ological variability. Not always easy to calculate, PSADT can be obtained online at: M www .pcngcincinnati.org/psa/index.htm. PROSTATE CANCER \200\224PSA DERIVATIVES AND KINETICS 321 PSADT is used to drive clinical management following treatment of PC. Reports from Johns Ho pkins con \201 rm that PSADT correlates with cancer- speci \201 c survival (CSS) followin g RP: 379 patients experiencing BCR where followed up for a median of 10y. Signi \201 cant risk factors included PSADT (cid:100)3 months, GS >7, and time to BCR (cid:100)3y. For exa mple, patients with a PSADT <3 months had a median survival of 6y; this reduced to only 3y if their GS was >7. Conversely, patients with none of these risk factors had a 100% CSS.2 W hen 21% of these patients had died of PC and 6% had died other causes, it was appreciated t hat only 15% of the PC deaths were associated with PSADT (cid:100)3 month while the majorit y (60%) of deaths were associated with PSADT of 3 \200\2239 months. PSADT >15 months had gr eater risk of death from competing causes.3 Other examples of PSADT in clinical practice in clude: <5y raises suspicion of the presence of PC; <3y often drives recommendation to treat a patient on active surveillance; (cid:100)6 months should drive recommendation of hormone therapy following radical treatment. 1 Carter HB, Pearson JD, Metter EF, et al. (1992) Longitudinal evaluation of prostate-speci \201 c antigen levels in men with and without prostate disease. JAMA 267:2215 \200\22320. 2 Freedland S, Humphreys EB, Mangold LA, et al. (2005) Risk of prostate cancer-speci \201 c mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433 \200 \2239. 3 Freedland S, Humphreys EB, Mangold LA, et al. (2007) Death in patients with recurrent pro s- tate cancer after radical prostatectomy: prostate-speci \201 c antigen doubling time su bgroups and their associated contributions to all-cause mortality. J Clin Oncol 25:1765 \200\22371. CHAPTER 7 Urological neoplasia 322 Prostate cancer: counseling before PSA testing Counseling is mandatory before offering a PS A and DRE to asymptomatic men, particularly to highlight the potential disadvantages of hav ing an ab- normal result. These must be weighed up against the potential bene \201 t of ha ving clinically signi \201 cant PC diagnosed at an earlier stage than it would have been w ithout these evaluations. There is currently no clear evidence of bene \201 t by screening for PC (see b p. 316). This forms the basis of the UK Department of Health NHS Prostate Ca ncer Risk Management Program (2002), whereby only men requesting the investigations and who have been appropriately counseled should be tested. Such counsel- ling is less fundamental when investigating a symptomatic patient because the diagnosis of PC could alter his clini cal management. However, all pa- tients should be informed when PSA testing is being consid ered. The following points should be used in counseling asymptomatic men: Cancer will be identi \201 ed in <5% of men screened. The bene \201 ts of PC screening remain controversial. Sen sitivity is 80%: a false-negative result is possible; there is no level of detectable PSA a t which PC can be excluded. Speci \201 city is 40 \200\22350%: a fals-positive result is p ossible; age-related benign hyperplasia and UTI are the most common causes. Prostatic biops y is uncomfortable (despite local anesthetic) and carries a risk of septicaemia or signi \201 cant bleeding, each 0.5%. Prostatic biopsy may miss a cancer. Repeat biopsy may be rec ommended (presence of persisting clinical suspicion or rising PSA). Treatment may not be ne cessary. Treatment may not be curative. Treatment-related morbidity could lead to a diminis hed quality of life. - PIN, ASAP, - This page intentionally left blank CHAPTER 7 Urological neoplasia 324 Prostate cancer: other diagnostic markers Given the limitations of PSA discussed on b pp. 3 18 \200\223321, there is con- siderable ongoing effort to identify better diagnostic marker s in both se- rum and \201 rst-voided urine following a DRE. These are mostly the RNA or protein products of genes commonly over- or underexpressed in PC tissue. Prostate cancer antigen 3 (PCA3) The \201 rst of these, already commercially available, i s the PCA3 test. This gene is overexpressed in 95% of PC, though its function is unclear. R NA transcripts are ampli \201 ed and detected from urine sediment. Speci \201 city for PC diagnosis is improved compared with serum PSA alone (around 70%) in men who have already u ndergone one negative biopsy, though sensitivity of 50 \200\22360% (i.e. at least 40% false -negative results) remains an issue when advising patients whether or not to undergo repeat biopsy re- gardless of PSA changes. Studies exploring potential improved sensitivity by co mbining detection of PCA3 with other molecular markers, e.g. the TMPRSS2-ERG fusion transcr ipt (see b p. 302) are ongoing. Engrailed 2 (EN2) protein EN2 is a transcription factor expressed in PC cell lines and secr eted into the urine by PC in men. First pass urine DRE is collected and EN2 pro- tein measu red by ELISA. A study of 82 men with PC and 102 controls demonstrated the presence of EN2 i n urine was highly predictive of PC, sensitivity of 66% and speci \201 city 88.2%. There w as no correlation with PSA levels. A large multicenter study to further evaluate the diagno stic potential of EN2 is justi \201 ed.1 Microseminoprotein-beta (MSMB) MSMB regulates apoptosis; using genome-wide association stud ies, the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing PC. MSMB expres- sion in benign and malignant prostate tiss ue was examined using immu- nohistochemistry. Urinary MSMB concentrations were determined b y ELISA and correlated with urinary PSA, the presence or absence of PC, rs10993994 genotype , and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with PC. Urinary MSMB was better than urinary PSA at differentiating men with PC at all Gleason grad es.2 Further studies are ongoing. A-methylacyl CoA racemase (AMACR) immunohistochemical overex- pression is 97% sensitive and 100% speci \201 c for PC diagnosis in needle biopsies. It is used routinely by histopatho logists. Efforts are ongoing to develop AMACR assay for testing on body \202 uids. Promotor hypermethylation of reducing enzyme glutathione-S-trans- ferase P1 (GSTP1) is the commonest epigenetic abnormality in PC, inac- tivating its transcription in 90% PCs and 70% of PIN lesions. Methylated GSTP1 DNA is detectable in both urine and serum. PROSTATE CANCER: OTHER DIAGNOSTIC MARKERS 325 Finally, human kallikrein 2 (hK2) is a member of the same protease fam- ily as PSA (which i s also known as hK3), bearing 78% sequence homology. hK2 is expressed almost exclusively by prostatic epithelium, in lesser quan- tity than PSA. It is relatively overexpressed in PIN and higher Gleason score cancers. The ratio of hK2:PSA mRNA in urinary sediments may help to distinguish aggressive or advanced cancers. 1 Morgan R, Boxall A, Bhatt A, et al. (2011) Engrailed-2 (EN2): a tumor speci \201 c urina ry biomarker for the early diagnosis of prostate cancer. Clin Cancer Res 17:1090 \200\2238. 2 Whittaker H. et al. (2010) The rs10993994 Risk Allele for Prostate Cancer Results in Clin ically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine. M http:/ /www. plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013363 M www.plosone.org/art icle/info% 3Adoi%2F10.1371%2Fjournal.pone.0013363. CHAPTER 7 Urological neoplasia 326 Prostate cancer: transrectal ultrasonography and biopsy The most common diagnostic modality for PC is transrectal ultrasonogra- phy (TRUS) with guided biopsies (Fig. 7.7). TRUS provi des imaging of the prostate and seminal vesicles using a 7.5mHz biplane rectal probe meas- uring approximately 1.5cm in diameter. The peripheral/transition zones, cysts, and calci \201 cations within the prostate can be seen. Hypoechoic and hyperechoic lesions in the per ipheral zone may be due to PC or in \202 amma- tory conditions, although most PCs are isoe choic and are not identi \201 ed. Seminal vesicles may be compared for asymmetry. Patients usually \201 nd the biopsy procedure uncomfortable, some painful. It takes about 5min and is undertaken on an outpatient basis with local anesthetic. Ultrasound-guided per iprostatic injection of 1 \200\2232% lignocaine is the gold standard; perianal GTN paste or inhalation of nitrous oxide/air (Entonox) are less effective alternatives. A DRE precedes insertion of the probe. Antiseptic rectal wall cleansing using aqueous iodine on a sponge s tick may reduce risk of sepsis if transrectal biopsies are planned. Broad-spectrum antimicr obial prophylaxis (usually oral quinolone 9 metronidazole) are given at least 30min prior a nd typically for 48h after the procedure. It is not safe to biopsy a warfarinized patient; the INR should be <1.5. However, biopsying patients on low-dose aspirin is not considered u nsafe. Other antiplatelet drugs (e.g. clopidogrel) are usually stopped for 10 days prior. Indications for TRUS alone - 3) = anteroposterior distance (cm) x Estimation of prostate volume (cm width (cm) x sagittal length (cm) x 0.52. Male infertilit y with azoospermia to look for seminal vesicle and ejaculatory duct obstruction due to calc ulus or M llerian cyst. Suspected prostatic abscess. Investigation of chronic pelvic pain, looking for prostatic cyst, abscess, or calculi. Indications for TRUS with biopsies The 2008 UK NICE guidelines stress the importance of dis cussing the risks and bene \201 ts of biopsy, individual risk factors, the use of nomogram s to predict results (see b pp. 310 \200\223314), and allowing time for decision- making be fore proceeding. - - - - - - An abnormal Previous biopsies showing multifocal Previous biopsies normal, but Previous bio psies showing low-risk localized As part of active surveillance protocol for low-risk local ized To con \201 rm viable being considered. DRE and/or an elevated PSA*. PIN or ASAP. PSA rising or DRE abnormal. PC**. PC. PC following treatment if a salvage treatment is Biopsy protocol Systematic 18g trucut needle biopsies are taken, including any palpable or sonographic target lesion. The traditional sextant protocol (a parasagittal base, midgland, and apex from each side) has been superseded by 8, 10, or TRANSRECTAL ULTRASONOGRAPHY AND BIOPSY 327 12 biopsies, adding samples from the far lateral peripheral zones (Fig. 7.8). Studies have demonstrated these extra biopsies detect up to 15% more cancers. Relating the number of bio psies to the prostatic volume seems logical; attempts have been made to optimize this conce pt, e.g. the Vienna nomogram (Table 7.18).1 Table 7.17 The Vienna nomogram: optimal number of cores on TRUS-guided prostate biopsy Prostate volume on TRUS (mL) Patient age (y) 60 \200\22370 <50 50 \200\22360 >70 20 \200\22329 8 8 8 6 30 \200\22339 12 10 8 6 40 \200\22349 14 12 10 8 50 \200\22359 16 14 12 10 60 \200\22369 \200\223 16 14 12 (cid:116)70 \200\223 18 16 14 Pubic symphysis Urethra Bladder Prostate gland Biopsy needle Spring-loaded biopsy needle \200\230gun \200\231 Peritoneum Seminal vesicles Ultrasound probe Rectum Fig. 7.7 Transrectal ultrasound scanning (TRUS). An ultrasound probe is inserted into the r ectum to guide the biopsy needle into the correct position so that several core biopsies ca n be taken from different areas of the prostate. Prostate cancer may also be diagnosed clinically (without histology) or by TURP histology. For example, it may be unnecessary to biopsy a frail elderly men with a craggy hard prostat e and PSA >100ng/mL prior to commencing palliative hormone therapy or those in whom a TURP is indicated for BOO with severe LUTS/retention. Some centers are performing \200\230mapping \200\231 transperineal template biopsies und er GA for patients considering active surveillance or focal therapy to exclude the presence of signi \201 cant anteriorly placed cancers. NICE guidance (2010) did not \201 nd evid ence to support these indications. CHAPTER 7 Urological neoplasia 328 Seminal vesicles (a) Base Posterior surface of prostate Traditional sextant Apex (b) 8-core (c) 12-core Fig. 7.8 Biopsy protocols. TRANSRECTAL ULTRASONOGRAPHY AND BIOPSY 329 Additional biopsies of each transition zone may be taken when a patient is undergoing repea t biopsies due to a rising PSA. If repeat biopsies fail to diagnose cancer in the setting o f a persistently rising PSA, saturation needle biopsies (between 20 and 40) may be taken tr ansrectally or trans- perineally using a template under general anesthesia. This enables th e anterior gland and apices to be properly sampled. Alternatively, some advocate resorting to transurethral resection biopsies, especially if the patient has a degree of BOO. Seminal vesicle biopsies occasionally add staging information and may in \202 uence treatment opt ions if they are posi- tive. A basal nodule or PSA >15ng/mL increases the likelihood of sem inal vesicle (SV) invasion. In future, TRUS and systematic biopsy may be replaced by multipara- metric MRI-guided biops y. T2-weighted MRI, supplemented by diffusion weighting and/or T1-dynamic contrast enhancem ent (gadolinium), is cur- rently undergoing validation studies following reports that it ca n detect cancers >0.5cm3 with 90% sensitivity and 88% speci \201 city.2 Complications of prostatic biopsy - - Occasional vasovagal \200\230fainting \200\231 immediately after the procedure. 0.5% risk of septicaemia or prostatic abscess which may be life- threatening (TRUS and biopsy). 0.5% risk of signi \201 cant rectal bleeding ( by DRE using a swab soaked in 1:10000 adrenaline or rectal balloon catheter. 2 \200\22311% acute or clot urinary retention (after saturatio n/transperineal biopsy). Likely mild haemospermia (for up to 3 weeks) and haematuria; 0.1% risk of clot urinary retention (TRUS). TRUS and biopsy); treated It is important that the patient understands that negative biopsies do not rule out PC and occasionally, repeat biopsies may be recommended (e.g. ASAP). 1 Remzi M, Fong YK, Dobrovits M, et al. (2005) The Vienna nomogram: validation of a novel b iopsy strategy de \201 ning the optimal number of cores based on patient age and total pro state volume. J Urol 174:1256 \200\22360. 2 Villers A, Puech P, Mouton D, et al. (2006) Dynamic contrast enhanced, pelvic phased arra y magnetic resonance imaging of localized prostate cancer for predicting tumor volume: corr elation with radical prostatectomy \201 ndings. J Urol 176:2432 \200\2237. CHAPTER 7 Urological neoplasia 330 Prostate cancer: suspicious lesions Two histological lesions are currently regarded as eith er pre- or peri- malignant. They are prostatic intraepithelial neoplasia and atypical small acinar proliferation. Prostatic intraepithelial neoplasia (PIN) PIN consists of architecturally benign prostatic acini and ducts lined by cytologically atypical cells. The basal cell layer is present, alt hough the basement membrane may be fragmented. PIN was formerly known as ductal dysplasia o r reported by pathologists as \200\230suspicious for cancer \200\231. PIN was classi \201 ed into low-grade (mild) and high-grade (moderate to severe) forms, based on the presence of prominent nucleoli. Subsequently pa- thologists have agreed to report only high-grade PI N since low-grade PIN reporting is very subjective and has no prognostic value. On the othe r hand, high-grade PIN is believed to be a precursor for intermediate or high-grade PC. PIN is reported in 5 \200\22310% of prostate needle biopsies. It does not appear to affect the serum PSA value. The site of the PIN is not indicative of the site of subsequently diagnos ed cancer nor is PIN always present in a prostate-containing cancer. When found in sextant prostate biopsies carries a 30 \200\22340% prediction of PC at subsequent biopsy. However, with the widespread use of more extensive biopsy protocols, the signi \201 cance of isolat ed PIN has become less clear, with some studies reporting a positive repeat biopsy rate tha t is equal or lower than the original cancer detection risk. Atypical small acinar proliferation (ASAP) This histopathological lesion reported by pathol ogists on needle biopsies as \200\230suspicious for cancer \200\231 must be taken seriousl y. The focus containing small acini is typically small, averaging 0.4mm in diameter. Acini are lined with cytologically abnormal epithelial cells and may exhibit atrophic fea- tures. The columnar cells have prominent nuclei containing nucleoli, while the basal layer is foc ally absent, according to high molecular weight cytok- eratin immunostaining. PIN may be pr esent in the same sample. Studies have shown ASAP in needle biopsies predict cancer at subs equent biopsy in over 40% of cases. Currently it is recommended that repeat systematic biopsies should be performed if any isol ated ASAP or multifocal PIN is reported on needle biopsy or TURP specimens. Most favor furt her PSA surveillance without repeat biopsy if a single focus of PIN is reported. The timing of repeat biopsy varies, although concern regarding antibiotic-resistant bowel \202 ora following the \201 rst biopsy has led to some authorities recommending a gap of 6 \200 \22312 weeks between procedures. PC: GENERAL CONSIDERATIONS BEFORE TREATMENT 331 Prostate cancer: general considerations before treatment (modi \201 ed from the 2008 UK NI CE Guidance) Once a diagnosis of PC has been made, it is essential to discuss the im- plica tions and management options with the patient and any relative or friend he wishes to invol ve. Treatment may or may not be appropriate; it may be given with curative or palliative intent. If treatment is not recommended, explain the advantage and disadvan- tages to help the patient understand why he is not being treated. Before starting treatment, inform the patient that it may result in: Altered physical appea rance. Altered sexual experience. Loss of sexual function, ejaculation, and fertility. Chan ges in urinary or bowel function. Other common side effects or complications. - - - Offer the patient: - Support in decision-making, access to written material, and specialist nurse services. Ongo ing access to erectile dysfunction services, if necessary. Ongoing access to specialist psy chosexual services, if necessary. A urological assessment if Sperm storage (if appropriate) . - - LUTS are present. Assess the risk category1 applicable to men with clinically-localized pros- tate cancer (Ta ble 7.19). Table 7.19 Assessing the risk category applicable to men with clinically localized prostate cancer*1 Risk PSA (ng/ mL) Gleason score Clinical stage by DRE Low <10 and (cid:100)6 and T1 \200\223T2a Intermediate 10 \200\22320 or 7 or T2b \200\223T2c High >20 or 8 \200\22310 or T3 \200\2234 \200\230Risk \200\231 relates to the chance of failure of local treatment: low <25%; inter mediate = 25 \200\22350%; high >50%. 1 D \200\231Amico AV, Whittington R, Malkowicz SB, et al. (1998) Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy f or clinically local- ized prostate cancer. JAMA 280:969 \200\22374. CHAPTER 7 Urological neoplasia 332 Prostate cancer: watchful waiting and active surveillance It can be understood from inciden ce, mortality, and survival data that the oft quoted statement \200\230more men die with p rostate cancer than because of it \200\231 is correct. This is because most PCs are slow-gr owing and the majority of men diagnosed are >70y, often with competing morbidities. This fo rms the basis for watchful waiting (WW) by deferring hormone therapy un- til the developmen t of metastatic disease for some men diagnosed with non-metastatic PC. The risks of developing metastatic disease and of death due to PC after 10 \200\22315y of W W can be considered using published data, according to biopsy grade. Table 7.20 summarizes these data. For survival and cumula- tive mortality from PC and other causes up to 20y afte r diagnosis, strati- \201 ed by age at diagnosis and Gleason. Table 7.20 Natural history of localized prostate cancer managed with no initial treatment Biopsy grade % risk of metastasis (10y) % risk of prostate cancer death (15y) Estimated lost years of life 2 \200\2234 19 4 \200\2237 <1y 5 42 6 \200\22311 4 6 42 18 \200\22330 4 7 42 42 \200\22370 5 8 \200\22310 74 56 \200\22387 6 \200\2238 Selection of patients for watchful waiting WW is the best option for patients with localize d PC and: - - Gleason score 2 \200\2234 disease at any age. Gleason score 5 and 6 disease in elderly or u n \201 t men, with life expectancy considered to be <10y, for whom radical curative treatm ent would not be contemplated. Stage T1a disease with normal progress compared to 68% with T1b). PSA (only 17% T1a patients will Watchful waiting protocols Most men with localized PC on WW are seen every 6 months for cli nical history, examination, including a DRE and a serum PSA test (before or after DRE). If the disease progresses during follow-up, palliative treat- ment (for example, androgen abla tion therapy) is recommended. The threshold for treatment was traditionally when symptoms a nd signs of ad- vanced disease appeared, for example, back pain and metastases on bone scan . However, the use of PSA kinetics (e.g. doubling time <12 months), the evidence of bene \201 t with earlier use of hormone therapy, and involve- PC: WATCHFUL WAITING AND ACTIVE SURVEILLANCE 333 ment of patient choice have driven earlier thresholds for treatment. Hence, an asymptomatic patient with a rising PSA may choose whether to treat his disease and accept the side effe cts or whether to maintain his current quality of life while leaving the disease untreated. Active surveillance (AS) With increasing numbers of low-risk cancers being diagnosed, there is concern that we are overtreating clinically insigni \201 cant disease, leading to unne cessary loss of quality of life for patients and consumption of health care resources. This issue will be ampli \201 ed by possible future introduction of PSA screening. AS has a di fferent goal from WW, which is to identify and treat localized cancers that are demonstrabl y progressing with cura- tive intent whilst avoiding overtreatment for the majority. The 2008 UK NICE Guidelines recommend AS as the \200\230preferred \200\231 option for men with low-risk (stage T1c \200\223T2a and Gleason score (cid:100)6 and PSA <10ng/mL) disease who might be considered for curative treatment. These men undergo more intensive evaluatio ns than WW: PSA testing every 3 months (for velocity or doubling time calculation), DRE 6-m onthly, and 2-yearly repeat biopsy to assess for upgrading. PSA velocity >1ng/ mL/y and dou bling times <3y are currently considered evidence of pro- gression, which prompts the recom mendation of curative treatment. The largest published series of AS comes from Toronto. Of 450 patients, median age 70y with median follow-up 6.8y, 60% remained alive and on AS long-term. About one-third of patients were treated for progression, of whom 50% subsequently relapsed. The majority of deaths we re due to non-PC causes.2 Other studies are ongoing in the UK and Europe. The risk with AS, suggested by the Toronto series, is that the disease may progress beyond the possibility of cure or that the disease is initially understaged. This has prompted som e centers to perform template map- ping biopsies prior to enrolling patients for AS. Random ized trials of AS vs immediate treatment are needed to identify subgroups of patients with localized PC who could most bene \201 t from AS, rather than undergoing immediate treatmen t. 1 Albertsen PC, Hanley JA, Fine J (2005) 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095 \200\223101. 2 Klotz L, Zhang L, Lam A, et al. (2010) Clinical results of long-term follow-up of a large , active surveillance cohort with localized prostate cancer. J Clin Oncol 28:126 \200\22331 . CHAPTER 7 Urological neoplasia 334 Prostate cancer: radical prostatectomy and pelvic lymphadenectomy Radical (total) prostatec tomy (RP) is excision of the entire prostate, in- cluding the prostatic urethra, with the s eminal vesicles. In 1867, Vienna \200\231s Billroth performed the \201 rst perineal prost atectomy for PC, later propa- gated by Young (Johns Hopkins) in 1904. The retropubic approa ch was \201 rst undertaken by Millin (London) in 1945, though re \201 nements in the 198 0 \200\231s led by Patrick Walsh gained its acceptance as the gold standard curative treatm ent for localized PC. Following excision of the prostate, reconstruction of the bladder nec k and vesicourethral anastomosis com- pletes the procedure. RP may be performed by open retropubic, open perineal, manual laparoscopic, or robot-assist ed laparoscopic approaches. The perineal approach does not allow a simultanous pelvic lymph node dissection. RP is indicated for the treatment (with curative intent) of \201 t men with localized PC whose life expectancy exceeds 10y. Patients with Gleason score 2 \200\2234 disease appear t o do as well in the long term with surveillance as with treatment. The 2008 UK NICE Guideli nes recommend RP for high-risk disease (PSA (cid:116)20 or Gleason score (cid:116)8 or cT3) only if there is a \200\230realistic prospect of long-term disease control \200\231, and for low-risk dis- ease (PSA <10 and Gleason score (cid:100)6 and cT1 \200\2232) if active s urveillance is offered and declined. The surgeon should take part in multidisciplinary team discussion of each case. The patient should consider all available treatment options and t he complications of RP before proceeding. Steps in open RP - The patient is under anesthetic, catheterized, and positioned supine with the middle of the table \200\230broken \200\231 to open up the entry to the pelvis. Through an 8cm lower mi dline incision, staying extraperitoneal, the retropubic space is opened. Bilateral obturato r lymphadenectomy is undertaken if the PSA >10 or the Gleason score is 7 or higher; extende d lymphadenectomy should be carried out in high-risk patients; frozen section histology is rarely requested. Incisions in the endopelvic fascia on either side allow access to the pro static apex and membranous urethra. Division and haemostatic control of the dorsal vein com plex passing under the pubic arch allows access to the membranous urethra which is divided at the prostatic apex. The prostate is mobilized retrogradely from apex to base, taking Den onvilliers fascia on its posterior surface. If nerve sparing is undertaken, the apical and posterior dissection is modi \201 ed, as described below. Denonvilliers fascia is incised at the prostatic base, allowing access to the vasa (divided) and seminal vesicles (excised) . The bladder neck is divided, thereby freeing the prostate; the ureteric ori \201 ces are identi \201 ed. PC: RADICAL PROSTATECTOMY AND PELVIC LYMPHADENECTOMY 335 The bladder neck is reconstructed to the approximate diameter of the membranous urethra. A vesicourethral anastomosis with six interrupted sutures is stented by a 16 Ch urethral cath eter, typically for 10 \200\22314 days. The wound is closed leaving a pelvic drain, typical ly for 24h. The \200\230interfascial \200\231 nerve-sparing modi \201 cation aims to reduce the risk of post-operative erectile dysfunction, minimizing cavernosal nerve injury as they pass fro m the autonomic pelvic plexus on either side in the groove between prostate and rectum duri ng mobilization of the prostate. The outer layer of prostatic fascia is incised to allow th ese nerves to fall away from the prostatic fascia and capsule. This should not be attempted in the presence of palpable disease as it may compromise cancer control. Non- nerve sparin g is, therefore, \200\230extrafascial \200\231 (Fig. 7.9). The tips of the seminal vesicle s may also be spared in cases with low risk of cancer involvement, potentially reducing ble eding and cavernosal nerve injury. Levatar ani fascia Prostatic fascia/ pseudo capsule Prostate Anterior extension of denonviller \200\231s fascia urethra Denonvillier \200\231s 2-layer fascia Neuro-vascular bundle Rectum Fig. 7.9 Axial view of prostate fascial anatomy. The interfascial plane of dissection is sh own on the left, while the extrafascial plane is shown on the right. Laparoscopic radical prostatectomy (LRP): was pioneered in the late 1990 \200\231s in a num ber of European centers. It is carried out transperitoneally or extraperitoneally, the latt er having much in common with the open ret- ropubic technique. Via \201 ve ports, with a 20 \200\22325 head-down tilt, extrap- eritoneal LRP is carried out in 12 steps shown belo w, with varying levels of dif \201 culty (I \200\223V).1 1. Trocar placement and dissectio n of the preperitoneal space: I. 2. Pelvic lymphadenectomy: II. 3. Incision of the endopelv ic fascia and dissection of the puboprostatic ligaments: I. 4. Santorini plexus ligation: III. 5. Anterior and lateral bladder neck dissection: II and dorsal bladder neck dissection: III. 6. Dissection and division of vasa deferentia: III. 7. Dissection of the seminal vesicles: III. 8. Incision of the posterior Denonvillier \200\231s fascia \200\224mobilization of the dorsal surface of the prostate from the rectum: III. 9. Dissection of the prostatic pedicles: III. 10. Nerve-sparing procedure: V. CHAPTER 7 Urological neoplasia 336 11. Apical dissection, urethral division: IV. 12. Urethrovesical anastomosis; dorsal circumference (4, 5, 6, 7, 8 o \200\231clock stitches): IV. 3 and 9 o \200\231clock stitches: II. Bladder neck closure and 11 and 1 o \200\231clock stitches: III. The improved view has allowed a more precise \200\230intrafascial \200\231 nerve-sparing m odi \201 cation during mobilization of the gland, with dissection between the prostatic ca psule and the inner layer of covering fascia (Fig. 7.9). In highly experienced hands, LRP o perating times are comparable to those of open RP. Robot-assisted RP: has gained popularity in the USA (where >80% RPs are now done this way) and increasingly in Europe since its introduction in 2000. As with laparoscopic/endoscopic prostatectomy, it is minimally invasive with advantages of reduced bleeding, pain, and reco very time. Beyond this, the bene \201 ts remain uncertain in the absence of randomized tri als. The training \200\230learning curve \200\231 is thought to be steeper than that of ma nual laparoscopy because of the intuitive \200\230wristed \200\231 instrumentation of the da Vinci surgical system. The patient is positioned in a steep reverse Trendelenberg so g reat care must be taken to avoid lower limb circulatory complications, e.g. compartment syn drome. It is carried out via six trans- peritoneal ports (one camera, three robot arms, two assistants). Steps fol- lowed are similar to those of LRP, except the vesicourethral anast omosis is completed with a double-ended continuous suture rather than inter- rupted sutures . The surgeon sits at a remote console, while the assistant stands with the robot \200\230 cart \200\231 at the patient side. The major disadvantage to robot-assisted RP is cost, cur rently approximately 1M plus 100K annual maintenance. Operating times also tend to be l onger than open RP. Bilateral pelvic lymphadenectomy (BPLND) There is no longer a place for frozen section anal ysis of lymph nodes, with a view to aborting RP if they are positive; aside from the techni cal issues concerning the pathological evaluation of frozen sections, at least two studies have demonstrated improved CSS in patients with lymph node in- vasion (LNI) who still under went RP compared to those who did not. The EAU 2012 Guidelines recommend no BPLND for low-r isk cases (because the risk of LNI <5%). High-risk localized disease and cT3 are associated with 15 \200\22340% and 45% risk of LNI, respectively. Limited (obturator fossae) BPLND in adequate for intermediate and high-risk cases, missing up to 60% of LNI compared with exten ded BPLND, which includes removal of internal and external iliac nodes. Extended BPLND should yield >20 nodes. It, therefore, gives more accurate pN staging and gu ides further management options. However, it increases operative time and complications (ly mphoedema, DVT, PE). Therapeutic bene \201 t is controversial; no randomized trial exists, demon- strating improved outcome following extended BPLND; number of nodes (regardless of status) removed is reported to correlate with BRFS and CSS; the greater number of positive nodes removed correlates with CSS in one report. PC: RADICAL PROSTATECTOMY AND PELVIC LYMPHADENECTOMY 337 1 Stolzenberg JU, Schwaibold H, Bhanot SM, et al. (2005) Modular surgical training for endo scopic extraperitoneal radical prostatectomy. BJU Int 96:1022 \200\2237. CHAPTER 7 Urological neoplasia 338 Prostate cancer \200\224radical prostatectomy: post-operative care and complications Post-o perative routine course after RP - Day 1: mobilize, check FBC, CandE; free \202 uids. - D ay 2: diet, drains removed, catheter care, encourage bowels. - Day 3: home. Some surgeons discharge their patients on day 2, even if bowels have not moved. Catheter time varies between 7 and 21 days; cystography is carried out if early removal (<7 days) is planned or if there has been a urine leak or persistent haematuria. Complications of RP General complications - Those of any major surgery (all rare 1 \200\2232%): bleeding requiring reoperation and/or t ransfusion (especially after open RP), infection, VTE, and lower limb compartment syndrome (possible after RARP). Risks are minimized by attention to haemostasis, prophylactic antimi crobials, careful positioning, and early mobilization. VTE prophylaxis consists of TED stoc kings, pneumatic calf compression, and SC LMWH (unfractionated heparin for patients with re nal impairment); NICE (2010) recommends continuing heparin for 28 post-operative days. Ches t infection may be prevented by physiotherapy and encouragement of deep breathing, especial ly in smokers. Post-operative death is estimated to occur <1 in 500 cases. Speci \201 c complications (early) - Perioperative ureteric or rectal injury (both rare, <0.5%): these should be managed immedia tely, if recognized; ureteric re-implantation, primary rectal closure with or without a loo p colostomy. Post-operative catheter displacement (rare): managed with careful replacement if within 48h; if >48h, urethrography may reveal no anastomotic leak. Post-operative urine or lymphatic leak (distinguished by dipstick glycosuria or creatinine concentration) throug h drains (occasional, 5%); managed by prolonged catheter and wound drainage; lymphatic leak s may require sclerotherapy with tetracycline. Speci \201 c complications (late) - Erectile dysfunction ( erections can return up to 3y p ost-operatively. Men >65y or with pre-existing ED are more likely to suffer long-term. Nerv e- sparing techniques imporve outcomes. 40 \200\22370% respond to oral PDE5 inhibitors at 6 months while others require intraurethral or intracavernosal prostaglandin E1 treatments, a vacuum device, or rarely a prosthesis. ED): affects 60 \200\22390% of patients; spontaneous PROSTATE CANCER \200\224RADICAL PROSTATECTOMY 339 Incontinence (stress type): requiring >1 pad/day affects 5% of patients beyond 6 months; th is is due to injury of the external urethral sphincter during division and haemostatic cont rol of the dorsal vein complex. Predisposing factors include age >65y and excessive bleedin g. Preoperative teaching of pelvic \202 oor exercises helps to regain continence; periure thral bulking injections, a urethral sling, or implantation of an arti \201 cial urinary s phincter are occasionally necessary. Incontinence may also develop secondary to bladder nec k stenosis or detrusor instability; \202 ow rates, post-void residual measurement, urodyn amics, and cystoscopy may help. Bladder neck stenosis: affects 5% of patients. It typically presents 3 \200\2239 months post-operatively, patients complaining of poor \202 ow and f requency/urgency of micturition. Predisposing factors include heavy bleeding, post-operativ e urinary leak, and previous TURP. It is treated by endoscopic bladder neck incision and ra rely becomes a recurrent problem. In experienced hands, the complications of laparoscopic/endoscopic/robot- assisted RP are c omparable to those of open RP. Blood loss is signi \201 - cantly less. Earlier full recove ry time (30 vs 47 days) has been reported. ED is reduced to 49% at 48 months by the robot-a ssisted nerve-sparing technique.1 1 Menon M. et al. (2007) Vattikuti Institute prostatectomy: contemporary technique and anal ysis of results. Eur Urology: 51, 648-58. CHAPTER 7 Urological neoplasia 340 Prostate cancer: oncological outcomes of radical prostatectomy While no randomized studies have compared RP outcomes to those of radiotherapy or brachytherapy, the Swedish SPCG-4 stu dy randomized 695 men aged <75 with low and intermediate risk to RP or WW.1 After a median follow-up of 12.8y, a 48% risk reduction in CSS (20.4% WW vs 14.6% RP, p=0.01) and a 26% ri sk reduction in OS (53% WW vs 46% RP, p=0.007) was demonstrated. The number of RP required to save one life was 15 overall, but only 7 for men <65y. In addition, 40% and 66% reduc- t ions in metastatic and local progression in favor of the RP group were reported. High-grade cancers were excluded from this trial. A retrospective analysis of >400 000 patients with localized PC treated by RP, radiotherapy , or observation showed CSS was best in patients up to the age of 80 treated surgically, al though patients with high-risk PC aged 70 \200\22379 survived equally well when treated eit her way.2 The long-awaited US-based PIVOT (RP vs observation RCT) study has been reported. A total of 731 patients with low- and intermediate-risk PC were randomized and followed up for a medi an of 10y. No signi \201 cant CSS difference was found between the two groups (5.8% in RP group vs 8.4%, p=0.09), though RP was associated with improved overall survival in men with PSA >10 (p=0.04) and possibly men with intermediate-risk disease (p=0.07).3 Excellent long-term results are seen in well selected patients follow- ing RP, particularly those with organ-con \201 ned disease and prior lower urinary tract symptoms due to bladd er out \202 ow obstruction. Serum PSA is measured a few days after RP, then 6-monthly; it should fall to <0.1ng/mL. The 5y outcomes LRP and RARP are similar to those of open RP. The 10y PSA progression rate following open RP for clinically localized PC, usually de \201 n ed as a serum PSA >0.2ng/mL, is about 30%. Of these, 80% will fail within 3y of RP and 5% w ill occur beyond 10y. Without additional treatment, the time to development of clinical dis ease after PSA progres- sion averages 8y.4 A 20y clinical disease-free survival of 60% is r eported.5 Outcome correlates with Gleason score, preoperative PSA, pathological T stage, an d surgical margin status. Certain tissue markers, yet to be used routinely, may also predic t PSA progression, e.g. aberrant p53 expression in biopsy or RP specimen.6