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Bladder (San Franc)
Bladder (San Franc)
Bladder
2327-2120
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10.14440/bladder.2024.0007
Perspective Article
Strategies to reduce bladder tumor recurrences following surgery for upper tract urothelial carcinoma
Head Dennis J.
Raman Jay D. *
Department of Urology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA 17033, United States of America
*Corresponding author: Jay D. Raman (jraman@pennstatehealth.psu.edu)
2024
31 7 2024
11 1 e2120000112 6 2024
02 7 2024
08 7 2024
© 2024 Bladder, All rights reserved.
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License: http://creativecommons.org/licenses/by-nc-sa/4.0
The incidence of upper tract urothelial carcinoma (UTUC) has been on the rise and the malignancy is more commonly managed surgically as higher proportions of in situ disease are being detected. One challenge facing urologists is the high rate of post-treatment intravesical recurrence (IVR) of UTUC (23 – 50%). Genomic research indicated that cells of recurrent bladder lesions are most often clonally derived from the primary UTUC and are likely to seed into the bladder after tumor manipulation. This calls for effective strategies to prevent the spread of UTUC. The methods we discuss here are the use of a ureteral access sheath during diagnostic ureteroscopy, application and timing of intravesical chemoprophylaxis, early ureteral ligation distal to UTUC, and formal bladder cuff excision. Urologic surgeons should aim to achieve a reduced rate of IVR when applying these techniques.

Keywords

Chemoprophylaxis
Nephroureterectomy
Ureteroscopy
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pmc1. INTRODUCTION

Upper tract urothelial carcinoma (UTUC) accounts for approximately 5% of urothelial cancers, with an increasing incidence over the past 30 years [1]. The proportion of in situ UTUC in databases reportedly has grown from 7.2% during the 1970s to 31% at present [1]. It is likely that improved diagnostics and formal guidelines have contributed to earlier and more timely diagnosis and, as a result, a larger proportion of patients can be managed by urologic surgery [1].

UTUC has been traditionally treated with radical nephroureterectomy (RNU) and bladder-cuff excision (BCE). RNU remains the gold standard for bulky, high-grade, or invasive UTUC. Endoscopic ablation has emerged as a treatment option for low-grade UTUC while increasing alternatives of chemotherapy and immunotherapy are available for patients requiring systemic therapy [2-4].

Even after management, however, UTUC is associated with the development of urothelial carcinoma in the bladder in 23 – 50% of the patients [5-8]. A wide array of risk factors has been reported to be responsible for intravesical recurrence (IVR) following UTUC. Patient factors, such as female gender and active tobacco use, pathological factors, including tumor size, focality, stage, and grade, and treatment variables, such as incomplete distal ureteral resection and post-operative systemic chemotherapy, all have been suggested as potential risks for IVR [5-7,9]

In reality, some of the associated risks are non-modifiable. However, emerging research underscored certain strategies related to all urologic practices that could reduce IVR following UTUC surgery. In this paper, we present and discuss practical approaches to reduce IVRs following ureteroscopy (URS) and RNU.

2. CLONALITY

A question presents itself: Are bladder tumors clonally related to antecedent UTUC cancer? Two theories have been proposed to explain the high rates of recurrence of UC in the bladder after treatment of UTUC (through either URS or RNU). One theory, called “field change,” proposes that panurothelial genetic mutations are present either congenitally, from infection, or toxin exposure, and render the entire urothelium independently susceptible to further mutations leading to cancer [10,11]. This could account for UC forming in both the upper and lower urinary tracts [11,12]. The other theory postulates that UTUC cells are displaced into the ureteral lumen during manipulation and instrumentation and seeded downstream into the bladder to cause UC in the bladder [11,12]. The rationale behind this theory is, in part, supported by the timing of the development of IVR after UTUC procedures, and by the occurrence of multifocal UTUC in an ipsilateral ureter, which suggests local spread. In addition, high-grade UTUC is associated with a five-fold increased rate of high-grade bladder recurrence, suggesting a possible clonal relationship between the upper and lower tract cell lines [5].

This origin of the IVR cancer cells has been studied by Audenet et al., who compared genetic mutations of three cohorts of tumors: urothelial carcinoma of the bladder alone, UTUC alone, and bladder carcinoma occurring after UTUC treatment [12]. The study reported differences between UTUC and bladder UC in certain genes, such as HRAS, FGFR3, TP52, ERBB2, and RB1 [12]. Notably, however, in the 29 patients with prior UTUC and subsequent bladder cancer, 86% of somatic mutations were present in both tumors [12]. These observations imply a high likelihood of clonal relatedness [12].

Similarly, Van Doeveren et al. found recurrent bladder cancer originated from UTUC cell lines by analyzing a panel of 41 genes and comparing tumor tissue to normal tissue in post-RNU patients [11]. The tumor tissue of the UTUC and recurrent bladder lesions shared specific DNA mutations, indicating a clonal relation in 11 out of 15 patients (73%) [11]. The authors concluded that the need for diagnostic URS should be carefully considered before RNU due to the risk of seeding cancer cells into the bladder [11]. They also called for steps to be taken during RNU to minimize the displacement of upper tract cells into the bladder and for intravesical chemotherapy to be administered perioperatively to minimize the viability of any potentially seeded cancer cells [11].

3. IVRS FOLLOWING URS FOR UTUC

There is concern about seeding cancer cells intraluminally through URS and associated endoscopic therapies for UTUC [13,14]. The majority of data regarding URS seeding was from patients who underwent RNU either with or without a prior diagnostic URS (d-URS). One such study found that d-URS had an odds ratio of 4.0 (95% CI [1.4 – 11.9], P = 0.01) for recurrence of cancer in the bladder [15]. Another similar study noted a hazard ratio of 5.6 (95% CI [1.7 – 18.5], P < 0.004) for d-URS before RNU [8]. One meta-analysis observed an IVR range of 39.2 – 60.7% with d-URS and a range of 16.7 – 46% without d-URS [16]. Due to the risks of cancer dissemination, it is recommended to avoid performing URS and instrumenting a normal contralateral ureter when performing d-URS for suspected UTUC [4].

Diagnostic URS has immense value in the evaluation of UTUC. Endoscopy provides key diagnostic information, including tumor appearance, focality, size, and pathological information (if biopsied). However, the approach to diagnosis and management of UTUC cannot be dogmatic. Certain clinical scenarios may preclude URS or render the risk of URS to outweigh the benefit. For example, when it comes to ureteral stricture disease, the risk of ureteral perforation exists and diagnosis may be better achieved by upper tract cytology through renal barbotage along with high-quality cross-sectional imaging of the tumor [4]. The AUA 2023 UTUC guidelines state that there are cases for which URS evaluation is not necessary and give the following examples: (1) high-grade selective cytology or another source of tissue diagnosis; (2) radiographic findings strongly indicating high-grade disease, such as an obvious enhancing, urothelial-based soft-tissue filling defect on contrast-enhanced imaging with urography; and (3) URS findings will not influence decision making, such as patients who are not willing or able to undergo treatment for UTUC [4]. Proceeding directly to RNU is permitted in the AUA and EAU guidelines in cases strongly suspected of high-grade disease based on cytological and imaging criteria even in the absence of pathohistological results [4,17].

Interestingly, a lower recurrence rate has been reported with d-URS using a ureteral access sheath (11.5% with sheath vs. 39.7% without sheath) [8]. In a single study, when a sheath was used, multivariate analysis revealed that the risk of d-URS for bladder cancer was mitigated, though insignificantly (HR 1.3, [0.3 – 6.4], P = 0.76) [8]. Therefore, although the evidence is limited, it is advisable to use a ureteral access sheath when performing d-URS for suspected UTUC. The rationale is two-fold. First, as discussed above, this can potentially decrease downstream bladder recurrences. Second, ureteral access sheath likely decreases intrapelvic pressures which may cause seeding of UTUC through pyelovenous backflow [16,18]. Importantly, the latter consideration remains theoretical. Indeed, Nison et al. found that d-URS did not impact extravesical recurrence in a multicenter study of 500 patients [16,18]. In either case, judicious use of a ureteral access sheath for UTUC d-URS is recommended whenever feasible [8]. Importantly, it is critical to first evaluate the ureter before sheath placement. Specifically, we recommend that urologists perform free-hand diagnostic URS to first evaluate the entire length of the ureter before sheath placement. Such a practice allows for adequate characterization of ureteral disease and avoids disruption of tissue architecture when a ureteral tumor is present. If a ureteral disease exists, an access sheath may still facilitate ureteroscopic intervention although the sheath must remain distal to the tumor site.

Limited data are available regarding IVR rates when placing a stent following diagnostic URS. Lee et al. found no significant difference in IVR-free survival when a stent was placed in a 41-patient retrospective cohort, with 53% receiving a stent following d-URS [19]. Our practice is similar to the management of urinary stone disease. Namely, the use of stents should be predicated on the clinical scenario. We believe that the management of ureteral tumors benefits from a ureteral stent for some duration (3 – 14 days), given the inherent edema that may occur post-procedure. Conversely, an uncomplicated treatment of a renal pelvic or calyceal lesion in an unobstructed system may not require temporary stenting. Future studies investigating the impact of stent placement on IVR rates would be of benefit.

The potential for intraluminal seeding from endoscopic ablation surgery for UTUC has not been well studied. Many cohort studies included a mix of UTUC disease with respect to grade, focality, and location, all of which could confound bladder recurrence rates. However, we can assume, for now, that the risks of IVR are at least equal to those of d-URS [20]. In a pooled analysis of the literature, Petros et al. noted a bladder cancer recurrence rate standing between 40% and 50% [20]. To minimize this risk, following tumor ablation and after ensuring there is no perforation of the upper or lower tracts, urologists may give one dose of pelvicalyceal or intravesical chemoprophylactic agent immediately after operation to kill displaced UTUC cells in the lumen of the ureter and bladder [4]. At present, there is no specific consensus on the specific drug type, instillation method, or dosing frequency. However, these authors believe that either 2 g of gemcitabine in 100 cc normal saline or 1 g of mitomycin-C in 50 cc normal saline post-URS are practical adjuvant therapies. Given the increase in low-grade cancer and strong recommendations of endoscopic ablation for low-grade UTUC by the AUA and EAU guidelines, more research is needed in this area [1,4].

4. IVRS FOLLOWING RNU

Recurrence of UC in the bladder after nephroureterectomy is attributable to multiple risks, including patient-specific factors (e.g., smoking at the time of diagnosis), tumor-specific factors (e.g., tumor grade/stage/size), and treatment-specific factors (e.g., surgical techniques). Of these, urological oncologists are most equipped to optimize the treatment-specific factors in an effort to reduce recurrence rates in the bladder. We discuss certain techniques that can be implemented to minimize the chances of recurrence due to surgical management.

The dissemination of UTUC to the bladder during RNU is likely due to kidney manipulation causing intraluminal displacement and drainage into the lower tract [21-23]. Retrospective studies of open versus laparoscopic RNU suggested that the surgical approach alone exerted little to no impact on IVR rates. Notably, one study found that the laparoscopic approach had a slightly higher IVR, possibly due to high abdominal pressure during laparoscopic approaches increasing flow into the lower tract [21-25]. In both open and minimally invasive approaches, early ureteral ligation is a key method used to reduce this risk. Specifically, the ureter is ligated immediately on gaining access to the retroperitoneal space and before ligating the renal artery [21]. This was studied in a prospective, multicenter trial by Yamashita et al. and the rate of IVR was 36% in the control group against 23% in the early ureteral ligation group [21]. In this study, the benefit was most notable for renal pelvic UTUC tumors. Admittedly, the efficacy of early ureteral ligation in UTUC of the ureter may be limited. Here, if the ureter is ligated cephalad to the tumor site, cancer cells can still migrate into the lower tract and adhere to the injured urothelium near the cystotomy site. Thus, it is advised to ligate below the tumor whenever possible [21,26].

Another method that urologists should focus on to lower IVR is adequate bladder cuff excision, which is recommended during RNU for the purpose of avoiding incomplete ureterectomy and subsequent IVR [4]. In other words, it is imperative not to leave any component of the ipsilateral upper urinary tract in situ. Multiple large retrospective studies have found high rates of IVR with incomplete bladder cuff excision, one of which reported a hazard ratio of 3.536 (95% CI, [2.245 – 5.568]) [27,28]. The approach for BCE can be extravesical, transvesical, or a combined endoscopic “pluck” technique [4,29]. The “pluck” technique has been criticized by some for possible tumor seeding through endoscopic manipulation, and mixed evidence showed that this technique had higher rates of IVR [4,29-31]. The extravesical and transvesical approaches are preferable given that they do not raise such concern, provided that the excision has achieved clean margins and the bladder is closed in a water-tight fashion to allow for the use of intravesical chemoprophylaxis [10]. Our personal practice uses an extravesical approach for lesions above the iliac vessels, whereas a transvesical approach is preferred for lesions below the iliac vessels.

Another method to reduce IVR is to instill a single dose of intravesical chemotherapeutic agent (mitomycin-C, gemcitabine, or pirarubicin) perioperatively when performing RNU or segmental ureterectomy [4,32,33]. While only half of urological oncologists endorsed administering bladder chemoprophylaxis after RNU in a 2016 survey, the data for use are quite compelling with current guidelines now supporting such treatment through a strong recommendation [4,34]. A large, prospective, randomized, and non-blinded control trial out of the United Kingdom by O’Brien et al. demonstrated an 11% absolute risk reduction and a 40% relative risk reduction in IVR after one dose of mitomycin-C was instilled into the bladder postoperatively after RNU [32]. A phase two clinical trial by Ito et al. yielded an IVR of 16.9% 2 years after pirarubicin treatment was administered postoperatively compared with 42.2% IVR in the control group [33]. A Cochrane database review similarly found a reduced risk of bladder cancer recurrence using bladder chemoprophylaxis over time, with a hazard ratio of 0.51 (95% CI: 0.32 – 0.82) [35]. Some urologists are also using gemcitabine due to its efficacy on UC of the bladder. However, the chemotherapeutic agent has not been formally studied prospectively in the context of preventing UTUC IVR [4,36-38]. Potential advantages of gemcitabine are as follows: (1) it is less likely to cause chemical peritonitis in the event of extravesical extravasation; (2) it does not require alkalization of the urine; (3) it is relatively cheaper; and (4) it is easy to formulate by hospital pharmacies [4,37,38].

The timing of using bladder chemoprophylaxis in the context of RNU varies with institutions. There is some evidence that intraoperative bladder chemoprophylaxis is safe and associated with lower bladder recurrence rates compared to post-operative administration. These observations are comparable to the decreased recurrence of low-grade bladder cancers that are well-established with immediate administration following resection [39-41]. Our practice involves instilling 2 g of gemcitabine in 100 cc normal saline into the bladder through a catheter clamped for the first 90 – 120 min of the RNU until the ureter is ligated distal to the tumor. Thereafter, the bladder may be drained with no additional chemoprophylaxis. One dose of chemoprophylaxis is thought to be sufficient to kill any displaced UTUC in the bladder lumen and this is supported by a study in which maintenance intravesical chemotherapy did not impact the rates of bladder recurrence compared to a single perioperative dose within 48 h of RNU [42].

5. CONCLUSIONS

Multiple factors impacting rates of IVR can be altered by practicing urologists. Such proactive strategies include the use of a ureteral access sheath during diagnostic URS, the use and timing of intravesical chemoprophylaxis, early ureteral ligation distal to UTUC, and formal bladder cuff excision. Surgeons employing each of these measures should appreciate the benefit of lower rates of IVR. Close surveillance after RNU is still required. Prospective data of recurrence rates after intraoperative bladder chemoprophylaxis are needed to recommend this practice more strongly. Further studies are regarding IVR after endoscopic ablation are also warranted since this technique is now strongly recommended for the treatment of low-grade UTUC.

ACKNOWLEDGMENTS

None.

FUNDING

This study is supported by The Ken and Bonnie Shockey Fund for Urologic Oncology Research at Penn State Health (grant no.: 3112410001).

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

Conceptualization: Jay D. Raman

Investigation: All authors

Methodology: All authors

Writing – original draft: All authors

Writing – review & editing: All authors

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA

Not applicable.
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REFERENCES

1. Raman JD Messer J Sielatycki JA Hollenbeak CS . Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int 2011;107 (7 ):1059–1064. doi:10.1111/j.1464-410X.2010.09675.x 20825397
2. Wu YP Lin YZ Lin MY . Risk factors for bladder cancer recurrence survival in patients with upper-tract urothelial carcinoma. Tumori J 2018;104 (6 ):451–458. doi:10.5301/tj.5000705
3. Leow JJ Liu Z Tan TW Lee YM Yeo EK Chong YL . Optimal management of upper tract urothelial carcinoma:Current perspectives. Onco Targets Ther 2020;13 :1–15. doi:10.2147/OTT. S225301 32021250
4. Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma:AUA/SUO Guideline. American Urological Association. Available from: https://www.auanet.org/guidelines-and-quality/guidelines/non-metastatic-upper-tract-urothelial-carcinoma [Last accessed on 2024 May 28]
5. Raman JD Ng CK Boorjian SA Vaughan ED Jr Sosa RE Scherr DS . Bladder cancer after managing upper urinary tract transitional cell carcinoma:Predictive factors and pathology. BJU Int 2005;96 (7 ):1031–1035. doi:10.1111/j.1464-410X.2005.05804.x 16225523
6. Koga F Nagamatsu H Ishimaru H Mizuo T Yoshida K . Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 2001;67 (2 ):135–141. doi:10.1159/000050969 11490207
7. Hisataki T Miyao N Masumori N . Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 2000;55 (5 ):663–667. doi:10.1016/s0090-4295(99)00563-4 10792075
8. Douglawi A Ghoreifi A Lee R . Bladder recurrence following diagnostic ureteroscopy in patients undergoing nephroureterectomy for upper tract urothelial cancer:Is ureteral access sheath protective?. Urology 2022;160 :142–146. doi:10.1016/j.urology.2021.11.026 34929237
9. Matsui Y Utsunomiya N Ichioka K . Risk factors for subsequent development of bladder cancer after primary transitional cell carcinoma of the upper urinary tract. Urology 2005;65 (2 ):279–283. doi:10.1016/j.urology.2004.09.021 15708038
10. Harris AL Neal DE . Bladder cancer--Field versus clonal origin. N Engl J Med 1992;326 (11 ):759–761. doi:10.1056/NEJM199203123261108 1738381
11. Van Doeveren T Nakauma-Gonzalez JA Mason AS . The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder. Int J Cancer 2021;148 (4 ):981–987. doi:10.1002/ijc.33327 33006377
12. Audenet F Isharwal S Cha EK . Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res 2019;25 (3 ):967–976. doi:10.1158/1078-0432.CCR-18-2039 30352907
13. Kauffman EC Raman JD . Bladder cancer following upper tract urothelial carcinoma. Expert Rev Anticancer Ther 2008;8 (1 ):75–85. doi:10.1586/14737140.8.1.75 18095885
14. Knoedler JJ Raman JD . Advances in the management of upper tract urothelial carcinoma:Improved endoscopic management through better diagnostics. Ther Adv Urol 2018;10 (12 ):421–429. doi:10.1177/1756287218805334 30574202
15. Baboudjian M Al-Balushi K Michel F . Diagnostic ureteroscopy prior to nephroureterectomy for urothelial carcinoma is associated with a high risk of bladder recurrence despite technical precautions to avoid tumor spillage. World J Urol 2020;38 (1 ):159–165. doi:10.1007/s00345-019-02768-w 30993427
16. Marchioni M Primiceri G Cindolo L . Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer:A systematic review and meta-analysis. BJU Int 2017;120 (3 ):313–319. doi:10.1111/bju.13935 28621055
17. EAU Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma - DISEASE MANAGEMENT - Uroweb. Uroweb - European Association of Urology. Available from: https://uroweb.org/guidelines/upper-urinary-tract-urothelial-cell-carcinoma/chapter/disease-management [Last accessed on 2024 May 31]
18. Nison L Rouprêt M Bozzini G . The oncologic impact of a delay between diagnosis and radical nephroureterectomy due to diagnostic ureteroscopy in upper urinary tract urothelial carcinomas:Results from a large collaborative database. World J Urol 2013;31 (1 ):69–76. doi:10.1007/s00345-012-0959-1 23070533
19. Lee JK Kim KB Park YH . Correlation between the timing of diagnostic ureteroscopy and intravesical recurrence in upper tract urothelial cancer. Clin Genitourin Cancer 2016;14 (1 ):e37–e41. doi:10.1016/j.clgc.2015.07.008 26459040
20. Petros FG Li R Matin SF . Endoscopic approaches to upper tract urothelial carcinoma. Urol Clin North Am 2018;45 (2 ):267–286. doi:10.1016/j.ucl.2017.12.009 29650142
21. Yamashita S Ito A Mitsuzuka K . Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma:A prospective single-arm multicenter clinical trial. Jpn J Clin Oncol 2017;47 (9 ):870–875. doi:10.1093/jjco/hyx085 28903527
22. Azémar MD Comperat E Richard F Cussenot O Rouprêt M . Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma:Frequency, risk factors, and surveillance. Urol Oncol 2011;29 (2 ):130–136. doi:10.1016/j.urolonc.2009.06.003 19762256
23. Xylinas E Kluth L Passoni N . Prediction of intravesical recurrence after radical nephroureterectomy:Development of a clinical decision-making tool. Eur Urol 2014;65 (3 ):650–658. doi:10.1016/j.eururo.2013.09.003 24070577
24. Shimura S Matsumoto K Ikeda M . A multi-institutional retrospective study of open versus laparoscopic nephroureterectomy focused on the intravesical recurrence. Asia Pac J Clin Oncol 2023;19 (1 ):71–78. doi:10.1111/ajco.13684 35404494
25. Favaretto RL Shariat SF Chade DC . Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients:Are recurrence and disease-specific survival associated with surgical technique?. Eur Urol 2010;58 (5 ):645–651. doi:10.1016/j.eururo.2010.08.005 20724065
26. See WA Miller JS Williams RD . Pathophysiology of transitional tumor cell adherence to sites of urothelial injury in rats:Mechanisms mediating intravesical recurrence due to implantation. Cancer Res 1989;49 (19 ):5414–5418 2766306
27. Kang M Jeong CW Kwak C Kim HH Ku JH . The characteristics of recurrent upper tract urothelial carcinoma after radical nephroureterectomy without bladder cuff excision. Yonsei Med J 2015;56 (2 ):375–381. doi:10.3349/ymj.2015.56.2.375 25683984
28. Hou CP Chang PL Chen CL Lin YH Tsui KH . Does adequate bladder cuff excision impact outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma. Chang Gung Med J 2011;34 (5 ):496–505 22035894
29. Braun AE Srivastava A Maffucci F Kutikov A . Controversies in management of the bladder cuff at nephroureterectomy. Transl Androl Urol 2020;9 (4 ):1868–1880. doi:10.21037/tau.2020.01.17 32944551
30. Smith AK Lane BR Larson BT . Does the choice of technique for management of the bladder cuff affect oncologic outcomes of nephroureterectomy for upper tract urothelial cancer?. J Urol 2009;181 (4S) :133–134. doi:10.1016/S0022-5347(09)60385-2
31. Xylinas E Rink M Cha EK . Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol 2014;65 (1 ):210–217. doi:10.1016/j.eururo.2012.04.052 22579047
32. O'Brien T Ray E Singh R Coker B Beard R . British Association of Urological Surgeons Section of Oncology Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma:A prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol 2011;60 (4 ):703–710. doi:10.1016/j.eururo.2011.05.064 21684068
33. Ito A Shintaku I Satoh M . Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma:The THP Monotherapy Study Group Trial. J Clin Oncol 2013;31 (11 ):1422–1427. doi:10.1200/JCO.2012.45.2128 23460707
34. Lu DD Boorjian SA Raman JD . Intravesical chemotherapy use after radical nephroureterectomy:A national survey of urologic oncologists. Urol Oncol 2017;35 (3 ):113.e1–113.e7. doi:10.1016/j.urolonc.2016.10.016
35. Hwang EC Sathianathen NJ Jung JH Kim MH Dahm P Risk MC . Single-dose intravesical chemotherapy after nephroureterectomy for upper tract urothelial carcinoma. Cochrane Database Syst Rev 2019;5 (5 )CD013160. doi:10.1002/14651858.CD013160.pub2
36. Messing EM Tangen CM Lerner SP . Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence:SWOG S0337 randomized clinical trial. JAMA 2018;319 (18 ):1880–1888. doi:10.1001/jama.2018.4657 29801011
37. Addeo R Caraglia M Bellini S . Randomized Phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer:Evaluation of efficacy and tolerance. J Clin Oncol 2010;28 (4 ):543–548. doi:10.1200/JCO.2008.20.8199 19841330
38. Freifeld Y Ghandour R Singla N . Intraoperative prophylactic intravesical chemotherapy to reduce bladder recurrence following radical nephroureterectomy. Urol Oncol 2020;38 (9 ):737.e11–737.e16. doi:10.1016/j.urolonc.2020.05.002
39. Moriarty MA Uhlman MA Bing MT . Evaluating the safety of intraoperative instillation of intravesical chemotherapy at the time of nephroureterectomy. BMC Urol 2015;15 (1 ):45. doi:10.1186/s12894-015-0039-0 26018765
40. Noennig B Bozorgmehri S Terry R Otto B Su LM Crispen PL . Evaluation of intraoperative versus postoperative adjuvant Mitomycin C with nephroureterectomy for urothelial carcinoma of the upper urinary tract. Bladder Cancer 2018;4 (4 ):389–394. doi:10.3233/BLC-180174 30417049
41. Bosschieter J Nieuwenhuijzen JA van Ginkel T . Value of an immediate intravesical instillation of Mitomycin C in patients with non-muscle-invasive bladder cancer:A prospective multicentre randomised study in 2243 patients. Eur Urol 2018;73 (2 ):226–232. doi:10.1016/j.eururo.2017.06.038 28705539
42. Harraz AM El-Shabrawy M El-Nahas AR El-Kappany H Osman Y . Single versus maintenance intravesical chemotherapy for the prevention of bladder recurrence after radical nephroureterectomy for upper tract urothelial carcinoma:A randomized clinical trial. Clin Genitourin Cancer 2019;17 (6 ):e1108–e1115. doi:10.1016/j.clgc.2019.07.019 31594736
