“rak sečnega mehurja” “urinary bladder cancer”

Transcription

13.
slovenski
urološki simpozij
v sodelovanju
z evropsko urološko šolo
in
9. simpozij urološke zdravstvene nege
“RAK SEČNEGA MEHURJA”
13th Slovene
Urological Simposium
with ESU participation
and
9th Urological Nurses Symposium
“URINARY BLADDER CANCER”
Velenje, Slovenija
2. in 3. junij 2011
June 2-3, 2011
Zbornik predavanj / The book of lectures
Urednik / Editor: Marko Zupančič
Za jezikovno pravilnost prispevkov so odgovorni avtorji sami
Linguistic corrections of the contributions are responsibility of the authors themselves
Organizacijski odbor / Organizing committe:
Predsednik / President: Glavni tajnik / Secretary General: Člani / Members: Marko Zupančič
Franc Kramer
Boris Pospihalj
Zoran Krstanoski
Ljubo Koršič
Ivan Parać
Andrej Grajn
Boris Košuta
Majda Topler
Cvetka Smrtnik
Naklada / Circulation: 200 izvodov
CIP - Kataložni zapis o publikaciji
Narodna in univerzitetna knjižnica, Ljubljana
616.62-006-08(082)
SLOVENSKI urološki simpozij v sodelovanju z Evropsko urološko šolo
(13 ; 2011 ; Slovenj Gradec)
Rak sečnega mehurja : [zbornik predavanj] = Urinary bladder cancer : [the book of lectures] / 13. slovenski urološki simpozij v sodelovanju z Evropsko
urološko šolo [in] 9. simpozij urološke zdravstvene nege = 13th Slovene Urological Symposium with European School of Urology Participation [and]
9th Urological Nurses Symposium, Slovenj Gradec, Slovenija, June 2-3, 2011 ; [urednik Marko Zupančič]. - Slovenj Gradec : Oddelek za urologijo,
Splošna bolnišnica = Department of Urology, General Hospital, 2011
ISBN 978-961-91364-6-1
1. Gl. stv. nasl. 2. Vzp. stv. nasl. 3. Zupančič, Marko, 26.5.1960- 4. Simpozij urološke zdravstvene nege (9 ; 2011 ; Slovenj Gradec)
256246784
13. SLOVENSKI UROLOŠKI SIMPOZIJ V SODELOVANJU Z EVROPSKO UROLOŠKO ŠOLO
13TH SLOVENE UROLOGICAL SYMPOSIUM WITH ESU PARTICIPATION
Kazalo / Index
Epidemiologija raka sečnega mehurja................................................................................................................. 7
Epidemiology of bladder cancer
Maja Primic Žakelj, Vesna Zadnik
Classification on non-invasive bladder neoplasms: is it time for a revised 2004 WHO scheme?............... 13
Rodolfo Montironi
ICUD Recommendations on Bladder Cancer..................................................................................................... 18
Mark S. Soloway
Diagnosis of Bladder Cancer: which are the best tools................................................................................... 21
Maria J. Ribal
TUR and Re-TUR in Non Muscle Invasive Bladder Cancer. TUR in Muscle Invasive Bladder Cancer ........ 22
Maurizio A. Brausi
Intravesical Chemotherapy: early and adjuvant................................................................................................ 23
Maria J. Ribal
Radical Surgery: Pros and Con of Different Techniques and Evaluation of Complications......................... 24
Maurizio A. Brausi
Neoadjuvant and adjuvant Chemotherapy in invasive or metastatic disease................................................ 25
Maria J. Ribal
Obravnava bolnikov z mišično neinvazivnim rakom sečnega mehurja: 5-letno sledenje............................. 29
Treatment of patient with non-muscle invasive Bladder Cancer: 5-years follow up
Z. Krstanoski, M. Zupančič, F. Kramer, L. Koršič, I. Parać
Uporaba Mitomycina C pri zdravljenju raka mehurja – naše izkušnje............................................................ 32
The use of Mitomycin C in Bladder Cancer treatment – our experiance
Klemen Jagodič, Igor Bizjak, Uroš Četina
Hyperthermia during intravesical doxorubicin application in patients with superficial Urinary Bladder
Carcinoma............................................................................................................................................................. 33
M.M. Bernat, Ž. Kaštelan, D. Hauptman, I. Krhen, I. Mokos, N. Knežević
Significance of Fluorescence in situ hybridisation in detection of Bladder Cancer reccurence................. 34
Ante Reljić, Sanja Mrsić, Silva Ćurić, Božo Krušlin, Ana-Maria Šimundić, Ognjen Kraus, Davor Trnski
Preprečevanje trzljajev mišic stegenskih adduktorjev z blokom obturatornega živca
pri transuretralni resekciji stransko ležečih tumorjev mehurja ...................................................................... 41
The prevention of obturator jerk reflex with obturator nerve block during transurethral resection
of lateral bladder wall tumors
Simon Hawlina, Jure Bizjak, Borut Gubina, Tomaž Smrkolj, Robert Kordič, Miro Mihelič, Dominik Cotič, Boris Sedmak
Bladder sparing treatment for muscle invasive Bladder Cancer: solution or an option?............................. 44
Aleksandar Janjić, Cane Tulić, Aleksandar Vuksanović, Nebojsa Bojanić, Nale Djordje
The role of partial cystectomy in the treatment of muscle invasive Bladder Cancer.................................. 49
V. Vukotić, M. Lazić, S. Savić. D. Kojić, S. Jovanović
Radical Surgical Treatment of the Urinary Bladder Cancer: Our Experiences............................................... 55
Anton Maričić, Maksim Valenčić, Romano Oguić, Stanislav Sotošek, Dean Markić, Josip Španjol, Kristian Krpina,
Juraj Ahel, Anton Gršković, Dražen Rahelić, Željko Fučkar
Modification of Padovana ileal neoblader . ....................................................................................................... 60
V. Sekulić, J. Bogdanović, G. Marušić, J. Đozić, R. Herin
Izkušnje z zdravljenjem bolnikov s karcinomom mehurja po odprti ali laparoskopski radikalni
cistektomiji v intenzivni enoti: retrospektivna analiza...................................................................................... 62
ICU experience with Bladder Cancer patients after open or laparoscopic radical cystectomy:
retrospective analysis
Jasna Uranjek, Darja Kasnik
Quality of life after radical cystectomy measured by “Sickness impact profile” score ............................... 67
A. Prcić, D. Aganović, B. Kulovac, O. Hadžiosmanović
Quality of life in patient with orthotopic neobladder........................................................................................ 68
I. Vuković, S. Mićić, N. Bojanić, D. Djordjević
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SAMO ZA STROKOVNO JAVNOST.
PRED PREDPISOVANJEM SI PREBERITE
CELOTEN POVZETEK GLAVNIH
ZNAČILNOSTI ZDRAVILA.
PROLIA® (denosumab) - SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Samo za strokovno javnost.
Pred predpisovanjem si preberite celoten povzetek glavnih značilnosti zdravila.
Denosumab je povsem humano monoklonsko protitelo (IgG2) proti ligandu receptorja za aktivacijo jedrnega dejavnika kB (angl. receptor activator of nuclear factor
kB ligand - RANKL), na katerega se veže z veliko afiniteto ter zelo specifično. Tako prepreči aktivacijo receptorja RANK na površini predhodnikov osteoklastov in
samih osteoklastov in s tem zavre nastajanje, delovanje in preživetje osteoklastov. Posledično denosumab zmanjša resorpcijo kosti v kortikalnem in trabekularnem
kostnem tkivu.
FARMACEVTSKA OBLIKA: Raztopina za injiciranje (injekcija).
KAKOVOSTNA IN KOLIČINSKA SESTAVA: Ena napolnjena injekcijska brizga vsebuje 60 mg denosumaba v 1 ml raztopine (60 mg/ml). Pomožne snovi s prepoznavnim
delovanjem: En mililiter raztopine vsebuje 47 mg sorbitola (E420).
TERAPEVTSKE INDIKACIJE: Zdravljenje osteoporoze pri ženskah po menopavzi z večjim tveganjem zlomov. Zdravilo Prolia® znatno zmanjša tveganje zlomov vretenc,
nevretenčnih zlomov in zlomov kolka. Zdravljenje izgubljanja kostne mase, povezanega z ablacijo hormonov pri moških z rakom na prostati, ki imajo večje tveganje
zlomov. Pri moških z rakom na prostati, ki prejemajo zdravljenje z ablacijo hormonov, zdravilo Prolia® znatno zmanjša tveganje zlomov vretenc.
ODMERJANJE IN NAČIN UPORABE: Priporočeni odmerek zdravila Prolia® je 60 mg enkrat na 6 mesecev v enkratni subkutani injekciji v stegno, trebuh ali zadnjo stran roke.
Bolniki morajo dobivati zadostne dodatke kalcija in vitamina D. Bolniki z okvaro ledvic: Prilagoditev odmerka ni potrebna. Bolniki z okvaro jeter: Varnost in učinkovitost
denosumaba pri bolnikih z okvaro jeter nista raziskani. Starejši bolniki (stari > 65 let): Prilagoditev odmerka ni potrebna. Pediatrični bolniki: Uporaba zdravila Prolia® ni
priporočljiva za pediatrične bolnike (stare < 18 let), ker njegovi učinkovitost in varnost pri teh bolnikih nista dokazani.
Zdravilo mora aplicirati oseba, ki se je za injiciranje ustrezno usposobila. Za subkutano uporabo.
KONTRAINDIKACIJE: Hipokalciemija in preobčutljivost za zdravilno učinkovino ali katerokoli pomožno snov.
POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Za vse bolnike je pomembno, da uživajo dovolj kalcija in vitamina D. Hipokalciemijo je treba še pred začetkom
zdravljenja odpraviti z zadostnim uživanjem kalcija in vitamina D. Bolniki s hudo okvaro ledvic (očistek kreatinina < 30 ml/min) in bolniki na dializi imajo večje tveganje
za pojav hipokalciemije. Pri bolnikih, ki so nagnjeni k hipokalciemiji, je priporočljivo klinično spremljati koncentracijo kalcija. Pri bolnikih, ki dobivajo zdravilo Prolia®,
se lahko pojavijo okužbe kože (predvsem celulitis), ki zahtevajo bolnišnično zdravljenje. Ob pojavu znakov ali simptomov celulitisa naj bolniki takoj poiščejo zdravniško
pomoč. Pri bolnikih, zdravljenih z denosumabom in difosfonati, ki predstavljajo še eno skupino antiresorpcijskih zdravil, je bila opisana osteonekroza čeljusti. Večinoma
je bila opisana pri bolnikih z rakom; nekaj primerov pa je bilo zabeleženih tudi pri bolnikih z osteoporozo. Osteonekrozo čeljusti so zabeležili redko v kliničnih študijah pri
bolnikih, ki so dobivali denosumab v odmerku 60 mg na 6 mesecev za zdravljenje.
Opisani pa so bili primeri osteonekroze v kliničnih študijah pri bolnikih z napredovalim rakom, ki so dobivali denosumab v raziskovanem odmerku 120 mg na
mesec. Znani dejavniki tveganja za osteonekrozo čeljusti so rak s kostnimi spremembami, sočasna zdravljenja (npr. kemoterapija, antiangiogena biološka zdravila,
kortikosteroidi, obsevanje glave in vratu), slaba ustna higiena, ekstrakcije zob in spremljajoče bolezni (npr. predhodna zobna bolezen, anemija, koagulopatija, okužba)
ter predhodno zdravljenje z difosfonati. Bolniki s sočasnimi dejavniki tveganja morajo pred zdravljenjem z zdravilom Prolia® opraviti zobozdravstveni pregled,
vključno z ustreznimi preventivnimi zobozdravstvenimi ukrepi. Med zdravljenjem se je treba pri teh bolnikih po možnosti izogniti invazivnim zobozdravstvenim
posegom. Med zdravljenjem z zdravilom Prolia® je treba skrbeti za dobro ustno higieno. Kirurški posegi v ustni votlini lahko poslabšajo stanje bolnikov, ki se jim
med zdravljenjem z zdravilom Prolia® pojavi osteonekroza čeljusti. Če se med zdravljenjem z zdravilom Prolia ®pojavi osteonekroza čeljusti, je treba stanje klinično
presoditi in oblikovati načrt zdravljenja za vsakega bolnika glede na individualno oceno koristi in tveganja. Pokrovček igle na napolnjeni injekcijski brizgi vsebuje
suho naravno gumo (derivat lateksa), ki lahko povzroči alergijske reakcije. Opozorila glede pomožnih snovi: Bolniki z redko prirojeno motnjo intolerance za fruktozo
ne smejo uporabljati zdravila Prolia®. To zdravilo vsebuje manj kot 1 mmol (23 mg) natrija na 60 mg, kar pomeni, da je praktično ,,brez natrija“.
MEDSEBOJNO DELOVANJE Z DRUGIMI ZDRAVILI IN DRUGE OBLIKE INTERAKCIJ: Študij medsebojnega delovanja niso izvedli. Kliničnih podatkov o sočasni uporabi
denosumaba in hormonskega nadomestnega zdravljenja (estrogena) ni, vendar je možnost farmakodinamičnih medsebojnih delovanj predvidoma majhna. Po
izsledkih študije, opravljene pri prehodu z alendronata na denosumab, predhodno zdravljenje z alendronatom pri ženskah po menopavzi z osteoporozo ni spremenilo
farmakokinetike in farmakodinamike denosumaba.
NOSEČNOST IN DOJENJE: O uporabi zdravila Prolia® pri nosečnicah ni zadostnih podatkov. Ni znano, ali se denosumab pri človeku izloča v materino mleko. Odločiti se je treba,
ali naj ženska neha dojiti ali naj neha uporabljati zdravilo Prolia®.
NEŽELENI UČINKI: Varnost zdravila Prolia® so ocenjevali v kliničnih preskušanjih II. in III. faze, kontroliranih s placebom, v katere je bilo vključenih 10.534 žensk po
menopavzi z osteoporozo (v trajanju do 5 let) ter bolnic oz. bolnikov z rakom na dojki ali na prostati, ki so se zdravili z ablacijo hormonov. Pogosti (≥ 1/100 do < 1/10):
okužba sečil, okužba zgornjih dihal, išias, katarakte, zaprtost, izpuščaj, bolečina v okončini. Občasni (≥ 1/1.000 do < 1/100): divertikulitis, celulitis, okužba ušesa, ekcem.
Zelo redek (< 1/10.000): hipokalciemija.
POSEBNA NAVODILA ZA SHRANJEVANJE: Shranjujte v hladilniku (pri temperaturi od 2 °C do 8 °C). Ne zamrzujte. Napolnjeno injekcijsko brizgo shranjujte v zunanji ovojnini za
zagotovitev zaščite pred svetlobo. Ne stresajte premočno. Zdravilo Prolia® se lahko shranjuje pri sobni temperaturi (do 25 °C ) do 30 dni v originalnem vsebniku. Ko vzamete
zdravilo Prolia® iz hladilnika, ga morate uporabiti v 30 dneh.
POSEBNI VARNOSTNI UKREPI ZA ODSTRANJEVANJE IN RAVNANJE Z ZDRAVILOM: Raztopino zdravila Prolia® je treba pred injiciranjem pregledati. Raztopine ne smete injicirati,
če vsebuje delce, če je motna ali obarvana. Za preprečitev nelagodja na mestu dajanja je treba zagotoviti, da napolnjena injekcijska brizga pred injiciranjem doseže sobno
temperaturo (do 25 °C), zdravilo pa je treba injicirati počasi. Injicirajte celotno vsebino napolnjene injekcijske brizge. Morebitni ostanek zdravila v napolnjeni injekcijski brizgi
je treba zavreči.
NAČIN IN REŽIM PREDPISOVANJA TER IZDAJE ZDRAVILA: Predpisovanje in izdaja zdravila je le na recept.
IMETNIK DOVOLJENJA ZA PROMET: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, Nizozemska
Dodatna pojasnila lahko dobite v lokalnih pisarnah:
Amgen zdravila d.o.o., Šmartinska 140, SI-1000 Ljubljana
GlaxoSmithKline d.o.o., Knezov štradon 90, 1001 Ljubljana
DATUM ZADNJE REVIZIJE BESEDILA: 20. september 2010
Podrobne informacije o zdravilu so objavljene na spletni strani Evropske agencije za zdravila http://www.ema.europa.eu
Literatura:
1. Povzetek glavnih značilnosti zdravila Prolia, 2010
Amgen zdravila d.o.o.
Šmartinska 140, SI-1000 Ljubljana
Tel.: +386 1 585 1767, faks: +386 1 585 2024, www.amgen.com
GSK d.o.o., Ljubljana
Knezov štradon 90, 1001 Ljubljana
Tel.: +386 1 28 02 500, faks: +386 1 28 02 550, www.gsk.si
SLO-DB-AMG-019-2011-M
Epidemiologija raka sečnega mehurja
Epidemiology of bladder cancer
Maja Primic Žakelj, Vesna Zadnik
Epidemiologija in register raka, Onkološki inštitut Ljubljana, Slovenija
Epidemiology end Cancer Registries, Institute of Oncology Ljubljana, Slovenia
Izvleček
Abstract
Rezultati: V Sloveniji je leta 2007 za rakom sečnega
mehurja zbolelo 281 ljudi, 203 moških in 78 žensk, umrlo
pa 168 bolnikov, 130 moških in 38 žensk. In situ primerov
je bilo registriranih 171, 130 pri moških in 41 pri ženskah.
Ocenjujemo, da je leta 2010 zbolelo okrog 313 ljudi, 220
moških in 93 žensk. Groba in starostno standardizirana
incidenčna stopnja se v zadnjih desetih večata pri obeh spolih,
bolj groba kot starostno standardizirana. Okrog polovica
bolnikov zboli v starosti 50–74 let, v letih 2003–2007 je bilo v
tej starostni skupini 65,2 % moških in 48,7 % žensk. Petletno
relativno preživetje vseh zbolelih v obdobju 2001–2005 je
bilo 51 %; bolniki, ki preživijo prvo leto, pa lahko pričakujejo
67-odstotno petletno relativno preživetje. Preživetje naših
bolnikov še vedno zaostaja za evropskim povprečjem.
Results: There were 281 cases of bladder cancer registered
in Slovenia in 2007, 209 in males and 78 in females and 171
in situ cases, 130 in males and 41 in females; there were
168 bladder cancer deaths, 130 in males and 38 in females.
It is estimated that in 2010 there were 313 new cases, 220
in males and 93 in females. The crude and age standardized
incidence rates have been increasing in the last 10 years,
more crude than age standardized. At diagnosis, about half
of patients are aged 50–74; in the period 2003–2007 there
were 65.2% of males and 48.7% of females in this age group.
The 5-year relative survival of patients diagnosed in 2001–
2005 was 51%; patients surviving the first year can expect
67% relative survival. The survival of Slovenian patients is
still lower than European average.
Zaključki: V preventivi raka sečnega mehurja je treba
preprečiti izpostavljenost delavcev znanim karcinogenom,
na ravni posameznika pa je najpomembnejše nekajenje in
opuščanje kajenja.
Conclusions: The most important primary prevention
measure is the state regulation of exposure of workers to
known occupational carcinogens, while at the individual level
nonsmoking and quitting smoking reduces bladder cancer
risk.
Ključne besede: rak sečnega mehurja, epidemiologija,
nevarnostni dejavniki, preventiva
Key words: bladder cancer, epidemiology, risk factors,
prevention
Izhodišča: Rak sečnega mehurja je bil leta 2008 pri moških
sedmi najpogostejši rak na svetu, pri ženskah je redkejši.
Kazalnike bremena raka, predvsem incidenco, je treba
primerjati med posameznimi državami pazljivo, saj registracija
raka sečnega mehurja po svetu ni enotna. Ponekod vštevajo
med raka tudi primere in situ in neinvazivni papilarni karcinom
(stadija Ta in Tis). Register raka Republike Slovenije (RRRS)
vsa leta upošteva pravilo, da v incidenco raka šteje le primere
invazivnega raka sečnega mehurja, površinskega (T1) in
mišično invazivnega (T2-T4), posebej pa vodi primere in situ
skupaj z nainvazivnim papilarnim karcinomom.
Na podlagi mednarodnih podatkovnih zbirk in podatkov
RRRS so opisani osnovni kazalniki bremena raka sečnega
mehurja v svetu, v Evropi in v Sloveniji: incidenca, umrljivost
in preživetje ter nevarnostni dejavniki in možnosti primarne in
sekundarne preventive.
Background: Bladder was the seventh most common
cancer site in males in 2008 worldwide, while it was less
frequent among females. The cancer burden indicators,
especially incidence, should be interpreted and even
more, compared between countries, with caution, as the
registration of bladder cancer is not uniform in all cancer
registries. In some registries, non-invasive bladder cancers
(in situ and noninvasive papillary carcinoma) are included in
cancer incidence (stages Tis and Ta). In the Cancer Registry
of Republic of Slovenia (CRRS), stages Tis and Ta are not
included in the bladder cancer incidence, but only stages T1–
T4. In this presentation, basic measures of bladder cancer
burden (incidence, prevalence and survival) are presented
using the data from international databases and the CRRS
database as well as bladder cancer risk factors and primary
and secondary prevention measures.
Uvod
Rak sečnega mehurja je bil leta 2008 pri moških sedmi
najpogostejši rak, pri ženskah je redkejši (1). Kazalnike
bremena raka, predvsem incidenco, je treba primerjati med
posameznimi državami pazljivo, saj registracija raka sečnega
mehurja v vseh registrih ni enotna. Ponekod vštevajo med
raka tudi primere in situ (Tis) in neinvazivni papilarni karcinom
(stadija Ta in Tis). RRRS vsa leta upošteva pravilo, da v
incidenco raka šteje le primere invazivnega raka sečnega
mehurja, površinskega (T1) in mišično invazivnega (T2T4), posebej pa vodi primere in situ skupaj z nainvazivnim
papilarnim karcinomom.
Breme raka sečnega mehurja v tem pregledu prikazujemo z
osnovnimi epidemiološkimi kazalniki, incidenco, umrljivostjo
in s preživetjem bolnikov. Povzeli smo jih iz objavljenih analiz
podatkov registrov raka in statistike umrljivosti (1, 2). Incidenca
pomeni število vseh v enem koledarskem letu na novo
ugotovljenih primerov raka v točno določeni populaciji. Groba
incidenčna stopnja je število novih primerov, preračunano
na 100.000 oseb opazovane populacije. Če analiziramo
incidenco v daljšem časovnem obdobju (in se starostna
struktura prebivalstva v času spreminja) ali če primerjamo
incidenco med populacijami z različno starostno strukturo,
je treba uporabiti eno od metod starostne standardizacije.
Starostno standardizirana stopnja je teoretična incidenčna
stopnja, pri kateri predpostavimo, da je starostna struktura
opazovane populacije enaka starostni strukturi v standardni
populaciji. V našem prikazu smo za standard uporabili
svetovno prebivalstvo (3).
Za Slovenijo so prikazani objavljeni in neobjavljeni podatki
RRRS (3, 4). Za prikaz incidence po stadiju nismo uporabili
klasične klasifikacije TNM, pač pa poenostavljeno, ki jo
uporabljajo registri. Po tej klasifikaciji se bolezen razvršča v
omejeni stadij, stadij regionalne razširitve, stadij oddaljene
razširitve ter neznani stadij (4). Preživetje bolnikov je
prikazano kot relativni odstotek preživetja, ki pomeni razmerje
med opazovanim preživetjem proučevane skupine in
preživetjem, ki bi ga pričakovali pri enako stari skupini istega
spola v slovenski populaciji. Je približek preživetja bolnikov v
primeru, da bi upoštevali kot vzrok smrti samo izbranega raka.
Metoda je natančneje opisana v knjigi Preživetje bolnikov z
rakom v Sloveniji 1991–2005 (5).
novih primerov je iz ekonomsko razvitejših svetovnih področij
in saharske Afrike. Ocenjena starostno standardizirana
incidenčna stopnja raka sečnega mehurja je bila leta 2008
pri moških največja v Izraelu, Španiji, Egiptu, na Danskem,
Češkem in v S Ameriki, pri ženskah pa na Islandiji, na
Danskem, Češkem in v S Ameriki (1).
V Evropi je bila pri moških leta 2008 ocenjena starostno
standardizirana incidenčna stopnja največja v Španiji, sledile
so Danska, Nizozemska, Norveška in Češka, najmanjša pa na
Finskem, v Sloveniji, v Luksemburgu, Angliji in Romuniji. Pri
ženskah je bila največja stopnja na Danskem, Nizozemskem,
Norveškem in Irskem, najmanjša pa v Franciji, Litvi, Grčiji in
na Cipru (2).
Za rakom sečnega mehurja je leta 2008 v svetu umrlo
150.282 ljudi, 112.308 moških in 37.974 žensk (1), v Evropi
pa 51.056 ljudi, 38.606 moških in 12.450 žensk.
Rak sečnega mehurja v Sloveniji
V Sloveniji je leta 2007 za rakom sečnega mehurja zbolelo
281 ljudi, 203 moških in 78 žensk, umrlo pa 168 bolnikov,
130 moških in 38 žensk. Med vsemi raki je bil rak sečnega
mehurja s 3,3 % vseh novih primerov na 7. mestu, pri ženskah
pa z 1,4 % na 16. mestu. In situ primerov je bilo registriranih
171, 130 pri moških in 41 pri ženskah. Ocenjujemo, da je leta
2010 za rakom sečnega mehurja zbolelo okrog 313 ljudi, 220
moških in 93 žensk (3).
Groba in starostno standardizirana incidenčna stopnja se
v zadnjih desetih letih (1998–2007) večata pri obeh spolih,
bolj groba kot starostno standardizirana. Ocenjeni delež
letne spremembe starostno standardizirane incidenčne
stopnje pri moških je 1 %, pri ženskah pa 2 % (3). Starostno
standardizirana umrljivostna stopnja je v zadnjih 10 letih pri
obeh spolih nista bistveno spremenili (Sliki 1 in 2) (3).
Slika 1. Groba in starostno standardizirana incidenčna
stopnja raka sečnega mehurja po spolu, Slovenija 1988–
2007.
Rak sečnega mehurja v svetu in v Evropi
Po ocenah Mednarodne agencije za raziskovanje raka je leta
2008 po svetu za rakom sečnega mehurja zbolelo 382.660
ljudi, 294.345 moških in 88.315 žensk in predstavlja 4,4 %
vseh rakov pri moških in 1,5 % vseh rakov pri ženskah (1).
Razmerje med spoloma je v splošnem okrog 3:1. Tri četrtine
Figure 1. Crude and age-standardized incidence rate of bladder cancer by sex, Slovenia 1988–2007.
Slika 2.
Groba in starostno standardizirana (SSS) umrljivostna stopnja raka sečnega mehurja po spolu, Slovenija 1988–2007.
Figure 2. Crude and age-standardized (ASR)mortality rate of bladder cancer by sex, Slovenia 1988–2007.
10
V obdobju 2003–2007 je bilo 95 % primerov raka sečnega
mehurja potrjenih s histološko preiskavo, 1 % samo s
citološko, drugi s kliničnimi preiskavami. Delež histološko
potrjenih primerov se v zadnjih 10 letih ni bistveno spremenil.
Največ bolnikov je imelo karcinom prehodnega epitela (87,4
%), 1,5 % je bilo adeno- in ploščatoceličnih karcinomov, pri
ostalih bolnikih histološka vrsta ni bila določena.
Okrog polovica bolnikov zboli v starosti 50–74 let, v letih
2003–2007 je bilo v tej starostni skupini 65,2 % moških in
48,7 % žensk. V starosti 75 let in več je v tem obdobju zbolelo
32 % moških in 47 % žensk. Rak sečnega mehurja je pri
obeh spolih pred 50. letom starosti izjemno redka bolezen,
starostno specifična incidenčna stopnja se pri obeh spolih
veča s starostjo (Slika 3) (3).
Slika 3. Starostno specifična incidenčna stopnja raka sečnega mehurja po spolu, Slovenija 2003–2007.
Figure 3. Age specific incidence ratesof bladder cancer by sex, Slovenia 2003–2007.
Največ bolnikov ima ob diagnozi omejeno bolezen; v letih
2003–2007 je bilo takih 72,3 % (40,8 % pT1 in 21,9 % pT2;
pri 9,6 % pT ni bil določen). Sedemnajst odstotkov bolnikov
je imelo ob diagnozi razširjeni stadij, 6,6 % pa razsejanega;
delež bolnikov z razsejanim stadijem se je od obdobja
1993–997 sicer nekoliko povečal, predvsem na račun boljše
opredelitve stadija, saj se je zmanjšal delež brez določenega
stadija. V letih 1993–1997 stadija ni imelo določenega 8 %
bolnikov, deset let kasneje pa 4 % (3).
V obdobju 2003–2007 ni bilo specifično zdravljenih 7,7
% bolnikov. Med specifično zdravljenimi se je pri 69 %
primerov prvo zdravljenje zaključilo z operacijo (natančnejših
podatkov o tem, koliko je bilo radikalnih cistektomij, koliko
pa transuretralnih resekcij, v RRRS ni), 12 % jih je bilo
poleg operacije dodatno zdravljenih s kemoterapijo, 6 %
pa z obsevanjem, 5 % je poleg operacije prejelo kemo- in
radioterapijo, 6 % pa je po operaciji prejelo še intravezikalno
zdravljenje; preostala 2 % bolnikov je bilo zdravljenih z
drugimi kombinacijami.
Relativno preživetje bolnikov z rakom sečnega mehurja,
zbolelih v letih 1991–2005, smo leta 2009 objavili v posebni
monografiji (5). Izkazalo se je, da se preživetje naših bolnikov
v 15 letih ni bistveno povečalo; v zadnjem obdobju se je celo
zmanjšalo (na 51 % v primerjavi z leti 1996–2000, ko je bilo
53 %), bolj pri ženskah kot pri moških. Stadij ob diagnozi
je sicer napovedni dejavnik izida bolezni, saj je preživetje
največje pri bolnikih z omejenim stadijem, vendar tudi pri
teh bolnikih v zadnjem obdobju ni pomembnega izboljšanja:
petletno relativno preživetje bolnikov z omejenim stadijem
v letih 2001–2005 je bilo 65-odstotno. Napovedni dejavnik
je tudi starost, saj je relativno preživetje najslabše pri
starih 75 let in več, pri katerih se je v zadnjem obdobju tudi
najbolj zmanjšalo; manjši napredek je le bil le pri bolnikih,
diagnosticiranih v starosti 50–74 let.
Petletno relativno preživetje vseh zbolelih v obdobju 2001–
2005 je bilo 51 %; bolniki, ki preživijo prvo leto, pa lahko
pričakujejo 67-odstotno petletno relativno preživetje.
Rezultati študije EUROCARE-4 za zbolele v obdobju 2000–
2002 kažejo, da je preživetje slovenskih bolnikov z rakom
sečnega mehurja statistično značilno manjše od evropskega
povprečja za 20 % (5).
11
Razloge za slabše preživetje pri nas je v svojem magistrskem
delu iskala Urška Bizjak Ogrinc. Zaključila je, da je eden od
razlogov za slabše preživetje pri nas verjetno tudi premajhen
delež bolnikov, zdravljenih z radikalno cistektomijo.
Ugotovila je, da je bilo v letih 1987, 1992 in 1997 samo
6,6 % bolnikov (5 % stadija T2 in 16 % stadija T3) deležnih
radikalne cistektomije (6). To je standardno zdravljenje
mišično invazivnega raka sečnega mehurja, s katerim je
mogoče ozdraviti okoli polovico bolnikov. V teh letih je 57
% bolnikov v okviru kirurškega zdravljenja imelo opravljeno
samo trensuretralno resekcijo (TUR), ki za večino bolnikov
ni najustreznejši način zdravljenja. Drugi način zdravljenja
za izbrane bolnike z mišično invazivnim rakom mehurja je
ohranitveno zdravljenje s TUR, kemoterapijo in obsevanjem.
To zdravljenje je primerno le za malo bolnikov z mišično
invazivnim rakom, zato je delež tako zdravljenih bolnikov
povsod po svetu, pa tudi pri nas, majhen. Pri nas je bilo
tako zdravljenih v letih 1992 in 1997 le okoli 6 % bolnikov z
mišično invazivnim rakom mehurja.
Nevarnostni dejavniki raka sečnega mehurja
Starost in spol: Najbolj zanesljiv nevarnostni dejavnik
raka sečnega mehurja je starost, saj se verjetnost bolezni
veča s staranjem. Večja pogostnost med moškimi ni v celoti
pojasnjena, lahko da gre na račun večje izpostavljenosti
karcinogenom; v kolikšni meri imajo vlogo pri nastanku spolni
hormoni in njihovi receptorji v mehurju, še ni znano (7).
Kajenje: Pomemben nevarnostni dejavnik je kajenje, ki ga
povezujejo s 65 % raka pri moških in 30 % pri ženskah.
Epidemiološke raziskave, opravljene v različnih populacijah
so pokazale, da je zveza med trajanjem in intenziteto kajenja
linearna in da je od svetlejšega nevarnejši temni tobak.
Domnevajo, da so za mehur nevarni 2-naftilamin in drugi
aromatski amini iz cigaretnega dima, ki jih je več v temnem
tobaku (8). Delež rakov, ki jih je mogoče pripisati kajenju, je
odvisen od stanja epidemije kajenja v posameznih svetovnih
področjih; v skupni analizi evropskih raziskav primerov s
kontrolami so ocenili, da je kajenju mogoče pripisati 66 %
primerov pri moških in 30 % pri ženskah (9, 10).
Poklicna izpostavljenost: Rak sečnega mehurja je prvi rak
notranjih organov, za katerega je bila ugotovljena povezanost
s kemičnimi karcinogeni na delovnem mestu. Že Rehn je leta
1895 poročal o 4 bolnikih z rakom sečnega mehurja, ki so
delali v tovarni anilinskih barvil (11). Danes veljajo za dokazane
karcinogene za sečni mehur štirje aromatski amini: benzidin,
2-naftilamin, 4-aminodifenil in 4-nitrodifenil, za potencialne pa
avramin, magenta, nekateri derivati benzidina in še nekateri
drugi aromatski amini. Nekatere teh snovi so se uporabljale
ali se še uporabljajo za izdelavo barv za tekstil, usnje, papir,
lase, pleskarske barve, kot antioksidanti v izdelavi gume
za avtomobilske pnevmatike in električne kable, pa tudi kot
dodatki pri izdelavi epoksidnih smol in poliuretanov. Nekatere
epidemiološke raziskave so bolj ali manj utemeljile sum, da
so karcinogeni za sečni mehur še aromatski ogljikovodiki v
premogovem prahu, sajah in katranu, plinih, ki se sproščajo
pri varjenju, v naftnih derivatih in neznane snovi v prahu
lesa, usnja in v pesticidih. Ocene deleža poklicne etiologije
v incidenci raka sečnega mehurja se v svetu razlikujejo,
kar gre pripisati razliki v uporabi karcinogenov v industriji v
posameznih državah. Tako so npr. v Angliji na osnovi dognanj
o karcinogenosti 2-naftilamina priznali raka sečnega mehurja
za poklicno bolezen že v začetku petdesetih let prejšnjega
stoletja, njegovo proizvodnjo in uporabo pa prepovedali sredi
šestdesetih; v ZDA so ga prepovedali šele leta 1970. Podobno
so države postopno prepovedale benzidin in 4-aminodifenil v
proizvodnji gume in barv za tekstil (12).
Poleg intenzitete in trajanja izpostavljenosti k verjetnosti
bolezni prispeva tudi individualna genetska občutljivost. V
razgradnji aromatskih aminov sodelujejo različni encimi, med
njimi N-acetiltransferaza in glutation-S-transferaza. Encimsko
aktivnost N-acetil-transferaze uravnavata dva gena, NAT1 in
NAT2, ki kažeta polimorfizem. Nekateri ljudje imajo manjšo
aktivnost encima, s tem je razgradnja aminov počasnejša,
njihova koncentracija v mehurju pa večja; počasni acetilatorji
imajo zato večje tveganje (13).
Zdravila: Tudi nekatera zdravila večajo tvaganje: ciklofosfamid,
fenacetinski analgetiki in izoniazid. Ciklofosfamid verejtno
zato, ker zavira imunsko obrambo, fenacetin, ker iz njega
v presnovi nastaja karcinogen metabolit, izoniazid pa prek
vpliva na presnovo triptofana (14).
Okužbe: V endemičnih področjih Afrike je rak sečnega
mehurja posledica kronične shistosomiaze; približno 70
% bolnikov s to okužbo zboli za ploščatoceličnim rakom
(15). Zaenkrat še ni dovolj dokazov, da bi bilo mogoče
raka sečnega mehurja povezati tudi z drugimi okužbami,
bakterijskimi ali virusnimi, čeprav proučujejo številne, med
drugim tudi okužbe s HPV (16).
Kava in alkohol: Čeprav so morebitno povezavo med pitjem
kave in alkoholnih pijač proučevali v številnih raziskava,
zaenkrat o večji ogroženosti ni soglasja; če tveganje obstoji,
je zelo majhno (16).
Zaključek
V preventivi raka sečnega mehurja je po eni strani pomembna
zakonodaja, s katero je treba prepovedati stik delavcev
z dokazanimi karcinogeni; na ravni posameznika pa je
najpomembnejše nekajenje in opuščanje kajenja.
12
Presejalni testi so pomembni za ogrožene skupine, kamor
sodijo izpostavljeni delavci, predvsem pa bolniki, ki so že
bili zdravljeni, saj se bolezen pogosto ponavlja. Ugotavljanju
mikrohematurije in citološki preiskavi se v zadnjem času
pridružujejo molekularne metode, njihovo širšo uporabnost
pa zaenkrat še preverjajo v raziskavah (17).
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11–20.
13
Classification on non-invasive bladder neoplasms: is it time
for a revised 2004 WHO scheme?
Rodolfo Montironi
Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United
Hospitals, Ancona, Italy
Introduction
The non-invasive urothelial lesions and neoplasms can be flat
(planophytic), papillary (exophytic) and inverted (endophytic),
depending on their growth pattern relationship with the
surface of the surrounding urothelial mucosa [1]. Extensive
clinico-pathological studies have been published related to
the first two growth patterns. The clinical significance of the
third has been dealt with only at a very limited extent.
Flat (planophytic) lesions and neoplasms
The 2004 WHO classification of the flat lesions includes flat
hyperplasia, dysplasia and carcinoma in situ. In addition,
this classification also lists reactive atypia, secondary to
inflammation, and atypia of unknown significance.
Flat urothelial hyperplasia
Urothelial hyperplasia is characterized by markedly
thickened urothelium with an increase in the number of cell
layers, usually 10 or more. The cells do not show cytological
abnormalities, although slight nuclear enlargement may be
focally present. Morphologic evidence of maturation from
base to surface is evident. Mitoses are absent. It has been
described in association with inflammatory disorders as well
as adjacent to low-grade papillary tumours [2]. Molecular
analyses have shown that this lesion may be clonally related
to the papillary tumours in bladder cancer patients and
suggest a role in the pathogenesis of low-grade papillary
urothelial carcinoma [3,4].
Urothelial dysplasia
Urothelial dysplasia is characterized by architectural
distortion and a variable degree of atypia. The thickness is
usually normal and cytological changes are restricted to the
intermediate and basal cells The nuclei are irregularly enlarged
with loss of polarity and pleomorphism. Scant is the mitotic
activity, usually involving only the basal and intermediate cell
layers. Overall the features are those of a neoplastic atypia
but fall short of the criteria for CIS. There is some evidence,
largely genetic, that dysplasia shares some abnormalities
with CIS and therefore likely represents a precursor lesion.
One study indicates a 19% risk of developing cancer with a
mean follow up of 4.9 years [5].
Urothelial carcinoma in situ (CIS)
CIS is characterized by architectural disorder and nuclear
pleomorphism. There is loss of nuclear polarity and the cells
show a high degree of atypia. Mitoses are generally frequent
and may be seen at any level of the epithelium. Since the
histological criteria for distinguishing severe dysplasia from
CIS are unreliable, it is recommended to combine them into
a single category, i.e., CIS. The development of invasion is
seen in 20 to 30% of the cases [6-11].
CIS with microinvasion (CISmic) of the urinary bladder is
defined by invasion into the lamina propria to a depth of 5
mm from the basement membrane, or, according to LopezBeltran et al, should not exceed 20 cells in the sub-epithelial
connective tissue [12,13]. CISmic is a clinically relevant
lesion. 34% of totally embedded cystectomy specimens
that contain extensive CIS, i.e., involving at least 25% of
the bladder, are found to contain microinvasion. 5.8% have
lymph node metastases and die of disease.
Papillary (exophytic) lesions and neoplasms
The lesions and neoplasms of this group grow exophytically
into the lumen of the urinary system with a papillary
configuration. According to the 2004 WHO classification,
this group includes urothelial papilloma, papillary urothelial
hyperplasia, papillary urothelial neoplasm of low malignant
potential (PUNLMP), low-grade papillary carcinoma and
high-grade papillary carcinoma.
Urothelial papilloma is characterized by a few fine papillary
fronds lined by normal urothelium and shows a very low
recurrence rate. Papillary urothelial hyperplasia is defined as
undulating urothelium arranged into thin mucosal papillary
folds of varying heights occurring in a non inflamed setting
[14]. The lack of cytological atypia and fibrovascular cores
characterize this lesion. Papillary urothelial hyperplasia
appears to be a precursor lesion to papillary urothelial
neoplasms, predominantly lower grade lesions [15].
Papillary urothelial neoplasm of low malignant potential,
low-grade papillary carcinoma and high-grade papillary
carcinoma show a morphological spectrum with similarities
with flat hyperplasia, dysplasia and CIS, respectively.
14
Papillary urothelial neoplasm of low malignant
potential
PUNLMP largely, though not completely, corresponds to
grade 1 papillary carcinoma of the 1973 WHO system. The
lesion consists of delicate papillae with little or no fusion.
The covering urothelium shows minimal architectural
irregularity. Nuclei lack significant nuclear hyperchromasia
or pleomorphism. The chromatin is fine and nucleoli are
inconspicuous. Mitoses are infrequent and basally located.
This tumor has a significantly lower rate of recurrence than
either low- or high-grade papillary carcinomas and a very low
rate of grade and stage progression. In a review of published
studies, a mean tumor recurrence rate to be 36% and stage
progression rate to be 3.7% [4].
Low-grade papillary carcinoma
The majority of cases would have been considered as
grade 2 in the 1973 WHO system. WHO grade 1 neoplasms
showing slight cytological atypia and mitoses, are diagnosed
in the 2004 WHO system as low-grade papillary urothelial
carcinomas. At low magnification there is a generally ordered
appearance of the cells within the epithelium. The nuclei
tend to be uniformly enlarged but retain the elongated to oval
shape of normal urothelial cells. The chromatin remains fine
with small nucleoli. Mitoses may be present but are few and
remain basally located. These tumors have a significantly
higher recurrence rate than for PUNLMP. They also have a
significantly higher rate of stage progression than PUNLMP
but significantly lower than for high-grade papillary carcinoma.
A review of the literature reveals a mean recurrence rate of
50% and mean stage progression rate of 10%.
High-grade papillary carcinoma
It corresponds to grade 3 papillary carcinoma in the 1973
WHO system. It includes WHO grade 2 lesions bordering on
higher grade lesions, which in many institutions are called
WHO grade 2-3. Individual cells are haphazardly arranged
within the epithelium and have a generally discohesive
nature. Nuclei are hyperchromatic and pleomorphic. The
chromatin is dense, irregularly distributed and often clumped.
Nucleoli may be single or multiple and are often prominent.
Mitoses are generally frequent and may be seen at any level
of the epithelium. It is often associated with invasive disease
at the time of diagnosis [16-23].These tumors not only have
a risk of invasion but have a significant risk of recurrence
and progression. The overall progression rate (to invasive
carcinoma) ranges from 15% to 40%.
Inverted (endophytic) lesions and neoplasms
The lesions and neoplasms of this group is basically
characterized by an epithelium that shows a non-infiltrative
growth into the subepithelial connective tissue, even though,
cystoscopically they might show a polypoid appearance.
von Brunn’s nests and cystitis cystica and glandularis are
the benign prototypes of inverted (endophytic) lesions. von
Brunn’s nests refer to small groups of basal-like cells lying
in the subepithelial connective tissue and attached the basal
cell layer of the urothelium. Cystitis glandularis is composed
of glands in the lamina propria which are lined by Cuboidal or
columnar cells surrounded by urothelial cells. Cystitis cystica
is made of cystically dilated von Brunn’s nests acquiring a
luminal space.
Inverted urothelial papilloma, included in the 2004 WHO
classification, shows a polypoid appearance and consists
of thin anastomosing trabeculae of urothelial cells within
the subepithelial connective tissue and covered by a normal
or attenuated urothelium [24-26]. There is no nuclear
pleomorphism and few mitoses can be seen. Inverted
papilloma is associated with a low risk of recurrence (<
5%). Cases of synchronous inverted papilloma and papillary
carcinoma are known.
Reports of a non-invasive urothelial carcinoma with inverted
growth pattern are found in the literature and mentioned
in some recent books [2,27-29]. The endophytic growth
pattern in this carcinoma has been described either as
inter-anastomosing cords and columns of urothelium, often
with a striking resemblance to inverted papilloma (inverted
papilloma-like pattern), or as broad, pushing bulbous
invaginations into the lamina propria (broad-front pattern)
(Table 1). A diagnosis of invasion requires the unquestionable
presence within the lamina propria of irregularly shaped
nests or single cells that may have evoked a desmoplastic or
inflammatory response. When a stromal response is absent,
irregularity of the contours of the invasive nests, architectural
complexity and recognition of single-cell invasion are helpful
(Table 2).
Morphologic spectrum of the non-invasive
urothelial neoplasms with an inverted growth
pattern
Morphologically the urothelial neoplasms with an inverted
growth pattern (other than inverted urothelial papilloma)
show a spectrum of architectural and cytological features. In
comparison with inverted urothelial papilloma, the architectural
features favouring a diagnosis of a urothelial neoplasm with an
inverted growth pattern include thick columns with irregularity
in their width and transition into more solid areas. The
characteristic orderly maturation, spindling, and peripheral
palisading seen in inverted papilloma are generally absent
or inconspicuous. The histological appearance of urothelial
neoplasms with a broad-front pattern is the pushing broadfront extension into the lamina propria, akin to cutaneous
15
and mucosal verrucous carcinoma and reminiscent of the
growth pattern of the von Brunn’s nests. The downward
projection can be so pronounced that the base of the tumour
lies on the muscularis propria. There is a wide range in the
severity of cytological atypia, such as nuclear pleomorphism,
irregularities of nuclear borders and chromatin distribution,
prominent nucleoli, and mitotic rate [30].
When diagnosing inverted urothelial neoplasms, pathologists
have used a variety of terms, including: inverted urothelial
papilloma, inverted urothelial papilloma with atypia [30],
inverted growth pattern of PUNLMP, urothelial carcinoma with
an inverted growth pattern, without any further specification
to the degree of cellular anaplasia, or even as invasive
urothelial carcinoma [30].
Similarly to the flat neoplasms, the overall cytological changes
range from hyperplasia to carcinoma in situ. Similarly to the
papillary neoplasms and in agreement with the approach
used in two books published very recently [30,31], three
subgroups could be defined in such range, i.e., neoplasms
that have the least degree of cytological atypia, neoplasms
with the most severe degrees of cytological atypia and those
that lie in between, i.e.,:
1. Inverted urothelial neoplasm of low malignant potential
(IUNLMP)
2. Low-grade inverted urothelial carcinoma
3. High-grade inverted urothelial carcinoma
Conclusions
The evaluation of the urothelial lesions and neoplasms
with an inverted or endophytic growth pattern shows a
morphological spectrum similar to that seen in the flat
and papillary counterparts (Table 3). However, this is not
fully recognized in the current literature in which, besides
inverted urothelial papilloma, only one form of neoplasms
is reported, i.e., urothelial carcinoma with an inverted growth
pattern. Scant molecular and clinical studies on the urothelial
carcinoma with an inverted growth pattern have been
published [28], mainly focussing on the differences with the
inverted urothelial papilloma. A classification and terminology
consistent with those of the flat and papillary urothelial lesions
and neoplasms should be adopted.
References
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A, Cheng L. Morphological diagnosis of urothelial
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2. Amin MB, Gómez JA, Young RH. Urothelial transitional cell
carcinoma with endophytic growth patterns: a discussion
of patterns of invasion and problems associated with
assessment of invasion in 18 cases. Am J Surg Pathol.
1997;21:1057-68.
3. Hodges KB, Lopez-Beltran A, Davidson DD, Montironi
R, Cheng L. Urothelial dysplasia and other flat lesions
of the urinary bladder: clinicopathologic and molecular
features. Hum Pathol 2010;41:155-62.
4. Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli
R, Cheng L. Morphological classification and definition of
benign, preneoplastic and non-invasive neoplastic lesions
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5. Cheng L, Cheville JC, Neumann RM, Bostwick DG.
Natural history of urothelial dysplasia of the bladder. Am
J Surg Pathol. 1999;23:443-7.
6. Birkhahn M, Mitra AP, Williams AJ, et al. Predicting
recurrence and progression of noninvasive papillary
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7. Burger M. Editorial comment on: prognostic accuracy of
individual uropathologists in noninvasive urinary bladder
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8. Guey LT, García-Closas M, Murta-Nascimento C, et al;
EPICURO/Spanish Bladder Cancer Study investigators.
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9. May M, Brookman-Amissah S, Roigas J, et al. Prognostic
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10. van Rhijn BW, Burger M, Lotan Y, et al. Recurrence and
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11. Yorukoglu K, Tuna B, Kirkali Z. Re: Matthias May,
Sabine Brookman-Amissah, Jan Roigas, et al.
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Eur Urol 2010;58: e7
12. Cheng L, Montironi R, Davidson DD, Lopez-Beltran
A. Staging and reporting of urothelial carcinoma of the
urinary bladder. Mod Pathol. 2009;22 (Suppl 2):S70-95.
13. Lopez-Beltran A, Cheng L, Andersson L, et al.
Preneoplastic non-papillary lesions and conditions of
the urinary bladder: an update based on the Ancona
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14. Taylor DC, Bhagavan BS, Larsen MP, Cox JA, Epstein JI.
Papillary urothelial hyperplasia. A precursor to papillary
neoplasms. Am J Surg Pathol 1996;20:1481-8.
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15. Readal N, Epstein JI. Papillary urothelial hyperplasia:
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16. Babjuk M. Second resection for non-muscle-invasive
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Eur Urol 2010;58:191-2.
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18. Divrik RT, Sahin AF, Ergör G. Reply from authors re:
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Ficarra. Does routine second transurethral resection
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22. Novara G, Ficarra V. Does routine second transurethral
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26. Sung MT, Maclennan GT, Lopez-Beltran A, Montironi R,
Cheng L. Natural history of urothelial inverted papilloma.
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27. Cheng L, Lopez-beltran A, MacLennan GT, Montironi
R, Bostwick DG. Neoplasms of the urinary bladder.
In: Bostwick DG, Cheng L, editors, Urologic Surgical
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2008. p. 289-292.
28. Hodges KB, Lopez-beltran A, MacLennan GT, Montironi
R, Cheng L. Urothelial lesions with inverted growth
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differential diagnosis and clinical management. BJU int
2010 (in press).
29. Jones TD, Zhang S, Lopez-Beltran A, et al. Urothelial
carcinoma with an inverted growth pattern can be
distinguished from inverted papilloma by fluorescence
in situ hybridization, immunohistochemistry, and
morphologic analysis. Am J Surg Pathol 2007;31:18617.
30. Epstein JI, Amin MB. Urothelial neoplasms with inverted
growth patterns. In: Epstein JI, Amin MB, editors. Biopsy
Interpretation of the Bladder, ed. 2. Philadelphia, USA:
Lippincot Williams & Wilkins 2010. p.79-93.
31. McKenney JK, Vankalakunti M. Overview of urinary
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Pathology: Genitourinary, ed. 1. Manitoba, Canada:
AMIRSYS 2010. p. 50.
17
Table 1. Morphologic, immunologic and molecular genetic features of inverted urothelial papilloma and urothelial carcinoma
with inverted pattern
Characteristic
Surface
Inverted urothelial papilloma
Smooth, domed shaped, usually intact
cytologically normal
Growth pattern
Endophytic, expansive, sharply delineated,
anastomosing cords and trabeculae
Cytologic features
Orderly polarized cells, some with spindling
and palisading at the periphery. No significant
atypia, mitoses rare
Immunohistochemistry
Low p53 expression and Ki-67 proliferation
index
Molecular analysis
Rare deletions at chromosome 9 or 17, rare
FGFR3 mutations, low rate of LOH**
Biological potential
Benign, rare recurrences*
*Rare recurrences related to incomplete excision
**Loss of heterozygosity
Urothelial carcinoma with inverted growth
Usually exophytic papillary lesions present
Endophytic, lesional circumscription variable
Variable, nuclear pleomorphism and atypia
present
Variable, usually high p53 and Ki-67
proliferation index
Frequent FGFR3 mutation, chromosome 9
and 17 deletions
Recurrences and progression may occur
Table 2. Urothelial carcinoma with inverted pattern. Criteria for invasion.
Features
Contours of neoplastic nests/cords
Size and shape of nests
Inflammatory and desmoplastic stroma
Non-invasive
Regular
Similar, rounded edges
Absent
Invasive
Irregular
Variable, irregular and jagged edges
Present
Table 3. Proposed sub-grouping of the non-invasive urothelial neoplasms with an inverted growth pattern
Group No 1. Flat
Group No 2. Papillary
Group No 3. Inverted
Urothelial hyperplasia
Papillary urothelial neoplasm
of low malignant potential
Inverted urothelial neoplasm
of low malignant potential
Urothelial dysplasia
Low-grade
papillary
carcinoma
Low-grade inverted urothelial
carcinoma
Urothelial carcinoma in situ
High-grade
papillary
carcinoma
High-grade inverted urothelial
carcinoma
18
ICUD Recommendations on Bladder Cancer
Mark S. Soloway
Department of Urology, Miller School of Medicine, University of Miami, USA
The decision making for the patient with a newly diagnosed or
recurrent bladder tumor requires a great deal of judgement.
Like many tumors BC is not one entity. There is a vast
spectrum of histologic types each of which can be further
defined by its grade and stage. Tumors are either unifocal
or may occur in multiple areas of the bladder. They may be
papillary or flat. Carcinoma in situ may be associated. These
and many other factors will play a part in the decision on
treatment. Then there is the technical aspects of treatment
– beginning with the initial endoscopic resection (urologist),
correct diagnosis (pathologist), and treatment plan (urologist,
medical oncologist, radiation oncologist depending on the
above variables).
The heterogeneity of BC is best illustrated by the great
difference between the low grade Ta tumor which rarely
impacts the patient’s life and the muscle invasive BC which
can be lethal. There are tumors which are in between
these extremes and their management requires the most
judgement. In my opinion these decisions are among the
most challenging in all of urologic oncology.
Over 100 experts in urology, urologic pathology, medical
and radiation oncology in 10 committees have worked for
12 months to outline a set of recommendations based on
the literature and where available prospective randomized
trials to guide us as we serve our patients with BC. The
culmination of their work was delivered at the EAU in an all
day symposium on March 18.
I was honored to be asked to organize and chair this effort
to summarize the state of the art in bladder cancer and
provide recommendations for treatment and am pleased to
present the highlights at the conference on bladder cancer
in Slovenia.
Here are some of the recommendations that were
presented.
Over 30 urologic pathologists combined their expertise
to emphasize the critical nature of providing an accurate
diagnosis. In most cases this is straightforward but there are
a number of ingredients involved in “getting it right”. These
were illustrated by the chair of this committee Mohammed
Amin. There are many subtypes of bladder cancer and in
certain instances, e.g. micropapillary, nested variant, small
cell, adenocarcinoma subtypes, the treatment will be different
from an urothelial (transitional cell) carcinoma.
Dr. Kamat and Dr. Hegarty discussed the recommendations
regarding the diagnostic work up beginning with hematuria
and proceeding to the endoscopy and proper tumor
resection. There have been some improvements in the
methodology of diagnosing and identifying bladder tumors
via the endoscope, e.g. blue light fluorescent endoscopy
and narrow band imaging. Are they now sufficiently useful
to be a part of routine endoscopy/tumor resection when a
patient has a bladder tumor? What is the role of urine based
markers including cytology? What is the role of imaging in the
diagnosis and staging of BC? These and many more areas
were discussed in this committee report.
Dr. Shariat discussed the role of urine based and tissue
markers as they relate to BC. There are many candidate
urine based markers that are approved by regulatory bodies
for the detection and monitoring of BC. How do they compare
with urinary cytology and in which circumstances, if any,
should they be used? Can they be used for an early detection
program in an effort to diagnose BC at an early stage? In
other words do we have a “PSA for BC”? At this moment the
answer is basically “no”.
Dr. Konety and Dr. Oosterlinck co chaired the committee on
low grade Ta BC. They emphasized the very low risk such
patients have to ever develop a life threatening BC and much
of the presentation dealt with the balance between minimizing
treatment (tumor resections, imaging, even endoscopy) and
monitoring for the relatively uncommon event of progression.
The recommendation for a single instillation of intravesical
chemotherapy after tumor resection is an attempt to minimize
the chance of a new or recurrent tumor yet avoiding multiple
instillations or the instillation of BCG for the low risk subset.
This group also stressed the avoidance of regular imaging
of the upper tract. There are cost and safety concerns with
repetitive imaging with radiation.
19
They also discussed the role of surveillance in some patients
with small low grade Ta tumors to delay or obviate the cost
and morbidity of repeated tumor resections.
The committee charged with discussing high grade (HG) Ta
and T1 BC was co chaired by Dr. Witjes and Dr. Burger. They
emphasized the critical nature of performing a complete
endoscopic resection.
Before initiating a treatment plan for the patient with a high
grade T1 tumor the urologist must consider returning the
patient to the operating theater and performing another TUR
to ensure there is no remaining tumor. Only then can the
clinician be certain of the grade and stage of the tumor. The
team delineated when it is necessary to abandon a bladder
preserving strategy and recommend bladder removal.
BC. She emphasized the role of cisplatin combination
chemotherapy (either with gemcitabine or as part of the 4
drug M – VAC regimen). What if the patient can not receive
cisplatin because of reduced renal function?
The final committee discussed the treatments for the 10% of
BCs which are not urothelial/transitional cell. These consist
of squamous cell, small cell, or adenocarcinoma. Total
cystectomy alone is the primary treatment for many of these
tumors however the patient with small cell carcinoma requires
initial treatment with chemotherapy. Thus back to the key role
of the pathologist. He/she must inform the urologist when
these unusal subtypes are found so the proper treatment can
be delivered. Dr. Baniel discussed the importance of proper
diagnosis and treatment for these non – urothelial bladder
cancers.
Dr. Stenzl discussed some of the recommendations from the
committee charged with assessing the literature concerning
muscle invasive BC. There are three parts to this discussion.
First there is the data regarding this major operative
intervention. How to safely perform it, what are acceptable
morbidity and mortality figures, and possibly who should be
performing these procedures? The second aspect presented
by Jason E an experienced radiation oncologist was the role
of bladder preservation using chemotherapy and external
beam radiation intervention. The third part of this committee
report was a summary of the data on perioperative systemic
chemotherapy with the hope of improving the survival of this
often lethal cancer. Dr. Quinn delivered this information.
Urinary diversion is an important aspect of the bladder removal
procedure. For the patient it is critical as it contributes to the
morbidity and recovery from this operation and he/she must
contend with the type of diversion they elect.
Dr Hautmann presented the recommendations of his group
and emphasized the rationale for electing one diversion vs
another. He stressed that a key component is the expertise
of the surgeon. In 2011 approximately 40% of men/women
elect a neobladder in leading centers who specialize in
cystectomy.
Dr. Palou discussed the importance of urothelial cancer of
the prostatic urethra. When should the urologist biopsy/resect
the prostatic urethra (PU) to determine whether an urothelial
cancer is present in the urothelium, ducts, or the stroma?
Should this be performed before deciding on a neobladder?
What is the treatment for CIS (carcinoma in situ) of the PU?
For TCC in the stroma of the prostate?
Cora Sternberg provided the data on what is to be expected
from systemic chemotherapy for the patients with metastatic
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21
Diagnosis of Bladder Cancer: which are the best tools
Maria J. Ribal
Department of Urology, Hospital Clínic, University of Barcelona, Spain
Bladder tumours are diagnosed with the same tools for more
that 20 years, and white-light cystoscopy and cytology are the
standard tools to diagnose bladder cancer (BC). Cystoscopy
and cytology are the standard methods used to detect and
monitor bladder urothelial cell carcinoma (UCC). Cystoscopy
is an invasive technique that has a high sensitivity (91%),
except in cases of flat malignancies such as Tis. Cytology
has the advantage of being noninvasive with a high specificity
(90-96%) but it lacks sensitivity (11-76%), especially for lowgrade disease.
Fluorescence cystoscopy has been shown in numerous
clinical studies to improve the detection of papillary
and flat bladder lesions over conventional cystoscopy.
Photosensitizing agents like aminolevulinic acid (ALA) and
its derivative hexaminolevulinate (HAL) have undergone the
most extensive investigation. Some prospective clinical trials
have demonstrated improved diagnostic ability, enhanced
tumour resection, and reduced tumour recurrence although
recently other randomized trials have questioned its value
in reducing recurrence and progression. Since the results
are still controversial the EAU Guidelines for Non MuscleInvasive Bladder Cancer recommend that photo-dynamic
diagnosis is most useful for detection of CIS, and therefore,
it should be restricted to those patients who are suspected
of harbouring a high-grade tumour, e.g. for biopsy guidance
in patients with positive cytology or with a history of highgrade tumour. Because of conflicting data on recurrence
rate this panel restricts the indication for PDD to patients
with positive cytology, presence of Cis, or as a teaching
tool in a recently published review. Optical coherence
tomography is an emerging technology that shows promise
in revealing subsurface information about bladder lesions
in real-time, potentially leading to more accurate staging.
Narrow-band imaging may augment standard endoscopic
tools by providing increased contrast between normal and
abnormal tissue. Raman molecular imaging (RMI) is an
optical technology that combines the molecular chemical
analysis of Raman spectroscopy with high-definition digital
microscopic visualization and has the potential to become
a powerful diagnostic tool that allows noninvasive, accurate
diagnosis of UC. Molecular markers are promising tools
for diagnosis of BC. Significant efforts have been made in
developing noninvasive methods for detecting and predicting
the biological behavior of UCC. In fact, the Food and Drug
Administration has already accepted some of these tumor
marker tests for use in routine patient care. Even though initial
studies with these markers were promising, later reports often
fail to confirm the results. It is likely that a panel of markers
will overcome the limitations of these single markers.
References
• Babjuk, M, Oosterlinck, W., Sylvester, R., Kaasinen,
E., Böhle, A., Palou, J., et al. (2011). Guidelines on
Non-muscle invasive Bladder Cancer ( TaT1 and CIS ).
Update, 1-36.
• Cauberg, E. C. C., Bruin, D. M. de, Faber, D. J., Leeuwen,
T. G. van, Rosette, J. J. M. C. H. de la, & Reijke, T. M.
de. (2009). A new generation of optical diagnostics for
bladder cancer: technology, diagnostic accuracy, and
future applications. European urology, 56(2), 287-96.
• Shah, J. B., & Kamat, A. M. (2010). Fluorescence
cystoscopy for nonmuscle invasive bladder cancer: is the
honeymoon over for the blue light special? Cancer, 1-2.
• Tatsugami, K., Kuroiwa, K., Kamoto, T., Nishiyama, H.,
Watanabe, J., Ishikawa, S., et al. (2010). Evaluation of
narrow-band imaging as a complementary method for
the detection of bladder cancer. Journal of endourology /
Endourological Society, 24(11), 1807-11.
• Gladkova, N., Streltsova, O., Zagaynova, E., Kiseleva,
E., Gelikonov, V., Gelikonov, G., et al. (2010). Crosspolarization optical coherence tomography for early
bladder-cancer detection: statistical study. Journal of
biophotonics, 14, 1-14.
• Shapiro, A., Gofrit, O. N., Pizov, G., Cohen, J. K., &
Maier, J. (2011). Raman molecular imaging: a novel
spectroscopic technique for diagnosis of bladder cancer
in urine specimens. European urology, 59(1), 106-12.
European Association of Urology.
• Mengual, L., Burset, M., Ribal, M. J., Ars, E., MarínAguilera, M., Fernández, M., et al. (2010). Gene
Expression Signature in Urine for Diagnosing and
Assessing Aggressiveness of Bladder Urothelial
Carcinoma. Clinical cancer research : an official journal
of the American Association for Cancer Research, 16(9),
2624-2633.
22
TUR and Re-TUR in Non Muscle Invasive Bladder Cancer (NMIBC).
TUR in Muscle Invasive Bladder Cancer (MIBC)
Maurizio A. Brausi,
Department of Urology, Ausl Modena, Italy
TUR and Re-TUR in NMIBC
The standard treatment for transitional cell carcinoma (TCC)
of the bladder is TUR of the bladder tumor under white light
cystoscopy. However TUR must be adequate.
The goals of an adequate TUR are to remove all the visible
tumours, to accurate stage the tumor (Detrusor Muscle
(DM) must be present in the specimen: if not is called Tx),
to evaluate the extension of the tumour (bladder biopsies)
and finally to avoid complications like bladder perforation or
bleeding (good hemostasis).
With a correct TUR pathologists should be able to tell us
if basal membrane or lamina propria are invaded, if DM is
present and/or invaded, if lymph-vascular invasion is present
together with CIS and finally tumour grade.
However even after an accurate and adequate TUR 50-70%
of patients will recur in time. Possible causes of recurrence
are an incomplete TUR, tumour not seen at the time of TUR,
tumour cell implantation and aggressive tumour biology.
Do we have parameters to evaluate the quality of our TUR?
Yes. The 3 month recurrence rate (3-RR), the presence of
DM in the specimen, the rate of CIS diagnosed.
The EORTC-GU group (Brausi et al 2002) evaluated the
adequacy of TUR by analysing the 3-RR in a phase III study
which include 2410 patients from European Institutions.
The results showed a great variability in £-RR between the
institutions, from 0 to 46% and this could not be explained
with the clinical and pathological parameters anaized. The
surgeon was indicated as responsible of these results.
A subsequent EORTC trial (Brausi et al 2004) that collected
informations on the quality of TUR confirmed that using a
bladder diagram at the time of cystoscopy and being a staff
member rather than a resident were important prognostic
factors in obtaining a lower 3-RR.
The presence of DM in the specimen is also an important
parameter of TUR quality. From different studies emerged
that it varies from 34% to 64% only, even in experienced,
tertiary urological centres. Why these results ? Because
urologists perform the first TUR in inadequate way.
However we can improve our results using : a) dedicating
teaching programs b) performing a second TUR c) using new
techniques and technologies (Bipolar resectoscope, PDD,
NBI, Physion).
TUR Alone in MIBC
The EAU 2009 guidelines state “ TUR alone is not
recommended as a curative treatment option for the majority
of patients with localised MIBC (Grade rec. B ). However
there are some patients who can benefit from this approach:
a) elderly patients with multiple comorbidities, at risk (ASA
score III-IV) b) patients refusing surgery c) patients refusing
surgery after neo-adjuvant chemotherapy has determined
the disappearance of the tumour (pT0).
Teoretically it is possible to remove all the bladder tumour
even if infiltrative with an adequate, deep and very accurate
TUR. However the real risk in MIBC is the presence of tumour
cells in the lamina propria and DM where the lymphatic and
blood vessels are well represented. The result is that the
risk of micrometastases and of systemic disease cannot be
prevented by TUR even if complete, deep and extended.
Can we cure a patient with cT2 TCC of the bladder with TUR
alone? The data tell us that up to 10-15% of patients with
MIBC treated with TUR alone have no pathological residual
disease at RC (pT0). Moreover long term studies support the
importance of down-staging to pT0 after TUR.
The 10-year DSS after TUR alone varied from 74-76% (Herr,
Solsona). However a delay in performing a RC increases the
risk of lymph-node metastases (from 15% to 30%). When
a bladder sparing procedure is planned a multi-modality
approach should be considered (TUR + Chemo, TUR + RT,
Neo-adjuvant Chemo + TUR + RT).
Summary
An initial, very accurate TUR is crucial for a correct staging,
future treatment and prognosis. A meticulous teaching of this
surgery should be a special part of the residency program.
New technologies should be incorporated and adopted to
improve results. A second TUR is indicated only in selected
cases (DM not present in the specimen, in referred patients,
when urologists and pathologists are uncertain, when a
bladder sparing approach is planned).
TUR alone is not reccomended for the treatment of MIBC.
When a bladder sparing approach is planned a multi-modality
treatment is a must.
23
Intravesical Chemotherapy: early and adjuvant
Maria J. Ribal
Bladder cancer is a heterogeneous disease; approximately
75% of its forms are non-muscle invasive neoplasms
(NMIBC). Standard treatment for NMIBC consists of complete
transurethral resection (TURB) of all visible lesions.
Recurrence and progression are the major problems for
many patients and are dependent on multiple clinical and
pathological factors, the most important of which are tumor
stage, grade, multifocality, size, recurrence patterns, and
the association with carcinoma in situ. Accurate assessment
of clinical stage and tumour grade is critical in determining
management and surveillance strategies. Recurrence rates
following TURB and intravesical chemoprophylaxis seem
to decrease to 25-50% in 2 years of follow-up. Adjuvant
therapy is effective in avoiding post-TURBT implantation of
tumour cells, eradicating residual disease, preventing tumour
recurrence, and to delay or reduce tumor progression through
direct cytoablation or immunostimulation.
Major controversies still exist with regard to the indication, type
and regimen of intravesical therapy for NMIBC. Mitomycin C
(MMC), the most commonly used intravesical chemotherapy
to date, decreases the risk of disease recurrence but not
disease progression when used after TURB compared with
TURB alone.
Immediate instillation of intravesical chemotherapy after
TURB of NMIBC is widely used. The practice is supported by
level 1a evidence from meta-analyses and is recommended
by the major international urological societies, including
the European Association of Urology (EAU) and American
Urological Association (AUA). In a meta-analysis of seven
randomised trials (1,476 patients), one immediate instillation
of chemotherapy after TURB significantly reduced recurrence
rate compared to TURB alone. In absolute values, the
reduction was 11.7% that implies a 24.2% decrease in the
corresponding relative risk. However, recent publications have
questioned its value in the clinical setting. No prospective data
are available showing that the single instillation significantly
reduces recurrence rates in patients with recurrent tumours.
Furthermore, there are no statistically relevant data that
address the role of immediate chemotherapy instillation
in tumours at high risk of progression before further BCG
intravesical treatment, and finally quality-of-life studies and
economic calculations have not been done.
References
• Babjuk, M., Oosterlinck, W., Sylvester, R., Kaasinen,
E., Böhle, A., Palou, J., et al. (2011). Guidelines on
Non-muscle invasive Bladder Cancer ( TaT1 and CIS ).
Update, 1-36.
• Sylvester RJ, van der Meijden AP, Oosterlinck W, et
al. Predicting recurrence and progression in individual
patients with stage TaT1 bladder cancer using EORTC
risk tables: a combined analysis of 2596 patients from
seven EORTC trials. Eur Urol 2006 Mar;49(3):466-5.
• Sylvester RJ, Oosterlinck W, Witjes JA. The schedule and
duration of intravesical chemotherapy in patients with non
muscle invasive bladder cancer: a systematic review of
the published results of randomized clinical trials. Eur
Urol 2008 Apr;53(4):709-19
• Au JL, Baladament RA, Wientjes MG, et al; International
Mitomycin C Consortium. International Mitomycin C
Consortium. Methods to improve efficacy of intravesical
mitomycin C: results of a randomized phase III trial. J Natl
Cancer Inst 2001 Apr;93(8):597-604
• Sylvester RJ, Oosterlinck W, van der Meijden AP. A single
immediate postoperative instillation
of chemotherapy decreases the risk of recurrence in
patients with stage Ta T1 bladder cancer: a metaanalysis
of published results of randomized clinical trials. J Urol
2004 Jun;171(6 Pt 1):2186-90.
• Böhle A, Leyh H, Frei C, et al. Single postoperative
instillation of gemcitabine in patients with non muscleinvasive transitional cell carcinoma of the bladder: a
randomised, double-blind, placebo controlled phase III
multicentre study. Eur Urol 2009 Sep;56(3):495-503
• Cai, T., Nesi, G., Tinacci, G., Zini, E., Mondaini, N., Boddi,
V., et al. Can early single dose instillation of epirubicin
improve bacillus Calmette-Guerin efficacy in patients with
nonmuscle invasive high risk bladder cancer? Results
from a prospective, randomized, double-blind controlled
study. The Journal of Urology, 2008 180(1), 110-5.
• Holmäng, S. (2009). Early Single-Instillation Chemotherapy
Has No Real Benefit and Should Be Abandoned in Non–
Muscle-Invasive Bladder Cancer. European Urology
Supplements,2009; 8(5), 458-463.
24
Radical Surgery: Pros and Con of Different Techniques
and Evaluation of Complications
Maurizio A. Brausi
Department of Urology, Ausl Modena, Italy
Radical Cystectomy (RC) is considered the treatment of
choice for infiltrative (T2-T4) and for recurrent, BCG resistant
Ta-T1 high grade bladder cancer (BC). The surgical technique
itself may play an important role on final results (Extensive
surgery + lymphadenectomy).
Delaying RC may impact on survival. From a systematic
review of the literature appear that the window of opportunity
is less than 12 weeks from diagnosis to RC (Fahmy et al
EUR Urol 2006).
The risk factors predicting survival are : stage, nodal status,
histology Type, age, pre-op RT, Lymph-vascular invasion,
surgical margins, concomitant Cis (International Consortium
Nomogram).
The Techniques of RC include:
•
•
•
•
Intraperitoneal RC + LAD (standard)
Extraperitoneal, mininvasive RC (Modena technique)
Prostate sparing/gynec sparing RC
Laparoscopic and Robotic RC
Unregardeless of the technique used an extended
lymphadenectomy should be performed with the removal of
more than 15-20 nodes.
They were in order: Ileus (32%), UTI (7.8%),wound dehiscence
(5.5%), Wound infection (5.2%), deep vein trombosis (4.7%).
The re-operation rate was 6.2-12%.
Laparoscopic and Robotic RC have been introduced in recent
years. The advantages of these techniques are:
• higher quality of dissection
• < blood loss
• < Post-op pain and use of analgesics
• Shorter hospital stay
• Earlier resumption work
The disadvantages:
• Prolongation of OR time
• Possible severe complications (bowel perforation)
• Conversion to open surgery (0.5-3%)
• Open surgery for urinary diversion
• LAD sometimes difficult (< nodes taken)
• > costs
• Possible tumour cell spreading (pneumoperitoneum
= high vein pressure) with appearance of unusual
metastatic sites in time (3 years)
For a complete and long term analysis of the
oncological results a longer follow-up is needed.
Oncological results
In the earlier studies the 5 year survival rate was 40%.
Recent reports show a 5-year survival of more than 60%.
The reasons are in the advances in medical therapy used
before and after surgery, improvements in anesthesiology
techniques, new surgical strategies, early diagnosis and
wider indications (Ta-T1 high grade).
The mortality rate of RC was up to 12% in old series (before
1990). In recent series it varies from 0 to 3%.
Complications
From the recent National Surgical Quality Improvement
Program (NSQIP) data on 2538 RCs appeared that 30.5% of
patients experienced medical or surgical complications.
25
Neoadjuvant and adjuvant Chemotherapy
in invasive or metastatic disease
Maria J. Ribal
Advanced bladder cancer (BC) is a chemosensitive tumour.
Response rates differ with respect to patient-related
factors and pretreatment disease. Prognostic factors for
response and survival have been established. A major
prognostic factor is the suitability of patients for treatment
with a cisplatin-based combination chemotherapy. Cisplatin
remains the most effective single agent for treatment of BC.
MVAC regimen increases overall survival. The combination
cysplatin-gemcitabine proved equal efficacy while reducing
side effects.
Although the widely spread use of adjuvant chemotherapy
in the setting of locally advanced bladder cancer, there is no
conclusive evidence, at present, of its benefits.
The standard treatment for patients with muscle-invasive
bladder cancer is radical cystectomy. However, this ‘gold
standard’ only provides 5-year survival in about 50% of
patients. In order to improve these unsatisfactory results, the
use of peri-operative chemotherapy has been explored since
the 1980s.
There are many advantages of neoadjuvant chemotherapy,
i.e. administering chemotherapy to patients with operable
urothelial carcinoma of the urinary bladder before the planned
definitive surgery (or radiation). These advantages include:
• Chemotherapy is delivered at the earliest time point, when
the burden of micrometastatic disease is
expected to be low
• In vivo chemosensitivity is tested
• The tolerability of chemotherapy is expected to be better
before than after cystectomy.
The disadvantages of neoadjuvant chemotherapy include:
• For clinical staging with CT or MRI, over- and understaging is likely to happen with a staging accuracy
of only 70%. Overtreatment is the possible negative
consequence
• Delayed cystectomy might compromise the outcome in
patients not sensitive to chemotherapy.
• Side effects of chemotherapy might affect outcome of
surgery and type of urinary diversion.
In the most recent meta-analysis, published in 2005 with
updated independent patient data (IPD) of 11 randomized
trials (3,005 patients), a statistically significant survival
benefit in favour of neoadjuvant chemotherapy was seen. The
results of this analysis confirmed the previously published
data and showed 5% absolute improvement in survival at
5 years. Of note, only cisplatin combination chemotherapy
with at least one additional chemotherapeutic agent resulted
in a meaningful benefit; the regimens tested were MVA(E)C,
CMV, CM, cisplatin/adriamycin, cisplatin/5- fluorouracil (5FU), and CarboMV. To date, it is unknown if more modern
chemotherapy regimen are as effective. Probably the major
unsolved question is which patients are those who really
benefit of neoadjuvant chemotherapy, since only one third
of the patients will response cumulating the already stated
survival advantage, while two third of the patients will not
response suffering side effects of chemotherapy and a delay
in cystectomy.
In metastatic patients the use of M-VAC and GC both result
in prolonged survival of up to 14.8 and 13.8 mo, respectively,
also with long-term follow-up. The lower toxicity of GC,
however, has resulted in GC increasingly becoming a new
standard regimen. Up to 50% of patients are ineligible for
cisplatin-containing chemotherapy, either because of a poor
PS and/or impaired renal function or because of comorbidity
preventing high volume hydration. In this situation carboplatin
based regimens are used. In those patients who failed to
Cisplatin based regimens second line regimens could be
tested. Second-line chemotherapy data are highly variable
in this setting. Vinflunine is a novel, third-generation vinca
alkaloid that has shown objective response rates of 18% and
disease control in 67% of trial subjects.
References
• Stenzl, A, Witjes, J A, Cowan, N C, Santis, M. D., Kuczyk,
M., Lebret, T., et al. (2011). Guidelines on Bladder Cancer
and Metastatic. Update.
• Stenzl, Arnulf, Cowan, Nigel C, De Santis, M., Kuczyk, M.
a, Merseburger, Axel S, Ribal, Maria José, et al. (2011).
Treatment of Muscle-invasive and Metastatic Bladder
Cancer: Update of the EAU Guidelines. European urology,
59(6), 1009-18. doi: 10.1016/j.eururo.2011.03.023.
26
• von der Maase H, Sengelov L, Roberts JT, et al. Longterm survival results of a randomized trial comparing
gemcitabine plus cisplatin, with methotrexate, vinblastine,
doxorubicin, plus cisplatin in patients with bladder cancer.
J Clin Oncol 2005 Jul;23(21):4602-8.
• Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant
chemotherapy plus cystectomy compared with
cystectomy alone for locally advanced bladder cancer. N
Engl J Med 2003 Aug;349(9):859-66.
• Advanced Bladder Cancer (ABC) Meta-analysis
Collaboration. Neoadjuvant chemotherapy in invasive
bladder cancer: update of a systematic review and metaanalysis of individual patient data advanced bladder
cancer (ABC) meta-analysis collaboration. Eur Urol 2005
Aug;48(2):202-205; discusión 205-6.
• Brausi MA. Words of wisdom. Re: open to debate. The
motion: perioperative chemotherapy in muscle invasive
bladder cancer improves survival. Eur Urol. 2010
Feb;57(2):354-5.
• David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM.
Low incidence of perioperative chemotherapy for stage III
bladder cancer 1998 to 2003: a report from the National
Cancer Data Base. J Urol. 2007 Aug;178(2):451-4.
• De Santis M, Bellmunt J, Mead G, et al. Randomized
phase II/III trial assessing gemcitabine/ carboplatin and
methotrexate/carboplatin/vinblastine in patients with
advanced urothelial cancer “unfit” for cisplatin based
chemotherapy: phase II--results of EORTC study 30986.
J Clin Oncol. 2009 Nov 20;27(33):5634-9.
• Sternberg CN, de Mulder PH, Schornagel JH, et al;
European Organization for Research and Treatment
of Cancer Genitourinary Tract Cancer Cooperative
Group. Randomized phase III trial of high-dose-intensity
methotrexate, vinblastine, doxorubicin, and cisplatin
(MVAC) chemotherapy and recombinant human
granulocyte colony-stimulating factor versus classic
MVAC in advanced urothelial tract tumors: European
Organization for Research and Treatment of Cancer
Protocol no. 30924. J Clin Oncol 2001 May;19(10):263846.
• Bellmunt J, Théodore C, Demkov T, et al. Phase III trial
of vinflunine plus best supportive care compared with
best supportive care alone after a platinum-containing
regimen in patients with advanced transicional cell
carcinoma of the urothelial tract. J Clin Oncol 2009 Sep
20;27(27):4454-61
SAMO ZA STROKOVNO JAVNOST
BHP - benigna hiperplazija prostate
kombinacijo dutasterida in antagonista alfa adrenegičnih receptorjev tamsulozina, kot med bolniki, ki te kombinacije niso
uporabljali. Vzročne povezanosti med dutasteridom (samim ali
v kombinaciji z antagonistom alfa) in srčnim popuščanjem niso
ugotovili. Preden se uvede zdravljenje z zdravilom Combodart,
je treba pri bolnikih z BHP opraviti digitalni rektalni pregled in
tudi druge preiskave, povezane z odkrivanjem raka na prostati
ali drugih bolezni, ki lahko povzročijo enake simptome kot
BHP, ter jih nato ponavljati v rednih časovnih presledkih. Serumska koncentracija za prostato specifičnega antigena (PSA)
je pomembna komponenta pri odkrivanju raka na prostati. Na
splošno: skupna serumska koncentracija PSA, večja od 4 ng/
ml (Hybritech), zahteva nadaljnje vrednotenje in razmislek o
biopsiji prostate. Pri bolnikih, ki jemljejo zdravilo Combodart,
vrednost PSA, nižja od 4 ng/ml, ne izključuje diagnoze raka na
prostati in tega se morajo zdravniki pri presojanju vrednosti zavedati. Pri bolnikih z BHP se po šestih mesecih jemanja zdravila
Combodart vrednosti PSA v serumu zmanjšajo za približno 50
%, in to celo v prisotnosti raka na prostati. Individualna odstopanja so sicer mogoča, kljub temu pa se sme predvidevati, da
se bodo vrednosti PSA zmanjšale za približno 50 %, saj je bilo
tako zmanjšanje opaženo pri vrsti izhodiščnih vrednosti PSA
(1,5 do 10 ng/ml). Pri moških, ki se šest mesecev ali več zdravijo z zdravilom Combodart, je tako treba med interpretacijo
posamezne vrednosti PSA le-to podvojiti, podvojena vrednost
pa je nato primerljiva z normalnimi vrednostmi pri moških,
ki se z zdravilom Combodart ne zdravijo. Taka prilagoditev
zagotavlja občutljivost in specifičnost testa PSA ter ohranja
njegovo sposobnost za odkrivanje raka na prostati. Vsako
vztrajno povečevanje vrednosti PSA pri bolnikih, ki se zdravijo
z zdravilom Combodart, je treba pazljivo ovrednotiti, treba pa
je oceniti tudi morebitno neustrezno jemanje zdravila. Skupne
serumske vrednosti PSA se v šestih mesecih po prekinitvi zdravljenja vrnejo na izhodiščne vrednosti. Razmerje med prostim in
skupnim PSA ostaja nespremenjeno tudi pod vplivom zdravila
Combodart. Če zdravniki izberejo odstotek prostega PSA kot
pomoč pri odkrivanju raka na prostati pri moških, ki se zdravijo
z zdravilom Combodart, odstotka prostega PSA domnevno ni
treba prilagoditi. Pri zdravljenju bolnikov s hudo okvaro ledvic
(očistek kreatinina manj kot 10 ml/min) je potrebna previdnost,
kajti uporaba pri teh bolnikih ni raziskana. Tako kot pri drugih
antagonistih alfa adrenergičnih receptorjev se lahko tudi med
zdravljenjem s tamsulozinom zniža krvni tlak, kar lahko v redkih primerih povzroči sinkopo. Bolnike, ki začenjajo zdravljenje
z zdravilom Combodart, je treba opozoriti, naj ob prvih znakih
ortostatske hipotenzije (omotica, šibkost) sedejo ali ležejo,
dokler simptomi ne minejo. Med operacijo katarakte so pri
nekaterih bolnikih, ki so trenutno ali predhodno dobivali tamsulozin, opažali medoperacijski sindrom ohlapne šarenice (IFIS
- Intraoperative Floppy Iris Syndrome, ki je različica sindroma
majhne zenice). IFIS lahko povzroči več postopkovnih zapletov
med operacijo. Zdravila Combodart zato ni priporočljivo vpeljati
bolnikom, pri katerih je predvidena operacija katarakte. Zdravniki, ki operirajo katarakto, in oftalmološke ekipe morajo med
predoperacijsko oceno preveriti, ali bolnik, predviden za operacijo katarakte, prejema ali je prejemal zdravilo Combodart, zato
da lahko pripravijo ustrezne ukrepe za obvladanje IFIS med
operacijo. Če se je tamsulozin prenehal uporabljati od 1 do 2
tedna pred operacijo katarakte, naj bi to v posameznih primerih
pomagalo, toda korist in ustrezen čas prenehanja zdravljenja
pred operacijo katarakte še nista ugotovljena. Dutasterid se absorbira skozi kožo, zato se morajo ženske, otroci in mladostniki
izogibati stiku s kapsulami, ki puščajo vsebino. Če pride do stika
z vsebino kapsule, je treba stično površino kože takoj umiti z
milom in vodo. Pri bolnikih z boleznijo jeter uporaba zdravila
Combodart ni bila raziskana. Pri dajanju zdravila Combodart
bolnikom z blago do zmerno okvaro jeter je potrebna previdnost. To zdravilo vsebuje barvilo sončno rumeno FCF (E 110),
ki lahko povzroči alergijske reakcije.
Medsebojno delovanje z drugimi zdravili in druge oblike
interakcij: Študij medsebojnega delovanja zdravila Combodart
z drugimi zdravili niso izvedli. Naslednje navedbe vsebujejo informacije, ki so na voljo za posamezni učinkovini. Dutasterid:
Za informacije o zmanjšanju serumskih vrednosti PSA med
zdravljenjem z dutasteridom in o smernicah glede odkrivanja
raka na prostati. Učinki drugih zdravil na farmakokinetične lastnosti dutasterida: Sočasna uporaba zaviralcev CYP3A4 in/ali
zaviralcev P-glikoproteina: Dutasterid se večinoma izloča s presnovo. Študije in vitro kažejo, da njegovo presnovo katalizirata
CYP3A4 in CYP3A5. Posebnih študij o interakcijah z močnimi
zaviralci CYP3A4 niso izvedli. Vseeno pa so bile pri majhnem
številu bolnikov, ki so bili v farmakokinetični populacijski študiji
sočasno zdravljeni z verapamilom ali diltiazemom (zmerna zaviralca CYP3A4 in zaviralca P-glikoproteina), ugotovljene večje
serumske koncentracije dutasterida kot pri drugih bolnikih, in
sicer pri sočasnem zdravljenju z verapamilom v povprečju za
1,6-krat in pri sočasnem zdravljenju z diltiazemom v povprečju
za 1,8-krat. Zaradi dolgotrajne uporabe dutasterida v kombinaciji z močnimi zaviralci encima CYP3A4 (npr. ritonavir, indinavir,
nefazodon, itrakonazol in ketokonazol v peroralni obliki) se
lahko serumske koncentracije dutasterida povečajo. Nadaljnja
inhibicija 5-alfa-reduktaze zaradi povečane izpostavljenosti
dutasteridu ni verjetna, vendar pa je pri pojavu neželenih učinkov treba oceniti možnost za podaljšanje časovnega intervala
med posameznimi odmerki dutasterida. Treba se je zavedati,
da se lahko ob encimski inhibiciji dolg razpolovni čas še dodatno podaljša in tako lahko sočasno zdravljenje traja več
kot 6 mesecev, preden se vzpostavi novo stanje ravnovesja.
Dajanje 12 g holestiramina eno uro pred dajanjem dutasterida
v enkratnem odmerku 5 mg ni vplivalo na farmakokinetične
lastnosti dutasterida. Učinki dutasterida na farmakokinetične
lastnosti drugih zdravil: V majhni dvotedenski študiji (n = 24)
pri zdravih moških dutasterid (v odmerku 0,5 mg na dan) ni
vplival na farmakokinetiko tamsulozina ali terazosina. Ta
študija prav tako ni pokazala farmakodinamičnih interakcij.
Dutasterid ne vpliva na farmakokinetične lastnosti varfarina ali
digoksina. To kaže, da dutasterid ne inhibira/inducira CYP2C9
ali transportnega P-glikoproteina. Študije interakcij in vitro
kažejo, da dutasterid ne inhibira encimov CYP1A2, CYP2D6,
CYP2C9, CYP2C19 ali CYP3A4. Tamsulozin: Sočasna uporaba
tamsulozinijevega klorida z zdravili, ki lahko znižajo krvni tlak,
vključno z anestetiki in drugimi antagonisti alfa-1 adrenergičnih receptorjev, lahko povzroči močnejše hipotenzivne učinke.
Kombinacije dutasterid-tamsulozin se ne sme uporabljati v
kombinaciji z drugimi antagonisti alfa-1 adrenergičnih receptorjev. Sočasna uporaba tamsulozinijevega klorida (0,4 mg) in
cimetidina (400 mg na šest ur šest dni) je zmanjšala očistek (26
%) in povečala AUC (44 %) tamsulozinijevega klorida. Če se
dutasterid-tamsulozin uporabi v kombinaciji s cimetidinom, je
potrebna previdnost. Definitivne študije medsebojnega delovanja med tamsulozinijevim kloridom in varfarinom niso izvedli.
Rezultati maloštevilnih študij in vitro in in vivo so nedokončni.
Če se sočasno uporabljata varfarin in tamsulozinijev klorid,
je potrebna previdnost. Pri uporabi tamsulozinijevega klorida
sočasno z atenololom, enalaprilom, nifedipinom ali teofilinom
niso opazili medsebojnih učinkov. Sočasna uporaba furosemida
povzroči znižanje koncentracije tamsulozina v plazmi, vendar
koncentracija ostane v normalnem območju, zato odmerjanja
ni treba prilagoditi. Diazepam, propranolol, triklormetiazid,
klormadinon, amitriptilin, diklofenak, glibenklamid in simvastatin in vitro ne spremenijo proste frakcije tamsulozina v človeški plazmi. Prav tako tamsulozin ne spremeni prostih frakcij
diazepama, propranolola, triklormetiazida in klormadinona. V
študijah z jetrnimi mikrosomskimi frakcijami (ki predstavljajo s
citokromom P450 povezani encimski sistem za presnovo zdravil) in vitro z amitriptilinom, salbutamolom in glibenklamidom
niso ugotovili interakcij na ravni jetrne presnove. Diklofenak pa
lahko poveča hitrost izločanja tamsulozina.
Nosečnost in dojenje: Pri ženskah je uporaba zdravila Combodart kontraindicirana. Študij o vplivu zdravila Combodart na
nosečnost, dojenje in plodnost niso izvedli. Naslednje navedbe
vsebujejo informacije, ki so na voljo za posamezni sestavini.
Plodnost: Poročali so, da dutasterid pri zdravih moških vpliva
na značilnosti semena (zmanjšano število semenčic, zmanjšan
volumen semena in gibljivosti semenčic). Možnosti zmanjšane
plodnosti moških ni mogoče izključiti. Vplivi tamsulozinijevega
klorida na število semenčic in njihovo funkcijo niso bili ovrednoteni. Nosečnost: Tako kot drugi zaviralci 5-alfa-reduktaze
tudi dutasterid zavira pretvorbo testosterona v dihidrotestosteron in lahko, če se daje nosečnicam, ki nosijo plod moškega
spola, zavre razvoj zunanjih spolovil ploda. V spermi oseb,
ki so prejemale dutasterid, so bile dokazane manjše količine
dutasterida. Na podlagi študij na živalih je malo verjetno, da
bi izpostavljenost nosečnice spermi bolnika, ki se zdravi z dutasteridom, škodljivo prizadela plod moškega spola (tveganje
je največje v prvih 16 tednih nosečnosti). Kljub temu pa se priporoča, tako kot pri uporabi vseh zaviralcev 5-alfa-reduktaze,
da bolnik v primeru, ko je partnerka noseča ali bi lahko bila
noseča, uporablja kondom in tako prepreči, da bi partnerka
prišla v stik s spermo. Uporaba tamsulozinijevega klorida pri
brejih podganah in kunčjih samicah ni pokazala škodljivosti za
plod. Dojenje: Ni znano, ali se dutasterid ali tamsulozin izločata
v materino mleko.
Vpliv na sposobnost vožnje in upravljanja s stroji: Študij o
vplivih zdravila Combodart na sposobnost vožnje in upravljanja
s stroji niso izvedli, vendar je bolnikom treba povedati, da med
jemanjem zdravila Combodart obstaja možnost pojava simptomov, povezanih z ortostatsko hipotenzijo, na primer omotice.
Neželeni učinki: Terapevtskih kliničnih preskušanj z zdravilom
Combodart niso izvedli, dokazana pa je bioekvivalentnost
zdravila Combodart ter sočasno uporabljenega dutasterida in
tamsulozina. Tukaj prikazani podatki se nanašajo na sočasno
uporabo dutasterida in tamsulozina iz dveletne analize študije
CombAT (Combination of Avodart and Tamsulosin), ki je primerjala dutasterid 0,5 mg in tamsulozin 0,4 mg enkrat na dan
štiri leta med sočasno uporabo ali kot monoterapijo. Vključene
so tudi informacije o profilu neželenih učinkov obeh posameznih učinkovin (dutasterida in tamsulozina).
SOČASNA UPORABA DUTASTERIDA IN TAMSULOZINA: Podatki iz kliničnih preskušanj: Podatki 2. leta študije CombAT
so pokazali, da je bila incidenca katerihkoli, po raziskovalčevi
presoji z zdravilom povezanih, neželenih učinkov v prvem oz.
drugem letu zdravljenja 22 % oz. 5 % za sočasno zdravljenje z
dutasteridom in tamsulozinom, 14 % oz. 5 % za monoterapijo z
dutasteridom in 13 % oz. 4 % za monoterapijo s tamsulozinom.
Večja incidenca neželenih učinkov v prvem letu zdravljenja v
skupini, ki je dobivala kombinirano zdravljenje, je posledica
večje incidence motenj reprodukcije, natančneje ejakulacijskih
motenj, v tej skupini. Naslednji, po raziskovalčevi presoji z zdravilom povezani, neželeni učinki so bili zabeleženi z incidenco, ki
je večja ali enaka 1 % v prvem letu zdravljenja v analizi študije
CombAT 2. Leto. Incidenca neželenih učinkov, glede na organski sistem v 1. letu zdravljenja (Dutasterid + tamsulozin (n =
1610); Dutasterid (n = 1623); Tamsulozin (n = 1611)) in v 2.
letu zdravljenja (Dutasterid + tamsulozin (n = 1424); Dutasterid
(n = 1457); Tamsulozin (n = 1468)): Motnje reprodukcijskega
sistema in dojk, psihiatrične motnje in preiskave: erektilna
disfunkcija v 1. letu zdravljenja ( 6,5%; 4,9%; 3,3%) v 2. letu
zdravljenja ( 1,1%; 1,3%; 0,7%); Sprememba (zmanjšanje) libida v 1. letu zdravljenja ( 5,2%; 3,8%; 2,5%) v 2. letu zdravljenja
( 0,4%; 0,9%; 0,6%); Ejakulacijske motnje v 1. letu zdravljenja
(8,9%; 1,6%; 2,7%) v 2. letu zdravljenja ( 0,5%; 0,3%; 0,5%);
Motnje dojk (vključno s povečanjem in/ali občutljivostjo dojk)
v 1. letu zdravljenja (2,0%; 1,8%; 0,8%) v 2. letu zdravljenja (
0,9%; 1,2%; 0,3%) ter bolezni živčevja v 1. letu zdravljenja (
1,4%; 0,6%; 1,3%) v 2. letu zdravljenja ( 0,2%; 0,1%; 0,4%).
MONOTERAPIJA Z DUTASTERIDOM: Podatki iz kliničnih
preskušanj: V treh s placebom kontroliranih študijah III. faze
zdravljenja z dutasteridom (n = 2167) v primerjavi s placebom
(n = 2158) sta bili vrsta in pogostnost po raziskovalčevi presoji
z zdravilom povezanih neželenih učinkov po enem in dveh letih
zdravljenja podobni kot v kraku monoterapije z dutasteridom v
študiji CombAT. V nadaljnjih dveh letih med odprto podaljšano fazo teh študij niso ugotovili sprememb profila neželenih
učinkov. Postmarketinški podatki: Neželeni učinki, opaženi
med spremljanjem zdravila po začetku trženja, temeljijo na
spontanih postmarketinških prijavah, zato njihova dejanska
incidenca ni znana. Bolezni imunskega sistema: Alergijske reakcije, vključno z izpuščajem, srbenjem, urtikarijo, lokaliziranim
edemom in angioedemom.
MONOTERAPIJA S TAMSULOZINOM: Podatki iz kliničnih preskušanj in postmarketinški podatki: Neželeni učinki in kategorije pogostnosti, temeljijo na javno dostopnih informacijah. Pogosti in občasni učinki se skladajo s tistimi, ki so bili ugotovljeni
v kliničnih preskušanjih, in kategorije pogostnosti na splošno
kažejo incidenco nad placebom. Redki in zelo redki učinki se
skladajo s tistimi, ki so bili ugotovljeni iz postmarketinških
poročil, in kategorije pogostnosti pomenijo prijavljene deleže.
Neželeni učinki razvrščeni po pogostnosti: pogosti: omotica;
občasni: palpitacije, zaprtost, driska, navzea, bruhanje, astenija,
glavobol, motnje ejakulacije, rinitis, izpuščaj, srbenje, urtikarija,
posturalna hipotenzija; redki: sinkopa, angioedem; zelo redki:
priapizem. Med postmarketinškim spremljanjem so z uporabo antagonistov alfa-1 adrenergičnih receptorjev, vključno s
tamsulozinom, povezali primere medoperacijskega sindroma
ohlapne šarenice (IFIS), različico sindroma majhne zenice, ki
se je pojavil med operacijo katarakte. Preveliko odmerjanje:
Podatkov o prevelikem odmerjanju zdravila Combodart ni.
Naslednje navedbe vsebujejo informacije, ki so na voljo za
posamezni učinkovini. Dutasterid: V študijah so prostovoljci v
obliki enkratnih dnevnih odmerkov 7 dni prejemali dutasterid
v odmerku do 40 mg/dan (80-kratni terapevtski odmerek), kar
ni povzročalo pomembnejših skrbi glede varnosti. V kliničnih
študijah so osebe šest mesecev prejemale dutasterid v odmerku 5 mg dnevno, pri čemer, razen neželenih učinkov, ki se
pojavijo že pri terapevtskih 0,5-mg odmerkih, niso opazili še
dodatnih neželenih učinkov. Za dutasterid specifični antidot ne
obstaja, tako je ob sumu, da gre za preveliko odmerjanje, treba
zagotoviti ustrezno simptomatsko in podporno zdravljenje.
Tamsulozin: Opisano je akutno preveliko odmerjanje s 5 mg
tamsulozinijevega klorida. Opazili so akutno hipotenzijo (sistolični krvni tlak 70 mmHg), bruhanje in drisko, ki so jih zdravili z
nadomeščanjem tekočine, in bolnika so lahko odpustili isti dan.
V primeru akutne hipotenzije po prevelikem odmerjanju je treba zagotoviti kardiovaskularno podporo. Krvni tlak je mogoče
korigirati, srčno frekvenco pa normalizirati tako, da se bolnik
uleže. Če to ne pomaga, se lahko uporabi ekspanderje plazme,
ali po potrebi vazopresorje. Treba je spremljati delovanje ledvic
in uporabiti splošne podporne ukrepe. Ni verjetno, da bi dializa
koristila, ker je tamsulozin v zelo veliki meri vezan na beljakovine v plazmi. Za preprečitev absorpcije se lahko uporabijo ukrepi, kot je sprožitev bruhanja. Če gre za zaužitje velike količine,
se lahko uporabi izpiranje želodca, aktivno oglje in osmotsko
odvajalo, na primer natrijev sulfat.
FARMACEVTSKI PODATKI
Inkompatibilnosti: Navedba smiselno ni potrebna. Vrsta
ovojnine in vsebina: Motne, bele plastenke iz polietilena velike gostote (HDPE) s polipropilensko, za otroke varno zaporko s
polietilensko prevlečenimi, folijskimi indukcijsko toplotno zaprtimi oblogami: 30 trdih kapsul v 100-ml plastenki.
IMETNIK DOVOLJENJA ZA PROMET: GSK d.o.o., Ljubljana,
Knezov štradon 90, 1000 Ljubljana, Slovenija; Tel:+386 1 280
25 00; E-pošta: medical.x.si@gsk.com.
DATUM ZADNJE REVIZIJE BESEDILA: 29.03.2010
Pred predpisovanjem, prosimo, preberite celoten povzetek
glavnih značilnosti zdravila.
Predpisovanje in izdaja zdravila je le na recept.
Za vse morebitne nadaljnje informacije o tem zdravilu se lahko
obrnete na imetnika dovoljenja za promet z zdravilom: GSK
d.o.o., Ljubljana, Knezov Štradon 90, 1000 Ljubljana, tel: +386
(0)1 280 25 00, medical.x.si@gsk.com
Combodart je zaščitena blagovna znamka skupine družb
GlaxoSmithKline. © 2010 GlaxoSmithKline. Vse pravice
pridržane.
Datum priprave materiala: maj 2011.
Veljavnost materiala 1 leto
SLO/DUTT/0004a/11
SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI
ZDRAVILA
IME ZDRAVILA
Combodart 0,5 mg/0,4 mg trde kapsule
KAKOVOSTNA IN KOLIČINSKA SESTAVA
Ena trda kapsula vsebuje 0,5 mg dutasterida in 0,4 mg tamsulozinijevega klorida (to ustreza 0,367 mg tamsulozina). Zdravilo
vsebuje barvilo sončno rumeno FCF (E 110). Ena kapsula vsebuje ≤ 0,1 mg barvila sončno rumeno FCF (E 110).
Seznam pomožnih snovi: Ovojnica trde kapsule: hipromeloza, karagenan (E 407), kalijev klorid, titanov dioksid (E
171), rdeči železov oksid (E 172), sončno rumeno FCF (E 110),
karnauba vosek, koruzni škrob. Vsebina mehke kapsule dutasterida: monogliceridi in digliceridi kaprilske/kaprinske kisline,
butilhidroksitoluen (E 321), Ovojnica mehke kapsule: želatina,
glicerol, titanov dioksid (E 171), rumeni železov oksid (E 172),
srednjeverižni trigliceridi, lecitin. Pelete tamsulozina: mikrokristalna celuloza, kopolimer metakrilne kisline in etilakrilata, 1 :
1, 30-odstotna disperzija (vsebuje tudi polisorbat 80 in natrijev
lavrilsulfat), smukec, trietilcitrat. Črno črnilo (SW-9010 ali SW9008): šelak, propilenglikol, črni železov oksid (E 172), kalijev
hidroksid (samo v črnem črnilu SW-9008).
KLINIČNI PODATKI
Terapevtske indikacije: Zdravljenje zmernih do hudih simptomov benigne hiperplazije prostate (BHP). Zmanjšanje tveganja
za akutno retenco urina (ARU) in potrebe po kirurškem posegu
pri bolnikih z zmernimi do hudimi simptomi BHP.
Odmerjanje in način uporabe: Odrasli (vključno s starejšimi
bolniki): Priporočeni odmerek zdravila Combodart je ena kapsula (0,5 mg/0,4 mg), ki se vzame peroralno, in sicer vsak dan
približno 30 minut po istem obroku. Bolnik mora kapsulo pogoltniti celo in je ne sme žvečiti ali odpirati. Ob stiku z vsebino
kapsule dutasterida, ki je v trdi ovojnici kapsule, lahko pride
do draženja ustne in žrelne sluznice. Kadar je to primerno, se
za poenostavitev zdravljenja lahko zdravilo Combodart uporabi
kot zamenjavo za sočasno uporabo dutasterida in tamsulozinijevega klorida v obstoječem dvotirnem zdravljenju. Kadar je
klinično primerno, se lahko pretehta možnost neposrednega
prehoda z monoterapije z dutasteridom ali tamsulozinijevim
kloridom na zdravilo Combodart. Okvara ledvic: Vpliv okvare
ledvic na farmakokinetične lastnosti dutasterida-tamsulozina
ni bil raziskan. Po predvidevanjih pri bolnikih z okvaro ledvic
odmerka ni treba prilagajati. Okvara jeter: Vpliv okvare jeter
na farmakokinetične lastnosti dutasterida-tamsulozina ni bil
raziskan, zato je pri bolnikih z blago do zmerno okvaro jeter potrebna previdnost. Pri bolnikih s hudo okvaro jeter je uporaba
zdravila Combodart kontraindicirana.
Kontraindikacije: Uporaba zdravila Combodart je kontraindicirana pri: - ženskah, otrocih in mladostnikih; bolnikih,
ki so alergični (preobčutljivi) na dutasterid, druge zaviralce
5-alfa-reduktaze, tamsulozin (vključno z angioedemom zaradi
tamsulozina) ali katerokoli pomožno snov zdravila Combodart;
bolnikih z anamnezo ortostatske hipotenzije; bolnikih s hudo
okvaro jeter.
Posebna opozorila in previdnostni ukrepi: Zdravilo Combodart je treba predpisati po natančni oceni koristi in tveganja
ter ob upoštevanju drugih možnosti zdravljenja, vključno z
možnostjo monoterapij. V štiriletni klinični študiji je bila incidenca srčnega popuščanja (sestavljeni dogodek poročanih
dogodkov, predvsem srčnega popuščanja in kongestivnega
srčnega popuščanja) večja med bolniki, ki so uporabljali
solifenacin
filmsko obložene tablete, 5 mg, 10 mg
Mehur
pod nadzorom!
Slovenija, 2011-14731, AG/MP.
Vse ostalo
je stvar odločitve.
Novo Krkino zdravilo za lajšanje simptomov
prekomerno aktivnega sečnega mehurja
Sestava Ena tableta vsebuje 5 mg ali 10 mg solifenacinijevega sukcinata, kar ustreza 3,8 mg ali 7,5 mg solifenacina. Tablete vsebujejo
laktozo. Terapevtske indikacije Simptomatsko zdravljenje urgentne inkontinence in/ali povečane pogostosti in nujnosti uriniranja, ki se
lahko pojavita pri bolnikih s sindromom prekomerno aktivnega sečnega mehurja. Odmerjanje in način uporabe Priporočeni odmerek
je 5 mg enkrat na dan. Po potrebi se odmerek lahko poveča na 10 mg enkrat na dan. Zdravilo Asolfena se jemlje peroralno. Tableto je
treba pogoltniti celo, s tekočino. Lahko se vzame s hrano ali brez nje. Varnost in učinkovitost pri otrocih še nista bili ugotovljeni, zato
zdravila Asolfena otroci ne smejo jemati. Za bolnike z blago do zmerno ledvično okvaro (kreatininski očistek > 30 ml/min) odmerka ni
treba prilagajati. Bolnike s hudo ledvično okvaro (kreatininski očistek ≤ 30 ml/min) je treba zdraviti previdno; ne smejo dobiti več kot
5 mg enkrat na dan. Pri bolnikih z blago jetrno okvaro prilagajanje odmerka ni potrebno. Bolniki z zmerno jetrno okvaro (Child-Pughova
lestvica od 7 do 9) ne smejo dobiti več kot 5 mg enkrat na dan. Največji odmerek zdravila Asolfena je treba omejiti na 5 mg, kadar
bolnik sočasno jemlje ketokonazol ali terapevtske odmerke drugih močnih zaviralcev CYP3A4, npr. ritonavirja, nelfinavirja, itrakonazola.
Kontraindikacije Preobčutljivost za zdravilno učinkovino ali katerokoli pomožno snov. Zastoj urina. Hude prebavne težave (vključno s
toksičnim megakolonom). Miastenija gravis. Glavkom ozkega zakotja in nevarnost za taka stanja. Hemodializa. Huda jetrna okvara. Huda
ledvična okvara ali zmerna jetrna okvara ter sočasno zdravljenje z močnim zaviralcem CYP3A4, npr. ketokonazolom. Posebna opozorila
in previdnostni ukrepi Pred začetkom zdravljenja je treba oceniti druge vzroke za pogosto uriniranje (npr. srčno popuščanje ali ledvično
bolezen). Če gre za okužbo sečil, je treba začeti s primernim protibakterijskim zdravljenjem. Previdnost je potrebna pri bolnikih: s
klinično pomembno zaporo sečnega mehurja, pri kateri lahko pride do zastoja urina; z zaporo v prebavilih; z nevarnostjo zmanjšane
gastrointestinalne motilitete; s hudo ledvično okvaro (kreatininski očistek ≤ 30 ml/min); z zmerno jetrno okvaro (Child-Pughova lestvica
od 7 do 9); pri bolnikih, ki sočasno dobivajo močan zaviralec CYP3A4, npr. ketokonazol; pri bolnikih s hiatusno kilo ali gastroezofagealnim
refluksom ter bolnikih, ki sočasno jemljejo zdravila, ki lahko povzročijo ali poslabšajo ezofagitis (npr. bisfosfonate); pri bolnikih z
avtonomno nevropatijo. Največji učinek zdravila Asolfena je mogoče ugotoviti šele po 4 tednih. Bolniki z dedno intoleranco za galaktozo,
laponsko obliko zmanjšane aktivnosti laktaze ali malabsorpcijo glukoze/galaktoze ne smejo jemati tega zdravila. Medsebojno delovanje
z drugimi zdravili in druge oblike interakcij Sočasno zdravljenje z drugimi zdravili z antiholinergičnimi lastnostmi lahko povzroči bolj
izražene terapevtske in neželene učinke. Po prenehanju zdravljenja z zdravilom Asolfena naj sledi približno en teden premora do začetka
zdravljenja z drugim antiholinergikom. Terapevtski učinek solifenacina lahko zmanjša sočasno dajanje agonistov holinergičnih receptorjev.
Solifenacin lahko zmanjša učinek zdravil, ki pospešujejo motiliteto prebavil, kot sta na primer metoklopramid in cisaprid. Solifenacin se
presnavlja s CYP3A4. Sočasno dajanje ketokonazola (200 mg na dan oz. 400 mg/dan) je povzročilo dvakratno oz. trikratno povečanje
površine pod krivuljo plazemske koncentracije (AUC) solifenacina. Kadar se Asolfena daje sočasno s ketokonazolom ali terapevtskimi
odmerki drugih močnih zaviralcev CYP3A4 (npr. ritonavirja, nelfinavirja, itrakonazola), je največji odmerek 5 mg. Sočasno zdravljenje s
solifenacinom in močnim zaviralcem CYP3A4 je kontraindicirano pri bolnikih s hudo ledvično okvaro ali zmerno jetrno okvaro. Jemanje
solifenacina ni spremenilo farmakokinetike R-varfarina ali S-varfarina ali njunega učinka na protrombinski čas niti ni imelo učinka na
farmakokinetiko digoksina. Nosečnost in dojenje Ni kliničnih podatkov. Pri predpisovanju zdravila nosečnicam je potrebna previdnost.
Ni podatkov o prehajanju zdravila v materino mleko. Zdravila Asolfena zato ne dajemo materam, ki dojijo. Vpliv na sposobnost vožnje
in upravljanje s stroji Solifenacin, kot drugi antiholinergiki, lahko povzroči zamegljen vid, včasih tudi zaspanost in utrujenost, kar lahko
negativno vpliva na vožnjo in upravljanje s stroji. Neželeni učinki Pogostost antiholinergičnih neželenih učinkov je povezana z odmerkom.
Zelo pogosti: suha usta. Pogosti: zamegljen vid, zaprtje, slabost, dispepsija, bolečine v trebuhu. Občasni: gastroezofagealna refluksna
bolezen, suho grlo, suha usta, suhe oči, suh nos, suha koža, okužba sečil, cistitis, zaspanost, sprememba okusa, težave pri uriniranju,
utrujenost, periferni edem. Redki: črevesna zapora, zapeka, zastoj urina. Ostali se pojavljajo zelo redko. Poročali so tudi o podaljšanju
intervala QT in ventrikularni tahikardiji, vendar pogostost teh dogodkov niti vloga solifenacina pri nastanku teh neželenih učinkov nista
bili določeni. Imetnik dovoljenja za promet Krka, tovarna zdravil, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija. Način
izdajanja Samo na zdravniški recept. Oprema 30 filmsko obloženih tablet po 5 mg ali 10 mg. Datum priprave besedila Januar 2011.
Samo za strokovno javnost.
Pred predpisovanjem preberite celoten povzetek glavnih značilnosti zdravila. Objavljen je tudi na www.krka.si.
Krka, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, www.krka.si
29
Obravnava bolnikov z mišično neinvazivnim rakom sečnega mehurja:
5-letno sledenje
Treatment of patient with non-muscle invasive Bladder Cancer:
5-years follow up
Z. Krstanoski, M. Zupančič, F. Kramer, L. Koršič, I. Parać
Oddelek za urologijo, Splošna bolnišnica Slovenj Gradec, Slovenija
Department of Urology, General Hospital Slovenj Gradec, Slovenia
Izvleček
Abstract
Izhodišča: Rak sečnega mehurja je najbolj pogost tumor
sečil. Pri moških je med raki na sedmem mestu, redkejši je
pri ženskah. Cilj naše raziskave je bila retrospektivna analiza
naših rezultatov 5-letnega spremljanja obravnave bolnikov z
mišično neinvazivnim rakom sečnega mehurja in primerjava
z objavljenimi rezultati.
Bolniki in metode: V raziskavi smo obravnavali 91 bolnikov,
ki so bili zaradi mišično neinvazivnega raka sečnega mehurja
prvič operirani v letih 2005 in 2006. 82(90%) bolnikom smo
1-2 uri po TUR tumorja sečnega mehurja intravezikalno
aplicirali 40 mg Mitomycina C. Za dodatno intravezikalno
imuno ali kemoterapijo smo se odločili pri vseh bolnikih s
stadijem bolezni T1 in pri vseh bolnikih s CIS. Med bolniki s
Ta pa so terapijo prejeli tisti, pri katerih je šlo za gradus II in III,
ali če je bil tumor multifokalen. Pri bolnikih s stadijem bolezni
T1 in Ta+CIS ali CIS ter bolnikih s ponovitvijo bolezni, smo
izvajali podaljšano imunoterapijo. Po prvih šestih aplikacijah
BCG so sledile 3 mesečne, 2 trimesečni, 2 šestmesečni in
nato 1 aplikacija letno.
Rezultati: Recidiv bolezni smo ugotovili pri 29(31,8%)
bolnikih, od katerih se je pri 16(55%) pojavil v prvem letu po
operaciji. Pri 9(31%) bolnikih je do ponovitve bolezni prišlo
2-3 krat. Od 29 bolnikov s ponovitvijo bolezni je pri 18(62%)
ob prvi operaciji šlo za 2-7 tumorjev, s stopnjo diferenciacije
G II-III. Pri 4(4,3%) bolnikih z recidivom bolezni smo ugotovili
progres v mišično invazivni stadij T2. Od 14 bolnikov, ki po
prvi operaciji niso prejeli imunoterapije ali kemoterapije, je
do ponovitve bolezni prišlo pri 4(29%), pri vseh pa je bil
izhodiščni stadij Ta G II.
Zaključek: Če primerjamo naše rezultate z objavljenimi v
strokovni literaturi, lahko ugotovimo, da so glede odstotka
ponovitve bolezni sicer boljši, vendar v obravnavanem
obdobju še nismo pri vseh bolnikih ocenjevali velikosti in
števila tumorjev ob prvem operativnem zdravljenju.
Objective: Urinary Bladder Cancer is the most common
malignant disease of urinary tract. Among cancers in men is
Bladder Cancer in seventh place and less common in women.
The aim of this study was retrospective analysis of our results
in five years follow up on patients with non-muscle invasive
Bladder Cancer and comparison with published data.
Patients and methods: From 2005 to 2006 we treated 91
patients with non-muscle invasive bladder cancer surgery. In
82(90%) patients 1-2 hours after TURB 40 mg of Mitomycin C
was instilled intravesically. For additional intravesical immuno
or chemotherapy, we decided in all patients with stage T1
disease and with CIS. Among patients with Ta, additional
therapy was given to those with Grade II and III, or if the
tumor was multifocal. In patients with stage T1, and those
with Ta+CIS or CIS, and patients with relapse, we performed
extended immunotherapy and after the first six applications,
BCG was followed 3-times monthly, 2-times every three
months, 2-times every six months and then 1 application per
year.
Results: Relapse of the disease was observed in 29(31.8%)
patients, of which in 16(55%) occurred within the first year
after surgery. In 9(31%) patients the recurrence of illness
was 2-3 times. Of the 29 patients with relapsed disease in
18(62%) at first operation were 2-7 tumors with Grade II-III.
In 4 (4.3%) patients with recurrence, disease progressed to
muscle invasive stage T2. In 14 patients who after the first
surgery did not receive immunotherapy or chemotherapy,
disease occurred again in 4(29%), and all of them had
starting stage G II.
Conclusion: If we compare our results with published in the
literature, we find that our data of recurrence of the disease
are better, but in this period we have not in all patients exactly
evaluated the size and number of tumors at the first operative
treatment.
30
Uvod
Rak sečnega mehurja je najbolj pogost maligni tumor sečil. Pri
moških je na sedmem mestu po pogostnosti raka, pri ženskah
je redkejši. Pojavi se lahko v kateremkoli obdobju življenja,
tudi v otroštvu. Srednja starost pri moških s tem rakom je
69 let, pri ženskah pa 71[1]. V Evropi vsako leto odkrijemo
20 novih primerov raka sečnega mehurja na 100.000
prebivalcev [2]. Prehodnocelični karcinom je najpogostejša
oblika in predstavlja 90% te bolezni. 75-85% rakov ob
prvi diagnozi je mišično neinvazivnih, in sicer omejenih na
mukozo (Ta) ali pa z zajetjem lamine proprie mukoze (T1).
Poseben problem so areali malignih celic, omejenih znotraj
mukoze (CIS). Možnost za ponovitev mišično neinvazivnega
raka sečnega mehurja je do 70% v prvih 5 letih, najpogosteje
v prvem letu po začetnem zdravljenju. Okoli 30% recidivnih
tumorjev ima višjo histološko stopnjo in okoli 10% napreduje
v mišično invazivno obliko tumorja, z visoko stopnjo
umrljivosti [3]. Prognostični dejavniki za ponovitev bolezni
so velikost tumorja, stadij, stopnja diferenciacije malignih
celic, pridružen CIS in multifokalnost. Dejavniki tveganja
za nastanek raka sečnega mehuja so aromatični amini,
kajenje, analgetična odvisnost, ciklofosfamid in kronična
vnetja sečnega mehurja [4]. Hematurija je najpogostejši
znak te bolezni, pogosto jo spremljata dizurija in urgentna
mikcija. V odkrivanju raka sečnega mehurja izvajamo klinični
pregled, standardno cistoskopijo, fluorescentno cistoskopijo,
UZ sečil, intravenozno urografijo, računalniško tomografijo,
pregled sedimenta urina, citološko analizo urina, urinske
molekularne teste in biopsijo sluznice sečnega mehurja [5-9].
TUR tumorjev je metoda izbire za prvo zdravljenje eksofitnih
tumorjev. V nadaljevanju lahko uporabimo intravezikalno
imuno ali kemoterapijo. V prispevku predstavljamo naše
izkušnje pri zdravljenju mišično neinvazivnega raka sečnega
mehurja in sicer 5-letno sledenje.
Pacienti in metode
V raziskavi smo obravnavali 91 bolnikov, ki so bili zaradi
mišično neinvazivnega raka sečnega mehurja prvič
operirani v letih 2005 in 2006. Večina smo diagnostično
obravnavali v naši ambulanti. Glavni razlog za pregled je bila
asimptomatska hematurija, redkeje mikrohematurija, dizurija
ali urgentna mikcija. Po kliničnem pregledu smo pri vseh
bolnikih naredili cistoskopijo in ocenili velikost, lokalizacijo in
multifokalnost tumorja. Pred operacijo je bila pri vseh bolnikih
narejena še UZ preiskava sečil in trebuha, pri nekaterih tudi
intravenozna urografija. Operativno zdravljenje je pomenilo
TUR tumorjev in/ali hladno biopsijo sumljivih predelov
sluznice sečnega mehurja. 82(90%) bolnikom smo 1-2 uri
po operaciji intravezikalno aplicirali 40 mg Mitomycina C.
V primerih solitarnih in majhnih tumorjev (<2 cm premera)
smo bolnikom urinski kateter odstranili naslednji dan po
operaciji in jih odpustili v domačo oskrbo. Če pa je bila
potrebna obsežnejša resekcija, zaradi večjih tumorjev ali
njihovega večjega števila, smo bolnikom urinski kateter
odstranili 2-3 dan po operaciji. Prvo kontrolo smo naredili po
enem mesecu in opravili cistoskopijo. Če je bila epitelizacija
sluznice zaključena, smo nekatere bolnike dodatno zdravili
z intravezikalno imunoterapijo ali kemoterapijo, v primerih
rezidualnega tumorja in pri bolnikih s stadijem T1 pa smo
znotraj enega meseca naredili ponovno TUR.
Za dodatno intravezikalno imuno ali kemoterapijo smo se
odločili pri vseh bolnikih s stadijem bolezni T1 in s CIS. Med
bolniki s Ta pa so terapijo prejeli tisti, pri katerih je šlo za G II
in III, ali če je bil tumor multifokalen (Tabela 1).
Kontrolne cistoskopije smo naredili en mesec po končani
imuno ali kemoterapiji. Če ni bilo recidiva, smo naslednjo
cistoskopijo naredili po 3 mesecih, nato v dveh letih vsakih 6
mesecev in naprej enkrat letno. Pri bolnikih s stadijem bolezni
T1 in Ta+CIS ali CIS ter bolnikih s ponovitvijo bolezni, smo
izvajali podaljšano imunoterapijo. Po prvih šestih aplikacijah
BCG so sledile 3 mesečne, 2 trimesečni, 2 šestmesečni in
nato 1 aplikacija letno.
Rezultati
V letih 2005 in 2006 smo na našem oddelku prvič obravnavali
91 bolnikov s patohistološko verificiranim mišično
neinvazivnim rakom sečnega mehurja. Povprečna starost
bolnikov je bila 64,5 let. 72(79%) je bilo moških in 19(21%)
žensk. Pri 75(82,4%) bolnikih je bil ugotovljen stadij Ta in pri
16(17,6%) stadij T1. Pri 3 je bil ugotovljen CIS, pri 3 Ta+CIS
in pri 2 T1+CIS. Glede stopnje diferenciranosti malignih celic
je bilo 45(49,4%) bolnikov z G I, 27(29,6%) z G II in 19(21%)
z G III. Recidiv bolezni smo ugotovili pri 29(31,8%) bolnikih,
od katerih se je pri 16(55%) recidiv pojavil v prvem letu po
operaciji. Pri 9(31%) bolnikih je do ponovitve bolezni prišlo
2-3 krat. Od 29 bolnikov, pri katerih smo ugotovili ponovitev
bolezni, je pri 18(62%) bolnikih ob prvi operaciji šlo za 2-7
tumorjev, s stopnjo diferenciacije G II-III. Pri 4(4,3%) bolnikih
z recidivom bolezni smo ugotovili progres v mišično invazivni
stadij T2. Od 14 bolnikov, ki po prvi operaciji niso dobivali
imunoterapije ali kemoterapije, je do ponovitve bolezni prišlo
pri 4(29%), pri vseh pa je bil izhodiščni stadij Ta G II.
Zaključki
Če primerjamo naše rezultate z objavljenimi v strokovni
literaturi, lahko ugotovimo, da so glede odstotka ponovitve
bolezni sicer boljši, vendar v obravnavanem obdobju
operativnega zdravljenja še nismo natančno oz. pri vseh
bolnikih ocenjevali velikosti in števila tumorjev ob prvem
operativnem zdravljenju [10]. Ugotavljamo tudi razmeroma
visok odstotek (85%) tistih, ki so prejeli adjuvantno
intravezikalno imuno ali kemoterapijo.
31
Literatura
1. Campbell’s Urology eight edition. Urothelial tumors of
the urinary tract 2003
2. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer
statistics 2000. CA Cancer J Clin 2000;50:7-33
3. Heney NM. Natural history of superficial bladder cancer.
Prognostic feautures and long-term disease course.
Urol Clin North Am 1992;19:429-33.
4. Kiemeney LALM, Witjes JA, Heijbroek RP, Verbeek
ALM, Debruyne FMJ. Predictability of reccurent and
progressive disease in individual patients with primary
superficial bladder cancer. J Urol 1993;150:60-4.
5. Goessl C, Knispel HH, Millar K, Klän R. Is routine
excretory urography necessary at first diagnosis of
bladder cancer? J Urol 1997 Feb;157(2):480-1
6. Palou J, Rodriguez-Rubio F, Huguet J, Segarra J, Ribal
MJ, Alcaraz A, Villavicencio H. Multivariate analysis of
clinical parameters of synchronous primary superficial
bladder cancer and upper urinary tract tumors. J Urol
2005 Sep;174(3):859-61; discussion 861.
7. Holmäng S, Hedelin H, Anderström C, Holmberg
E, Johansson SL. Long-term follow-up of a bladder
carcinoma cohort: routine followup urography is not
necessary. J Urol 1998 Jul;160(1):45-8.
8. Millán-Rodríguez F, Chéchile-Toniolo G, SalvadorBayarri J, Huguet-Pérez J, Vicente-Rodríguez J. Upper
urinary tract tumors after primary superficial bladder
tumors: prognostic factors and risk groups. J Urol 2000
Oct;164(4):1183-7.
9. Raitanen M-P, Aine R, Rintala E, Kallio J, Rajala P,
Juusela H, Tammela TL; FinnBladder Group. Differences
between local and review urinary cytology and diagnosis
of bladder cancer. An interobserver multicenter analysis.
Eur Urol 2002 Mar;41(3):284-9.
10. Brausi M, Collette L, Kurth K, van der Meijden AP,
Oosterlinck W, Witjes JA, Newling D, Bouffioux C,
Sylvester RJ; EORTC Genito-Urinary Tract Cancer
Collaborative Group. Variability in the recurrence rate
at first follow-up cystoscopy after TUR in stage Ta T1
transitional cell carcinoma of the bladder: a combined
analysis of seven EORTC studies. Eur Urol 2002
May;41(5):523-31.
Tabela 1: Uvedba intravezikalne imuno ali kemoterapije
BCG 27 mg
Mitomycin C 40 mg
Ta G I
(multifokalen)
35
-
Ta
G II
23
-
Ta
GIII
4
-
T1
GI-III
8
2
CIS
3
-
Ta/T1+CIS
GI-III
4
-
32
Uporaba Mitomycina C pri zdravljenju raka mehurja – naše izkušnje
The use of Mitomycin C in Bladder Cancer treatment – our experiance
Klemen Jagodič, Igor Bizjak, Uroš Četina
Urološki oddelek, Splošna bolnišnica Celje, Slovenija
Department of Urology, General Hospital Celje, Slovenia
Rak mehurja predstavlja 3% vseh malignomov. Moški
zbolevajo 3 krat pogosteje kot ženske. Ocenjujemo, da smo
leta 2010 na novo odkrili 202 bolnikov in 76 bolnic z rakom
mehurja. Bolezen se najpogosteje pojavlja med 60 in 75
letom starosti.
Diagnozo raka mehurja postavimo s cistoskopijo in
histopatološkim pregledom reseciranega tumorja. Zdravljenje
in prognoza sta odvisna od histopatološke ocene in stadija
bolezni.
Na našem oddelku smo zgodnjo instalacijo mitomycina
po TUR tumorja mehurja uvedli leta 2004. Bolnik prejme
mitomycin 2 uri po TUR v dozi 40 mg. Kateter klemamo za 2
uri. V primeru krvavitve po TUR počakamo, da se urin zbistri
in instaliramo mitomycin do 24 ur po posegu.
2010 smo na našem oddelku opravili 258 TUR tumorjev
mehurja. Zdravili smo 192 bolnikov in 39 bolnic, s povprečno
starostjo 69 let. Pri petih bolnikih je histološki pregled potrdil
rak debelega črevesja, ki je infiltriral v mehur, pri ostalih
bolnikih je šlo za prehodnocelični karcinom mehurja. 7
bolnikov je imelo mišično invazivni rak mehurja. 81% bolnikov
s površinskim rakom mehurja je imelo nizko do zmerno
tveganje za napredovanje bolezni (solitarni, Ta, <3cm; TaT1, G1-G2, multifokalni, >3cm).
Med instalacijo mitomycina in neposredno po njej nismo
opažali nobenih hujših komplikacij.
Zgodnja instalacija mitomycina po TUR tumorja mehurja
zmanjša možnost ponovitve površinskih rakov mehurja za
polovico. V našo analizo smo zajeli le posege opravljene v
letu 2010. Tako nismo zajeli podatkov o morebitnih zgodnjih
recidivih raka mehurja v letu 2010 pri bolnikih, ki so bili
zdravljenji že v drugi polovici leta 2009 in bolnikov, pri katerih
je prišlo do zgodnjega recidiva v prvi polovici leta 2011.
Literatura:
1. Rak v Sloveniji 2007. Ljubljana: Onkološki inštitut
Ljubljana, Epidemiologija in register raka, Register raka
Republike Slovenije, 2010.
2. Tolley DA et al. The effect of intravesical mitomycin C on
recurrence of newly diagnosed bladder cancer: a further
report with 7 years followup. J Urol 1996; 155: 1233-8.
Pri 22 bolnikih smo v istem letu opravili vsaj 2 TUR. Pri 4
bolnikih je šlo za hemostatske posege zaradi inoperabilnega
tumorja mehurja. Pri 3 bolnikih smo opravili dodatno resekcijo
po na novo odkritem tumorju mehurja (2 T1 G3, 1 T2), pri
čemer je bil histološki izvid negativen. Pri 9 bolnikih je šlo
za recidiv nizko do srednje rizičnega karcinoma mehurja
(Ta, T1, G1, G2), 4 bolniki so imeli recidiv visoko rizičnega
karcinoma mehurja (T1, G3), 2 bolnika sta imela ponovno
mišično invazivni rak mehurja.
Po posegu je mitomycin prejelo 91% bolnikov. Mitomycina
niso prejeli bolniki, kjer smo makroskopsko ocenili, da tumorja
ni možno resecirati v zdravo, ter pri bolnikih, pri katerih smo
po posegu opažali močnejšo krvavitev.
33
Hyperthermia during intravesical doxorubicin application in patients
with superficial Urinary Bladder Carcinoma
M.M. Bernat, Ž. Kaštelan, D. Hauptman, I. Krhen, I. Mokos, N. Knežević
Clinical Hospital Center Zagreb, Clinic for Urology, Zagreb, Croatia
Introduction: Despite successful transurethral resection
and adjuvant intravesical chemotherapy, there is still a
high incidence of the superficial urinary bladder carcinoma
recurrence. Thermochemotherapy primarily addresses this
specific problem.
This paper presents our initial experience with hyperthermia
as a treatment method in patients with superficial urinary
bladder carcinoma.
Methods: We started the application of the hyperthermia
device in Clinic for urology using unithermic catheters after
histologically proven higher grade (Ta i T1) malignancy
transitional papillary carcinoma. The duration of a single
procedure was 45 minutes at a temperature of up to 45°C.
Prior to the treatment, and after the transurethral tumor
resection, the urinary culture was sterile. The patient age was
between 45 and 60 years.
Results: Successful intravesical doxorubicin instillation with
6 weekly applications was performed in 9 patients. In one
patient it was not possible to apply the hyperthermia due to
the unsuitable anatomy and prostatic urethra relations for
positioning of the universal unithermic catheter, which so
that the pump could not start. In two patients the therapy
was aborted due to urinary infection and was successfully
resumed after appropriate treatment. During a two-year
follow-up no recurrence was observed in any of the patients.
Conclusion: Intravesical doxorubicin application with
hyperthermia is a safe method in selected group of patients
with superficial carcinoma of the urinary bladder. This
method is well tolerated and does not cause inconvenience
for the patient. A larger number of patients and longer followup period are necessary for reporting of results in terms of
success and recurrence.
34
Significance of Fluorescence in situ hybridisation (fish urovysion) in
detection of Bladder Cancer reccurence
Ante Reljić(1), Sanja Mrsić(2), Silva Ćurić(3), Božo Krušlin(4), Ana-Maria Šimundić(5), Ognjen Kraus(1),
Davor Trnski(1)
1. University clinical Center Sestre milosrdnice, Clinic of urology, Zagreb, Croatia
2. University clinical Center Zagreb, Clinical Departmen of laboratory diagnostics, Zagreb, Croatia
3. University clinical Center Sestre milosrdnice, Clinic of internal diseases, Department of hemathology,
Laboratory for cytological diagnostisc, Zagreb, Croatia
4. University clinical Center Sestre milosrdnice, Clinical Department for Pathology, Zagreb, Croatia
5. University clinical Center Sestre milosrdnice, Clinical Department for Chemistry, Zagreb, Croatia
Abstract
The primary objective of this study were to determine the
clinical utility of FISH UroVysion test in comparison with
conventional cytological examination in early detection of
bladder cancer reccurence.
We analysed 113 patients with reccurent bladder cancer
and 40 patients with benign urological disease as controls.
All patients were tested by cytology, FISH UroVysion, iv.
urography and cystoscopy. In presence of tumor transurethral
resection and hystological examination of tissue were
performed.
Overall sensitivity and diagnostic accuracy was significantly
higher in favour of FISH UroVysion (p=0,001 and p<0,001).
Specificity of two methods was without statistical significance
(p=0,162). When tumors were stratified by stage and grade
the sensitivity of FISH UroVysion was significantly higher
for noninvasive (Ta, p<0,001) and poorly differentiated (G3,
p=0,038) tumors. When FISH UroVysion test reveal genetic
stable tumor one can exclude invasive (T≥1) and poor
differentiated (G3) likewise probably G2 (p=0,058) tumors.
On te contrary, if FISH UroVysion detect an unstable tumor,
this finding is not informative in terms of stage but one can
safely rule out well differentiated (G1) tumors.
FISH UroVysion test can reliable reduce the number of
unnecessary cystoscopies in case of following up the TaG1
tumors and negative test result. If one deal with G3 tumors
FISH UroVysion is preferable method in order to secure early
accurate diagnosis. We consider it advisebly to perform further
study particular for TaG1 tumors, using the FISH UroVysion
method, with the aim of defining different types of tumor on
the basis of genetic. Laboratory report of FISH UroVysion
test result should contain the type of genetic disorder which
makes test positive.
1. Introduction
Urothelial cancer is limited on the bladder mucosa (Ta, Cis)
or submucosal tissue (T1) in 80% and infiltrative disease
(T≥2) is present in 20% of cases. Since reccurences and
progression are prominent features of the superfitial bladder
cancer (SBC) a frequent, and sometimes a lifelong, followup is neccessary. That´s why the bladder cancer (BC) is
called „the most expensive disease of the western world“(1).
Standard follow-up (FU) examinations are represented by
urinary cytology and cystoscopy. Recent literature data warn
us that sensitivity of urinary cytology is poor not only for well
diferentiated but for G3 tumors also (2,3,4). Cystoscopy
is invasive, expensive and has her own limitations in
false positive and negative results as we learned from the
experience with „fluorescence cystoscopy“ (5,6,7).
That leads investigators to search for the new, less subjective
and more precise, methods of noninvasive detection of bladder
cancer cells in the urine. There is almost 20 tumor markers
in use nowdays. FISH UroVysion is newone, grounded in
the molecular cytogenetic principles, which detect numerical
and structural genetic changes in the exfoliated tumor cells.
The meaning of this marker and his place in daily urologic
practice is not undoubtly defined yet.
The primary objective of this study were to determine the
clinical utility of FISH UroVysion test in comparison with
conventional cytological examination in detection of bladder
cancer reccurence. Additionally we analysed the relationship
between tumor stage/grade and the kind of genetic changes,
detectable by FISH UroVysion test, in order to define the role
of this test in bladder cancer patients under surveillance.
2. Methods
From February 1st 2003. to July 31st 2004. we included 171
patients (age range 17-93y, median 71y). There were 124
35
with BC (90 males and 34 females; age median 72y) and
47 subjects (35 males and 12 females; age median 68) in
control group. In all patients urinary cytology, FISH UroVysion
test, cystoscopy and IVU were performed. In patients with
proven BC transurethral resection (TURBT) and hystological
analisys were undertaken.
collected with local urethral analgesia in men. Tranusrtheral
resection of the bladder tumor (TURBT) were performed
under spinal anesthesia and specimens of tumor tissue and
the muscular layer were sent to pathology separate.Tumors
were staged based on TNM classification (1997) and graded
according to WHO system (1999).
Urinary cytology was performed on spontaneous
voided specimens collected on three consecutive days.
Papanicolau´s procedure was used to evaluate the slides.
Inconculsive findings were scored as positive.
Age of the patients was showed by range and median.
Discriminating power of cytology and FISH UroVysion
was tested by analyzing the diagnostic exactness and
expressed with following parameters: sensitivity, specificity
and accuracy. Statistical significance of difference between
categorical attributes was tested with χ² and z-teset using the
cut-off for P value < 0,05.
For FISH UroVysion test urine specimens (50 ml) were taken
prior to cystoscopy, kept in refrigerator in 2% CarboWax
solution until sending to laboratory.The laboratory process
was undertaken following the manufacturer instructions
(Vysis, Downers Grove, IL, USA) through next four steps:
specimens processing, slide preparation, hybridisation and
specimens evaluation. Criteria for FISH UroVysion test
positivity was used as follow: at least 25 cells were analysed;
identification of polyploidia of minimally two chromosomes 3,
7, or 17 in at least four cells or homozygous deletion 9p21 in
at least 12 nuclei are considered positive result.
Cystoscopy were done after the urin specimens were
3. Results
Among 171 included patients there were observed no
difference in gender distribution between subjects with BC
and controls (χ², p=0,956). Age median of all patients was
71 (range 17-93), in patients with BC 72 (range 70-73) and
in control group 68 (range 17-89). The age of males with BC
and controls was similar (T-test, p=0,230) but women in the
control group were significantly younger in comparison with
diseased women (Mann-Whiney test, p=0,025) (table 1).
Control group
n=47
median (range)
P=
Female examinee
Patients with BC
n=124
median (range)
74 (49-93)
59 (45-84)
Male examinee
72 (46-86)
69 (17-89)
0,025
0,230
Table 1 – age distribution of females and males in the patient group and controls
From the further analysis 11 subjects (6,4%) were excluded
due to low amount of cells in the urine specimens. Acellular
sample was equaly frequent among cytological (7,6%) and
FISH specimens (7,6%). All of 11 patients with BC and too
low cells in sample had nonivasive G1/2 tumor.
tumor grade
tumor
Finally, we analysed 153 subjects including 113 with BC and
40 controls. Distribution of tumors depending on combination
of stage and grade reveal table 2.
stage
∑
G1
Ta
30
Tis
0
T1
7
T≥2
0
37 (32,7%)
G2
21
0
15
3
39 (34,5%)
G3
5
4
10
18
37 (32,7%)
∑
56
(49,6%)
4
(3,5%)
32
(28,3%)
21
(18,6%)
113
Table 2 – distribution of tumors depending on combination of stage and grade
36
Overall sensitivity of cytological examination was 53,98% and
for FISH UroVysion test 75,22% (p=0,001). Overall specificity
was not showed difference (p=0,16) but it was slightly higher
for FISH UroVysion and accuracy was significantly better in
favour of FISH (z-test, p<0,001). FISH UroVysion test had a
substantially higher sensitivity only for Ta (p<0,001) and poor
differentiated (G3) tumors (p=0,03) although this method was
better than cytology across all stages and grades.
Comparison of FISH UroVysion sensitivity in comparison
with cytology regarding the combination of stage and grade
criterion revealed significantly higher sensitivity for FISH in
TaG1 tumors (p=0,009) only while other categories of tumors
was not reveal statistical significance.
In cytologycal inconclusive findings (suspected cells)
(20,9%) we found almost equal proportion among patients
with BC and controls (χ² test, p=0,69). In this particular group
of tumors, with inconclusive cytologycal results, sensitivity
of FISH UroVysion test was 60,0% and was not better than
among all tumors (χ², p==0.196, CI 95% 38-78). However,
this group included substantial proprtions of G3 and T≥2
tumors which were correctly detected by FISH UroVysion
and remaind unrecognised by cytology.
After that, we categorized tumors according to genetical
disorders in two groups. Genetically stable urothelial
tumors were detected by FISH UroVysion due to isolated
homozygous deletion of LSI 9p21 and this group constitute a
minority (16,5%) of all tumors. The remnant majority (83,5%)
represent genetically unstable tumors detected due to
polyploidia of at least two chromosomes 3,7 or 17. Only well
differentiated tumors were stable and unstable with similar
frequency (p=0.76) and all others, regardless stage and
grade, were geneticaly unstable. FISH UroVysion test result
of unstable genetic disorder can hide any tumor stage but
seldom good differentiated tumor (G1 vs. G2, p=0,02).
Genetically stable tumors were far more frequent noninvasive
(Ta) than T1 (p<0,001) and more probably well differentiated
than G2 (p=0,058). There were no Cis, T2 and G3 tumors
which was genetically stable. In the TaG1 group of tumors
we observed that their genetical disorder, detectable by FISH
UroVysion test, contitute almost equal proprtion of stable and
unstable carcinomas(z-test, p=0,516).
4. Discussion
BC is group of hetregoneous diseases with innocent forms on
the one and life threatening on the other end of the spectrum.
Due to capabillity to reccure and progress to higher stage
and grade a frequent FU examinations are neccessary (2).
Reccurence and progression probability for Ta/T1 tumors
during the 5 years is 31-78% and <1-45%, respectively (8).
Moreover, prognosis of T≥2 cancer, wich developed from
the lower tumor stage, was poorer than for initially infiltrative
disease (9). That´s why the early and correct diagnosis
of some tumor types (at least all G3 because of potential
influence on mortality) is of utmost importance.
Cytology and cystoscopy represent conventional route of
FU but neither have a diagnostic accuracy high enough as
recorded by recent literature (1,4,10-13). Newer molecular
and cytogenetic cognitions offer a more clear picture of
different pathways to BC developement and progression
(2,14,15) and potentially more precise marker tests for
noninvasive detection of BC (16,17). Meloni at al predicted
a similar scenario almost 20 years ago (18). Moreover,
genetical stratification of different BC entities is not highly
coincident with histological classification (19,20). Superfitially
invasive (T1) and muscle-infiltrative (T≥2) tumors are very
similar at genetic level (14,19). Those findings forse us to
conclude how genetic changes neccessary for development
of T2 tumor were alredy present while he was superfitial. It is
in concordance with clinical results of cystectomies survival
for T1 vs.T≥2 published by Mainz group even 14 years ago
(21).
Since Sokolova at al described and defined a FISH
UroVysion® test he became a promising tool for noninvasive
detection of reccurent BC (22). Present study analysed FU
populations of patients and reveal a higher sensitivity, in
comparison with cytology, in overall patients (p=0,001) and
across all stages and grades but significance was observed
in Ta and G3 tumors only. Similar figures of sensitivity were
observed in another analyses of overall sensitivity in range of
71% to 86% (17,23-26). It is worthwhile to remark that some
of them, but not all, analysed a patients under FU, so results
cannot be comparable without caution. In this sence it might
be that a review article by Van Rhijn at al is a best choice for
results comparison (17).
In our study specificity were not significantly differ between
two methods (p=0,162) although FISH overperformed
cytology. In the abovementioned review specificity for
UroVysion had median 70 with range 66-93 (17). FISH
UroVysion has unique charcteristic among all BC urinary
markers regarding high specificity comparable with notorious
prominent specificity of cytology. However, cytology is
useless with intravesical chemo- or immunotherapy just as
after urinary diversion but those circumstances do not affect
the FISHUroVysion specificity (27-30). Particular practical
problem might be a situation when FISH is positive and
37
cystoscopy negative. It´s looks like false-positive result but
some literature data underline the predictive value of FISH
regarding reccurence and called that an „anticipatory positive
result“ (APR) istead of false-positive (24,29,31). In opposition
to mentioned argumentation we are still addherent to opinion
that APR might pose a significant practical danger especially
for patient in unpatient urologists hands.
Accuracy in our study was significantlly higher for FISH than
cytology (p<0,001). Placer et al find insignificant difference
between two methods regarding accuracy (25). Possibility of
acellular urine specimen was equally frequent in cytology and
FISH arm just as in patients group vs. controls. Veermachaneni
at al recorded frequency of 3% urine samples without cells
in cytology specimens and even 30% inadequate samples in
FISH arm (32).
We observed significantly better sensitivity of UroVysion
for noninvasive and poor differentiated tumors and sound
reasonably, according to our results, to recommend FISH
UroVysion instead of cytology for FU of those tumors. So,
in Ta-low grade tumors FISH offer a rational possibility to
reduce the number of cystoscopies during FU. At the same
time, high specificity prevent the number of unneccessary
invasive examinations. On the other hand, if we have the
patient with previously detected G3 tumor where early
detection of reccurence is imperative, proved significantly
higher sensitivity of FISH is important in order to miss as
low as possible reccurences. Moreover, if we use the FISH
as an adjunct to cytology only, high specificity od FISH is
cordially wellcome for G3 cancers. One can insist on opinion,
so frequent among urologists, that combination of cytology
and frequent cystoscopies is still the best FU-strategy for G3
cancers (17,34,35,36). It is wise to remind that only 40% of
patients received FU-cystoscopy on regular basis during the
first 3 FU years (33).
Majority of Ta tumors are of low grade and with good
prognosis according to hystological and clinical risk factors.
We observed that Ta tumors are significantly often geneticaly
unstable (p<0,001) and that G1 tumors are stable and
unstable with equal frequency (p=0,767). It seems that
hystological and clinical parameters, in case of Ta low grade
tumor, combine genetically different entities. Such result
deserve a further analyses.
From the practical viewpoint it is not very interesting about
dependance of genetical changes on stage or grade (since
TURBT is alredy done). The right question is whether the
FISH UroVysion offer any significant information regarding
stage and/or grade of tumor before we undertake an invasive
procedure (cystoscopy, biopsy or TURBT)? According to
our findings positive FISH result of an unstable tumor is
meaningless regarding stage but very probably we are
not dealing with G1 reccurence. On the opposite, if FISH
UroVysion detect reccurence of stable genetic disorder all
G3 and T≥2 can be safely excluded. Moreover, in group
of genetically stable tumors Ta were significantly frequent
than T1 (p<0,001) and difference between G1 and G2 is
borderly significant (p=0,058). Although proportion of stable
tumors in our study was small (16,5%) and abovementioned
conclusions must be confirmated on larger number of
patients with stable tumors we consider that laboratoy report
of FISH UroVysion test should include information about type
of genetic disorder.
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(histrelin implant)
Nova era
udobja
Vantas – enoletni implantat
za raka prostate
Vantas implantat
je mehak in fleksibilen.
(dejanska velikost 3,5 cm x 3 mm)
(histrelin implant)
Skrajøana navodila za uporabo
Vantas© implantat vsebuje 50 mg histrelinijevega acetata, iz katerega se v povpreœju sproøœa 50 µg histrelina v 24 urah. Priporoœeni odmerek
zdravila Vantas je en implantat na 12 mesecev. Implantat vstavimo subkutano na notranjo stran nadlahti.
Indikacije: Paliativno zdravljenje napredovalega raka prostate.
Kontraindikacije: Zdravilo Vantas je kontraindicirano pri bolnikih s preobœutljivostjo za histrelin ali katerokoli pomoæno snov implantata, GnRH,
agoniste ali analoge GnRH ali stearinsko kislino. Poroœali so tudi o anafilaktiœnih reakcijah na sintetiœni LHRH ali na agoniste in analoge LHRH.
Posebna opozorila oziroma previdnosti: Tako kot drugi agonisti LHRH, tudi Vantas v prvem tednu zdravljenja povzroœa prehodno poveœanje
koncentracije testosterona v serumu Pri bolnikih se lahko zato poslabøajo simptomi ali pa se pojavijo novi, na primer boleœine v sklepih, boleœine v
kosteh, nevropatija, hematurija ali zapora iztoka iz seœnice ali seœnega mehurja. V povezavi z uporabo agonistov LHRH so poroœali tudi o primerih
zapore seœnice in kompresije hrbtenjaœe, ki lahko vodi do paralize z zapleti, ki se lahko konœajo s smrtjo ali brez njih. Bolnike z metastatskimi lezijami
vretenc in/ali zaporo seœil je treba skrbno spremljati v prvih nekaj tednih zdravljenja. Ti bolniki bi lahko bili primerni za profilaktiœno zdravljenje z
antiandrogeni. Œe pride do kompresije hrbtenjaœe ali ledviœne okvare, pri bolniku uvedite obiœajno zdravljenje teh zapletov.
Neæeleni uœinki: Tako kot drugi agonisti LHRH, lahko tudi Vantas povzroœi ginekomastijo ali impotenco, ki traja razliœno dolgo. Mogoœe je torej
priœakovati, da bodo daljøa obdobja medikamentozne kastracije pri moøkih vplivala na kostno gostoto. V kliniœnih preskuøanjih je najpogostejøi
neæelen uœinek povezan z Vantasom sama reakcija ob implantiranju, ki je poveœini blaga ter se umiri v prvih tednih. Vstavljanje implantata je kirurøki
poseg. Za zmanjøanje tveganja zapletov in zavrnitveno reakcijo, priporoœamo natanœno sledenje priporoœenim navodilom za vstavljanje in odstranitev
implantata.
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PFI 21-11
TOVIAZ 4 mg / 8 mg tablete s podaljšanim sproščanjem
Sestava in oblika zdravila: Ena tableta s podaljšanim sproščanjem vsebuje 4 mg / 8 mg fesoterodinijevega fumarata kar ustreza 3,1 mg / 6,2 mg fesoterodina. 4 mg in 8 mg tablete vsebujejo sojin lecitin in laktozo monohidrat. Indikacije: Zdravljenje simptomov
(povečana pogostnost uriniranja in/ali urgentna mikcija in/ali urgentna inkontinenca), ki se lahko pojavijo pri bolnikih s sindromom čezmerno aktivnega sečnega mehurja. Odmerjanje in način uporabe: Priporočen začetni odmerek je 4 mg enkrat na dan. Glede
na odziv posameznika se odmerek lahko poveča na 8 mg enkrat na dan. Največji dnevni odmerek je 8 mg. Poln učinek zdravljenja so opazili med 2 in 8 tedni. Odmerek TOVIAZA je potrebno glede na delovanje ledvic in jeter ter v primeru sočasne uporabe zaviralcev
CYP3A4 ustrezno zmanjšati, v nekaterih primerih se je potrebno zdravljenju s TOVIAZOM izogniti ali je celo kontraindicirano. Uporaba pri otrocih: uporaba TOVIAZA pri otrocih in mladostnikih, mlajših od 18 let ni priporočljiva. Kontraindikacije: Preobčutljivost za
zdravilno učinkovino, arašide ali sojo ali katerokoli pomožno snov; retencija urina; želodčna retencija; nenadzorovan glavkom z zaprtim zakotjem; miastenija gravis; hude motnje v delovanju jeter (stopnje C po Child-Pughu); sočasna uporaba močnih zaviralcev CYP3A4
pri bolnikih z zmerno do hudo okvaro jeter ali ledvic; hud ulcerozni kolitis; toksični megakolon. Posebna opozorila in previdnostni ukrepi: TOVIAZ je treba uporabljati previdno pri bolnikih: s klinično pomembno obstrukcijo mehurja s tveganjem za retencijo urina;
z gastrointestinalnimi obstruktivnimi motnjami; z gastroezofagealnim refluksom in/ali bolnikih, ki sočasno jemljejo zdravila, ki lahko povzročijo ali poslabšajo ezofagitis; z zmanjšano gastrointestinalno gibljivostjo; z avtonomno nevropatijo; z nadzorovanim glavkomom
z zaprtim zakotjem. Previdnost pri odmerjanju ali povečevanju odmerka je potrebna pri bolnikih z okvaro jeter ali ledvic, ki sočasno uporabljajo močne ali zmerne zaviralce CYP3A4 ali močne zaviralce CYP2D6. Pred kakršnimkoli zdravljenjem z antimuskarinskimi
zdravili je potrebno izključiti organske in druge vzroke (zdravljenje srčnega popuščanja, ledvične bolezni ali okužbe sečil) za pojav simptomov. TOVIAZ je treba pri bolnikih s tveganjem za podaljšanje intervala Q-T in z že obstoječimi srčnimi boleznimi uporabljati
previdno. Medsebojno delovanje z drugimi zdravili: Sočasna uporaba TOVIAZA in drugih antimuskarinskih in antiholinergičnih zdravil lahko povzroči bolj izražene terapevtske in neželene učinke. Močni zaviralci CYP3A4 povečajo vrednost Cmax aktivnega presnovka
fesoterodina. Induktorji CYP3A4 zmanjšajo Cmax aktivnega presnovka fesoterodina in lahko zmanjšajo koncentracijo fesoterodina v plazmi pod terapevtsko raven. Nosečnost in dojenje: Uporaba med nosečnostjo in dojenjem ni priporočljiva Vpliv na sposobnost
vožnje in upravljanja s stroji: Potrebna je previdnost pri vožnji ali uporabi strojev zaradi možnosti pojava neželenih učinkov, kot so zamegljen vid, omotica in zaspanost. Neželeni učinki: Zelo pogosti: suha usta; pogosti: omotica, glavobol, suhe oči, suho grlo,
bolečina v trebuhu, diareja, dispepsija, zaprtje, navzea, disurija. Način in režim izdajanja: Izdaja zdravila je le na recept. Imetnik dovoljenja za promet: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, Velika Britanija. Datum zadnje revizije
besedila: 10/2010
“SAMO ZA STROKOVNO JAVNOST”
CARDURA XL 4 mg in 8 mg tablete s podaljšanim sproščanjem
Sestava in oblika: tableta s podaljšanim sproščanjem vsebuje 4 mg ali 8 mg doksazosina. Indikacije: hipertenzija; benigna hiperplazija prostate. Odmerjanje in način uporabe: odmerek 4 mg enkrat na dan se lahko zaužije s hrano ali brez. Tablete je treba pogoltniti
cele, z zadostno količino tekočine. Odmerek se po štirih tednih lahko poveča na 8 mg enkrat na dan. Največji priporočen odmerek je 8 mg enkrat na dan. Kontraindikacije: preobčutljivost za kinazoline (npr. prazosin, terazosin, doksazosin) ali katerokoli pomožno snov;
ortostatska hipotenzija; benigna hiperplazija prostate in sočasni zastoj zgornjih sečil, kronična okužba sečil ali kamni v mehurju; zapora prebavil, zapora požiralnika ali kakršnakoli stopnja zmanjšanja premera svetline prebavil; dojenje; hipotenzija; (pri monoterapiji)
prenapolnjen mehur ali anurija, z napredujočo insuficienco ledvic ali brez nje. Posebna opozorila in previdnostni ukrepi: Navodila za bolnike: naj se ne vznemirjajo, če bodo občasno v blatu opazili nekaj, kar je podobno tableti. Zdravilo se nahaja v ovojnici, ki se
ne absorbira. Nenormalno zmanjšan čas prehoda skozi gastrointestinalni trakt lahko vpliva na nepopolno absorpcijo zdravila. Začetek zdravljenja: nadzorujemo krvni tlak, da bi zmanjšali možne posturalne učinke. V času uvajanja terapije naj se bolnik izogiba situacijam,
v katerih lahko pride do poškodb zaradi vrtoglavice ali slabosti. Previdnost pri nekaterih akutnih srčnih stanjih. Jetrna okvara: uporablja naj se previdno, pri hudi jetrni okvari se uporaba ne priporoča. Zaviralci PDE-5: sočasna uporaba zahteva previdnost, saj lahko
pride do simptomatske hipotenzije. Operacija katarakte: možen medoperacijski sindrom ohlapne šarenice. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: zaviralci PDE-5, ostali zaviralci adrenergičnih receptorjev alfa in antihipertenzivi.
Nosečnost in dojenje: uporaba le, če pričakovana korist odtehta potencialno tveganje. Dojenje je kontraindicirano. Vpliv na sposobnost vožnje in upravljanja s stroji: lahko vpliva na sposobnost vožnje in upravljanja s stroji, zlasti ob uvajanju terapije. Neželeni
učinki: okužbe dihal, okužbe sečil; omotica, glavobol, somnolenca; vrtoglavica; palpitacije, tahikardija; hipotenzija, posturalna hipotenzija; bronhitis, kašelj, dispneja, rinitis; bolečine v trebuhu, dispepsija, suha usta, navzea; pruritus; bolečina v hrbtu, mialgija; cistitis,
inkontinenca; astenija, bolečine v prsnem košu, gripi podobni simptomi, periferni edemi. Preveliko odmerjanje: v primeru hipotenzije, je bolnika treba nemudoma položiti vznak z glavo v nižjem položaju in po presoji uporabiti druge podporne ukrepe. Način izdajanja
zdravila: zdravilo se izdaja le na recept. Imetnik dovoljenja za promet: Pfizer Luxembourg SARL, 51, Avenue J. F. Kennedy, L-1855 Luxembourg, Luksemburg. Datum zadnje revizije besedila: 24.9.2009
41
Preprečevanje trzljajev mišic stegenskih adduktorjev z blokom
obturatornega živca pri transuretralni resekciji stransko ležečih
tumorjev mehurja
The prevention of obturator jerk reflex with obturator nerve block
during transurethral resection of lateral bladder wall tumors
Simon Hawlina, Jure Bizjak, Borut Gubina, Tomaž Smrkolj, Robert Kordič, Miro Mihelič,
Dominik Cotič, Boris Sedmak
Klinični oddelek za urologijo, Univerzitetni klinični center Ljubljana, Slovenija
Clinical Department of Urology, University Clinical Center Ljubljana, Slovenia
Izvleček
Uvod: Med transuretralno resekcijo stransko ležečih tumorjev
mehurja lahko pride do stimulacije obturatornega živca in
posledično trzljaja mišic stegenskih adduktorjev.
Metoda: Med februarjem in aprilom 2011 smo na naši kliniki
evaluirali deset bolnikov s stransko ležečimi tumorji mehurja.
Vsi so pred transuretralno resekcijo tumorjev mehurja (TUR)
prejeli tako spinalno anestezijo, kot tudi blok obturatornega
živca (BOŽ). Pri nobenem bolniku ni prišlo do trzljaja mišic
stegenskih adduktorjev. Za BOŽ smo uporabili 22G spinalno
iglo, elektrostimulacijsko napravo in 10-20 ml 2% lidokaina,
ki smo ga infiltrirali v obturatorni živec v predelu mišic
stegenskih adduktorjev.
Rezultati: Pri vseh desetih bolnikih smo uspešno izvedli
enostranski BOŽ. Trzljaja mišic stegenskih adduktorjev
nismo opazili pri nobenem izmed njih.
Zaključek: BOŽ je uspešna tehnika za preprečevanje trzljajev
mišic stegenskih adduktorjev pri TUR stransko ležečih
tumorjev mehurja. Preprečuje globoke in nekontrolirane reze
stranske stene mehurja med TUR tumorjev. Pri bolnikih ni
potrebna splošna anestezija z relaksacijo, operativni čas je
krajši, metoda pa ti omogoča natančnejši in bolj radikalen
poseg. Elektrostimulacija obturatornega živca pred aplikacijo
anestetika je enostavna, lahko ponovljiva, varna in visoko
uspešna metoda.
Abstract
The obturator nerve may be stimulated by transurethral
resection of lateral bladder wall tumors, causing obturator
jerk reflex.
Methods: Between February 2011 and April 2011 10 patients
who undergone TURBT on the lateral bladder wall were
evaluated at our clinic. All of them received spinal anesthesia
with obturator nerve block (ONB). No obturator jerk reflex
were observed in the patients. ONB was obtained with 10
ml of 2% lidocaine infiltrated through a 22G spinal needle
using a nerve stimulation approach.
Results: Successful ONB was performed unilateral in all of
patients. Muscle spasms were absent in all of them.
Conclusions: ONB for the prevention of obturator jerk
reflex is a useful technique for the prevention of deep and
uncontrolled cuts in the lateral part of the bladder wall
during TURBT. There is no need for general anesthesia with
relaxation, operating time is shorter, the procedure is more
meticulous and radical. The nerve stimulation approach is a
simple, safe, highly reproducible and easy procedure, with a
high success rate.
Uvod
Obturatorni živec poteka skozi obturatorni kanal in oživčuje
mišice adduktorjev stegna. Izhaja iz lumbalnega pleksusa
od L2 do L4 in vsebuje tako motorična, kot tudi senzorična
živčna vlakna. Znotraj male medenice je njegov potek v
bližini prostatične uretre, vratu mehurja in inferolateralne
stene mehurja.
Med transuretralno resekcijo tumorjev mehurja (TURM), ko
mehur močneje napolnimo s tekočino, je obturatorni živec v
tesnem stiku z lateralno steno mehurja. Tako med posegom,
kjer uporabljamo električni tok, električni tokovi brez težav
stimulirajo obturatorni živec, kar vodi v trzljaj mišic stegenskih
adduktorjev. Ob tem lahko pride do perforacije mehurja,
razlitja tumorski celic v perivezikalno področje in močnejše
krvavitve. Zaradi strahu operaterja, da bo bolniku z globoko
resekcijo povzročil škodo, pa je resekcija stransko ležečih
tumorjev mehurja največkat neradikalna.
TURM največkrat opravljamo v spinalni anesteziji, ki pa ne
zavre elektrostimulacije obturatornega živca. Za blokado
elektrostimulacije moramo bolnika relaksirati. Potrebna
je endotrahealna intubacija, ki je visoko invaziven poseg,
42
celotna operacija traja dlje, nekateri pacienti niso primerni
za endotrahealno intubacijo zaradi rizičnih dejavnikov. Tako
je Prentiss leta 1965 prvi predlagal uporabo regionalne
anestezije za blokado obturatornega živca in trzljaja mišic
adduktorjev stegna.
Kljub temu, da so trzljaji mišic adduktorjev stegna glavni
faktor, ki negativno vpliva na izid operacije sransko ležečih
tumorjev mehurja, pa do sedaj še ni izdelanih natančnih
smernic. Menim, da pri TURM na stranski steni, s kombinacijo
spinalne anestezije in regionalnega bloka obturatornega
živca, uspešno preprečimo trzljaje mišic adduktorjev
stegna. Regionalni blok obturatornega živca je enostaven,
hiter, visoko uspešen in nenevaren poseg. S preglednim
prispevkom želim prikazati metodo, da bi jo lahko v vsakdanji
klinični praksi uporabljalo čimveč urologov.
INDIKACIJE za regionalni blok obturatornega živca
Tumorji mehurja locirani na stranski steni.
KONTRAINDIKACIJE za regionalni blok obturatornega
živca
1. koagulopatije,
2. povečane ingvinalne bezgake,
3. infekcija kože v ingvinalnem predelu,
4. otežen dostop (kontrakture)
Anatomija
Obturatorni živec izhaja iz lumbalnega pleksusa od L2 do L4.
Vsebuje tako motorična, kot tudi senzorična živčna vlakna.
Poteka ob notranjem robu mišice psoas, nato po mišici
obturator internus, preide skozi zgornji del obturatornega
foramna in končno vstopi v mišice adduktorjev stegna.
Ko zapusti obturatorni foramen se cepi v dve veji in sicer
v anteriorno in posteriorno vejo. Anteriorna veja oživčuje
mišice adduktor brevis, adduktor longus in gracilis, medtem
ko oživčuje posteriorna veja mišici adduktor magnus
in obturator eksternus. Senzorična veja oživčuje kožo
notranjega, zgornjega dela stegna.
V klinični praksi je potrebno obturatorni živec blokirati preden
se cepi v anteriorno in posteriorno vejo.
Farmakologija
Obturatorni živec je periferni živec s senzorno in motorno
funkcijo. Motorna živčna vlakna so iz skupine A, ki so
debelejša. Za uspešen obturatorni blok mora koncentracija
anestetika dvakrat preseči koncentracijo, ki je potrebna za
blokado občutka za bolečino in temperaturo, ki se sicer
prevaja po tankih A in C vlaknih. Tako je bolje uporabiti 2%
koncentracijo lidokaina ali 0,25% koncentracijo bupivakaina.
Klinično imamo na voljo dve skupini lokalnih anestetikov.
Tiste s hitrim pričetkom delovanja, a so kratkodelujoči in
tiste, ki potrebujejo dalj časa za pričetek delovanja, a so
dolgodelujoči. V prvo skupino spadata lidokain in mepirakain.
Lidokain je najprimernejši, saj začne delovati že po cca 4
minutah, deluje pa do 40 minut. Z 2% koncentracijo v količini
10-20 ml uspešno blokiramo obturatorni živec. V drugo
skupino spadata tetrakain in bupivakain (markain).
Dodatek epinefrina lokalnemu anestetiku podaljša delovanje
lokalnega anestetika z vazokonstrikcijo, ki onemogoči
izplavljanje lokalnega anestetika iz mesta delovanja.
Oprema
Osnovna oprema za izvedbo bloka obturatornega živca:
1. sterilne rokavice
2. 20-ml brizga
3. injekcijska igla (5-8 cm v dolžini)
4. lokalni anestetik (2% lidokain or 0.25% bupivakain)
5. elektrostimulator
Anatomske orientacijske točke so tuberkel pubisa, kot kostna
orientacijska točka, femoralna arterija kot žilna orientacijska
točka in tetiva adduktor longusa kot mišična orientacijska
točka.
Tehnika
Na voljo imamo dva pristopa, ki sta po uspešnosti primerljiva.
Prvi je slep, anatomski pristop, kjer se orientiraš glede na
anatomske oporne točke. Drug je elektrostimulacijski
pristop, kjer z elektrostimulacijsko napravo z iglo najdeš
najprimernejše mesto za aplikacijo anestetika.
Slep, anatomski pristop
1. Bolnika namestimo v litotomijski položaj
2. Vstopna točka igle je 1,5 cm (dva prsta) lateralno in 1,5
cm (dva prsta) inferiorno od tuberkla osis pubis.
3. Vstopno mesto igle je že anestezirano prek spinalne
anestezije, tako, da kože ni potrebno dodatno infiltrirati
z lokalnim anestetikom
4. Iglo zabodemo v kožo skoraj pod pravim kotom
5. Ko smo z iglo na mestu, ki ga mislimo lokalno anestezirati,
opravimo aspiracijo. Če v brizgo ne priteka kri, apliciramo
v predel obturatornega živca anestetik (0.25% bupivakain
ali 2% lidokain)
6. Ponavljamo točke 3 do 5, skupaj trikrat.
Elektrostimulacijski pristop
1. Točke 1 do 3 so iste, le da uporabimo posebno
iglo, ki je priključena na elektrostimulativno napravo.
Elektrostimuliramo s tokom od 1 do 1,5 mA. Trzljaji in
moč trzljajev mišic stegenski adduktorjev nam kažejo na
pravilno mesto vboda..
2. Ko najdemo pravilno mesto na obturatornem živcu bodo
mišice stegenski adduktorjev ob vskem elektrostimulusu
močno trznile.
43
3. Ko menimo, da smo na pravem mestu, znižamo
elektrostimulativni tok na 0,3 mA. Intenziteta trzlajjev
mišic se zmanjša, a je še vedno prisotna, v kolikor je
mesto pravo. V ta predel apliciramo anestetik (0.25%
bupivakain ali 2% lidokain), dokler kontrakcije ne izzvenijo
(cca 10-20 ml).
4. Nekaj minut po končani aplikaciji anestetika, ponovno
ocenimo trzljaje mišic ob višjem toku (1,5mA). Če
kontrakcij ni, je bil blok uspešen.
Komplikacije
1. Slabša blokada obturatornega živca lahko vodi v trzljaj
mišic stegenskih aduktorjev, kar je redko.
2. Ob obturatornemu živcu poteka obturatorna arterija, ki
jo teoretično lahko z iglo poškodujemo in povzročimo
krvavitev s hematomom. Omenjene komplikacije v
literaturi nisem zasledil.
Pregled literature
Glede na Augsurqer et al., je uspešnost inhibicije trzljaja mišic
stegenskih adduktorjev s slepo, anatomsko metodo med
83.8% in 85.7%. Z elektrostimulativno metodo dosegamo
boljše rezultate in sicer glede na Gasparich et al. and
Kobayashi et al., 89.4%-100%.
Zaključek
Pravilno razumevanje anatomije obturatornega živca in
njegove inervacije, kot tudi pravilna aplikacija lokalnega
anestetika nam omogočajo popolno blokado trzljajev mišic
stegenskih adduktorjev med TUR tumorjev na stranski steni
mehurja. Z blokom preprečujemo globoke in nekontrolirane
reze stranske stene mehurja med TUR tumorjev, ki vodijo
v večjo krvavitev, perforacijo mehurja in razlitje tumorskih
celic v perivezikalno področje. Pri bolnikih ni potrebna
splošna anestezija z relaksacijo, operativni čas je krajši,
metoda pa ti omogoča natančnejši in bolj radikalen poseg.
Elektrostimulacija obturatornega živca pred aplikacijo
anestetika je enostavna, lahko ponovljiva, varna in visoko
uspešna metoda.
Reference
1. Brown DL. Atlas of Regional Anesthesia. Philadelphia,
PA: WB Saunders, 1992:103-8.
2. Moore DC, ed. Obturator Nerve Block. Regional Block,
4th ed. Springfield, IL: Charles C. Thomas, 1965:28993.
3. Berberoglu M, Uz A, Ozmen MM, Bozkurt C, Erkuran
C, Taner S, Tekin A, Tekdemir I. Corona mortis: an anatomic study in seven cadavers and an endoscopic study
in 28 patients. Surg Endosc 2001;15:72-5.
4. Mydlo JH, Weinstein R, Shah S, Solliday M, Macchia
RJ. Long-term consequences from bladder perforation
and/or violation in the presence of transitional cell
carcinoma: results of a small series and a review of the
literature. J Urol 1999;161:1128-32.
5. Hahn RG, Sandfeldt L, Nyman C R. Double-blind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral
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6. Collado A, Chechile GE, Salvador J, Vicente J. Early
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contractions during transurethral resection. L Mount
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8. Hobika JH, Clarke BG. Use of neuromuscular blocking
drugs to counteract thigh-adductor spasm induced by
electrical shocks of the obturator nerve during transurethral resection of bladder tumors. J Urol 1961;85:2956.
9. Prentiss RJ, Harvey GW, Bethard WF, et al. Massive
adductor muscle contraction in transurethral surgery:
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10. Augspurger RR, Donohue R E. Prevention of obturator
nerve stimulation during transurethral surgery. J Urol
1980;123:170-2.
11. Parks CR, Kennedy WF Jr. Obturator nerve block: a
simplified approach. Anesthesiology 1967;28:775-8.
12. Hradec E, Soukup F, Novak J, Bures E. The obturator
nerve block. Preventing damage of the bladder wall
during transurethral surgery. Int Urol Nephrol 1983;15:
149-53.
13. Hong Y, O’Grady T, Lopresti D, Carlsson C. Diagnostic
obturator nerve block for inguinal and back pain: a recovered opinion. Pain 1996;67:507-9.
14. Bouaziz H, Vial F, Jochum D, Macalou D, Heck M,
Meuret P, Braun M, Laxenaire MC. An evaluation of
the cutaneous distribution after obturator nerve block.
Anesth Analg 2002;94:445-9.
15. Atanassoff PG, Weiss BM, Brull SJ. Lidocaine plasma
levels following two techniques of obturator nerve block.
J Clin Anesth 1996;8:535-9.
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44
Bladder sparing treatment for muscle invasive Bladder Cancer:
solution or an option?
Aleksandar Janjić, Cane Tulić, Aleksandar Vuksanović, Nebojsa Bojanić, Nale Djordje,
Urology Clinic, Clinical Centre of Serbia, Belgrade, Serbia
Abstract
Background: Radical cystectomy and lymphadenectomy is
the gold standard for the treatment of muscle-invasive bladder
cancer (MIBC) Neither transurethral resection of the bladder
(TURB) nor radiation alone provides adequate local control
for unselected patients. Recent organ-preservation strategies
combining TURB, chemotherapy, and radiation (trimodality
treatment) have shown local control and progression results
comparable to cystectomy series. In very selected patients,
invasive bladder cancers can be cured by TURB alone or
neoadjuvant chemotherapy and TURB.
Objective: To determine outcome of bladder sparing
treatment in patients with muscle invasive bladder cancer
treated with TURBT and chemotherapy.
Method: 21 patient, all males, 61 to 79 years old were
eligible, fulfilling inclusion criteria for bladder preservation:
Muscle invasive Transitional cell bladder cancer diagnosed
after TURBT, absence of CiS, no signs of upper tract tumors,
size of tumor less then 5 cm, reliable and cooperative
patients. Patients included were chosen because of refusal of
cystectomy, (9) or serious co morbid conditions not allowing
cystectomy.(12) After initial TURBT patients were treated with
chemotherapy M –VAC (4) and Gemcitabine Cis platinum
(17) with 3 or 4 cycles. In three months period second TUR
BT was done. On the basis of histological findings patients
were treated with salvage cystectomy if muscle invasive
disease exists, partial cystectomy if feasible, or if complete or
partial response were achieved patients received two more
cycles of chemotherapy. Regular cystoscopies in 3 months
intervals, CT scans twice a year and reevaluation thereafter
were done threw a mean follow up period of 27,5 months.
Results: After first TURBT, 5 complete responses (pTo) were
documented, 5 superficial relapses, one endoscopical CR
with inconclusive histology, and 10 patients with still present
MIBC. Of those 10 patients 6 were salvaged with cystectomy,
other 4 treated with partial cystectomy. 15 patients were alive
with their bladders after 12 months, after 4 years 6 patients
died, 4 have had salvage cystectomy after 2 to 3 years, and 5
patients were alive with functional bladders, without evidence
of disease progression, and good quality of life.
Conclusion: In appropriately selected and cooperative
patients, meticulously followed, combined-modality therapy
can preserve a tumor-free bladder without compromising
survival, maintaining the good quality of life.
Introduction
Bladder cancer ranks ninth in worldwide cancer incidence.
The age standardized incidence is 10.1 per 100.000 for males
and 2.5 per 100.000 for females. One fourth of bladder cancer
(BC) are muscle invasive at diagnosis and account for 80%
of disease related deaths. Approximately one third of patients
diagnosed with muscle invasive bladder tumors (MI BC) have
undetected dissemination at the time of primary treatment,
while up to 25% patients undergoing radical cystectomy
have lymph node involvement at time of surgery. Radical
cystectomy results in a 5 year survival of about 50% .One
major reason for early death is unrecognized micrometastatic
spread that ultimately develops into macrometastatic
detectable dissemination and/or local recurrence.
As a matter of principle, operable (neoadjuvant approach),
as well as unresectable primary tumours are expected to
respond to systemic chemotherapy. However, chemotherapy
alone rarely produces durable complete responses of the
bladder primary tumours. Down staging with 2-4 cycles of
MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)
or Gemcitabine Cisplatinum might be one benefit. Pathological
complete responses of bladder primary tumors were reached
in 12-50% of patients after MVAC and in 12-22% of patients
after gemcitabine/cisplatin (GC).
Patients who refused cystectomy after receiving neoadjuvant
chemotherapy for muscle-invasive bladder cancer had a 64%
rate of relapses in the bladder with an additional mortality of
30%.
Such patients might jeopardize their survival due to the
lack of definitive treatment of the primary bladder tumor, by
developing relapsing tumors in the bladder.
Response to chemotherapy may be confounded by patient
selection. However, it is a prognostic factor for treatment
outcome and eventual survival.
45
For bladder preservation strategies, response is evaluated
by cystoscopy/re-TURB plus eventual CT-imaging, followed
by close surveillance. This approach is prone to an immanent
staging error and might put the patient at risk for local
recurrence and/ or consecutive metastatic disease. Radical
cystectomy with extended lymphadenectomy is by far the
best therapeutic option for MIBC. For very selected patients
with localized disease, a bladder conserving strategy
with TURB and systemic cisplatin-based chemotherapy,
preferably with MVAC, or Gemcitabine – Cisplatinum has
been shown to allow long term survival with intact bladder. Of
note, this approach cannot be recommended for routine use,
employed mainly for patients refusing cystectomy or patients
unfit for major surgery due to co morbid conditions.
Patients and methods
21 bladder cancer patient, all males, 61 to 79 years old were
eligible, fulfilling inclusion criteria for bladder preservation:
Muscle invasive Transitional cell bladder cancer documented
after TURBT, endoscopicaly radical TUR, disappearance
of hardened zones in the bladder wall after resection on
bimanual palpation. absence of CiS, no signs of upper tract
tumors, size of tumor less then 5 cm., reliable, motivated and
cooperative patients.
Patients included were chosen because of cystectomy
refusal and motivation to preserve the bladder (9) or serious
co morbid conditions not allowing cystectomy.(12) After initial
TURBT patients were treated with chemotherapy M –VAC
(4) and Gemcitabine Cis platinum (17) with 3 or 4 cycles.
In three months period second TUR BT was done. On the
basis of histological findings patients were treated with
salvage cystectomy if muscle invasive disease exists, partial
cystectomy if feasible, or if complete or partial response were
achieved patients received two more cycles of chemotherapy.
Regular cystoscopies in 3 months intervals, CT scans twice
a year and reevaluation thereafter were done threw a mean
follow up period of 27,5 months. (10 to 45 months)
MIBC was primarily diagnosed in 12 pts (57.14%), 9 patients
were included after progression of previously treated tumors
(42.85%)
Histopathology was transitional cell cancer (TCC) in 12
pts (57.14%) and TCC with squamocelullar and adenoid
components in 9 cases (42.85%). CiS was found in 6 patients
(28.57%) in peritumoral specimens, without concomitant and
diffuse CiS.
Tumor size was less then 3 cm in 8 pts (38%), and 3 – 5
cm in 13 pts. ( 62%) In one patient nephroureterectomy was
done 2 years before bladder cancer, the other 20 patients
were without signs of ureteric or renal pelvic tumors.
Hydronephrosis was present in 4 patients, in 3 drained with
nephrostomy tube, in one resolved during treatment.
Pathology reports were examined by four uropathologists
during the follow up.
Table 1 – Patient characteristics
Age 61 – 79
Patients
Mean 70
Tumors
Primary
12 (57.1%)
Progressed
9 (42.8%)
Hystopathology
TCC only
12 (57.14%)
TCC+Sqc.
9 (42.8%)
Grades
II
10 (47%)
III
11 (52.3%)
CiS
Peritumoral
6 (28.57%)
Diffuse
0
Size
< 3 cm:
8 (38%)
3-5 cm:
13 (62%)
Upper tracts
Tumors :
0
Hydroneph.
4 (19.0%)
Stage after TURBT
pT2 :
11 (52.4%)
>pT2 :
10 (47.6%)
9 (42.8%)
Comorbidities
12 (57.2%)
Reason for bladder sparing Refusal of cystectomy
After complete TURBT patients were treated with neoadiuvant
chemotherapy with M VAC (methotrexate, doxoeubicine,
viblastine, Cisplatinum) or Gemcitabine-Cisplatinum
protocols with general oncological criteria for inclusion to
chemotherapy: Age below 75, Hemoglobin level over 90 g/l,
WBC of more then 3000, Liver function tests within 1.5 of
upper normal limit, creatinine clearance of more then 60 ml/
min, performance status ECOG of 2 or less. Patients have
had 3 do 4 cicles. 5 patients discontinued treatment due
to toxic effects of chemotherapy, and were excluded from
further follow up, other patients did not experienced major
toxic effects, with dose delays due to neutripenia and low
platelet counts (Gemsar / Cisplatinum group) most common.
10 Patients (47.6%) had 3 cycles, 11 (52.4%) had a 4 cycles
of chemotherapy.
46
superficial tumors, 2 tumors were MIBC from first diagnosis of
stage pT2 with 3 tumor size. No CiS was found in peritumoral
mucosa. All complete responders were treated with minimum
4 cicles of chemotherapy (maximum 6) with good tolerance
profile during therapy. 3 CR were achieved with GemcitabineCisplatinum protocol, a 2 with M VAC.
Table 2- Neoadiuvant chemotherapy after TURB
Protocol
M VAC
Patients
4 (19%)
GC
17 (81%)
Toxicity
Neutropenia
Mucositis
Transfusions
Neutropenia
Low Plt.c.
Infection
Mucositis
1
6 (35%)
9 (53%)
2 (11%)
2 (11%)
Results
After first TURBT, and completed neoadiuvant chemotherapy
5 complete responses (pTo) were documented, 5 superficial
relapses, one endoscopical CR with inconclusive histology,
and 10 patients with still present MIBC. Of those 10 patients
6 were salvaged with cystectomy, other 4 treated with partial
cystectomy. 15 patients were alive with their bladders after
12 months, after 4 years 6 patients died, 4 have had salvage
cystectomy after 2 to 3 years, and 5 patients were alive with
functional bladders, without evidence of disease progression,
and good quality of life. No evidence of late toxicities were
recorded due to chemotherapy .
Table 3- Resposnes after neoadiuvant chemotherapy
after second TURBT
RESPONSE
CR (pTo)
PTS.
5
%
23.8
Superficial rec.
5
23.8
Invasive tumor
10
47.6
Endoscopicaly negative with
inconclusive hystology
1
4.76
Invasive bladder tumor in a group of 10 pts. (47.6%) after
second TURBT was treated with cystectomy in 6 pts (28.5%)
and partial cystectomy in 4 patients (19.04%)15 patients
(71.4%) remain with their bladders for minimal follow up of
12 months with additional two courses of chemotherapy.
After 45 months, about half of patients (10 or 47.6%) were
operated (salvage cystectomy), 6 died of metastatic disease,
and 5 (23.8%) are alive, with functioning bladders and
good life quality . Of those patients 4 are from neoadiuvant
chemotherapy group after TURBT, one was with spared
bladder and complete response with TURBT, chemotherapy
and partial cystectomy. Mean age of patients was 72 years.
In 3 patients tumors progressed from previously treated
Table 4 – Results after follow up
Cystectomy - salvage
10 (47.6%)
Dead of disease
6 (28.5%)
Disease free - bladder spared
5 (23.8%)
Regular cystoscopic evaluation did not recorded marked
bladder contracture or decrease in capacity. Most prominent
finding was mucosal edema and hypervascularity. Patients
with spared bladders most often have urgency, nicturia, but
also other symptoms of lower urinary tract symptoms due
to BPH . Sexual function was preserved at the level before
initiating treatment.
Quality of life was qualified as satisfactory and very good in
patients with retained bladders.
Discussion
In a prospective study, Solsona et al reported on 133
candidates for conservative treatment. The inclusion criteria
for this group were histological confirmation of muscular
infiltration, endoscopic radical TUR, disappearance of
hardened areas on the bladder wall after resection on
bimanual examination, and negative biopsies of the depth
and periphery of the tumor bed. The control group consisted
of 76 patients with invasive pathologic stage pT2-3a, N03 bladder cancer treated with cystectomy and followed for
more than 5 years. After 5 years, 61 patients (45.9%) in the
TUR group relapsed, 35 (26.3%) had disease recurrence,
and 37 (27.8%) had disease progression.
Of the original 133 patients, 59 were followed for a median
of 10 years, and there was no significant statistical difference
in survival in the two groups vs the control group. At 5 and
10 years, the cause-specific survival rates were 80.5% and
79.5% and bladder preservation rates were 82.7% and 79.0%,
respectively, in each group. This was not a randomized study;
selection bias toward cystectomy and TUR could be present.
Evidence of CIS was the only significant statistical variable
to predict progression. Other series in the literature present
overall survival from 31%-68% as follows: stage T2 at 57%
70%, stage T3a at 14%-57%, and stage T3b at 2%-7%.
A recent series by Memorial Sloan-Kettering evaluated 170
consecutive patients who underwent recent TUR for bladder
47
tumors by a referring physician. A total of 150 patients had
repeat TUR, with 114 (76%) having residual tumor on repeat
TUR. In patients with superficial (Ta, Tis, T1) bladder tumors,
72 (75%) had residual tumor and 28 (29%) were upstaged
to muscleinvasive disease. Only 12 (22%) of patients with
an initial T2 pathologic stage had no residual tumor with
repeat TUR. These data stress the importance of a repeat
TUR on patients considered for bladder-sparing protocols
and suggest that bladder preservation be used in controlled
protocol studies and not as a standard treatment. Recent data
show only a 9% incidence of nodal metastasis in patients
with pathologic stage T2 on radical cystectomy specimen
compared with 37% of pathologic stage T3 patients. This
suggests that a tumor amenable to complete resection by
TUR will have a low incidence of nodal metastasis. Herr
et al. reported on 111 patients with clinical T2-3, N0, M0
transitional cell carcinoma of the bladder who were treated
with neoadjuvant M-VAC, after repeat maximum TURBT. Of
60 patients with complete responses, 28 refused definitive
treatment beyond TURBT,15 patients underwent partial
cystectomy, and 17 patients underwent radical cystectomy.
No patient received radiation. Of these 60 patients, 38
(63%) had presented with T2 disease and 22 (37%) with T3
disease.
Patients with clinical T3 disease were disproportionately
selected for radical cystectomy over bladder-sparing surgery
by 45% vs 18%. The overall survival at 10-year follow-up was
70% in the bladder-sparing treatment arm and 65% in the
radical cystectomy arm. These good results were obtained
without the use of radiation therapy.
Partial cystectomy as a treatment for muscle - invasive bladder
cancer may be considered in patients with a tumor that is
primary, solitary, and amenable to removal with 2cm surgical
margins. A biopsy must be performed on the remaining
urothelium to ensure that it is normal. Several publications
of retrospective series, with the above criteria as well as
less restrictive, resulted in the use of partial cystectomy in
5.8%-18.9% of all patients undergoing cystectomy for
bladder cancer These studies show a 5-year overall survival
rate of approximately 25%-60%, with local overall and
recurrence rates ranging from 40%-78%. The suboptimal
survival observed in many series of partial cystectomy may
be attributed to loosely interpreted inclusion criteria. At the
time of partial cystectomy, a frozen section is necessary for
evaluation of the margins by a uropathologist.
In this small series of patients choosed for bladder sparing
treatment it is apparent that patient selection is crucial. It
is beyond question that radical cystectomy is life sparing
procedure in MIBC, but its negative drawbacks (major
surgery risks, high complication rates, urinary diversion,
havy impact on life quality, sexual and reproductive function,
social implications) may put some MIBC in very high risk if
some serious comorbid conditions coexists. It is also true
for patients who refuse this type of surgery, or are willing to
take the chance to retain their bladders, awared of high risk
and need for close follow up . Important role of neoadiuvant
chemotherapy after initial endoscopical resection is its
effect on micro metastatic sites, evaluation of tumor chemo
sensitivity, possibility of achieving tumor free status with
TURBT combined with Cisplatinum chemotherapy (pTo),
or downstaging of primary tumor to operable stage (for
cT4 stages) As inclusion criteria for chemotherapy are less
rigid then for cystectomy, so this approach gives an option
to achieve long survival rates with functional bladders in
unfit patients. Also, if neoadiuvant treatment fails, salvage
cystectomy is still an option regardless of eventual toxic effects
of chemotherapy. In half of our patients we used opportunity,
in all cases operation was techicaly feasible. 5 patients out of
21 spared bladders, without signs of metastatic spread and
local reccurences. Toxic effects of chemotherapy, frequent
cystoscopies were not significantly affected outcome.
Conclusion
In appropriately selected and cooperative patients,
meticulously followed, combined-modality therapy can
preserve a tumor-free bladder without compromising survival,
maintaining the good quality of life.
Response to chemotherapy may be confounded by patient
selection. However, it is a prognostic factor for treatment
outcome and eventual survival. Patientrelated factors
combined with molecular markers (p53, p21, mdm-2, bcl2) and gene profiling might help to identify those who will
respond well to chemotherapy and to further select patients
for bladder preservation strategies. Prospective translational
research programs should be incorporated in clinical trials to
validate their role.
In the palliative setting, unresectable tumours or bladder
primary tumours in advanced or metastasised patients,
chemotherapy can promote local control in a substantial
number of patients and a survival benefit.
For very selected patients with localised disease, a bladder
conserving strategy with TURB and systemic cisplatin-based
chemotherapy, preferably with MVAC, and GC, has been
shown to allow long term survival with intact bladder. Of note,
this approach cannot be recommended for routine use, it is
still an option, not a solution.
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48
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49
The role of partial cystectomy in the treatment of muscle invasive
Bladder Cancer
V. Vukotić, M. Lazić, S. Savić. D. Kojić, S. Jovanović
Clinical Center “Dr Dragiša Mišović”, Department of Urology, Belgrade, Serbia
Abstract: Muscle invasive bladder cancer is usually treated
by radical cystectomy, but in some selected cases with
solitary tumor with appropriate localisation partial cystectomy
can be the treatment of choice achieveing long term results
with bladder preservation. We reviewed records of 18
patients treated by partial cystectomy in our institution in a
9 year period from June 2002 to june 2010 according to
the size of the tumor, localisation, histology , multifocality,
pathological and clinical stage, sex, age and survival. Male:
female ratio was 2:1, mean age of the patients beeing 67
years. All patients but one had solitary lesions located in the
bladder dome in 3, on lateral sides in 9 pts, 6 patients had
a tumor in diverticulum. TCC Gr 1 was diagnosed in one
patient, Gr 2 in 7 pts, TCC Gr 3 in 8 pts , while squamous
carcinoma was detected in 2 patients. Lymphadenectomy
was performed in 5 pts, in only one lymph nodes were with
metastasis. Sixt patients died, five from the progression of
bladder cancer, one from other reason. Mean survival time
is 33 months ( 3 to 77 months). Local reccurences treated
with TUR were present in 3 patients. Bladder capacity is
adequate in all patients resulting in good quality of life. Our
results suggest that in selected patients, cancer control
can be achieved with partial cystectomy. Better selection
of patients with multimodal treatment might achieve better
results with preserved bladder.
Introduction: Transitional cell carcinoma of the bladder is
the fifth most common malignancy in Western countries.
Standard treatment protocol for patient with bladder tumor
is transurethral resection with curative intent or for obtaining
biopsy specimens. If tumor(s) is muscle invasive as is in
20% of patients at first presentation, additional treatment is
required. For those patients, radical cystectomy with urinary
diversion is considered a treatment of choice1. While in the
treatment of malignancies, organ preservation protocols
have become the standard options, for muscle invasive
bladder cancer, organ preservation is still limited to selected
cases. Bladder preservation is a challenging option for a
patient confronted to bladder cancer for many reasons such
as functional and continent bladder with preserved potency
in male patients. Efforts in preserving a bladder with muscle
invasive cancer can be obtained with uni or multimodal
approach2. The most challenging one is a surgical removal of
the tumor with preservation of continent bladder and potency
in males without adjuvant radio or haemiotherapy. Partial
cystectomy can achieve such goals in patients with solitary
tumor located primarily in the bladder dome or posterolateral
sides of the bladder which can not be adequately treated
with TUR alone. Wide excision of the whole thickness of
the bladder wall with resection of adjacent peritoneum and
regional lymphadenectomy can provide accurate staging
along with adequate disease control comparable to radical
cystectomy results in adequately selected patients. Adequate
selection of patients is of crucial importance for the results of
partial cystectomy3.
RESULTS : in the 9 year period from june 2002 to june 2010,
hundred and sixty seven patients have been surgically
treated by radical or partial cystectomy for muscle invasive
bladder cancer. The distribution of surgical treatment is
shown on table 1.
Table 1: Surgical treatment for muscle invasive bladder
cancer
2002
2003
2004
2005
2006
2007
2008
2009
2010
Radical cystectomy
16
12
20
15
27
16
11
11
21
149
Partial Cystectomy
1
0
2
0
3
5
2
0
5
18
Only charts for 18 patients in whom partial cystectomy
was performed for T2 bladder cancer have been analyzed.
Patients treated with partial cystectomy for benign conditions
or in wh0m partial cstectomu was performed for distal ureteral
tumor were excluded from analysis. The mean age of the
50
patients was 67 (52- 80 years), 12 males ande 6 females.
All patients had a T2 tumor. Only one patient had metastasis
in lymph nodes confirmed hystologically at the time of partial
cystectomy. The tumor was solitary in all but one patient. The
localisation was at the bladder dome in 3 patients, on lateral
sides in 9 patients , while tumor was in the diverticulum in 6
patients. One patient with the bladder dome tumor had also a
urachal cyst bearing also a TCC tumor which was extirpated
along with the bladder dome. Ureteral reimplantation was
necessary in 5 patients due to the proximity of the tumor in
order to achieve a wide margin. TCC grade 1 was diagnosed
in 1 patient , Grade 2 in7 pts and Grade 3 in 8 pts while two
patients had a squamous carcinoma of the bladder. Mean
tumor size was 3 cm but the biggest one was 7 cm in diameter.
Characteristic of the patients are shown on table 2.
Table 2: Clinical and pathological characteristics of
patients
Sex:
F:
M:
6
12
Tumor histopathology
TCC:
Squamous :
Tumor grade:
1:
2:
3:
16
2
1
7
8
Tumor localistaion:
Bladder diverticulum
Bladder dome
Lateral
6
3
9
Lymph node status:
Pos:
Neg:
1
4
Ureterocystoneostomy:
Yes:
No:
5
13
Grade of the tumor did not influence survival (p=0.47) ,
but the tumor size correlated with survival, the best results
achived with smaller tumors Fig 1.
Fig 1. Tumor size influencing survival
Negative margins were achieved in all patients.
Lymphadenectomy was not performed routinely in all
patients, only one patient out of five in whom it was done,
had hystologically proven metastasis in lymph nodes and is
disease free for 3 years. One of four patients without lymph
node metastases developped them in next 6 months, dying
from disseminated bladder cancer 9 monts after partial
cystectomy. None of the patients received neoadjuvant
or adjuvant chemotherapy or radiotherapy. In one patient
cystectomy was performed one month after partial cystectomy
due to persistent urinary fistula, no tumor was found in the
bladder.
Partial cystectomy is a simple surgical procedure, the median
duration of intervention was 76 mnutes. There were no major
complications of surgery. All of our patients preserved good
bladder capacity which made them continent day ad night.
The median survival is 33 months with the range of 3 to 75
months.
DISCUSSION
The main issue in every surgical attempt with curative intent
for malignancy is the achivment of long term disease free
survival. Quality of life is the other issue and should be
balanced with the primary treatment goal.
The golden standard for the treatment of muscle invasive
bladder cancer is radical cystectomy, so the results of
treatment options should be compared with the results of
radical cystectomy according to oncological results and
quality of life. Oncological results of radical cystectomies
are not impressive, with 5 year overall survival for patients
51
with T1-4 tumors of 59-66%4. The common recurrence
and progression stress the concept that surgery only for
locally advanced cancers is unsuccessful and has to be
complemented with systemic treatment5. Recently two
randomized large randomized trials confirmed that beest
results for deeply invasive bladder cancer are achieved
with neoadjuvant chemotherapy followed by definitive local
therapy, as compared with cystectomy or radiotherapy
alone6.
The main disadvantage of radical cystectomy as perceived
by now is urinary diversion. Contient reconstruction and
formation of neobladder with nearly normal bladder function
was a reason to perform early radical cystectomies but
continent diversion are used less than expected, especially
in elderly patients7. Continent diversion was expected to
achieve better quality of life but in a recent study continent
reconstuction was not estimated superior to conduit
diversion8.
The rationale favoring radical cystectomy instead of partial
is the multifocality of the disease and the high reccurence
rate. Patients should be aware of life long controls and
possible option of salvage cystectomy 9. The other issue is
also important when comparing partial to radical cystectomy.
Partial cystectomy is less skill demanding and with less early
or late complications, which can induce it’s innapropriate use
in low cystectomy volume hospitals, in elderly patients and
female patients10. Since the introduction of laparoscopic
partial cystectomy11 which was proven to be safe and
feasible in selected patient12, partial cystectomy may become
increasingly popular.
Many efforts are made in order to preserve of the bladder.
One of the possible options is multimodal treatment including
TUR, radiotherapy and chemotherapy with results that are
comparable to radical cystectomy13. Since rates of significant
late pelvic toxicity for patients completing combined-modality
therapy for invasive bladder cancer and retaining their native
bladder are low, this treatment is gaining in importance14.
With diverse possibilty of treatment of muscle invasive
bladder cancer, what are our results suggesting? The
limitation of our study is the short postoperative follow up
period, but our results are in accordance to other authors.
Acceptable outcome can be achieved with partial cystecomy
in highly selected cases15, comparable in regard of 5 year
overall survival to patients treated with radical cystectomy16,
although quality of life might be even more important then
quantity.
Grade and stage of tumor are known predictor of disease
progression, although in our patients only tumor volume was
the predictor of survival. The localisation had no impact on
postoperative course nor on survival according to our limited
experience.
Better selection of patient might improve the results. A
promising new marker FGFR3 mutation selectively identifies
patients with favorable bladder cancer . The mutation was
extremely rare in patients with cancer-positive nodes so it
might be used to guide decision making on adjuvant therapy
after RC17. The other possible marker which can be in
order to select patients with better possible outcome used
is C Reactive Protein18. Better results might be obtained with
multimodal treatment such as neoadjuvant chemotherapy19
even in patients witj partial cystectomy.
CONCLUSION: Radical cystectomy remains the standard
of care for muscle-invasive bladder tumors but in selected
patiens partial cystectomy offers acceptable oncological and
quality of life outcomes.
References:
1 Kuczuk M., Turkri L., Hammerer P. Raverzy V., Is there a
role for bladder preserving strategies in the treatment of
muscle invasive bladder cancer? Euro Urol 2003; 44:5764
2 Tores-Rocca JF: Bladder preservation protocols in the
treatment of musle invasive bladder cancer. Cancer
control, 2004:11(6):358-363
3 Laufer M: Transurethral resection and partial cystecyomy
for invasive bladder cancer. J surg Oncol, 2000; 18:296299
4 Shariat SF., Karakiewicz PI., Palapattu G., Lotan Y,
Rogers CG et al: Outcomes of radical cystectomy for
transitional cell carcinoma of the bladder: a contemporary
series from the bladder cancer reasearch consortium. J
Urol, 2006; 176:2414-2422
5 Malmström PU. Bladder tumours: time for a paradigm
shift? BJU Int. 2011 May;107(10):1543-5..
6 International Collaboration of Trialists on behalf of the
Medical Research Council Advanced Bladder Cancer
Working Party (now the National Cancer Research
Institute Bladder Cancer Clinical Studies Group), the
European Organisation for Research and Treatment.
International Phase III Trial Assessing Neoadjuvant
Cisplatin, Methotrexate, and Vinblastine Chemotherapy
for Muscle-Invasive Bladder Cancer: Long-Term Results
of the BA06 30894 Trial. J Clin Oncol. 2011 Apr 18. [Epub
ahead of print]
7 Gore JL, Saigal CS, Hanley JM, Schonlau M, Litwin
MS; Urologic Diseases in America Project. Variations
in reconstruction after radical cystectomy. Cancer. 2006
Aug 15;107(4):729-37.
8 Gerharz E., Mansoon A., Hunt Sonja, Skinner E., Manson
W., Quality of life after cystectomy and urinary diversion:
an evidence based analysis. J Urol, 2005; 174: 17291736
52
9 Mickisch GH. Partial Cystectomy for Invasive Bladder
Cancer. European Urology Supplements 4 (2005) 67–
71
10 Hollenbecj BK., Taub DA., Dunn RL., Wei JT. Quality
of care : partial cystectomy for bladder cancer- a case
of inappropriate use? J Urol. 2005 Sep;174(3):1050-4;
discussion 1054
11 Wang CK, Chueh SC. Laparoscopic partial cystectomy
with endo-GIA stapling device in bladder diverticular
carcinoma. J Endourol. 2007 Jul;21(7):772-5.
12 Tai HC, Chung SD, Wang SM, Chueh SC, Yu HJ.
Laparoscopic partial cystectomy for various bladder
pathologies. BJU Int. 2007 Aug;100(2):382-5.
13 Rene NJ, Cury FB, Souhami L. Conservative treatment
of invasive bladder cancer. Curr Oncol 2009;16:36–47.
14 Efstathiou JA., Bae K. Shipley WU., Kaufman DS, Hagan
MP., Heney NM., Sandler HM. Late Pelvic Toxicity After
Bladder-Sparing Therapy in Patients With Invasive
Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06. J
Clin Oncol 2009: 27:4055-4061
15 Holybeierlein JM., Lopez- Corona E., Bochner BH.,
Herr HW., Donat M., Russo P et al.: Partial cystecomy:
16
17
18
19
a contemporary review of the Memorial Sloan-Kettering
Cancer Center experience and recommendation for
patient selection. J Urol 2004 ; 172:878-881
Michaelson MD, Shipley WU, Heney NM, Zietman AL,
Kaufman DS. Selective bladder preservation for muscleinvasive transitional cell carcinoma of the urinary bladder.
Br J Cancer. 2004 Feb 9;90(3):578-81.
Van Rhijn, B.W.G., Bostrom, P.J., Shariat, S.F., Finelli, A.,
Sagalowsky, A.I., et al . The FGFR3 mutation identifies
patients with favorable disease at radical cystectomy for
bladder cancer. Abstract presented at the 26th Annual
Congress of the European Association of Urologyrt
Gakis G., Todenhoefer T. , Renninger R. , Schilling
D., Sievert K-D., Schwentner C. , Arnulf Stenzl A.
Development of a new outcome prediction model in
carcinoma invading the bladder based on preoperative
serum C-reactive protein and standard pathological risk
factors: the TNR-C score. B J U International April
2011, Epub ahead of print
HW Herr HW, Scher HI. Neoadjuvant chemotherapy and
partial cystectomy for invasive bladder cancer Journal of
Clinical Oncology, Vol 12, 975-980,
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55
Radical Surgical Treatment of the Urinary Bladder Cancer :
Our Experiences
Anton Maričić, Maksim Valenčić, Romano Oguić, Stanislav Sotošek, Dean Markić, Josip Španjol, Kristian
Krpina, Juraj Ahel, Anton Gršković, Dražen Rahelić, Željko Fučkar
Clinic of Urology, University Hospital »Rijeka«, Rijeka, Croatia
Abstract
The goal of the paper was the analysis of patients suffering
from the urinary bladder cancer who underwent radical
surgical treatment of the urinary bladder and establishing
urine derivation. In the 1972-2010 period 2731 patients
with the urinary bladder cancer were treated, 315 (11.5%)
of whom underwent radical surgical treatment. The average
age was between 60 and 80 years – in 224 (71%) patients. In
our patients there were 290 patients (92 %) with transitional
cell cancers. According to TNM classification, T3 stage in
139(44,1%) patients and T2 stage in 131 (42%) patients
were predominant in our study. According to histological
criteria, the most common stage was G3 stage – in 224 (71%)
patients. Radical cystectomy or combined with urethrectomy
was performed in 273 (86,7%) patients. Unfortunately, in
42 (13,3% of them (T3 and T4 stages) the inner iliac blood
vessels were tied off due to a progressive cancer. The outer
supravesical urine derivation (Bricker, U-tubing nephrostomy,
ureterocutaneostomy) was done in 251 (79,7%) patients. The
inner derivation (Coffey, ureteroileosigmoidostomy, MainzPouch II) was performed in 28 (8,9%) patients and neovesica
(Hautmann,Studer) in 35 (11.1%) patients. There were 79
(25%) patients with early postoperative complications. Among
them the most dominant were the surgical complications – in
32 (10,2%) patients and distant organ complications – in 23
(7,3%) patients. In 129 (41%) patients with negative nodes
the survival rate was 55% after five years. In 98 (31%)
patients with positive nodes the survival rate was 27% after
five years.
Key words: urinary bladder neoplasm, cystectomy, urinary
diversion, incontinent ileostomy
Introduction
Urinary bladder cancer is the most frequent malignant tumour
of the urinary tract, mostly occurring between the age 50 and
70. The risk in the urban areas is 50-150 times greater than in
the rural areas¹. Some industries are specifically connected
with the urinary bladder cancer. They are chemical, paint,
varnish, rubber, oil and gas industries². The workers in high
risk industries have 30 times greater chances to get the
urinary bladder cancer in comparison with other population.
Four chemical industry carcinogens were discovered: 4amino-diphenyl-xenylamine, ß-napthylamine, benzidine and
4-nitrodiphenyl.
Radical cystectomy is transperitoneal “en block“ extirpation
of the urinary bladder, prostate and vesicles together with
pelvic lymph nodes. As a rule, this operation includes the
extirpation of the uterus, adnexa and the proximal third of the
vagina in woman. Nowadays, this surgical intervention is most
frequently carried out in case of the invasive urinary bladder
tumours. Histological finding of nodes at lymphadenectomy
is the only reliable criterion for the assessment of the regional
expansion of the disease.
This surgical treatment is closely connected with problem of
urinary derivation. Each new method of the urinary derivation
has been enthusiastically accepted by urologists during this
century as a hope that it will be the perfect form of the urinary
bladder substitute. Unfortunately, they became disappointed
after some time. Each new method of derivation would be
more or less accompanied with the same complications:
impossibility of physiological way of urination, social
problems connected with the artificial orifice and later serious
complications, with kidneys especially.
Supravesical urinary derivation is called the artificial urinary
derivation above the bladder level on the abdomen or into the
intestine. It can be performed directly (ureterocutaneostomy),
or by the isolated intestinal segment (the ileum or “the colonconduit“). Bringing the ureter to the intestine can be dual,
either with preserved intestinal continuity or using the isolated
intestinal segment representing one form of the urinary
bladder substitute. Urine can be directly derivated from the
kidney, like in surgical and percutaneous nephrostomy.
Simon (1875) is considered to be the first one in the history
of urology who performed the urinary derivation by simple
ureterostomy3. Tizzoni and Foggi (1888) experimentally
applied the intestinal segment for the same purpose,
while Couvelaire introduced supravesical derivation using
the intestine in contemporary surgery4,5. Since then the
supravesical urinary derivation has been developed using
the most varied methods of the intestinal applications.
56
Ureteroileocutaneostomy or “the ileum conduit“ was introduced
by Bricker in 1951 in order to avoid bad points (stenosis and
infection) of the direct ureterostomy6. The advantages of this
method are unquestionable: the possibility of required radical
methods in the pelvis and good renal tolerance in this kind
of derivation. Bad points are permanent urinary fistula and
permanent carrying of the receptaculum.
Continent sigma bladder is no doubt the ideal method of
preserving physiological and anatomical integrity of the
patient7. However, this method is indicated only in primary
invasive carcinoma of supratrigonal localisation. The rectal
bladder with perineal colostomy according to Nedelec does
not leave any physiological orifice the patient would be aware
of, enables required radical methods, but it is characterized
by greater surgical mortality and greater number of early
complications in comparison with other methods8.
Since late eighties the priority has been given to reservoirs
formed by detubularised intestinal segment. The first urinary
bladder substitute by detubularised segment of the ileum
was published by Giertz in 19579. The technique with 65
cm long and split segment of the ileum has been known as
Camey. Hautmann detubulated the segment of the ileum and
reconstructed it in the form of the letter W or M10.
Nowadays, the methods of forming isolated urinary continent
ileum reservoirs, urinary depots, requesting intermittent
catheterization, raise great interest. The first results were
presented in 1982 by (Kock)¹¹.
The so called “inner urinary derivations“, like
ureterosigmoidostomy, introduced in 1911 by (Coffey) still
remained¹². It generates hyperchloremic acidosis. Then
ureteroileosigmoidostomy was introduced in order to avoid
the aforementioned complications.
Consequently, there are no ideal methods of derivation. Each
of them is characterised, except the common ones, by its
specific permanent morbidity, early or late complications, and
even a high mortality rate.
Patients and Methods
The goal of this study was monitoring the patients with the
urinary bladder cancer who underwent radical surgical
treatment at the Clinic of Urology, University Hospital
»Rijeka«, Rijeka, Croatia during the 1972-2010 period. Two
thousand seven hundred and five patients suffering from this
disease were treated and 315 (11.5%) of them underwent
radical surgical treatment (Table 1). Most of the patients, 224
(71%) of them, were between 60 and 80 years old. There
were 242 (76.8%) male and 73 (23.2%) female patients.
Anamnestic haematuria was the most frequent and the most
important symptom of the urinary bladder tumour, being
constant in 107 (34%) patients, frequently intermittent in 82
(26%) patients, combined with dysuria in 73 (23.2%) patients
or complicated with anuria and uremia in 28 (8,9%) patients.
Less frequent symptom was dysuria in 25 (7,9%) patients.
Diagnostic treatment included IVU, the abdominal or
transrectal ultrasonography, cystoscopy, endoscopic biopsy
and CT.
The clinical stage of the disease was assessed on the basis
of results of the aforementioned procedures and determined
using the TNM classification.
The tumours were divided according to the histological
criteria on well differentiated (G1), moderately differentiated
(G2) and poorly differentiated (G3) (Table 2).
Radical surgical treatment was indicated after the endoscopic
verification of the tumour and its TNM and histological
classification, depending on the clinical state of the patient.
Radical cystectomy, alone or in combination with urethrectomy,
was successfully performed in 273 (86,7%) patients
(Table 3). In connection with this operation, the problem
of the urinary derivation poses itself. The outer derivation,
ureteroileocutaneostomy sec. Bricker was most frequently
used in our patients – in 245 (77.8%) of them (Table 4).
We divided our postoperative complications into the early
ones and the late ones. There were 79 (25%) patients with
early postoperative complications (Table 5).
Control examinations have been performed in 3-month
intervals. The control includes the analysis of laboratory findings
and the acidic basal status, abdominal ultrasonography and
chest x-ray. The shortest observation lasts three months, and
the longest 20 years. The progression of the disease during
the observation time implies the occurrence of metastases
and the progression of local findings.
Results
During the 1972-2010 period 2731 patients with the urinary
bladder cancer were treated, 315 (11,5%) of whom underwent
radical surgical treatment (Table 1)13. The progressive
increase of newly detected carcinomas and the number of
radical operations are evident.
Males have been exposed to a greater than females. The
sex ratio is being changed with a change of social role of
females. This relation was 8:1 in the early 19th century, being
nowadays only 2-3:1 in favour of males. There were 242
males and 73 females .
High frequency of the urinary bladder cancer has been also
observed in people who smoke more than 22 cigarettes a
day. There were 207 (65,7%) smokers.
Haematuria is the most frequent and the most important
symptom of the urinary bladder cancer. It is either continuous
or, frequently, intermittent with intervals without bleeding. It
can be macroscopical and microscopical and the level of
haemorrhage does not correspond to the tumour volume.
Haematuria, alone or combined with dysuria, dominated in
57
our patients - in 289 (91,7%) of them. The next symptoms
were dysuric difficulties characterized by frequent and painful
urination in 8,3% of the patients¹. The symptoms caused by
distant metastases made the third group. These symptoms
were significantly less frequent in this kind of tumour,
compared with the other kinds of carcinomas, because about
70% of the carcinomas were localised in the urinary bladder
at the moment of the first diagnosis, and only 7% of them
showed the clinical signs of distant metastases1.
Most of these tumours are the transitional cell carcinomas.
Planocellular tumours make only 5% of the epithelial tumours
of the urinary bladder. Finally, 1% of the epithelial tumours
belong to adenocarcinomas, which are considered to originate
from the aberrant prostatic acinuses. In our population there
were 290 (92%) patients with transitional cell carcinoma, 19
(6%) patients with planocellular tumours and 6 (2%) patients
with adenocarcinomas.
The invasive urinary bladder tumour metastasizes in the
regional lymph nodes16. Lymphadenectomy was performed
in 227 (72%) patients. The nodes were positive in 98 (31%).
Haematogenous dissemination regularly develops during the
later stage of the disease, involving bones (the pelvis and the
lumbar spine), then liver, the kidneys and the lungs.
Discussion
There are three basic characteristics of the urinary bladder
tumour, on which the prognosis of the disease and the
therapy choice depend: the tendency to wall penetration, the
tendency of transitional cell dysplasia and the tendency to
change the quality of the mucous membrane of the primary
tumour surroundings.
According to TNM classification, T3 stage in 139 (44.1%)
patients and T2 stage in 131 (42%) patients were predominant
in our study. According to histological criteria the most
common stage was G3 stage in 224(71%) patients.
It is very important to make preoperative preparatory
measures before bringing decision on surgical treatment. It
is especially important for the patients with accompanying
diseases that encumber postoperative recovery. There were
accompanying diseases in 119 (37,8%) patients. The most
common were: heart and lungs diseases in 74 (23.3%)
patients, diabetes in 37 (11,7%) patients and the diseases of
the digestive system in 8 (2,5%) patients.
Radical cystectomy alone or combined with urethrectomy,
was performed in 273 (86,7%) patients (Table 3). Three
patients underwent unilateral nephroureterectomy because
of renal dysfunction. One uremic patient underwent bilateral
nephroureterectomy before the cystectomy was performed.
Unfortunatelly, the inner iliac blood vessels were tied off in
13,3% of patients (T3 and T4 stages) due to progressive
tumours.
The great problem is what kind of urinary derivation has to
be done. Demands for normal social activities do not fit into
medical criteria, into postulates of radical oncologic surgery
especially. Consequently, various nonmedical conditions
influence the choice of method of derivation: the age of
patient, occupation, the stage of civilisation and health
education, financial – economic potentials etc. One of the
pioneers of modern urology Howard Hanley says that it is a
pure hypocrisy from us to claim that we healed the patient
who underwent the abdominal urinary derivation and has
been forced to carry the receptaculum under his shirt for the
rest of his life17.
The continent bladder, that would ensure safe excretion
under own control and in a standing position (men), most
frequently eliminates the possibility of radical intervention
(cystourethrectomy). A golden mean that would meet both
the criteria has not been found yet. In other words, all kinds of
urinary derivations are predominantly methods of necessity.
Modern era of ureterointestinal derivations started in 1911 with
Coffey`s description of “tunnel“ technique for the implantation
of ureters into the colon. Ureterosigmoidostomy represented
the most popular way of the urinary derivation till 1950, when
Bricker described ureteroileal cutaneous derivation. We used
this kind of derivation in 16 (5%) patients till 1985. This method
of supravesical derivation has been almost abandoned
nowadays because of numerous complications which can
be divided into the early ones and the late ones. The most
frequent early complication is anuria developing from the
oedema or the obstruction of ureterocolic anastomosis with
faeces and the mucous membrane. Urine drainage can occur
on the anastomosis with the ileus as the consequence. Late
complications are pyelonephritis, calculi, ureteral obstruction
and electrolytic instability. Seven of our patients developed
hyperchloremic acidosis as the commonest complication.
They were treated with bicarbonate compensation. One
of them developed paralytic ileus. However, it must not
be forgotten that this method has certain advantages, like
low immediate operative mortality and morbidity. It is also
important to point out that ureterosigmoidostomy does not
leave any outer artificial orifice. Making efforts to improve this method because of numerous
complications, the ureteroileosigmoidostomy was developed.
This is so called antireflux ureterosigmoidostomy or “the
inner Bricker“18. The interposed segment of the ileum,
together with antireflux barrier on the anastomosis with the
colon, prevents reflux from the large intestine. In spite of the
decreased number of manifest pyelonephritises, persistent
hyperchloremic acidosis occurred in 1/3 of our patients. This
method was performed in 9 (2,9%) of our patients.
Ureteroileocutaneostomy or “the ileum conduit“ was
introduced by Bricker in order to avoid bad points (stenosis
58
and infection) of the direct ureterostomy6. The advantages
of this method are unquestionable: the possibility of required
radical treatment in the pelvis and good renal tolerance in
this kind of derivation. Bad points are permanent urinary
fistula and permanent carrying the receptaculum. This
method of derivation was performed in most of the patients,
i.e. in 245 (77.8%) of them (Table 4). It was usually carried
out in combination with radical cystectomy or without it in
inoperable cases with ligation of the iliac blood vessels.
Since late eighties the priority has been given to reservoirs
formed by detubulated intestinal segment. Hautmann
detubulated the segment of the ileum and reconstructed it
in the form of the letter W or M. Studer (1988) described
asymmetrically joined segment of the ileum 65 cm long,
in the shorter end which he implanted the ureters. He split
longitudinally the longer part and connected it into a hypotonic
bladder19. It is especially important because the orthotopic
bladder substitute enables the physiological way of urination
and higher quality of life.
New bladder sec. Hautmann was performed in 34 (10,8%)
patients. Neovesica sec. Studer was carried out in one
female patient, what is very rare in women.
U-tubing nephrostomy or ureterocutaneostomy were
performed in the remaining kidney in 6 (1,9%) patients in case
of the disfunction of one kidney or the former nephrectomy.
Mainz-Pouch II of the inner derivation was performed in two
patients.
There were 79 (25%) patients with early postoperative
complications. Among them
dominated the surgical
complications in 32 (10,2%) patients and distant organs
complications in 23 (7,3%) patients (Table 5). Wound
dehiscence in 9 (2.8%) patients and ileus in 8 (2.5%)
patients were the most frequent surgical complications. The
secondary sutures were placed in cases of dehiscence.
Two patients with the ileus underwent adhesiolysis and one
patient adhesiolysis and ileotransversostomy. One ileus was
solved with the ileum resection and ileostomy. Four patients
with ileus were treated conservatively using Miller-Abbott
tube.
Bronchopneumonias in 7 (2.2%) patients and cerebral insults
in 4 (1.3%) patients dominated among organ complications,
and they were treated conservatively. One patient with
melena was treated by washing out and blood transfusions.
Pyloroplasty and vagotomy were done in one bleeding
duodenal ulcer. Two pulmonary embolisms were the most
difficult complications which ended lethally.
Hyperchloremic acidosis was the most frequent complication
in 11 (3,5%) patients connected with operation sec. Coffey
and ureteroileosigmoidostomy. It was treated with adequate
bicarbonate doses.
There were unclear febrile cases among general
complications in 13 (4,2%) patients. Four patients developed
septic temperatures. Pseudomonas aeruginosa in 2
patients, Seratia in 1 patient and Staphilococcus pyogenes
in 1 patient were isolated in haemoculture. Urinary infection
in 12 (3.8%) patients and ileus in 7 (2.2%) patients that
were mainly treated conservatively, dominated among
late complications. Two patients underwent adhesiolysis.
Two ureteral strictures, calculus in the urinary bladder, two
ureteral tumours and three ureteral stenoses were treated
with endoscopy. There were three stomal stenoses and four
stomal hernias that were solved with front abdominal wall
plastic. The abscess of postoperative section was treated
with the incision and drainage in three patients, while one
patient with ureterorrhagia from the residual part of the ureter
underwent urethrectomy. One stercoral fistula was solved
conservatively.
In 129 (41%) patients with negative nodes the survival rate
was 55% after five years. In 98 (31%) patients with positive
nodes the treatment continued with radiotherapy and
chemotherapy. The survival rate was 27% after five years.
The worst prognosis was in the group of patients (13,3%) in
whom cystectomy could not be done due to the progressive
process. The iliac blood vessels were tied off in these patients,
and they were treated with radiotherapy and chemotherapy.
The survival rate was about 7% after one year.
Conclusion
Urinary bladder cancer is the most frequent malignant tumour
of the urinary system. It has been in tremendous increase.
During 1972-1980 period there were 89 patients and in the
2000-2010 period even 1809 patients. It is the increase of 21
times, partly because of better diagnostics and education of
the inhabitants.
Three hundred fifteen patients underwent radical surgical
treatment. Most of them, 224 (71%) patients, were over 60
years old. The cancers are more and more malignant and
progressive in the diagnostic T3 stage patients (44.1%).
Surgical treatment is a method of choice and the way of
giving chances for full cure, if carried out in the early stage.
The survival rate in this group of patients was 55% after five
years.
Supravesical urinary derivation is the attractive intervention
for the surgeon and desperate solution for the patient, which
cannot always fulfil the medical and social aspects of treatment
of frequently incurable disease. Medical and social aspects
of supravesical urinary derivation most often reciprocally
clash, because fulfilling medical criteria aggravates or makes
impossible the social life of the patient.
The continent bladder, that would ensure safe excretion
under own control and in a standing position (in men), most
frequently eliminates the possibility of radical treatment
59
(cystourethrectomy). In other words, all kinds of the urinary
derivations are predominantly methods of necessity. Thus,
majority of our patients (77.8%) have ileostomy, because
they underwent surgical intervention in the progressive stage
of tumour, and in whom neovesica could not be done due to
the progressive process in the pelvis.
Finally, the prognosis of the disease and the quality of patient’s
life depend on as early and as fast as possible diagnosis, as
well as on adequate surgical treatment.
Table 2
CLASSIFICATION ACCORDING
CRITERIA
References
Table 3
TYPES OF SURGICAL TREATMENTS
1.
2. 3. 4. 5. 6. 7. 8. 9. LEVIN ML, J Natl Cancer Inst, 24 (1960) 1243.
VEYS C, Br J Ind Med, 31 (1974) 65.
SIMON CJ, Samml Klinik Vort, 88 (1875) 694.
TIZZONI G, FOGGI A, Centrbl Chir, 50 (1888) 921.
COUVELAIRE R, J Urol, 57 (1951) 408.
BRICKER EM, Surgery, 32 (1952) 372.
HRADEC E, Urologie, 2 (1966) 56.
NEDELEC M, Urol Int, 22 (1967) 47.
GIERTZ G, FRANKSSON C, Acta Chir Scan, 113 (1957)
218.
10. HAUTMANN RE, EGGHARDT G, FROHNEBERG D,
MILLER K, Urologie, 26 (1987) 67.
11. KOCK NG, NILSON AE, NOVLEN L, SUNDIN T, TRASTI
H, Scand J Urol Nephrol, 49 (1978) 23.
12. COFFEY RC, JAMA, 56 (1911) 397.
13. ĐORĐEVIĆ G, PEITL V, SINOŽIĆ E, MUSTAĆ E,
Medicina, 42 (2004) 147.
14. FLOCH RH, JAMA, 145 (1951) 295.
15. NOVAK R, DIMANOVSKI J, FIŠTER H, KRAUS O,
TRNSKI D, Lijec Vjesn, 106 (1984) 402.
16. PUGH RCB, Course of the British Council on urological
malignancies, London, 1979.
17. HANLEY HG, Br J Urol, 39 (1967) 693.
18. NOVAK R, Eur Urol, 7 (1981) 118.
19. STUDER U, ACKERMAN D, CASANOVA GA, ZINNG
EJ, Semin Urol, 6 (1988) 57.
Table 1
NUMBER OF RADICAL URINARY BLADDER OPERATIONS
WITH THEIR ANNUAL DISTRIBUTION
No. of patients
No. of radical
operations
19721980
89
14
19811989
196
23
19901999
637
125
2000- Total
2010
1809 2731
153
315
Tumour grading
G1
G2
G3
TO
HISTOLOGICAL
No. of patients (%)
12 (3.8%)
79 (25,1%)
224 (71.1%)
Type of operation
Radical cystectomy
Radical cystectomy + urethrectomy
Radical cystectomy +
nephroureterectomy
Ligatura aa. Illiaca
Cystectomy and resection of colon
sygmoideum
No. of patients (%)
221 (70.2%)
47 (14,9%)
5 (1.6%)
41 (13%)
1 (0.3%)
Table 4
TYPES OF SURGICAL DERIVATION
Type of operation
Ureterosigmoidostomy sec. Coffey
Ureteroileosigmoidostomy
Ureteroileocutaneostomy sec.
Bricker
Neovesica sec. Hautmann and
Studer
Mainz-Pouch II
U-nephrostomy and UCNS
No. of patients (%)
16 (5%)
9 (2.9%)
245 (77.8%)
35 (11.1%)
3 (0.9%)
6 (1.9%)
Table 5
EARLY POSTOPERATIVE COMPLICATIONS
Type of complications
Surgical complications
Complications on distant organs
Metabolic complications
General complications
No. of patients (%)
32 (10,2%)
23 (7,3%)
11 (3.5%)
13 (4,1%)
60
Modification of Padovana ileal neoblader
V. Sekulić, J. Bogdanović, G. Marušić, J. Đozić, R. Herin
Clinic of Urology, Clinical Centre of Vojvodina, Novi Sad, Serbia
Objective: This paper is aimed to present our modification of
Padovana ileal neobladder using 40 cm of isolated segment.
We are not aware of any previous report of similar technique
in available literature.
Material and methods: 10 patients uderwent modified
Padovana ileal neobladder following radical cystectomy at
our institution during the period 2008 to 2010. Median age of
patients were 59 years (range 45-70). Median follow up was
16 months (range 6 -36). Patients have been monitored using
standard follow-up protocol according to the EAU giuidelines
with urodynamic evaluation 6 months after surgery.
Results: Perioperative, early and late postoperative mortality
have not been noticed. There were only 2 major complications:
1 patient (10%) with prolonged postoperative ileus and 1
with prolonged urinary leakague requiring percutaneous
nephrostomy and subsequent ureteral reimplantation due
to stenosis of ureterovesical anastomosis. There was no
significant metabolic disorders.
Average ileal neobladder capacity was 450 ml. Daytime and
night continence were achieved in 9 (90%) and 6 (60%) of
patients, respectively.
Conclusion: This modification of VIP neobladder has
not been difficult to perform in our hands. In our opinion
this technique provides clear advantage in easier ureteral
implantation proximally than in original technique, requireing
less length of ureter. Initial encouraging results should be
confirmed in further clinical pratice.
Introduction
Urinary diversion has a history of nearly 150 years (1), and
the ileal conduit has been considered as gold standard for
urinary diversion. Orthotopic bladder substitution following
radical cystectomy is well established currently. This
procedure avoids an abdominal stoma and improve quality
of life for patients undergoing radical cystectomy. (2,3,4,)
In 1958, Maurice Camey, was using an ileal segment,
performed an othotopic ileal bladder substitute for the urethra.
After animal experiments in 1983 and 1984, ileal orthotopic
bladder substitute with afferent ileal loop was introduced
by UE Studer from University of Bern. In 1985, Hauttman
created detubularized ileal neobladder. During the 1980s and
1990s, various orthotopic ileal neobladder urinary diversion
techniques have been described, such as the Kock ileal
neobladder in 1986, Vesica Ileale Padovana (VIP) in 1990
which we prefer.(2, 5,6,7, 8,9, 10, 11)
In our institution we have used Studer, Hattman and VIP
continent diversion after radical cystectomy. In the present
study, we reviewd our modification VIP ortotopic bladder
substitution.
During the period 2001 to 2011, 319 patinets underwent
radical cystectomy in our instituion. Out of them, 79 patinets
received ileal orthotopic bladder substitution: Padovana ileal
neobladder, modified padovana neobladder, Hautman and
Studer orthotopic bladder replacement in 35, 10, 25 and 19
patients respectively. Other patients underwent heterotopic
urinary diversion using dry or wet stoma.
During the last 3 years 10 patients underwent modified VIP
following radical cystectomy.
Technique
Briefly, an ileal segmet 40 cm in length was isolated 25 to
30 cm proximal to ileocecal valve. An isolated ileal segment
was detubularised along antimesenteric border in full lenght
(Figure 1a). Aboral part of isolated ileum was folded inV-shape
in the length 9 cm. Bladder neck is created by 2 running vicryl
3/0 sutures as shown on Figure 1b. The rest of isolated ileal
segment is folded in form of letter M. The medial armes of M
letter serve for creation of a 4 cm serosal tunel for ureteres,
providing anireflux mechanism. (Figure 1c). Ureteral
anastomoses are protected by splint 6 to 8 Fr. Finaly, created
“M” plane is folded anteriorly and sutured to anterior part
of neobladder neck using vicryl+ 3/0. Neobladder-urethral
anastomosis is created with 6 interrupted sutures over 18 Fr
three channel Foley catheter.
Follow-up
All patients were followed every 3 months during the first year,
thereafter 2 times and once yearly, before and after 5 years
respectively. Upper urinary tracts status was assesed using
IVP or CT urography. Renal function was analysedusing
a blood urea nitrogen and a creatinine measurement, and
metabolic funtion was assesed using a blood gas analysis.
Lower urianry tract function was measured by uroflowmetry
and urodynamic evaluation 6 months after surgery.
61
than in original technique, requireing less length of ureter.
Initial encouraging results should be confirmed in further
clinical pratice.
Literature
Daytime and nighttime
interviwe.
incontinence was asses by
Figure 1. a) isolated ileal segment 2) detubuarized ileal
segment with creation of bladder neck 3) “M|” shaped dorsal
side of neobladder with serosal tunels providing antireflux
mechanism 4) final aspect of modified bladder
Results
Perioperative, early an late postoperative mortality have
not been noticed. There were only 2 major complications:
1 patient (10%) with prolonged postoperative ileus and 1
with prolonged urinary leakague requiring percutaneous
nephrostomy and subsequent ureteral reimplantation due
to stenosis of ureterovesical anastomosis. There was no
significant metabolic disorders.
Average ileal neobladder capacity was 450 ml. Daytime and
night continence were achieved in 9 (90%) and 6 (60%) of
patients, respectively.
Conclusion
1. Simon J. Ectopia vesicae (absence of the anterior wall
of the bladder and pubic abdominal parietes): operation
for directing the orifices of the ureters into the rectum.
Temporary success: subsequent death: autopsy. Lancet
1952;2:568
2. Basic DT, Hadzi-Djokic J, Ignjatovic I, The history of
urinary diversion. ACI Vol. LIV, 9-17
3. Wataru Obara, Kazumasa Isurugi, Daisuke Kudo, Ryo
Takata, Karen Kato,Mitsugu Kanehira, Kazuhiro Iwasaki,
Susumu Tanji, Ryuichiro Konda and Tomoaki Fujioka,Eight
Year Experience with Studer Ileal Neobladder Jpn. J.
Clin. Oncol. (July 2006) 36(7): 418-424
4. Studer UE, Danuser H, Merz VW, Springer JP, Zingg EJ.
Experience in 100 patients with an ileal low pressure
bladder substitute combined with an afferent tubular
isoperistaltic segment. J Urol 1995;154:46–56
5. Hautmann RE, Miller K, Steiner U, Wenderoth U. The
ileal neobladder: 6 years of experience with more than
200 patients. J Urol 1995;150:40–5
6. Studer UE, Danuser H, Thalmann GN, Springer JP,
Tunner WH. Antireflux nipples or afferent tubular segment
in 70 patients with ileal low pressure bladder substitutes:
long-term results of a prospective randomized trial. J
Urol 1996;156:1913–17
7. Hautmann RE, Abol-Enein H, Hafez K, Haro I, Mansson
W, Mills RD, et al. Urinary diversion. Urology 2007;69:1749
8. Hautmann RE. Urinary diversion: ileal conduit to
neobladder. J Urol 2003;169:834-42
9. Abol-Enein H, Ghoneim MA. Functional results of
orthotopic ilealneobladder with serous-lined extramural
ureteral reimplantation:experience with 450 patients. J
Urol 2001;165:1427–32.
10.Giacomo Novara, Vincenzo Ficarra,, Anila Minja, Vincenzo
De Marco, Walter Artibani. Functional Results Following
Vescica Ileale Padovana (VIP)Neobladder: Midterm
Follow-up Analysis with ValidatedQuestionnaires Eur
Urol ; 57: 1045 – 1051
11. Pagano F, Artibani W, Ligato P, Piazza R, Garbeglio A,
Passerini G.Vescica Ileale Padovana: a technique for
total bladder replacement. Eur Urol. 1990;17(2):149-54
This modification of VIP neobladder has not been dificult to
perform in our hands. In our opinion this technique provides
clear advantage in easier ureteral implantation proximally
62
Izkušnje z zdravljenjem bolnikov s karcinomom mehurja po odprti ali
laparoskopski radikalni cistektomiji v intenzivni enoti:
retrospektivna analiza
ICU experience with Bladder Cancer patients after open or laparoscopic radical cystectomy: retrospective analysis
Jasna Uranjek, Darja Kasnik
Oddelek za anesteziologijo in intenzivno medicino operativnih strok,
Splošna bolnišnica Slovenj Gradec, Slovenija
Department for anaesthesiology and intensive care medicine,
General Hospital Slovenj Gradec, Slovenia
Introduction:
Bladder cancer is the second most common genitourinary
malignancy and it ranges from mild disease with a low
mortality rate to extremely high-grade tumors associated with
high mortality (1).
Radical cystectomy with pelvic lymphadenectomy (open or
laparoscopic approach) remains the gold standard for the
treatment of muscle invasive bladder cancer (2,3). Since
bladder cancer is a tumor entity of the elderly who have many
coexistent diseases these patients need good peri-operative
care. Different peri-operative protocols, adapted to hospital
possibilities and capabilities, are used. So, we performed an
analysis of our protocol and looked for ways how to improve
it.
Material and methods:
A retrospective analysis of medical charts of patients who
had radical cystectomy due to bladder carcinoma and were
treated in our Intensive Care Unit (ICU) from 1.1.2000 till
30.4.2011 was made.
Till 2004 only open radical cystectomy (ORC) was performed
in our hospital, since May 2004 also laparoscopic radical
cystectomy (LRC) is performed. The change in surgery type
changed some postoperative needs and protocols, so we
decided to analyse and compare postoperative course after
ORC and LRC.
Patients were divided into group O (open) and group L
(laparoscopic) according to the surgery type. Patient’s
biometrical, anaesthesiological and surgical data were
collected. All complications during ICU stay, ICU and hospital
length of stay (LOS), ICU and hospital mortality rate and six
month, one year and five years survival rate were recorded.
Data was analysed with SPSS 16.0 programme and p value
< 0, 05 was considered as statistical significant different.
Results:
65 patients were treated in our ICU during reviewed period.
Type and frequency of the operation are shown in graph 1.
Patients’ major differences in biometrical, anaesthesiological
and surgical data are shown in Table 1.
No serious anaesthesiological complications were recorded.
All but 3 patients were admitted to our ICU directly after
surgery for more intensive monitoring and supervision.
The ICU complications during early post-operative period
developed statistically significant more frequently in group O.
The most frequent complications were wound infection (9%
group O, 4, 7% group L), pneumonia (7% group O, 0% group
L), anastomotic leakage on different anastomosis (6, 8%
group O, 0% group L) and SIRS/sepsis (9% group O, 4, 7%
group L). There was no statistical difference between groups
in frequency of either of stated complications. Re-admittance
to ICU was more frequent in group O with longer second ICU
LOS (3,8±8,9 days in group O versus 0,14±0,6 days in group
L, t-test, p=0,04).
Follow up data are inconclusive because 21 patients (47%)
in group O and 16 patients (76%) from group L were only
operated in our hospital. Their later, regular follow up is/
was done by their home urologists. So the results might be
different/better if we had all the data.
The survival curve of the known data is showed on graph
2 and it suggests better survival after LRC, although not
statistically significant (Log Rank 0,094).
Discussion:
The collected data showed increasing number of laparoscopic
operations which had less intra-operative blood loss with
consequently smaller needs for intra-operative blood
transfusion, lower early ICU complication rate, smaller needs
for re-admittance to ICU and shorter hospital LOS.
63
However, laparoscopic operations do carry a distinct risk of
complications despite of minimal invasiveness and according
to some studies the incidence of typical anaesthesiological
complications is higher compared to open operations (4). No
record of serious anaesthesiological complications was found
in our reviewed medical charts. We believe that one of the
reasons for this is our experience with laparoscopy because
laparoscopic operations are standard and routine practice
in all fields of surgery in our hospital although urological
laparoscopic operations do have their own entities (5).
Smaller intra-operative blood loss with consequently smaller
needs for blood transfusion is one of the biggest advantages
of LRC over ORC since peri-operative anaemia and blood
transfusion are associated with excess morbidity and
mortality (6).
Our ORC group had higher intra-operative blood loss and
higher early post-operative complications rate. Besides
blood loss, known risk factors for serious peri-operative
complications are age, ASA score >2 and prior pelvic/
abdominal surgery (7).
Other three factors didn’t differ between both our groups.
Nevertheless, besides higher blood transfusion rate in ORC
group, post-operative fasting was longer in ORC group.
The benefits of early enteral nutrition post-operatively for
reduction of infection rate, better nitrogen balance, shorter
hospital LOS with tendency for risk reduction for anastomotic
dehiscence have been confirmed may times (8).
Also, early enteral nutrition does not lead to increased rate of
post-operative ileus or to oral food intolerance (9).
In last few years our ICU protocol does include early postoperative enteral feeding for all patients.
Our hospital LOS is a little longer as cited by the literature
(10).
We believe one of the reasons for this is the fact, that
approximately half of the patients operated in our hospital
don’t live near. So, we want to be sure in everything before
patient’s discharge which sometimes prolongs hospital LOS.
Finally, our analysis showed postoperative follow up which
should/could be better.
The patients who didn’t live near our hospital returned to our
institute only for the first postoperative check, later they were
followed by their home urologists or oncologists and were
lost from our follow up system. How to improve that is one of
the problems which were revealed with this study.
Literature:
1. Sharma S, Ksheersagar P, Sharma P. Diagnosis and
treatment of bladder cancer. Am Fam Physician. 2009
Oct 1;80(7):717-23.
2. Castillo OA, Abreu SC, Mariano MB, Tefilli MV, Hoyos
J, Pinto I, Cerqueira JB, Gonzaga LF, Fonseca GN.
Complications in laparoscopic radical cystectomy. The
South American experience with 59 cases.Int Braz J
Urol 2006;32:300-05.
3. Madersbacher S, Hochreiter W, Burkhard F, Thalmann
GN, Danuser H, Markwalder R, Studer UE: Radical
cystectomy for bladder cancer today – a homogeneous
series without neoadjuvant therapy. J Clin Oncol 2003;
21:690–696.
4. Complications and contraindications of laparoscopic
surgery.In: Crozier TA. Anaesthesia for minimally
invasive surgery.Cambridge University Press 2004
5. I. D. Conacher*, N. A. Soomro and D. Rix Anaesthesia
for laparoscopic urological surgery. Br J Anaesth 2004;
93: 859–64
6. Kumar A. Perioperative management of anemia: limits
ob blood transfusion and alternatives to it. Cleve Clin J
Med 2004:76 Suppl 4;S112-8.
7. Shabsigh A, Korets R, Vora KC, et al. Defining early
morbidity of radical cystectomy for patients with bladder
cancer using a standardized reporting methodology. Eur
Urol 2009;55:164.
8. Shrikhande SV,Shetty GS,Singh K,Ingle S. Is early
feeding after major gastrointestinal surgery a fashion or
an advance? Evidence based review of literature.J Can
Res Ther 2009;5:232-9.
9. Han-Geurts IJ,Hop WC,Kok NF,Lim A,Brouwer KL,Jeekel
J. Randomized clinical trial of the impact of early enteral
feeding on postoperative ileus and recovery. Br J Surg
2007;94:555-61.
10. Hautmann RE,Volkmer BG, Schumacher MC et.al.
Long-term results of standard procedures in urology:
the ileal neobladder. World J Urol 2006;24:305-314.
Conclusion:
From ICU point of view, LRC has many advantages over
ORC and should be done whenever possible according to
surgical and oncological demands.
64
Graph 1: The number and type of the operation
Graph 2: Survival data
65
Table 1: Patientsd biometrical, anaesthersiological and surgical datas
GROUP O
GROUP L
P VALUE
Number
44
21
Age (years)*
65,0±9,44
67,0±9,26
0,43
Sex (male/female)
37/7
16/5
0,44
BMI *
26,0±4,10
28,1±3,86
0,50
ASA score*
1,89±0,78
1,81±0,60
0,78
Operative time (minutes)*
360±98,1
390±83,2
0,22
Estimated blood loss (ml)*
1483±480
475±35
0,01
Intraoperative blood transfusion (yes/no)**
40/2
1/20
<0,001
Postoperative blood transfusion (yes/no)**
27/17
5/16
0,005
Postoperative fasting >24 hours (yes/no)
21/23
4/17
0,02
First ICU LOS (days) **
4,23±3,6
4,81±7,9
0,73
ICU complication rate during first ICU stay**
20
3
0,01
Re-admittance to ICU(yes/no)**
11/33
1/20
0,04
ICU death (number)**
3
1
0,73
Hospital LOS(days)*
30,8±27,2
19,9±7,0
0,07
Six month survival**
13
32
0,37
One year survival**
9
28
0,11
Five years survival**
8
1
0,16
BMI – body mass index, ASA – American Society of Anesthesiologists, ICU- Intensive care medicine, LOS – length of stay,
*t-test, **χ2 test
67
Quality of life after radical cystectomy measured
by “Sickness impact profile” score
A. Prcić, D. Aganović, B. Kulovac, O. Hadžiosmanović
Urology Clinic, Clinical Center University of Sarajevo, Bosnia and Herzegovina
Objective: to evaluate the quality of life among patients with
orthotopic urinary diversion and ileal conduit following the
radical cystectomy.
Methodology: the quality of life in the period of 6 months
following the radical cystectomy has been analysed among
98 patients who underwent surgery at the Urology Clinic of
the Clinical Center University of Sarajevo between January
2007 and January 2011. Patients were divided in two groups,
one with orthotopic urinary diversion developed by Hautmann
and Ghoneim, and the other with ileal conduit diversion.
‘Sickness Impact Profile’ (SIP) score has been used in this
paper as a tool to measure the quality of life.
Results: 98 patients with ortotopic diversion and ileal conduit
urinary diversion have been evaluated during four years
period. Average age of the patients was 65.15 years. 75 male
and 23 female patients were treated for invasive bladder
cancer. 20 patients underwent orthotopic diversion according
to Hautmann and 12 according to Ghoneim. Remaining 66
patients underwent ileal conduit urinary diversion. Average
SIP score amounted to 35% among patients who underwnet
ileal conduit and 19% among those who underwent orthotopic
diversion.
Conclusion: Analyses of the quality of life measured by
SIP score gives considerable advantage to patients with
orthotopic diversion in comparison with those with ileal conduit
diversion. More importantly, it has been demonstarted that
quality of life, as measured by SIP score, is reasonable and
applicable for both groups of patients.
68
Quality of life in patient with orthotopic neobladder
I. Vuković, S. Mićić, N. Bojanić, D. Djordjević
Clinic of Urology, Clinical center of Serbia, Belgrade, Serbia
Abstract:
Introduction: The aim of this study was to estimate the QoL
in patients with orthotopic neobladder (sec Hauptman) and
ileal conduit after the radical cystectomy and to show the
possible advantages of orthotopic urinary diversions.
Patients and methods: From 1998 to 2010 orthotopic
derivation sec. Hauptman was performed in 65 pts due to
bladder carcinoma at urologic clinic in Belgrade, but only 34
patients answered the questionnaire. Ileal conduit group had
34 patients of similar age and gender. The quality of life after
the radical cystectomy in these two groups of patients was
analysed with FACT-BL (Functional Assessment of Cancer
Therapy-Blader) questionnaire.
similar to normal bladder. On the other hand, the life without
stoma from psychological and cosmetic reasons allows easier
rehabilitation, better incorporation to regular life activities,
better social accommodation and finally overcoming of all
psychological problems connected with stoma. Frequently,
this type of operation presents some type of compromise
between medical and social needs. Naturally, the ideal
method of continent urinary diversions does not exist but
there is permanent need to do better surgical procedure
which can provide similar functional characteristics of normal
bladder.
Results: We have not found statistical differences among
the investigated groups using the FACT-G questionaire in
some domains. The difference in QoL achieved for orthotopic
neobladder with FACT-G in total score was annulated by
the results of the questions from specific subscale and the
total score of FACT-BL has shown no statistical difference
between the groups. The only difference was found for some
questions in specific subscale concerning the incontinence
and body image.
From 1998 to 2010 orthotopic derivation sec. Hauptman was
performed in 65 pts due to bladder carcinoma at urologic
clinic in Belgrade. The QoL questionnaire was sent to all, but
only 34 patients reply with full field questions. The Hauptman
procedure was performed according to the original operative
technique, the preservation of external sphincter was
achieved with Walsh technique of radical prostatectomy. The
other group consists of 34 patients with radical cystectomy
and ileal conduit of similar age and gender due to achieve the
homogeneity of groups.
The quality of life after the radical cistectomy with orthotopic
derivation and ileal conduit was analysed with FACTBL (Functional Assessment of Cancer Therapy-Bladder)
questionnaire translated and adjusted to serbian language.
According to this questionnaire we compare the QoL of the
same number of patients with orthotopic bladder and ileal
conduit urinary derivation.
The questionnaire consists of FACT-G (the standard version
for accuracy of malignant disease treatment) which was
analysed in different type of malignant diseases and Appendix,
consisting of 12 questions connected with simptoms of
urinary and digestive organs as well as sexual function which
makes it specific for patients operated due to bladder cancer
and presents specific subscale.
The score of the specific subscale, plus the score of FACTG, present FACT-BL.
At the end of the questionnaire, an additional question was
included:
Would you suggest the same derivation to other patients with
invasive bladder cancer?
Conclusion: Using the FACT-BL questionaire statistical
differences in QoL between orthotopic neobladder and
ileal conduit group could not be achieved. Despite this fact,
orthotopic neobladder group would suggest this type of
urinary derivation to others because of the preservation of
the body image despite the presence of some level of night
incontinence.
Introduction
Ileal conduit, the gold standard in urinary derivation, started
to step away in front of new numerous orthotopic derivations
twenty years ago.
Different orthotopic derivation was formed from different
parts of small bowel or colon and had the same goal to
improve the patient’s quality of life. The basic principals of
newly formed reservoirs were big capacity, low intraluminal
pressure, high compliance, to protect upper urinary tract,
minimal urinary absorption, continence and to allow
urination per urethra. The medical aspect was satisfied
with orthotopic bladder because it was functionally very
69
The above mentioned FACT-G, include the following four
domains analysed:
Physical well-being (maximum points is 28)
Social and family well-being (maximum points is 28)
Emotional well-being (maximum points is 24)
Functional well-being (maximum points is 28)
The first four domains are same for all types of malignancies
and make FACT-G questionaire with maximal score of 108.
Specific subscale of additional worries, as the last group
of 12 questions, is concerned the simptoms of urinary and
digestive tract and the mark of sexual function.
Two questions concerning only to patients with stoma as
well as the question about the erection was not calculated in
the total score of specific subscale. Higher number in each
domain as well as in total score (FACT-G and FACT-BL)
suggest better QoL.
The parameters were analysed with Student t-test at the level
of significance p<0.05.
Results
The results of questionnaire are presented in Table 1.
The first domain (physical well-being) in both groups had
high scores but without statistically significant differences.
The same has happend with the second domain. The third
domain also has no statistically differences. The fourth
domain also did not reach statistical differences. The total
score of all four domains, what form FACT-BL, was 86,53 to
84,06 (p=0,020).
QoL was better in the group of orthotopic bladder derivation
according to the Student t-test despite the fact that the
difference was not present among the domains separately.
The last group of questions, concerning to the additional
worries, had the same scores in both groups (p>0.05).
In the subscale group, higly significant statistical difference
was found for the question concerning the continence in the
ileal group of patients, 1,6 to 3,1 (p=0, t= -5,753), and on the
other hand the question about the body image in the group
of orthotopic neobladder, 3.9 to 2,2 (p=0, t=9,470), but withut
the effect on the total score of specific subscale.
The sum of FACT-G points and specific subscale points which
form the FACT-BL was 112,21 in the orthotopic bladder group
and 109,47 in the ileal conduit group (p=0,055).
Student t-test did not show any difference among the
groups so we did not succed to show statisticaly significant
difference in the QoL in the orthotopic bladder group over the
ileal conduit group of patients.
91% of pateints with orthotopic bladder vs 41% of ileal conduit
group positively answered the question - would you suggest
the same derivation to other patients with invasive bladder
cancer.
Discussion
According to the study that we have performed, QoL
analysed by FACT-BL questionnaire in the group of patients
with orthotopic neobladder had no statistical differences
with ileal conduit group. Differences was shown only in the
group of questions concerning cosmetic effects of surgical
procedure where the personal satisfaction of the cosmetic
effect was statistically significantly higher in the group with
orthotopic neobladder. The orthotopic neobladder group
of patients shown through the questionnaire certain level
of dissatisfaction with micturition control, especially with
frequent night voiding. The loss of libido was present in both
group of patients without the differences. High percentage
of erectile disfunction was present in both groups of patients
despite the type of derivation.
The most of the patients with orthotopic neobladder (91%)
versus 41% of patient in the ileal conduit group would suggest
this type of operation to others despite the lack of difference
between them. These results are almost the same to results
in literature.
The most of the authors didnot find the difference in the QoL
among the different types of derivations using the same type
of questionnaire (Dutta et al, Kikuchi et al and Mason et al.).
Only Hobish et al. using the QLQ C 30 questionaire shown
superiority of orthotopic urinary derivations. Yoneda et al
and Weijrman et al used SIP questionnaire also had not sow
the difference. Despite the fact that the most of patients ask
and accept orthotopic urniary derivation, would suggest this
type of derivation to others and that they are satisfied with it,
there is no statistical significance in QoL over to incontinent
derivations. It is obvious that existing types of questionnaire
are not sensitive enough and there is a necesity to make
the new questionnaires to show the evident advantages of
orthotopic urinary derivations.
References
1. Kulaksizoglu H, Toktas G, Kulaksizoglu IB, et al.
When should quality of life be measured after radical
cystectomy? Eur Urol 2002;42:350 –355
2. Hardt J, Filipas D, Hohenfellner R, et al. Quality of life
in patients with bladder carcinoma after cystectomy: first
results of a prospective study. Qual Life Res 2000;9:1–
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3. Hobisch A, Tosun K, Kinzl J, et al. Life after cystectomy
and orthotopic neobladder versus ileal conduit urinary
diversion. Semin Urol Oncol 2001;19:18 –23.
4. Fujisawa M, Isotani S, Gotoh A, et al. Health-related quality
of life with orthotopic neobladder versus ileal conduit
according to SF-36 survey. Urology 2000;55:862– 865.
70
5. Kikuchi E, Horiguchi Y, Nakashima J, Ohigashi T, Oya
M, Nakagawa K, Miyajima, Murai M. Assessment of
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712-6.
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reconstruction Int J Urol. 2003;10(3):119-25.
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Table 1
Group
Physical well-being
Soc/Family well-being
Emotional well-being
Func. well-being
Total FACT-G
Specific subscal
Total FACT-BL
(max.)
(28)
(28)
(24)
(28)
(108)
(36)
(144)
Neobladder
(mean ± SD)
24,06 ± 3,02
23,97 ± 1,09
17,21 ± 1,55
21,29 ± 2,41
86,53 ± 4,08
25,68 ± 3,69
112,21 ± 5,94
Ileal conduit
(mean ± SD)
22,88 ± 3,65
23,68 ± 1,43
16,71 ± 2,42
20,79 ± 2,31
84,06 ± 4,47
25,41 ± 3,04
109,47 ± 5,60
p<0,05
P=0,150
p=0,343
p=0,314
p=0,385
p=0,020
p=0,748
p=0,055

“rak sečnega mehurja” “urinary bladder cancer”

Transcription

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