Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy

Authors

  • Brian R. Lane MD, PhD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
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  • Armine K. Smith MD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
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  • Benjamin T. Larson MD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
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  • Michael C. Gong MD, PhD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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  • Steven C. Campbell MD, PhD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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  • Derek Raghavan MD, PhD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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  • Robert Dreicer MD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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  • Donna E. Hansel MD, PhD,

    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
    3. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio
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  • Andrew J. Stephenson MD

    Corresponding author
    1. Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio
    2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
    • Glickman Urological & Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue, Q10-1, Cleveland, OH 44195
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    • Fax: (216) 636-4492


Abstract

BACKGROUND:

The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under-developed, this has important implications on patients' ability to receive cisplatin-based combination chemotherapy (CBCC).

METHODS:

Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m2 was used to determine the presence of CKD and eligibility for CBCC.

RESULTS:

Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m2. Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2-pT4 and/or pN1-pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively.

CONCLUSIONS:

CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high-risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy. Cancer 2010. © 2010 American Cancer Society.

Upper tract urothelial carcinoma (UTUC) includes urothelial malignancies occurring within the renal pelvis and ureter. These tumors account for approximately 5% of all urinary tract cancers, which occur far more commonly in the bladder.1 Although UTUC commonly present as high-grade and advanced stage cancers, multimodality treatment paradigms for this malignancy are underdeveloped because of its low incidence and the paucity of data from randomized trials. As such, the standard treatment of UTUC is surgical excision by nephroureterectomy (NU), or distal ureterectomy in select patients with distal ureteral tumors. Oncologic outcomes following definitive surgical management of high-grade and/or muscle-invasive UTUC have been poor, with estimates of cancer-specific survival ranging between 60% and 80% at 5 years.2-4

The relatively poor outcomes of NU for invasive UTUC may be because of a multitude of factors, including delays in diagnosis and treatment, more aggressive tumor biology, and inferior treatment strategies. Regarding the latter, there is increasing evidence that the removal of an increasing number of lymph nodes at the time of radical cystectomy for invasive bladder cancer leads to improved survival.5-7 In contrast, retroperitoneal or pelvic lymph node dissection is not uniformly performed for UTUC.2, 3, 8-10 Likewise, the management of patients with invasive bladder cancer at risk for recurrence typically involves radical cystectomy and perioperative cisplatin-based combination chemotherapy (CBCC), in either the neoadjuvant or the adjuvant setting. Few patients with UTUC receive neoadjuvant or adjuvant CBCC and there is a paucity of evidence in the literature (either from retrospective series or clinical trials) of a benefit.2, 3, 8-10

The use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy for invasive bladder cancer before definitive local treatment confers an approximately 7% absolute improvement in overall survival compared with cystectomy or primary radiotherapy alone.5-7 Although similar evidence in support of adjuvant CBCC is lacking, many in the genitourinary oncology community extrapolate from the neoadjuvant MVAC experience and hypothesize that the benefits of CBCC are likely to be similar if it is administered in the adjuvant setting. By the same logic, perioperative CBCC for UTUC is frequently deferred to the adjuvant setting, particularly given the inability to document the presence of invasive UTUC before NU.

The decline in estimated glomerular filtration rate (eGFR) caused by NU may render a substantial number of patients ineligible to receive CBCC if it is deferred to the adjuvant setting. Patients undergoing radical nephrectomy for renal cell carcinoma have a significantly increased risk of chronic kidney disease (CKD; defined as eGFR less than 60 mL/min/1.73 m2) compared with those treated by nephron-sparing surgery.11 In a recent study, 26% of kidney cancer patients had CKD preoperatively, which increased to 65% postoperatively for those treated by radical nephrectomy.11 The prevalence of CKD in the UTUC patient population, before and after nephrouretectomy, is poorly defined. Compared with the renal cell carcinoma population, patients with UTUC are typically older and have a higher prevalence of comorbid medical conditions, often related to tobacco use, which may compromise renal function. Likewise, some patients may have compromised renal function because of obstructive uropathy caused by the UTUC itself. In some populations, analgesic nephropathy is the cause of UTUC, again with compromise of renal function. Thus, the presence of pre-existing and NU-induced CKD may have important implications on patients' ability to receive perioperative CBCC. Patients who are unable to receive CBCC may have compromised survival based on the inferiority of carboplatin versus cisplatin in the management of advanced urothelial carcinoma.12

In the present study, we evaluated the renal function of patients with UTUC before and after NU to determine the proportion of patients with optimal renal function to be considered for CBCC.

MATERIALS AND METHODS

Between 1992 and 2008, 470 patients with known or suspected urothelial carcinoma of the renal pelvis and/or ureter were treated at Cleveland Clinic (Cleveland, Ohio) by NU, ureterectomy, nephron-sparing surgery, and/or endoscopic resection. The focus of this study is 336 patients who underwent NU for UTUC and had sufficient data for analysis of renal function and oncologic outcomes. Patients undergoing partial nephrectomy (n = 8), ureterectomy without nephrectomy (n = 18), endoscopic resection (n = 48), or having incomplete data (n = 60) were excluded. A subgroup of patients at high risk for recurrence (n = 144) was identified based on the presence of muscle-invasive UTUC and/or lymph node-positive disease at the time of NU. Patient information and follow-up data were obtained from an institutional review board-approved database.

Pathologic staging was performed according to the 2002 American Joint Committee on Cancer guidelines based on archived pathology reports. Selected cases were re-reviewed by a genitourinary pathologist to determine stage, grade, and the presence of lymphovascular invasion when not initially available. All postoperative creatinine levels and clinical information pertaining to renal function were obtained from the electronic medical records, contact with referring physicians, or patient-completed questionnaires. Preoperative creatinine levels were obtained within 1 month of NU and the lowest creatinine level obtained within 3 months after NU or before initiation of any adjuvant therapy was selected as the postoperative creatinine level.13 The eGFR was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation (GFR in ml per minute per 1.73 m2 = 186 × sCr−1.154 × age−0.203 × (0.742 if female) × (1.210 if black).14 CKD was defined as eGFR <60 mL/minute/1.73m,2 according to National Kidney Foundation guidelines.15, 16

The preferred initial treatment approach for patients with UTUC at Cleveland Clinic during the time period of this study was definitive surgical resection with or without lymphadenectomy. The decision to perform a lymph node dissection and extent of this dissection varied widely according to surgeon preference and technique. Only those patients with locally advanced disease were considered for neoadjuvant chemotherapy. Adjuvant chemotherapy was administered only to patients with advanced pathological features (≥pT2 or pN1-pN3) and who had adequate health and renal function to receive it. However, among these patients, the decision to administer adjuvant chemotherapy was left to the discretion of the treating physician and no standardized protocols were employed at our institution during this time period. In general, patients were followed postoperatively with regular clinical assessments, cystoscopy, urinary cytology, renal function determinations, and imaging studies of the chest, abdomen, and pelvis. Survival was determined by chart review and telephone contact, and death from any cause was verified using the Social Security death index.17

Statistical analyses were performed by using JMP version 8.0 (SAS, Cary, NC). Kaplan-Meier survival methodology was used to generate survival estimates and curves. The Mann-Whitney U test was used to compare nonparametric continuous data and chi-square and Fisher exact tests to compare nominal data. The study was conducted according to Health Insurance Portability and Accountability Act guidelines and received institutional review board approval.

RESULTS

Data on 336 patients that underwent NU are depicted in Table 1. Median age was 72 years (interquartile range [IQR], 62-78) and 79% of patients had no or minimal comorbidity (Charlson comorbidity index = 0 or 1). Overall, high-risk features (as defined by the presence of muscle-invasive disease and/or lymph node metastasis) were present in 144 patients (43%). At histological analysis, high-grade UTUC was present in 75% and stage was Ta/Tis, T1, and T2 or higher in 35%, 21%, and 45% of patients, respectively. Retroperitoneal and/or pelvic lymph node dissection was performed in 78 (23%) patients, and 32 (41%) of these patients had lymph node metastasis (10% overall). Over a median follow-up of 19 months (IQR, 5-42), 154 patients (46%) died, 94 of whom died from progressive UTUC. Overall, the median and 3-year survival were 42 months (95% confidence interval [CI), 33-51) and 54% (95% CI, 48-61), respectively. Considering only those patients with high-risk features, the median and 3-year survival were 16 months (95% CI, 12-20) and 19% (95% CI, 5-33), respectively. For patients with or without preoperative CKD, the median survival and 3-year survival were 37 months (95% CI, 29-44) and 51% (95% CI, 42-59) and 64 months (95% CI, 34-104) and 58% (95% CI, 49-68), respectively (P = .007).

Table 1. Characteristics of Patients Undergoing NU for UTUC
 All Patients N=336Potential Candidates for CBCCa n=144
No. (%)No. (%)
  • NU indicates nephroureterectomy; UTUC, upper tract urothelial carcinoma; CBCC, cisplatin-based combination chemotherapy; IQR, interquartile range.

  • Data unavailable for grade (n=25), stage (n=24), LVI status (n=50).

  • a

    Defined as pT2-pT4 and/or pN1-pN3.

Median age, years [IQR]72 [62-79]73 [63-79]
No. of males241 (72)107 (74)
Race  
 Caucasian314 (93)135 (94)
 African American12 (4)4 (3)
 Other10 (3)5 (3)
No. with Charlson Comorbidity Index  
  0183 (54)76 (53)
  185 (25)37 (26)
  >168 (21)31 (21)
No. with prior history of bladder cancer126 (37)46 (40)
  Previous cystectomy12 (4)12 (8)
No. of laparoscopic procedures207 (62)87 (60)
High grade234 (75)142 (99)
Tumor stage  
 pTa/pTis108 (35)3 (2.1)
 pT165 (21)2 (1.4)
 pT236 (12)36 (25)
 pT375 (24)75 (52)
 pT428 (9)28 (19)
Positive surgical margins30 (9)27 (19)
Lymphovascular invasion83 (25)75 (52)
Lymph node metastases at time of surgery32 (10)32 (22)
Positive metastases at time of surgery11 (3)11 (8)
Median follow up, years [IQR]1.5 [0.4-3.5]1.2 [0.5-2.8]
No. receiving any neoadjuvant treatment108
No. receiving any adjuvant treatment4341
No. of deaths154 (46)101 (70)
 No. cancer-specific deaths94 (28)73 (51)

Overall, 8 (2%) patients received neoadjuvant chemotherapy (Table 2), which consisted of CBCC in only 3 (<1% of UTUC patients). Adjuvant chemotherapy was administered to 43 patients (13% of all patients, 30% of high-risk patients). Specific adjuvant regimens included CBCC in 11 patients, carboplatin-based regimens in 18, and other regimens in 6 (Table 2).

Table 2. Neoadjuvant and Adjuvant Treatments Used in Patients Undergoing NU for UTUC
 Neoadjuvant (n=8)Adjuvant (n=43)
  • NU indicates nephroureterectomy; UTUC, upper tract urothelial carcinoma.

  • a

    1 patient each also received chemotherapy with a cisplatin-based, carboplatin-based, or unknown regimen.

  • b

    1 patient also received 2 cycles of neoadjuvant gemcitabine after completing 6 cycles of the initial regimen.

  • c

    1 patient each received neoadjuvant immunotherapy for presumed renal cell carcinoma, adjuvant bone marrow transplant, and adjuvant doxitaxel/temozolomide.

Radiotherapya04
Systemic chemotherapy  
Cisplatin-based regimen311
 Methotrexate/vinblastine/doxorubicin/cisplatin13
 Gemcitabine/cisplatin26
 Cisplatin/paclitaxel02
Carboplatin-based regimen417
 Paclitaxel/carboplatin411
 Gemcitabine/carboplatinb05
 Etoposide/carboplatin01
Nonplatin-based regimen18
 Paclitaxel/gemcitabine02
 Paclitaxel02
 Gemcitabine02
Otherc12
 Unknown regimen06

The cancer-specific survival for patients with high-risk features was significantly reduced compared with those without high-risk features (3-year survival 31% [95% CI, 21-41] vs 86% [95% CI, 79-93]; P < .001) (Fig. 1). The cancer-specific survival for high-risk patients treated with and without adjuvant chemotherapy was not significantly different (21% [95% CI, 7-34] vs 33% [95% CI, 22-43]; P = .7).

Figure 1.

Cancer-specific survival of patients undergoing NU for UTUC according to risk status is depicted. Low-risk subgroup (red) included patients with pT0 to pT1 disease at NU. High-risk subgroup (blue) included patients with pathologic evidence of stage ≥pT2 disease at NU (including those with positive locoregional metastases) and those who underwent radical cystectomy for UC and, therefore, might be considered for neoadjuvant chemotherapy. NU indicates nephroureterectomy; UTUC, upper tract urothelial carcinoma.

Preoperative and postoperative eGFR are listed in Table 3. Median preoperative eGFR was 59 (IQR, 47-77). The overall proportion of patients ineligible to receive CBCC because of preoperative eGFR <60 mL/min/1.73m2 was 52%. Median postoperative eGFR was 48 mL/min/1.73m2 (IQR, 38-59) corresponding to a median 21% relative loss of renal function. The proportion of patients ineligible to receive adjuvant CBCC based on postoperative optimal eGFR <60 mL/min/1.73m2 increased significantly to 78% (P < .0001). Restricting the analysis to the 144 high-risk patients, who might appropriately be considered for CBCC, the proportions of ineligible patients before and after NU are 60% and 76%, respectively (P = .009). Thus, the opportunity to receive CBCC after NU was lost in 61% of patients (and 49% of high-risk patients) able to receive it preoperatively (Table 4).

Table 3. Renal Function of Patients Before and After NU for UTUC
 All Patients N=336Potential Candidates for CBCC n=144
  1. NU indicates nephroureterectomy; UTUC, upper tract urothelial carcinoma; eGFR, estimated glomerular filtration rate; IQR, interquartile range.

Median SCr prior to NU, mg/dL (IQR)1.2 (1.0-1.5)1.2 (1.0-1.5)
 No. with SCr>1.4 mg/dL87 (26%)43 (30%)
Median eGFR prior to NU, (IQR)59 (48-77)56 (45-74)
 No. with eGFR<60 mL/min/1.73m2174 (52%)87 (60%)
Median SCr after NU, mg/dL (IQR)1.4 (1.2-1.8)1.5 (1.1-1.8)
 No. with SCr>1.4 mg/dL169 (50%)68 (47%)
Median eGFR after NU, (IQR)48 (38-59)47 (37-60)
 No. with eGFR<60 mL/min/1.73m2261 (78%)109 (76%)
Median renal functional loss, % (IQR)21% (10%-35%)19% (0%-33%)
Table 4. Loss of Candidacy to Receive Cisplatin-Based Chemotherapy Following NU for UTUC
 Based on eGFR<60
All Patients N=336Potential Candidates for CBCC n=144
Candidate After NUNot a Candidate After NUCandidate After NUNot a Candidate After NU
  1. NU indicates nephroureterectomy; UTUC, upper tract urothelial carcinoma; eGFR, estimated glomerular filtration rate; CBCC, cisplatin-based combination chemotherapy.

Candidate before NU63992928
Not a candidate before NU12162681
Percentage losing candidacy after NU 61% (99/162) 49% (28/57)

DISCUSSION

CKD is associated with a significant increase in cardiovascular events and death from any cause, independent of competing comorbidities.18 CKD may also render patients ineligible to receive CBCC because of concerns of nephrotoxicity. Although CKD as a consequence of radical nephrectomy for renal cell carcinoma has been reported previously, the present study is the first to document and quantify the risk of CKD associated with NU for UTUC and the consequence of NU-induced eGFR decline in terms of the delivery of perioperative CBCC. In the present study, we demonstrate that CKD is present in 52% of patients with UTUC at the time of diagnosis. Following NU, a median 21% relative reduction in renal function was observed and the proportion of patients with CKD increased significantly to 78%. Based on a minimum eGFR of 60 mL/min/1.73m2 to receive CBCC, 61% of NU patients (and 49% of high-risk patients) were rendered ineligible to receive CBCC by NU. These findings have important implications for the management of patients with UTUC, as NU may eliminate a potentially important therapeutic option for patients at risk for metastatic cancer progression.

Because of concerns of nephrotoxicity, tolerability and/or ease of administration, carboplatin (or other agents) may be substituted for cisplatin in patients with urothelial carcinoma in need of chemotherapy. In the present series, CBCC was administered to only 3 of 8 patients (38%) receiving neoadjvuant therapy and 11 of 36 (31%) patients receiving adjuvant therapy. However, carboplatin-based and other noncisplatin based regimens are widely considered to be inferior to MVAC and gemcitabine-cisplatin.12, 19-21 For example, in a randomized trial of MVAC versus methotrexate-vinblastine-carboplatin in patients with metastatic UC, a significantly reduced cancer-specific survival was seen in patients receiving methotrexate-vinblastine-carboplatin (median 9 vs 16 months, P = .03).19 A single-study arm phase 2 trial of neoadjuvant paclitaxel-gemcitabine-carboplatin for muscle-invasive UC of the bladder also reported fewer pathologic complete responses than had been reported in other trials of neoadjuvant CBCC in similar patients.22 Thus, any substitution for CBCC as adjuvant therapy after NU for high-risk UTUC because of NU-induced eGFR decline is likely to lead to inferior results.

Given the lack of prospective trials of perioperative chemotherapy for UTUC, it is common practice to extrapolate from the bladder cancer experience as there is little evidence to suggest that UTUC differs biologically from UC of the bladder. The use of neoadjuvant CBCC before definitive local treatment for invasive UC of the bladder is supported by level I evidence of an overall survival benefit in a randomized trial by the Southwest Oncology Group and a meta-analysis of other randomized trials.5-7 In the former, a 25% and 40% relative risk reductions in all-cause and cancer-specific mortality, respectively, was observed in patients receiving 3 cycles of MVAC before radical cystectomy compared with radical cystectomy alone.5 A 5% absolute improvement in survival was also reported in a meta-analysis of 11 other phase 3 trials of neoadjuvant CBCC before radical cystectomy or primary radiotherapy.6, 7 Similar evidence for adjuvant chemotherapy for invasive UC of the bladder is lacking, although the existing trials have been limited by the use of suboptimal regimens, flawed methodology, and/or inadequate power.23-29

The use of perioperative chemotherapy for UTUC is controversial as there is no definitive evidence of a benefit but certain potential for toxicity. To our knowledge, there are currently no open or planned trials evaluating the role of neoadjuvant or adjuvant CBCC for UTUC. Thus, if 1 is to employ perioperative CBCC in the management of patients with UTUC, it must (by necessity) be based on extrapolation from the bladder cancer experience and the feasibility of its administration in the neoadjuvant or adjuvant setting. Regarding the latter issue, our results indicate that only 48% of patients have sufficient eGFR to receive neoadjuvant CBCC and this proportion decreases to only 22% after NU. Thus, if perioperative CBCC is to be given to patients with UTUC, it should be administered in the neoadjuvant setting as roughly 50% would be rendered ineligible to receive it if deferred to the adjuvant setting due to NU-induced CKD. Although it is difficult to establish the presence of muscle-invasive UTUC before NU, the presence of biopsy-proven, high-grade UTUC in the presence of a sizable mass on preoperative imaging may be sufficient evidence to justify neoadjuvant CBCC. The level I evidence in favor of neadjuvant CBCC for UC of the bladder (and lack of evidence of adjuvant CBCC) is further justification for administering perioperative CBCC for UTUC in the neoadjuvant setting.

Similar to previous reports, the outcome of patients with muscle-invasive and/or lymph node-positive UTUC was poor.2-4 Factors that may have contributed to the relatively poor outcome of these patients in our series and others was the under-utilization of a complete retroperitoneal and/or pelvic lymphadenectomy and perioperative CBCC. If perioperative CBCC is to be adopted as a standard treatment paradigm with NU for UTUC, it should ideally be supported by evidence from prospective clinical trials. Given the relative rarity of this disease, such a trial would require multi-institutional collaboration within the cooperative group or intergroup mechanisms. Based on the results of our study, it would also seem rational that the design of such a trial should include neoadjuvant (rather than adjuvant) CBCC. In the absence of such a trial, physicians must rely on the available evidence for the potential benefits and harms of perioperative CBCC when making treatment recommendations for patients with UTUC.

The impact of radical nephrectomy for renal cell carcinoma on the development of CKD has renewed the emphasis on nephron-sparing approaches for small renal masses. In a recent update of its treatment guidelines for small renal masses, the American Urological Association recommends nephron-sparing approaches whenever feasible.30 Given the incidence of pre-existing CKD in patients with UTUC and the substantial risk of NU-induced CKD, it is appropriate to reconsider the role of NU for all patients with UTUC. Tumors that are small, noninvasive, low-grade, and amenable to a complete resection or ablation may be effectively treated by the ureteroscopic approach (the risk of tumor seeding has limited the appeal of the percutaneous endoscopic approach). The development of smaller and more functional flexible ureteroscopes and laser fibers has facilitated the treatment and surveillance of UTUC. Currently, ureteroscopic management is generally considered only for patients with a solitary kidney, pre-existing CKD, or who are unfit to undergo NU. However, given the risk of CKD with NU and the low risk of progression associated with small, low-grade lesions, ureteroscopic laser ablation may be a reasonable alternative for these patients. However, given the inaccuracy of clinical grading and staging for UTUC and the risk of recurrence, close surveillance is mandatory for patients managed endoscopically.

CONCLUSION

In this retrospective analysis of a large case series of NU for UTUC, we observed that NU caused a 21% median relative reduction in renal function and that less than 50% of patients with sufficient renal function to receive CBCC preoperatively had sufficient renal function after NU to receive it postoperatively. The use of perioperative CBCC for UTUC is controversial. If 1 adopts a strategy of perioperative CBCC for UTUC, our study suggests that it should be administered in the neoadjuvant setting because of the decline in renal function caused by NU.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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