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MALE INFERTILITY

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MALE INFERTILITY Epidemiology, aetiology, pathophysiology, and risk factors Comprehensive Review Article Part 1 Prof. Dr. Semir. A. Salim. Al Samarrai Definition and classification: Infertility is defined by the inability of a sexually active, non-contraceptive couple to achieve spontaneous pregnancy within 1 year [1]. Primary infertility refers to couples that have never had a child and cannot achieve pregnancy after at least 12 consecutive months having sex without using birth control methods. Secondary infertility refers to infertile couples who have been able to achieve pregnancy at least once before (with the same or different sexual partner). Recurrent pregnancy loss is distinct from infertility and is defined as two or more failed pregnancies [2,3]. Epidemiology/aetiology/pathophysiology/risk factors: Introduction About 15% of couples do not achieve pregnancy within 1 year and seek medical treatment for infertility. One in eight couples encounter problems when attempting to conceive a first child and one in six when attempting to conceive a subsequent child [4]. In 50% of involuntarily childless couples, a male-infertility-associated factor is found, usually together with abnormal semen parameters [1]. For this reason, all male patients belonging to infertile couples should undergo medical evaluation by a urologist trained in male reproduction. Male fertility can be impaired as a result of [1]: • congenital or acquired urogenital abnormalities. • gonadotoxic exposure (e.g., radiotherapy or chemotherapy). • malignancies. • urogenital tract infections. • increased scrotal temperature (e.g., as a consequence of varicocele). • endocrine disturbances. • genetic abnormalities. • immunological factors. In 30-40% of cases, no male-associated factor is found to explain impairment of sperm parameters and historically was referred to as idiopathic male infertility. These men present with no previous history of diseases affecting fertility and have normal findings on physical examination and endocrine, genetic and biochemical laboratory testing, although semen analysis may reveal pathological findings. Unexplained male infertility is defined as infertility of unknown origin with normal sperm parameters and partner evaluation. Between 20 and 30% of couples will have unexplained infertility. It is now believed that idiopathic male infertility may be associated with several previously unidentified pathological factors, which include but are not limited to endocrine disruption as a result of environmental pollution, generation of reactive oxygen species (ROS)/sperm DNA damage, or genetic and epigenetic abnormalities [5]. Advanced paternal age has emerged as one of the main risk factors associated with the progressive increase in the prevalence of male factor infertility [6–13]. Likewise, advanced maternal age must be considered over the management of every infertile couple, and the consequent decisions in the diagnostic and therapeutic strategy of the male partner [14,15]. This should include the age and ovarian reserve of the female partner, since these parameters might determine decision-making in terms of timing and therapeutic strategies (e.g., assisted reproductive technology [ART] vs. surgical intervention) [6–9]. Table 1 summarises the main male-infertility-associated factors. Table 1: Male infertility causes and associated factors and percentage of distribution in 10,469 patients Diagnostic work-up: Focused evaluation of male patients must always be undertaken and should include: a medical and reproductive history; physical examination; semen analysis – with strict adherence to World Health Organization (WHO) reference values for human semen characteristics [17], and hormonal evaluation. Other investigations (e.g., genetic analysis and imaging) may be required depending on the clinical features and semen parameters. Medical/reproductive history and physical examination: Medical and reproductive history Medical history should evaluate any risk factors and behavioural patterns that could affect the male partner’s fertility, such as lifestyle, family history (including, testicular cancer), comorbidity (including systemic diseases; e.g., hypertension, diabetes mellitus, obesity, MetS, testicular cancer, etc.), genito-urinary infections (including sexually transmitted infections), history of testicular surgery and exclude any potential known gonadotoxins [18]. Typical findings from the history of a patient with infertility include: • cryptorchidism (uni- or bilateral). • testicular torsion and trauma. • genitourinary infections. • exposure to environmental toxins. • gonadotoxic medications (anabolic drugs, chemotherapeutic agents, etc.). • exposure to radiation or cytotoxic agents. Physical examination Physical examination Focused physical examination is compulsory in the evaluation of every infertile male, including presence of secondary sexual characteristics. The size, texture and consistency of the testes must be evaluated. In clinical practice, testicular volume is assessed by Prader’s orchidometer [19]; orchidometry may overestimate testicular volume when compared with US assessment [20]. There are no uniform reference values in terms of Prader’s orchidometer-derived testicular volume, due to differences in the populations studied (e.g., geographic area, nourishment, ethnicity and environmental factors) [19–21]. The mean Prader’s orchidometer-derived testis volume reported in the European general population is 20.0 ± 5.0 mL [19], whereas in infertile patients it is 18.0 ± 5.0 mL [19,22,23]. The presence of the vas deferens, fullness of epididymis and presence of a varicocele should be always determined. Likewise, palpable abnormalities of the testis, epididymis, and vas deferens should be evaluated. Other physical alterations, such as abnormalities of the penis (e.g., phimosis, short frenulum, fibrotic nodules, epispadias, hypospadias, etc.), abnormal body hair distribution and gynecomastia, should also be evaluated. Typical findings from the physical examination of a patient with characteristics suggestive for testicular deficiency include: • abnormal secondary sexual characteristics. • abnormal testicular volume and/or consistency. • testicular masses (potentially suggestive of cancer). • absence of testes (uni-bilaterally). • gynaecomastia. • varicocele. Semen analysis A comprehensive andrological examination is always indicated in every infertile couple, both if semen analysis shows abnormalities, and even in the case of normal sperm parameters as compared with reference values [24]. Important treatment decisions are based on the results of semen analysis and most studies evaluate semen parameters as a surrogate outcome for male fertility. However, semen analysis cannot precisely distinguish fertile from infertile men [25]; therefore, it is essential that the complete laboratory work-up is standardised according to reference values (Table 2). Table 2: Lower reference limits (5th centiles and their 95% CIs) for semen characteristics There is consensus that modern semen analysis must follow these guidelines. Ejaculate analysis has been standardised by the WHO and disseminated by publication of the most updated version of the WHO Laboratory Manual

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Non-muscle-invasive Bladder Cancer Part 2

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Non-muscle-invasive Bladder Cancer Part 2 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai PREDICTING DISEASE RECURRENCE AND PROGRESSION: TaT1 tumours Treatment should take into account a patient’s prognosis. In order to predict the risk of disease recurrence and/ or progression, several prognostic models for specified patient populations have been introduced. Scoring models using the WHO 1973 classification system The 2006 European Organisation for Research and Treatment of Cancer (EORTC) scoring model to be able to predict both the short- and long-term risks of disease recurrence and progression in individual patients, the EORTC Genito-Urinary Cancer Group (GUCG) published a scoring system and risk tables based on the WHO 1973 classification in 2006 [1]. The scoring system is based on the 6 most significant clinical and pathological factors in patients mainly treated by intravesical chemotherapy: • Number of tumours; • Tumour diameter; • Prior recurrence rate; • T category; • Concurrent CIS; • WHO 1973 tumour grade. Using the 2006 EORTC scoring model, individual probabilities of recurrence and progression at 1 and 5 years may be calculated (https://www.omnicalculator.com/health/eortc-bladder-cancer). The model for patients with Ta G1/G2 (WHO 1973) tumours treated with chemotherapy Patients with Ta G1/G2 tumours receiving chemotherapy were stratified into 3 risk groups for recurrence, taking into account the history of recurrences, history of intravesical treatment, tumour grade (WHO 1973), number of tumours and adjuvant chemotherapy [2]. Club Urologico Español de Tratamiento Oncologico (CUETO) scoring model for BCG-treated patients A model that predicts the risk of recurrence and progression, based on 12 doses of intravesical BCG over a 5 to 6 months period following TURB, has been published by the CUETO (Spanish Urological Oncology Group). It is based on an analysis of 1,062 patients from 4 CUETO trials that compared different intravesical BCG treatments. No immediate post-operative instillation or second TURB was performed in these patients. The scoring system is based on the evaluation of seven prognostic factors: • gender; • age; • prior recurrence status; • number of tumours; • T category; • associated CIS; • WHO 1973 tumour grade. Using this model, the calculated risk of recurrence is lower than that obtained by the EORTC tables. For progression, probability is lower only in high-risk patients [3]. The lower risks in the CUETO tables may be attributed to the use of BCG in this study. The prognostic value of the EORTC scoring system has been confirmed by data from the CUETO patients treated with BCG and by long-term follow-up in an independent patient population [4, 5]. The 2016 EORTC scoring model for patients treated with maintenance BCG In 1,812 intermediate- and high-risk patients without CIS treated with 1 to 3 years of maintenance BCG, the EORTC found that the prior disease-recurrence rate and number of tumours were the most important prognostic factors for disease recurrence, stage and WHO 1973 grade for disease progression and diseasespecific survival, while age and WHO 1973 grade were the most important prognostic factors for OS. T1 G3 patients did poorly, with 1- and 5-year disease-progression rates of 11.4% and 19.8%, respectively. Using these data, EORTC risk groups and nomograms for BCG-treated patients were developed [6]. Scoring model using the WHO 2004/2016 and WHO 1973 classification systems EAU NMIBC 2021 scoring model To update the risk of disease progression and create new prognostic factor risk groups using both the WHO 1973 and WHO 2004/2016 classification systems (without central pathology review), individual patient data from 3,401 primary patients treated from 1990 to 2018 were used [7]. Only patients treated with TURB ± intravesical chemotherapy were included, those treated with adjuvant intravesical BCG were excluded because BCG may reduce the risk of disease progression. From the multivariate analysis, tumour stage, WHO 1973 grade, WHO 2004/2016 grade, concomitant CIS, number of tumours, tumour size and age were independent predictors of disease progression [7]. Further prognostic factors Further prognostic factors have been described in selected patient populations: • In T1G3 tumours, important prognostic factors were female sex, CIS in the prostatic urethra in men treated with an induction course of BCG, and age, tumour size and concurrent CIS in BCG-treated patients (62% with an induction course only) [8, 9]. • Attention must be given to patients with T1G3 tumours in bladder (pseudo) diverticulum because of the absence of muscle layer in the diverticular wall [10]. • In patients with T1 tumours, the finding of residual T1 disease at second TURB is an unfavourable prognostic factor [11-13]. In patients with T1G2 tumours treated with TURB, recurrence at 3 months was the most important predictor of progression [14]. • The prognostic value of pathological factors has been discussed elsewhere. More research is needed to determine the role of molecular markers in improving the predictive accuracy of currently available risk tables [4, 15]. • Pre-operative neutrophil-to-lymphocyte ratio may have prognostic value in NMIBC. This data, however, needs further validation [16]. Carcinoma in situ Without any treatment, approximately 54% of patients with CIS progress to muscle-invasive disease [17]. There are no reliable prognostic factors, but some studies, however, have reported a worse prognosis in concurrent CIS and T1 tumours compared to primary CIS [18,19], in extended CIS [20] and in CIS in the prostatic urethra [8]. The response to intravesical treatment with BCG or chemotherapy is an important prognostic factor for subsequent progression and death caused by BC [3–5, 14]. Approximately 10 to 20% of complete responders eventually progress to muscle-invasive disease, compared with 66% of non-responders [21, 22]. Patient stratification into risk groups To be able to facilitate treatment recommendations, the Guidelines Panel recommends the stratification of patients into risk groups based on their probability of progression to muscle-invasive disease. The new risk group definitions provided in these EAU Guidelines are based on an IPD analysis in primary patients and the calculation of their progression scores (2021 EAU NMIBC scoring model) [7]. For calculation of the risk group in individual patients, either one, or both, of the WHO 1973 and WHO 2004/2016 classification systems may be used. The probability of

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Non-muscle-invasive Bladder Cancer

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Non-muscle-invasive Bladder Cancer Part 1 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY: Epidemiology Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, while it drops to tenth when both genders are considered [1]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 in men and 2.4 in women [1]. In the European Union the age-standardised incidence rate is 20 for men and 4.6 for women [1]. Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.3 for men vs. 0.86 for women [1]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, partly caused by the different methodologies used and the quality of data collection [2]. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative agents [3]. Approximately 75% of patients with BC present with a disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1); in younger patients (< 40 years of age) this percentage is even higher [4]. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality compared to T2-4 tumours [1,2]. Aetiology Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases [2,3, 5–7]. The risk of BC increases with smoking duration and smoking intensity [6]. Low-tar cigarettes are not associated with a lower risk of developing BC [6]. The risk associated with electronic cigarettes is not adequately assessed; however, carcinogens have been identified in urine [8]. Environmental exposure to tobacco smoke is also associated with an increased risk of BC [2]. Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally excreted. Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC, accounting for about 10% of all cases. This type of occupational exposure occurs mainly in industrial plants which process paint, dye, metal, and petroleum products [2, 3, 9, 10]. In developed industrial settings these risks have been reduced by work-safety guidelines; therefore, chemical workers no longer have a higher incidence of BC compared to the general population [2, 9, 10]. Recently, greater occupational exposure to diesel exhaust has been suggested as a significant risk factor (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08–2.40) [11]. While family history seems to have little impact [12] and, to date, no overt significance of any genetic variation for BC has been shown; genetic predisposition has an influence on the incidence of BC via its impact on susceptibility to other risk factors [2, 13–17]. This has been suggested to lead to familial clustering of BC with an increased risk for first- and second-degree relatives (hazard ratio [HR]: 1.69; 95% CI: 1.47−1.95) [18]. Although the impact of drinking habits is uncertain, the chlorination of drinking water and subsequent levels of trihalomethanes are potentially carcinogenic, also exposure to arsenic in drinking water increases risk [2, 19]. Arsenic intake and smoking have a combined effect [20]. The association between personal hair dye use and risk remains uncertain; an increased risk has been suggested in users of permanent hair dyes with a slow NAT2 acetylation phenotype [2] but a large prospective cohort study could not identify an association between hair dye and risk of most cancer and cancer-related mortality [21]. Dietary habits seem to have limited impact, recently protective impact of flavonoids has been suggested and a Mediterranean diet, characterised by a high consumption of vegetables and non-saturated fat (olive oil) and moderate consumption of protein, was linked to some reduction of BC risk (HR: 0.85, 95% CI: 0.77−0.93) [22–27]. The impact of an increased consumption of fruits has been suggested to reduce the risk of BC; to date, this effect has been demonstrated to be significant in women only (HR: 0.92; 95% CI: 0.85–0.99) [28]. Exposure to ionizing radiation is connected with increased risk; a weak association was also suggested for cyclophosphamide and pioglitazone [2, 19, 29]. The impact of metabolic factors (body mass index, blood pressure, plasma glucose, cholesterol, and triglycerides) is uncertain [30]. Schistosomiasis, a chronic endemic cystitis based on recurrent infection with a parasitic trematode, is also a cause of BC [2]. PATHOLOGICAL STAGING AND CLASSIFICATION SYSTEMS: Definition of non-muscle-invasive bladder cancer LE 2a 3 3 Tumours confined to the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively, according to the Tumour, Node, Metastasis (TNM) classification system [31]. Intra-epithelial, highgrade (HG) tumours confined to the mucosa are classified as CIS (Tis). All of these tumours can be treated by transurethral resection of the bladder (TURB), eventually in combination with intravesical instillations and are therefore grouped under the heading of NMIBC for therapeutic purposes. The term ‘non-muscle-invasive BC’ represents a group definition and all tumours should be characterised according to their stage, grade, and further pathological characteristics. Tumour, Node, Metastasis Classification (TNM) The latest TNM classification approved by the Union International Contre le Cancer (UICC) (8th Edn.) is referred to (Table 1) [31]. Table 1: 2017 TNM classification of urinary bladder cancer T1 subclassification The depth and extent of invasion into the lamina propria (T1 sub-staging) has been demonstrated to be of prognostic value in retrospective cohort studies [32, 33]. Its use is recommended by the most recent 2016 World Health Organization (WHO) classification [34]. T1 sub-staging methods are based either on micrometric (T1e and T1m) or histo-anatomic (T1a and T1b) principles; the optimal classification system, however, remains to be defined [34, 35]. Carcinoma in situ and its classification Carcinoma in situ is a flat, HG, non-invasive urothelial carcinoma. It can be missed or misinterpreted as an inflammatory lesion during cystoscopy if not biopsied. Carcinoma in situ is often multifocal and can occur in the bladder, but also in the upper urinary tract (UUT), prostatic ducts, and

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Overactive Urinary Bladder

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Overactive Urinary Bladder Diagnostic and Evaluation Comprehensive Review Article Part 2 Prof. Dr. Semir. A. Salim. Al Samarrai Taking a thorough clinical history is fundamental to the process of clinical evaluation. Despite the lack of high-level evidence to support taking a history, there is universal agreement that it should be the first step in the assessment of anyone with lower urinary tract symptoms (LUTS). The history should include a full evaluation of LUTS, as well as sexual, gastrointestinal and neurological symptoms. Details of urgency episodes, the type, timing and severity of urinary incontinence (UI), and some attempt to quantify symptoms should also be made. The history should help to categorise LUTS as storage, voiding and post-micturition symptoms, and classify UI as stress urinary incontinence (SUI), urge urinary incontinence (UUI), mixed urinary incontinence (MUI) or overflow incontinence; the latter being defined as “the complaint of UI in the symptomatic presence of an excessively (over-) full bladder (no cause identified)” [1]. The history should also identify patients who need referral to an appropriate clinic/specialist. These may include patients with associated pain, haematuria, history of recurrent urinary tract infection (UTI), pelvic surgery or radiotherapy, constant leakage suggesting a fistula, new-onset enuresis or suspected neurological disease. A neurological, obstetric and gynaecological history may help to understand the underlying cause and identify factors that may affect treatment decisions. Guidance on history-taking and diagnosis in relation to UTIs, neuro-urological conditions and chronic pelvic pain (CPP) can be found in the relevant EAU Guidelines [2,3,4]. Patients should also be asked about other comorbidity as well as smoking status, previous surgical procedures and current medications, as these may affect LUTS. There is little evidence from clinical trials that carrying out a clinical examination improves outcomes, but widespread consensus suggests that clinical examination remains an essential part of assessment of patients with LUTS. Examination should include abdominal examination, to detect an enlarged urinary bladder or other abdominal mass, and digital examination of the vagina and/or rectum. Pelvic examination in women includes assessment of oestrogen status, pelvic floor muscle (PFM) function and careful assessment of any associated pelvic organ prolapse (POP). A cough stress test is necessary to look for stress urinary incontinence (SUI). Among women with genital prolapse, the cough test was found to show good agreement with urodynamic studies (UDS) in the detection of SUI. Urethral mobility can be assessed. Pelvic floor muscle contraction strength can also be assessed digitally. A focused neuro-urological examination should also be routinely undertaken. Patient questionnaires include symptom scores, symptom questionnaires/scales/indices, patient-reported outcome measures (PROMs) and health-related quality of life (QoL) measures. Questionnaires should have been validated for the language in which they are being used, and, if used for outcome evaluation, should have been shown to be sensitive to change. The US Food and Drug Administration (FDA) published guidance for industry on PROM instruments (questionnaires) in 2009 [5]. Patient bladder diaries include measurement of the frequency and severity of LUTS and is an important step in the evaluation and management of LUT dysfunction. Bladder diaries are a semi-objective method of quantifying symptoms, such as frequency of urinary incontinence (UI) events, number of nocturia episodes, etc. Fluid intake and voided volume measurement can be used to support diagnoses and management planning, for example in overactive bladder (OAB), and for identifying 24-hour or nocturnal polyuria. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance [6,7]. Diary durations between three and seven days are routinely reported in the literature. The urinalysis and urinary tract infection investigations are a very important steps in the evaluation and therapy of UTI. Reagent strip (dipstick) urinalysis may indicate proteinuria, haematuria or glycosuria, or suggest UTI requiring further assessment. Urine dipstick testing is a useful adjunct to clinical evaluation in patients in whom urinary symptoms are suspected to be due to UTI. Urinalysis negative for nitrite and leukocyte esterase may exclude bacteriuria in women with LUTS [8], and should be included, with urine culture when necessary, in the evaluation of all patients with LUTS. Urinary incontinence or worsening of LUTS may occur during UTI [9] and existing UI may worsen [10]. The rate and severity of UI were unchanged after eradication of asymptomatic bacteriuria in nursing home residents [11]. The post-void residual volume measurement is also important step in the evaluation and management of OAB and obstruction LUT-Disorders. Post-void residual (PVR) volume is the amount of urine that remains in the bladder after voiding. It is a measure of voiding efficiency, and results from a number of contributing factors. The detection of significant PVR volume is important because it may worsen symptoms and, more rarely, may be associated with UTI, upper urinary tract (UUT) dilatation and renal insufficiency. Both BOO and/or detrusor underactivity (DU) can potentially contribute to the development of significant PVR volume. Post-void residual volume can be measured by catheterisation or ultrasound (US). Most studies investigating PVR volume have assessed mixed populations including those with neurogenic UI. In general, the data on PVR volume can be applied with caution to women with non-neurogenic LUTS. The results of studies investigating the best method of measuring PVR volume [11-16] have led to the consensus that US measurement of PVR volume is preferable to catheterisation due to its favourable risk–benefit profile. In peri- and postmenopausal women without significant LUTS or pelvic organ symptoms, 95% had a PVR volume < 100 mL [17]. In women with UUI, PVR volume > 100 mL was found in only 10% of cases [18]. Other research has found that a high PVR volume is associated with pelvic organ prolapse (POP), voiding symptoms and an absence of SUI [17, 19–21]. In women with SUI, the mean PVR volume was 39 mL measured by catheterisation and 63 mL measured by US, with 16% of women having PVR volume > 100 mL [22]. Some authors have suggested that it is reasonable to consider a PVR volume > 100 mL to be significant, although many women may remain

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Overactive Urinary Bladder

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Overactive Urinary Bladder Epidemiology, aetiology, pathophysiology Comprehensive Review Article Part 1 Prof. Dr. Semir. A. Salim. Al Samarrai Overactive bladder is defined by the International Continence Society (ICS) as “urinary urgency, usually accompanied by frequency and nocturia, with or without (Urge Urinary Incontinence (UUI), in the absence of Urinary Tract Infection (UTI) or other obvious pathology” [1]. Overactive bladder is a chronic condition and can have debilitating effects on QoL. The hallmark urodynamic feature is Detrusor Overactivity (DO), although this may not be demonstrated in a large proportion of Overactive Bladder (OAB) patients, which may partly be due to failure to reproduce symptoms during urodynamic assessment. The EPidemiology of InContinence (EPIC) study was one of the largest population-based surveys of the prevalence of LUTS and OAB [2]. It was a cross-sectional telephone survey of adults aged > 18 years conducted in five countries, including Canada, Germany, Italy, Sweden and the UK. The study included > 19,000 participants and demonstrated an overall prevalence of OAB symptoms of 11.8% (10.8% in men and 12.8% in women). Other studies have reported prevalences of up to 30 to 40%, with rates generally increasing with age [3]. Various theories have been proposed to explain the pathophysiology of OAB, mainly relating to imbalances in inhibitory and excitatory neural pathways to the bladder and the urethra or sensitivity of bladder muscle receptors. However, no definite identifiable causes have been established. Overactive bladder is generally classified into wet and dry, based on the presence or absence of associated Urinary Incontinence (UI). Evaluation of symptoms of OAB follows the general pathway of evaluation of women with LUTS. The Diaries are particularly helpful in establishing and quantifying symptoms of frequency, urgency and UI, and may be valuable in assessing change over time or response to treatment. Several observational studies have demonstrated a close correlation between data obtained from bladder diaries and standard symptom evaluation [4–7]. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance. Diary duration of three to seven days is routinely used in the literature. The Urodynamics is essential in establishing the presence of DO, but its absence does not preclude diagnosis of OAB, which is based on symptoms alone. A Cochrane review of seven RCTs showed that use of urodynamic tests increased the likelihood of prescribing drugs or avoiding surgery. However, there was no evidence that this influence on decision-making altered the clinical outcome of treatment [8]. A sub-analysis of an RCT comparing fesoterodine to placebo [9] showed that the urodynamic diagnosis of DO had no predictive value for treatment response. A single report (SR) and meta-analysis indicated that the urinary tract nerve growth factor (Urinary NGF) and Brain-divided neurotrophic factor or abneurin are members of the neurotrophic family of growth factors were increased in female OAB patients as urinary biomarker compared to healthy controls, whereas no difference was found for the prostaglandins E2 (PGE2) level normalized to the concentration of the urinary creatine was elevated and higher in the BPH/OAB than in the BPH/non-groups [10]. The current data is inadequate to assess any other potential biomarkers, such as urinary malondialdehyde (UMDA), ATP, and cytokines, in the management of OAB in female patients. Further studies are needed to establish their potential as diagnostic and management tools in OAB women. The conservative management of the overactive bladder has long been recommended as first in clinical practice, because they usually carry the lowest risk of harm. While this remains true for non-pharmacological conservative treatments [e.g., pelvic floor muscle training (PFMT)], increasing concerns regarding the adverse events of some pharmacological treatments used to treat LUTS (e.g., anticholinergic drugs), particularly regarding cognitive function, have emerged and patients should be fully counselled regarding this potential risk. It is possible that improvement of associated disease may reduce the severity of the lower urinary tract symptoms (LUTS), especially in elderly patients, which are associated with multiple comorbid conditions including: • cardiac failure; • chronic renal failure; • diabetes; • chronic obstructive pulmonary disease; • neurological disease; • general cognitive impairment; • sleep disturbances, e.g., sleep apnoea; • depression; • metabolic syndrome. The Lifestyle factors that may be associated with UI include obesity, smoking, level of physical activity, regulation of bowel habit and fluid intake. Modification of these factors may improve symptoms of OAB. The caffeine intake in many drinks contain caffeine are particularly coffee, tea and cola. Conflicting epidemiological evidence of urinary symptoms being aggravated by caffeine intake has focused on whether caffeine reduction improves LUTS [11, 12]. A scoping review of fourteen interventional and twelve observational studies reported that reduction in caffeine intake may reduce symptoms of urgency, but the certainty of evidence was low, with significant heterogeneity in study populations [13]. The fluid intake modification are particularly restriction, and is a strategy commonly used by people with OAB to relieve symptoms. Any advice on fluid intake given by HCPs should be based on 24-hour fluid intake and urine output measurements as retrieved from the bladder diary. From a general health point of view, it should be advised that fluid intake should be sufficient to avoid thirst and that an abnormally low or high 24-hour urine output should be investigated. The few RCTs that have been published provide inconsistent evidence [14-16]. In most studies, the instructions for fluid intake were individualised and it was difficult to assess participant adherence. All available studies were in women. An RCT showed that a reduction in fluid intake by 25% improved symptoms in patients with OAB but not UI [16]. Personalised fluid advice compared to generic advice made no difference to continence outcomes in people receiving anticholinergics for OAB, according to an RCT comparing drug therapy alone to drug therapy with behavioural advice [17]. Patients should be warned of the potential consequences of fluid restriction such as worsening of constipation or development of UTI. The obesity and overweight have been identified as a risk factors for LUTS in many epidemiological studies [18, 19]. There is

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Prostate Cancer Salvage Therapy Comprehensive Review Article Part 7

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Prostate Cancer Salvage Therapy Comprehensive Review Article Part 7 Prof. Dr. Semir. A. Salim. Al Samarrai Salvage radiotherapy combined with androgen deprivation therapy (cTxcN0, without PET/CT): Data from RTOG 9601 suggest both CSS and OS benefit when adding 2 years of bicalutamide (150 mg o.d.) to SRT [1]. However, SRT combined with either goserelin or placebo showed similar DSS and OS rates [2]. Table 1 provides an overview of these two RCTs. Table 1. Randomised controlled trials comparing salvage radiotherapy combined with androgen deprivation therapy vs. salvage radiotherapy alone Target volume, dose, toxicity There have been various attempts to define common outlines for ‘clinical target volumes‘ of PCa [3–6] and for organs at risk of normal tissue complications [7]. A benefit in biochemical PFS but not metastasis-free survival has been reported in patients receiving whole pelvis SRT (± ADT) but the advantages must be weighed against possible side effects [8]. Two RCT’s were recently published (Table 2). Intensity-modulated radiation therapy plus IGRT was used in 57% of the patients in the SAKK-trial [9] and in all patients of the Chinese trial [10]. No patient had a PSMA PET/CT before randomisation. Table 2. Randomized trials investigating dose escalation for SRT without ADT and without PET-CT Salvage RT is associated with toxicity. In one report on 464 SRT patients receiving median 66.6 (max. 72) Gy, acute grade 2 toxicity was recorded in 4.7% for both the GI and GU tract. Two men had late grade 3 reactions of the GI tract, but overall, severe GU tract toxicity was not observed. Late grade 2 complications occurred in 4.7% (GI tract) and 4.1% (GU tract), respectively, and 4.5% of the patients developed moderate urethral stricture [11]. Salvage RT with or without ADT (cTx CN0/1) with PET/CT In a prospective multi-centre study of 323 patients with BCR, PSMA PET/CT changed the management intent in 62% of patients as compared to conventional staging. This was due to a significant reduction in the number of men in whom the site of disease recurrence was unknown (77% vs. 19%, p < 0.001) and a significant increase in the number of men with metastatic disease (11% vs. 57%) [12]. Metastasis-directed therapy for rcN+ (with PET/CT) Radiolabelled PSMA PET/CT is increasingly used as a diagnostic tool to assess metastatic disease burden in patients with BCR following prior definitive therapy. A review including 30 studies and 4,476 patients showed overall estimates of positivity in a restaging setting of 38% in pelvic LNs and 13% in extra-pelvic LN metastases [13]. The percentage positivity of PSMA PET/CT was proven to increase with higher PSA values, from 33% (95% CI: 16–51) for a PSA of < 0.2 ng/mL, to 45% (39–52), 59% (50–68), 75% (66–84), and 95% (92–97) for PSA subgroup values of 0.2–0.49, 0.5–0.99, 1.00–1.99, and > 2.00 ng/mL, respectively [13]. Salvage lymph node dissection The surgical management of (recurrent) nodal metastases in the pelvis has been the topic of several retrospective analyses [14-16] and a systematic review [17]. The reported 5-year BCR-free survival rates ranged from 6% to 31%. Five-year OS was approximately 84% [17]. Biochemical recurrence rates were found to be dependent on PSA at surgery and location and number of positive nodes [18]. Addition of RT to the lymphatic template after salvage LN dissection may improve the BCR rate [19]. Management of PSA failures after radiation therapy Therapeutic options in these patients are ADT or salvage local procedures. A systematic review and metaanalysis included studies comparing the efficacy and toxicity of salvage RP, salvage HIFU, salvage cryotherapy, SBRT, salvage LDR brachytherapy, and salvage HDR brachytherapy in the management of locally recurrent PCa after primary radical EBRT [20]. The outcomes were BCR-free survival at 2 and 5 years. Salvage radical prostatectomy Salvage RP after RT is associated with a higher likelihood of adverse events (AEs) compared to primary surger because of the risk of fibrosis and poor wound healing due to radiation [21]. Oncological outcomes In a systematic review of the literature, Chade, et al., showed that SRP provided 5- and 10-year BCR-free survival estimates ranging from 47–82% and from 28–53%, respectively. The 10-year CSS and OS rates ranged from 70–83% and from 54–89%, respectively. Pathological T stage > T3b (OR: 2.348) and GS (up to OR 7.183 for GS > 8) were independent predictors for BCR (see Table 3). Table 3. Oncological results of selected salvage radical prostatectomy case series Morbidity Compared to primary open RP, SRP is associated with a higher risk of later anastomotic stricture (47 vs. 5.8%), urinary retention (25.3% vs. 3.5%), urinary fistula (4.1% vs. 0.06%), abscess (3.2% vs. 0.7%) and rectal injury (9.2 vs. 0.6%) [22]. In more recent series, these complications appear to be less common [21,23,24]. Functional outcomes are also worse compared to primary surgery, with urinary incontinence ranging from 21% to 90% and ED in nearly all patients (see table 4) [23,24]. Table 4. Peri-operative morbidity in selected salvage radical prostatectomy case series Stereotactic ablative body radiotherapy (CyberKnifeR or linac-based treatment) is a potentially viable new option to treat local recurrence after RT. Carefully selected patients with good IPSS-score, without obstruction, good PS and histologically proven localised local recurrence are potential candidates for SABR. Table 5 summarises the results of the two larger SABR series addressing oncological outcomes and morbidity. Table 5. Treatment-related toxicity and BCR-free survival in selected SABR studies including at least 50 patients Salvage high-intensity focused ultrasound Salvage HIFU has emerged as an alternative thermal ablation option for radiation-recurrent PCa. Being relatively newer than SCAP the data for salvage HIFU are even more limited. A systematic review and metaanalysis included 20 studies (n = 1,783) assessing salvage HIFU [20]. The overwhelming majority of patients (86%) received whole-gland salvage HIFU. The adjusted pooled analysis for 2-year BCR-free survival for salvage HIFU was 54.14% (95% CI: 47.77–60.38%) and for 5-year BCR-free survival 52.72% (95% CI: 42.66–62.56%). However, the certainty of the evidence was low. Table 6 summarises the results of a selection of the largest series on salvage HIFU to

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Prostate Cancer Hormonal therapy Comprehensive Review Article Part 6

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Prostate Cancer Hormonal therapy Comprehensive Review Article Part 6 Prof. Dr. Semir. A. Salim. Al Samarrai Hormonal therapy: Different types of hormonal therapy The hormonal therapy is the fourth modality of PCA treatment, there are different types of hormonal therapy. Androgen deprivation can be achieved by suppressing the secretion of testicular androgens in different ways. This can be combined with inhibiting the action of circulating androgens at the level of their receptor which has been known as complete (or maximal or total) androgen blockade (CAB) using the old-fashioned antiandrogens [1]. Testosterone-lowering therapy (castration): Castration level The testosterone-lowering therapy (castration) aims to decrease the testosterone level to castration level, which means the castration level of testosterone is < 50 ng/dL (1.7 nmol/L), which was defined more than 40 years ago when testosterone testing was less sensitive. Current methods have shown that the mean value after surgical castration is 15 ng/dL [2]. Therefore, a more appropriate level should be defined as < 20 ng/dL (1 nmol/L). Bilateral orchiectomy The castration modality with Bilateral orchiectomy or subcapsular pulpectomy is still considered the primary treatment modality for ADT. It is a simple, cheap and virtually complication-free surgical procedure. It is easily performed under local anaesthesia, and it is the quickest way to achieve a castration level which is usually reached within less than twelve hours. It is irreversible and therefore does not allow for intermittent treatment [3]. Oestrogens One of the hormonal therapy modality is the treatment with oestrogens results in testosterone suppression and is not associated with bone loss [4]. Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side effects, especially thromboembolic complications, even at lower doses these drugs are not considered as standard first-line treatment [5–7]. Luteinising-hormone-releasing hormone agonists Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH are delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly, basis. The first injection induces a transient rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’ or ‘flare-up’ phenomenon which starts two to three days after administration and lasts for about one week. This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status [8]. Luteinising-hormone-releasing hormone antagonists Luteinising-hormone-releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot formulation with, so far, only monthly formulations being available. Degarelix is a LHRH antagonist. The standard dosage is 240 mg in the first month followed by monthly injections of 80 mg. Most patients achieve a castrate level at day three [9]. Relugolix is an oral gonadotropin-releasing hormone antagonist. It was compared to the LHRH agonist leuprolid in a randomised phase III trial [10]. The primary endpoint was sustained testosterone suppression to castrate levels through 48 weeks. There was a significant difference of 7.9 percentage points (95% CI: 4.1–11.8) showing non-inferiority and superiority of relugolix. The incidence of major adverse cardiovascular events was significantly lower with relugolix (prespecified safety analysis). Relugolix has been approved by the FDA [11]. The anti-androgens The anti-androgens are oral compounds and classified according to their chemical structure as: • steroidal, e.g., cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate; • non-steroidal or pure, e.g., nilutamide, flutamide and bicalutamide. Both classes compete with androgens at the receptor level. This leads to an unchanged or slightly elevated testosterone level. Conversely, steroidal anti-androgens have progestational properties leading to central inhibition by crossing the blood-brain barrier. The steroidal anti-androgens These compounds are synthetic derivatives of hydroxyprogesterone. Their main pharmacological side effects are secondary to castration (gynaecomastia is quite rare) whilst the non-pharmacological side effects are cardiovascular toxicity (4–40% for CPA) and hepatotoxicity. Non-steroidal anti-androgens Non-steroidal anti-androgen monotherapy with e.g., nilutamide, flutamide or bicalutamide does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved [12]. Non-androgen-related pharmacological side effects differ between agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide [800]. The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy. The androgen pharmacological side effects are mainly gynaecomastia (70%) and breast pain (68%). However, non-steroidal anti-androgen monotherapy offers clear bone protection compared with LHRH analogues and probably LHRH antagonists [12,13]. All three agents share the potential for liver toxicity (occasionally fatal), requiring regular monitoring of patients’ liver enzymes. New androgen pathway targeting agents (ARTA) Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent mechanisms. In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells and an over-expression of the AR has been observed, suggesting an adaptive mechanism [14]. This has led to the development of several new compounds targeting the androgen axis. In mCRPC, AAP and enzalutamide have been approved. In addition to ADT (sustained castration), AAP, apalutamide and enzalutamide have been approved for the treatment of metastatic hormone sensitive Pca (mHSPC) by the FDA and the EMA. For the updated approval status see EMA and FDA websites [15–19]. Finally, apalutamide, darolutamide and enzalutamide have been approved for non-metastatic CRPC (nmCRPC) at high risk of further metastases [20–24]. Abiraterone acetate Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By blocking CYP17, abiraterone acetate significantly decreases the intracellular testosterone level by suppressing its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). This compound must be used together with prednisone/prednisolone to prevent drug-induced hyperaldosteronism [15,18]. Apalutamide, darolutamide, enzalutamide (alphabetical order) These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus and

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Prostate Cancer Treatment Deferred (active surveillance/watchful waiting), Surgical & Radiation Therapy Comprehensive Review Article Part 5

Prostate Cancer Treatment Deferred Part 5

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Prostate Cancer Treatment Deferred (active surveillance/watchful waiting), Surgical & Radiation Therapy Comprehensive Review Article Part 5 Prof. Dr. Semir. A. Salim. Al Samarrai Figure 1. Active Surveillance and Long-Term Outcomes in Early Stage Prostate Cancer Treatment modalities: The treatment modalities contain different criterias, after first modality in the deferred treatment (active surveillance/watchful waiting). Deferred treatment (active surveillance/watchful waiting) In localised disease a life expectancy of at least 10 years is considered mandatory for any benefit from active treatment. Data are available on patients who did not undergo local treatment with up to 25 years of follow-up, with endpoints of overall survival (OS) and cancer specific survival (CSS). Several series have shown a consistent CSS rate of 82–87% at 10 years [1–6], and 80–95% for T1/T2 and ISUP grade < 2 PCas [512]. In three studies with data beyond 15 years, the DSS was 80%, 79% and 58% [3,5,6], and two reported 20-year CSS rates of 57% and 32%, respectively [3,5]. The observed heterogeneity in outcomes is due to differences in inclusion criteria, with some older studies from the pre-PSA era showing worse outcomes [5]. In addition, many patients classified as ISUP grade 1 would now be classified as ISUP grade 2–3 based on the 2005 Gleason classification, suggesting that the above-mentioned results should be considered as minimal. Patients with well-, moderately- and poorly differentiated tumours had 10-year CSS rates of 91%, 90% and 74%, respectively, correlating with data from the pooled analysis [7]. Observation was most effective in men aged 65–75 years with low-risk PCa [8]. Co-morbidity is as important as age in predicting life expectancy in men with PCa. Increasing co-morbidity greatly increases the risk of dying from non-PCa-related causes and for those men with a short life expectancy. In an analysis of 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI score > 2 had died from competing causes at 10 years follow-up regardless of their age at time of diagnosis. Tumour aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at 10 years, especially for well or moderately-differentiated lesions [9]. This highlights the importance of assessing co-morbidity before considering a biopsy. In screen-detected localised PCa the lead-time bias is likely to be greater. Mortality from untreated screen-detected PCa in patients with ISUP grade 1–2 might be as low as 7% at 15 years follow-up [10]. Consequently, approximately 45% of men with PSA-detected PCa are suitable for close follow-up through a robust surveillance programme. There are two distinct strategies for conservative management that aim to reduce over-treatment: AS and WW (Table 1). Table 1. Definitions of active surveillance and watchful waiting Active surveillance Active surveillance aims to avoid unnecessary treatment in men with clinically localised PCa who do not require immediate treatment, but at the same time achieve the correct timing for curative treatment in those who eventually do [11]. Patients remain under close surveillance through structured surveillance programmes with regular follow-up consisting of PSA testing, clinical examination, MRI imaging and repeat prostate biopsies, with curative treatment being prompted by pre-defined thresholds indicative of potentially life-threatening disease, which is still potentially curable, while considering individual life expectancy. Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment from the outset, and patients are clinically ‘watched’ for the development of local or systemic progression with (imminent) disease-related complaints, at which stage they are then treated palliatively according to their symptoms in order to maintain QoL. Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised in a systematic review [12]. More recently, the largest prospective series of men with low-risk PCa managed by AS was published [13]. Table 2 summarises the results of selective AS cohorts. Table 2. Active surveillance in screening-detected prostate cancer (large cohorts with longer-term follow-up) It is clear that the long-term OS and CSS of patients on AS are extremely good. However, more than one-third of patients are ‘reclassified’ during follow-up, most of whom undergo curative treatment due to disease upgrading, increase in disease extent, disease stage, progression or patient preference. Watchful waiting The Outcome of watchful waiting compared with active treatment showed the SPCG-4 study which was a RCT from the pre-PSA era, randomising patients to either WW or RP (Table 3) [14]. Table 3. Outcome of SPCG-4 at a median follow-up of 23.6 years The study found radical prostatectomy (RP) to provide superior cancer-specific survival (CSS), overall survival (OS) and biochemical progression-free survival (PFS) compared to watchful waiting (WW) at a median follow-up of 23.6 years (range 3 weeks–28 years). The overall evidence indicates that for men with asymptomatic, clinically localised PCa and with a life expectancy of < 10 years based on co-morbidities and/or age, the oncological advantages of active treatment over WW are unlikely to be relevant to them. Consequently, WW should be adopted for such patients. Radical Prostatectomy The second treatment modality with radical prostatectomy showed that the goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic organ function [15]. The procedure involves removing the entire prostate with its capsule intact and SVs, followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and potential for preservation of erectile function [16]. The main results from multi-centre RCTs involving RP are summarised in Table 4. Table 4. Oncological results of radical prostatectomy in organ-confined disease in RCTs Pre-operative preparation: Pre-operative patient education As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative education has been shown to improve long-term patient satisfaction following RP [17]. Augmentation of standard verbal

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Prostate Cancer

أفضل مركز مسالك بولية دبي / myar nasser

Prostate Cancer Diagnostic Evaluation Comprehensive Review Article Part 3 Prof. Dr. Semir. A. Salim. Al Samarrai Figure 1. Schematic representation of traditional and proposed mpMRI-molecular-biomarker-directed prostate cancer diagnostic pathway. CaP, prostate cancer; PSA, prostate serum antigen; DRE, digital rectal examination; mpMRI, multiparametric magnetic resonance imaging. Text color of FDA/CLIA-approved molecular markers represents tissue of origin: yellow—urine derived; red—blood derived; brown—tissue derived. The diagnostic evaluations are a very important measures in the screening and early detection of prostate cancer in decreasing of cancer-specific mortality by developing early and precise treatment and strategy. Prostate cancer mortality trends range widely from country to country in the industrialised world [1]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries. The integration of MRI in the biopsy protocol may reduce the number of men that undergo biopsies while detecting more clinically significant and less clinically insignificant PCa [2,3]. Men at elevated risk of having PCa are those > 50 years [4] or at age > 45 years with a family history of PCa (either paternal or maternal) [5] or of African descent [6,7]. Men of African descent are more likely to be diagnosed with more advanced disease [8] and upgrade was more frequent after prostatectomy as compared to Caucasian men (49% vs. 26%) [9]. Germline mutations are associated with an increased risk of the development of aggressive PCa, i.e. BRCA2 [10,11]. Prostate-specific antigen screening in male BRCA1 and 2 carriers detected more significant cancers at a younger age compared to non-mutation carriers [12,13]. Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60 years are at decreased risk of PCa metastasis or death from PCa several decades later [14,15]. Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [16]. The use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to in experience, and can therefore not be recommended to exclude PCa [17]. Prostate-specific antigen measurement and DRE need to be repeated [18]. This could be every 2 years for those initially at risk, or postponed up to 8 years in those not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative family history [19]. Risk calculators, combining clinical data (age, DRE findings, PSA level, etc.) may be useful in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby reducing the number of unnecessary biopsies. Prostate MRI stratifies suspected PCa in lower- and higher risk, based on a 1- to 5- risk scale of having csPCa [PI-RADS v2.1 guidelines 2019]. A recent meta-analysis of this risk assessment tool showed (on a patient level) a significant cancer detection rate of 9% (5–13%) for PI-RADS 2 scores, 16% (7–27%) for PI-RADS 3 scores, 59% (39–78%) for PI-RADS 4 scores, and 85% (73–94%) for PI-RADS 5 scores [20]. Men with PI-RADS assessment scores of 3 to 5 are recommended to undergo biopsy [21]. Prostate MRI and related MRI-directed biopsies have shown to be at least as diagnostically effective as systematic biopsies alone in diagnosing significant cancers [22]. However, if the MRI-directed biopsy decision strategy (without performing systematic biopsies) can reduce the number of unnecessary biopsy procedures, this will be at the expense of missing a small percentage of csPCas [23]. PSA-density (PSA-D) is the strongest predictor in risk calculators. Combinations of PSA-D and MRI have been explored [24-29], showing guidance in biopsy-decisions whilst safely avoiding redundant biopsy testing. Increasing evidence supports the implementation of genetic counselling and germline testing in early detection and PCa management [30]. Several commercial screening panels are now available to assess main PCa risk genes [31]. However, it remains unclear when germline testing should be considered and how this may impact localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in approximately 0.2% to 0.3% of the general population [32]. It is important to understand the difference between somatic testing, which is performed on the tumour, and germline testing, which is performed on blood or saliva and identifies inherited mutations. Genetic counselling is required prior to and after undergoing germline testing. Germline mutations can drive the development of aggressive PCa. Therefore, the following men with a personal or family history of PCa or other cancer types arising from DNA repair gene mutations should be considered for germline testing: • Men with metastatic PCa; • Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years; • Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died from PCa cancer; • Men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family. Further research in this field (including not so well-known germline mutations) is needed to develop screening, early detection and treatment paradigms for mutation carriers and family members (table 1). Table 1. Germline mutations in DNA repair genes associated with increased risk of prostate cancer By the clinical diagnosis evaluation, prostate cancer is usually suspected on the basis of DRE and/or PSA levels. Definitive diagnosis depends on histopathological verification of adenocarcinoma in prostate biopsy cores. In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [50]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5–30% [51]. The use of PSA as a serum marker has revolutionised PCa diagnosis [52]. Prostate-specific antigen is organ but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. As an independent variable, PSA is a better predictor of cancer than either DRE or TRUS [53]. There are no agreed standards defined for measuring PSA [54]. It is a continuous parameter,

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Prostate Cancer PART 2

Blog, Readers' Blog, The Professor Artilces, Uncategorized, أحدث المقالات, أفضل مركز مسالك بولية دبي / myar nasser

Prostate Cancer Classification Comprehensive Review Article Part 2 Prof. Dr. Semir. A. Salim. Al Samarrai The objective of a tumour classification system is to combine patients with a similar clinical outcome. This allows for the design of clinical trials on relatively homogeneous patient populations, the comparison of clinical and pathological data obtained from different hospitals across the world, and the development of recommendations for the treatment of these patient populations. Throughout these Guidelines the 2017 Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 1) [1], Table 1. Clinical Tumour Node Metastatis (TNM) classification of PCa and the EAU risk group classification, which is essentially based on D’Amico’s classification system for PCa, are used (Table 2) [2]. Table 2. EAU risk groups for biochemical recurrence of localized and locally advanced prostate cancer The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Magnetic resonance imaging and targeted biopsy may cause a stage shift in risk classification systems [3]. Clinical T stage only refers to digital rectal examination (DRE) findings; local imaging findings are not considered in the TNM classification. Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical TNM, except for clinical stage T1 and the T2 substages. Pathological stages pT1a/b/c do not exist and histopathologically confirmed organ-confined PCas after RP arempathological stage pT2. The current Union for International Cancer Control (UICC) no longer recognises pT2 substages [1]. Of note: the EANM recently proposed a ‘miTNM’ (molecular imaging TNM) classification, taking into account prostate-specific membrane antigen positron emission tomography–computed tomography (PSMA PET/CT) findings [4]. The prognosis of the miT, miN and miM substages is likely to be better to their T, N and M counterparts due to the ‘Will Rogers phenomenon’; the extent of this prognosis shift remains to be assessed as well as its practical interest and impact [5]. In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour architecture were distinguished, but in the 2005 and subsequent 2014 International Society of Urological Pathology (ISUP) Gleason score (GS) modifications Gleason grades 1 and 2 were eliminated [6,7]. The 2005 ISUP modified GS of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common (secondary) pattern, if two are present. If one pattern is present, it needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent. The grade of intraductal carcinoma should also be incorporated in the GS [8]. In addition to reporting of the carcinoma features for each biopsy, an overall (or global) GS based on the carcinoma-positive biopsies can be provided. The global GS takes into account the extent of each grade from all prostate biopsies. The 2014 ISUP endorsed grading system limits the number of PCa grades, ranging them from 1 to 5 (see Table 2 and table 3) [8,9]. Table 3. International Society of Urological Pathology 2014 grade (group) system Further sub-stratification of the intermediate-risk group can be made and specifically the National Cancer Center Network (NCCN) Guidelines subdivide intermediate-risk disease into favourable intermediate-risk and unfavourable intermediate-risk, with unfavourable features including ISUP grade 3, and/or > 50% positive biopsy cores and/or at least two intermediate-risk factors [10]. The descriptor ‘clinically significant’ is widely used to differentiate PCa that may cause morbidity or death from types of PCa that do not. This distinction is particularly important as insignificant PCa that does not cause harm is so common [11]. Unless this distinction is made, such cancers are at high risk of being overtreated, with the treatment itself risking harmful side effects to patients. The over-treatment of insignificant PCas has been criticised as a major drawback of PSA testing [12]. However, defining what is clinically significant and what is insignificant PCa is difficult. In large studies of RP specimens which showed only ISUP grade 1 disease, extra prostatic extension (EPE) was extremely rare (0.28% of 2,502 cases) and seminal vesicle (SV) invasion or lymph node (LN) metastasis did not occur at all [13,14]. International Society for Urological Pathology grade 1 disease itself can therefore be considered clinically insignificant. Whilst ISUP grade 1 bears the hallmarks of cancer histologically, ISUP grade 1 itself does not behave in a clinically malignant fashion. However, ISUP grade 1 is first diagnosed at biopsy and guides management decisions, not after the prostate has been removed. The current standard practice of MRI-targeted and template biopsies has reduced diagnostic inaccuracy [15], however sampling error may still occur such that higher grade cancer could be missed. This should be especially considered if the prior MRI showed a suspicious lesion, but only ISUP grade 1 was found at biopsy. Another complexity in defining insignificant cancer is that ISUP grade 1 may progress to higher grades over time, becoming clinically significant at a later biopsy [16]. Therefore, although ISUP grade 1 itself can be described as clinically insignificant, it is important to take into account other factors, including imaging prior to biopsy and adequate sampling core number. When combined with low-risk clinical factors (see Table 2), ISUP grade 1 represents low-risk PCa, with its recommendation of preferred management being active surveillance (AS) or watchful waiting (WW). It should be noted, therefore, that defining ISUP grade 1 as insignificant cancer does not mean it should be ignored, but safely observed. Epidemiological and autopsy data also suggest that a proportion of ISUP grade 2 PCas would remain undetectable during a man’s life [17] and therefore may be overtreated. In current guidelines deferred treatment may be offered to select patients with intermediate-risk PCa [10], but evidence is lacking for appropriate selection criteria [18]. Recent papers have defined clinically significant cancer differently, commonly using ISUP grade 2 and above and even ISUP grade 3 and above, demonstrating the lack of consensus and evolution of its definition [19-22]. Some papers

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