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 Progression-free probabilities in four prognostic groups are shown in Table 7.21.7 Probabil ity of biochemical recurrence-free survival following radical prostatectomy can be predicte d for individual patients using pre- operative or post-operative factors (PSA, PSA doubling time, pT stage, and Gleason score) using various tables,8 nomograms,9,10 (Fig. 7.10) or es timated online, at: M http://www.mskcc.org/mskcc/applications/nomo- grams/PostRad Prostatec tomy.aspx. Neoadjuvant hormone therapy (hormone therapy given 3 months prior to RP) does not alter the biochemical recurrence-free survival, despite apparently reducing the incidence of positiv e surgical margins. PC: ONCOLOGICAL OUTCOMES OF RADICAL PROSTATECTOMY 341 Management of biochemical relapse post-RP The de \201 nition of rising PSA is controversia l, though most agree >0.2ng/mL. Biopsy of the vesicourethral anastomosis is not recommended unless there is a palpable abnormality. Studies have shown that CT and bone scans are rare ly helpful in searching for metastatic disease unless the PSA is >7ng/mL. 11C-choline PET/C T is reported be helpful even when PSA <1.0. Current management options include observation, pelvic radiotherapy (66Gy), or hormone ther apy. A good response to pelvic radiotherapy is likely if: - PSA - PSA - PSA - Low-grade and low-stage disease. rise is delayed > 1y post-RP. doubling time >12 months. is <1ng/mL. If the PSA never falls below 0.2 or it rises in the \201 rst year with a doubling time of less than 10 months, the response to pelvic radiotherapy is usually disappointing. It is l ikely in these circumstances that metastatic disease is present; hormone therapy, either no n-steroidal antiandrogen mono- therapy (e.g. bicalutamide 150mg daily) or androgen deprivat ion, may be recommended. There are no comparative outcomes data in this clinical setting so discussion focuses on the side effects. Adjuvant vs salvage RT Standard care in the UK has been to refer for salvage radiotherapy i f the PSA rises consecutively above 0.2ng/mL following RP. It is unclear whether patients c onsidered at risk of relapse bene \201 t in terms of overall survival from immediate (adju vant) RT. However, three randomized tri- als (EORTC 22911, German intergroup, and SWOG 8794 ) have shown signi \201 cant improvements in biochemical disease-free survival and SWOG 87 94 demonstrated improved metastasis-free survival following adjuvant RT (compared with salv age RT) for pT3 and margin-positive patients. In UK, the RADICALS trial is ongoing. The eff ect of adjuvant RT on conti- nence recovery following RP also merits investigation. CHAPTER 7 Urological neoplasia 342 Table 7.21 Progression-free probabilities in four prognostic groups by PSA and by margin st atus, following RP Pathological stage Progression- free 5y (%) Progression- free 10y (%) Gleason 2 \200\2236, T1 \200\2233, margin \200\223ve 97 95 Gleason 2 \200\2236, T1 \200\2233, margin +ve OR Gleason 7, T1 \200\2233, margin \200\223v e 86 72 Gleason 8 \200\22310, T1 \200\2232, margin +/ \200\223ve, OR Gleason 8 \200\22310, T3, marg in \200\223ve OR Gleason 7 \200\22310, T3, margin +ve 62 41 Any LN +ve 37 13 PSA <4 91 PSA 4 \200\2239.9 87 PSA 10 \200\22319.9 70 PSA 20 \200\22350 50 Margin clear 81 Margin positive 36* Only 40 \200\22350% of patients with a positive surgical margin after RP develop a rising P SA. 0 10 20 30 40 50 60 70 80 90 100 Points PSA 0.1 1 2 3 4 6 7 8 9 10 12 16 20 30 45 70 110 T2a T2c T3a Clinical Stage T1c T1ab T2b \211 2+3 3+ \211 2 \211 4+* \211 3+ \211 4 \211 2+ \211 2 Biopsy Gleason Sum 3+3 0 20 40 60 80 100 120 140 160 180 200 Total Points 60 Month Rec. Free Prob. .96 .93 .9 .85 .8 .7 .6 .5 .4 .3 .2 .1 .05 Instructions for Physician: Locate the patient \200\231s PSA on the PSA axis. Draw a line s traight upwards to the Points axis to determine how many points towards recurrence the pati ent receives for his PSA. Rapeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time drawing straight upward to the Points axis. Sum the points achieved for ea ch predictor and locate this sum on the Total Points axis. Draw a line straight down to fin d the patient \200\231s probability of remaining recurrence free for 60 months assuming he does not die of another cause first. Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatctomy, You can use this only on a man who has already selected radical prostatectom y as treatment for his prostate cancer. Instruction to Patient: \200\234Mr. X, if we had 100 man exactly like you, we would expect between <predicated percentage from nomogram \200\223 10%> and <predicated percentage + 1 0%> to remain free of their disease at 5 years following radical prostatectomy, and recurre nce after 5 years is very rare. \200\235 1997 Michael W. Kattan and Peter T. Scardino Scott Department of Urology Fig. 7.10 A pre-operative nomogram per prostate cancer recurrence. Reproduced from Kattan.1 1 PC: ONCOLOGICAL OUTCOMES OF RADICAL PROSTATECTOMY 343 1 Bill-Axelson A, Holmberg L, Ruutu M, et al. (2011) Radical prostatectomy versus watchful wait- ing in early prostate cancer. N Engl J Med 364:1708 \200\22317. 2 Abdollah F, Sun M, Thuret R, et al. (2011) A competing-risks analysis of survival after a lternative treatment modalities for prostate cancer patients: 1988-2006. Eur Urol 59:88 \200\22395. 3 Wilt T et al. (2012) Radical prostatectomy versus observation for localized prostate canc er. NEJM 367: 203 \200\223213. 4 Pound CR, Partin AW, Eisenberger MA, et al. (1999) Natural history of progression after P SA elevation following radical prostatectomy. JAMA 281:1591 \200\2237. 5 Swanson GP, Riggs MW, Earle JD, et al. (2002) Long-term follow-up of radical retropubic p ros- tatectomy for prostate cancer. Eur Urol 42:212 \200\2236. 6 Brewster SF, Oxley JD, Trivella M, et al. (1999) Preoperative p53, bcl-2, CD44 and E-cadh erin immunohistochemistry as predictors of biochemical relapse after radical prostatectomy. J Urol 161:1238 \200\22343. 7 Khan MA, Partin AW, Mangold LA, et al. (2003) Probability of biochemical recurrence by an al- ysis of pathologic stage, Gleason score, and margin status for localized prostate cance r. Urology 62:866 \200\22371. 8 Freedland SJ, Humphreys EB, Mangold LA, et al. (2007) Death in patients with recurrent pr os- tate cancer after radical prostatectomy: prostate-speci \201 c antigen doubling time s ubgroups and their associated contributions to all-cause mortality. J Clin Oncol 25:1765 \200\22371. 9 Kattan MW, Eastham JA, Stapleton AM, et al. (1998) A preoperative nomogram for disease re - currence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90:766 \200\22371. 10 Katttan MW, Wheeler TM, Scardino PT (1999) Postoperative nomogram for disease recur- ren ce after radical prostatectomy for prostate cancer. J Clin Oncol 17:1499 \200\223507. 11 Kattan MW et al. (1999) Postoperative nomogram per disease recurrence after radical pros - tatectomy. J Clin Oncol 17:1499 \200\223507. CHAPTER 7 Urological neoplasia 344 Prostate cancer: radical external beam radiotherapy (EBRT) Since the early 1980 \200\231s, advances in radiotherapy for localized prostate can- cer have included the advent of linear accelerators, conformal, and inten- sity-modulated techniques to minimize toxicity to the rectum and bladder. Increasing the doseage, shaping the beam intensity using multileaf coll ima- tors, and more accurate treatment planning by TRUS-guided insertion of gold \201 duc ial markers are becoming the standard of care. EBRT is admin- istered with curative intent to men with a life expectancy >5y, accompa- nied by 24 months of neoadjuvant/adjuvant andro gen deprivation therapy in high-risk cases. A small, randomized study has demonstrated bene \201 t in terms of progression and survival for patients treated with 6 months (2 months each of neoadjuvant, concurrent, and adjuvant) androgen abla- tion in addition to radiother apy compared with radiotherapy alone.1 Indication All risk clinically localized prostate cancer, Gleason score (cid:116)6. Patient s with Gleason score 2 \200\2235 disease appear to do as well with surveillance as with any other treatment at 15y follow-up. The UK 2008 NICE Guidelines recommend low-risk cases (PS A <10 and Gleason score (cid:100)6 and cT1 \200\2232) should \201 rst be offered active s urveillance. Contraindications - - - Severe lower urinary tract symptoms. In \202 ammatory bowel disease. Previous pelvic irrad iation. Protocol UK 2008 NICE Guidelines recommend conformal fractions (up to 2Gy per treatment), a mounting to a minimum dose of 74Gy. Side effects - Transient moderate/severe \201 lling-type permanent). Haematuria, contracted bladder 4 \200\22323%. Moderate to severe gastrointestinal symptoms, bloody diarrhea, pain, rectal st enosis 3 \200\22332%. Erectile dysfunction gradually develops in 30 \200\22350%. The risk o f a second solid pelvic malignancy is estimated to be 1 in 300, falling to 1 in 70 long-ter m survivors. LUTS (common, rarely Outcomes of EBRT De \201 nitions of treatment failure: the 2005 Phoenix de \201 nition is the time at which the PSA rises by 2ng/mL or more above the nadir. This has suc- ceeded th e complicated and \202 awed 1996 ASTRO (American Society of Therapeutic Radiation Oncolog ists) de \201 nition which required three con- secutive PSA increases above the nadir meas ured 4 months apart. Pretreatment prognostic factors: PSA, Gleason score, clinical stage, p er- centage of positive biopsies. PC: RADICAL EXTERNAL BEAM RADIOTHERAPY (EBRT) 345 10-year biochemical disease-free survival using IMRT delivered at 81Gy is: - - - 81% for 78% for 62% for low-risk disease (T1 \200\2232a and PSA <10ng/mL and Gleason (cid:100)6). intermediate-risk disease (T2b or PSA 10 \200\22320 or Gleason 7). high-risk disease (T2c or PSA >20ng/mL or Gleason 8 \200\22310). Treatment of PSA relapse post-EBRT Hormone therapy, either with antiandrogens or androgen d eprivation, is currently the mainstay of treatment in this setting. However, local salvage treatments appear attractive, potentially offering another chance of cure if metastases can not be demonstrated at repeat staging. Salvage radical prostatectomy is seldom undertaken b ecause it is associated with highly morbidity and disappointing oncological outcomes. Other local salvage treatments include brachytherapy, cryotherapy and high-intensity focused ul- trasound (HIFU) (see b p. 348). If salvage local treatment is under consid- eration, repea t prostatic biopsies should be taken to demonstrate viable tumor cells. This should be at l east 18 months post-EBRT, because fatally damaged cells may survive a few cell divisions. Individual predictions of 6y progression-free probability can be found online at: M http:// nomograms.mskcc.org/Prostate/SalvageRadiationTherapy.aspx. 1 D \200\231Amico AV et al. (2004) 6-month androgen suppression plus radiotherapy vs. radia tion alone for patients with clinically-localized prostate cancer: a randomized drug trial. JAMA 292:821 \200\2237. CHAPTER 7 Urological neoplasia 346 Prostate cancer: brachytherapy (BT) The commonly used low-dose rate (LDR) BT is ultrasound- guided trans- perineal implantation of radioactive seeds, usually I125, into the prostate. It is currently popular, having failed in the 1970 \200\231s, prior to transrectal ul- tras onography. BT is minimally invasive, requires general anesthesia, and is completed in one o r two stages. Either way, approximately 150Gy is delivered and this may be augmented by an EBRT boost in high-risk cases. Another approach, high-dose rate (HDR) BT is to use iridium1 92 wires, left for several hours in situ in a series of applications, either before or afte r EBRT. The treatment is expensive due to the cost of the consumables. Indications for BT: low- and intermediate-risk localized prostate can- cer, cT1 \200\2232, and Gleason (cid:100)7 and PSA <20; life expectancy >5y. The 2008 UK NICE Guidance suggests patients with low-risk disease (PSA <10 and Gleason score (cid:100)6 and cT1 \200\2232) sh ould \201 rst be offered active surveil- lance and for those with intermediate-risk disea se, radical prostatectomy or conformal radiotherapy are preferred treatments. Indications for BT with EBRT: T1 \200\2233, Gleason 7 \200\2238, PSA <20, pros- tate cancer . Contraindications to BT: previous TURP (increases risk of incon- tinence); large volume pro state (>60mL) causes dif \201 culty with seed placement due to pubic arch interference unl ess cytoreductive hormone therapy is used; moderate to severe lower urinary tract symptoms, IPSS >12 (increases risk of retention). Complications of LDR BT - - Perineal haematoma (occasional). Lower urinary tract symptoms (common) due to prostatic oed ema post-implant. Urinary retention (5 \200\22320%); and to improve the chance of successfu l trial without catheter in patients with urinary retention. Incontinence (5%), usually if retention. A-blockers are often used to treat LUTS TURP is required to treat urinary ED- - affects up to 50% of patients, gradual onset. Seed migration; second primary cancer (rare). Outcomes of BT PSA rises in the \201 rst 3 months post-implant ( \200\230PSA bounce \200 \231), then sub- sequently declines. As with EBRT, the ASTRO or Phoenix de \201 nitions (s ee b p. 344) are used to de \201 ne progression. Neoadjuvant androgen ablation therapy is often used. - 7y biochemical progression-free survival (b PFS) for low-risk disease (cT1c \200\2232a, Gle ason <7, PSA <10ng/mL) is 80 \200\22390%; 10y bPFS for low- risk disease is 60%. 7y b 7) is 70 \200\22380%. 7y b 50 \200\22360%. PFS for intermediate-risk disease (T2b, PSA 10 \200\22320ng/mL, Gleason PFS for high-risk disease (T2c, PSA >20ng/mL, Gleason >7) is PROSTATE CANCER: BRACHYTHERAPY (BT) 347 Individual predictions of 5y progression-free probability can be found online at: M http:// www.mskcc.org/mskcc/applications/nomograms/ PreTreatment.aspx. Outcomes of BT plus EBRT (usually with androgen ablation) - 15y b - 15y b - 15y b PFS for low-risk disease is 86%. PFS for moderate-risk disease is 80%. PFS for high-risk di sease is 68%. Comparisons of BT or BT plus EBRT with RP or EBRT alone These are confounded by treatment h eterogeneity. There are no random- ized studies. In non-randomized comparisons, an age and tumor-matched radical prostatectomy series at 8y yielded a progression-free survival of 98%, compared to 79% with BT alone. Outcome of BT al one appears inferior to EBRT and RP in men with PSA >10 and Gleason score 7 \200\22310. Rising PSA post-BT Salvage radical prostatetcomy, EBRT, cryotherapy, or HIFU are options if local recurrence is suspected; calculation of PSA doubling time, repeat biopsy, and stagin g are necessary to select suitable cases. Whilst offering a further chance of cure, morbidi ty is higher with all, compared to their use in primary treatment (e.g. prostate \200\223re ctal \201 stula rates are (cid:116)5% vs 1% for primary cases). If metastatic disease is suspected or proven, further local treatment is unjusti \201 ed. Salvage brachytherapy following EBRT treatment failure is gaining popu- larity in some cent ers. Biochemical 5y disease-free rates of 34 \200\22353% are reported, with moderate toxici ty. CHAPTER 7 Urological neoplasia 348 Prostate cancer (minimally invasive management of localized and radio-recurrent prostate ca ncer): cryotherapy, high-intensity focused ultrasound, and photodynamic therapy Minimally i nvasive treatments for localized prostate cancer currently evolving are attractive to patie nts and their doctors. Proponents claim them to be alternatives to radical surgery or radio therapy with shorter hospital stay and less morbidity; they are also the only potentially c ura- tive options for \200\230salvage \200\231 treatment of organ-con \201 ned recurrent disease following radical radiotherapy since most surgeons will not offer salvage prostatec tomy. Careful patient selection and mentored training is important to achieve good results. No ra ndomized outcomes data exist. The 2008 UK NICE guidance recommended that these technologies should be used only in the setting of a controlled clinical trial. Cryotherapy This involves transperineal ultrasound-guided placement of cryoprobes deliverin g argon or liquid nitrogen at temperature \200\22320 C to \200\22340 C. When applied in two cycles of freeze thaw, cellular necrosis occurs. The diame- ter of the ice ball is mon itored using ultrasound; precautions are taken to protect the urethra, external sphincter, and rectal wall such as warming devices. An anesthetic is required although this is a day c ase procedure which can be repeated. Results: PSA nadir is usually achieved within 3 months ; 25 \200\22348% of men with localized disease achieve a PSA nadir of <0.1ng/mL in 3 months and 96% of men achieved PSA <0.2ng/mL within 6 months. Positive biopsies are observed in 8 \200\22325% of patients after cryotherapy. Complications Erectile dysfunction (40 \200\22380%); incontinence (4 \200\22327%); lower ur inary tract symptoms due to urethral sloughing; pelvic pain; transient penile numb- ness; r ectourethral \201 stula (rare). In the salvage setting, good short-term PSA responses are reported in 66% of men at the exp ense of signi \201 cant morbidity, including inconti- nence and urinary retention (70% eac h). In a contemporary UK series, 5y freedom from PSA progression (ASTRO de \201 nition) wa s 73%, 45%, and 11% in low-, medium-, and high-risk patients, respectively. Careful disease staging with prostate biopsy and MRI is important; the best results are seen when the PSA is <4ng/mL. Persistent incontinence developed in 13% of patients while 1% developed rectour ethral \201 stula. PROSTATE CANCER: CRYOTHERAPY, HIFU, PDT 349 HIFU HIFU allows the selective destruction of tissues at up to 4cm depth with- out damaging intervening structures, most importantly the rectal wall. Tissue is heated to the point of coagulative necrosis (over 85 C) by high energy ultrasound transmitted to the prostate us ing a transrectal device. Numerous 6 x 2 x 2mm cigar-shaped lesions are produced side by si de to create a continuous volume in which the tissue is ablated. An anesthetic is required although this is a day case procedure which can be repeated. Results: from a large (n=463) French series, PSA nadir is usually achieved within 4 months; 77% patients achieve PSA nadir 0.5ng/mL or less. At 2y median follow-up, 64% remained dise ase-free by the Phoenix de \201 nition. In a Japanese series of 181 patients, half of whom received neoadjuvant androgen ablation, the 3y BDFS (ASTRO de \201 nition) for low-, inte rmedi- ate-, and high-risk PC was 94%, 75% and 35%, respectively. Complications: erectile dysfunction (50%), urinary retention 8%, urethral stricture (10 \200\22325%), stress incontinence (2%), and rectourethral \201 stula (1%). Data for HIFU in the salvage setting are scarce. Good PSA responses are reported in 61% of men, with 38% remaining disease-free in a mixed group of patients. Morbidity is increased i n the salvage treatment setting, rectourethral \201 stula or osteomyelitis are seen in (c id:116)5%. Another technology, photodynamic therapy (PDT), is also under investigation in the salvage setting. This involves parenteral administration of a chlorophyll-derived photosensitizing drug (Tookad ) followed by light activation using transperineal template-guided interstiti al laser. The free radicals generated cause thrombosis of nearby vasculature and ischaemic tissue necrosis. Phase I studies have yielded promising results and multi- center phase II PDT studies are in progress. Focal therapy Whilst currently treating the whole prostate, these technologies are potentia lly suitable for focal ablation of localized PC; such a strategy could reduce morbidity, tr eatment time, and cost; currently under investigation in the UK and USA. CHAPTER 7 Urological neoplasia 350 Prostate cancer: management of locally advanced non-metastatic disease (T3 \200\2234 N0M0) Radical prostatectomy (RP) RP has traditionally been discouraged for men with cT3 disease i n the UK. However, younger men with apparently non-metastatic mobile di- sease may bene \201 t from surgery as part of a multimodality treatment plan. Proponents accept that 50 \200\22380% will require additional treatment, but argue that 27% of cT3 cases are patholog ically organ-con \201 ned. Cyto-reductive surgery for pT3 disease could reduce morbidity f rom local progression and improve oncological outcome while concurrent extended BPLND (lymp hadenectomy) provides additional staging and possible therapeutic value. A 10y cancer-speci \201 c survival following RP plus BPLND for cT3 PC is 73% for low-grade, dropping to 30% for high-grade disease. Outcomes are better for patients with PSA <10ng/mL. Lymph node meta stases will be found in around 40% of patients with cT3 PC. There are survival data suggest ing that RP should not be abandoned if lymph node metastases are identi \201 ed at time of surgery (frozen section of nodes should not be done) and that removal of the prostate may reduce risk of development of metastases compared with radiotherapy treatment.1 EAU 2012 Gu idelines state that RP is an option for selected, well-informed, \201 t patients with cT3 a PC, PSA <20ng/mL, and Gleason score (cid:100)8. Clinical trials in this area are urgently required. EBRT in combination with androgen ablation therapy (AAT) is cur- rently the gold standard t reatment for cT3 \200\2234 PC in \201 t men. The combi- nation consistently demonstrated better outcomes compared to EBRT alone, which is associated with a 15 \200\22330% 10y survi val. In a European ran- domized study,2 the ADT group received LHRH analogs for 3y starting at time of EBRT. The 5y overall survival was 79% compared to 62% in the group treated with EBRT alone; the 5y cancer-speci \201 c survival was 85% compared to 48%. A randomized tri al (MRC PR07) of hormone therapy alone vs EBRT plus hormone therapy of 1200 patients with c T3N0M0 PC reported recently cancer-speci \201 c survival at 7y follow-up was signi \201 c antly (8%) better in the combination arm. The optimal timing and duration of AAT remains un clear; the 2008 UK NICE Guidance recommends neoad- juvant and concomitant AAT for 3 \200 \2236 months, increasing to a minimum of 2y if the Gleason score (cid:116)8; the EAU 2011 G uidelines recommend EBRT dose of (cid:116)74Gy with 3y of concomitant and adjuvant AAT. Pelvic EBRT may be considered if risk of N+ disease >15%, according to the Roach formula: 2 /3 PSA + (10 x [Gleason score \200\223 6]). However, the historic evidence of bene \201 t for whole pelvic EBRT in locally advanced PC is unconvincing; randomized trials involving contemporary patients are ongoing. Minimally-invasive treatments such as LDR brachytherapy, HIFU, and cryotherapy are not reco mmended outside clinical trials. High-dose rate brachytherapy in combination with AAT is be coming popular, though long- term trial outcomes are awaited. PC: MANAGEMENT OF T3 \200\2234 NOMO 351 Bisphosphonates are not currently recommended to prevent PC bone metastases. Hormone therapy alone is an option for symptomatic elderly patients or those unwilling to u ndergo EBRT, especially if the disease is bulky, the PSA is >25ng/mL, or the PSA doubling t ime is <1y. In this setting, a non- steroidal antiandrogen, such as bicalutamide 150mg dail y, has equivalent ef \201 cacy to androgen ablation by orchidectomy or LHRH analog, with r educed side effects. Patient counseling should include the explanation that hormone therapy is not a curative treatment. Watchful waiting is an option for non-metastatic T3 disease in an elderly asymptomatic patient who may prefer to avoid side effects of treatment. Palliative treatment of locally advanced disease See also b p. 362. Palliative TURP or medi cal therapy for LUTS or uri- nary retention may be necessary. Incontinence can be a problem due to sphincter involvement, though bladder out \202 ow obstruction and instability shou ld be considered. A urinary convene sheath or catheter may be re- quired. Patients may pres ent in renal failure; percutaneous nephrostomy or ureteric stenting are occasionally necess ary for bypassing ureteric ob- struction. ADT in this setting may relieve this tumor compre ssion of the distal ureters. Very rarely, a colostomy is necessary to bypass a rectal ste- nosis. Palliative EBRT may be useful for treatment of persistent prostatic haematuria or pe rineal pain. 1 Zelefsky MJ et al., (2010) Metastasis after radical prostatectomy or external beam radiot herapy for patients with clinically localized prostate cancer: a comparison of clinical coh orts adjusted for case mix. J Clin Oncol 28: 1508 \200\22313. 2 Bolla M, Gonzalez D, Warde P, et al. (1997) Improved survival in patients with locally ad vanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295 \200 \223300. CHAPTER 7 Urological neoplasia 352 Prostate cancer: management of advanced disease \200\224hormone therapy I Metastatic diseas e is the cause of nearly all prostate cancer-related death. Currently incurable, the 5y sur vival is about 35%; 10% survive <6 months, while <10% survive >10y. The gold standard treat ment is hormone thera- py (usually androgen ablation), with cytotoxic chemotherapy for prog res- sion and novel treatments (such as growth factor inhibitors, angiogenesis inhibitors, immunotherapy) in development. The concept of hormone therapy was realized in 1941 when Chi cago physicians, Charles Huggins and Clarence Hodges, reported favorable symptomatic and bi ochemical (acid and alkaline phosphatase) responses in metastatic PC patients when castrate d or given oestrogens.1 Hormone dependence of prostate cancer All prostate epithelial cells, with the exception of rare undifferentiat- ed stem cells, are dependent on androgens and fail to grow or under- g o programmed cell death (apoptosis) in their absence. Similarly, most previously untreated prostate cancer cells are dependent on androgens. In men, 95% of circulating androgen, main ly testosterone, is produced by the testicular Leydig cells under the in \202 uence of lut einising hormone (LH). The anterior pituitary synthesizes LH, stimulated by hypothalamic LH -releasing hormone (LHRH). The remaining 5% of circulating andro- gen (mainly dehydoepiandr osterone) is synthesized by the adrenal cortex from cholesterol, under the in \202 uence o f pituitary ACTH. Testosterone is metabolized to the more 5-fold more potent dihydrotestost erone (DHT), by 5A-reductase (5AR) enzymes types 1 and 2. DHT binds cytoplasmic androgen re ceptor which translocates to the nucleus, there activating transcription of androgen-respon sive genes which drive the cell cycle or inhibit apoptosis. Androgen deprivation results in a reduction in PSA and clinical improve- ments in >70% of p atients. However, most patients with metastatic disease will still die within 5y due to the emergence of castrate-resistant growth. This may be due to selection of androgen-independe nt cell clones or intra- cellular androgen biosynthesis. The mean time to disease progressi on after androgen deprivation is 14 months in men with metastatic disease. Prognostic factors Predictors of poor hormone therapy response include: (cid:116)- 5 metast atic lesions at presentation. - - - - Elevated alkaline phosphatase at presentation. Anemia at presentation. Poor performance sta tus (level of activity) at presentation. Low serum testosterone at presentation. PROSTATE CANCER: HORMONE THERAPY I 353 Failure of bone pain to improve within 3 months of treatment. PSA to normalize (to <4ng/mL) within 6 months of Failure of treatment; (conversely a PSA nadir (= lowest value) of <0.1n g/mL predicts a long-term response). 1 Huggins C, Hodges CV (1941) Studies on prostate cancer: I. The effect of castration, of e strogen and of androgen injection on serum phosphatases in metastatic carcinoma of the pros tate. Cancer Res 1: 293 \200\2237. CHAPTER 7 Urological neoplasia 354 Prostate cancer: management of advanced disease \200\224hormone therapy II Methods of andro gen ablation therapy - - Surgical castration: Medical castration: agonists. \200 \200 antagonists. \200 Maxima l androgen blockade ( antiandrogen. bilateral orchidectomy. LHRH LHRH Oestrogens. MAB): medical or surgical castration plus Both forms of castration have equivalent ef \201 cacy so patients can be given the choice. Oestrogens are no longer used \201 rst-line due to the signi \201 cant cardiovascular m orbidity observed when they were the only alternative to orchidectomy. MAB has a theoretica l advantage over castration in blocking the effects of the adrenal androgens; signi \201 c ant clinical advan- tages (>5% improved 5y survival) have not been demonstrated by trial me ta-analyzes. Bilateral orchidectomy (subcapsular technique) A simple procedure, usually carried out unde r general anesthesia. Through a midline scrotal incision, both testes may be accessed. The tunica albug- inea of each testis is incised and the seminiferous tubules removed, after wh ich the capsule is closed. The epididymes and testicular appendages are preserved. Post-ope rative complications include scrotal haematoma or in- fection (both rare). Serum testostero ne falls within 8h to <50ng/dL. LHRH agonists LHRH agonists (or analogs) were developed in the 1980 \200\231s, giving pa- t ients an alternative to bilateral orchidectomy, with which they are consid- ered clinically equivalent. They are given by subcutaneous or intramuscu- lar injection, as monthly or 3-m onthly depots. Examples include goserelin, triptorelin, and leuprorelin acetates. A 6-month ly triptorelin formulation is recently available. When the anterior pituitary is overstimulated by an agonist of LHRH, it switches off LH syn thesis, although serum testosterone rises in the \201 rst 14 days due to a surge of LH. T his can result in \200\230tumor \202 are \200\231, manifest in a small number of patient s by increased symptoms, including catastrophic spinal cord compression. To prevent this, c over with antiandrogen is rec- ommended for a week before and two weeks after the \201 rs t dose of LHRH agonist. There is awareness that on occasions, the serum testosterone level may not be suppressed to castrate levels by all LHRH agonists. One LHRH antagonist, degarelix, is currently licensed in Europe. Given by monthly subcutane ous injection, it rapidly reduces serum testosterone to castrate, abolishing the issue of t umor \202 are and antiandrogen cover. To date there are no published clinical trials comp aring immediate or long- term outcomes of LHRH agonists and antagonists. PRSOTATE CANCER: HORMONE THERAPY II 355 Side effects of bilateral orchidectomy and LHRH agonists/antagonists - - Loss of sexual interest and Hot \202 ushes and sweats can be frequent and troublesome dur ing work or social activity. Weight gain. Lethargy, fatigue. Gynaecomastia. Anemia. Cogniti ve changes, depression, and memory loss. Osteoporosis and pathological fracture (particular ly of the hip): secondary to osteoporosis may occur in patients on long-term (>5y) treatmen t. A single yearly dose of the bisphosphonate, zoledronic acid, appears to maintain bone mi neral density, though the clinical advantage this may confer remains uncertain. ED. - - - -