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(Supplementary Figure 2), but the difference in RFS did not
reach significance (36% vs 52%; p = 0.08). On multivariable
analysis, NAC receipt remained associated with worse RFS
(HR 1.75, 95% CI 1.13–2.71; p = 0.01), CSS (HR 1.85, 95% CI
1.25–2.75; p = 0.002), and OS (HR 1.87, 95% CI 1.29–2.69;
p < 0.001) for patients with ypT2–4 or ypN+ rUCB at RC
after NAC (Supplementary Table 4).
Sensitivity analyses (1) restricted to patients who
received cisplatin-based combination chemotherapy,
(2) excluding pNx patients, and (3) additionally adjusting
for clinical T stage when available did not meaningfully
impact the study findings (Supplementary Table 5).
To the best of our knowledge, this is the first study to
demonstrate that patients with rUCB after NAC, particularly
those with residual muscle-invasive or nodal metastatic
disease, have worse oncologic outcomes compared to
pathologic stage–matched patients who underwent RC
alone. There are several potential explanations for and
implications from our data. First, rUCB after NAC may
represent chemoresistant disease, and its presence in an RC
specimen may suggest the presence of chemoresistant
micrometastases elsewhere. Second, NAC may induce
chemoresistance by applying selective pressures Third,
given the retrospective design of our analyses, it is possible
that patients receiving NAC + RC had inherently worse
disease at diagnosis compared to RC controls. However,
even if this is so, the message remains the same: the
prognosis of a given ypT stage cannot simply be considered
the same as the corresponding pT stage.
Our findings of excellent long-term outcomes for
patients with ypT0N0 (complete response) or <ypT2N0
(downstaged to non–muscle-invasive UCB) were expected
and are consistent with the results from prior series
Furthermore, our results support data suggesting that the
degree of downstaging following NAC, as well as the
amount and stage of rUCB after NAC at RC, is associated with
subsequent survival outcomes . Our study contributes
additional insight to the existing literature by comparing
outcomes for patients with rUCB at RC after NAC to
pathologic stage–matched controls.
Of note, our study does not contradict the randomized
trials in which patients who received NAC had lower
pathologic stages compared to patients who had RC alone.
By contrast, our study artificially matched on pathologic
stage (ypT0N0/pT0N0) to better compare the prognosis of
pathologic stage based on NAC exposure.
A comparison of systematic use of NAC before RC and
selective use of adjuvant chemotherapy or observation after
upfront RC based on pathology may be warranted in a
clinical trial setting, especially in view of emerging data from
the National Cancer Data Base suggesting that the latter
approach may be associated with a survival benefit .
As in all such observational studies, we must acknowl-
edge that selection bias cannot be ruled out. Specifically, we
cannot distinguish the relative contribution of aggressive
behavior caused by NAC from selected NAC use in cancers
with underlying aggressive biology. In addition, as data for
clinical T stage were missing for 227 patients, we were only
able to indirectly evaluate downstaging.
In summary, while patients achieving a complete
response to NAC and RC have excellent survival outcomes,
those with rUCB after NAC, particularly those with residual
muscle-invasive or nodal metastatic disease, have a worse
prognosis compared to pathologic stage–matched controls
undergoing RC alone. These data argue for evaluation in a
clinical trial setting of the role of immunotherapy or other
novel agents as adjuvant therapy after RC when rUCB is
found at surgery, particularly if locally advanced disease
remains. These findings also underscore the need to develop
and implement clinical tests (eg, analysis of genomic tumor
alterations in ERCC2, ATM, RB1, and FANCC) to identify which
patients are most likely to achieve ypT0 status and
downstaging from NAC .
Author contributions: Bimal Bhindi 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: Boorjian, Bhindi.
Acquisition of data: Cheville, Thapa, Tarrell.
Analysis and interpretation of data: Bhindi, Thapa, Tarrell, Boorjian.
Drafting of the manuscript: Bhindi, Boorjian.
Critical revision of the manuscript for important intellectual content: All
authors.
Statistical analysis: Bhindi, Tarrell, Thapa.
Obtaining funding: None.
Administrative, technical, or material support: Frank, Boorjian.
Supervision: Boorjian, Frank.
Other: None.
Financial disclosures: Bimal Bhindi 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: None.
Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
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