EURURO Vol. 72 No. 4

491 656

We fully acknowledge all the important points made in the
editorial by Kulkarni and Klaassen accompanying our
comparative effectiveness assessment of trimodal therapy
(TMT) versus radical cystectomy (RC) in the hospital-based
National Cancer Data Base (NCDB) .
Indeed, several key baseline characteristics when
comparing such treatment modalities for muscle-invasive
bladder cancer (MIBC) are not documented in the NCDB.
Specifically, we could not account for completeness of
transurethral resection of bladder tumor, tumor size and
focality, [35_TD$DIFF]as well as the presence of concomitant CIS or
hydronephrosis in our propensity score model predicting
receipt of TMT versus RC. From a statistical standpoint, we
did perform additional sensitivity analyses without
assumptions using the method described by Ding and
VanderWeele to fully highlight the strength of the
association between treatment approach and overall
survival (OS). The impact of unmeasured confounders on
our findings was assessed by estimating the magnitude of
the joint bounding factor for various combinations of the
odds of receiving TMT in the presence of unmeasured
confounders (ORTMT-U) and the likelihood of OS in the
presence of unmeasured confounders (HROS-U). It is
noteworthy that under the most plausible scenarios, the
adverse effect of TMT versus RC on long-term OS would
remain significant ).
Moreover, it is correct to suggest that patients in our
model may fall short of the perfect application of TMT;
however, the reality is that many patients who receive
bladder-sparing protocols for MIBC are those who are
considered ‘‘too sick’’ for RC. Thus, there may commonly be
obstacles to ‘‘perfect’’ application of TMT. For evaluation
purposes, we would argue that assessment of TMT as it is
actually performed is more relevant.
The critique about OS versus disease-specific survival is
also important, but we believe less relevant for MIBC. While
distinction is vital for a disease such as prostate cancer for
which competing risks can confound comparisons of
therapies (eg, sicker men may be more likely to receive
radiation therapy), it is less important for MIBC, for which
competing risks rarely obviate aggressive treatment, and
very many men and women may succumb within months
from either the disease or its complications.
Kulkarni and Klaassen mention two small, retrospective,
single-institution series suggesting equivalent survival
between TMT and RC . While these studies were able
to account for granular clinical variables that we were
unable to—[36_TD$DIFF]they suffer from the inevitable limitations of
single-institution data—findings from one institution,
especially esteemed high-volume bladder cancer centers
such as the University of Toronto, are unlikely to be valid at
a larger national scale, where most bladder cancer care is
performed in a community setting.
Although our results are limited by the observational
study design, potential for unmeasured confounders, and
our inability to ensure ‘‘perfect’’ application of the
principles of TMT, our data constitute the only national-
level report comparing OS associated with TMT versus RC as
both therapies are actually performed. Our data may help in
bridging the randomized evidence gap to guide clinical
decision-making for the management of MIBC.
Conflicts of interest: The authors have nothing to disclose.
Acknowledgments: 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.
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