Incorporating Hypofractionated Radiotherapy Improves Management of Canine Urothelial Carcinoma: A Retrospective Study

ABSTRACT

This retrospective study evaluated a novel hypofractionated radiation therapy (RT) protocol for canine urothelial carcinoma (UC). Medical records of dogs diagnosed with UC and treated were retrospectively reviewed. Inclusion criteria included diagnosis of UC, treatment with hypofractionated RT, absence of prostatic involvement or metastatic disease, and adequate follow‐up. The RT protocol consisted of 25 Gy delivered to the planning target volume (PTV) in five fractions on an every‐other‐day schedule. Dynamic adaptive radiation therapy (DART) was used in select bladder tumors to minimize geographic miss. Data on adverse events, clinical response, adjuvant therapies, and prognostic factors were evaluated in relation to progression‐free survival (PFS) and overall survival (OS). Eighteen dogs met the inclusion criteria. All received nonsteroidal anti‐inflammatory drugs (NSAIDs), and 67% also received chemotherapy after RT. Tumor location included bladder only (55%), urethra only (28%), or both (17%). RT was well tolerated, with only low‐grade gastrointestinal (17%) or urinary (6%) adverse events observed. Measurable tumor response was observed in 82% (14/17) with follow‐up imaging. Median PFS was 394 days (95% CI: 169–619), and median OS was 565 days (95% CI: 497–632). Dogs with urethral involvement demonstrated a shorter PFS compared to those without (median = 182 vs. 457 days, respectively [p = 0.02]). Chemotherapy did not impact PFS or OS. The novel hypofractionated RT protocol was well tolerated alone and in combination with other treatments. Tumor responses and survival times were improved compared to historical data on dogs receiving NSAIDs and/or chemotherapy alone.

1. Introduction

Carcinomas are the most common neoplasms affecting the canine lower urinary tract [1, 2]. Histologic subtypes include transitional cell (urothelial) carcinoma—accounting for approximately 75%–90% of cases—adenocarcinoma, and poorly differentiated carcinoma [3]. In dogs, bladder tumors most frequently present as invasive, intermediate‐ to high‐grade urothelial carcinoma (UC) [2]. Within the prostate, the predominant tumor types are UC of the prostatic urethra, prostatic adenocarcinoma, and carcinomas exhibiting mixed urothelial and glandular phenotypes [4]. However, accurately differentiating these histologic subtypes can be challenging, as prostatic adenocarcinoma and UC of the prostatic urethra are histologically similar. To address this diagnostic complexity and clinical similarity, the term canine genitourinary carcinoma (CGUC) has been adopted [5]. This classification encompasses UC, adenocarcinoma, and solid carcinomas of the urinary bladder (UB), prostate, ureters, urethra, vulva, and vagina, all of which share similar biological behaviors and therapeutic strategies [5].

UC is rarely amenable to surgical intervention due to its locally invasive nature and common location in the trigone and/or urethra [1, 2]. Without treatment, lower urinary tract obstruction is a frequent complication and remains the most common reason for euthanasia of affected dogs [6, 7]. Primary management for UC centers on medical therapy, including chemotherapy and cyclooxygenase (COX) inhibitors and, more recently, targeted therapies [1, 2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. In dogs with UC confined to the UB, treatment with nonsteroidal anti‐inflammatory drugs (NSAIDs) alone results in an 18%–20% reduction in measurable tumor size and median survival time (MST) of approximately 6 months [14, 16]. Combining mitoxantrone with piroxicam results in remission in about 35% of cases, extending survival to a median of 291 days [13]. Although medical therapy is rarely curative, it can prolong survival and improve quality of life in dogs with UC for up to 1 year [1].

Ionizing radiation therapy (RT) provides an alternative approach for controlling the primary tumor in this locally invasive disease. Prescribed radiation doses have ranged from 27 to 57 Gy in 6 to 20 fractions, with reported MSTs varying between 1 and 21 months [11, 19, 20, 21, 22, 23, 24, 25]. In a 2004 study evaluating coarse fractionated RT (5.75 Gy × 6 weekly doses) combined with piroxicam and mitoxantrone, the MST was 326 days, which did not appear to be superior to that of medical therapy alone [22]. In a 2016 study of 13 dogs with UC of the bladder or urethra treated with a low‐dose palliative RT protocol (10 daily fractions of 2.7 Gy) reported a response rate of 61% and an MST of 179 days [19]. In contrast, a 2012 study of 21 dogs with CGUC treated with full‐course intensity‐modulated radiotherapy (IMRT; 54–58 Gy in 20 fractions) with or without adjunctive treatment had a subjective response rate of 61% and an MST of 654 days [21]. Reported adverse effects of RT include colitis, colonic stricture, cystitis, urinary incontinence, and fibrosis of the bladder or urethra [11, 19, 21]. Although RT shows promise in treating UC, further research is needed to optimize treatment protocols and reduce associated side effects.

This retrospective study aimed to assess the tolerability, progression‐free survival (PFS), and overall survival (OS) associated with a novel, moderately coarse‐fractionated RT protocol. The protocol delivered 25 Gy to the planning target volume (PTV) over five fractions, with some bladder tumors treated with dynamic adaptive radiotherapy (DART) to avoid geographic miss. This approach was selected to provide a shorter treatment course with potentially fewer adverse effects, while aiming to improve survival outcomes in dogs with UC.

2. Methods

2.1. Patient Selection and Data Collected

A search of the RT database at the University of Georgia Veterinary Teaching Hospital was conducted to identify dogs with UC treated with a novel hypofractionated RT protocol between June 2018 and October 2023. This protocol used IMRT to deliver a total dose of 25 Gy to the PTV over five fractions, administered every other day over 11 days. The goal was to provide palliation of clinical signs and durable tumor control over months to a year.

To be included, dogs were required to (1) have a diagnosis of UC confirmed via cytology, histopathology, or a positive Cadet BRAF test in the presence of a measurable urinary tract mass; (2) have undergone hypofractionated RT as a part of initial treatment for UC, with no prior chemotherapy; and (3) have adequate follow‐up through death or for at least 1 year post‐RT, whichever occurred first.

Dogs were excluded if they had prostatic involvement, regional lymph node or distant metastases, or lacked measurable disease at the time of RT. Dogs with prostatic involvement were excluded to minimize heterogeneity in the study population due to the inability to reliably differentiate between primary prostatic carcinoma and secondary extension of UC. Additionally, cases were excluded if follow‐up data were insufficient to assess RT‐related side effects, disease progression, or survival outcomes.

Data were extracted from the medical records at the University of Georgia Veterinary Teaching Hospital for all cases that met the inclusion criteria. Collected data included patient signalment, body weight, presence of comorbidities, presenting clinical signs, date of diagnosis, staging diagnostics performed and their results, tumor location, response to RT, RT‐associated side effects, adjuvant treatments, date of disease progression and/or death, and cause of death. When necessary, referring veterinarians were contacted to obtain additional follow‐up information. Radiation treatment plan parameters were recorded, including D2, D98, and D50 for the PTV, as well as the maximum point dose and mean dose delivered to organs at risk (OAR), such as the spinal cord, small intestine, large intestine, and urethra.

2.2. RT Planning and Treatment

Dogs underwent abdominal computed tomography (CT) scans using a Somatom Sensation 64 scanner (Siemens, Berlin and Munich, Germany) within 2 weeks prior to RT. Scans were performed under general anesthesia with a slice thickness of 2–3 mm, depending on patient size. Dogs were positioned in lateral recumbency on a urethane Vac‐Lok Cushion (Civco Radiotherapy, Coralville, IA, USA), with pelvic limbs separated by an AccuForm Cushion (also from Civco). Intravenous Omnipaque iohexol contrast (GE Healthcare, Chicago, IL, USA) was administered to obtain both pre‐ and post‐contrast images. Dose calculations were based on pre‐contrast imaging, with post‐contrast images incorporated through image fusion to enhance delineation of target volumes and OAR. All CT studies were reviewed in collaboration with a board‐certified veterinary radiologist.

Treatment plans were generated using Eclipse planning software (versions 13.5 and 16, Varian, Palo Alto, CA, USA) with heterogeneity correction via the Anisotropic Analytical Algorithm. Gross tumor volume (GTV) was delineated based on the visible tumor on CT or the entire UB in cases with bladder involvement. Clinical target volume (CTV) was defined by expanding the GTV by 2 cm, confined to the urethra and bladder, and PTV was created by adding a 0.5 cm margin to the CTV. PTV was not excluded from OAR. The OAR, including the bladder, urethra, small intestine, and large intestine, was contoured. No wedges, blocks, or boluses were used as beam modifiers.

Dynamic IMRT plans used five or seven coplanar, equally weighted 6 MV x‐ray beams, delivered isocentrically (100 cm source‐to‐axis distance) via a Trilogy linear accelerator (Varian, Palo Alto, CA, USA), equipped with a high‐definition multileaf collimator (2.5 or 5 mm leaves). Treatment plans aimed to deliver 25 Gy to ≥95% of the PTV, administered in five fractions on an every‐other‐day schedule over 11 days. The every‐other‐day schedule was selected to mitigate acute gastrointestinal toxicity in this moderately hypofractionated regimen.

For bladder tumors extending beyond the PTV, hybrid or offline DART was employed to account for day‐to‐day anatomical changes as described by Nieset et al. [25]. This approach allowed consistent target coverage and avoidance of geographic miss throughout the treatment course. Hybrid DART involves pre‐generated plans (e.g., big, medium, and small bladder plans) and utilizes the appropriate plan on the day of the treatment based on the bladder volume. Online DART involves same‐day imaging and plan adaptation immediately before treatment delivery, whereas offline DART is treatment plan adaptations between fractions based on the trend of anatomical change observed over a period of time. Multiple plans were generated for variable bladder volumes, with daily plan selection based on bladder size assessed using cone‐beam CT (CBCT) acquired on the linear accelerator. If hybrid DART was inadequate, online DART was performed using CBCT‐based replanning while the patient was under anesthesia.

All treatment plans were reviewed using isodose distributions and dose volume histograms and approved by both an American College of Veterinary Radiology board‐certified veterinary radiation oncologist and an American board‐certified therapeutic medical physicist. Quality assurance was performed using a dosimetry system (Sun Nuclear MapCheck, Sun Nuclear Corporation, Melbourne, FL, USA) with acceptance defined as ≥95% gamma pass rate (3%/3 mm criteria). In vivo dosimetry was not performed.

Prior to treatment, patients were walked to encourage bladder emptying, then anesthetized for treatment delivery. Positioning was verified via kilovoltage port films and CBCT, with corrections applied using a 6‐degrees‐of‐freedom Protura Couch (CIVCO Radiotherapy, Orange City, IA, USA).

2.3. Assessment of Tumor Response and Radiation Toxicity

Clinical improvement was evaluated based on owners’ reports of changes in clinical signs and quality of life following RT. Objective tumor responses were assessed by comparing tumor dimensions from the RT planning CT or pre‐RT ultrasound with follow‐up ultrasound measurements when available [26]. The timing of follow‐up imaging and staging was determined by the attending clinician. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines when measurement data were available [27]. Complete response (CR) required the total disappearance of tumors. Partial response (PR) required at least a 30% reduction in the longest diameter or the sum of the longest diameters of all measurable tumors. Progressive disease (PD) was defined as an increase greater than 20% in tumor size or the occurrence of urinary tract obstruction or metastatic disease. The overall response rate (ORR) included CR and PR, whereas clinical benefit (CB) covered CR, PR, or SD.

Radiation‐related toxicities were assessed and graded according to acute and late morbidity criteria outlined in the ACVR and ECVDI consensus statement: Reporting elements for Toxicity Criteria of the Veterinary Radiation Therapy Oncology Group v2.0 [28].

2.4. Statistical Analysis

Descriptive statistics were calculated for patient, tumor, and treatment variables. Normality of continuous data was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Nonparametric tests were applied for non‐normally distributed data. Categorical variables were compared using chi‐square tests or Fisher's exact tests when expected values were <5. Age and body weight were categorized as dichotomous variables using the median as a cutoff.

OS was defined as the interval from the first RT session to the date of death; dogs still alive at the last follow‐up were censored. The PFS was defined as the time from the first RT to documented disease progression. PD included RECIST‐defined progression, development of urinary obstruction, or metastatic disease. Median OS and PFS were estimated using Kaplan–Meier survival analysis.

Potential prognostic factors assessed for association with PFS and OS included age, body weight, sex, clinical signs, urethral involvement at diagnosis, stent placement, use of DART, RT dose, chemotherapy administration, and RT response. Kaplan–Meier survival curves were generated, and the log‐rank test was used to compare groups. Results are presented as median survival (±95% confidence interval [CI]). Hazard ratios (HR) and 95% CI were obtained through univariate Cox proportional hazards modeling. A p value < 0.05 was considered significant. All statistical analyses were performed using SPSS software (v.29.0.2.0, IBM, Armonk, NY, USA).

3. Results

3.1. Patient Demographics and Diagnostics

Forty‐one dogs with suspected CGUC were treated with RT at the University of Georgia Veterinary Teaching Hospital during the study period. Eighteen dogs met the inclusion criteria. Reasons for exclusion included RT administered after PD from another treatment (n = 3), use of an alternative RT protocol (n = 5), prostatic involvement (n = 11), metastatic disease at diagnosis (n = 2), and inadequate follow‐up (n = 2). The median time from diagnosis to RT start was 17 days (range 4–73).

Patient characteristics and diagnostic findings are summarized in Table 1. The majority of dogs were spayed females (56%), and there was no clear breed predilection. All dogs underwent abdominal CT scans as part of their RT planning. The choice of other baseline staging tests was determined by the treating veterinarian. The Cadet BRAF test was performed in 12 dogs (67%), and a mutation was detected in 75%. Cystoscopy was performed in seven dogs (39%). Diagnosis of UC was made by histopathology in 10 dogs (56%) and cytology in 2 dogs (11%). In the remaining six dogs (33%), UC diagnosis was based on a positive BRAF mutation in the face of a measurable urinary tract mass.

TABLE 1.

Patient and treatment characteristics.

Age (median, range)	9.5 (7.5–14.5) years
Weight (median, range)	17.9 (2.5–43.0) kg
Sex
Neutered male	8 (44%)
Spayed female	10 (56%)
Breed
Mixed breed	7 (38%)
Labrador retriever	1 (6%)
Dachshund	1 (6%)
Other pure breeds	9 (50%)
Clinical signs
Pollakiuria	11 (61%)
Hematuria	7 (39%)
Urinary obstruction
Complete	2 (11%)
Partial	5 (28%)
Asymptomatic	2 (11%)
CGUC location
Urinary bladder only	10 (55%)
Urethra only	5 (28%)
Bladder and urethra	3 (17%)
Initial diagnostics
Thoracic radiographs	7 (35%)
Thoracic CT scan	11 (65%)
Abdominal ultrasound + CT scan	18 (100%)
Cystoscopy	7 (39%)
Cytology	2 (11%)
Biopsy	10 (56%)
Cadet Urine BRAF test	12 (67%)
BRAF mutation detected	9 (75%)
Initial treatment
Radiation therapy	16 (89%)
Stent	2 (11%)
Adjuvant treatment
NSAID
Piroxicam	15 (83%)
Meloxicam	2 (11%)
Deracoxib	1 (6%)
Chemotherapy	12 (67%)
First chemotherapy drug
Vinblastine	11 (92%)
Mitoxantrone	1 (8%)

Abbreviations: CGUC, canine genitourinary carcinoma; CT, computed tomography; NSAID, nonsteroidal anti‐inflammatory drug; UC, urothelial carcinoma.

At diagnosis, the UB was the sole site of involvement in 10 dogs (55%), whereas both the bladder and urethra were affected in 3 dogs (17%). In five dogs (28%), only the urethra was involved (Table 1).

3.2. Treatments and Tolerability

All dogs completed the planned hypofractionated RT protocol without treatment interruptions. Dose metrics for the PTV are shown in Table 2. Four dogs required the use of the hybrid or offline DART technique.

TABLE 2.

Radiation dose information for the planning target volume (PTV), large intestine, urethra, bladder, small intestine, and spinal cord.

	Mean (Gy)	D98 (Gy)	D2 (Gy)	Maximum point dose (Gy)
PTV	26.4 (25.4–27.4)	20.9 (17.2–25.5)	27.2 (26.1–28.3)	27.16 (26.3–28.2)
Large intestine	12.4 (1.0–18.3)	—	—	26.8 (25.4–28.3)
Urethra	25.0 (3.5–27.8)	—	—	26.9 (25.8–28.1)
Bladder	23.31 (0.2–27.4)	—	—	26.8 (26.0–28.0)
Small intestine	0.5 (0.1–11.3)	—	—	27.0 (25.6–28.3)
Spinal cord	0.2 (0.1–0.5)	—	—	0.99 (0.5–16.9)

Note: The mean radiation dose, along with the mean D98 (representing the near‐minimum dose), mean D2 (indicative of the near‐maximum dose), maximum point dose, and mean radiation dose delivered to the PTV, are presented with their respective ranges in parentheses.

RT was well tolerated overall. Two weeks post‐RT, nine dogs (50%) showed owner‐reported clinical improvement, one dog experienced worsened stranguria, while the remainder had no reported change. Adverse events were observed in five dogs (28%). Acute gastrointestinal side effects (diarrhea or hematochezia), attributed to RT, occurred in three dogs (17%) and were graded as VRTOG v2.0 Grade 1 in two and Grade 2 in one [28]. One dog experienced worsened stranguria during RT, classified as Grade 1 urinary toxicity [28]. As two patients had previously documented urinary incontinence prior to RT, only one patient (6%) developed new‐onset urinary incontinence post‐RT. No definitive late RT effects were identified; however, PD‐related signs (stranguria [n = 4], hematuria [n = 1], and pollakiuria [n = 1]) seen in some dogs could have masked late RT side effects.

All dogs received NSAIDs initiated before or at the time of RT. NSAIDs were the sole adjuvant therapy for six dogs (33%). Urethral stents were placed in the peri‐RT period in two dogs. Chemotherapy was administered to 12 dogs (67%), initiated a median of 14 days (range 14–39) post‐RT in 11 dogs, and at disease progression (160 days post‐RT) in one dog. Vinblastine (mean 2.3 mg/m²) was the most commonly used first‐line chemotherapy, followed by mitoxantrone (mean 5.0 mg/m²). Seven dogs (39%) received additional chemotherapy protocols following disease progression. Treatment timing and outcomes of individual dogs are summarized in Figure 1.

FIGURE 1.

Individual outcome timelines for all 18 dogs with UC treated with hypofractionated radiation therapy. Each horizontal bar represents a single dog, with time (in days) shown on the x‐axis. Key clinical events, including stent placement, initiation of adjuvant chemotherapy, disease progression, death, or censoring, are annotated to visualize treatment response and disease course. OS, overall survival; PD, progressive disease; PFS, progression‐free survival; RT, radiation therapy.

3.3. Tumor Response and Survival

Follow‐up evaluations for tumor response were available in 17 dogs (94%), assessed by abdominal ultrasound or digital rectal palpation (for dogs with disease confined to the urethra). The remaining dog was not re‐evaluated until 150 days post‐RT, when iliac lymph node metastasis was detected on ultrasound and confirmed cytologically. The median time to first posttreatment abdominal ultrasound was 77 days (range, 23–132 days). Tumor responses based on RECIST [27] criteria included CR in 4 dogs (24%), PR in 10 dogs (59%), and SD in 3 dogs (18%), yielding an ORR of 82% and CB of 100%. Among the five dogs who did not receive chemotherapy and had follow‐up measurements, CR occurred in two dogs (40%), PR in one dog (20%), and SD in two dogs (40%) (ORR = 60% and CB = 100%).

PD was confirmed in 16 dogs (89%). Disease progression was due to local disease in 10 dogs (56%), metastasis in 5 dogs (31%), and both local progression and metastasis in 1 dog. No specific patient or tumor factors, including clinical signs or tumor location at diagnosis, were associated with disease progression occurrence or type.

Median PFS was 394 days [95% CI: 169–619] (Figure 2A). Dogs with urethral involvement had a significantly shorter PFS (median, 182 days) compared to those without urethral involvement (median, 457 days) (p = 0.02) (Figure 2B). Stent placement at the time or immediately prior to RT was also associated with increased risk of progression (Table 3).

FIGURE 2.

(A) Kaplan–Meier curve of progression‐free survival (PFS) in 18 dogs with urothelial carcinoma (UC) treated with hypofractionated radiation therapy. The median PFS was 394 days (95% CI: 169–619). Dogs were censored (indicated by a hash mark) if they had not developed progressive disease at their last follow‐up. (B) Kaplan–Meier curve comparing PFS between dogs with and without urethral involvement. Dogs with urethral involvement had a significantly shorter PFS. Dogs were censored (indicated by hash mark) if they had not developed progressive disease at their last follow‐up.

TABLE 3.

Prognostic factors associated with overall survival (OS) and progression‐free survival (PFS) in dogs treated with radiation therapy for urothelial carcinoma (UC).

		Overall survival				Progression‐free survival
	n	MST (95% CI), days	p	HR (95% CI)	p	n	PFS (95% CI), days	p	HR (95% CI)	p
Sex			0.14		0.14			0.14		0.15
Male, castrated	8	644 (556–732)		1.0		7	457 (419–495)		1.0
Female, spayed	10	461 (179–743)		2.4 (0.7–8.4)		10	275 (170–360)		0.7 (0.4–1.2)
Stranguria			0.41		0.42			0.83		0.83
No	10	527 (298–613)		1.0		10	293 (109–477)		1.0
Yes	8	565 (516–632)		1.6 (0.5–5.1)		7	457 (0–1163)		0.9 (0.3–2.5)
Urinary obstruction			0.81		0.81			0.78		0.78
No	11	527 (273–780)		1.0		10	293 (109–477)		1.0
Yes	7	625 (533–716)		0.9 (0.3–2.6)		7	457 (0–1163)		0.8 (0.3–2.4)
Urethral involvement			0.29		0.29			0.02*		0.03*
No	10	625 (529–720)		1.0		10	457 (428–486)		1.0
Yes	8	461 (163–759)		1.8 (0.6–5.6)		7	182 (161–202)		3.6 (1.2–11.1)
First treatment			0.96		0.95			0.001*		0.02*
RT	16	565 (502–627)		1.0		15	442 (235–649)		1.0
Stent	2	277 (NR)		1.0 (0.2–4.6)		2	150 (NR)		4.3 (1.3–14.4)
Chemotherapy			0.86		0.85			0.30		0.31
No	6	527 (291–762)		1.0		6	461 (97–825)		1.0
Yes	12	625 (418–831)		0.9 (0.3–2.8)		11	293 (64–522)		1.8 (0.6–5.3)

Note: The * and bold text were placed originally to identify visually which results were statistically significant at p< 0.05.

Abbreviations: CI, confidence interval; HR, hazard ratio; MST, median survival time; PFS, progression free survival.

Median OS was 565 days [95% CI: 497–632] (Figure 3). At the time of analysis, 15 dogs (83%) were deceased. Three (17%) dogs were alive at the last follow‐up; of these, two had PD, and one experienced a partial remission and had not progressed 395 days after RT. UC was the confirmed cause of death for 14 of the 15 deceased dogs (93%). One dog died due to gastric perforation 625 days post‐RT; a direct link to UC or RT could not be confirmed upon necropsy.

FIGURE 3.

Kaplan‐Meier curve showing overall survival (OS) in 18 dogs with UC treated with hypofractionated radiation therapy. Median OS was 565 days (95% CI: 497–632). Censoring is indicated by hash marks. Dogs were censored at the time of the last follow‐up if they were still alive.

Several potential prognostic factors were analyzed for association with OS (Table 3). Use of adjuvant chemotherapy was not associated with improved survival (median OS: 625 vs. 527 days; p = 0.86) (Table 3).

4. Discussion

In this retrospective study of 18 dogs with UC treated with a novel, moderately hypofractionated radiation protocol as a part of their medical treatment regimen, we observed an objective response rate of 82% and minimal treatment‐related toxicity. The median OS was 565 days, and the median PFS was 394 days. The protocol was well‐tolerated, with only 17% of dogs developing grade 1–2 acute gastrointestinal toxicities and one patient (6%) with a urinary adverse event. Urethral involvement and urethral stent placement were significantly associated with shorter PFS. Although the prescribed total dose would not traditionally be considered tumoricidal for gross disease, durable local control was observed in a substantial proportion of dogs. We hypothesize that this outcome reflects a convergence of favorable tumor biology, cohort selection favoring localized disease, and meticulous image‐guided and adaptive treatment delivery, minimizing geographic miss, rather than dose escalation alone.

In designing the RT protocol for this study, the alpha‐beta ratio of CGUC was a key consideration. Alpha‐beta ratio is commonly used as a surrogate for the capacity of sublethal DNA damage repair post‐RT, indicating a tumor's radioresistance [29]. Tumors with low alpha‐beta ratios may be better treated with higher dose per fraction RT protocols due to their enhanced repair capabilities. Notably, CGUC has an estimated low alpha‐beta ratio of 3.3 based on in vitro data, supporting the use of hypofractionation [30]. However, higher doses per fraction (e.g., 8 Gy) theoretically increase the risk of late toxicity, particularly in adjacent organs such as the large intestine, rectum, bladder, and ureters, potentially causing serious complications such as stricture of the rectum, large intestine, or the ureters, fibrosis of the bladder, and, in rare cases, large intestine perforation [31]. To balance palliative efficacy and safety, we selected a moderately hypofractionated regimen (5 Gy per fraction) aimed at achieving clinically meaningful local disease control and symptom relief while limiting toxicity. The intent of this protocol was not definitive tumor eradication, but rather durable palliation with acceptable risk of acute and late complications. We chose 5 Gy per fraction to avoid large fraction sizes (e.g., ≥8 Gy), which may increase the risk of late effects in adjacent dose‐limiting organs, while keeping the total dose below definitive levels to mitigate normal tissue injury.

Compared to prior studies, this protocol demonstrated favorable tolerability. Acute gastrointestinal adverse events occurred in 17% of dogs, and urinary adverse events (stranguria, incontinence) occurred in one dog (6%). No definitive late effects were documented in this study, though progression‐related clinical signs may have masked late toxicity. Acute radiation toxicity has been previously reported to be mild and self‐limiting in other studies of dogs receiving hypofractionated or full‐course IMRT [11, 32]. Previous studies of definitive‐intent RT for CGUC have reported late complications, including colitis, colonic stricture, cystitis, urinary incontinence, and fibrosis of the bladder or urethra [11, 19, 21, 24]. In a 2021 study using a prescription of 57 Gy delivered in 20 fractions, permanent urinary incontinence was reported in 31% of dogs at a median of 70 days after RT [11]. In a recent study evaluating the updated classification of radiation toxicities (VRTOG_v2.0), a larger proportion of late toxicities, including persistent incontinence and urethral obstructions without PD resulting in euthanasia, were found in 42.9% of cases treated with a definitive‐intent protocol (45 Gy delivered in 12 fractions) [32]. Acute and late urogenital tract side effects may be hard to separate from PD, secondary bacterial infections, or tumor‐associated inflammation or hemorrhage. In addition, imaging‐based tumor measurements may not properly assess tumor progression versus late side effects such as fibrosis. These findings underscore the challenge of differentiating between true radiation‐induced late effects and disease‐related complications such as infection, fibrosis, or obstruction.

Multimodal therapy is likely to become the standard of care for CGUC. Prior studies report median OS of 1–21 months using various combinations of RT, NSAIDs, and chemotherapy [11, 19, 20, 22, 24]. In our study, dogs treated with RT and NSAIDs, with or without chemotherapy, achieved a median OS of 565 days. Although the addition of chemotherapy did not significantly prolong survival in our cohort, this may reflect the study's small sample size and variability in chemotherapy initiation and agents used. The protocol presented here offers a less time‐intensive, more accessible, and well‐tolerated RT option than traditional definitive course protocols, while achieving comparable survival outcomes. Further studies could explore the benefits of adjuvant therapies and the influence of the timing of such treatments on OS in dogs treated with this RT protocol.

As in previous studies, dogs with urethral involvement had a shorter PFS and a higher risk of disease progression, likely due to the higher risk of urinary obstruction in this region [33]. Dogs requiring urethral stent placement also had significantly shorter PFS, likely reflecting more advanced disease at presentation. These findings support further investigation into dose escalation to the urethra to improve local control. In a 2024 study, McKenna et al. [6] found that the primary cause of euthanasia for dogs with UC was considered to be local progression in 62% of cases; therefore, better local control will be essential to prolonging the survival of patients with UC.

Assessment of therapeutic response in canine UC remains a diagnostic challenge, particularly due to the limitations associated with imaging‐based tumor measurements. The RECIST criteria, which rely on linear measurements, are not ideally suited for evaluating bladder tumors in dogs, as these tumors often exhibit irregular and variable morphology [27]. Most response assessments in clinical veterinary practice and research are based upon two‐dimensional ultrasonography; however, these measurements are highly dependent on bladder distension and demonstrate poor inter‐observer reliability. Previous studies have shown that both operator variability and changes in bladder volume can significantly impact sonographic measurements, to the extent that response classification may be altered [34]. In addition, linear measurements tend to overestimate or inaccurately reflect tumor burden compared to volume‐based assessments, which are considered more representative of actual tumor response [26, 35]. In the present study, the retrospective nature limited response evaluation to two‐dimensional linear measurements in the majority of cases, which must be acknowledged as a limitation. However, in cases where the tumor was no longer visible on follow‐up ultrasound or digital rectal examination—despite prior identification—there was greater confidence in classifying those cases as demonstrating an objective response. In certain instances, PD was suspected based on signs of urinary obstruction; however, other causes, such as urinary tract infection or late RT side effects, could not always be excluded. To more accurately evaluate the efficacy of hypofractionated RT in canine UC, future prospective studies using standardized and volumetric measurement protocols are warranted.

Other limitations of this study include its retrospective design, variable diagnostic approaches, factors inherent to studying canine UC, and variability of adjuvant treatments. In order to reduce biological and clinical heterogeneity, dogs with prostatic involvement were excluded to minimize heterogeneity in the study population due to the inability to reliably differentiate between primary prostatic carcinoma and secondary extension of UC. Although this could be considered a limitation, as prior studies have shown that prostatic involvement is not necessarily associated with worse outcomes, we elected to focus on bladder and urethral disease to improve consistency and interpretability of treatment response and survival outcomes. In addition, cytological or histopathologic confirmation was not available in one‐third of cases, with diagnosis based on BRAF mutation and imaging. In addition, false positive results with the BRAF test could falsely include cases that would have been expected to behave differently from those with histopathologically confirmed UC [36]. We feel, however, that the population of dogs was representative of what cases and extent of diagnostics would be performed in everyday practice. Additionally, variability of adjuvant treatments, follow‐up schedules, and imaging modalities complicates the assessment of treatment response and survival outcomes. Chemotherapy use was not standardized, and DART was not uniformly applied. Because of this variability of adjuvant treatments, the true influence of other treatments like chemotherapy or stent placement on RT outcomes could not be assessed in this study.

In conclusion, this novel hypofractionated radiation protocol was well tolerated in dogs and resulted in encouraging tumor responses and survival outcomes when combined with NSAIDs, with or without chemotherapy. Compared to previous protocols, it offers a more practical and less intensive option for managing UC in dogs. Further prospective studies are warranted to evaluate optimal integration with adjuvant therapies, clarify the role of DART, and improve local control in dogs with urethral involvement.

Author Contributions

Conception and design of the work: Koichi Nagata and Dawn M. Clarke. Data acquisition: Jishnu Rao Gutti, Dawn M. Clarke, and Koichi Nagata. Analysis and interpretation of data: Dawn M. Clarke and Jishnu Rao Gutti. Drafting the article: Koichi Nagata, Jishnu Rao Gutti, Dawn M. Clarke, and Corey Saba. Reviewing article for intellectual content: Koichi Nagata, Dawn M. Clarke, Jishnu Rao Gutti, and Corey Saba. Final approval: Koichi Nagata, Dawn M. Clarke, Jishnu Rao Gutti, and Corey Saba.

Funding

The authors have nothing to report.

Disclosure

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.