthesia or with the use of sedatives. TUIA is not suitable for prostates > 75 ml or isolated bladder neck obstruction. Since TUIA cannot effectively target the middle lobe of the prostate, it is not clear whether the procedure is beneficial for men with a large middle lobe.
3.4■ Patient selection
The choice of therapy depends on the results of the examination, the ability of the therapy to change such results, the preferences of the individual patient, as well as expectations regarding the speed of onset of effect, efficacy, side effects, quality of life and disease progression (Table 5). It should be noted that therapy options can be combined to provide different effects.
Lifestyle changes, with or without drug therapy, are usually the therapy of choice. Figure 2 shows a diagram that illustrates the choice of therapy in accordance with the principles of evidence-based medicine and patient profiles.
UPDATED
Table 5. The rate of manifestation of the effect and the impact on the main parameters of conservative, drug or surgical treatment of symptoms of the lower urinary tract in men*
Treatment Rate of onset of LUTS effect (IPSS) Uroflowmetry Prostate size Residual urine volume Disease progression
Conservative and drug therapy
Expectant management, lifestyle changes Months + (-1.3 to -5.7 points) - - - ?
Sc-adrenergic receptor antagonists Days ++ (-31 to -48.2%) ++ (+1.4 to +3.2 ml/s) - -/+ (-17 to -39%) + ++ (symptoms)
5a-reductase inhibitors Months + (-13.3 to -38.6%) ++ (+1.4 to +2.2 ml/s) + to ++ (-15 to -28%) - +++ (urinary retention)
Muscarinic receptor antagonists Weeks ++ (storage symptoms) (from -35.3 to -54%) - - + (from 0 to +49 ml) ?
PDE5 inhibitors (tadalafil) Days ++ (-17 to -37%) -/+ - -/+ (+9 to -19 ml) ?
Sc-adrenergic antagonists plus 5a-reductase inhibitors Days ++ (-38 to -49.7%) ++ (+2.3 to 3.8 ml/s) + to ++ (-11, 9 to -27.3%) -/+ +++ (symptoms + urinary retention)
SC-adrenergic antagonists plus muscarinic receptor antagonists Days ++ (from -31.8 to -66.4%) ++ - ?
Surgical treatment after catheter removal
TURP-TUIP Hours ++++ (-63 to -88%) ++++ (+6.9 to 22.9 ml/s) +++ ++++ ++++
Open prostatectomy Hours ++++ (-62 to -86%) ++++ (+7.0 to +21.4 ml/s) ++++ (-88%) ++++ (from -86 to -98%) ++++
TUMT Weeks +++ (-40 to -87%) +++ (+2.4 to 8.4 ml/s) ++ (-8.1 to -33.0%) ++ (from -34 to -84.1%) +++
TUIA Weeks +++ (45 to -56%) +++ (+4.7 to 6.5 ml/s) ++ + (-20 ml to -22%) ++
Ho1_EP/Ho1_1*P Hours ++++ (-66% to -92%) ++++ (+10.9 to 23.0 ml/s) ++++ (-34 to -54% ) ++++ (-68 to -98%) ++++
CTE/Green Laser Days +++ (-31 to -75%) +++ (+4.7 to 14.9 ml/s) +++ (-44 to -63%) +++ ( -57 to -91%) +++
Diode laser Clock +++ (-55 to -84.3%) +++ (+5.1 to 13.7 ml/s) +++ (-30.3 to -58.1%) Decrease according to PSA +++ (from -58.1 to -87.7%) +++
Thulium laser: TIiUaR, TIiUaRR and TIiUER Hours +++ (-63 to 85.4%) +++ (12.8 to 18.7 ml/s) +++ (-35.7 to -88 %) Decrease according to PSA +++ (-72.4 to -94.4%) +++
Prostatic stents Hours ++ (-10 to -19 points) ++ (+3 to 13.1 ml/s) - +++ ?
Note. BTX - botulinum toxin; HoLEP - enucleation of the prostate with a holmium laser; HoLRP - resection of the prostate with a holmium laser; IPSS - International Prostate Symptom Scale; KTP - green laser vaporization based on potassium - titanyl - phosphate; LUTS - symptoms from the lower urinary tract; PDE5 inhibitor - phosphodiesterase type 5 inhibitor; PSA - prostate-specific antigen; PVR - volume of residual urine; Qmax - maximum flow rate; ThuVaP - vaporization of the prostate with a laser based on thulium - yttrium - aluminum - garnet (Tm: YAG); ThuVaRP - Tm:YAG vaporectomy; ThuVEP - Tm:YAG vapoenucleation; TUMT - transurethral microwave therapy; TUIA - transurethral needle ablation; TUIP - tarnurethral dissection of the prostate; TURP - transurethral resection of the prostate. - No influence. + - Easy influence. ++ - Moderate impact. +++ - Strong influence, mm - Very strong influence. ? - Unknown.
* It should be noted that drug therapy trials typically use data after the run-in phase as a baseline, while invasive therapy does not.
Surgical treatment is usually required only if the patient has recurrent or refractory urinary retention, urinary incontinence due to bladder overflow, recurrent UTIs, bladder stones or diverticula, refractory macroscopic hematuria due to BPH, or upper urinary tract dilatation due to BPH, accompanied or not accompanied by renal failure (absolute indications for surgery, the need for surgical intervention). In addition, patients usually require surgical treatment in case of insufficient relief of LUTS or a decrease in the volume of residual urine after conservative or drug therapy (relative indications for surgery). The choice of surgical method depends on the size of the prostate gland, the patient's comorbidities, the ability to tolerate anesthesia, the patient's preferences, the willingness to tolerate the side effects associated with the operation, the presence of surgery.
logical equipment in the clinic and the experience of the surgeon in this area. The algorithm for choosing a surgical method of treatment is shown in Figure 3.
3.5. Follow-up
Patients who choose follow-up should be reassessed after 6 months and then reassessed annually unless symptoms worsen or an absolute indication for surgery develops.
Patients who receive α1-blockers, muscarinic receptor antagonists, or combination therapy with α1-blockers and 5-AM or muscarinic receptor antagonists should be examined after 4-6 weeks. after the start of taking drugs to determine the response to therapy. If the patient shows improvement in symptoms in the absence of disturbing adverse events, drug therapy can be continued. Patients need
The decision on therapy depends on the results of the initial examination (0). The absence (“No”) or the presence (“Yes”) of the disease are indicated by circles (o). It should be noted that patient preferences may lead to changes in treatment decisions. PDE5 = phosphodiesterase type 5
Patients who receive 5-AM should be examined after 12 weeks. - 6 months to determine response to therapy and adverse events. Men taking 5-AM should be monitored regularly with serial PSA tests if life expectancy is > 10 years and a diagnosis of prostate cancer may change the approach to therapy. After 6 months it is necessary to determine a new baseline PSA level, only a confirmed increase in PSA concentration during 5-AM therapy should be recorded.
In patients receiving Desmopressin, the concentration of sodium in the blood should be measured on the 3rd and 7th days, and also after 1 month. and then every 3 months. provided that the
sodium intake remains within the normal range. After increasing the dose of the drug, you should start the examination schedule again.
Patients after prostate surgery should be examined after 4-6 weeks. after removal of the catheter to assess response to therapy and adverse events. If the patient shows improvement in symptoms and no adverse events, no further testing is required.
This symptom-oriented guide provides practical guidance for managing men with LUTS. The full version is available online (www.uroweb.org/gls/pdf/ (M, 12_Mak_SNMP.rbO. ^
You can request a complete list of references from the editorial office.
Figure 3. Algorithm for the management of bothersome lower urinary tract symptoms (LUTS) refractory to medical/drug therapy or for absolute indications for surgery (eg, urinary retention, recurrent urinary tract infections, bladder stones or diverticula refractory to macroscopic hematuria or dilatation of the upper urinary tract due to benign prostatic obstruction (BPH), with or without renal failure)
(1) Modern Standard/Main Choice. Alternative therapies are listed in alphabetical order.
It should be noted that this regimen is stratified by the patient's ability to tolerate anesthesia, risk of cardiovascular events, and prostate size; however, the choice of surgical method also depends on the preference of the patient, willingness to tolerate the side effects associated with the operation, the availability of surgical equipment, and the experience of the surgeon in the field. HoLEP - enucleation of the prostate with a holmium laser; laser vaporization includes vaporization with green thulium and diode lasers; laser enucleation includes enucleation with holmium and thulium lasers; TUIP - transurethral dissection of the prostate; TUMT - transurethral microwave therapy; TUIA - transurethral needle ablation of the prostate; TURP - transurethral resection of the prostate (monopolar or bipolar)
Cialis® 5 mg
BRIEF INSTRUCTIONS FOR THE USE OF CIALIS 5 MG
Trade name of the drug: Ciapis* International (non-proprietary) name: Tadalafil. Dosage form: Tablets, film-coated.
Pharmacotherapeutic group: Erectile dysfunction treatment, PDE-5 inhibitor. Indications for use: Erectile dysfunction. Lower urinary tract symptoms in patients with benign prostatic hyperplasia. Erectile dysfunction in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia
Contraindications: Hypersensitivity to tadapafil or to any substance that is part of the drug; In the case of taking drugs containing any organic nitrates; Use in persons under 18 years of age; The presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days, unstable angina pectoris, the occurrence of an angina attack during intercourse, chronic heart failure II-IV classes according to the NYHA classification, uncontrolled arrhythmias, arterial hypotension ( BP less than 90/50 mm Hg), uncontrolled arterial hypertension, ischemic stroke within the last 6 months; Loss of vision due to non-arterial anterior ischemic optic neuropathy (regardless of the connection with the intake of PDE-5 inhibitors); Simultaneous administration of doxazosin, as well as drugs for the treatment of erectile dysfunction; Often (more than 2 times a week) use in patients with chronic renal failure (creatinine clearance less than 30 ml / min); Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
Dosage and administration: For oral administration. Using Cialis? for erectile dysfunction (ED). For patients with frequent sexual activity (more than twice a week): the recommended frequency of administration is daily, once a day, 5 mg, at the same time,
regardless of food intake. The daily dose may be reduced to 2.5 mg depending on individual sensitivity. For patients with infrequent sexual activity (less than twice a week): it is recommended to prescribe Cialis® at a dose of 20 mg, immediately before sexual activity, according to the instructions for the medical use of the drug. The maximum daily dose of Cialis® is 20 mg. Using Cialis? according to the indication of BPH or ED/BPH. The recommended dose of Cialis® when used once a day is 5 mg; the drug should be taken at approximately the same time of day, regardless of the time of sexual activity. The duration of treatment is determined by the doctor individually. In patients with mild renal insufficiency (creatinine clearance from 51 to 80 ml / min) and moderate severity (creatinine clearance from 31 to 50 ml / min), dose adjustment is not required. In patients with severe renal impairment (creatinine clearance<30 мл/мин и на гемодиализе): применение препарата Сиалис® один раз в сутки не рекомендуется.
Side effect: The most common adverse events in patients with erectile dysfunction are headache and dyspepsia, as well as back pain, myalgia, flushing of the face, nasal congestion.
The most common adverse events in patients with ED/BPH
are headache and dyspepsia, pain in the extremities, gastroesophageal reflux, myalgia. Release form: Film-coated tablets, 2.5 mg, 5 mg. 14 tablets in a blister consisting of laminated aluminum foil and PVC/PE/PCTFE film. 1 or 2 blisters, together with instructions for use, are placed in a cardboard pack.
For complete information, please refer to the instructions for medical use of the drug Cialis!® 5 mg
European association of urology guidelines on priapism
Salonia A1, Eardley I2, Giuliano F3, Hatzichristou D4, Moncada I5, Vardi Y6, Wespes E7, Hatzimouratidis K8.
Source
- Department of Urology, University Vita-Salute San Raffaele, Milan, Italy.
- Department of Urology, St. James University Hospital, Leeds, UK.
- Versailles Saint Quentin en Yvelines University, Garches, France, Neurology-Urology-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France
- Aristotle University of Thessaloniki, Center for Sexual and Reproductive Health and 2nd Department of Urology, Thessaloniki, Greece.
- Department of Urology, Hospital Sanitas La Zarzuela, Madrid, Spain.
- Neuro-Urology Unit, Rambam Healthcare Campus, and the Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
- Department of Urology, CHU de Charleroi, Hôpital Erasme, Brussels, Belgium.
- 2nd Department of Urology, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address: [email protected]
Priapism is defined as a penile erection that persists after or is not associated with sexual stimulation. It can be divided into ischemic (low outflow), arterial (high inflow), or intermittent (recurrent or intermittent).
Target
Develop guidelines for the diagnosis and treatment of priapism.
Evidence base
Systematic literature search on the epidemiology, diagnosis and treatment of priapism. Articles with the highest evidence were chosen to form the basis of these recommendations.
Synthesis of evidence
Ischemic priapism is usually idiopathic and the most common form. Arterial priapism usually occurs after blunt trauma to the perineum. The anamnesis is the basis of diagnosis and helps to determine the pathogenesis. Laboratory studies are used to confirm clinical data.
Ischemic priapism is a medical emergency. Intervention should begin within 4 to 6 hours, including decompression of the cavernous bodies by aspiration and intracavernous injections of sympathomimetics (eg, phenylephrine). Surgical treatment is recommended when conservative treatment fails, although the choice of intervention is not yet clear. Immediate implantation of a prosthesis should be considered for prolonged priapism.
Arterial priapism is not an emergency. Selective embolization is a proposed treatment modality and has a high success rate. Intermittent priapism is poorly understood, and the main therapeutic goal is to prevent its recurrence. This can be achieved pharmacologically, but efficacy data are limited.
conclusions
These guidelines summarize current information on priapism. An extended version is available on the European Association of Urology website (www.uroweb.org/guidelines/).
Summary for patients
Priapism is a persistent, often painful erection of the penis lasting more than 4 hours, not associated with sexual stimulation. It is more common in patients with sickle cell anemia. This article presents abridged EAU guidelines on priapism based on a systematic review of the literature.
Priapism is classified as ischemic (low outflow), arterial (high inflow), or intermittent (recurrent). Treatment of ischemic priapism must be prompt to avoid the risk of permanent erectile dysfunction. This does not apply to arterial priapism.
Keywords
Arterial, diagnostics, EAU principles, ischemic, health-improving procedures, priapism, intermittent, treatment.
