Original Study

Effectiveness of Intravesical Doxorubicin

Immediately Following Resection of Primary
Nonemuscle-invasive Bladder Cancer: A
Propensity Score-matched Analysis
Wataru Fukuokaya,1,2 Takahiro Kimura,1 Jun Miki,1 Shoji Kimura,1
Hisaki Watanabe,1,2 Fan Bo,2 Daigo Okada,2 Koichi Aikawa,1,2 Atsuhiko Ochi,2
Koichiro Suzuki,2 Naoki Shiga,2 Hirokazu Abe,2 Shin Egawa1
Abstract
We conducted a propensity score-matched analysis evaluating the additive value of single immediate post-
operative intravesical instillation of doxorubicin to transurethral resection in patients with nonemuscle-inva-
sive bladder cancer. Single immediate postoperative intravesical instillation of doxorubicin use was
significantly associated with a lower risk of recurrence.
Background: The purpose of this study was to investigate whether adding single immediate postoperative intravesical
instillation of doxorubicin (SID) to transurethral resection of bladder tumor (TURBT) significantly reduced the risk of
recurrence in patients with nonemuscle-invasive bladder cancer (NMIBC). Materials and Methods: We retrospec-
tively analyzed the records of 720 patients diagnosed with primary NMIBC between 2002 through 2018 at the Kameda
Medical Center. The primary outcome measure was time to recurrence. Time to progression was also compared. The
cohort of SID and the cohort of TURBT alone were matched one-to-one by propensity scores. Matching was done by
patient age, gender, and factors of the European Organization of Research and Treatment of Cancer recurrence risk
table. The associations of adding SID and clinical outcomes were assessed with uni- and multivariate competing-risk
regression models. Results: After matching, a total of 364 patients, including 182 receiving SID and 182 receiving
TURBT alone, were analyzed. No statistically significant differences existed among the measured baseline charac-
teristics in propensity score-matched cohorts. In the multivariate analysis, there was a significantly longer time to
recurrence in patients receiving SID (subdistribution hazard ratio, 0.68; 95% confidence interval, 0.49-0.95; P ¼ .024)
in propensity score-matched cohorts. There was no significant difference in time to progression (subdistribution
hazard ratio, 0.61; 95% confidence interval, 0.11-3.49; P ¼ .58) in univariate analysis. Conclusions: Our results
demonstrated that SID significantly reduced the recurrence risk of primary NMIBC. Doxorubicin could be an inex-
pensive alternative to other evidenced-based chemotherapeutic agents for single immediate intravesical
chemotherapy.

Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved.
Keywords: Bladder cancer, Doxorubicin, Intravesical chemotherapy, Propensity score

Introduction urothelial carcinoma. Approximately 75% of bladder cancer is

Bladder cancer is the tenth most common cancer worldwide1 nonemuscle-invasive at diagnosis.2 Because of its high recurrence
in 2018, and the most common type of bladder cancer is rate, frequent monitoring with a cystoscopic examination is

1
Department of Urology, The Jikei University School of Medicine, Minato-ku, Tokyo, Address for correspondence: Wataru Fukuokaya, MD, Department of Urology, The
Japan Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo
2
Department of Urology, Kameda Medical Center, Kamogawa City, Chiba, Japan 105-8461 Japan
E-mail contact: wfukuokaya@gmail.com
Submitted: Jul 4, 2019; Revised: Aug 26, 2019; Accepted: Sep 10, 2019

1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.clgc.2019.09.005 Clinical Genitourinary Cancer Month 2019 -1
 Doxorubicin for Single Intravesical Chemotherapy
required. Recurrent tumors are usually treated by repeat tran-
surethral resection of bladder tumor (TURBT) surgery. The high
frequency of these procedures is costly; thus, bladder cancer
seems to be the most expensive type of cancer.3 Attempts have
been made to decrease these high recurrence rates and the
associated costs.
Several previous randomized trials have shown that a single
intravesical instillation of chemotherapeutic agent, including mito-
mycin C,4,5 epirubicin,6 and gemcitabine,7 reduces the risk of
recurrence after TURBT in nonemuscle-invasive bladder cancer
(NMIBC). However, these agents are generally costly; thus, an
inexpensive alternative is required.
Doxorubicin, which intercalates deoxyribonucleic acid (DNA)
and inhibits its replication and transcription, is one of the most
potent antineoplastic drugs. It is prescribed alone or in combination
with other agents in patients with various hematologic malignancies
and solid tumors.8,9 The usefulness of intravesical instillation of
doxorubicin as adjuvant therapy in reducing the risk of recurrence
in patients with NMIBC had been shown in several studies,10,11
although it was reported that a single postoperative intravesical
instillation of doxorubicin provided an insignificant impact on
recurrence of NMIBC.12 Because of inadequate statistical power of
the study and limited data available regarding the effect of doxo-
rubicin, the effect of doxorubicin use for single postoperative
intravesical chemotherapy remains debatable.
Therefore, we sought to evaluate the impact of single immediate
postoperative intravesical instillation of doxorubicin (SID) on
disease recurrence in patients with NMIBC. A propensity score-
matching methodology was used to minimize the effects of con-
founding by indication in different treatment groups.
Materials and Methods
Patient and Data Collection
After institutional review board approval, we reviewed the medical
records of 720 consecutive patients with histologically confirmed
primary bladder cancer between 2002 and 2018 at Kameda Medical
Center. Patients were excluded if they had muscle-invasive bladder
cancer (n ¼ 120), had at least 1 metastatic lesion (n ¼ 31), or had non-
urothelial carcinoma of the bladder (n ¼ 22); there was some patient
overlap. The remaining 582 patients were further analyzed.
TURBT, Instillation Therapy, and Additional Treatments
All patients had cystoscopically proven urothelial carcinoma of
the bladder and underwent complete TURBT. No patients received
photodynamic diagnostic TURBT. Patients received 30 mg of
doxorubicin in 30 mL of normal saline within 24 hours after
TURBT on the basis of guidelines at that time and physicians’
discretion. Urethral catheters were unclamped after 1 hour of
instillation. None of the patients had upper tract urothelial carci-
noma at diagnosis. The indication of additional treatments
including repeat transurethral resection (TUR) and intravesical
Bacillus Calmette-Guerin (BCG) therapy was generally European
Organization for Research and Treatment of Cancer (EORTC)
high-risk tumor. Intravesical BCG therapy was limited to an 8-week
induction course. Patients were treated with neither maintenance
intravesical BCG therapy nor additional intravesical chemotherapy.
2 - Clinical Genitourinary Cancer Month 2019
Outcome Measures
The primary outcome measure was time to recurrence (TTR),
which was defined as the time from TURBT to the date of the first
recurrence. Patients who were alive and without recurrence were
censored at the date of the last available cystoscopy follow-up. All-
cause deaths before recurrence were analyzed as a competing risk.
The secondary measure was time to progression (TTP). TTP was
defined as the time from TURBT to the progression to muscle-
invasive urothelial cancer or the emergence of lymph node or
distant metastases. Generally, assessment by cystoscopy was con-
ducted once every 3 months for 2 years, semi-annually for 3 years,
and annually thereafter.
Statistical Analysis
Descriptive statistics for categorical variables were reported as fre-
quencies and percentages, whereas continuous variables were reported
as the median and interquartile range (IQR). The association between 2
categorical variables was evaluated using Fisher exact tests, and 1
continuous and 1 categorical variable with the Wilcoxon rank-sum test.
Propensity scores were calculated through logistic regression
modeling on the basis of the following covariates: age, gender,
number of tumors (single, 2-7, or  8), tumor size (< 3 cm or  3
cm), pathologic T stage (Ta or T1), the presence of concomitant in
situ carcinoma (yes or no), and histologic grade (G1, G2, or G3).
Subjects receiving either SID or TUR alone were matched 1:1 with
these propensity scores via the nearest neighbor matching algorithm
without replacement.13 A caliper size of 0.1 times the logarithm of
the standard deviation of the propensity score was used to minimize
treatment bias.14
The date of TURBT was defined as the baseline date. The risk of
TTR and TTP was estimated using competing risk cumulative
incidence estimators according to Marubini and Valsecchi. After
matching, time-to-event functions between 2 groups were compared
using the Gray test. Uni- and multivariate modelling of time-
to-event was performed with the Fine and Gray subdistribution
hazards model. Variables with a P value < .05 in univariate analysis
were further analyzed in multivariate competing-risk regression
models. Subgroup analyses were exploratory, and no adjustments
for multiplicity were made. Subdistribution hazard ratios (SHRs)
estimated from the Fine and Gray subdistribution hazard model
were reported as relative risks with corresponding 95% confidence
intervals (CIs).
All statistical analyses were performed using Stata version 15.1
(StatCorp, LLC, College Station, TX). A 2-sided P < .05 was
considered statistically significant.
Results
The median follow-up for the entire study population was 41.8
months (95% CI, 38.5-45.3 months). The resulting propensity
score-matched cohorts included 364 patients; 182 (50.0%) patients
in the SID group and 182 (50.0%) patients in the TUR alone
group. Before propensity score matching, individuals receiving SID
were significantly older (P ¼ .03), had larger tumors ( 3 cm)
(P < .001), had more overall tumors (P ¼ .003), and high path-
ologic T stage tumor (P < .001) (Table 1). No statistically signif-
icant differences existed among measured baseline covariates in
 Wataru Fukuokaya et al
Table 1 Patient Characteristics

Before Propensity Score Matching After Propensity Score Matching

TURBT Alone SID Group TURBT Alone
SID Group Group (n [ 229), (n [ 182), Group (n [ 182),
Characteristic (n [ 364), n (%) n (%) P for Difference n (%) n (%) P for Difference
Median age at 72 (65-79) 75 (66-81) .03 76 (69-81) 74 (66-81) .14
diagnosis, y (IQR)
Gender .16 1
Male 291 (79.9) 194 (84.7) 152 (83.5) 153 (84.1)
Female 73 (20.1) 35 (15.3) 30 (16.5) 29 (15.9)
Number of tumors .003 .11
Single 147 (40.4) 90 (39.3) 63 (34.6) 75 (41.2)
2-7 200 (54.9) 111 (48.5) 109 (59.9) 90 (49.5)
8 17 (4.7) 28 (12.2) 10 (5.5) 17 (9.3)
Tumor size, cm <.001 .7
<3 306 (84.1) 159 (69.4) 142 (78.0) 146 (80.2)
3 58 (15.9) 70 (30.6) 40 (22.0) 36 (19.8)
Pathologic T stage <.001 .41
Tis 8 (2.2) 9 (3.9) 4 (2.2) 9 (4.9)
Ta 240 (65.9) 112 (48.9) 104 (57.1) 101 (55.5)
T1 116 (31.9) 108 (47.2) 74 (40.7) 72 (39.6)
Concomitant in .13 .65
situ carcinoma
Yes 40 (11.0) 35 (15.3) 24 (13.2) 28 (15.4)
No 324 (89.0) 194 (84.7) 158 (86.8) 154 (84.6)
Grade .069 .87
G1 23 (6.3) 14 (6.1) 10 (5.5) 12 (6.6)
G2 181 (49.7) 90 (39.3) 79 (43.4) 81 (44.5)
G3 158 (44.0) 118 (51.6) 93 (51.1) 89 (48.9)
Repeat TUR .21 .79
Yes 68 (18.7) 53 (23.1) 38 (20.9) 35 (19.2)
No 296 (81.3) 176 (76.9) 144 (79.1) 147 (80.8)
Intravesical BCG 1 1
therapy
Yes 84 (23.1) 52 (22.7) 46 (25.3) 45 (24.7)
No 280 (76.9) 177 (77.3) 136 (74.7) 137 (75.3)

Abbreviations: BCG ¼ Bacillus Calmette-Guerin; IQR ¼ interquartile range; SID ¼ single immeidate postoperative intravesical instillation of doxorubicin; TUR ¼ transurethral resection;
TURBT ¼ transurethral resection of the bladder tumor.

propensity score-matched cohorts (Table 1). There were 231
(39.0%) and 149 (40.9%) recurrences during a follow-up period in
the full and propensity score-matched cohort, respectively. The
respective 1-year recurrence and survival rates were 25.8% (153/
593) and 2.7% (16/577). The respective 5-year recurrence and
survival rates were 38.1% (226/593) and 12.7% (75/593). One
hundred twenty-one (20.4%) patients received repeat TUR and 136
(22.9%) patients received intravesical BCG therapy. Grade 3 or
higher adverse events were similarly distributed in both group
(7 [3.8%] in SID group and 12 [6.5%] in TUR alone group;
P ¼ .35) in propensity score-matched cohorts.
Effect of SID on TTR
The median TTR was 18.7 months (95% CI, 16.4-23.3 months)
and 17.9 months (95% CI, 15.8-23.3 months) in the full and
propensity score-matched cohort, respectively. Competing risk cu-
mulative incidence estimators demonstrated a lower cumulative
incidence of recurrence in patients receiving SID in the propensity
score-matched (P ¼ .028; Gray test) cohorts (Figure 1).
Propensity score-matched univariate Fine and Gray sub-
distribution hazards model showed the significant association be-
tween SID use and TTR (SHR, 0.69; 95% CI, 0.50-0.96;
P ¼ .028). Other significant predictors for TTR included repeat
TUR (SHR, 0.61; 95% CI, 0.39-0.95; P ¼ .031) and intravesical
BCG therapy (SHR, 0.61; 95% CI, 0.42-0.90; P ¼ .012).
Adjusting for covariates on the multivariate analysis, SID use
remained significantly associated with longer TTR (SHR, 0.68;
95% CI, 0.49-0.95; P ¼ .024) (Table 2). The significant associa-
tions between additional treatments and TTR could not be
observed in multivariate settings of this cohorts (Table 2).

Clinical Genitourinary Cancer Month 2019 -3

 Doxorubicin for Single Intravesical Chemotherapy
group; SHR, 0.61; 95% CI, 0.11-3.48; P ¼ .58). The respective
Figure 1 Time to Recurrence in the Propensity Score-matched
Cohorts according to SID Use; a Competing Risk median TTP was 40.5 months (95% CI, 37.9-43.9 months) and
Cumulative Incidence Estimator Based Upon SID Use 43.2 months (95% CI, 39.0-48.8 months) in the full and pro-
for the Cumulative Probability of Remaining pensity score-matched cohort. No significant association was
Recurrence-free After the Instillation of Doxorubicin observed between SID use and TTP (SHR, 0.61; 95% CI,
in the Propensity Score-matched Cohorts 0.11-3.49; P ¼ .58) in univariate compering-risk regression model
in propensity score-matched cohorts (see Supplemental Table 1 in
the online version).
Cumulative Incidence of recurrence

Gray’s test p=0.028
Time from instillation, day
Abbreviation: SID ¼ single immediate intravesical instillation of doxorubicin.
Similar to a previous study,15 SID use significantly reduced the
risk of disease recurrence in patients with an EORTC recurrence
score < 5 in the propensity score-matched cohorts (SHR, 0.60;
95% CI, 0.38-0.98; P ¼ .039) (Figure 2). In contrast, SID did not
significantly reduce the risk of recurrence in patients with an
EORTC recurrence score  5 (SHR, 0.77; 95% CI, 0.50-1.21;
P ¼ .26).
Effect of SID on TTP
During the follow-up, 6 patients had progression in propensity
score-matched cohorts (2 in the SID group and 4 in the TUR alone
Discussion
In the present study, we demonstrated that a doxorubicin
instillation within 24 hours after TURBT for NMIBC significantly
reduces the risk of recurrence and improved TTR compared with
the patients receiving TUR alone. SID use reduced the relative risk
of recurrence by 32% (SHR, 0.68; 95% CI, 0.49-0.95), which
concurs well with previous prospective studies of other agents for
single postoperative intravesical chemotherapy (gemcitabine: hazard
ratio [HR], 0.66; 95% CI, 0.48-0.90; mitomycin C: HR, 0.58;
95% CI, 0.46-0.72; epirubicin: HR, 0.63; 95% CI, 0.54-0.74).7,15
Our findings suggested that SID use was effective for patients with
tumors with EORTC recurrence score < 5.
Doxorubicin, which is known to interfere with topoisomerase 1
and 2 and intercalate into DNA, has shown great treatment po-
tential. It is regarded as one of the most potent Food and Drug
Administration-approved chemotherapeutic drugs.9 Despite its
extensive clinical utilization, doxorubicin has the potential to cause
life-threatening toxicity to most major organs including the heart,
liver, and kidney.16 On the other hand, several previous studies have
shown that intravesical doxorubicin therapy was well-tolerated and
had few serious adverse events.10,11,17
Several studies have previously shown the usefulness of adjuvant
intravesical doxorubicin in decreasing the likelihood of recurrence in
patients with NMIBC.10,11,18 In contrast, a recent study using SID
with fluorescent cystoscopy-assisted TUR concluded that single

Table 2 The Results of Competing-risk Regression Analyses of Predictors of Time to Recurrence in Propensity Score-matched
Cohorts

Univariate Analysis Multivariate Analysis

Characteristic SHR (95% CI) P Value SHR (95% CI) P Value
Intravesical instillation of 0.69 (0.50-0.96) .028 0.68 (0.49-0.95) .024
doxorubicin (yes or no)
Age at diagnosis, y 1.01 (0.99-1.03) .13
(continuous)
Gender (male or female) 0.61 (0.37-1.01) .055
Number of tumors (single, 2-7, 1.04 (0.77-1.39) .8
or 8)
Tumor size, cm (<3 or 3) 1.08 (0.71-1.64) .71
Pathologic T stage (Ta or T1) 0.84 (0.64-1.11) .22
Concomitant in situ carcinoma 0.62 (0.38-1.03) .064
(yes or no)
Grade (G1, G2, or G3) 1.03 (0.80-1.32) .83
Repeat TUR (yes or no) 0.61 (0.39-0.95) .031 0.72 (0.44-1.20) .21
Intravesical BCG therapy 0.61 (0.42-0.90) .012 0.84 (0.55-1.28) .41
(yes or no)

Abbreviations: BCG ¼ Bacillus Calmette-Guerin; CI ¼ confidence interval; IQR ¼ interquartile range; SHR ¼ subdistribution hazard ratio; SID ¼ single immediate postoperative intravesical instillation
of doxorubicin; TUR ¼ transurethral resection.

4 - Clinical Genitourinary Cancer Month 2019


Figure 2 Associations of SID Use and Time to Recurrence according to EORTC Recurrence Scores. Competing Risk Cumulative
Incidence Estimators of Disease Recurrence Based Upon SID Use in Propensity Score-matched Cohorts
Cumulative Incidence of recurrence
Cumulative Incidence of recurrence
Gray’s test p=0.26
Time from instillation, day
Abbreviations: EORTC ¼ European Organization for Research and Treatment of Cancer; SID ¼ single immediate intravesical instillation of doxorubicin; TUR ¼ transurethral resection.
early postoperative instillation of doxorubicin did not have a sta-
tistically significant impact on disease recurrence.12 Although this
study was prospective and randomized, the difference in patient
characteristics among groups and the large proportion of the pa-
tients with intermediate disease (67.0%) raised questions as to the
results.12 Additionally, it was possible that the use of fluorescent
technology might trump the effect of intravesical chemotherapy.
Thus, the efficacy of doxorubicin use as an immediate intravesical
chemotherapy in those with NMIBC remained unclear.
In the present study, after propensity score-matching, we
demonstrated that SID use was significantly associated with lower
risk of recurrence. Moreover, SID use did not significantly affect
disease progression. A lack of benefit for patients with tumor of an
EORTC recurrence score  5 agreed with findings of other study
using other agents for single intravesical chemotherapy including
mitomycin C, epirubicin, and pirarubicin.15 Based on the results of
this study, single postoperative intravesical instillation of doxoru-
bicin is not recommended in patients with multiple tumors, where
at least 1 of the tumors is  3 cm, and with an EORTC recurrence
score  6.
Additionally, among currently approved drugs for intravesical
chemotherapy, doxorubicin 30 mg ($9.42) is the lowest-priced drug
compared with most cost-effective in other drugs for intravesical
chemotherapy including epirubicin 80 mg ($54.80), mitomycin C
40 mg ($1,126.50), and gemcitabine 2000 mg ($59.00). Although
a comparison in the treatment effects between these drugs in a
prospective randomized study is needed, doxorubicin could be the
best cost-effective alternative among these drugs for intravesical
chemotherapy.
Wataru Fukuokaya et al
Gray’s test p=0.039
Time from instillation, day
This study has some limitations. The number of patients was
small because of the propensity score-matching. Despite the appli-
cation of propensity score methods, unmeasured confounding may
exist with regard to treatment allocation. Because the current study
is based on single-institute retrospective data, patient follow-up
could not be completely standardized; all medical comorbidity
data of the study cohort were not available, and this prohibited
inclusion of the Charlson comorbidity score as a variable in the
statistical models. Additionally, treatment at recurrence and subse-
quently was not completely monitored, which could affect TTP.
Therefore, the findings of the current study are for generating hy-
potheses. A multicenter prospective validation to reduce the selec-
tion bias is required. Only one-fifth and one-fourth of patients
received repeat TUR and intravesical BCG therapy according to the
treatment guideline,19 respectively, which might have affected the
outcomes of patients. However, because other studies reported
similar rates of adherence,7,20,21 our data may represent real-world
situations. Several surgeons and genitourinary pathologists were
involved, but all were experienced physicians from a high-volume
center. TUR quality and surgeon performance were not
controlled. Cases of recurrent NMIBC were not included in the full
cohort, resulting in limited events of recurrence and progression
compared with a previous study.22 Finally, we could not completely
capture adverse events owing to the retrospective nature of the
present study.
Conclusions
In summary, we retrospectively analyzed medical records and
demonstrated that SID use significantly reduced disease recurrence
Clinical Genitourinary Cancer Month 2019 -5
 Doxorubicin for Single Intravesical Chemotherapy
in patients with NMIBC, on a propensity score-matched analysis.
Additionally, SID was not significantly associated with disease
progression. Doxorubicin could be an inexpensive alternative to
other evidence-based chemotherapeutic agents in patients receiving
single immediate intravesical chemotherapy. Our results suggest
that randomized trials are needed to eliminate selection bias in
treatment assignment in order to accurately compare outcomes
between patients receiving SID and those receiving TUR alone.
Clinical Practice Points
 The use of doxorubicin for single postoperative intravesical
chemotherapy may reduce the risk of recurrence of NMIBC.
 Although doxorubicin was the lowest priced drug among other
agents for intravesical chemotherapy, it showed a similar efficacy
profile.
 Doxorubicin might be a cost-effective agent for patients
with NMIBC receiving single postoperative intravesical
chemotherapy.
Disclosure
S. Egawa is a paid consultant/advisor to Takeda, Astellas,
AstraZeneca, Sanofi, Janssen, and Pfizer. The remaining authors
have stated that they have no conflicts of interest.
Supplemental Data
Supplemental table accompanying this article can be found in the
online version at https://doi.org/10.1016/j.clgc.2019.09.005.
References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for
36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424.
2. Messing EM, Madeb R, Young T, et al. Long-term outcome of hematuria home
screening for bladder cancer in men. Cancer 2006; 107:2173-9.
3. Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics
of bladder cancer: a comprehensive review of the published literature. Pharma-
coeconomics 2003; 21:1315-30.
4. Tolley DA, Parmar MK, Grigor KM, et al. The effect of intravesical mitomycin C
on recurrence of newly diagnosed superficial bladder cancer: a further report with 7
years of follow up. J Urol 1996; 155:1233-8.
5. Solsona E, Iborra I, Ricós JV, Monrós JL, Casanova J, Dumont R. Effectiveness
of a single immediate mitomycin C instillation in patients with low risk
superficial bladder cancer: short and long-term followup. J Urol 1999; 161:
1120-3.
6 - Clinical Genitourinary Cancer Month 2019
6. Oosterlinck W, Kurth KH, Schröder F, Bultinck J, Hammond B, Sylvester R.
A prospective European Organization for Research and Treatment of Cancer
Genitourinary Group randomized trial comparing transurethral resection followed
by a single intravesical instillation of epirubicin or water in single stage Ta, T1
papillary carcinom. J Urol 1993; 149:749-52.
7. Messing EM, Tangen CM, Lerner SP, et al. Effect of intravesical instillation of
gemcitabine vs saline immediately following resection of suspected low-grade non-
muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized
clinical trial. JAMA 2018; 319:1880-8.
8. Petrioli R, Fiaschi AI, Francini E, Pascucci A, Francini G. The role of doxorubicin
and epirubicin in the treatment of patients with metastatic hormone-refractory
prostate cancer. Cancer Treat Rev 2008; 34:710-8.
9. Carvalho C, Santos RX, Cardoso S, et al. Doxorubicin: the good, the bad and the
ugly effect. Curr Med Chem 2009; 16:3267-85.
10. Akaza H, Koiso K, Kotake T, et al. Long-term results of intravesical chemopro-
phylaxis of superficial bladder cancer: experience of the Japanese Urological Cancer
Research Group for Adriamycin. Cancer Chemother Pharmacol 1992; 30(Suppl):
S15-20.
11. Shinohara N, Nonomura K, Tanaka M, et al. Prophylactic chemotherapy with
anthracyclines (adriamycin, epirubicin, and pirarubicin) for primary superficial
bladder cancer. The Hokkaido University Bladder Cancer Collaborative Group.
Cancer Chemother Pharmacol 1994; 35(Suppl):S41-5.
12. Rolevich AI, Zhegalik AG, Mokhort AA, et al. Results of a prospective randomized
study assessing the efficacy of fluorescent cystoscopy-assisted transurethral resection
and single instillation of doxorubicin in patients with non-muscle-invasive bladder
cancer. World J Urol 2017; 35:745-52.
13. Austin PC. The performance of different propensity score methods for estimating
marginal hazard ratios. Stat Med 2013; 32:2837-49.
14. Austin PC. Optimal caliper widths for propensity-score matching when estimating
differences in means and differences in proportions in observational studies. Pharm
Stat 2011; 10:150-61.
15. Sylvester RJ, Oosterlinck W, Holmang S, et al. Systematic review and individual
patient data meta-analysis of randomized trials comparing a single immediate
instillation of chemotherapy after transurethral resection with transurethral resec-
tion alone in patients with stage pTa-pT1 urothelial carcinoma. Eur Urol 2016; 69:
231-44.
16. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer mo-
lecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 2013;
65:157-70.
17. Cheng CW, Chan PS, Chan LW, Chan CK, Ng CF, Lai MM. 17-year follow-
up of a randomized prospective controlled trial of adjuvant intravesical doxo-
rubicin in the treatment of superficial bladder cancer. Int Braz J Urol 2005; 31:
204-11.
18. Kurth K, Tunn U, Ay R, et al. Adjuvant chemotherapy for superficial transitional
cell bladder carcinoma: long-term results of a European Organization for Research
and Treatment of Cancer randomized trial comparing doxorubicin, ethoglucid and
transurethral resection alone. J Urol 1997; 158:378-84.
19. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle
invasive bladder cancer: AUA/SUO guideline. J Urol 2016; 196:1021-9.
20. Palou J, Pisano F, Sylvester R, et al. Recurrence, progression and cancer-
specific mortality according to stage at re-TUR in T1G3 bladder cancer pa-
tients treated with BCG: not as bad as previously thought. World J Urol 2018;
36:1621-7.
21. Gendy R, Delprado W, Brenner P, et al. Repeat transurethral resection for non-
muscle-invasive bladder cancer: a contemporary series. BJU Int 2016;
117(Suppl):54-9.
22. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence
and progression in individual patients with stage Ta T1 bladder cancer using
EORTC risk tables: a combined analysis of 2596 patients from seven EORTC
trials. Eur Urol 2006; 49:466-75, discussion: 475-477.
 Wataru Fukuokaya et al
Supplemental Data

Supplemental Table 1 The Results of Univariate Competing-risk Regression Analyses of Predictors of Time to Progression in
Propensity Score-matched Cohorts

Characteristic SHR (95% CI) P Value

Intravesical instillation of doxorubicin (yes or no) 0.61 (0.11-3.49) .58
Age at diagnosis, y (continuous) 1.07 (0.99-1.16) .08
Gender (male or female) 3.39 (0.61-18.81) .16
Number of tumors (single, 2-7, or 8) 1.39 (0.53-3.65) .51
Tumor size, cm (<3 or 3) NA NA
Pathologic T stage (Ta or T1) 1.05 (0.11-10.26) .96
Concomitant in situ carcinoma (yes or no) 4.75 (0.84-27.0) .078
Grade (G1, G2, or G3) 4.65 (0.63-34.4) .13
Repeat TUR (yes or no) 2.60 (0.47-14.4) .27
Intravesical BCG therapy (yes or no) 2.17 (0.41-11.54) .37

Abbreviations: BCG ¼ Bacillus Calmette-Guerin; CI ¼ confidence interval; SHR ¼ subdistribution hazard ratio; TUR ¼ transurethral resection.

Clinical Genitourinary Cancer Month 2019 - 6.e1