Pros tate gland, which is a rel a tively small or gan in the ... New and Ex per i men tal Tech niques in the Treat ment of Benign Prostatic Diseases

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1 /STRU^NI RAD UDK DOI: /ACI P New and Ex per i men tal Tech niques in the Treat ment of Benign Prostatic Diseases... Tomislav Pej~i} 1, Zoran D`ami} 1, Miodrag A}imovi} 1, Boris Kajmakovi} 1, Jovan Had`i-Djoki} 2 1 Clin i cal Cen ter of Ser bia, Clinic of Urol ogy, Bel grade, Ser bia. 2 Ser bian Acad emy of Sci ences and Arts, Bel grade, Ser bia Background: Benign prostatic hyperplasia (BPH) and chronic pros ta ti tis (CP) are dis or ders with high prev a lence and have a great im pact on over - all mor bid ity in men. The pa tients that do not re - spond to med i cal ther apy for lower uri nary tract symp toms (LUTS) re lated to BPH are can di dates for sur gery. How ever, the num ber of men with BPH/LUTS seek ing for non- sur gi cal, or for less in va sive treat ment is grow ing. Aim: To pres ent the basic information about minimally invasive treatment mo dal i ties for BPH and CP: intraprostatic in jec tions, urethral lift procedures, modifications of transurethral mi cro wave thermotherapy (TUMT), pros tatic ar tery embolization etc. Conclusion: The ma jor ity of these tech niques is still in ex per i men tal phase and not widely ac cepted. How ever, it is very likely that new, safe and min i mally in va sive tech niques will ap pear in the near fu ture. Key words: be nign pros tatic hy per pla sia; intraprostatic in jec tions; min i mally in va sive treat ment; ure thral lift pro ce dures rezime INTRODUCTION Pros tate gland, which is a rel a tively small or gan in the hu man body, has a sig nif i cant im pact on over all mor - bid ity and mor tal ity of men. Be nign pros tatic hy per pla sia (BPH) as so ci ated with lower uri nary tract symp toms (LUTS) is the fourth most com mon dis ease, af ter cor o - nary ar tery dis ease and hyperlipidemia, hy per ten sion and di a be tes type-2 1. With the over all prev a lence of 8%, chronic pros ta ti tis is the most com mon uro log i cal dis or - der in men un der 50 years 2. Fi nally, pros tate can cer (PCa) is among the three most com mon ma lig nant dis eases in the world. Al though urol ogy and re lated dis ci plines of fer a huge range of dif fer ent treat ment mo dal i ties, there is a con stant need for new, safe and ef fec tive treat ments for pros tate dis eases. In ad di tion, the ma jor ity of pa tients would choose a treat ment which is less in va sive, an es the sia-free and with out side ef fects. In this text, some of new emerg ing tech niques and treat ment mo dal i ties are briefly de scribed. Still, the ma - jor ity of these tech niques are not widely ac cepted. INTRAPROSTATIC INJECTIONS Intraprostatic in jec tions of an ti bi ot ics for chronic pros ta ti tis Chronic pros ta ti tis/chronic pel vic pain syn drome (CP/CPPS) is very com mon dis or der of mod ern man, with a high ten dency to re cur. The sig nif i cant per cent age of CPs re curs, due to the for ma tion of intraprostatic bac - te rial biofilms that ob struct the an ti bi otic dif fu sion into pros tatic glands. This is why a num ber of urol o gists tried to in ject the an ti bi ot ics di rectly into pros tatic tis sue in men with CP. In 1983, Baert et al. de scribed pos i tive ef fects of intrapros tatic in jec tion of the com bi na tion of amikacin, cefazolin, gentamicin, and thiamphenicol glycinate with lidocaine. Leon ard (1988), Jimenez-Cruz (1988), Yamamoto (1996) and oth ers, also ad vo cated di rect in jec tion of an ti - bi ot ics into the pros tate. Jimenez-Cruz et al re ported 51 pa tients with gram-neg a tive CP treated suc cess fully with amikacin (500 mg) and tobramycin (100 mg) weekly for 2-4 weeks. The an ti bi ot ics were in jected into the pe riph - eral zone un der ultrasonographic con trol, via per i neal route. Guercini et al. (2000, 2005) added ste roid betamethasone to the com bi na tion of an ti bi ot ics. The trial in - cluded 320 pa tients with CP with se vere and re cur rent symptoms. All pa tients re ceived the intraprostatic cock - tail at the be gin ning of the study, than af ter 7 and 14 days. At the end of the study, 68% of pa tients were clas si - fied as cured, while 13% were non-re spond ers. Hemospermia was the most com mon ad verse ef fect, while per i - neal or pros tatic pain was rel a tively rare 3. So far, the ma jor ity of urol o gists think that intrapros - tatic in jec tions are as ef fec tive as in tra mus cu lar in jec tion of an ti bi ot ics and that its wide use is not likely, due to significant ad verse ef fects. The most com mon com pli ca - tions of intraprostatic in jec tions are in fec tions (transrectal

2 76 T. Pej~i} et al. ACI Vol. LXI route), se vere pain (transperineal route), hemospermia and hematuria. In the fu ture, ste roids in the in jec tion could be re placed with some new immunomodulatory, or anti-in flam ma tory agents ef fec tive for the abacterial pros - ta ti tis, as well. On this way, immunosuppression would be de liv ered only to the pros tate, with the avoid ance of side ef fects. In ad di tion, if com pli ca tion rates can be re - duced this treat ment could be po ten tially ben e fi cial for pa tients with CP/CPPS 4. Intraprostatic in jec tions for the treat ment of be nign pros - tatic hy per pla sia The idea of BPH/LUTS treat ment by sim ple in jec tion of ac tive drug is rel a tively old. In In dia, Sir James Rob - erts was first to use intraprostatic in jec tion to releieve re - ten tion of the urine due to en large ment of the pros tate. Talwar (1966), Shipman (1967) and Sharma (1977) de - scribed succesful treat ment of pa tients with BPH and se - vere comorbidities us ing the intraprostatic in jec tions com posed of phe nol 2%, gla cial ace tic acid 2%, and glycerin 4%, in dis tilled wa ter. The in jec tions of a vol ume from 2 to 3 ml were given via transpernieal route 5-7. Intraprostatic in jec tions can be per formed us ing the transrec tal, transurethral, or transperineal route. (Fig ure 1). FIGURE 1: TRANSRECTAL ROUTE FOR INTRAPROSTATIC IN JEC - TIONS (SOPHIRIS BIO INC.) INTRAPROSTATIC INJECTIONS OF ABSOLUTE ETH A NOL In the ca nine pros tate, ab so lute (de hy drated, 95-98%) eth a nol causes in flam ma tion, coagulative ne cro sis, cell mem brane lysis and ab la tion of pros tatic tis sue, re sult ing in cav ity for ma tion. The first at tempt to treat pa tients with BPH with intraprostatic eth a nol in jec tion (IEI) was made by Goya et al. in The group of 10 pa tients un der went IEI transurethrally, with 3.5 to 12 ml of eth a nol given at 4 to 8 sites in the pros tate. The au thors noted sig nif i cant im - prove ment in uri nary symp toms and uri nary flow 8. So far, the ef fects of IEI were stud ied in sev eral tri als. Eth a nol was usu ally in jected in a liq uid state, or as a gel, us ing a 20 to 22 gauge nee dles. The vol ume of the in - jected eth a nol de pended on to tal pros tate vol ume (TPV) and ranged from 2 ml to 25 ml. The av er age du ra tion of the pro ce dure was 30 min utes; af ter the pro ce dure, the ma jor ity of pa tients needed a ure thral cath e ter. Af ter a mean fol low up rang ing from 3-48 months, the ma jor ity of tri als dem on strated a sig nif i cant re duc tion in symp - toms, im prove ment in the max i mum uri nary flow rate (Qmax) and a sig nif i cant TPV de crease. How ever, there was a sig nif i cant num ber of retreatments within the first year af ter the pro ce dure; af ter three years, the retreatment rate was up to 41%. The most com mon ad verse events were per i neal pain, blad der stor age symp toms, hematuria, uri nary tract in fec tion and uri nary re ten tion 9. In the re cent pa per, Li et al. tested the group of 70 men with BPH and poor re sponse on med i cal ther apy of LUTS. In ad di tion, all pa tients had sig nif i cant comorbidity, or re fused sur gery for BPH. Af ter 24 months of treat ment, TPV, In ter na tional pros tate symp tom score (IPSS) and postvoiding re sid ual urine (PVR) were sig nif - i cantly re duced, while Qmax sig nif i cantly in creased. In the group which re ceived high dose of eth a nol, four pa - FIGURE 2: CORONAL SECTION OF CANINE PROSTATE ONE MONTH AF TER BTX-A OR SA LINE IN JEC TION. CHUANG YC, TU CH, HUANG CC, LIN HJ, CHIANG PH, YOSHIMURA N, CHAN CEL LOR MB - BMC UROL (2006) tients had se vere com pli ca tion- liq ue fac tion ne cro sis and uri nary tract in jury. How ever, in the group which received re duced dose of eth a nol, no pa tient had com pli ca - tions 10 Al co hol gel com posed of 97% de na tured al co hol and a poly mer to cause vis cos ity seems to have some ad van - tages over liq uid al co hol. The vis cos ity of the gel al lows pre cise im ag ing un der the ul tra sound and pre vents the dis persal of the al co hol out of the pros tate. Larson pub - lished the re sults from 65 pa tients which un der went IEI of av er age 8 ml of eth a nol gel. All pa tients showed sta - tis ti cally sig nif i cant im prove ments in uri nary symp toms and uri nary flow 11. INTRAPROSTATIC INJECTIONS OF BOTULINUM TOXIN A Bot u li num toxin A (BT-A, Botox) in jected into the rat pros tate in duced se lec tive denervation and the pros tatic in vo lu tion. BT-A in duces the apoptosis of pros tatic stromal and ep i the lial cells and de creases smooth mus cle con trac til ity 12.

3 Br. 1 New and Ex per i men tal Tech niques in the Treat ment of Be nign Pros tatic Dis eases 77 weight de creased and pros tatic tis sue showed signs of at - ro phy. No sys temic ef fects were noted 16. INTRAPROSTATIC IN JEC TIONS OF PSA-AC TI VATED PORE-FORM ING TOXIN (PRX302) Pros tate spe cific an ti gen (PSA)-ac ti vated pore-form ing pro tein toxin, PRX302 is a po ten tial novel agent for intraprostatic in jec tion ther apy. Denmeade et al in jected PRX302 into the right and left tran si tion zone to the sub - jects with BPH/LUTS. Af ter one year of fol low up, ap - prox i mately 60% of men had the im prove ment of uri nary symp toms and a re duc tion of pros tate vol ume 17.Fig ure 3. INTRAPROSTATIC IN JEC TIONS OF NX-1207 PRO - TEIN FIGURE 3: PRX302 MECH A NISM OF AC TION (SOPHIRIS BIO INC.). FIGURE 4: PROS TATE ARTERIOGRAM MADE BY MI CROCATH E - TER IN SERTED INTO THE PROS TATIC AR TER IES (F.C. CARNEVALE). In a group of 30 pa tients with BPH, Maria et al. injected 4 ml of so lu tion with 200 units of BT-A. Two months later, 13 pa tients re ported sub jec tive re lief. In a group of 77 men with BPH, Brisinda in jected 200 units of BT-A. Af ter 30 months, all pa tients had sig nif i cant improvement of symp toms and uri nary flow and TPV reduction 13, 14. (Fig ure 2). INTRAPROSTATIC IN JEC TIONS OF CARDIOTOXIN D The main le thal com po nent of co bra toxin is the ba sic polypeptide cardiotoxin, which pro duces cell mem brane de po lar iza tion and de fin i tive cytolysis. Omran et al. in - ves ti gated the ac tion of co bra venom on pros tate can cer cell lines. They found that snake venom pro duced cell frag men ta tion, cytosol con den sa tion, the swell ing and fi - nally, de struc tion of the cells 15. Becker et al. in jected cardiotoxin D in ven tral pros tates of the lab o ra tory rats. Af ter two weeks the an i mals were sac ri ficed; pros tatic New po ten tial agent for intraprostatic BPH ther apy, NX-1207 is a pro tein with se lec tive pro-apoptotic prop er - ties, which can be ad min is tered in an of fice-based pro ce - dure by transrectal intraprostatic in jec tion un der ul tra - sound guid ance. NX-1207 in duces fo cal cell loss in pros - tate lead ing to pros tate vol ume re duc tion and the im - prove ment of the uri nary symp toms. In a rat model, NX-1207 pro duced a 40 47% de crease in pros tate vol - ume. In four US clin i cal tri als, NX-1207 has shown ev i - dence of symp tom atic im prove ment sub stan tially better than cur rently ap proved BPH med i ca tions with no sig nif - i cant safety is sues 18, 19. Nymox Phar ma ceu ti cal Cor po ra tion an nounced the sat - is fac tory safety pro file of NX-1207 in the treat ment of BPH. In ad di tion, NX-1207 showed the re duc tion in pros tate can cer pro gres sion in an on go ing phase II trial. The trial en rolled 146 pa tients with lo cal ized low-risk pros tate can cer which re ceived intraprostatic in jec tions of NX-1207 and the pa tients in ac tive sur veil lance only. The drug was in jected in the area of the pros tate where the can cer was de tected. In the fol low up of up to 22 months, re peated bi op sies found the sig nif i cant re duc tion in can cer vol ume and Gleason score pro gres sion in the group with NX-1207, com pared to the group with ac tive sur veil lance. The in ves ti ga tors hope that the drug will of - fer men with low-risk pros tate can cer a real chance to avoid ra di a tion and/or sur gery. HISTOTRIPSY The term histotripsy de notes tis sue de struc tion pro - duced by high in ten sity ul tra sound pulses. Lake et al. treated 11 an es the tized dogs with high-in - ten sity ul tra sound pulses. Af ter treat ment, patho log i cal ex am i na tion re vealed the pres ence of the cav ity con tain - ing liq ue fied ma te rial, at the ab la tion site. In ter est ingly, a nar row mar gin of cel lu lar in jury was noted, be yond which no tis sue dam age was ev i dent 20. URE THRAL LIFT PRO CE DURES Pros tatic Ure thral Lift (PUL) rep re sents a new, min i - mally in va sive treat ment for symp tom atic BPH. The ac - tion of PUL is me chan i cal open ing of the pros tatic ure - thra, with out tis sue ab la tion or re sec tion. The first ex pe ri - ences re gard ing the ef fec tive ness of the pro ce dure, as well as its safety and fea si bil ity, are en cour ag ing.

4 78 T. Pej~i} et al. ACI Vol. LXI Woo et al. were among the first in ves ti ga tors which per formed PUL pro ce dure. In a se ries of 19 men, they im planted small su ture-based im plants transurethrally un - der cystoscopic vi su al iza tion, to take apart en croach ing lat eral pros tatic lobes. Post op er a tive ad verse ef fects were mild and tran sient and in cluded dysuria and hematuria 21. Chin, Woo et al. treated 64 men with PUL. In clu sion cri te ria in cluded IPSS >13, Qmax of 5-12 ml/sec ond, and pros tate spe cific an ti gen (PSA) < 10 ng/ml. All pa - tients were tested for sex ual dys func tion, us ing male sex - ual health ques tion naires. They con cluded that ure thral lift im proved LUTS and urine flow with out com pro mis - ing sex ual func tion. No pa tient re ported ret ro grade ejac u - la tion at any fol low-up visit 22, 23. Roehrborn and other in ves ti ga tors en gaged in multicen ter L.I.F.T. study in serted 140 ure thral lifts in men with a pros tate vol umes rang ing from 30 to 80 ml. The sub jects were fol lowed to one year and as sessed for LUTS, uri nary flow and sex ual func tion. They con cluded that PUL pro vides rapid and sus tained im prove ment in symp toms and flow, while pre serv ing sex ual func tion. In the ex ten sion of the L.I.F.T. study, McVary et al. con - 24, firmed the pre vi ous con clu sions 25. The same in clu sion cri te ria were in cluded in the fol - low ing pro spec tive multicentric stud ies: IPSS=12, Qmax =12 ml, and TPV be tween 30 and 80 ml. Shore et al. treated 51 men; by one month, 86% of sub jects achieved high qual ity re cov ery, mea sured by a score of = 80 on the Qual ity of Re cov ery Vi sual An a log Scale. Ninety per cent of sub jects re ported im prove ment in their con di tion and 75% of sub jects would rec om mend the pro ce dure to a friend. Symp tom re sponse, flow rate im prove ment, and sex ual func tion pres er va tion were com pa ra ble to pub - lished stud ies. There were no se ri ous ad verse events 26. In the multicentric study in 19 cen ters in the USA, Can - ada and Aus tra lia, Cantwell et al. placed per ma nent PUL im plants into the lat eral lobes of the pros tate to en large the ure thral lu men. Uri nary symp tom re lief, health-re - lated qual ity of life (HRQL) im pact, uri nary flow pa ram - e ters, sex ual func tion, and ad verse events were as sessed. Symp tom, flow, HRQL and sex ual func tion as sess ments showed re sponse im prove ments from base line re sults, sim i lar to re sults from other pub lished stud ies. In ad di - tion, symp tom, flow, and HRQL im prove ments were du - ra ble over the 12 months of the study. Ad verse events were tran sient and mild to mod er ate; one pa tient (2%) re - quired re inter ven tion with transurethral re sec tion of the pros tate in the first year. There were no oc cur rences of ejac u la tory or erec tile dys func tion 27. In con clu sion, PUL is min i mally in va sive pro ce dure that can be per formed un der lo cal an es the sia, al lows pa - tients to quickly re turn to nor mal ac tiv ity, pro vides rapid and du ra ble im prove ment in symp toms, and pre serves sex ual func tion. The PUL of fers better IPSS im prove - ment when com pared to med i cal ther apy, but worse than sur gi cal ther apy. Ad di tional ad van tages of the PUL in com par i son to other sur gi cal ther a pies are the use of a lo - cal an es the sia and, in some cases, post op er a tive pe riod with out catheterization. How ever, it is very un likely that PUL will re place tra di tional ab la tive sur gi cal tech niques; its use could be in di cated only in strictly se lected cases 28. NEW MOD I FI CA TIONS OF TRANSURETHRAL MI CRO WAVE THERMOTHERAPY (TUMT) Mi cro wave thermodilatation sys tem (Prolieve ) con sists of the spe cial cath e ter, with a heat ing an tenna and a small bal loon. The sys tem si mul ta neously com - presses the pros tate with a 46F bal loon and de liv ers mi - cro wave en ergy into the pros tate. The pro ce dure lasts ap - prox i mately 45 min utes. If the tem per a ture reaches the heat ing limit, the sys tem will shut off au to mat i cally. In a clin i cal trial, 74% (68/92) of Prolieve Sys tem pa tients ex pe ri enced a = 30% im prove ment of their AUA to tal score at one year. Larson et al. found that the ne crotic zones ap peared af ter the tem per a ture ex ceeds 45 C. In ad di tion, peak tem per a tures of 51.8 C ap peared at 7 mm away from the pros tatic ure thra. The av er age tem per a - tures were greater near the blad der neck and mid-gland than near the pros tatic apex. One hour af ter the treat ment, void ing cystourethrograms showed widely pat ent pros - tatic ure thras 29. High en ergy TUMT fol lowed by intraprostatic in - jec tions of mepivacaine and adren a line (MA) showed sig nif i cant re duc tion of TPV, with re duced pain and short ened treat ment time. In a re cent study, Stenmark et al. treated 283 men with LUTS/BPH by intraprostatic in - jec tions of MA, fol lowed by HE-TUMT. Ap prox i mately 87% pa tient re sponded to ther apy. The av er age TPV was 74 ml and av er age treat ment time was 13 min utes. The re duc tion of TPV was 26% for the pros tates with TPV < 100 ml and 31% for the pros tates with TPV = 100 ml 30. Cooled Thermo Ther apy (CTT) con sists of the heat - ing an tenna and the small chan nels which pro vide the circulation of the cooled fluid, to pro tect sur round ing healthy ure thral tis sue. Usu ally, the sig nif i cant symp tom improvement is no ticed within 6-12 weeks af ter the procedure. PROS TATE AR TERY EMBOLIZATION Pros tate ar tery embolization (PAE) is a non-sur gi cal way of treat ing a BPH/LUTS by block ing off the ar ter ies that feed the pros tate gland. The pro ce dure is per formed by an interventional ra di ol o gist. PAE was first per formed in 2009, and since then over 200 men have had the pro - ce dure per formed pre dom i nantly in Por tu gal and Brazil. The pro ce dure is usu ally per formed un der lo cal an es the - sia, us ing the microcatheter 1mm in di am e ter and 300- to 500 ìm large microspheres. Carneval et al. re ported the pros tate vol ume re duc tion of up to 48%, if the bi lat eral PAE was per formed 31. Re - cent find ings from a pro spec tive United States clin i cal trial to eval u ate the ef fi cacy and safety of PAE showed that embolization was tech ni cally suc cess ful in 18 of 20 pa tients and un suc cess ful in two pa tients with atheroscle rotic oc clu sion of pros tatic ar ter ies. Pros tate vol ume de creased 18% af ter six months, while the uri nary symp - tom scores and the sex ual func tion, im proved sig nif i - cantly 32. (Fig ure 4). DIS CUS SION Be nign pros tatic hy per pla sia (BPH) and chronic pros ta - ti tis sig nif i cantly in flu ence on over all mor bid ity of male pop u la tion. In mod ern era, the num ber of men with these

5 Br. 1 New and Ex per i men tal Tech niques in the Treat ment of Be nign Pros tatic Dis eases 79 con di tions is grow ing, to gether with the av er age life span. There fore, there is a con stant need for new, ef fec - tive and min i mally in va sive treat ments fol lowed by mild side ef fects. Intraprostatic in jec tions can be ap plied as sim ple, out - pa tient pro ce dures and are po ten tially ideal for the treat - ment of BPH and pros ta ti tis. Fifty years ago the first at - tempts have been made in this sub ject. Intraprostatic in - jec tions can be per formed us ing the transrectal, transurethral, or transperineal route. The great est se ries in cluded the sub jects treated with intraprostatic eth a nol in jec tions. How ever, greater ran dom ized stud ies are needed to con - firm the ef fec tive ness and the safety of this method. Ac - cord ing to 2012 EAU Guide lines, intraprostatic eth a nol in jec tions should be per formed only in clin i cal tri als. There is a grow ing ev i dence of pos i tive ef fects of other agents in jected into the pros tate, like bot u li num toxin A, cardiotoxin D, PSA-ac ti vated pore-form ing toxin (PRX 302) and NX-1207 pro tein. All this ther a peu tic mo dal i - ties will prove its ef fi cacy in the near fu ture. While histotripsy and ure thral lift pro ce dures are still ex per i men tal, TUMT is well known pro ce dure and its new mod i fi ca - tions (thermodilatation, cooled etc.) will prob a bly increase its pop u lar ity. Fi nally, pros tate ar tery embolization can be per formed un der lo cal an es the sia and al lows pa - tients to quickly re turn to nor mal ac tiv ity. Al though PUL of fers better re sults than med i cal ther apy, it is still in fe - rior to sur gery and could be con sid ered only in strictly se lected cases. SUM MARY NOVE I EKSPERIMENTALNE TEHNIKE U LE^ENJU BENIGNIH BOLESTI PROS TATE Uvod: Benigna hiperplazija pros tate (BHP) i hroni~èni pros ta ti tis (HP) su bolesti sa visokom prevalencijom, koje imaju veliki uticaj na ukupni morbiditet kod muškaraca. Bolesnici kod kojih je medikamentozna terapija za simptome donjeg urinarnog trakta (LUTS) koji su posledica BHP, neuspešna, zahtevaju hirurško leè~enje. Medjutim, sve više bolesnika sa BHP je zainteresovano za nehirurško, ili minimalno invazivno le~èenje. Cilj rada: predstaviti osnovne informacije o minimalno invazivnim naè~inima le~èenja BHP i HP, kao što su intraprostatiè~ne injekcije, pro ce dure podizanja uretre, novije modifikacije transuretralne mikrotalasne termoterapije (TUMT), embolizacije arterija pros tate itd. Zaklj~èak: Ve}ina minimalno invazivnih metoda je još u eksperimentalnoj fazi i nije široko prihva}ena. Medjutim, vrlo je verovatno da }e se novije, efikasnije i sigurnije tehnike pojavljivati u bliskoj budu}nosti. 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