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Survival After Partial Cystectomy for Variant Histology Bladder Cancer Compared With Urothelial Carcinoma: A Population-based Study
Journal Pre-proof Survival after partial cystectomy for variant histology bladder cancer compared to urothelial carcinoma: a population-based study Stefano Luzzago, Carlotta Palumbo, Giuseppe Rosiello, Sophie Knipper, Angela Pecoraro, Marina Deuker, Francesco Alessandro Mistretta, Zhe Tian, Gennaro Musi, Emanuele Montanari, Shahrokh F. Shariat, Fred Saad, Alberto Briganti, Ottavio de Cobelli, Pierre I. Karakiewicz PII:
S1558-7673(19)30320-9
DOI:
https://doi.org/10.1016/j.clgc.2019.10.016
Reference:
CLGC 1378
To appear in:
Clinical Genitourinary Cancer
Received Date: 8 August 2019 Revised Date:
1 October 2019
Accepted Date: 6 October 2019
Please cite this article as: Luzzago S, Palumbo C, Rosiello G, Knipper S, Pecoraro A, Deuker M, Mistretta FA, Tian Z, Musi G, Montanari E, Shariat SF, Saad F, Briganti A, de Cobelli O, Karakiewicz PI, Survival after partial cystectomy for variant histology bladder cancer compared to urothelial carcinoma: a population-based study, Clinical Genitourinary Cancer (2019), doi: https://doi.org/10.1016/ j.clgc.2019.10.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Microabstract
Within the SEER database, we evaluated cancer-specific mortality (CSM) in 248 T1-2N0M0 variant histology bladder cancer patients (nonUCUB) treated with partial cystectomy (PC). In Cox regression models, nonUCUB PC treated patients exhibited higher CSM, compared to urothelial carcinoma patients treated with PC. Conversely, nonUCUB patients treated with PC had similar CSM when compared to nonUCUB patients treated with radical cystectomy.
1
Survival after partial cystectomy for variant histology bladder cancer compared
2
to urothelial carcinoma: a population-based study
3
Stefano Luzzagoa,b, Carlotta Palumboa,c Giuseppe Rosielloa,d, Sophie Knippera,e,
4
Angela Pecoraroa,f, Marina Deukerg, Francesco Alessandro Mistrettaa,b, Zhe Tiana,
5
Gennaro Musib, Emanuele Montanarih, Shahrokh F. Shariati,l,m,n,o, Fred Saada,
6
Alberto Brigantib, Ottavio de Cobellib,p, Pierre I. Karakiewicza
7 8 9
a
Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health
Center, Montreal, Quebec, Canada
10
b
11
c
12
Radiological Science and Public Health, University of Brescia, Italy
13
d
14
IRCCS San Raffaele Scientific Institute, Milan, Italy
15
e
16
Germany
17
f
18
g
19
h
20
of Milan, Milan, Italy
21
i
22
Austria
23
l
24
m
25
n
Department of Urology, Second Faculty of Medicine, Charles University, Prag, Czech Republic
26
o
Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical
27
University, Moscow, Russia
28 29 30 31 32 33 34 35 36 37
p
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Word count (abstract): 250
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Word count (manuscript): 2378
Department of Urology, European Institute of Oncology, Milan, Italy
Urology Unit, ASST Spedali Civili of Brescia. Department of Medical and Surgical Specialties,
Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute,
Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg,
Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany. Department of Urology, IRCCS Fondazione Ca’ Granda-Ospedale Maggiore Policlinico, University
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna,
Departments of Urology, Weill Cornell Medical College, New York, New York, USA Department of Urology, University of Texas Southwestern, Dallas, Texas, USA
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Corresponding author: Stefano Luzzago, MD Department of Urology, European Institute of Oncology, Milan, Italy Via Giuseppe Ripamonti, 435 20141 Milan, Italy Tel: +39 33354249298 E-mail: [email protected]
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1
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Declarations of interest: none
43 44 45 46
List of abbreviations
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PC: Partial cystectomy
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RC: Radical cystectomy
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UCUB: Urothelial carcinoma of the urinary bladder
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nonUCUB: Variant histology bladder cancer
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CSM: cancer-specific mortality
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SEER: Surveillance, Epidemiology and End Results
53
ICD-O: International Classification of Disease for Oncology
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WHO: World Health Organization
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IPTW: Inverse Probability of Treatment Weighting
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IQR: interquartile range
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CI: confidence interval
58
HR: Hazard Ratio
59 60
2
61
Abstract
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Background
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To test cancer-specific mortality (CSM) after partial cystectomy (PC) for variant histology bladder
64
cancer (nonUCUB), relative to urothelial carcinoma of the urinary bladder (UCUB) and relative to
65
radical cystectomy (RC).
66 67
Materials and Methods
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Within the Surveillance, Epidemiology, and End Results registry (2001–2016), we identified
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T1-2,N0,M0 nonUCUB and UCUB patients treated with PC and corresponding groups treated with
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RC. Non-UCUB included adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma, other
71
histological subtypes. First, CSM after PC was compared between nonUCUB and UCUB. Second,
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CSM after PC was compared to RC in nonUCUB. Kaplan Meier plots and multivariable Cox
73
regression models were used before and after Inverse Probability of Treatment Weighting (IPTW)
74
adjustment.
75 76
Results
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Overall, 248 (16.3%) patients treated with PC harboured nonUCUB. Of those, 115 (46.5%) vs. 50
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(20%) vs. 34 (14%) vs. 49 (19.5%) were, respectively, adenocarcinoma vs. squamous carcinoma vs.
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neuroendocrine carcinoma vs. other histological subtypes. Five-year CSM rates after PC were 23%
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vs. 27% vs. 27% vs. 15% vs. 19% for adenocarcinoma vs. squamous carcinoma vs. neuroendocrine
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carcinoma vs. other vs. UCUB, respectively. The comparison between PC in nonUCUB vs. PC in
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UCUB showed higher CSM in nonUCUB patients (HR:1.4;p=0.03). The comparison between PC
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in nonUCUB vs. RC in nonUCUB showed no CSM differences.
84 85
Conclusions
3
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PC for nonUCUB results in higher mortality than PC for UCUB. However, PC instead of RC in
87
select nonUCUB patients does not undermine survival. In consequence, the excess CSM is
88
unrelated to cystectomy type, but originates from tumor biology. These results may act as
89
generating hypothesis for future trial design.
90 91
Keywords: neuroendocrine carcinoma; adenocarcinoma; squamous carcinoma; other histological subtypes
4
92 93
Introduction
Partial cystectomy (PC) represents an alternative to radical cystectomy (RC) in well selected
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patients with urothelial carcinoma of the urinary bladder (UCUB) 1. The NCCN Guidelines 2
95
recommend that PC should be reserved to patients with ≤cT2 disease, with a solitary lesion and in
96
location amenable to segmental resection with adequate negative surgical margins. Moreover, in
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some elderly patients, the morbidity associated with RC may be prohibitive 3,4 and PC outside of
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this definition may be contemplated. Despite adequate data supporting the use of PC in UCUB 5,6,
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virtually no data exist regarding use of PC in patients with variant histology (nonUCUB) 7–11.
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To address this void, we examined PC use in nonUCUB patients and compared cancer-specific
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mortality (CSM) according to PC in UCUB. Moreover, we also tested CSM rates according to PC
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vs. RC in nonUCUB patients. Our analyses were meant to test two specific concepts, namely
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whether CSM is affected by tumor biology, cystectomy type, or both in nonUCUB patients.
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5
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Materials and methods
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Study population
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Within the Surveillance, Epidemiology and End Results (SEER) 12 database (2001–2016),
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we focused on patients aged 18 years or older with histologically confirmed bladder cancer
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(International Classification of Disease for Oncology [ICD-O] site codes C67.0-67.9). Death
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certificate only and autopsy cases were excluded. Patients with urachal location of the tumor (ICD-
111
O site code C67.7) were not considered for the analyses. According to NCCN Guidelines 2, only
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patients with T1-2, N0, M0 bladder cancer were considered (n=11,542). Study population consisted
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of two specific cohorts. The first cohort included patients treated with PC (n=1,526) with either
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nonUCUB (n=248; 16.3%) or UCUB (1,278; 83.7%) histology. The second cohort consisted of
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nonUCUB or UCUB patients that were either treated with PC (n=248 and n=1,278) or RC (n=698
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and n= 9,318).
117 118 119
Variables definition Within the nonUCUB cohort and according to the 2016 World Health Organization (WHO)
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classification of bladder tumors 13, four major histological variants were recognized:
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adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma and other histological subtypes
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(Supplementary Table 1). Demographic characteristics consisted of age, gender, year of diagnosis
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(2001-2006 vs. 2007-2011 vs. 2012-2016), marital status (married, unmarried, unknown), race
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(White, Black, Hispanic, Other) and socioeconomic status (1 quartile vs. 2-3-4 quartile). Tumor
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size, T stage (T1 vs. T2) and rates of chemotherapy and radiation therapy were also considered.
126 127 128
Statistical analyses Descriptive statistics relied on tests of means and proportions and, respectively, used the t-
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test and the chi-square. Two types of specific comparisons that relied on CSM rates were
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performed. First, PC in nonUCUB was compared to PC in UCUB. Kaplan-Meier plots and
6
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multivariable Cox regression models tested the effect of histology on CSM before and after Inverse
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Probability of Treatment Weighting (IPTW) adjustment 14. Second, PC was compared to RC in
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nonUCUB and UCUB patients. Here, Inverse Probability of Treatment Weighting (IPTW) was used
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to minimize potential differences that might exist in patients’ characteristics, according to PC vs.
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RC status 14. IPTW adjusted Kaplan-Meier plots graphically depicted the relationship between PC
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and RC on CSM according to histology. Moreover, IPTW adjusted multivariable Cox regression
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models tested the effect of PC vs. RC on CSM within each histological variant. In all analyses,
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IPTW-adjustment relied on the following variables: age, gender, race, socioeconomic status, marital
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status, year of diagnosis, T stage, chemotherapy and radiation therapy administration. R software
140
environment was used in all statistical analyses and graphics (version 3.4.3). All tests were two
141
sided with a level of significance set at p <0.05.
7
142
Results
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Descriptive analyses
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Within the first cohort that consisted of 1,526 patients treated with PC, 1,278 (83.7%) and
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248 (16.3%) harboured UCUB vs. nonUCUB (Table 1a). Patients with nonUCUB were younger
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(65 vs. 73 years; p<0.001), and more frequently female (39.5% vs. 21.2%; p<0.001) and unmarried
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(40.7% vs. 33.1%; p=0.04). Median (interquartile range [IQR]) tumor size was 34 (20-50) vs. 30
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(20-50) in nonUCUB vs. UCUB, respectively (p=0.2). The percentage of T1 vs. T2 tumors was
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38.7% vs. 61.3% and 45.5% vs. 54.5% in nonUCUB vs. UCUB, respectively (p=0.06). Among
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patients with nonUCUB, 115 (46.5%), 50 (20%), 34 (14%) and 49 (19.5%) harboured
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adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma and other histological subtypes,
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respectively.
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Within the second cohort, 248 (26%) and 698 (74%) patients with nonUCUB were treated with PC
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and RC, respectively (Table 1b). Patients treated with PC had lower median tumor size (34 [20-50]
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vs. 40 [25-53]; p=0.01) and more frequently harboured T1 stage (38.7% vs. 23.8%) vs. less
156
frequently harboured T2 stage (61.3% vs. 76.2%; p<0.001). Moreover, nonUCUB patients treated
157
with PC less frequently underwent lymph node dissection (39.9% vs. 74.2%; p<0.001) and
158
chemotherapy (17.3% vs. 30.7%; p<0.001), but more frequently underwent radiation therapy (7.3%
159
vs. 3%; p=0.006).
160 161 162
Survival analyses between PC nonUCUB and PC UCUB patients Median follow-up time was 42 (IQR: 19-87) and 46 (IQR: 18-88) months for nonUCUB and
163
UCUB, respectively. Overall, 68 vs. 439 deaths were recorded during the study period, in
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nonUCUB vs. UCUB. Five-year CSM rates were 23% vs. 19% for nonUCUB vs. UCUB (p=0.3;
165
Figure 1a). Moreover, five-year CSM rates were 23% vs. 27% vs. 27% vs. 15% for adenocarcinoma
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vs. squamous carcinoma vs. neuroendocrine carcinoma vs. other histological subtypes (p=0.5;
167
Figure 2). In a subgroup analysis of T1 patients, 5-year CSM rates were respectively 15% vs. 13% 8
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for nonUCUB vs. UCUB (p=0.8; Figure 1c). Conversely, in a subgroup analysis of T2 patients, 5-
169
year CSM rates were respectively 28%, vs. 24% for nonUCUB vs. UCUB (p=0.3; Figure 1d).
170
In multivariable Cox regression models, nonUCUB was associated with higher CSM both before
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(Hazard Ratio [HR]: 1.4, 95% confidence interval [CI]: 1.0-2.0; p=0.03; Table 2a) and after IPTW
172
adjustment (HR: 1.3, 95% CI: 1.0-1.6; p=0.04; Table 2b), compared to UCUB. Moreover, in
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multivariable Cox regression models, squamous carcinoma was associated with higher CSM (HR:
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1.7, 95% CI: 1.0-3.2; p=0.04; Table 2c), compared to UCUB. Conversely, adenocarcinoma (HR:
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1.2; 95% CI: 0.8-1.9; p=0.4), neuroendocrine carcinoma (HR: 1.2; 95% CI: 0.6-2.6; p=0.6) and
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other histological subtypes (HR: 1.6; 95% CI: 0.8-3.1; p=0.1) were not associated with higher
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CSM, compared to UCUB.
178 179
Survival analyses between PC and RC for nonUCUB and UCUB patients
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In IPTW adjusted Kaplan-Meier plots focusing on nonUCUB, 5-year CSM rates were
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respectively 23.5% vs. 21% (p=0.9) for patients treated with PC vs. RC (Figure 3a). In IPTW
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adjusted Kaplan-Meier plots focusing on UCUB, 5-year CSM rates were respectively 18% vs. 17%
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(p=0.2) for patients treated with PC vs. RC (Figure 3b). In IPTW adjusted Kaplan-Meier plots
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focusing on adenocarcinoma, 5-year CSM rates were respectively 22% vs. 16% (p=0.9) for patients
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treated with PC vs. RC (Figure 3c). In IPTW adjusted Kaplan-Meier plots focusing on squamous
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carcinoma, 5-year CSM rates were respectively 27% vs. 20% (p=0.2) for patients treated with PC
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vs. RC (Figure 3d). In IPTW adjusted Kaplan-Meier plots focusing on neuroendocrine carcinoma,
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5-year CSM rates were respectively 28% vs. 22% (p=0.5) for patients treated with PC vs. RC
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(Figure 3e). In IPTW adjusted Kaplan-Meier plots focusing on other histological subtypes, 5-year
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CSM rates were respectively 19% vs. 32% (p=0.2) for patients treated with PC vs. RC (Figure 3f).
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In multivariable IPTW adjusted Cox regression models, PC was not associated with higher CSM
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neither in nonUCUB (HR: 1.1, 95% CI: 0.8-1.4; p=0.6), nor in UCUB (HR: 1.0, 95% CI: 0.9-1.1;
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p=0.5), adenocarcinoma (HR: 1.0, 95% CI: 0.6-1.8; p=0.9), squamous carcinoma (HR: 1.6, 95% 9
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CI: 0.9-2.7; p=0.07), neuroendocrine carcinoma (HR: 1.2, 95% CI: 0.6-2.3; p=0.5) or other
195
histological subtypes (HR: 0.8, 95% CI: 0.5-1.5; p=0.5), compared to RC.
196 197
Natural history within PC nonUCUB subtypes
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Finally we performed a descriptive analysis of specific variant histology subtypes that were
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treated with PC (Figure 4). Among patients with adenocarcinoma (Figure 4a), 64 (56%), 7 (6%), 1
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(1%), 31 (27%), 8 (7%) and 4 (3%) patients had adenocarcinoma NOS, bronchio-alveolar, clear-
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cell, mucinous, papillary and signet-ring histology, respectively. Of those, 7 (11%), 1 (14%), 7
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(22%), 3 (37.5%) and 3 (75%) patients with adenocarcinoma NOS, bronchio-alveolar, mucinous,
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papillary and signet-ring histology experienced CSM after a median follow-up time of 56 (IQR: 30-
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87) months.
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Among patients with squamous carcinoma (Figure 4b), 47 (94%) and 3 (6%) had squamous NOS
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and papillary histology, respectively. Of those, 11 (24%) patients with squamous NOS histology
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experienced CSM after a median follow-up time of 27 (IQR: 13-59) months.
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Among patients with neuroendocrine carcinoma (Figure 4c), 22 (65%), 10 (30%) and 2 (5%) had
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small cell, carcinoid and paraganglioma histology, respectively. Of those, 4 (19%) and 3 (30%)
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patients with small cell and carcinoid histology experienced CSM after a median follow-up time of
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28 (IQR: 10-98) months.
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Among patients with other histological subtypes (Figure 4d), the following histologies were
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recorded: carcinoma NOS (n=14; 29%), carcinosarcoma (n=7; 14%), fibromatous carcinoma (n=1;
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2%), giant and spindle cell (n=5; 10%), melanoma (n=1; 2%), myomatous carcinoma (n=17; 35%),
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papillary (n=2; 4%), pheocromocytoma (n=1; 2%) and sarcoma (n=1; 2%). Of those, 3 (21%), 1
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(14%), 1 (100%), 1 (100%), 2 (12%), 1 (50%) and 1 (100%) patients with carcinoma NOS,
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carcinosarcoma, fibromatous carcinoma, melanoma, myomatous carcinoma, papillary and
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pheocromocytoma histology experienced CSM after a median follow-up time of 43 (IQR: 17-93)
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months. 10
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Discussion
PC has not been studied in patients with nonUCUB. Based on lack of data on that topic 7–11,
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we performed two separate analyses. First, we compared CSM rates after PC between nonUCUB
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and UCUB. Second, we compared CSM rates after PC vs. RC in nonUCUB patients.
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The first comparison demonstrated that nonUCUB is associated with higher CSM in patients
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treated with PC, compared to UCUB. Moreover, in analyses that were stratified according to
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specific nonUCUB subtypes, higher CSM was recorded, albeit the differences were not significant,
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except for squamous carcinoma. These observations indicate higher mortality after PC in nonUCUB
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patients, relative to their UCUB counterparts, despite most detailed adjustment for the effect of
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patient related differences. Moreover, stratification according to nonUCUB subtype suggests that all
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nonUCUB subtypes confer higher mortality after PC, relative to PC for UCUB. Based on sample
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size considerations, only the comparison between PC in squamous carcinoma vs. PC in UCUB
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resulted in statistically significant differences. Given the novelty of these findings, we cannot
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directly compare these results with similar analyses of previous reports that focused on PC.
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However, some authors examined the effect of nonUCUB on survival in RC cohorts. Within the
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National Cancer Database (NCDB), Vetterlein et al. 15 reported worse overall survival for patients
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with squamous carcinoma and neuroendocrine carcinoma, relative to UCUB. Moschini et al. 16
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showed worse CSM (HR: 1.5) for pure nonUCUB treated with RC, when compared to UCUB.
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Moreover, in several previous institutional RC series 10,17–19, histological variants were associated
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with worse outcomes in univariable, but not in multivariable models.
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Our second comparison focused on PC vs. RC in nonUCUB patients. Here the opposite
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findings were recorded. Specifically, regardless of cystectomy type (PC vs. RC), no CSM
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differences were recorded. Further stratification according to nonUCUB subtype also revealed no
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differences between PC vs. RC in all six histological subtype comparisons. These findings indicate
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that cystectomy type (PC vs. RC) does not affect the treated the natural history of T1-2 nonUCUB
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bladder cancer. Taken together, the results of both analyses indicate that tumor biology, namely 11
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presence of nonUCUB instead of UCUB, increases CSM. However, once the patient is diagnosed
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with nonUCUB, use of PC in properly selected patients is not associated with worse CSM, relative
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to similar nonUCUB patients treated with RC. This implies that similar consideration for PC may
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be given to properly selected nonUCUB patients as much as in properly selected UCUB patients 2.
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Unfortunately, we were not capable of validating these observations after controlling for specific
251
information regarding tumor focality, location and/or presence of carcinoma in situ, as
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recommended for UCUB 2. In the last part of our study, we performed a detailed descriptive analysis of nonUCUB
253 254
patients treated with PC, stratified by histological subtypes. These analyses demonstrated important
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variability with respect to CSM within each histological subtype. We identified specific histological
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subgroups within the main histological subtypes that are associated with particularly adverse CSM
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patterns. For example 75% of patients with signet-ring adenocarcinoma died during follow-up 20.
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However, very few of these patients (n=4) were identified within the SEER database 12. Conversely,
259
some variant histology subgroups are associated with more favourable prognosis. For example, no
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patient with papillary squamous (n=3), paraganglioma (n=2) 21 or giant and spindle cell carcinoma
261
(n=5) died during follow-up. Finally, many variant histology subgroups showed variability with
262
respect to prognosis, where some patients have not experienced an event even with long periods of
263
observation. In summary, these observations indicate very important variability within specific
264
subgroups of nonUCUB. Even though particularly aggressive subgroups were identified, these
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subgroups contained very few observations and recorded outcomes may be affected by small
266
sample size and selection biases. Similar considerations need to be made about more favourable
267
subgroups. In consequence, even a very large database such as the SEER 12 has limit ability to
268
convey specific prognostic information about nonUCUB subtypes beyond indicating that on
269
average higher mortality should be expected compared to UCUB. Despite its novelty, our study has limitations. First, as previously stated, the SEER database
270 271
12
lacks important details regarding specific treatment assignment, such as tumor multifocality or 12
272
concomitant carcinoma in situ and also lacks specific patient characteristics that could have
273
disqualified some patients either from PC or RC. Second, we were unable to examine specific
274
recurrence and progression trends, since this information is not available within the SEER 12. Third,
275
the SEER database 12 does not provide central review. Indeed, previous studies showed that
276
histological variants are commonly under-recognized in community practice 22,23. Fourth, SEER 12
277
represents one of the largest data repositories in the United States. Nonetheless, it represents an
278
informative 33% sample of the United States population designed to reflect population
279
characteristics and racial distribution. However, partial sampling may invariably result in systematic
280
biases and residual confounding relative to the entire population. Unfortunately, no existing data
281
repository allows to assess the totality of the United States population.
13
282
Conclusion
283
PC for nonUCUB results in higher mortality than PC for UCUB. However, PC instead of
284
RC in select nonUCUB patients does not undermine survival. In consequence, the excess CSM is
285
unrelated to cystectomy type, but originates from tumor biology. These results may act as
286
generating hypothesis for future trial design.
287
14
288
Acknowledgments: None
289
Funding: This research did not receive any specific grant from funding agencies in the public,
290
commercial, or not-for-profit sectors
291
15
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361 362
18
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Figure legends
364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380
Figure 1. Kaplan-Meier curves depicting cancer-specific survival according to histological subtype (urothelial carcinoma of the urinary bladder [UCUB] vs. variant histology [nonUCUB]) in patients with T1-2N0M0 bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Overall; b) After Inverse Probability of Treatment Weighting (IPTW) adjustment; c) Patients with T1 disease; d) Patients with T2 disease
381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397
Figure 3. Inverse Probability of Treatment Weighting (IPTW) adjusted Kaplan-Meier curves depicting cancer-specific survival according to cystectomy type (radical cystectomy vs. partial cystectomy) in patients with T1-2N0M0 bladder cancer, identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Variant histology (nonUCUB); b) Urothelial carcinoma of the urinary bladder (UCUB); c) Adenocarcinoma; d) Squamous carcinoma; e) Neuroendocrine carcinoma; f) Other histological subtype
Figure 2. Kaplan-Meier curves depicting cancer-specific survival according to histological subtype (urothelial carcinoma of the urinary bladder [UCUB] vs. Adenocarcinoma vs. Squamous carcinoma vs. Neuroendocrine carcinoma vs. Other histological subtype) in patients with T12N0M0 bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. 95% confidence interval are provided. a) Overall; b) UCUB; c) Adenocarcinoma; d) Squamous carcinoma; e) Neuroendocrine carcinoma; f) Other histological subtype
Figure 4. Graphical representation of time to event sorted by follow up time in patients with T12N0M0 variant histology bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Adenocarcinoma; b) Squamous carcinoma; c) Neuroendocrine carcinoma; d) Other histological subtype BCa: Bladder Cancer; NOS: not otherwise specified
398 399 400
19
Table 1. Descriptive characteristics of 11,542 patients with histologically confirmed bladder cancer, treated with partial cystectomy (PC) or radical cystectomy (RC) and identified within the Surveillance, Epidemiology, and End Results database from 2001 to 2016. A) Patients treated with PC and stratified according to histology: urothelial carcinoma of the urinary bladder (UCUB) vs. variant histology (nonUCUB) B) Patients are stratified according to cystectomy type: PC vs. RC IQR: interquartile range A)
Age at diagnosis (years)
Gender, n (%) Race, n (%)
Marital status, n (%)
Socioeconomic status, n (%) Year of diagnosis, n (%)
Size (mm)
T stage, n (%) Histological subtypes, n (%)
Lymph node dissection, n (%) Chemotherapy, n (%) Radiation therapy, n (%)
Mean Median IQR Male Female Caucasian African-American Other Married Unmarried Unknown 1 quartile 2-3-4 quartile 2001-2006 2007-2011 2012-2016 Mean Median IQR T1 T2 UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other No Yes No/Unknown Yes No/Unknown Yes
Overall (n=1,526) 70 72 62-80 1,157 (75.8) 369 (24.2) 1,315 (86.2) 121 (7.9) 90 (5.9) 937 (61.4) 524 (34.3) 65 (4.3) 413 (27.1) 1,113 (72.9) 550 (36) 506 (33.2) 470 (30.8) 37 30 20-50 677 (44.4) 849 (55.6) 1,278 (83.7) 115 (7.5) 50 (3.3) 34 (2.2) 49 (3.2) 1,025 (65.2) 501 (34.8) 1,205 (79) 321 (21) 1,443 (94.6) 83 (5.4)
UCUB (n=1,278; 84) 72 73 64-80 1,007 (78.8) 271 (21.2) 1,112 (87) 94 (7.4) 72 (5.6) 802 (62.8) 423 (33.1) 53 (4.1) 347 (27.2) 931 (72.8) 471 (36.9) 422 (33) 385 (30.1) 35.5 30 20-50 581 (45.5) 697 (54.5) 1,278 (100) 0 (0) 0 (0) 0 (0) 0 (0) 846 (66.2) 432 (33.8) 1,000 (78.2) 278 (21.8) 1,213 (94.9) 65 (5.1)
nonUCUB (n=248; 16) 65 65 55-76 150 (60.5) 98 (39.5) 203 (81.9) 27 (10.9) 18 (7.3) 135 (54.4) 101 (40.7) 12 (4.8) 66 (26.6) 182 (73.4) 79 (31.9) 84 (33.9) 85 (34.3) 42.5 34 20-50 96 (38.7) 152 (61.3) 0 (0) 115 (46.5) 50 (20) 34 (14) 49 (19.5) 149 (60.1) 99 (39.9) 205 (82.7) 43 (17.3) 230 (92.7) 18 (7.3)
p-value <0.001
<0.001 0.09
0.04
0.9 0.3
0.2
0.06 <0.001
0.1 0.1 0.2
B)
Age at diagnosis (years)
Gender, n (%) Race, n (%)
Mean Median IQR Male Female Caucasian African-American
UCUB (n=10,596; 92) PC RC (n=1,278; 12) (n=9,318; 88) 72 67 73 64-80 1,007 (78.8) 271 (21.2) 1,112 (87) 94 (7.4)
68 60-75 7,348 (78.9) 1,970 (21.1) 8,407 (90.2) 450 (4.8)
p-value
PC (n=248; 26)
<0.001
65
nonUCUB (n=946; 8) RC (n=698; 74) 66
65 55-76 150 (60.5) 98 (39.5) 203 (81.9) 27 (10.9)
67 59-75 449 (64.3) 249 (35.7) 609 (87.2) 61 (8.7)
0.9 <0.001
p-value 0.2
0.3 0.06
Marital status, n (%)
Socioeconomic status, n (%) Year of diagnosis, n (%)
Size (mm)
T stage, n (%) Histological subtypes, n (%)
Lymph node dissection, n (%) Chemotherapy, n (%) Radiation therapy, n (%)
Other Married
72 (5.6) 802 (62.8)
461 (4.9) 6,118 (65.7)
0.07
18 (7.3) 135 (54.4)
28 (4) 432 (61.9)
0.1
Unmarried Unknown 1 quartile
423 (33.1) 53 (4.1) 347 (27.2)
2,790 (29.9) 410 (4.4) 2,419 (26)
0.4
101 (40.7) 12 (4.8) 66 (26.6)
235 (33.7) 31 (4.4) 194 (27.8)
0.8
2-3-4 quartile 2001-2006
931 (72.8) 471 (36.9)
6899 (74) 2,851 (30.6)
<0.001
182 (73.4) 79 (31.9)
504 (72.2) 217 (31.1)
0.9
2007-2011 2012-2016 Mean Median IQR T1 T2 UCUB
422 (33) 385 (30.1) 35.5 30 20-50 581 (45.5) 697 (54.5) 1,278 (100)
3,120 (33.5) 3,347 (35.9) 40 35 20-50 2,494 (26.8) 6,824 (73.2) 9,318 (100)
84 (33.9) 85 (34.3) 42.5 34 20-50 96 (38.7) 152 (61.3) 0 (0)
249 (35.7) 232 (33.2) 47 40 25-53 166 (23.8) 532 (76.2) 0 (0)
Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other No
0 (0) 0 (0)
0 (0) 0 (0)
115 (46.5) 50 (20)
0 (0)
0 (0)
34 (14)
175 (25.1) 244 (35) 144 (20.6)
0 (0) 846 (66.2)
0 (0) 2,114 (22.7)
<0.001
49 (19.5) 149 (60.1)
135 (19.3) 180 (25.8)
<0.001
Yes No/Unknown
432 (33.8) 1,000 (78.2)
7,204 (77.3) 6,338 (68)
<0.001
99 (39.9) 205 (82.7)
518 (74.2) 484 (69.3)
<0.001
Yes No/Unknown
278 (21.8) 1,213 (94.9)
2,980 (32) 9,213 (98.9)
<0.001
43 (17.3) 230 (92.7)
214 (30.7) 677 (97)
0.006
Yes
65 (5.1)
105 (1.1)
18 (7.3)
21 (3)
0.007
<0.001 1.0
0.01
<0.001 <0.001
Table 2. Multivariable Cox regression models predicting cancer-specific (CSM) and overall mortality (OM), in patients with bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Urothelial carcinoma of the urinary bladder (UCUB) vs. variant histology (nonUCUB) b) UCUB vs. nonUCUB after Inverse Probability of Treatment Weighting (IPTW) c) UCUB vs. adenocarcinoma vs. squamous carcinoma vs. neuroendocrine carcinoma vs. other histological subtype
HR: Hazard ratio CI: confidence interval a)
Histology Age at diagnosis (years) Gender T stage Chemotherapy Radiation therapy
UCUB nonUCUB Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) p-value Ref. 1.4 (1.0-2.0) 0.03 1.0 (1.0-1.0) <0.001 Ref. 1.0 (0.8-1.3) 0.9 Ref. 1.5 (1.2-2.0) 0.001 Ref. 0.9 (0.7-1.2) 0.5 Ref. 1.6 (1.1-2.9) <0.001
OM HR (95% CI) p-value Ref. 1.1 (0.8-1.4) 0.7 1.1 (1.0-1.1) <0.001 Ref. 1.1 (0.9-1.4) 0.3 Ref. 1.3 (1.1-2.6) 0.006 Ref. 0.8 (0.7-1.1) 0.1 Ref. 1.8 (1.5-2.8) <0.001
b)
Histology Age at diagnosis (years) Gender T stage Chemotherapy Radiation therapy
UCUB nonUCUB
Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) Ref. 1.3 (1.0-1.6) 1.0 (1.0-1.0) Ref. 1.1 (0.9-1.5) Ref. 1.5 (1.1-1.9) Ref. 1.0 (0.8-1.4) Ref. 1.4 (1.1-2.7)
p-value 0.04 <0.001
0.3 0.003 0.8 <0.001
OM HR (95% CI) Ref. 1.0 (0.8-1.2) 1.1 (1.0-1.1) Ref. 1.2 (0.9-1.5) Ref. 1.3 (1.1-1.6) Ref. 0.9 (0.7-1.1) Ref. 1.8 (1.5-2.8)
p-value 0.9 <0.001
0.08 0.005 0.2 <0.001
c)
Histology
Age (years) Gender T stage Chemotherapy Radiation therapy
UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) Ref. 1.2 (0.8-1.9) 1.7 (1.0-3.2) 1.2 (0.6-2.6) 1.6 (0.8-3.1) 1.0 (1.0-1.0) Ref. 1.0 (0.8-1.3) Ref. 1.5 (1.2-2.0) Ref. 0.9 (0.7-1.2) Ref. 1.6 (1.1-2.9)
p-value 0.4 0.04 0.6 0.1 <0.001 0.9 <0.001 0.5 <0.001
OM HR (95% CI) p-value Ref. 0.9 (0.6-1.4) 0.7 1.2 (0.7-2.1) 0.4 0.9 (0.5-1.8) 0.8 1.3 (0.7-2.1) 0.4 1.1 (1.0-1.1) <0.001 Ref. 1.1 (0.9-1.4) 0.3 Ref. 1.3 (1.1-1.6) 0.005 Ref. 0.8 (0.7-1.1) 0.1 Ref. 1.9 (1.3-2.9) <0.001
Supplementary Table 1. Histological subtypes of 1,526 patients with bladder cancer treated with partial cystectomy identified within the Surveillance, Epidemiology, and End Results database from 2001 to 2016, stratified according to International Classification of Disease for Oncology 3 [ICD-O-3] site codes Histological subtypes (n= 1,526) Urothelial carcinoma of the urinary bladder (n= 1,278)
Neuroendocrine carcinoma (n= 34)
Squamous carcinoma (n= 50)
Adenocarcinoma (n= 115)
Other (n= 49)
8120 (TRANSITIONAL CELL CARCINOMA, NOS) 8122 (TRANSITIONAL CELL CARCINOMA, NOS) 8130 (PAPILLARY TRANS. CELL CARCINOMA) 8131 (PAPILLARY TRANS. CELL CARCINOMA) 8020 (CARCINOMA, UNDIFF., NOS) 8082 (LYMPHOEPITHELIAL CARCINOMA) 8041 (SMALL CELL CARCINOMA, NOS) 8240 (CARCINOID TUMOR, MALIGNANT) 8246 (CARCINOID TUMOR, MALIGNANT) 8680 (PARAGANGLIOMA) 8051 (PAPILLARY CARCINOMA, NOS) 8052 (PAPILLARY CARCINOMA, NOS) 8070 (SQUAMOUS CELL CARCINOMA, NOS) 8071 (SQUAMOUS CELL CARCINOMA, NOS) 8140 (ADENOCARCINOMA, NOS) 8144 (ADENOCARCINOMA, NOS) 8255 (BRONCHIOLO-ALVEOLAR ADENOCA) 8260 (PAPILLARY ADENOCARCINOMA, NOS) 8261 (PAPILLARY ADENOCARCINOMA, NOS) 8262 (PAPILLARY ADENOCARCINOMA, NOS) 8263 (PAPILLARY ADENOCARCINOMA, NOS) 8310 (CLEAR CELL ADENOCARCINOMA, NOS) 8480 (MUCINOUS ADENOCARCINOMA) 8481 (MUCINOUS ADENOCARCINOMA) 8490 (SIGNET RING CELL CARCINOMA) 8560 (ADENOSQUAMOUS CARCINOMA) 8010 (CARCINOMA, NOS) 8032 (GIANT & SPINDLE CELL CARCINOMA) 8033 (GIANT & SPINDLE CELL CARCINOMA) 8035 (GIANT & SPINDLE CELL CARCINOMA) 8050 (PAPILLARY CARCINOMA, NOS) 8700 (PHEOCHROMOCYTOMA) 8720 (NEVI & MELANOMAS) 8804 (SARCOMA, NOS) 8830 (FIBROUS HISTIOCYTOMA, MAL.) 8890 (MYOMATOUS NEOPLASMS) 8896 (MYOMATOUS NEOPLASMS) 8980 (CARCINOSARCOMA, NOS)
ICD-0-3 SEER SITE/HISTOLOGY VALIDATION LIST Transitional cell carcinoma, NOS Trans. cell carcinoma, spindle cell Papillary trans. cell carcinoma Transitional cell carcinoma, micropapillary CARCINOMA, UNDIFFERENTIATED, NOS Lymphoepithelial carcinoma SMALL CELL CARCINOMA, NOS CARCINOID TUMOR, MALIGNANT Neuroendocrine carcinoma PARAGANGLIOMA malignant Verrucous carcinoma, NOS Papillary squamous cell carcinoma SQUAMOUS CELL CARCINOMA, NOS Sq. cell carcinoma, keratinizing, NOS ADENOCARCINOMA, NOS Adenocarcinoma, intestinal type Adenocarcinoma with mixed subtypes PAPILLARY ADENOCARCINOMA, NOS Adenocarcinoma in villous adenoma Villous adenocarcinoma Adenocarcinoma in tubulovillous adenoma CLEAR CELL ADENOCARCINOMA, NOS MUCINOUS ADENOCARCINOMA Mucin-producing adenocarcinoma SIGNET RING CELL CARCINOMA ADENOSQUAMOUS CARCINOMA CARCINOMA, NOS Spindle cell carcinoma Pseudosarcomatous carcinoma Carcinoma with osteoclast-like giant cells PAPILLARY CARCINOMA, NOS PHEOCHROMOCYTOMA Malignant melanoma, NOS Epithelioid sarcoma FIBROUS HISTIOCYTOMA, MAL.): Leiomyosarcoma, NOS Myxoid leiomyosarcoma CARCINOSARCOMA, NOS
n 616 15 635 4 3 5 22 1 9 2 1 2 32 15 60 3 7 2 3 1 2 1 23 8 4 1 14 1 3 1 2 1 1 1 1 16 1 7
Supplementary Table 2. Multivariable Cox regression models, performed after Inverse Probability of Treatment Weighting (IPTW), predicting cancer-specific (CSM) and overall mortality (OM), in patients with bladder cancer treated with partial (PC) or radical cystectomy (RC) and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. All models were adjusted for age at diagnosis, gender, T stage (T1 vs. T2), as well as chemotherapy and radiation therapy administration. HR: Hazard ratio CI: confidence interval UCUB: urothelial carcinoma of the urinary bladder nonUCUB: variant histology bladder cancer
nonUCUB UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other histological subtypes
PC vs. RC PC vs. RC PC vs. RC PC vs. RC PC vs. RC PC vs. RC
CSM HR (95% CI) p-value 1.1 (0.8-1.4) 0.6 1.0 (0.9-1.1) 0.5 1.0 (0.6-1.8) 0.9 1.6 (0.9-2.7) 0.07 1.2 (0.6-2.3) 0.5 0.8 (0.5-1.5) 0.5
OM HR (95% CI) p-value 1.0 (0.8-1.3) 0.9 1.0 (0.9-1.1) 0.3 1.1 (0.7-1.7) 0.8 1.3 (0.8-1.9) 0.2 1.1 (0.6-2.0) 0.6 0.9 (0.5-1.5) 0.6
Clinical Practice Points: •
Small scale studies analyzed cancer-specific mortality in patients with variant histology bladder cancer treated with partial cystectomy
•
In patients treated with partial cystectomy, variant histology bladder cancer was associated with higher cancer-specific mortality, compared to urothelial carcinoma of the urinary bladder
•
In patients with variant histology of bladder cancer, cystectomy type (namely: partial vs. radical cystectomy) is not associated with worse survival outcomes
•
Important variability with respect to cancer-specific mortality was recorded within each non urothelial histological subtype
•
These results may act as generating hypothesis for future trial design
S1558-7673(19)30320-9
DOI:
https://doi.org/10.1016/j.clgc.2019.10.016
Reference:
CLGC 1378
To appear in:
Clinical Genitourinary Cancer
Received Date: 8 August 2019 Revised Date:
1 October 2019
Accepted Date: 6 October 2019
Please cite this article as: Luzzago S, Palumbo C, Rosiello G, Knipper S, Pecoraro A, Deuker M, Mistretta FA, Tian Z, Musi G, Montanari E, Shariat SF, Saad F, Briganti A, de Cobelli O, Karakiewicz PI, Survival after partial cystectomy for variant histology bladder cancer compared to urothelial carcinoma: a population-based study, Clinical Genitourinary Cancer (2019), doi: https://doi.org/10.1016/ j.clgc.2019.10.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Microabstract
Within the SEER database, we evaluated cancer-specific mortality (CSM) in 248 T1-2N0M0 variant histology bladder cancer patients (nonUCUB) treated with partial cystectomy (PC). In Cox regression models, nonUCUB PC treated patients exhibited higher CSM, compared to urothelial carcinoma patients treated with PC. Conversely, nonUCUB patients treated with PC had similar CSM when compared to nonUCUB patients treated with radical cystectomy.
1
Survival after partial cystectomy for variant histology bladder cancer compared
2
to urothelial carcinoma: a population-based study
3
Stefano Luzzagoa,b, Carlotta Palumboa,c Giuseppe Rosielloa,d, Sophie Knippera,e,
4
Angela Pecoraroa,f, Marina Deukerg, Francesco Alessandro Mistrettaa,b, Zhe Tiana,
5
Gennaro Musib, Emanuele Montanarih, Shahrokh F. Shariati,l,m,n,o, Fred Saada,
6
Alberto Brigantib, Ottavio de Cobellib,p, Pierre I. Karakiewicza
7 8 9
a
Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health
Center, Montreal, Quebec, Canada
10
b
11
c
12
Radiological Science and Public Health, University of Brescia, Italy
13
d
14
IRCCS San Raffaele Scientific Institute, Milan, Italy
15
e
16
Germany
17
f
18
g
19
h
20
of Milan, Milan, Italy
21
i
22
Austria
23
l
24
m
25
n
Department of Urology, Second Faculty of Medicine, Charles University, Prag, Czech Republic
26
o
Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical
27
University, Moscow, Russia
28 29 30 31 32 33 34 35 36 37
p
38
Word count (abstract): 250
39
Word count (manuscript): 2378
Department of Urology, European Institute of Oncology, Milan, Italy
Urology Unit, ASST Spedali Civili of Brescia. Department of Medical and Surgical Specialties,
Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute,
Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg,
Department of Urology, San Luigi Gonzaga Hospital, University of Turin, Turin, Italy Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany. Department of Urology, IRCCS Fondazione Ca’ Granda-Ospedale Maggiore Policlinico, University
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna,
Departments of Urology, Weill Cornell Medical College, New York, New York, USA Department of Urology, University of Texas Southwestern, Dallas, Texas, USA
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Corresponding author: Stefano Luzzago, MD Department of Urology, European Institute of Oncology, Milan, Italy Via Giuseppe Ripamonti, 435 20141 Milan, Italy Tel: +39 33354249298 E-mail: [email protected]
40
1
41 42
Declarations of interest: none
43 44 45 46
List of abbreviations
47
PC: Partial cystectomy
48
RC: Radical cystectomy
49
UCUB: Urothelial carcinoma of the urinary bladder
50
nonUCUB: Variant histology bladder cancer
51
CSM: cancer-specific mortality
52
SEER: Surveillance, Epidemiology and End Results
53
ICD-O: International Classification of Disease for Oncology
54
WHO: World Health Organization
55
IPTW: Inverse Probability of Treatment Weighting
56
IQR: interquartile range
57
CI: confidence interval
58
HR: Hazard Ratio
59 60
2
61
Abstract
62
Background
63
To test cancer-specific mortality (CSM) after partial cystectomy (PC) for variant histology bladder
64
cancer (nonUCUB), relative to urothelial carcinoma of the urinary bladder (UCUB) and relative to
65
radical cystectomy (RC).
66 67
Materials and Methods
68
Within the Surveillance, Epidemiology, and End Results registry (2001–2016), we identified
69
T1-2,N0,M0 nonUCUB and UCUB patients treated with PC and corresponding groups treated with
70
RC. Non-UCUB included adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma, other
71
histological subtypes. First, CSM after PC was compared between nonUCUB and UCUB. Second,
72
CSM after PC was compared to RC in nonUCUB. Kaplan Meier plots and multivariable Cox
73
regression models were used before and after Inverse Probability of Treatment Weighting (IPTW)
74
adjustment.
75 76
Results
77
Overall, 248 (16.3%) patients treated with PC harboured nonUCUB. Of those, 115 (46.5%) vs. 50
78
(20%) vs. 34 (14%) vs. 49 (19.5%) were, respectively, adenocarcinoma vs. squamous carcinoma vs.
79
neuroendocrine carcinoma vs. other histological subtypes. Five-year CSM rates after PC were 23%
80
vs. 27% vs. 27% vs. 15% vs. 19% for adenocarcinoma vs. squamous carcinoma vs. neuroendocrine
81
carcinoma vs. other vs. UCUB, respectively. The comparison between PC in nonUCUB vs. PC in
82
UCUB showed higher CSM in nonUCUB patients (HR:1.4;p=0.03). The comparison between PC
83
in nonUCUB vs. RC in nonUCUB showed no CSM differences.
84 85
Conclusions
3
86
PC for nonUCUB results in higher mortality than PC for UCUB. However, PC instead of RC in
87
select nonUCUB patients does not undermine survival. In consequence, the excess CSM is
88
unrelated to cystectomy type, but originates from tumor biology. These results may act as
89
generating hypothesis for future trial design.
90 91
Keywords: neuroendocrine carcinoma; adenocarcinoma; squamous carcinoma; other histological subtypes
4
92 93
Introduction
Partial cystectomy (PC) represents an alternative to radical cystectomy (RC) in well selected
94
patients with urothelial carcinoma of the urinary bladder (UCUB) 1. The NCCN Guidelines 2
95
recommend that PC should be reserved to patients with ≤cT2 disease, with a solitary lesion and in
96
location amenable to segmental resection with adequate negative surgical margins. Moreover, in
97
some elderly patients, the morbidity associated with RC may be prohibitive 3,4 and PC outside of
98
this definition may be contemplated. Despite adequate data supporting the use of PC in UCUB 5,6,
99
virtually no data exist regarding use of PC in patients with variant histology (nonUCUB) 7–11.
100
To address this void, we examined PC use in nonUCUB patients and compared cancer-specific
101
mortality (CSM) according to PC in UCUB. Moreover, we also tested CSM rates according to PC
102
vs. RC in nonUCUB patients. Our analyses were meant to test two specific concepts, namely
103
whether CSM is affected by tumor biology, cystectomy type, or both in nonUCUB patients.
104
5
105
Materials and methods
106
Study population
107
Within the Surveillance, Epidemiology and End Results (SEER) 12 database (2001–2016),
108
we focused on patients aged 18 years or older with histologically confirmed bladder cancer
109
(International Classification of Disease for Oncology [ICD-O] site codes C67.0-67.9). Death
110
certificate only and autopsy cases were excluded. Patients with urachal location of the tumor (ICD-
111
O site code C67.7) were not considered for the analyses. According to NCCN Guidelines 2, only
112
patients with T1-2, N0, M0 bladder cancer were considered (n=11,542). Study population consisted
113
of two specific cohorts. The first cohort included patients treated with PC (n=1,526) with either
114
nonUCUB (n=248; 16.3%) or UCUB (1,278; 83.7%) histology. The second cohort consisted of
115
nonUCUB or UCUB patients that were either treated with PC (n=248 and n=1,278) or RC (n=698
116
and n= 9,318).
117 118 119
Variables definition Within the nonUCUB cohort and according to the 2016 World Health Organization (WHO)
120
classification of bladder tumors 13, four major histological variants were recognized:
121
adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma and other histological subtypes
122
(Supplementary Table 1). Demographic characteristics consisted of age, gender, year of diagnosis
123
(2001-2006 vs. 2007-2011 vs. 2012-2016), marital status (married, unmarried, unknown), race
124
(White, Black, Hispanic, Other) and socioeconomic status (1 quartile vs. 2-3-4 quartile). Tumor
125
size, T stage (T1 vs. T2) and rates of chemotherapy and radiation therapy were also considered.
126 127 128
Statistical analyses Descriptive statistics relied on tests of means and proportions and, respectively, used the t-
129
test and the chi-square. Two types of specific comparisons that relied on CSM rates were
130
performed. First, PC in nonUCUB was compared to PC in UCUB. Kaplan-Meier plots and
6
131
multivariable Cox regression models tested the effect of histology on CSM before and after Inverse
132
Probability of Treatment Weighting (IPTW) adjustment 14. Second, PC was compared to RC in
133
nonUCUB and UCUB patients. Here, Inverse Probability of Treatment Weighting (IPTW) was used
134
to minimize potential differences that might exist in patients’ characteristics, according to PC vs.
135
RC status 14. IPTW adjusted Kaplan-Meier plots graphically depicted the relationship between PC
136
and RC on CSM according to histology. Moreover, IPTW adjusted multivariable Cox regression
137
models tested the effect of PC vs. RC on CSM within each histological variant. In all analyses,
138
IPTW-adjustment relied on the following variables: age, gender, race, socioeconomic status, marital
139
status, year of diagnosis, T stage, chemotherapy and radiation therapy administration. R software
140
environment was used in all statistical analyses and graphics (version 3.4.3). All tests were two
141
sided with a level of significance set at p <0.05.
7
142
Results
143
Descriptive analyses
144
Within the first cohort that consisted of 1,526 patients treated with PC, 1,278 (83.7%) and
145
248 (16.3%) harboured UCUB vs. nonUCUB (Table 1a). Patients with nonUCUB were younger
146
(65 vs. 73 years; p<0.001), and more frequently female (39.5% vs. 21.2%; p<0.001) and unmarried
147
(40.7% vs. 33.1%; p=0.04). Median (interquartile range [IQR]) tumor size was 34 (20-50) vs. 30
148
(20-50) in nonUCUB vs. UCUB, respectively (p=0.2). The percentage of T1 vs. T2 tumors was
149
38.7% vs. 61.3% and 45.5% vs. 54.5% in nonUCUB vs. UCUB, respectively (p=0.06). Among
150
patients with nonUCUB, 115 (46.5%), 50 (20%), 34 (14%) and 49 (19.5%) harboured
151
adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma and other histological subtypes,
152
respectively.
153
Within the second cohort, 248 (26%) and 698 (74%) patients with nonUCUB were treated with PC
154
and RC, respectively (Table 1b). Patients treated with PC had lower median tumor size (34 [20-50]
155
vs. 40 [25-53]; p=0.01) and more frequently harboured T1 stage (38.7% vs. 23.8%) vs. less
156
frequently harboured T2 stage (61.3% vs. 76.2%; p<0.001). Moreover, nonUCUB patients treated
157
with PC less frequently underwent lymph node dissection (39.9% vs. 74.2%; p<0.001) and
158
chemotherapy (17.3% vs. 30.7%; p<0.001), but more frequently underwent radiation therapy (7.3%
159
vs. 3%; p=0.006).
160 161 162
Survival analyses between PC nonUCUB and PC UCUB patients Median follow-up time was 42 (IQR: 19-87) and 46 (IQR: 18-88) months for nonUCUB and
163
UCUB, respectively. Overall, 68 vs. 439 deaths were recorded during the study period, in
164
nonUCUB vs. UCUB. Five-year CSM rates were 23% vs. 19% for nonUCUB vs. UCUB (p=0.3;
165
Figure 1a). Moreover, five-year CSM rates were 23% vs. 27% vs. 27% vs. 15% for adenocarcinoma
166
vs. squamous carcinoma vs. neuroendocrine carcinoma vs. other histological subtypes (p=0.5;
167
Figure 2). In a subgroup analysis of T1 patients, 5-year CSM rates were respectively 15% vs. 13% 8
168
for nonUCUB vs. UCUB (p=0.8; Figure 1c). Conversely, in a subgroup analysis of T2 patients, 5-
169
year CSM rates were respectively 28%, vs. 24% for nonUCUB vs. UCUB (p=0.3; Figure 1d).
170
In multivariable Cox regression models, nonUCUB was associated with higher CSM both before
171
(Hazard Ratio [HR]: 1.4, 95% confidence interval [CI]: 1.0-2.0; p=0.03; Table 2a) and after IPTW
172
adjustment (HR: 1.3, 95% CI: 1.0-1.6; p=0.04; Table 2b), compared to UCUB. Moreover, in
173
multivariable Cox regression models, squamous carcinoma was associated with higher CSM (HR:
174
1.7, 95% CI: 1.0-3.2; p=0.04; Table 2c), compared to UCUB. Conversely, adenocarcinoma (HR:
175
1.2; 95% CI: 0.8-1.9; p=0.4), neuroendocrine carcinoma (HR: 1.2; 95% CI: 0.6-2.6; p=0.6) and
176
other histological subtypes (HR: 1.6; 95% CI: 0.8-3.1; p=0.1) were not associated with higher
177
CSM, compared to UCUB.
178 179
Survival analyses between PC and RC for nonUCUB and UCUB patients
180
In IPTW adjusted Kaplan-Meier plots focusing on nonUCUB, 5-year CSM rates were
181
respectively 23.5% vs. 21% (p=0.9) for patients treated with PC vs. RC (Figure 3a). In IPTW
182
adjusted Kaplan-Meier plots focusing on UCUB, 5-year CSM rates were respectively 18% vs. 17%
183
(p=0.2) for patients treated with PC vs. RC (Figure 3b). In IPTW adjusted Kaplan-Meier plots
184
focusing on adenocarcinoma, 5-year CSM rates were respectively 22% vs. 16% (p=0.9) for patients
185
treated with PC vs. RC (Figure 3c). In IPTW adjusted Kaplan-Meier plots focusing on squamous
186
carcinoma, 5-year CSM rates were respectively 27% vs. 20% (p=0.2) for patients treated with PC
187
vs. RC (Figure 3d). In IPTW adjusted Kaplan-Meier plots focusing on neuroendocrine carcinoma,
188
5-year CSM rates were respectively 28% vs. 22% (p=0.5) for patients treated with PC vs. RC
189
(Figure 3e). In IPTW adjusted Kaplan-Meier plots focusing on other histological subtypes, 5-year
190
CSM rates were respectively 19% vs. 32% (p=0.2) for patients treated with PC vs. RC (Figure 3f).
191
In multivariable IPTW adjusted Cox regression models, PC was not associated with higher CSM
192
neither in nonUCUB (HR: 1.1, 95% CI: 0.8-1.4; p=0.6), nor in UCUB (HR: 1.0, 95% CI: 0.9-1.1;
193
p=0.5), adenocarcinoma (HR: 1.0, 95% CI: 0.6-1.8; p=0.9), squamous carcinoma (HR: 1.6, 95% 9
194
CI: 0.9-2.7; p=0.07), neuroendocrine carcinoma (HR: 1.2, 95% CI: 0.6-2.3; p=0.5) or other
195
histological subtypes (HR: 0.8, 95% CI: 0.5-1.5; p=0.5), compared to RC.
196 197
Natural history within PC nonUCUB subtypes
198
Finally we performed a descriptive analysis of specific variant histology subtypes that were
199
treated with PC (Figure 4). Among patients with adenocarcinoma (Figure 4a), 64 (56%), 7 (6%), 1
200
(1%), 31 (27%), 8 (7%) and 4 (3%) patients had adenocarcinoma NOS, bronchio-alveolar, clear-
201
cell, mucinous, papillary and signet-ring histology, respectively. Of those, 7 (11%), 1 (14%), 7
202
(22%), 3 (37.5%) and 3 (75%) patients with adenocarcinoma NOS, bronchio-alveolar, mucinous,
203
papillary and signet-ring histology experienced CSM after a median follow-up time of 56 (IQR: 30-
204
87) months.
205
Among patients with squamous carcinoma (Figure 4b), 47 (94%) and 3 (6%) had squamous NOS
206
and papillary histology, respectively. Of those, 11 (24%) patients with squamous NOS histology
207
experienced CSM after a median follow-up time of 27 (IQR: 13-59) months.
208
Among patients with neuroendocrine carcinoma (Figure 4c), 22 (65%), 10 (30%) and 2 (5%) had
209
small cell, carcinoid and paraganglioma histology, respectively. Of those, 4 (19%) and 3 (30%)
210
patients with small cell and carcinoid histology experienced CSM after a median follow-up time of
211
28 (IQR: 10-98) months.
212
Among patients with other histological subtypes (Figure 4d), the following histologies were
213
recorded: carcinoma NOS (n=14; 29%), carcinosarcoma (n=7; 14%), fibromatous carcinoma (n=1;
214
2%), giant and spindle cell (n=5; 10%), melanoma (n=1; 2%), myomatous carcinoma (n=17; 35%),
215
papillary (n=2; 4%), pheocromocytoma (n=1; 2%) and sarcoma (n=1; 2%). Of those, 3 (21%), 1
216
(14%), 1 (100%), 1 (100%), 2 (12%), 1 (50%) and 1 (100%) patients with carcinoma NOS,
217
carcinosarcoma, fibromatous carcinoma, melanoma, myomatous carcinoma, papillary and
218
pheocromocytoma histology experienced CSM after a median follow-up time of 43 (IQR: 17-93)
219
months. 10
220 221
Discussion
PC has not been studied in patients with nonUCUB. Based on lack of data on that topic 7–11,
222
we performed two separate analyses. First, we compared CSM rates after PC between nonUCUB
223
and UCUB. Second, we compared CSM rates after PC vs. RC in nonUCUB patients.
224
The first comparison demonstrated that nonUCUB is associated with higher CSM in patients
225
treated with PC, compared to UCUB. Moreover, in analyses that were stratified according to
226
specific nonUCUB subtypes, higher CSM was recorded, albeit the differences were not significant,
227
except for squamous carcinoma. These observations indicate higher mortality after PC in nonUCUB
228
patients, relative to their UCUB counterparts, despite most detailed adjustment for the effect of
229
patient related differences. Moreover, stratification according to nonUCUB subtype suggests that all
230
nonUCUB subtypes confer higher mortality after PC, relative to PC for UCUB. Based on sample
231
size considerations, only the comparison between PC in squamous carcinoma vs. PC in UCUB
232
resulted in statistically significant differences. Given the novelty of these findings, we cannot
233
directly compare these results with similar analyses of previous reports that focused on PC.
234
However, some authors examined the effect of nonUCUB on survival in RC cohorts. Within the
235
National Cancer Database (NCDB), Vetterlein et al. 15 reported worse overall survival for patients
236
with squamous carcinoma and neuroendocrine carcinoma, relative to UCUB. Moschini et al. 16
237
showed worse CSM (HR: 1.5) for pure nonUCUB treated with RC, when compared to UCUB.
238
Moreover, in several previous institutional RC series 10,17–19, histological variants were associated
239
with worse outcomes in univariable, but not in multivariable models.
240
Our second comparison focused on PC vs. RC in nonUCUB patients. Here the opposite
241
findings were recorded. Specifically, regardless of cystectomy type (PC vs. RC), no CSM
242
differences were recorded. Further stratification according to nonUCUB subtype also revealed no
243
differences between PC vs. RC in all six histological subtype comparisons. These findings indicate
244
that cystectomy type (PC vs. RC) does not affect the treated the natural history of T1-2 nonUCUB
245
bladder cancer. Taken together, the results of both analyses indicate that tumor biology, namely 11
246
presence of nonUCUB instead of UCUB, increases CSM. However, once the patient is diagnosed
247
with nonUCUB, use of PC in properly selected patients is not associated with worse CSM, relative
248
to similar nonUCUB patients treated with RC. This implies that similar consideration for PC may
249
be given to properly selected nonUCUB patients as much as in properly selected UCUB patients 2.
250
Unfortunately, we were not capable of validating these observations after controlling for specific
251
information regarding tumor focality, location and/or presence of carcinoma in situ, as
252
recommended for UCUB 2. In the last part of our study, we performed a detailed descriptive analysis of nonUCUB
253 254
patients treated with PC, stratified by histological subtypes. These analyses demonstrated important
255
variability with respect to CSM within each histological subtype. We identified specific histological
256
subgroups within the main histological subtypes that are associated with particularly adverse CSM
257
patterns. For example 75% of patients with signet-ring adenocarcinoma died during follow-up 20.
258
However, very few of these patients (n=4) were identified within the SEER database 12. Conversely,
259
some variant histology subgroups are associated with more favourable prognosis. For example, no
260
patient with papillary squamous (n=3), paraganglioma (n=2) 21 or giant and spindle cell carcinoma
261
(n=5) died during follow-up. Finally, many variant histology subgroups showed variability with
262
respect to prognosis, where some patients have not experienced an event even with long periods of
263
observation. In summary, these observations indicate very important variability within specific
264
subgroups of nonUCUB. Even though particularly aggressive subgroups were identified, these
265
subgroups contained very few observations and recorded outcomes may be affected by small
266
sample size and selection biases. Similar considerations need to be made about more favourable
267
subgroups. In consequence, even a very large database such as the SEER 12 has limit ability to
268
convey specific prognostic information about nonUCUB subtypes beyond indicating that on
269
average higher mortality should be expected compared to UCUB. Despite its novelty, our study has limitations. First, as previously stated, the SEER database
270 271
12
lacks important details regarding specific treatment assignment, such as tumor multifocality or 12
272
concomitant carcinoma in situ and also lacks specific patient characteristics that could have
273
disqualified some patients either from PC or RC. Second, we were unable to examine specific
274
recurrence and progression trends, since this information is not available within the SEER 12. Third,
275
the SEER database 12 does not provide central review. Indeed, previous studies showed that
276
histological variants are commonly under-recognized in community practice 22,23. Fourth, SEER 12
277
represents one of the largest data repositories in the United States. Nonetheless, it represents an
278
informative 33% sample of the United States population designed to reflect population
279
characteristics and racial distribution. However, partial sampling may invariably result in systematic
280
biases and residual confounding relative to the entire population. Unfortunately, no existing data
281
repository allows to assess the totality of the United States population.
13
282
Conclusion
283
PC for nonUCUB results in higher mortality than PC for UCUB. However, PC instead of
284
RC in select nonUCUB patients does not undermine survival. In consequence, the excess CSM is
285
unrelated to cystectomy type, but originates from tumor biology. These results may act as
286
generating hypothesis for future trial design.
287
14
288
Acknowledgments: None
289
Funding: This research did not receive any specific grant from funding agencies in the public,
290
commercial, or not-for-profit sectors
291
15
292
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Figure legends
364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380
Figure 1. Kaplan-Meier curves depicting cancer-specific survival according to histological subtype (urothelial carcinoma of the urinary bladder [UCUB] vs. variant histology [nonUCUB]) in patients with T1-2N0M0 bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Overall; b) After Inverse Probability of Treatment Weighting (IPTW) adjustment; c) Patients with T1 disease; d) Patients with T2 disease
381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397
Figure 3. Inverse Probability of Treatment Weighting (IPTW) adjusted Kaplan-Meier curves depicting cancer-specific survival according to cystectomy type (radical cystectomy vs. partial cystectomy) in patients with T1-2N0M0 bladder cancer, identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Variant histology (nonUCUB); b) Urothelial carcinoma of the urinary bladder (UCUB); c) Adenocarcinoma; d) Squamous carcinoma; e) Neuroendocrine carcinoma; f) Other histological subtype
Figure 2. Kaplan-Meier curves depicting cancer-specific survival according to histological subtype (urothelial carcinoma of the urinary bladder [UCUB] vs. Adenocarcinoma vs. Squamous carcinoma vs. Neuroendocrine carcinoma vs. Other histological subtype) in patients with T12N0M0 bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. 95% confidence interval are provided. a) Overall; b) UCUB; c) Adenocarcinoma; d) Squamous carcinoma; e) Neuroendocrine carcinoma; f) Other histological subtype
Figure 4. Graphical representation of time to event sorted by follow up time in patients with T12N0M0 variant histology bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Adenocarcinoma; b) Squamous carcinoma; c) Neuroendocrine carcinoma; d) Other histological subtype BCa: Bladder Cancer; NOS: not otherwise specified
398 399 400
19
Table 1. Descriptive characteristics of 11,542 patients with histologically confirmed bladder cancer, treated with partial cystectomy (PC) or radical cystectomy (RC) and identified within the Surveillance, Epidemiology, and End Results database from 2001 to 2016. A) Patients treated with PC and stratified according to histology: urothelial carcinoma of the urinary bladder (UCUB) vs. variant histology (nonUCUB) B) Patients are stratified according to cystectomy type: PC vs. RC IQR: interquartile range A)
Age at diagnosis (years)
Gender, n (%) Race, n (%)
Marital status, n (%)
Socioeconomic status, n (%) Year of diagnosis, n (%)
Size (mm)
T stage, n (%) Histological subtypes, n (%)
Lymph node dissection, n (%) Chemotherapy, n (%) Radiation therapy, n (%)
Mean Median IQR Male Female Caucasian African-American Other Married Unmarried Unknown 1 quartile 2-3-4 quartile 2001-2006 2007-2011 2012-2016 Mean Median IQR T1 T2 UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other No Yes No/Unknown Yes No/Unknown Yes
Overall (n=1,526) 70 72 62-80 1,157 (75.8) 369 (24.2) 1,315 (86.2) 121 (7.9) 90 (5.9) 937 (61.4) 524 (34.3) 65 (4.3) 413 (27.1) 1,113 (72.9) 550 (36) 506 (33.2) 470 (30.8) 37 30 20-50 677 (44.4) 849 (55.6) 1,278 (83.7) 115 (7.5) 50 (3.3) 34 (2.2) 49 (3.2) 1,025 (65.2) 501 (34.8) 1,205 (79) 321 (21) 1,443 (94.6) 83 (5.4)
UCUB (n=1,278; 84) 72 73 64-80 1,007 (78.8) 271 (21.2) 1,112 (87) 94 (7.4) 72 (5.6) 802 (62.8) 423 (33.1) 53 (4.1) 347 (27.2) 931 (72.8) 471 (36.9) 422 (33) 385 (30.1) 35.5 30 20-50 581 (45.5) 697 (54.5) 1,278 (100) 0 (0) 0 (0) 0 (0) 0 (0) 846 (66.2) 432 (33.8) 1,000 (78.2) 278 (21.8) 1,213 (94.9) 65 (5.1)
nonUCUB (n=248; 16) 65 65 55-76 150 (60.5) 98 (39.5) 203 (81.9) 27 (10.9) 18 (7.3) 135 (54.4) 101 (40.7) 12 (4.8) 66 (26.6) 182 (73.4) 79 (31.9) 84 (33.9) 85 (34.3) 42.5 34 20-50 96 (38.7) 152 (61.3) 0 (0) 115 (46.5) 50 (20) 34 (14) 49 (19.5) 149 (60.1) 99 (39.9) 205 (82.7) 43 (17.3) 230 (92.7) 18 (7.3)
p-value <0.001
<0.001 0.09
0.04
0.9 0.3
0.2
0.06 <0.001
0.1 0.1 0.2
B)
Age at diagnosis (years)
Gender, n (%) Race, n (%)
Mean Median IQR Male Female Caucasian African-American
UCUB (n=10,596; 92) PC RC (n=1,278; 12) (n=9,318; 88) 72 67 73 64-80 1,007 (78.8) 271 (21.2) 1,112 (87) 94 (7.4)
68 60-75 7,348 (78.9) 1,970 (21.1) 8,407 (90.2) 450 (4.8)
p-value
PC (n=248; 26)
<0.001
65
nonUCUB (n=946; 8) RC (n=698; 74) 66
65 55-76 150 (60.5) 98 (39.5) 203 (81.9) 27 (10.9)
67 59-75 449 (64.3) 249 (35.7) 609 (87.2) 61 (8.7)
0.9 <0.001
p-value 0.2
0.3 0.06
Marital status, n (%)
Socioeconomic status, n (%) Year of diagnosis, n (%)
Size (mm)
T stage, n (%) Histological subtypes, n (%)
Lymph node dissection, n (%) Chemotherapy, n (%) Radiation therapy, n (%)
Other Married
72 (5.6) 802 (62.8)
461 (4.9) 6,118 (65.7)
0.07
18 (7.3) 135 (54.4)
28 (4) 432 (61.9)
0.1
Unmarried Unknown 1 quartile
423 (33.1) 53 (4.1) 347 (27.2)
2,790 (29.9) 410 (4.4) 2,419 (26)
0.4
101 (40.7) 12 (4.8) 66 (26.6)
235 (33.7) 31 (4.4) 194 (27.8)
0.8
2-3-4 quartile 2001-2006
931 (72.8) 471 (36.9)
6899 (74) 2,851 (30.6)
<0.001
182 (73.4) 79 (31.9)
504 (72.2) 217 (31.1)
0.9
2007-2011 2012-2016 Mean Median IQR T1 T2 UCUB
422 (33) 385 (30.1) 35.5 30 20-50 581 (45.5) 697 (54.5) 1,278 (100)
3,120 (33.5) 3,347 (35.9) 40 35 20-50 2,494 (26.8) 6,824 (73.2) 9,318 (100)
84 (33.9) 85 (34.3) 42.5 34 20-50 96 (38.7) 152 (61.3) 0 (0)
249 (35.7) 232 (33.2) 47 40 25-53 166 (23.8) 532 (76.2) 0 (0)
Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other No
0 (0) 0 (0)
0 (0) 0 (0)
115 (46.5) 50 (20)
0 (0)
0 (0)
34 (14)
175 (25.1) 244 (35) 144 (20.6)
0 (0) 846 (66.2)
0 (0) 2,114 (22.7)
<0.001
49 (19.5) 149 (60.1)
135 (19.3) 180 (25.8)
<0.001
Yes No/Unknown
432 (33.8) 1,000 (78.2)
7,204 (77.3) 6,338 (68)
<0.001
99 (39.9) 205 (82.7)
518 (74.2) 484 (69.3)
<0.001
Yes No/Unknown
278 (21.8) 1,213 (94.9)
2,980 (32) 9,213 (98.9)
<0.001
43 (17.3) 230 (92.7)
214 (30.7) 677 (97)
0.006
Yes
65 (5.1)
105 (1.1)
18 (7.3)
21 (3)
0.007
<0.001 1.0
0.01
<0.001 <0.001
Table 2. Multivariable Cox regression models predicting cancer-specific (CSM) and overall mortality (OM), in patients with bladder cancer treated with partial cystectomy and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. a) Urothelial carcinoma of the urinary bladder (UCUB) vs. variant histology (nonUCUB) b) UCUB vs. nonUCUB after Inverse Probability of Treatment Weighting (IPTW) c) UCUB vs. adenocarcinoma vs. squamous carcinoma vs. neuroendocrine carcinoma vs. other histological subtype
HR: Hazard ratio CI: confidence interval a)
Histology Age at diagnosis (years) Gender T stage Chemotherapy Radiation therapy
UCUB nonUCUB Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) p-value Ref. 1.4 (1.0-2.0) 0.03 1.0 (1.0-1.0) <0.001 Ref. 1.0 (0.8-1.3) 0.9 Ref. 1.5 (1.2-2.0) 0.001 Ref. 0.9 (0.7-1.2) 0.5 Ref. 1.6 (1.1-2.9) <0.001
OM HR (95% CI) p-value Ref. 1.1 (0.8-1.4) 0.7 1.1 (1.0-1.1) <0.001 Ref. 1.1 (0.9-1.4) 0.3 Ref. 1.3 (1.1-2.6) 0.006 Ref. 0.8 (0.7-1.1) 0.1 Ref. 1.8 (1.5-2.8) <0.001
b)
Histology Age at diagnosis (years) Gender T stage Chemotherapy Radiation therapy
UCUB nonUCUB
Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) Ref. 1.3 (1.0-1.6) 1.0 (1.0-1.0) Ref. 1.1 (0.9-1.5) Ref. 1.5 (1.1-1.9) Ref. 1.0 (0.8-1.4) Ref. 1.4 (1.1-2.7)
p-value 0.04 <0.001
0.3 0.003 0.8 <0.001
OM HR (95% CI) Ref. 1.0 (0.8-1.2) 1.1 (1.0-1.1) Ref. 1.2 (0.9-1.5) Ref. 1.3 (1.1-1.6) Ref. 0.9 (0.7-1.1) Ref. 1.8 (1.5-2.8)
p-value 0.9 <0.001
0.08 0.005 0.2 <0.001
c)
Histology
Age (years) Gender T stage Chemotherapy Radiation therapy
UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other Female Male T1 T2 No/Unknown Yes No/Unknown Yes
CSM HR (95% CI) Ref. 1.2 (0.8-1.9) 1.7 (1.0-3.2) 1.2 (0.6-2.6) 1.6 (0.8-3.1) 1.0 (1.0-1.0) Ref. 1.0 (0.8-1.3) Ref. 1.5 (1.2-2.0) Ref. 0.9 (0.7-1.2) Ref. 1.6 (1.1-2.9)
p-value 0.4 0.04 0.6 0.1 <0.001 0.9 <0.001 0.5 <0.001
OM HR (95% CI) p-value Ref. 0.9 (0.6-1.4) 0.7 1.2 (0.7-2.1) 0.4 0.9 (0.5-1.8) 0.8 1.3 (0.7-2.1) 0.4 1.1 (1.0-1.1) <0.001 Ref. 1.1 (0.9-1.4) 0.3 Ref. 1.3 (1.1-1.6) 0.005 Ref. 0.8 (0.7-1.1) 0.1 Ref. 1.9 (1.3-2.9) <0.001
Supplementary Table 1. Histological subtypes of 1,526 patients with bladder cancer treated with partial cystectomy identified within the Surveillance, Epidemiology, and End Results database from 2001 to 2016, stratified according to International Classification of Disease for Oncology 3 [ICD-O-3] site codes Histological subtypes (n= 1,526) Urothelial carcinoma of the urinary bladder (n= 1,278)
Neuroendocrine carcinoma (n= 34)
Squamous carcinoma (n= 50)
Adenocarcinoma (n= 115)
Other (n= 49)
8120 (TRANSITIONAL CELL CARCINOMA, NOS) 8122 (TRANSITIONAL CELL CARCINOMA, NOS) 8130 (PAPILLARY TRANS. CELL CARCINOMA) 8131 (PAPILLARY TRANS. CELL CARCINOMA) 8020 (CARCINOMA, UNDIFF., NOS) 8082 (LYMPHOEPITHELIAL CARCINOMA) 8041 (SMALL CELL CARCINOMA, NOS) 8240 (CARCINOID TUMOR, MALIGNANT) 8246 (CARCINOID TUMOR, MALIGNANT) 8680 (PARAGANGLIOMA) 8051 (PAPILLARY CARCINOMA, NOS) 8052 (PAPILLARY CARCINOMA, NOS) 8070 (SQUAMOUS CELL CARCINOMA, NOS) 8071 (SQUAMOUS CELL CARCINOMA, NOS) 8140 (ADENOCARCINOMA, NOS) 8144 (ADENOCARCINOMA, NOS) 8255 (BRONCHIOLO-ALVEOLAR ADENOCA) 8260 (PAPILLARY ADENOCARCINOMA, NOS) 8261 (PAPILLARY ADENOCARCINOMA, NOS) 8262 (PAPILLARY ADENOCARCINOMA, NOS) 8263 (PAPILLARY ADENOCARCINOMA, NOS) 8310 (CLEAR CELL ADENOCARCINOMA, NOS) 8480 (MUCINOUS ADENOCARCINOMA) 8481 (MUCINOUS ADENOCARCINOMA) 8490 (SIGNET RING CELL CARCINOMA) 8560 (ADENOSQUAMOUS CARCINOMA) 8010 (CARCINOMA, NOS) 8032 (GIANT & SPINDLE CELL CARCINOMA) 8033 (GIANT & SPINDLE CELL CARCINOMA) 8035 (GIANT & SPINDLE CELL CARCINOMA) 8050 (PAPILLARY CARCINOMA, NOS) 8700 (PHEOCHROMOCYTOMA) 8720 (NEVI & MELANOMAS) 8804 (SARCOMA, NOS) 8830 (FIBROUS HISTIOCYTOMA, MAL.) 8890 (MYOMATOUS NEOPLASMS) 8896 (MYOMATOUS NEOPLASMS) 8980 (CARCINOSARCOMA, NOS)
ICD-0-3 SEER SITE/HISTOLOGY VALIDATION LIST Transitional cell carcinoma, NOS Trans. cell carcinoma, spindle cell Papillary trans. cell carcinoma Transitional cell carcinoma, micropapillary CARCINOMA, UNDIFFERENTIATED, NOS Lymphoepithelial carcinoma SMALL CELL CARCINOMA, NOS CARCINOID TUMOR, MALIGNANT Neuroendocrine carcinoma PARAGANGLIOMA malignant Verrucous carcinoma, NOS Papillary squamous cell carcinoma SQUAMOUS CELL CARCINOMA, NOS Sq. cell carcinoma, keratinizing, NOS ADENOCARCINOMA, NOS Adenocarcinoma, intestinal type Adenocarcinoma with mixed subtypes PAPILLARY ADENOCARCINOMA, NOS Adenocarcinoma in villous adenoma Villous adenocarcinoma Adenocarcinoma in tubulovillous adenoma CLEAR CELL ADENOCARCINOMA, NOS MUCINOUS ADENOCARCINOMA Mucin-producing adenocarcinoma SIGNET RING CELL CARCINOMA ADENOSQUAMOUS CARCINOMA CARCINOMA, NOS Spindle cell carcinoma Pseudosarcomatous carcinoma Carcinoma with osteoclast-like giant cells PAPILLARY CARCINOMA, NOS PHEOCHROMOCYTOMA Malignant melanoma, NOS Epithelioid sarcoma FIBROUS HISTIOCYTOMA, MAL.): Leiomyosarcoma, NOS Myxoid leiomyosarcoma CARCINOSARCOMA, NOS
n 616 15 635 4 3 5 22 1 9 2 1 2 32 15 60 3 7 2 3 1 2 1 23 8 4 1 14 1 3 1 2 1 1 1 1 16 1 7
Supplementary Table 2. Multivariable Cox regression models, performed after Inverse Probability of Treatment Weighting (IPTW), predicting cancer-specific (CSM) and overall mortality (OM), in patients with bladder cancer treated with partial (PC) or radical cystectomy (RC) and identified within the Surveillance, Epidemiology and End Results database from 2001 to 2016. All models were adjusted for age at diagnosis, gender, T stage (T1 vs. T2), as well as chemotherapy and radiation therapy administration. HR: Hazard ratio CI: confidence interval UCUB: urothelial carcinoma of the urinary bladder nonUCUB: variant histology bladder cancer
nonUCUB UCUB Adenocarcinoma Squamous carcinoma Neuroendocrine carcinoma Other histological subtypes
PC vs. RC PC vs. RC PC vs. RC PC vs. RC PC vs. RC PC vs. RC
CSM HR (95% CI) p-value 1.1 (0.8-1.4) 0.6 1.0 (0.9-1.1) 0.5 1.0 (0.6-1.8) 0.9 1.6 (0.9-2.7) 0.07 1.2 (0.6-2.3) 0.5 0.8 (0.5-1.5) 0.5
OM HR (95% CI) p-value 1.0 (0.8-1.3) 0.9 1.0 (0.9-1.1) 0.3 1.1 (0.7-1.7) 0.8 1.3 (0.8-1.9) 0.2 1.1 (0.6-2.0) 0.6 0.9 (0.5-1.5) 0.6
Clinical Practice Points: •
Small scale studies analyzed cancer-specific mortality in patients with variant histology bladder cancer treated with partial cystectomy
•
In patients treated with partial cystectomy, variant histology bladder cancer was associated with higher cancer-specific mortality, compared to urothelial carcinoma of the urinary bladder
•
In patients with variant histology of bladder cancer, cystectomy type (namely: partial vs. radical cystectomy) is not associated with worse survival outcomes
•
Important variability with respect to cancer-specific mortality was recorded within each non urothelial histological subtype
•
These results may act as generating hypothesis for future trial design