Article

Clinical outcomes of dogs with transitional cell carcinoma receiving

medical therapy, with and without partial cystectomy
Marcus L. Bradbury, Christine M. Mullin, Shaban D. Gillian, Chick Weisse, Philip J. Bergman,
Michelle A. Morges, Lauren R. May, David M. Vail, Craig A. Clifford

Abstract — The objective of this retrospective study was to evaluate the effects of surgery on outcome for dogs
with naturally occurring urinary bladder transitional cell carcinoma. Forty-seven dogs met the inclusion criteria.
Thirty-one dogs (Group A) were treated with partial cystectomy and adjunctive medical therapy and 16 dogs
(Group B) were treated with medical therapy alone. Overall survival was greater in dogs treated with partial
cystectomy and adjunctive medical therapy (498 days for Group A versus 335 days for Group B, hazard
ratio 2.5; 95% confidence interval: 1.1 to 5.7; P = 0.026). Progression-free survival was not different between
groups (85 days for Group A versus 83 days for Group B; P = 0.663). No prognostic factors were identified for
progression-free survival. Due to the many cases in Group A that were lost to follow-up, time-to-event survival
analysis was performed. No significant difference in overall survival was noted, and no prognostic factors were
identified in the time-to-event analysis. Prospective, randomized studies are needed to determine the role of partial
cystectomy in the treatment of transitional cell carcinoma.

Résumé — Résultats cliniques des chiens atteints d’un carcinome à cellules transitionnelles recevant un
traitement médical, avec et sans cystectomie partielle. L’objectif de cette étude rétrospective était d’évaluer les
effets de la chirurgie sur les résultats chez des chiens atteints d’un carcinome à cellules transitionnelles de la vessie
d’origine naturelle. Quarante-sept chiens répondaient aux critères d’inclusion. Trente et un chiens (Groupe A) ont
été traités par cystectomie partielle et traitement médical d’appoint et 16 chiens (Groupe B) ont été traités par
thérapie médicale seule. La survie globale était plus élevée chez les chiens traités par cystectomie partielle et
traitement médical d’appoint (498 jours pour le Groupe A contre 335 jours pour le Groupe B, rapport de risque
de 2,5; intervalle de confiance à 95 % : 1,1 à 5,7; P = 0,026). La survie sans progression n’était pas différente entre
les groupes (85 jours pour le Groupe A contre 83 jours pour le Groupe B; P = 0,663). Aucun facteur pronostique
n’a été identifié pour la survie sans progression. En raison des nombreux cas dans le Groupe A qui ont été perdus
de vue lors du suivi, une analyse du temps de survie a été realisée. Aucune différence significative dans la survie
globale n’a été notée et aucun facteur pronostique n’a été identifié dans l’analyse du temps de survive. Des études
prospectives randomisées sont nécessaires pour déterminer le rôle de la cystectomie partielle dans le traitement du
carcinome à cellules transitionnelles.
(Traduit par Dr Serge Messier)
Can Vet J 2021;62:133–140

Hope Veterinary Specialists, Surgery Department, 40 Three Tun Road, Malvern, Pennsylvania 19355, USA (Bradbury, Mullin, May,
Clifford); Koret School of Veterinary Medicine, The Hebrew University in Jerusalem, Yehoshua Hankin St 21, Rehovot 76100, Israel
(Gillian); The Animal Medical Center, Interventional Radiology and Endoscopy, 510 East 62nd Street, New York, New York 10065,
USA (Weisse); Katonah Bedford Veterinary Center, Medical Oncology Department, 546 Bedford Road, Bedford Hills, New York
10507, USA (Bergman); Red Bank Veterinary Hospital, Medical Oncology Department, 197 Hance Avenue, Tinton Falls, New
Jersey 07724, USA (Morges); Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison,
2015 Linden Drive, Madison, Wisconsin 53706, USA (Vail).
Address all correspondence to Dr. Marcus Bradbury; e-mail: mlb0021@auburn.edu
Dr. Bradbury’s current address is Coastal Empire Veterinary Surgery, 355 Stephenson Avenue, Savannah, Georgia 31405, USA.
Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA
office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.

CVJ / VOL 62 / FEBRUARY 2021 133

 Introduction
U
rinary bladder transitional cell carcinoma (TCC) is an
important neoplasm in dogs, with the most common
clinical signs being hematuria, dysuria, and pollakiuria (1–2).
Additionally, canine urinary bladder TCC has been used as a
model to study the muscle-invasive form of urothelial carcinoma
in human patients (3–4). The invasive nature of TCC and its
A R T I C LE
propensity to develop in the trigone of the bladder contribute
to the historically poor prognosis associated with this cancer in
dogs (3). Lymph node metastasis is reported in 16% of dogs
with TCC at the time of diagnosis (4). Distant metastasis to the
lung or liver is reported in 14% of dogs at the time of diagnosis
and in 50% by the time of death (4).
Treatments for dogs with urinary bladder TCC include medi-
cal therapy, radiation therapy, and surgery (4). The most often
used medical therapies for canine TCC involve cyclooxygenase
(COX) inhibitors, systemic chemotherapeutic agents, or some
combination thereof (4). Previous studies have evaluated overall
response rates, remission duration, and survival times for vari-
ous medical therapies (5–7). It is the authors’ opinion that no
consensus exists as to the “gold standard” of therapy.
Although beneficial in local control, the high incidence of
severe late radiation-associated toxicoses associated with con-
ventional definitive radiation protocols has precluded radia-
tion from being included as standard of care treatment (8–10).
However, intensity-modulated radiation therapy allows for
conformity of radiation dose and use of smaller treatment fields
to limit exposure to normal tissue and ultimately decrease the
adverse events previously noted (11). Further investigation is
needed, but this has promise in the treatment of TCC in dogs.
In humans, radical cystectomy for muscle-invasive urothelial
carcinoma improves outcomes but requires urinary diver-
sion techniques (12). Although complete cystectomy provides
a surgical solution to canine tumors affecting the trigone,
few veterinary studies have examined the feasibility of total
cystectomy with ureteral diversion, given the postoperative
challenges associated with home management after complete
cystectomy (13–15).
Common sequelae of complete cystectomy in the dog are
permanent urinary incontinence, pyelonephritis, and azote-
mia (13–15). Thus, if confirmed to improve outcome, partial
cystectomy and/or cytoreductive surgeries would be considered
desirable options.
Several studies have suggested cytoreductive surgeries may
benefit dogs with TCC (16–18). In 1 report, a benefit was
noted following complete excision of non-metastatic bladder
tumors, with a median survival time (MST) of 365 d following
surgery alone (16). Extent of tumor excision was prognostic,
with an MST of 120 d when . 50% but , 100% of the
tumor was removed, and 75 d when , 50% of the tumor was
removed (16). A separate study noted 6/10 dogs with urinary
bladder TCC treated with partial cystectomy, with or without
ureteral re-implantation, survived over 1 y with or without
chemotherapy and/or radiation therapy (17). A retrospec-
tive study evaluating the combination of doxorubicin and
piroxicam for canine TCC noted that the subset of dogs first
134
treated with partial cystectomy had aimproved MST (217 d
with surgery compared to 133 d without surgery, P = 0.02) but
not progression-free survival (PFS) (18). A more recent study
by Marvel et al (19) evaluated 37 dogs with TCC treated with
partial cystectomy and COX inhibitors, with or without other
medical therapies. The MST for all dogs was 348 d, but dogs
with non-trigonal bladder TCC treated with full-thickness
partial cystectomy and daily piroxicam (6 chemotherapy) had
improved survival (772 d, P # 0.0001) (19). Although these
latter results are promising, it is still unclear whether initiating
surgery before medical therapy improves disease-free survival
compared to medical therapy alone.
The goal of the current retrospective study was to compare
the outcomes of dogs with urinary bladder TCC treated with
partial cystectomy and adjuvant chemotherapy and COX inhibi-
tors versus those treated with chemotherapy and COX inhibitors
alone. A secondary aim was to identify prognostic factors for
PFS and overall survival (OS) for the same patient groups.
Materials and methods
Case selection
Medical records of dogs that were presented over a 9-year
interval (September 2003 through November 2012) to 3 multi­
disciplinary referral hospitals (Red Bank Veterinary Hospital,
Tinton Falls, New Jersey, USA; The Animal Medical Center,
New York, New York, USA; and The Koret School of Veterinary
Medicine of the Hebrew University of Jerusalem, Israel) were
retrospectively reviewed to identify dogs diagnosed with urinary
bladder TCC. Dogs were included if they were diagnosed with
TCC by either histopathology (surgical or endoscopic biopsies)
or by cytology (obtained via traumatic catheterization or fine-
needle aspiration) and were treated with systemic injectable
chemotherapy and COX inhibitors. Dogs were then grouped
to compare those that were also treated with partial cystectomy
to those that received medical therapy alone. Partial cystectomy
was defined as removal of any portion of the urinary bladder
with the intent of tumor cytoreduction. This was further cat-
egorized into removal of all visible disease or partial resection
of visible disease as noted at the time of surgery. Dogs were
excluded if they were not followed with sequential abdominal
ultrasound after the initial 2 cycles of chemotherapy and then
every 2 to 4 cycles thereafter. Dogs were also excluded if infor-
mation in regard to abdominal ultrasonography findings, type
and/or dose of chemotherapy, and type of COX inhibitor used
was missing. Data collected from the medical records included
breed age, gender, weight, date of diagnosis, staging tests per-
formed, date of surgery, tumor location in bladder based on
abdominal imaging, surgical procedure (removal of all visible
disease versus partial resection of visible disease), histopathol-
ogy results, adjuvant therapy (chemotherapy, COX inhibitors),
date of recurrence, date and cause of death, or loss to follow-up.
Tumor location was based on the site of attachment or origin
of the tumor and was assigned to 1 of 4 anatomic regions of
the bladder: apex, body, trigone, or neck. The apex was defined
as the region immediately surrounding the previous urachal
attachment site at the cranial/proximal 25% of the bladder.
The body was defined as the region between the apex and the
CVJ / VOL 62 / FEBRUARY 2021
trigione. The trigione was defined as the triangular area, near
the neck, on the dorsal surface of the bladder immediately sur-
rounding the implantation site of the ureters. The neck was
defined as the region ventral and distal to the trigione and was
site of bladder termination and urethral origin. Ureteral involve-
ment was defined as visualization of tumor within one or both
ureters at the time of initial ultrasonographic examination or
at the time of surgery. Prostatic involvement was determined
based on ultrasonographic evidence of tumor extension into the
prostate, with prostate enlargement and mineralization. After
initiation of treatment, dogs were periodically reassessed with
physical examinations, clinical laboratory data, and imaging.
Urinary tract ultrasonography was employed to determine tumor
response and remission status, using World Health Organization
(WHO) criteria. Tumor size was calculated as the product of
the longest diameter and the greatest perpendicular diameter.
Complete remission was defined as disappearance of all measur-
able disease, partial remission was defined as . 50% decrease
in tumor size from baseline measurements, stable disease was
defined as , 25% increase in tumor size from baseline measure-
ment, and progressive disease was defined as . 25% increase in
tumor size, based on baseline measurement or the appearance
of new lesions (either locally or at a distant site).
Dogs were assigned to 1 of 2 groups: Group A — dogs that
underwent a partial cystectomy, followed by treatment with
systemic chemotherapy and COX inhibitors; and Group B —
dogs receiving only medical therapy with chemotherapy and
COX inhibitors. Median PFS and median OS were compared
between the 2 groups. Data were also evaluated for prognostic
factors across both groups. Dogs in Group A were restaged using
ultrasonography for detection of tumor recurrence following
surgery and chemotherapy initiation; whereas, dogs in Group B
were monitored for change in tumor status from baseline follow-
ing initiation of chemotherapy. Ultrasonography was done after
the initial 2 cycles of chemotherapy, then every 2 to 4 cycles
thereafter. Progressive disease (PD) was determined in both
Groups A and B by ultrasonographic evaluation.
Histology
All biopsy samples were reviewed and the diagnosis of TCC
confirmed by Board-certified anatomic pathologists. Histologic
margins were classified as complete or incomplete.
Cytology
All cytology samples were reviewed and the diagnosis of TCC
was confirmed by Board-certified clinical pathologists.
Statistical analysis
Continuous data were expressed as median and range, and cat-
egorical data as frequencies and percentages. Progression-free
survival and OS were calculated from the date of first chemo-
therapy to the date of PD or death from any cause, and death,
respectively. Dogs were censored if they had not developed PD
or died at the time of data analysis, or if they were lost to follow-
up. The cases that were lost to follow-up were then uncensored
and a time-to-event (TTE) comparison was done for OS.
Continuous variables were compared between groups of patients
CVJ / VOL 62 / FEBRUARY 2021
using a 2-sample t-test or Mann-Whitney test, depending on
normality of the data. Categorical variables were compared
between cohorts using a Fisher’s Exact test. The Kaplan-Meier
method was used to estimate and display the distribution of
PFS and OS. Differences between potential prognostic subsets
and between study arms were compared using the log-rank
test. All reported P-values are 2-sided and P , 0.05 was used
A R T I C LE
to determine statistical significance. All statistical analyses were
completed using a commercial software package (Prism v. 6.0b;
GraphPad Software, La Jolla, California, USA).
Results
Forty-seven dogs met the inclusion criteria (Group A; n = 31
and Group B; n = 16). Information regarding signalment is
presented in Table 1. Clinical signs included; hematuria (n = 32;
68%), pollakiuria (n = 23; 49%), stranguria (n = 21; 45%), dys-
uria (n = 10; 21%), polydipsia (n = 3; 6%), 2 cases each of leth-
argy, urine dribbling, and polyuria, and 1 case each of urinary
incontinence, tenesmus, kyphosis, and recurrent lower urinary
tract infection. In 3 dogs (Group A, n = 2; Group B, n = 1) the
diagnosis was incidental, and the dogs had no clinical signs.
Twenty-four (51%) dogs had a urinalysis and 11 (23%)
dogs had a urine culture completed before initiation of treat-
ment. Urinalysis revealed atypical transitional cells in 6 of the
24 dogs and bacterial culture was positive in 5 of the 11 dogs.
Bacteria isolated included Escherichia coli, Proteus mirabilis,
and Staphylococcus intermedius. All dogs underwent an initial
abdominal ultrasonographic examination that identified a
bladder mass and 91% (n = 43) had a detailed description
of the mass location available for review. The most common
location was the trigone (Group A, n = 8; Group B, n = 13),
followed by apical (Group A, n = 11; Group B, n = 1), and neck
(Group A, n = 2; Group B, n = 1). Ten dogs (Group A, n = 7;
Group B, n = 3) had multifocal disease. Three dogs (Group A,
n = 1; Group B, n = 2) had ultrasonographic evidence of ure-
teral involvement, 10 dogs (Group B, n = 10) had evidence of
urethral involvement, and 5 dogs (Group A, n = 2; Group B,
n = 3) had evidence of prostatic involvement. No dogs had ultra-
sonographic evidence of metastasis to abdominal organs outside
the urinary tract. No dogs had evidence of regional lymph node
involvement at the time of initial diagnosis. Baseline thoracic
radiographs were done for 60% of the dogs (n = 28). All dogs
in Group A and 3 dogs (19%) in Group B had diagnosis
confirmed via histopathology (surgically retrieved samples for
Group A and cystoscopic biopsies for Group B). The diagnosis
of TCC was confirmed in the remaining Group B dogs (n =13;
81%) by evaluation of cytology samples collected via traumatic
catheterization (n = 10; 63%) or fine-needle aspiration (n = 3;
19%). Five dogs (38%) diagnosed via cytology had evidence of
concurrent lower urinary tract infection.
Thirty-one dogs (66%; Group A) were treated with partial
cystectomy, followed by systemic chemotherapy and COX inhibi-
tors. Sixteen dogs (34%; Group B) were treated with systemic
chemotherapy and COX inhibitors alone. One dog had a left
neocystoureterostomy, due to left ureteral involvement. No dogs
with urethral involvement were in Group A. Except for 1 case,
dogs with prostatic extension and those with trigonal tumors had
135
 Table 1. Characteristics of dogs in Groups A and B.
Group A Group B
Parameter (31 dogs) (16 dogs) P-value
Age (y)
Median (range) 10.3 (5.3 to 15.3) 11.1 (5.6 to 15.6) 0.256a
Gender
Spayed female 18 (58%) 8 (50%) 0.718b
A R T I C LE

Neutered male 9 (29%) 7 (44%)

Intact male 3 (10%) 0 (0%)
Intact female 1 (3%) 1 (6%)
Weight (kg)
Median (range) 14.2 (2.3 to 80) 12.7 (7.1 to 46.4) 0.953a
Breed
Mixed breed 7 (23%) 3 (19%) 0.761b
Beagle 6 (19%) 3 (19%)
West highland white terrier 2 (6%) 1 (6%)
Other (n = 1 each breed) 16 (52%) 9 (56%)
a t-test.
b Chi-square test.

Table 2. Summary of medical therapy protocols for dogs in Groups A and B.

Group A Group B
Medical therapy protocols (31 dogs) (16 dogs)
Single agent 20 (65%) 9 (56%)
Doxorubicin 13 (42%) 4 (25%)
Mitoxantrone 4 (13%) 2 (13%)
Vinblastine 3 (10%) 1 (6%)
Carboplatin 0 2 (13%)
Multi agent 11 (35%) 7 (44%)
Vinblastine/doxorubicin 3 (10%) 2 (13%)
Mitoxantrone/doxorubicin/carboplatin 3 (10%) 1 (6%)
Mitoxantrone/doxorubicin 2 (6%) 3 (19%)
Vinblastine/mitoxatrone 1 (3%) 0
Doxorubicin/carboplatin 0 1 (6%)
Doxorubicin/vinblastine/mitoxantrone/carboplatin 1 (3%) 0
Cisplatin/carboplatin/gemcitabine/cyclophosphamide 1 (3%) 0
Rescue protocol 2 (6%) 1 (6%)
Cyclophosphamide 2 (6%) 0
Cyclophosphamide/gemcitabine 0 1 (6%)
COX inhibitor
derocoxib 16 (52%) 6 (38%)
piroxicam 9 (29%) 7 (44%)
meloxicam 1 (3%) 0
carprofen 0 1 (6%)
multiple 5 (16%) 2 (13%)

partial thickness cytoreductive surgeries that did not disrupt the
ureterovesicular junction. Based upon the surgical report, complete
excision of all gross disease was achieved in 16 dogs (52%) and par-
tial excision of gross disease achieved in 15 (48%). Histopathology
reports were available for review for all 31 cases and margins were
deemed complete in 6 dogs (19%), incomplete in 21 dogs (68%),
and histologic margins were not noted in the histopathology report
in 4 cases (13%). One dog had regional lymph node biopsy per-
formed at the time of cystectomy and no evidence of metastatic
disease was detected histologically. Specific information on peri-
operative surgical complications was not available, but all dogs
survived to discharge. One dog (2.7%) developed tumor seeding to
the abdominal wall associated with the surgical scar 95 d after sur-
gery, following a diagnosis via fine-needle aspiration and cytology.
All study dogs were treated with a COX inhibitor at stan-
dard anti-inflammatory doses. The COX inhibitors used for
both treatment groups are summarized in Table 2. Twenty-two
dogs (47%) received deracoxib only, 16 (34%) received piroxi-
cam only, 1 (2%) received carprofen only, and 1 (2%) received
meloxicam only. Seven dogs (15%) were switched from one
COX inhibitor to another at varying times throughout therapy,
due to patient intolerance to a specific drug. The most com-
monly intolerable drug was piroxicam and the most common
undesirable side effects were vomiting, diarrhea, and azotemia.
Three dogs (6%) received sequential piroxicam then deracoxib,
and 1 (2%) each received sequential piroxicam then meloxicam,
piroxicam then carprofen, piroxicam then firocoxib, and piroxi-
cam then carprofen then deraxocib.

136 CVJ / VOL 62 / FEBRUARY 2021

 Table 3. Prognostic factors evaluated for progression-free survival (PFS) and overall survival (OS) for
dogs treated with partial cystectomy and medical therapy or medical therapy alone.
PFS OS OS TTE
Variable (days) P-value (days) P-value (days) P-value
Surgery 0.026
Yes 85 0.663 498 HR 2.5 276 0.200
No 83 335 95% CI (1.1–5.7) 306

A R T I C LE
Age
Above median 121 0.499 363 0.341 306 0.434
Below median 79 424 302
Gender
Male 122 0.117 484 0.738 329 0.620
Female 61 424 210
Body weight
Above median 85 0.331 424 0.784 363 0.989
Below median 61 276 216
Multifocal
Yes 67 0.414 535 0.134 461 0.112
No 85 306 220
Trigonal
Yes 57 0.149 363 0.360 215 0.267
No 104 374 329
Diffuse 60 0.204 484 0.115 309 0.117
Polypoid 146 616 498
Ureteral involvement
Yes 168 168
No 79 0.819 432 0.266
Urethral involvement
Yes 125 363 363
No 77 0.895 484 0.066 306 0.407
Prostate involvement
Yes 125 329 0.257 270
No 77 0.873 484 363 0.377
Complete gross excision 85 424 276
Gross cytoreduction 72 0.379 616 0.487 287 0.948
Margins
Complete 70 0.558 329 0.340 248 0.296
Incomplete 57 484 242
Deracoxib 56 276 226 0.465
Piroxicam 104 0.521 424 0.793 364
HR — Hazard ratio; CI — Confidence interval.

All study dogs received chemotherapy using various agents
and protocols. The chemotherapy protocols used for both treat-
ment groups are summarized in Table 2. First-line protocols
were recorded for all 47 dogs. Twenty-nine dogs (62%) received
a single agent protocol consisting of either doxorubicin given
once every 21 d for 4 to 6 treatments (n = 17; 36%), mito-
xantrone given once every 21 d for 4 to 6 treatments (n = 6;
13%), vinblastine given once every 7 d for 5 or 6 treatments
(n = 4; 9%), or carboplatin given once every 21 d for 5 or
6 treatments (n = 2; 4%). Eighteen dogs (38%) received multia-
gent therapy. Combination mitoxantrone/doxorubicin was given
as alternating doses every 21 d for 2 or 3 cycles (n = 5; 11%).
Combination vinblastine/doxorubicin with vinblastine was
given on week 1, doxorubicin on week 2, and week 3 was off.
This cycle was repeated for a total of 4 to 6 cycles (n = 5; 11%).
Combination mitoxantrone/doxorubicin/carboplatin was given
as sequential doses every 21 d for 2 or 3 cycles (n = 4; 9%).
Vinblastine/mitoxantrone with vinblastine was given on week 1,
mitoxantrone on week 2, and week 3 was off. This cycle was
repeated for 2 cycles (n = 1, 2%). Doxorubicin/carboplatin was
given as sequential doses every 21 d for 3 cycles (n = 1, 2%).
Doxorubicin/­vinblastine/carboplatin/mitoxantrone was given as
sequential doses every 21 d for 6 cycles (n = 1, 2%). Cisplatin,
carboplatin, and gemcitabine/cyclophosphamide were admin-
istered with cisplatin and carboplatin given sequentially, then
gemcitabine and oral cyclophosphamide given concurrently.
These were administered every 21 d for 3 cycles (n = 1, 2%).
Upon confirmation of progressive disease, rescue protocols
utilizing oral cyclophosphamide (n = 2, 4%) and combination
gemcitabine oral cyclophosphamide (n = 1, 2%) were instituted.
Twelve dogs (39%) in Group A and 2 dogs (13%) in Group B
were censored in OS analysis due to being lost to follow-up.

CVJ / VOL 62 / FEBRUARY 2021 137

 100
90
Progression-free probability
80 Surgery
70 Median PFS = 85 days
60
No surgery
50
Median PFS = 83 days
40
30 P = 0.663
A R T I C LE
20
10
0 0
0 100 200 300 400
Days following treatment initiation
Figure 1. Kaplan–Meier curve comparing the progression-free
survival for dogs treated with partial cystectomy and medical
therapy (Surgery — solid line) versus those treated with medical
therapy alone (No surgery — dashed line). Vertical tick marks
indicate censored cases.
Only 1 dog in Group A (3%) and no dogs in Group B were
lost to follow-up with respect to date of progression. The mean
and median times to censoring for dogs lost to follow-up in
Group A were 491 d (mean) and 364 d (median); and for
Group B were 447 d (mean) and 447 d (median). Twenty-seven
dogs (87%) in Group A and all dogs in Group B died or were
euthanized due to progression of disease. Dogs that were lost to
follow-up were presumed to have died from progressive disease
if tumor progression was confirmed at the date of last contact.
Four dogs (13%) in Group A and no dogs in Group B died
or were euthanized due to causes unrelated to TCC. Causes
of death in these 4 Group A dogs included acute collapse and
cardiopulmonary arrest during exercise, progression of dilated
cardiomyopathy, euthanasia due to progression of chronic renal
failure and abscessation of a cutaneous plasmocytoma, and
severe cervical pain suspected to be secondary to intervertebral
disc disease. The dog that died of acute cardiopulmonary arrest
was treated with doxorubicin; however, the total cumulative
dose was 150 mm/m2. The dog that died of progressive dilated
cardiomyopathy had this diagnosis before being diagnosed with
TCC but was managed medically and was stable at the time of
TCC diagnosis. This dog was not treated with doxorubicin but
rather vinblastine. The dog that was euthanized due to progres-
sive chronic renal failure and abscessation of cutaneous plasmo-
cytoma was treated with the COX inhibitor piroxicam. At the
time the cutaneous abscess was diagnosed, the owner of this dog
elected euthanasia rather than surgical treatment of the cutane-
ous abscess. All 6 dogs that had histologically complete tumor
excision died or were euthanized due to progression of disease.
Outcome and prognostic factors
Disease progression was documented in all 47 dogs. Progression
was confirmed via abdominal ultrasonography and characterized
by recurrence within the bladder lumen (n = 41), evidence of
metastasis to sub-lumbar lymph nodes (n = 1), local extension
into the prostate or urethra (n = 1), and abdominal wall seed-
ing (n = 1).
The outcomes and potential prognostic variables for both
treatment groups are summarized in Table 3. The median PFS
138
Surgery
Median OS = 498 days
100
No surgery
90
Median OS = 335 days
80
Survival probability
70 P = 0.026 HR = 2.5
60
95% CI = 1.1–5.7
50
40
30
20
10
500 600 0 100 200 300 400 500 600
Days following treatment initiation
Figure 2. Kaplan–Meier curve comparing the overall survival
for dogs treated with partial cystectomy and medical therapy
(Surgery — solid line) versus those treated with medical therapy
alone (No surgery — dashed line). Hazard ratio (HR); 95% CI
(confidence interval). Vertical tick marks indicate censored cases.
for dogs undergoing cytoreductive surgery (Group A) and dogs
not undergoing surgery (Group B) were not different (85 d
versus 83 d, P = 0.663; Figure 1). No variables were prognostic
for PFS (Table 2). The median OS for dogs undergoing cyto-
reductive surgery (Group A) was greater than that for dogs not
undergoing surgery (Group B) when lost to follow-up cases were
censored (498 d versus 335 d, hazard ratio 2.5; 95% CI: 1.1 to
5.7; P = 0.026; Figure 2). There was no difference in PFS or OS
between dogs with histologically complete versus histologically
incomplete tumor resection (PFS 70 d for complete versus 57 d
for incomplete, P = 0.558 and OS 329 d for complete versus
484 d for incomplete, P = 0.340; Table 3). No other prognostic
factors were identified.
Table 3 also reports OS time to event (TTE) with lost to
follow-up (LTF) cases uncensored due to the high numbers of
LTF in dogs in the surgery group (Group A). In this scenario,
the median OS for dogs undergoing cytoreductive surgery
(Group A) was not different from that for dogs not undergoing
surgery (Group B) (276 d versus 306 d, P = 0.200; Figure 2).
In Group B dogs, stable disease was noted in 10 dogs (63%)
and progressive disease in 6 dogs (38%). No dogs in Group B
had a complete or partial response to therapy.
Discussion
Previous veterinary studies have formally evaluated effects of
surgery on outcomes for dogs with naturally occurring urinary
bladder TCC (13–19). However, to the authors’ knowledge,
there are no studies comparing the outcomes of canine patients
with urinary bladder TCC receiving surgery and adjunctive
medical therapy, compared to those receiving medical therapy
alone, with case controls from the same time interval and
­institutions. Our study population was similar with respect to
breed, gender, and clinical signs to previously reported popula-
tions of dogs with urinary bladder TCC (2,3,19,20).
In the study reported here, the median OS for dogs treated
with partial cystectomy and adjuvant systemic chemotherapy/
COX inhibitors (Group A), was 498 d compared to 335 d for
dogs treated with systemic chemotherapy/COX inhibitors alone
(Group B) (P = 0.026). The median PFS of 83 d and median
CVJ / VOL 62 / FEBRUARY 2021
OS of 335 d for dogs in Group B (medical therapy only) were
comparable to previously published survival times for dogs
treated with medical therapies alone (2,5,7,21). The OS of
498 d for dogs in Group A, seemed greater than the reported
median OS of approximately 1 y for dogs undergoing partial
cystectomy, with or without adjuvant chemotherapy in other
reports (16,18,19).
Knowing the substantial number of LTF cases in Group A
may have influenced outcomes, a TTE analysis was performed.
In this analysis, median OS was not significantly different
between the 2 groups. While censoring LTF cases likely arti-
ficially prolonged the median OS for Group A, uncensoring
these cases for TTE calculation may have underestimated the
median OS calculation. Although the exact dates of death were
unknown, 11 (92%) of the dogs that were LTF in Group A had
ultrasonographic evidence of progressive disease and were alive
at the date of last contact, with median time for LTF of 491 d.
This approaches the censored median OS of 498 d and it is
reasonable to presume these patients subsequently died or were
euthanized due to their disease shortly thereafter.
In our study, the impact of extent of surgery was unclear, as
surgical dose (complete visual excision versus gross debulking) and
histologic completeness of excision were not significantly associ-
ated with outcome. This finding was in contrast to that of Marvel
et al (19), in which dogs that underwent full thickness cystectomy
had significantly improved PFI and median OS compared to dogs
that had partial thickness tumor excision. That surgical dose is
prognostic is also suggested by data reported by Knapp et al (4),
who noted improved median OS for patients under­going cyto-
reductive surgery and adjuvant medical therapy (4). The lack of
significance of surgical dose in the current study could be attrib-
uted to inadequate power due to low case numbers.
Tumor location away from the trigone was not associated
with an improvement in median OS (374 d, P = 0.360) (using
both the censored and uncensored data, Table 3). This was in
contrast to the study by Marvel et al (19) in which tumor loca-
tion away from the trigone was a prognostic factor that signifi-
cantly improved survival. In our study, dogs with non-trigonal
tumors, were in fact, more likely to undergo surgery prior to
medical therapy (74% versus 38%). The propensity for patients
with non-trigonal tumors to undergo surgery more commonly
than patients with trigonal tumors was likely explained by
surgical decision-making, as full-thickness partial cystectomy
or total cystectomy for trigonal tumors is a more challenging
surgical procedure with higher morbidity than partial cystec-
tomy for tumors at non-trigonal locations. In a pilot study, total
cystectomy with ureterocolonic anastomosis in 10 dogs with
TCC was associated with a poor prognosis and adverse effects
related to systemic uremia (15). Total cystectomy with vaginal
or preputial ureteral diversion in 10 dogs yielded an MST of
385 d and cutaneous ureteral diversion in 4 dogs was associated
with an MST of 279 d (13,14). These patients were persistently
incontinent, making at home management more difficult and
it is the authors’ opinion that these surgical approaches would
be less acceptable to owners.
An alternative explanation would be that surgery does
not improve outcome, rather it is purely a result of anatomic
CVJ / VOL 62 / FEBRUARY 2021
and functional impact differences in where the tumor arises
(and recurs). This latter alternative is supported by the fact that
surgery did not improve PFS in our study. This implies, and is
intuitive, that progression away from the trigone (and therefore
away from ureters and urethra) is less likely to affect quality of
life and indeed, life-threatening outflow problems. In such a
scenario, PFS duration that was not improved by surgery may
A R T I C LE
not have as grave an impact on survival based on an anatomically
more favorable location and therefore, that patient would live
longer despite, not because of, surgery.
Similar to other reports (18,19), complete histologic excision
was not prognostic in our study. This repeatable finding may
be explained by the field cancerization effect within the bladder
lining and/or the likelihood of TCC cell exfoliation and implan-
tation in other locations within the urinary tract.
Comparison of benefit achieved with the various chemo-
therapy protocols and COX inhibitors used in this study was
not possible, as the agents used, dose intensity, and duration
were not uniform. Given the findings supporting the theory of
field cancerization effect, the exfoliative nature of this tumor,
locoregionally aggressive behavior, and considerable risk of
metastasis with TCC, adjuvant chemotherapy should be con-
sidered, even in cases of complete excision with no evidence of
metastasis (4). This recommendation is supported by the fact
that 43 dogs (91%) in this study died or were euthanized due
to progressive disease.
Serial abdominal ultrasound was used to monitor response
to therapy and assess for progressive disease. In a recent study,
experienced observers using a standardized protocol (WHO
or RECIST criteria) reliably determined urinary bladder TCC
dimensions using 2D ultrasonography (22).
Intra-operative complications were not specifically reported in
this study, but all dogs survived to discharge, and no dogs died
due to peri-operative surgical or anesthetic complications. One
dog developed tumor seeding to the abdominal wall associated
with the surgical scar; this represented 2.7% of cases undergoing
partial cystectomy in our study, considerably lower than the 10
to 11% incidence reported by others (19,23)
Limitations of this study were primarily due to its retrospec-
tive nature. These include the relatively small number of cases, a
protracted case accrual period, lack of review by one pathologist,
non-standardized follow-up schedule, and non-uniform report-
ing of data in the medical record precluding accurate determina-
tion of TNM stage and verification of tumor response using the
cRECIST criteria. The retrospective nature also did not allow for
standardization of systemic therapy protocols. A further limita-
tion was the potential for case selection bias towards surgery for
dogs with non-trigonal tumors. This potential bias could mean
these cases with non-trigonal tumors benefited the most from
surgical treatment. Given the anatomy of the trigone region,
elimination of this bias in future studies would require investi-
gation of non-trigonal tumors separate from trigonal tumors,
or further development of surgical techniques for neobladder
in the dog.
In summary, dogs treated with partial cystectomy, systemic
chemotherapeutics, and daily COX inhibitors had an improved
median OS of 498 d compared to 335 d for dogs receiving
139
 medical therapy alone [hazard ratio: 2.5; 95% CI: 1.1 to 5.7;
P = 0.026]. No prognostic factors were identified for PFS. The
findings of our study supported the recommendation for partial
cystectomy with systemic chemotherapeutics and daily COX
inhibitors in the treatment of this disease. The current study also
supported the need for prospective, randomized controlled trials
evaluating dogs with primary urinary bladder TCC to determine
A R T I C LE
12. Lee RK, Abol-Enein H, Artibani W, et al. Urinary diversion after radical
cystectomy for bladder cancer: Options, patient selection, and outcomes.
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13. Ricardo Huppes R, Crivellenti LZ, Barboza De Nardi A, et al. Radical
cystectomy and cutaneous ureterostomy in 4 dogs with trigonal tran-
sitional cell carcinoma: Description of technique and case series. Vet
Surg 2016;46:111–119.
14. Saeki K, Fujita A, Fujita N, Nakagawa T, Nishimura R. Total cystec-
tomy and subsequent urinary diversion to the prepuce or vagina in

dogs with transitional cell carcinoma of the trigone area: A report of

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