The Professor Artilces

MALE INFERTILITY The Varicocele testis and the male accessory gland infections Comprehensive Review Article Part 2 Prof. Dr. Semir. A. Salim. Al Samarrai At present, the clinical management of varicocele is still mainly based on physical examination; nevertheless, scrotal colour Doppler US is useful in assessing venous reflux and diameter, when palpation is unreliable and/or in detecting recurrence/persistence after surgery [1]. Definitive evidence of reflux and venous diameter may be utilised in the decision to treat. Scrotal US is able to detect changes in the proximal part of the seminal tract due to obstruction. Especially for CBAVD patients, scrotal US is a favourable option to detect the abnormal appearance of the epididymis. Given that, three types of epididymal findings are described in CBAVD patients: tubular ectasia (honeycomb appearance), meshwork pattern, and complete or partial absence of the epididymis [2,3]. Transrectal US: For patients with a low seminal volume, acidic pH and severe oligozoospermia or azoospermia, in whom obstruction is suspected, scrotal and transrectal US are of clinical value in detecting CBAVD and presence or absence of the epididymis and/or seminal vesicles (SV) (e.g., abnormalities/agenesis). Likewise, transrectal US (TRUS) has an important role in assessing obstructive azoospermia (OA) secondary to CBAVD or anomalies related to the obstruction of the ejaculatory ducts, such as ejaculatory duct cysts, seminal vesicular dilatation or hypoplasia/atrophy, although retrograde ejaculation should be excluded as a differential diagnosis [1,4]. Special Conditions and Relevant Clinical Entities: Cryptorchidism Cryptorchidism is the most common congenital abnormality of the male genitalia; at 1 year of age nearly 1% of all full-term male infants have cryptorchidism [5]. Approximately 30% of undescended testes are nonpalpable and may be located within the abdominal cavity. These guidelines will only deal with management of cryptorchidism in adults. Classification The classification of cryptorchidism is based on the duration of the condition and the anatomical position of the testes. If the undescended testis has been identified from birth, then it is termed congenital while diagnosis of acquired cryptorchidism refers to men that have been previously noted to have testes situated within the scrotum. Cryptorchidism is categorised on whether it is bilateral or unilateral and the location of the testes (inguinal, intra-abdominal or ectopic). Aetiology and pathophysiology It has been postulated that cryptorchidism may be a part of the so-called testicular dysgenesis syndrome (TDS), which is a developmental disorder of the gonads caused by environmental and/or genetic influences early in pregnancy, including exposure to endocrine disrupting chemicals. Besides cryptorchidism, TDS includes hypospadias, reduced fertility, increased risk of malignancy, and Leydig/Sertoli cell dysfunction [6]. Cryptorchidism has also been linked with maternal gestational smoking [7] and premature birth [8]. Pathophysiological effects in maldescended testes: Degeneration of germ cells The degeneration of germ cells in maldescended testes is apparent even after the first year of life and varies, depending on the position of the testes [9]. During the second year, the number of germ cells declines. Early treatment is therefore recommended (surgery should be performed within the subsequent year) to conserve spermatogenesis and hormone production, as well as to decrease the risk for tumours [10]. Surgical treatment is the most effective. Meta-analyses on the use of medical treatment with GnRH and hCG have demonstrated poor success rates [11,12]. It has been reported that hCG treatment may be harmful to future spermatogenesis; therefore, the Nordic Consensus Statement on treatment of undescended testes does not recommend it use on a routine basis [13]. See also the EAU Guidelines on Paediatric Urology [14]. There is increasing evidence to suggest that in unilateral undescended testis, the contralateral normal descended testis may also have structural abnormalities, including smaller volume, softer consistency and reduced markers of future fertility potential (spermatogonia/tubule ratio and dark spermatogonia) [15,16]. This implies that unilateral cryptorchidism may affect the contralateral testis and patients and parents should be counselled appropriately. Relationship with fertility Semen parameters are often impaired in men with a history of cryptorchidism [17]. Early surgical treatment may have a positive effect on subsequent fertility [18]. In men with a history of unilateral cryptorchidism, paternity is almost equal (89.7%) to that in men without cryptorchidism (93.7%). In men with bilateral cryptorchidism, oligozoospermia can be found in 31% and azoospermia in 42%. In cases of bilateral cryptorchidism, the rate of paternity falls to 35-53% [19]. It is also important to screen for hypogonadism, as this is a potential long-term sequela of cryptorchidism and could contribute to impaired fertility and potential problems such as testosterone deficiency and MetS [20]. Germ cell tumours As a component of TDS, cryptorchidism is a risk factor for testicular cancer and is associated with testicular microcalcifications and intratubular germ cell neoplasia in situ (GCNIS), formerly known as carcinoma in situ (CIS) of the testes. In 5-10% of testicular cancers, there is a history of cryptorchidism [21]. The risk of a germ cell tumour is 3.6-7.4 times higher than in the general population and 2-6% of men with a history of cryptorchidism will develop a testicular tumour [5]. Orchidopexy performed before the onset of puberty has been reported to decrease the risk of testicular cancer [22]. However, there is evidence to suggest that even men who undergo early orchidopexy still harbour a higher risk of testicular cancer than men without cryptorchidism [23]. Therefore, all men with a history of cryptorchidism should be warned that they are at increased risk of developing testicular cancer and should perform regular testicular self-examination [24]. There is also observational study data suggesting that cryptorchidism may be a risk factor for worsening clinical stage of seminoma but this needs to be substantiated with future prospective studies [25]. Disease management: Hormonal treatment Human chorionic gonadotropin or GnRH is not recommended for the treatment of cryptorchidism in adulthood. Although some studies have recommended the use of hormonal stimulation as an adjunct to orchidopexy to improve fertility preservation, there is a lack of long-term data and concerns regarding impairment to spermatogenesis with the use of these drugs [26]. Surgical treatment In adolescence, removal of an intra-abdominal testis (with a normal

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

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