Upper Urinary Tract Recurrence After Radical Cystectomy for Bladder Cancer—Who is at Risk?

Upper Urinary Tract Recurrence After Radical Cystectomy for Bladder Cancer—Who is at Risk? Bjoern G. Volkmer,*,† Thomas Schnoeller,‡ Rainer Kuefer,‡ Kilian Gust,‡ Florian Finter‡ and Richard E. Hautmann‡ From the Department of Urology, University of Ulm, Ulm (BGV, TS, RK, KG, FF, REH), and Department of Urology, Klinikum Kassel, Kassel (BGV), Germany

Abbreviations and Acronyms CIS ⫽ carcinoma in situ CT ⫽ computerized tomography DOD ⫽ died of disease IVP ⫽ excretory urogram MSKCC ⫽ Memorial SloanKettering Cancer Center RR ⫽ risk ratio TCC ⫽ transitional cell carcinoma USC ⫽ University of Southern California UUT ⫽ upper urinary tract UUTR ⫽ upper urinary tract recurrence Submitted for publication April 11, 2009. Presented at annual meeting of American Urological Association, Chicago, Illinois, April 25–30, 2009. * Correspondence: Department of Urology, Klinikum Kassel, Moenchebergstrasse 41– 43, 34125 Kassel, Germany (telephone: ⫹49-561-9804030; FAX: ⫹49-561-980-6981; e-mail: bjoern. [email protected]). † Financial interest and/or other relationship with GE Healthcare Bucheler. ‡ Nothing to disclose.

Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2988 and 2989.

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Purpose: Patients who underwent radical cystectomy for bladder cancer are at risk for upper urinary tract recurrence. We identified subgroups of patients at increased risk for upper urinary tract recurrence. Materials and Methods: All 1,420 patients who underwent radical cystectomy for bladder cancer at our center between January 1986 and October 2008 were included in the study. Negative frozen sections of the ureteral margins were obtained from all patients. Data analysis included preoperative tumor history, pathological findings of the cystectomy specimen and complete followup. Survival was calculated using the Kaplan-Meier method. Results: Until October 2008, 25 cases of upper urinary tract recurrence were observed. The overall rate of upper urinary tract recurrence at 5, 10 and 15 years was 2.4%, 3.9% and 4.9%, respectively. Of the patients 3 had superficial tumors of the renal pelvis and 22 had invasive upper tract transitional cell carcinoma. Upper urinary tract recurrence did not develop in any patients with nontransitional cell carcinoma. Four risk factors for upper urinary tract recurrence were identified including history of carcinoma in situ (RR 2.3), history of recurrent bladder cancer (RR 2.6), cystectomy for nonmuscle invasive bladder cancer (RR 3.8) and tumor involvement of the distal ureter in the cystectomy specimen (RR 2.7). Patients with transitional cell carcinoma who had none of these risk factors had an upper urinary tract recurrence rate of only 0.8% at 15 years. This rate increased with the number of positive risk factors, ie 8.4% in patients with 1 to 2 risk factors and 13.5% in those with 3 to 4 risk factors. Conclusions: Patients who underwent cystectomy for transitional cell carcinoma and with at least 1 risk factor for upper urinary tract recurrence should have closer followup regimens than those with nontransitional cell carcinoma or without any of these risk factors. Key Words: cystectomy, urinary bladder neoplasms, urologic neoplasms, urinary tract MULTIFOCAL metachronous tumors often develop in patients with urothelial carcinoma. Explanations are the so-called panurothelial field defect with independent transformation of epithelial cells at different sites, and the intraluminal seeding and implantation of tumor cells deriving from an initial clone.1– 4

Since more than 90% of the epithelial surface of the urinary tract is located in the bladder, the incidence of urothelial bladder cancer is greater than that of upper tract tumors. In patients with primary bladder cancer the risk of UUTR is less than 4%.5,6 In patients with primary UUT cancer the risk of tumor recurrence at the bladder

0022-5347/09/1826-2632/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 182, 2632-2637, December 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.046

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RESULTS

Figure 1. Rate of UUTR after cystectomy for bladder cancer, Kaplan-Meier method.

is up to 50%.7 We identified factors predicting higher rates of UUTR from a large cystectomy series.

MATERIALS AND METHODS Between January 1986 and October 2008 a total of 1,420 radical cystectomies with pelvic lymphadenectomy for bladder cancer were performed at our institution (in 1,138 males and 282 females, a ratio of 4:1). Median age at cystectomy was 63.9 ⫾ 9.9 years (range 23 to 91). The pathology report revealed transitional cell carcinoma in 93.5% of cases while adenocarcinoma (1.0%), squamous cell carcinoma (3.9%), small cell/oat cell/neuroendocrine carcinoma (1.2%) or signet ring cell carcinoma (0.5%) were observed less frequently. A frozen section analysis of the ureteral margins was mandatory. If carcinoma in situ or dysplasia was diagnosed, further resection of the ureter was performed until the pathologist confirmed a clean margin. A complete followup was obtained until death or until October 2008. Mean followup was 58 months (range 0 to 271). All patients had regular oncological followup examinations for at least 5 years. However, we gave the strong recommendation for further lifelong followup of the function of the urinary diversion and long-term complications. After the first 5 years patients had at least regular examinations with urinalysis and abdominal ultrasound. Regular oncological followup included visits every 3 months with clinical examination, abdominal ultrasound and urine cytology. Chest x-ray and abdominal CT were done every 6 months, with bone scan and IVP every 12 months. Additional symptom driven imaging was recommended if necessary. We collected oncological followup data on all patients with UUTR. Using mailed questionnaires and telephone interviews we asked all patients about regular followup examinations. Data on overall survival were obtained from German inhabitant registries. The probability of upper tract recurrence and overall survival was calculated using the Kaplan-Meier method, and survival rates were compared using the log rank test.

Until October 2008 UUTR developed in 25 of 1,420 patients (1.8%) with a median interval from cystectomy to UUTR of 39 months (range 5 to 142). The overall probability of UUTR was 2.4% at 5, 3.9% at 10 and 4.9% at 15 years after cystectomy (fig. 1). Three patients had noninvasive upper tract tumor recurrence and in 2 of these patients recurrence was an incidental finding when a hydronephrotic kidney was removed. The third patient had panurothelial disease. He underwent nephroureterectomy of 1 kidney with subsequent resection of the contralateral ureter and renal pelvis, and simultaneous cystectomy and urethrectomy. In this patient an ileal conduit to the renal calices was also performed. Several recurrent papillary Ta tumors subsequently developed that required laser therapy. The other 22 patients had invasive disease, including TCC of the ureter in 8 and TCC of the renal pelvis in 14. Of these patients 16 died of metastatic or recurrent invasive UUT TCC after bladder cancer was cured. The disease specific survival rate after diagnosis of upper tract recurrence was 60.8%, 44.2%, 27.6% and 27.6% at 1, 2, 5 and 10 years, respectively (fig. 2). The probability of detecting noninvasive TCC of the UUT did not change when routine oncological followup examinations were replaced by less extensive examinations at 5 years postoperatively. All 8 ureteral tumors presented with hydronephrosis. Of the 17 renal pelvis tumors 1 was detected by regular pyeloscopy, 2 were detected by positive urine cytology, 2 by hydronephrosis and 10 by gross hematuria. The remaining 2 cases were incidental findings in nephroureterectomy specimens. No patients with nonTCC bladder cancer had UUTR. No patient with UUTR had tumor involvement of the urethra or the prostate in the cystectomy specimen. Of the 970 patients who underwent

Figure 2. Rate of overall survival after diagnosis of UUTR, Kaplan-Meier method.

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orthotopic bladder replacement 18 had UUTR. Of 377 patients with a nonrefluxing LeDuc ureteroneovesical anastomosis 11 had UUTR (mean time to UUTR 57 months, range 5 to 142). Of 593 patients with a freely refluxing Wallace II ureteroneovesical anastomosis 7 had UUTR (mean time to UUTR 59 months, range 26 to 132). Four factors could be identified that were associated with an increased risk ratio for UUTR, including history of carcinoma in situ (RR 2.3), history of recurrent bladder cancer (RR 2.6), cystectomy for noninvasive bladder cancer (RR 3.8) and tumor involvement of the distal ureter in the cystectomy specimen (RR 2.7) (table 1). There were 19 patients with a history of UUT tumors treated with nephroureterectomy or partial ureterectomy before cystectomy. Only 1 of these patients had contralateral UUTR. Tumor grading did not influence the risk of UUTR. With the exception of these 4 risk factors all other patients had a low risk of UUTR. Patients without any of these risk factors had a UUTR rate of 0.8% at 15 years, while this rate was 8.2% in those with 1 or 2 risk factors and 13.1% in those with 3 or 4 risk factors (fig. 3). With routine followup IVP at years 1, 2, 3, 4 and 5 the probability of detecting UUTR on IVP was 1:432 in patients without risk factors, 1:93 in those with 1 or 2 risk factors and 1:53 in those with 3 or 4 risk factors. Table 1

History of CIS: No. No. UUTR (%) % UUTR at 15 yrs History of recurrent bladder Ca: No. No. UUTR (%) % UUTR at 15 yrs Cystectomy for noninvasive bladder Ca: No. No. UUTR (%) % UUTR at 15 yrs Tumor involvement of distal ureter in cystectomy specimen: No. No. UUTR (%) % UUTR at 15 yrs NonTCC bladder Ca: No. No. UUTR (%) % UUTR at 15 yrs History of UUT tumor before cystectomy: No. No. UUTR (%) % UUTR at 15 yrs GI/GII tumor in cystectomy specimen: No. No. UUTR (%) % UUTR at 15 yrs

Yes

No

Total

292 10 (3.4) 9.1

1,128 15 (1.3) 3.9

1,420 25 (1.8) 4.9

360 11 (3.1) 9.2

1,060 14 (1.3) 4.2

294 13 (4.4) 10.0

1,126 12 (1.0) 2.6

64 2 (3.1) 12.6

1,356 23 (1.7) 4.7

95 0 (0.0) 0.0

1,325 25 (1.9) 5.1

19 1 (5.3) 20.0

1,401 24 (1.7) 4.8

216 6 (2.8) 5.2

1,204 19 (1.6) 5.0

Figure 3. Rate of upper tract survival after cystectomy for bladder cancer according to risk profile of 0 vs 1 to 2 vs 3 to 4 risk factors, Kaplan-Meier method.

DISCUSSION The rationale for followup after radical cystectomy was to detect tumor recurrence at an early stage with an acceptable relationship between cost and effect, and to provide a better prognosis for patients with recurrence detected at this stage.8 In a recent population based study Wright et al analyzed the risk of UUTR in a large cohort of approximately 100,000 patients with bladder cancer.9 They found an overall rate of 0.8% with 71% of tumor recurrence detected within 5 years. This study included only 6,216 cases treated with cystectomy, only 26 of which had UUTR (0.4%). Wright et al emphasized that most publications on UUTR after cystectomy are presented by tertiary care referral centers and, therefore, may not be an accurate representation. This argument can easily be refuted. Tertiary care referral centers differ from other centers in terms of surgical experience, complication rates and tumor specific survival rates, but there is nothing a surgeon could do during cystectomy that might influence the risk of UUTR. These tertiary care centers perform much more meticulous followup analyses than any population based study. Reviewing the literature for UUTR after radical cystectomy for bladder cancer we were able to identify at least 8 larger series at MSKCC; USC/ Norris Comprehensive Cancer Center; University of Texas, M.D. Anderson Cancer Center; University of Miami; University of Bern, Switzerland; Fundacio Puigvert, Barcelona, Spain; Kobe University, Japan and Mayo Clinic (table 2).10 –19 Including our series all 9 groups analyzed a total of

92.3 81.8 80.0 At least 55.6 (CIS) 87.5 Rate of UUTR ⫹ at least 1 risk factor (%)

64% Progression 80% DOD Overall 20 mos

% Diagnosed by symptoms % Bilat UUTR Survival after UUTR

56 31 Overall 10 mos

78

80

45

47

93.3

70% Progression

17 67% DOD at 3 yrs 66.7

At least 71.4 (CIS/ureter)

52 4 Disease specific 27.6% at 5 yrs 84.0 21 79% DOD

Ureteral involvement, multifocal CIS Multifocal TCC, recurrent TCC Superficial bladder TCC, vesicoureteral reflux 58 Pos ureteral margins, history of UUT tumors Ureteral involvement Urethral involvement Ureteral involvement

Prostatic urethra involvement

40 (8–100) 32 (5–71) 28 (1–86) 36 (12–69) 40 (9–56) 39.6

Ureteral involvement, CIS, superficial TCC, recurrent TCC

6,381 205 (3.2) (3.3)

1986–2008 1,420 25 (1.8) 2.4 39 (5–142) 1984 425 14 1995–2003 583 12 (2.1) 1980–1994 568 26 (4.6) 1985–2006 322 15 (4.7) 1981–1988 430 11 (2.6) 1992–2003 235 5 (2.1)

1985–2001 1,069 27 (2.5) 3 40 (4–112) 1990–2004 1,329 80 (6.0) 7 25 (1–107)

Time No. pts No. UUTR (%) 5-Yr UUTR rate (%) Mos radical cystectomy– UUTR (range) Risk factor

Miami15 USC13 MSKCC11,12

Table 2. Upper tract recurrence in larger cystectomy series

MD Anderson14

Bern16

Barcelona17

Kobe18

Mayo Clinic19

Present Series

Totals

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6,381 patients who underwent cystectomy. Of these patients 205 (3.2%) had upper tract recurrence, a rate 8 times higher than that presented by Wright et al in their analysis of 6,216 patients treated with cystectomy.9 Since the indications for cystectomy are similar in the population based study by Wright et al and in the large cystectomy series, and because the risk of UUTR is not directly dependent on the quality of surgery, the UUTR rate must be related to the thoroughness of followup examinations which might be greater at tertiary care referral centers. It might be assumed that a larger proportion of patients treated with cystectomy in the population based study may have died of progressive and metastatic disease without the correct diagnosis of UUTR. The risk of local tumor recurrence or metastatic disease decreases over time. More than 50% of recurrence is observed within the first 12 months postoperatively.8 In contrast to primary tumor progression, UUTR behaves like a de novo malignancy that develops independently from bladder cancer therapy. Since the followup periods of the published series vary, the overall rates of UUTR are difficult to compare. Series with a shorter mean followup will have a lower number of UUTRs than those with long-term followup. Thus, the overall rate of 3.2% for the complete series of 6,381 patients from these 9 centers will increase over time. In our series we observed a linear increase in the rate of UUTR over time with a cumulative rate of 1% in 3 years. The MSKCC and USC groups had a similar linear increase in UUTR rate, but their 3-year cumulative UUTR rate was 1.5% to 2%11 and even 4% to 6%.13 The MSKCC rates are distinctively higher than those in all other series. While the mean interval from cystectomy to diagnosis of tumor recurrence was 32 to 40 months in all other series, it was only 25 months at MSKCC with the first UUTR observed at only 1 month postoperatively. This finding might represent some patients with undetected upper tract tumors at cystectomy. The number of patients with long-term followup was also low. Only 20% of the population had a followup of 5 years or more (35% in the current series). In each of these studies attempts were made to identify risk factors for UUTR. Because the majority of series had only small numbers of UUTR, the statistical relevance should be questioned. Ureteral involvement of the tumor was identified as a risk factor by 4 groups with a strong correlation to ipsilateral tumor recurrence. Two groups found involvement of the prostatic urethra or female urethra was correlated to UUTR, but they were unable to identify any other risk factors. Further influencing factors were multifocal tumors, recurrent tumors, cystectomy for superficial tumors and carcinoma in

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situ. Among these factors involvement of the urethra was of no relevance in our series. Multifocality could not be assessed since we did not have data for all cases. In contrast to other publications we not only studied cases with CIS in the cystectomy specimen but also included those cases that presented with CIS in the past. It appeared that concomitant CIS was not always included in the pathology report of the cystectomy specimen but that it was always in the reports of the specimens from transurethral bladder tumor resection. The risk factors identified in this study are surrogate parameters for a high potential of recurrent and multifocal tumor growth. Tumor involvement of the distal ureter in a cystectomy specimen means synchronous multifocal tumor spread. When cystectomy is performed for noninvasive bladder cancer this may be an indirect parameter for tumors too large and/or too multifocal to be managed transurethrally. It is not always possible to transfer these risk factors to other series published in the literature since some publications only mention the rate of ureteral involvement or CIS. From the published data one can conclude that more than 80% of all patients with UUTR had at least 1 of these risk factors at cystectomy. The rate in patients without any of these risk factors and at a low risk for UUTR is high, and ranges from approximately 30% in the MSKCC series (CIS rate of 58%) to 54% in our series.13 The majority of UUTR is diagnosed by symptom driven examination and not by routine imaging. Most of these tumors are only detected in an advanced or metastatic state, which is reflected in the poor survival rates. Despite more or less intensified followup regimens the rate of progression and tumor specific death after UUTR is similar in all presented series. Of these patients 70% to 80% will die of progressing UUTR. To our knowledge there exists no adequate followup regimen to detect the majority of UUTR at an early stage. Cystectomy and urinary diversion may have an impact on this delay. In patients with a history of bladder cancer without cystectomy symptoms like hematuria or hydronephrosis would initiate immediate further examinations. These symptoms are much more common in a cystectomy population and are often caused by the urinary diversion itself. Chronic urinary tract infections and urinary diversions with intestinal segments may distort the value of urine cytology and tests like NMP-22®. Retrograde urography and ureteroscopy are standard examinations for UUTR when the bladder is still

intact. In many patients with urinary diversion the site of ureteral implantation to the reservoir is not detectable or accessible and, thus, requires a much more invasive percutaneous or even open access procedure to clarify the situation, with much higher rates of false-positive findings in the cystectomy population. We have to assume that a larger proportion of advanced UUTR would have been detected earlier if the patients had not previously undergone cystectomy and urinary diversion. UUTR must be considered a de novo malignancy in a panurothelial field defect. On the other hand, the risk of tumor cell implantation has been well documented. Palou et al found an increased UUTR rate in 30 patients with a history of transurethral bladder tumor resection for bladder cancer in renal units with vesicoureteral reflux.10 This finding might be a hint of the possibility of tumor cell implantation but it was not analyzed in a cystectomy series. After cystectomy there are no tumor cells refluxing from the bladder to the kidneys. Therefore, we would not expect an impact of the type of ureteral implantation (refluxing vs nonrefluxing) on the rate of UUTR. This was demonstrated by our data from 970 patients with orthotopic bladder replacement with different ureteral implantation techniques which demonstrated even lower UUTR rates for refluxing ureteroneovesical anastomoses.

CONCLUSIONS These results show that there is no followup regimen for UUTR that can be generally recommended for all patients. In high risk patients followup regimens for UUTR should not be limited to the first 5 years postoperatively since the risk of UUTR remains stable with time. In these patients routine intervals for upper tract examination with IVP, CT or magnetic resonance imaging may be too long. In the high risk group a more aggressive diagnostic approach should be recommended when early symptoms (eg hematuria, hydronephrosis and positive urine cytology) are noted. Regular followup examinations with radiation exposure have a poor detection rate in patients without any risk factors for UUTR (0.8% in 15 years). In these patients urinalysis, urine cytology and ultrasound examinations might be sufficient to guarantee a safe followup regimen. These examinations should be performed anyway to prevent long-term complications such as urinary tract infections or obstructive upper tract uropathy.

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REFERENCES 1. Sidransky D, Frost P, von Eschenbach A et al: Clonal origin of bladder cancer. N Engl J Med 1992; 326: 737. 2. Lunec J, Challen C, Wright C et al: c-erbB-2 amplification and identical p53 mutations in concomitant transitional carcinomas of renal pelvis and urinary bladder. Lancet 1992; 339: 439. 3. Habuchi T, Takahashi R, Yamada H et al: Metachronous multifocal development of urothelial cancers by intraluminal seeding. Lancet 1993; 342: 1087. 4. Kakizoe T: Development and progression of urothelial carcinoma. Cancer Sci 2006; 97: 821. 5. Canales BK, Anderson JK, Premoli J et al: Risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage Ta bladder cancer. J Urol 2006; 175: 74.

8. Volkmer BG, Kuefer R, Bartsch GC Jr et al: Oncological followup after radical cystectomy for bladder cancer–is there any benefit? J Urol 2009; 181: 1587. 9. Wright JL, Hotaling J and Porter MP: Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol 2009; 181: 1035. 10. Palou J, Farina LA, Villavicencio H et al: Upper tract urothelial tumor after transurethral resection for bladder tumor. Eur Urol 1992; 21: 110. 11. Tran W, Serio AM, Raj GV et al: Longitudinal risk of upper tract recurrence following radical cystectomy for urothelial cancer and the potential implications for long-term surveillance. J Urol 2008; 179: 96.

6. Sanderson KM and Roupret M: Upper urinary tract tumour after radical cystectomy for transitional cell carcinoma of the bladder: an update on the risk factors, surveillance regimens and treatments. BJU Int 2007; 100: 11.

12. Balaji KC, McGuire M, Grotas J et al: Upper tract recurrences following radical cystectomy: an analysis of prognostic factors, recurrence pattern and stage at presentation. J Urol 1999; 162: 1603.

7. Seaman EK, Slawin KM and Benson MC: Treatment options for upper tract transitional-cell carcinoma. Urol Clin North Am 1993; 20: 349.

13. Sanderson KM, Cai J, Miranda G et al: Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the

bladder: an analysis of 1,069 patients with 10-year followup. J Urol 2007; 177: 2088. 14. Kenworthy P, Tanguay S and Dinney CP: The risk of upper tract recurrence following cystectomy in patients with transitional cell carcinoma involving the distal ureter. J Urol 1996; 155: 501. 15. Sved PD, Gomez P, Nieder AM et al: Upper tract tumour after radical cystectomy for transitional cell carcinoma of the bladder: incidence and risk factors. BJU Int 2004; 94: 785. 16. Meissner C, Giannarini G, Schumacher MC et al: The efficiency of excretory urography to detect upper urinary tract tumors after cystectomy for urothelial cancer. J Urol 2007; 178: 2287. 17. Huguet-Pérez J, Palou J, Millán-Rodriguez F et al: Upper tract transitional cell carcinoma following cystectomy for bladder cancer. Eur Urol 2001; 40: 318. 18. Furukawa J, Miyake H, Hara I et al: Upper urinary tract recurrence following radical cystectomy for bladder cancer. Int J Urol 2007; 14: 496. 19. Zincke H, Garbeff PJ and Beahrs JR: Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer. J Urol 1984; 131: 50.

EDITORIAL COMMENT This article raises 3 important issues. 1) The risk of upper tract recurrence after radical cystectomy is small (4.9% at 15 years). 2) If there is upper tract recurrence it is usually fatal (22 of 25 patients with upper tract recurrence had invasive disease and a dismal survival rate). 3) If patients do not have a risk factor (CIS, muscle invasive disease, recurrent bladder cancer and distal ureteral involvement) they do not require routine upper tract monitoring. Of these findings the most disturbing is that despite

undergoing urine cytology and renal ultrasound every 3 months, CT every 6 months, and bone scan and IVP yearly, upper tract recurrence is rarely detected at a curable stage. New monitoring paradigms are needed for patients at high risk for upper tract recurrence after radical cystectomy. David P. Wood, Jr. Department of Urology University of Michigan Ann Arbor, Michigan