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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).
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 , 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 , our locally weighted regres-
sion 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 condi-
tion 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 . This may bemore 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 . 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 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 method-
ologically 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 .
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, Roupreˆt, 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, Roupreˆt, 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 Roupreˆt 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, Pro-
metheus 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 Genen-
tech. 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.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
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