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Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma

Editorial comment from Piotr Chlosta: Results suggest that radical nephroureterectomy in addition to systemic chemotherapy may improve overall survival in patients with metastatic upper tract urothelial carcinoma.

Abstract

Given the growing body of evidence supporting the benefit of primary tumor control for a wide range of metastatic malignancies, we hypothesized that chemotherapy plus radical nephroureterectomy (RNU) is associated with an overall survival (OS) benefit compared to chemotherapy alone for metastatic upper tract urothelial carcinoma (mUTUC). Within the National Cancer Data Base (2004–2012), we identified 398 (38.4%) and 637 (61.6%) patients who received chemotherapy plus RNU and chemotherapy alone, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves showed that 3-yr OS was 16.2% (95% confidence interval [CI] 12.1–20.3) for chemotherapy plus RNU and 6.4% (95%CI 4.1–8.7) for chemotherapy alone (p < 0.001). In IPTW-adjusted Cox regression analysis, chemotherapy plus RNU was associated with a significant OS benefit (hazard ratio 0.70, 95% CI 0.61–0.80; p < 0.001). Despite the usual biases related to the observational study design, our findings show a net OS benefit for fit patients who received chemotherapy plus RNU for mUTUC relative to their counterparts treated with chemotherapy alone.

Patient summary

We examined the role of radical nephroureterectomy in addition to systemic chemotherapy for metastatic upper tract urothelial carcinoma. We found that such treatment may be associated with an overall survival benefit compared to chemotherapy alone in fit patients.

Take Home Message

Chemotherapy plus radical nephroureterectomy may be associated with an overall survival benefit compared to chemotherapy alone for fit patients with metastatic upper tract urothelial carcinoma. These preliminary results warrant further consideration in randomized control trials addressing this question.

Keywords: Urothelial carcinoma, Ureteral neoplasms, Ureter, Renal pelvis, Drug therapy, Propensity score, Survival.

Approximately 10% of patients with upper tract urothelial carcinoma (UTUC) present with involvement of extraregional lymph nodes and/or other distant sites at initial diagnosis [1]. Although it can vary tremendously according to baseline characteristics [2], prognosis for these individuals is ominous, as 3-yr overall survival (OS) rates for metastatic UTUC (mUTUC) do not exceed 10% [1].

Cisplatin-based combination chemotherapy alone is currently considered the standard of care for fit patients with mUTUC [3]. Nonetheless, the paradigm for treating metastatic tumors is continuously evolving, with increasing evidence supporting the benefit of controlling the primary focus, notably for metastatic urothelial carcinoma of the bladder [4]. However, to date, there are no data available on the role of radical nephrouretectomy (RNU) in the treatment of mUTUC.

Thus, our objective was to test the impact of RNU on OS in a select cohort of patients from the National Cancer Data Base, who were deemed fit to receive systemic chemotherapy for mUTUC. We hypothetized that for these individuals, chemotherapy plus RNU is associated with an OS benefit compared to chemotherapy alone.

From a population of 43 431 men and women diagnosed with ureter or renal pelvis tumor between 2004 and 2012 (ICD-O-3 codes C65.9–C66.9), we identified 1182 individuals who received multiple-agent systemic chemotherapy for unilateral mUTUC at presentation. Further exclusion criteria are presented in Supplementary Fig. 1. Our final study population included 1035 individuals, who were dichotomized into a chemotherapy plus RNU group and a chemotherapy-alone group.

To account for potential selection bias, observed differences in baseline characteristics between patients who received chemotherapy plus RNU and those who received chemotherapy alone were controlled for with an inverse probability of treatment weighting (IPTW)–adjusted analysis [5]. Balance in covariates between treatment groups before and after IPTW adjustment was assessed using the standardized difference approach. IPTW-adjusted Kaplan-Meier curves and log-rank test were used to compare OS between patients who received chemotherapy plus RNU and those who received chemotherapy alone [6]. In addition, we performed multivariable Cox regression analysis to estimate the corresponding IPTW-adjusted hazard ratio (HR) [5].

Given the prognostic value of metastases locations for mUTUC, we calculated separate IPTW-adjusted HRs for chemotherapy plus RNU versus chemotherapy alone in subgroups of patients with positive extraregional lymph nodes only and bone/visceral involvement at initial diagnosis by using interaction terms in the multivariable Cox model. Finally, we assessed the impact of baseline characteristics on the treatment effect by conducting a locally weighted regression.

All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). Two-sided statistical significance was defined as p < 0.05. An institutional review board waiver was obtained before the study was conducted.

Overall, 398 patients with mUTUC received chemotherapy plus RNU (38.4%) and 637 (61.6%) received chemotherapy alone (Supplementary Fig. 1). In the chemotherapy plus RNU group, 357 (89.7%) and 41 (10.3%) patients received surgery before and after chemotherapy, respectively.

Unweighted and weighted baseline characteristics of eligible patients, stratified according to treatment group, are reported in Table 1. Results of multivariable logistic regression analysis predicting receipt of chemotherapy plus RNU versus chemotherapy alone are reported in Supplementary Table 1. Following IPTW adjustment, all standardized differences were <10%, indicating that the treatment groups were comparable (Supplementary Fig. 2).

Table 1

Baseline characteristics of patients who received chemotherapy plus radical nephroureterectomy versus chemotherapy alone for metastatic upper tract urothelial carcinoma in unweighted and weighted study populations from the National Cancer Data Base, 2004–2012

 

Characteristics Unweighted study population, n (%) Weighted study population, %
Overall CTx + RNU CTx alone SD (%) Overall CTx + RNU CTx alone SD (%)
Number of patients 1,035 (100) 398 (38.4) 637 (61.6)
Median age, yr (IQR) 68.0 (61.0–75.0) 67.0 (61.0–75.0) 68.0 (61.0–76.0) 5.2 68.0 (61.0–75.0) 68.0 (62.0–74.0) 68.0 (61.0–75.0) 0.6
Age category 7.2
 <70 yr 570 (55.1) 228 (57.3) 342 (53.7) 54.8 55.5 54.1 2.8
70 yr 465 (44.9) 170 (42.7) 295 (46.3) 45.2 44.5 45.9
Charlson comorbidity index 11.8
 0 789 (76.2) 297 (74.6) 492 (77.2) 77.1 77.3 77.0 0.9
 1 195 (18.9) 75 (18.9) 120 (18.9) 18.0 17.9 18.2
 ≥2 51 (4.9) 26 (6.5) 25 (3.9) 4.9 4.8 4.8
Gender 10.7
 Male 616 (59.5) 224 (56.3) 392 (61.5) 59.2 59.3 59.1 0.4
 Female 419 (40.5) 174 (43.7) 245 (38.5) 40.8 40.7 40.9
Race/ethnicity 13.7
 Non-Hispanic White 952 (92.0) 372 (93.5) 580 (91.1) 92.1 92.1 92.0 0.5
 Non-Hispanic Black 49 (4.7) 12 (3.0) 37 (5.8) 4.7 4.7 4.7
 Other/unknown 34 (3.3) 14 (3.5) 20 (3.1) 3.2 3.2 3.3
Median income for ZIP code 16.9
 Above median income 628 (60.7) 249 (62.6) 379 (59.5) 61.1 61.1 61.1 2.3
 Below median income 370 (35.7) 142 (35.7) 228 (35.8) 35.7 35.8 35.5
 Unknown 37 (3.6) 7 (1.7) 30 (4.7) 3.2 3.1 3.4
Educational attainment for ZIP code 20.3
 Above median education 662 (64.0) 269 (67.6) 393 (61.7) 62.9 62.6 63.3 3.5
 Below median education 337 (32.5) 123 (30.9) 214 (33.6) 33.9 34.4 33.3
 Unknown 36 (3.5) 6 (1.5) 30 (4.7) 3.2 3.0 3.4
Insurance status 12.8
 Medicare 583 (56.3) 221 (55.5) 362 (56.8) 56.8 56.6 57.0 3.2
 Private insurance/managed care 370 (35.8) 151 (38.0) 219 (34.4) 35.3 35.5 35.2
 Medicaid/other government 39 (3.8) 14 (3.5) 25 (3.9) 3.4 3.2 3.5
 Not insured 24 (2.3) 8 (2.0) 16 (2.5) 2.5 2.5 2.4
 Unknown 19 (1.8) 4 (1.0) 15 (2.4) 2.0 2.2 1.9
County category 11.1
 Metropolitan county 831 (80.3) 320 (80.4) 511 (80.2) 80.3 80.5 80.2 3.0
 Urban county 143 (13.8) 59 (14.8) 84 (13.2) 14.0 14.1 13.9
 Rural county 17 (1.6) 7 (1.8) 10 (1.6) 1.6 1.6 1.6
 Unknown 44 (4.3) 12 (3.0) 32 (5.0) 4.1 3.8 4.3
CoC facility type 19.7
 Not academic/research program 642 (62.0) 270 (67.8) 372 (58.4) 63.5 64.1 62.9 2.5
 Academic/research program 393 (38.0) 128 (32.2) 265 (41.6) 36.5 35.9 37.1
US census division for CoC facility 8.8
 East 459 (44.4) 166 (41.7) 293 (46.0) 43.2 42.8 43.6 1.7
 Central 434 (41.9) 176 (44.2) 258 (40.5) 43.0 43.3 42.6
 West 142 (13.7) 56 (14.1) 86 (13.5) 13.8 13.9 13.8
Year of diagnosis 11.9
 2004–2006 250 (24.1) 92 (23.1) 158 (24.8) 24.2 24.4 24.0 1.4
 2007–2009 311 (30.1) 133 (33.4) 178 (27.9) 29.8 30.0 29.7
 2010–2012 474 (45.8) 173 (43.5) 301 (47.3) 46.0 45.6 46.3
Primary tumor site 2.9
 C65.9: renal pelvis 737 (71.2) 309 (77.6) 428 (67.2) 70.6 70.4 70.9 1.4
 C66.9: ureter 298 (28.8) 89 (22.4) 209 (32.8) 29.4 29.6 29.1
Clinical T stage 19.2
 ≤cT2 123 (11.9) 36 (9.0) 87 (13.6) 11.4 11.3 11.5 1.3
 ≥cT3 375 (36.2) 163 (41.0) 212 (33.3) 37.6 37.9 37.3
 Unknown 537 (51.9) 199 (50.0) 338 (53.1) 51.0 50.8 51.2
Clinical N stage 34.9
 cN0 211 (20.4) 97 (24.4) 114 (17.9) 20.3 20.1 20.4 0.9
 cN+ 486 (47.0) 145 (36.4) 341 (53.5) 47.0 47.3 46.8
 Unknown 338 (32.6) 156 (39.2) 182 (28.6) 32.7 32.6 32.8
Metastasis location 8.2
 Extraregional lymph nodes only 96 (9.3) 39 (9.8) 57 (8.9) 8.6 8.4 8.8 1.5
 Bone/visceral involvement 808 (78.1) 315 (79.1) 493 (77.4) 78.7 79.0 78.5
 Unknown 131 (12.6) 44 (11.1) 87 (13.7) 12.7 12.6 12.7

CTx = chemotherapy; RNU = radical nephroureterectomy; SD = standardized difference; IQR = interquartile range; ZIP = zone improvement plan; CoC = Commission on Cancer; US = United States.

The median follow-up was 25.0 mo (interquartile range 11.4–52.2). IPTW-adjusted Kaplan-Meier curves (Fig. 1) showed that 3-yr OS was 16.2% (95% confidence interval [CI] 12.1–20.3) for chemotherapy plus RNU and 6.4% (95% CI 4.1–8.7) for chemotherapy alone (p < 0.001). In IPTW-adjusted Cox regression analysis, chemotherapy plus RNU was associated with a significant OS benefit (HR 0.70, 95% CI 0.61–0.80; p < 0.001; Supplementary Table 2). Similar results were observed for patients with positive extraregional lymph nodes only (HR 0.51, 95%CI 0.30–0.89; p = 0.01) or bone/visceral involvement (HR 0.74, 95% CI 0.63–0.83; p < 0.001).

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Fig. 1

Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis of overall survival among patients who received chemotherapy plus radical nephroureterectomy (RNU) versus chemotherapy alone for metastatic upper tract urothelial carcinoma.

 

Locally weighted regression showed that at 12-mo follow-up, chemotherapy plus RNU was associated with an OS benefit compared to chemotherapy alone, regardless of the predicted risk of overall mortality (p = 0.6 for interaction; Supplementary Fig. 3).

In line with a previous report suggesting an OS benefit of high-intensity local treatment for metastatic urothelial carcinoma of the bladder [4], we found that mUTUC patients who received chemotherapy plus RNU were 30% less likely to die than their counterparts who received chemotherapy alone. This remained significant for patients with bone/visceral involvement, although it was less pronounced than for those with positive extraregional lymph nodes only. In contrast to findings for other urological malignancies [7], our locally weighted regression analysis also suggested that all measured baseline characteristics had little impact on the treatment effect of chemotherapy plus RNU.

Nonetheless, it is noteworthy that poor general condition and/or impaired renal function could largely limit the use of RNU for mUTUC overall, as radical removal of the kidney unit has been previously shown to decrease eligibility for delivery of full-dose adjuvant cisplatin-based chemotherapy [8]. This may be more likely to occur in older patients, but beyond age, low preoperative estimated glomerular filtration rate represents the most important risk factor for postoperative renal failure [9]. Thus, we believe that meticulous pre-RNU selection of mUTUC patients is critical to identify those with general condition and renal function allowing for concomitant use of a cisplatin-based regimen. Accordingly, our analyses were focused on individuals who were deemed fit to receive systemic chemotherapy, but the recent advent of non-nephrotoxic immune checkpoint inhibitors [10] could help to enhance the role of RNU for mUTUC.

Of note, although we were able to distinguish individuals who received RNU before and after initiation of systemic chemotherapy, the low number of those treated with the latter strategy prevented us from performing any methodologically adequate comparison; further studies should determine the most efficient treatment sequence, which is likely to consist of the delivery of chemotherapy followed by RNU on the basis of evidence available for metastatic urothelial carcinoma of the bladder [4].

In conclusion, we report a net OS benefit for fit patients who received chemotherapy plus RNU for mUTUC relative to their counterparts treated with chemotherapy alone. Although these findings are limited by the biases related to the observational study design, our preliminary data add substantial evidence supporting the role of aggressive local treatment of the primary tumor for metastatic urothelial carcinoma. The present results should be considered as hypothesis-generating for future randomized control trial addressing this question.


Author contributions: Firas Abdollah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Seisen, Abdollah.

Acquisition of data: Seisen, Jindal, Sood, Karabon, Vetterlein.

Analysis and interpretation of data: Seisen, Bellmunt, Rouprêt, Leow, Sun, Alanee, Choueiri, Abdollah.

Drafting of the manuscript: Seisen, Jindal, Sood, Abdollah.

Critical revision of the manuscript for important intellectual content: Seisen, Jindal, Karabon, Sood, Bellmunt, Rouprêt, Leow, Vetterelein, Sun, Alanee, Choueiri, Trinh, Menon, Abdollah.

Statistical analysis: Karabon.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Trinh, Menon, Abdollah.

Other: None.

Financial disclosures: Firas Abdollah certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas Seisen, Tarun Jindal, Patrick Karabon, Akshay Sood, Jeffrey J. Leow, Malte W. Vetterlein, Maxine Sun, Quoc-Dien Trinh, and Mani Menon have nothing to disclose. Joaquim Bellmunt has received consulting/advisory fees from Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, and Novartis; institutional research funding from Millennium Pharmaceuticals and Sanofi; and travel/accommodation expenses from Pfizer and MSD Oncology. Morgan Rouprêt has received consulting/advisory fees from Sanofi Pasteur and IPSEN. Shaheen Alanee has received consulting/advisory fees from Takeda Pharmaceuticals. Toni K. Choueirin has received honoraria from the National Comprehensive Cancer Network and UpToDate; consulting/advisory fees from Pfizer, Bayer AG, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Genentech, Eisai, Prometheus Labs, Foundation Medicine Research, Cerulean Pharma, AstraZeneca, and Peloton; and institutional funding from Pfizer, Novartis, Merck, Exelixis, TRACON Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, and Genentech. Firas Abdollah has received consulting/advisory fees from GenomeDx Biosciences.

Funding/Support and role of the sponsor: None.

Acknowledgments: The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators. Shaheen Alanee is supported by research funding from Vattikuti Urology Institute, Merck & Co Inc., and the National Institutes of Health. Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute, a Clay Hamlin Young Investigator Award from the Prostate Cancer Foundation, and a Genentech BioOncology Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology.

References

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Footnotes

a Center for Outcomes Research, Analytics and Evaluation, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA

b Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

c Department of Urology, Pitié Salpétrière Hospital, Assistance Publique des Hôpitaux de Paris, Pierre and Marie Curie University, Paris, France

d Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Corresponding author. Vattikuti Urology Institute, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. Tel. +1 348 7357124; Fax: +1 313 9169539.