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1 /STRU^NI RAD UDK Local Recurrence of Bladder Cancer after Cystectomy with Orthotopic Bladder Substitution and Conduit... Pejcic T 1, Hadzi-Djokic J 1, Acimovic M 1, Markovic B 2, Maksimovic H 2, Milkovic B 1, Kajmakovic B 1. 1 Clinical Center of Serbia, Institute for Urology and Nephrology, Belgrade 2 Clinical Center of Serbia, Institute for Radiology, Belgrade Objective: To present the local recurrence rates after radical cystectomy for advanced bladder cancer and to compare them between patients with orthotopic neobladder and ileal conduit. Patients and methods: 97 patients with radical cystectomy were analyzed: 75 patients with orthotopic ileal neobladder, operated from to 2006, and 22 patients with ileal conduit, operated from to Results: Overall recurrence rate was 41.3% in the neobladder group, and 50% in the ileal conduit group. The rate of pelvic, upper urinary tract and urethral recurrence was 13.3%, 8%, and 10.6% in the neobladder group, and 9.1%, 13.6% and 9.1% in the ileal conduit group. Conclusion: Comparable recurrence rates, operative time, the complexity of the surgical technique and the results between two groups, strongly support the construction of orthotopic neobladder, as superior in functional, esthetic, and psychological point of view. Key words: radical cystectomy, orthotopic neobladder, ileal conduit, recurrence rate, advanced bladder cancer rezime INTRODUCTION Radical cystectomy is the standard procedure for the treatment of muscle-invasive bladder cancer T2-T4a, N0-NX, M0. Other indications are high-risk superficial tumors (T1 G3 and BCG-resistant Tis) and extensive papillary disease that cannot be controlled with conservative measures. The operative mortality is 1.2%-3.7%. The 5-year survival rate is between 40 and 60% 1. Indications for the creation of the orthotopic bladder are the same as the indications for the radical cystectomy. During the last decades, ileal conduit has been the most common treatment for urinary diversion. Nowadays, together with cancer control, it is important to preserve the quality of life and patients body image by constructing continent bladder substitute. An orthotopic neobladder possesses some typical characteristics of the normal bladder, like continence mechanism, sufficient capacity at a low intravesical pressure and an antireflux mechanism competent to prevent dilatation of the upper urinary tract 2. (Figure 1) Opposite to ileal conduit, orthotopic neobladder offers the potential for almost normal voiding function, continence, easier urethral surveillance with a lowered urethral recurrence rate, and a superior body image. Moreover, the structural changes, which occur in neobladder mucosa, make the neobladder very similar to real bladder: initially, the inflammation leads to reduction of microvilli, and later, regressive changes create a flat mucosa and a stratified epithelium However, orthotopic neobladder reconstruction has to be reserved for selected patients 3. (Figure 2). REASONS FOR TUMOR RECURRENCE AFTER CYS- TECTOMY 1. Polychronotopism Whitmore introduced the term Polychronotopism to describe the capability of transitional cell carcinoma (TCC) of the urinary tract for multicentric growth in space and time. The highest incidence of transitional cell tumors appearance possesses the bladder (90%), while the incidence is much lower in the urethra (6-8%) and upper urinary tract (2-4%). So, the incidence ratio between bladder and upper tract TCC is 1: 30, with the exception of Balkan endemic nephropathy (BEN), where this ratio is 40: 1 (Petkovic, 1971.) The risk rate for the appearance of bladder TCC in the presence of upper tract TCC is 30-50%, and in the presence of concomitant TCC in the renal pelvis and the ureter, the risk is even higher, about 75% (Kakizoe, 1980.). Moreover, in the past, when the standard procedure for

2 64 Local recurrence of bladder cancer after cystectomy with ACI Vol. LIV orthotopic bladder substituional and ileal conduit FIGURE 1 HAUTMANN S ILEAL LADDER the treatment of renal pelvis TCC was simple nephrectomy, the rate of recurrences in the ispilateral ureteral stump was 84%! Partial nephroureterectomy was associated with the recurrence in the ureteral stump in 30-60%. In contrast, bladder TCC caries the risk of upper tract TCC appearance of 2-3% (Babaian, 1980.) However, according to Whitmore, this percentage would be much higher if the greater number of patients would have survived the bladder cancer! 2. Implantation of tumor cells The theory of implantation of tumor cells gives the possible explanation for tumor recurrence, in cases of low stage/ low-grade bladder TCC, without nodal or distant disease, and without TCC in the urethra or upper tract. The implantation of cancer cells can be local, during the handling of tumor during cystectomy, or this implantation can be vascular or lymphatic, as a result of surgical manipulation. 3. The presence of tumor beyond the surgical margins in the time of cystectomy Tumor cells can be present after cystectomy as a result of surgical failure and positive surgical margins, at bladder neck, urethra, or intramural ureter, or as a micro-metastases in lymphatic vessels and nodes. MATERIAL AND METHODS A total of 75 radical cystectomies with the formation of ileal neobladder were performed in the period from to Sixty seven patients underwent surgery in the Clinical Center of Serbia, Urological Clinic and eight patients were operated in other Serbian clinics. From FIGURE 2 STUDER S ORTHOTOPIC ILEAL LADDER to 2006, 22 radical cystectomies with ileal conduit derivation were performed in the Clinical Center of Serbia, Urological Clinic. RESULTS Overall recurrence rate was 41.3% in the neobladder group, and 50% in the ileal conduit group. There were no significant differences in the pelvic, upper urinary tract and urethral recurrence rate between two groups. Recurrence rates are comparable with the results published in the literature (Table 1, Table 2.)

3 Br. 4 Pejcic T et al. 65 TABLE 1 TUMOR RECURRENCE RATE Urinary derivation Number Nodes/Distant Pelvic/Local Upper UT Inside IC/ORB Urethral Overall recc neobladder 75 6(8%) 10(13.3%) 6(8%) 3(4%) 8(10.6%) 31(41/3%) conduit 22 3(13/6%) 2(9,1%) 3(13.6%) 1(4.5%) 2(9.1%) 11(50%) All 97 9(9,3%) 12(12.3%) 9(9.3%) 4(4.1%) 10(10.3%) 42(43/2%) TABLE 2 Author/year DISCUSSION No Hautmann Hautmann 2001 Hatmann/Studer Akkad TUMOR RECURRENCE RATE AFTER RADICAL CYSTECTOMY Urinary derivation Ali-el-Dein Lebret all N Oberneder Yossepowitch Hassan Ali-El-Dein Nodes/ Distants According to Hautmann, the primary goal of bladder replacement is the attempt to improve patient quality of life, not to increase survival, affect cancer prognosis or decrease renal metabolic complications. Pelvic/ Lical Upper UT Omsode OC/ORB 43(12%) 24(6,7%) 10(2,8%) Urethral 43(10%) 11(2.5%) 5)1.1%) 2-3% 4%-5% 1.5-5% 1(2,1%) 2(4.3%) 6(4.1%) 18(12,4%) 2(1.4%) 18(11%) Overall recc rate 46(64.8%) 7(11%) 9(14%) 6(9%) 3(5%) 16(25%) 19(9%) 23(11%) 4(1.8%) 6(2,8%) 4(1.8%) 62(29%) 3*(5.5%) Stenzl (3.5%) Tsui IC 5(8.2%) Ali-El-Dein Clark *(0.3%) 1(0.5%) 47(4.5%) 62(31.6%) Tumor recurrence rates after radical cystectomy show little variations between authors (Table 2.). However, there are some differences in the definition of local recurrence: some authors make the difference between local pelvic/pelvic flour, and the recurrence inside the neoblad-

4 66 Local recurrence of bladder cancer after cystectomy with ACI Vol. LIV orthotopic bladder substituional and ileal conduit der, the others do not. Maybe, the correct classification would be as follows: 1. Upper urinary tract recurrence 2. Recurrence inside the neobladder 3. Urethral recurrence 4. Local pelvic recurrence 5. Recurrence in pelvic lymph nodes 6. Distant recurrence Using this classification, it could be possible to distinguish between recurrence as a consequence of tumor polychronotopism and a recurrence after preoperative staging or surgical failure. Overall recurrence rate in the large series of radical cystectomies is as follows: In his large series, Hautmann 4,5,6 published local recurrence rates of 10-12%, recurrence inside the neobladder of 4-5%, in the upper tract of 2-3% and urethral recurrence of 1.5-5%. Oberneder 7 and Yossepowitch 8 published similar results: local recurrence rate of 14% and 11%, respectively. The upper tract recurrence was found in 4.6%; the half of these patients had the tumor in the intramural or juxtavesical ureter on the cystectomy specimen 8. In the group of 258 patients with orthotopic neobladder, Stenzl 9 found upper tract TCC in 3.5%. He described several factors responsible for upper tract recurrence: multifocal TCC, presence of carcinoma in situ (CIS) in the bladder and/or distal ureter, locally advanced bladder tumor and the invasion of the intramural ureter. His opinion is that a longer observation period of patients with an orthotopic neobladder and longer survival rates may reveal an increase in the incidence of upper tract tumors in the future. In the older study of patients after radical cystectomy and ileal conduit, from 1996, Tsuji 10 found malignant ureteral obstruction in 8.2%. Almost all patients had metachronous upper tract TCC, with very long period to recurrence, up to 10 years! The incidence of urethral recurrence is slightly lower than in the upper tract. Akkad 11 found urethral recurrence in 2.3% of women after cystectomy, and Hasan 12 found only one patient of 196 with cystectomy and neobladder, with urethral recurrence. In the large series of 1054 patients with radical cystectomy and various forms of urinary derivation, Clark 13 found urethral recurrence in 4.5%, after 18 months of follow up, average. Two thirds of patients had symptomatic recurrence (bloody urethral discharge, pain, or a palpable mass), while one third were asymptomatic, with abnormal cytology. Most authors agree that the most important risk factors for tumor recurrence after cystectomy are the presence of tumors at the bladder neck and recurrent multifocal tumors. These patients need multiple urethral biopsies, urethral brushings and frozen section of the membranous urethra before an orthotopic lower urinary tract reconstruction. Moreover, the significant risk for anastomotic recurrence presents the involvement of the intramural or juxtavesical ureteral segment at cystectomy, irrespective of surgical margin status. TABLE 3 OVERALL RECURRENCE RATE IN THE LARGE SERIES OF RADICAL CYSTECTOMIES Recurrence Range (%) 1 Upper urinary tract Inside the neobladder Urethral Local pelvic 10, Pelvic lymph nodes/distant However, CIS of the bladder not involving the bladder neck, and muscle invasive tumors with or without lymph node involvement are not significantly correlated with urethral recurrence. CONCLUSION Despite the poor prognosis in the presence of bladder TCC metastases in the regional lymph nodes, it is justified to propose a neobladder replacement to well selected patients, as the preferential diversion. Today, the absolute contraindications for neobladder formation are urinary stress incontinence, damaged rhabdosphincter, severely impaired renal and liver function, severe intestinal diseases or an oncological condition requiring urethrectomy. As Hautmann concluded, the survival of patients after local TCC recurrence is limited despite multimodal therapy, but most patients may expect normal neobladder function even in the presence of recurrent disease or until death. Thus, it is safe to create orthotopic diversion after cystectomy in patients with locally advanced bladder cancer, including positive lymph nodes. In our series, the recurrence rates are comparable between neobladder and ileal conduit group. Comparable operative time, the complexity of the surgical technique and the results, strongly support the construction of orthotopic neobladder, as superior in functional, esthetic, and psychological point of view. SUMMARY Cilj rada: prikazati stope recidiva uznapredovalog karcinoma mokra}ne be{ike posle radikalne cistektomije i uporediti ih u grupi bolesnika sa ortotopskom be{ikom i ilealnim konduitom. Bolesnici i metode: analizirano je 97 bolesnika sa radikalnom cistektomijom: 75 sa ortotopskom be{ikom, operisanih od do i 22 bolesnika sa ilealnim kondjuitom, operisanih od do godine. Rezultati: Ukupna stopa recidiva je iznosila 41.3% u grupi sa ortotopskom be{ikom i 50% u grupi sa ilealnim kondjuitom. Stopa recidiva u maloj karlici, gornjem urotraktu i u uretri je iznosila 13.3%, 8%, and 10.6% u grupi sa ortotopskom be{ikom i 9.1%, 13.6% and 9.1% u grupi sa ilealnim kondjuitom.

5 Br. 4 Pejcic T et al. 67 Zaklju~ak: S obzirom da nema ve}ih razlika izmedju stope recidiva, operativnog vremena, slo enosti hirur{ke procedure i rezultata izmedju dve grupe, izvodjenje ortotopske supstitucije be{ike ima funkcionalnu, estetsku i psiholo{ku prednost u odnosu na ilealni kondjuit. Klju~ne re~i: radikalna cistektomija, ortotopska be{ika, ilealni kondjuit, stopa recidiva, uznapredovali karcinom be{ike REFERENCES 1. G. Jakse, F. Algaba, S. Fossa, A Stenzl, C Sternberg. Guidelines on bladder cancer. Muscle-invasive and metastatic. In: European Association of urology guidelines, 2007 edition. 2. Benson MC, Seaman EK, Olsson CA. The ileal neobladder is associated with a high success and low complication rate. J Urol 1996; 155: Studer UE, Ackermann D, Cassanova GA, Zingg EJ. Three years experience with an ileal low pressure bladder substitute. Br J Urol 1989; 63: Hautmann RE, simon J. neobladder and local recurrence of bladder cancer: patterns of failure and impact on function in men Dec;162(6): Hautmann RE, (15 years experience with the ileal neobladder. What have we learned? 2001 Sep;40(5): Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE, Studer UE. Long-term results of standard procedures in urology: the ileal neobladder Aug;24(3): Oberneder R, Staudte S, Waidelich R, Schmeller N, Hogstetter A. Local recurrence in patients after radical cystectomy and orthotopic ileal neobladder: impact on function. 2003;35(2): Yossepowitch O, Dalbagni G, golijanin D, donat SM, bochner BH, Herr HW, Fair WR, Russo P. Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence Jan;169(1): Stenzl a, Bartsch G, Rogatsch H. The remnant urothelium after reconstructive bladder surgery Feb;41(2): Tsuji Y, Nakamura H, Ariyoshi A. Upper urinary tract involvement after cystectomy and ileal conduit diversion for primary bladder carcinoma. 1996;29(2): Akkad T, Gozzi C,Deibl M, Muller T, Pelzer AE, Pinggera GM, Bartsch G, Steiner H. Tumor recurrence in the remnant urothelium of females undergoing radical cystectomy for transitional cell carcinoma of the bladder: long-term results from a single center Apr;175(4): ; discussion Hassan JM, Cookson MS, smith JA Jr, Chang Ss. Urethral recurrence in patients following orthotopic urinary diversion Oct;172(4 Pt 1): Clark PE, Stein JP, Groshen SG, Miranda G, Cai J, Lieskovsky G, Skinner DG. The management of urethral transitional cell carcinoma after radical cystectomy for invasive bladder cancer Oct;172(4 Pt 1):