Veterinary and Comparative Oncology
ORIGINAL ARTICLE OPEN ACCESS
Outcome and Toxicity Profile of Stereotactic Body Radiation Therapy for Adrenal Tumours in Dogs
Lily Thorsen1 | Kimberley Law2 | Jillian Walz2 D | Valerie Morales Coll3 | Ada Naramor3 | Charles Maitz3 D Lyndsay Kubicek4 | Zebulon Thorsen5 İD Jishnu Rao Gutti1 | Marilia Takada1 İD
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1Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA | 2MSPCA-Angell Animal Medical Center, Boston, Massachusetts, USA | 3Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, USA | 4Colorado Animal Specialty & Emergency, Boulder, Colorado, USA | 5North Shore Center for Medical Aesthetics, LTD, Northbrook, Illinois, USA
Correspondence: Marilia Takada (mtakada@ufl.edu)
Received: 2 May 2025 | Revised: 4 November 2025 | Accepted: 10 December 2025
Keywords: adrenal tumour | adrenocortical carcinoma | dogs | pheochromocytoma | stereotactic body radiation therapy
ABSTRACT
Stereotactic body radiation therapy (SBRT) has become a non-invasive alternative option for canine adrenal tumours with high surgical risks; however, its clinical benefits and risks are still to be fully understood. The goal of this multi-institutional retrospec- tive study was to describe the clinical outcome and safety of SBRT for the treatment of 21 dogs with adrenal tumours. Ten were suspected pheochromocytomas, two adenocarcinomas, and the diagnosis was unknown in nine dogs. Vascular invasion was present in 81% of cases (17/21). Thirteen dogs received 3 fractions of 6 to 11 Gy, 7 received 5 fractions of 6 to 9 Gy, and 1 received 4 fractions of 6 Gy. For the 20 patients with follow-up imaging, 9 (43%) had partial response, 10 (47%) stable disease, and 1 (5%) progressive disease. Progression-free survival was 16.8 months (95% CI: 3.4-23), and overall survival time was 16.8 months (95% CI: 3.7-23.7). Twelve patients (57%) experienced acute adverse events (AEs); of those, seven were gastrointestinal grade ≥III, including one grade V. Late AEs were suspected in seven dogs (33%), including gastrointestinal grade V in four of them. A total of five dogs (24%) died from radiation-related toxicities. Although SBRT seems to be effective against adrenal tumours, it was associated with a high morbidity and mortality rate, suggesting that re-evaluation of radiation therapy protocols is necessary for maintaining patient safety.
1 Introduction
Canine malignant adrenal tumours are challenging to manage since many patients are diagnosed at a late stage of disease. The most common adrenal malignancies are adrenocortical carcinomas and pheochromocytomas for which vascular inva- sion is present in 20%-82% of cases, with a reported metastatic rate of up to 40%-50% [1, 2]. The most common clinical signs result from excessive secretion of glucocorticoids like increased
appetite, polyuria, polydipsia, alopecia, lethargy and muscle weakness; or excessive amounts of catecholamines, including weakness, episodic collapse, panting, anxiety, exercise intoler- ance, decreased appetite and weight loss [3].
Surgery is the current gold standard treatment. However, fa- vourable outcomes are limited to smaller tumours (≤3cm in diameter) with no vascular invasion. In these cases, 76% of dogs were still alive at 2 years [4]. Advanced stage adrenal tumours of
Abbreviations: AEs, adverse events; CTV, clinical target volume; GI, gastrointestinal; GTV, gross tumour volume; ORR, objective response rate; OST, overall survival time; PFS, progression-free survival; PTV, planning tumour volume; SBRT, stereotactic body radiation therapy; TTP, time to progression.
Preliminary results of this study were presented at the American College of Veterinary Radiology Annual Scientific Conference, New Orleans, LA in 2023.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
@ 2025 The Author(s). Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.
size ≥ 5 cm in diameter and with presence of metastatic disease are associated with survival times of 5.2 and 4 months, respec- tively [5]. In addition, major surgery-related complications occur in 11%-47% of cases, including bleeding, hypotension, kidney injury, and respiratory arrest, which results in a mortality rate of 8%-24% [1, 2, 4-7].
With the advent of image-guided intensity-modulated capabili- ties, stereotactic body radiation therapy (SBRT) has increasingly been considered, particularly for inoperable adrenal tumours. Although limited, the current literature has shown promising tumour response and minimal reported radiation-related tox- icities. One study reported on nine dogs that received either 10 Gyx 3 or 7.8 to 9 Gy × 5 daily. There was a 30% mean reduction in tumour size with an overall survival time (OST) of 34 months. Adverse events (AEs) were mild and self-limiting [8]. In another study, 8 dogs with pheochromocytoma were treated with either 7Gy×5 on alternate days or 11 Gy×3 daily. Objective response rate (ORR) was seen in four dogs (50%). OST was not reached with a median follow-up time of 19.7 months. Three patients were reported to develop a grade I acute gastrointestinal (GI) toxicity [9].
Our goal with this retrospective study was to contribute to the current knowledge of the use of SBRT for canine adrenal tu- mours by looking at a larger number of cases and assessing if the same outcome with minimal AEs held true.
2 Methods
This is a multi-institutional retrospective study of dogs diag- nosed with adrenal tumours treated with SBRT. Participating institutions included: University of Florida, University of Missouri, Angel Animal Medical Center, and Colorado Animal Specialty and Emergency. Databases were searched for dogs that had a diagnosis of adrenal tumour based on im- aging, cytology, and/or histopathology that were treated with radiation therapy between December 2022 and May 2025. Patients who completed SBRT protocols and had available follow-up information were included. Medical records were reviewed for information on clinical signs, tumour charac- teristics, staging, radiation protocol, dose statistics, radiation toxicities, use of adjuvant therapies, response to treatment, and patient outcome.
Response to treatment was retrospectively classified according to the response evaluation criteria for solid tumours in dogs (v1.0) [10]. AEs from radiation were retrospectively graded based on the toxicity criteria of the Veterinary Radiation Therapy Oncology Group (v2.0) [11]. When unavailable in the hospital medical records, outcome information was obtained by telephone with referring veterinarians or owners. Time to progression (TTP) was defined as the time from the first day of SBRT until disease progression based on abdominal imaging. Progression-free survival (PFS) was defined as the period from the first day of SBRT until local progression, metastasis or death from any cause. OST was defined as the period from the first day of SBRT until death of any cause. Median TTP, PFS and OST were estimated using the Kaplan-Meier method of analysis on Prism 9 (GraphPad).
3 Results
3.1 Patient Population
A total of 21 dogs met the inclusion criteria for this retrospec- tive study. See patients signalment and tumour characteristics in Table 1. Clinical signs at diagnosis included polyuria/polydipsia (8), hyporexia (6), excessive panting (5), diarrhoea (5), hyper- tension (4), vomiting (3), lethargy (3), abdominal distension (3), ataxia of the hindlimbs (3), ascites (2), alopecia (2) and hema- turia (1). The two patients with ascites required once to twice weekly therapeutic abdominocentesis. A total of nine patients (43%) were receiving treatment for hypertension during SBRT; nine dogs were treated with phenoxybenzamine and five with amlodipine.
| Age, year Weight, kg | 10 (6-17) 14.4 |
|---|---|
| (3.3-58.3) | |
| Breed, n | |
| Mixed breed dog | 7 |
| Golden retriever | 2 |
| Shetland sheepdog | 2 |
| Old English Sheepdog, Boston Terrier, | 1 each |
| French Bulldog, Yorkshire Terrier, Dachshund, Chihuahua, Pit Bull Terrier, Border Collie, Pomeranian, and Boxer | |
| Sex, n (%) | |
| Castrated male | 12 (57%) |
| Spayed female | 9 (43%) |
| Cancer diagnosis, n (%) | |
| Pheochromocytoma | 10 (48%) |
| Confirmed pheochromocytoma | 2 (10%) |
| Suspected pheochromocytoma | 8 (38%) |
| Suspected cortisol-secreting tumour | 2 (10%) |
| Unknown | 9 (42%) |
| Adrenal tumour largest diameter, cm | 4.5 (3-11.6) |
| Adrenal tumour location | |
| Left | 11 (52%) |
| Right | 10 (48%) |
| Vascular invasion, n (%) | 17 (81%) |
| Vascular invasion length, cm | 5.5 (1-12.6) |
| Suspected metastasis at the time of diagnosis, n (%) | |
| Regional lymph nodes | 4 (19%) |
| Pulmonary | 2 (10%) |
| Not present | 15 (71%) |
Four dogs (19%) had a history of prior other neoplasia that in- cluded anal sac adenocarcinoma (2), mast cell tumour (1) and lacrimal gland adenocarcinoma (1). The dog with a mast cell tumour had surgery to remove the masses and did not require follow-up chemotherapy. Both dogs with a history of anal sac adenocarcinoma had the tumour excised, and one of them received adjuvant mitoxantrone chemotherapy. The dog with a lacrimal gland adenocarcinoma had surgery to remove the tumour and then received adjuvant carboplatin/fluorouracil chemotherapy.
3.2 | Diagnostic Evaluation
All patients had measurable disease at the time of SBRT. One dog had received prior surgery to remove the adrenal tumour, but the mass recurred 7 months later. The most common diagnosis was pheochromocytoma, present in 10 dogs (47%). Histopathology was available in two cases (one from prior surgery and one from necropsy findings) that confirmed the diagnosis of pheochromo- cytoma. For the remaining eight dogs, suspicion of pheochromo- cytoma was based on the elevation of the urine metanephrine creatinine ratio (3), clinical signs alone (3) and cytology (4). Two dogs (10%) had suspected adrenocortical adenocarcinoma based on the evidence of hyperadrenocorticism from an ACTH stim or low-dose dexamethasone suppression test. The diagnosis was unknown in the remaining nine cases (43%).
There was a near-even split between right and left adrenal tu- mours, with 48% being right-sided (10) and 52% being left-sided (11). Based on CT imaging review, the average largest tumour diameter was 4.5cm (range, 3 to 11.6cm). Vascular invasion was present in 17 of the 21 cases (81%). The average length of vascular invasion for the cases where information was avail- able was 5.5cm (range, 1 to 12.6 cm). The invasion extended cranial to the diaphragm in three cases but did not extend be- yond the hilum of the liver in the remaining cases where infor- mation was available (n = 8). Abdominal effusion characterised as a modified transudate was present in two cases, resultant from caval syndrome due to the severity of vascular invasion.
All dogs had thoracic and abdominal imaging before treatment. Two cases had thoracic radiographs and an abdominal CT while the remainder had a thoracic and abdominal CT. Metastatic disease was suspected in 5 cases (24%). Regional lymph nodes were the most common site of suspected metastasis in a total of 4 cases (19%) that included mesenteric (n=2), periaortic (n=1) and sternal location (n=1). Two dogs (9%) had one or multiple lung nodules. However, one of these dogs was also found to have bilateral thyroid masses on CT, and it is unclear whether the metastatic disease was from the adrenal or thyroid tumours. Cytology was not performed to confirm metastatic disease in any of the cases where it was suspected.
3.3 | Radiation Therapy
All dogs were placed in a vacuum-sealed mattress for positioning during CT simulation of the abdomen. A total of 16 patients were in prone position (10 tail-first and 6 head-first), and five were in contralateral lateral recumbency (4 tail-first and 1 head-first). CT
scans were imported into software for computer-based inverse treatment planning: Eclipse (17) and Monaco (4). Treatment planning parameters varied between institutions. Treatment plans were reviewed and approved by a board-certified radia- tion oncologist. The gross tumour volume (GTV) encompassed a contrast-enhancing mass, including intravascular areas of contrast-enhancement. An adjacent lymph node was included in the GTV in one out of four cases with suspected lymph node metastasis. In five cases with intravascular invasion, the clinical target volume (CTV) had a mean expansion of 4.8 mm (range, 3 to 8 mm) of the GTV, anatomically confined to the intravascular areas. From these five cases, the planning target volume (PTV) had a mean expansion of 4 mm (range, 2 to 6 mm) of the CTV in four of them, and PTV was not used in one of them. In 11 cases with no CTV, PTV had a mean expansion of 2.7 mm (range, 2 to 4 mm) of the GTV. One case had no CTV or PTV.
In four cases, a CT of the abdomen was performed with respi- ratory gating (band around the abdomen applying pressure to record full respiratory cycle). A maximum intensity projection (MIP) was created by combining the respiratory gated CT im- ages. An internal target volume (ITV) was used as an expansion of GTV based on the MIP to cover tumour position during respi- ratory motion. For these cases, PTV was a 1.5 mm expansion of the ITV. Measures to account for respiratory motion were not applied in the remaining 17 patients.
Treatment plans were performed isocentrically and either VMAT with 1 or 2 arcs or IMRT with 6 to 13 static coplanar beams using 6 or 10 MV photon energies. Quality analysis was performed for all plans. Electronic portal imaging device dosimetry verification (Varian portal dosimetry) with criteria of 100% of points passing a gamma analysis at 2%/2mm dose difference/DTA was used in one institution, a 2D diode array (MapCHECK) with criteria of ≥95% of all points passing at 3%/3 mm at another institution, and a 3D array of diode detectors (ArcCHECK) with ≥94% of all points passing at 3%/3mm at the third institution. The information on the verification process at the fourth institution was not available.
Treatment was delivered using the following linear accelera- tors: Varian TrueBeam (7), Varian Edge (5), Elekta Infinity (4), Varian 21EX (4) and Varian Halcyon (1). The radiation protocols varied across institutions and clinicians delivering treatment (Table 2). SBRT protocols had an average and median total dose of 31.4 and 30Gy (range, 18-45), respectively, and the average and median fraction size was 8.6 and 8 Gy (range, 6-11), respec- tively. Dose statistics from target and organ at risk volumes can be found in Table 3. The heterogeneity index had a median value of 1.1 (range, 1.0 to 1.4), while the conformity index had a me- dian value of 1 (range, 0.02 to 2.9).
Cone beam CT scans were taken daily to ensure patient posi- tioning. All patients were under general anaesthesia for treat- ment. Standard protocol of anaesthesia was performed during treatment in 14 out of 21 patients with available information. Dogs received pre-medication, followed by an induction agent (propofol or alfaxolone), then inhalant anaesthetic (isoflu- rane or sevoflurane). The most common complication was hypotension, which responded to fluid boluses and dopamine CRIS. One dog also experienced arrhythmias and hyperten- sion related to the pheochromocytoma that was being treated.
| AE gradeª | Acute GI | Late GI | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5b | 1 | 2 | 3 | 4 | 5b | OR | |
| 6 Gyx3 QD (18 Gy) | X ☒ | X ☒ | PR | ||||||||
| 6 Gyx4 QD (24Gy) | X ☒ | PR | |||||||||
| 6 Gy×5 EOD (30Gy) | X ☒ | PR | |||||||||
| 7Gy×5 EOD (35 Gy) | SD | ||||||||||
| 7 Gy×5 EOD (35 Gy) | X ☒ | X ☒ | PR | ||||||||
| 8 Gyx3 QD (24Gy) | PR | ||||||||||
| 8 Gyx3 QD (24 Gy) | PR | ||||||||||
| 8 Gyx3 QD (24 Gy) | SD | ||||||||||
| 8 Gyx3 QD (24Gy) | X ☒ | SD | |||||||||
| 8 Gyx3 QD (24Gy) | X ☒ | X ☒ | SD | ||||||||
| 8 Gyx5 QD (40Gy) | SD | ||||||||||
| 9 Gyx5 QD (45 Gy) | X ☒ | X ☒ | SD | ||||||||
| 9 Gyx5 QD (45 Gy) | X ☒ | PR | |||||||||
| 9 Gyx5 QD (45 Gy) | X ☒ | SD | |||||||||
| 10 Gy ×3 QD (30Gy) | PR | ||||||||||
| 10 Gy ×3 QD (30Gy) | SD | ||||||||||
| 10 Gy×3 QD (30Gy) | SD | ||||||||||
| 11 Gy×3 EOD (33 Gy) | X ☒ | N/A | |||||||||
| 11 Gy×3 EOD (33 Gy) | X ☒ | X ☒ | PD | ||||||||
| 11 Gy×3 EOD (33 Gy) | X ☒ | PR | |||||||||
| 11 Gyx3 QD (33 Gy) | X ☒ | SD | |||||||||
Abbreviations: EOD, every other day; OR, best objective response based on imaging within 3 months post-SBRT; QD, once per day.
ªAEs from radiation retrospectively graded based on VRTOG v2 toxicity criteria guideline [11]. bToxicity resulting in death or euthanasia.
However, all complications were mild and responded to med- ical management.
3.4 | Chemotherapy
Eight dogs (38%) received chemotherapy following SBRT. Toceranib was administered in four patients at dosages that ranged from 2.3 to 2.9 mg/kg orally on a Monday, Wednesday and Friday schedule. One patient was only on toceranib for 2.5 months due to side effects (diarrhoea and lethargy). Three patients re- ceived cycles of vincristine (0.6mg/m2), cyclophosphamide (116 to 256 mg/m2 given over 3-4 days) and dacarbazine (800 to 900 mg/ m2). One patient started on this protocol after having progressive disease 2 years after receiving SBRT and being on toceranib. One dog received single-agent cyclophosphamide at 16mg/m2 once daily, and the final dog received carboplatin (275mg/m2) every 3 weeks for four doses following left hind limb amputation due to osteosarcoma 2 years after being treated for his adrenal tumour.
I
3.5 Radiation Adverse Events
Acute AEs were noted in 12 of the 21 patients (57%). Acute GI side effects were the most common AEs in 10 of 12 patients (83%): grade II in 3 dogs treated with 6Gyx4 (1) and 11 Gy×3 (2); grade III in 4 dogs treated with 8Gyx3 (1), 6Gy×5 (1), and 9Gy×5 (2); grade IV in 2 dogs treated with 7Gyx5 (1) and 11 Gy×3 (1); and grade V in 1 dog treated with 9Gyx5. GI symptoms were variable and in- cluded hyporexia, anorexia, vomiting, diarrhoea and nausea. Two of these patients required 2-3 days of hospitalisation for manage- ment of acute AEs. One patient treated with a protocol of 9Gy×5 daily died from pancreatitis 24 days after completion of SBRT. One patient was reported to develop grade II skin effects, doubtfully related to radiation therapy, that required no treatment. Another patient developed polyuria and polydipsia without a definitive ae- tiology 4 months post-treatment (ACTH stim and LDDS not sup- portive of Cushing’s disease), also doubtfully related to radiation therapy. See Table S1 for detailed scoring scheme of relevant AEs reported here.
| Target | Volume (cm3) | Min (Gy) | Max (Gy) | Mean dose (Gy) | Dose-volume parameter |
|---|---|---|---|---|---|
| GTV | 102 (2-614) | 29 (1-46) | 36 (25-49) | 34 (25-49) | D98%= 32 Gy (23-48) D2% =35 Gy (26-49) D50%=34 Gy (25-50) |
| CTV (n=10) | 172 (2-817) | 32 (23-46) | 39 (28-49) | 39 (28-49) | D98% = = 37 Gy (27-47) D2%=40 Gy (30-50) D50% = 38 Gy (38-49) |
| PTV | 146 (6-915) | 26 (16-40) | 34 (25-48) | 34 (25-48) | D98% =31 (22-44) D2% = 36 Gy (27-50) |
D50% = 34 Gy (24-48)
| Organ | Volume (cm3) | Mean Dose (Gy) | Dose-volume parameter |
|---|---|---|---|
| Ipsilateral kidney | 47 (5-130) | 8 (1-15) | D2%=23 Gy (9-43) |
| Contralateral kidney | 45 (4-106) | 6 (0.2-13) | D2%=15 Gy (0.4-25) |
| Both kidneys | 93 (8-236) | 7 (1-14) | V15Gy=11% (0.2-21) |
| V18Gy=6% (0-12) V23Gy=3% (0-8) | |||
| Bowelª | 703 (114-2053) | 7 (3-16) | V20Gy=5% (0-28) V30Gy=1% (0-9) D5%=19 (10-33) D2%=23 (12-34) |
| Liverª | 621 (136-1653) | 4 (0-13) | D50%=4Gy (0.2-13) D98%=1 Gy (0-6) V17Gy=5% (0-22) |
| Stomachª | 149 (29-365) | 6 (0.2-15) | D98%=3 Gy (0.1-10) D2%= 15 Gy (0.4-29) |
| Pancreasª | 17 (2-50) | 13 (1-28) | D98%=6 Gy (0.2-19) D2%=23 Gy (8-37) |
ªStatistics available for 14 out of 21 patients included in the study.
Late AEs were suspected in 7 of 21 dogs (33%). Four patients with suspected grade V late effect from radiation died after ne- crosis of gastrointestinal mucosa and perforation. Symptoms were first observed at an average of 126 days (range, 97 to 157). Two dogs were treated with 9Gyx5 daily, one was treated with 11 Gyx3 daily, and one was treated with 11 Gyx3 on alternate days. There were also two patients that developed grade I (7Gy×3) and grade III (6Gy×3) chronic diarrhoea after 208 and 686 days post-SBRT, respectively, requiring in- termittent supportive therapy. Finally, there was one patient treated with 8 Gyx3 who developed chronic pancreatitis over 1 year following SBRT that was managed with diet and sup- portive care.
In total, 5 of 21 patients (24%) treated with SBRT for adrenal tumours died of suspected AEs from radiation. No significant acute or late renal or hepatic toxicity was noted in this study.
3.6 | Tumour Response and Patient Outcome
Most dogs, 20 out of 21, had information on follow-up abdom- inal imaging at approximately 3 months post-SBRT. There
were 14 patients (70%) with follow-up CT scans and six pa- tients (30%) with follow-up ultrasound. The ORR based on im- aging was 43%. Nine (43%) patients had a partial response, 10 (47%) had stable disease and 1 (5%) experienced progressive disease at approximately 3 months post-SBRT. A strong partial response 21 months after SBRT is graphically represented in Figure 1.
During the study period, there were seven patients that expe- rienced progressive disease confirmed on diagnostic imaging. Median TTP for these seven patients was 503 days (range, 102 to 1274). Four of them progressed locally, one developed metasta- sis to the liver, one to both liver and lungs and one to the bone resulting in pathological fracture. Upon disease progression, one dog received a second course of SBRT but declined shortly after leading to euthanasia; one dog received palliative radiation therapy (5x5 Gy daily) to the primary tumour and restarted to- ceranib; one was started on metronomic chemotherapy with cy- clophosphamide; and the remainder did not receive any further treatment.
Median PFS was 503 days (95% CI: 103-692) and OST was 503 days (95% CI: 112-712). Four patients were still alive at
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the time of preparation of the manuscript. Five died from radiation-related AEs, five from disease progression, two from suspected cardiac arrest, one from acute on chronic kid- ney disease and the cause of death from the remaining four dogs was unknown. Excluding the five patients that died from radiation-related AEs, PFS was 681 days (95% CI: 218-717) and OST was 692 days (95% CI: 281-886). These results are shown in Figure 2.
Two dogs with abdominal effusion before SBRT did not require further therapeutic abdominocentesis after 1 week following treatment. All nine dogs but one with hypertension showed improvement on follow-up blood pressure measurements. The one dog that did not improve was the patient who had progres- sive disease at just 3 months following treatment. Two patients that had elevated urine metanephrine to creatinine ratio before treatment showed a steady decrease of about 30%-60% at each
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recheck (3 months to 1 year apart) until about 1.4 to 2 years when both patients had progressive disease. One patient experienced resolution of Cushing’s disease just 3 months following SBRT based on a normal ACTH stim. This patient also experienced the resolution of all clinical signs associated with hyperadreno- corticism within this time. None of the clinical signs recurred until time of death.
4 Discussion
Surgical resection of adrenal tumours is the current gold stan- dard treatment. However, there are limitations for resectability, as excision of large invasive tumours can have severe complica- tions. The technology for radiation delivery has evolved over the years in veterinary medicine, enabling treatments with high ac- curacy and conformity. Although radiation therapy has become an alternative approach for adrenal tumours, especially those with high surgical risks, its clinical benefits and risks are still to be fully understood.
To the best of our knowledge this is the largest study describing the outcome and radiation-related toxicities of dogs with adrenal
tumours treated with SBRT. Two other similar studies showed favourable outcomes with minimal radiation-related AEs [8, 9]. In our study, many patients experienced a clinical benefit, such as decrease in tumour burden as well as improvement of clinical signs (i.e., hypertension, abdominal effusion). The ORR of 43% (partial response in 9/21 dogs) at about 3 months post-treatment suggests that hypofractionated radiation is effective against ad- renal tumours. Stable disease was seen in 47% (10/21) of dogs, which perhaps suggests a positive control of tumour growth; however, it may also reflect the nature of slow growing tumours. It is important to note that in 30% of dogs, recheck-imaging was performed via ultrasound, which has been associated with lower accuracy, limited field of view, and higher interobserver variability when compared to CT scan [12-14].
The adrenal tumours were overall large (median largest diame- ter 4.5 cm, range 3-11.6) and extensive (81% vascular invasion), thus many were likely high risk and/or unresectable tumours. Large (≥5 cm) and invasive tumours that require adrenalectomy and cavotomy are associated with a shorter OST of 5-18 months, and a higher mortality rate before discharge of 24% [6, 7]. In the present study, both median PFS and OST were 18.4 months, suggesting that SBRT may be contemplated particularly in dogs
| Organ | # fx | Volume | Threshold dose | Max point dose | Endpoint (grade ≥3) | Ref. |
|---|---|---|---|---|---|---|
| Stomach Duodenum Jejunum/ileum Bowel Kidneys | 3 | <10 cc | 16.5 Gy | 22.2 Gy | Ulceration/fistula | [15] |
| 3 | <5 cc | 22.5 Gy | 30 Gy | Ulceration/fistula | [16] | |
| 3 | <5 cc | 21 Gy | Ulceration/fistula | [17, 18] | ||
| 5 | <10 cc | 18 Gy | 32 Gy | Ulceration/fistula | [15] | |
| 5 | <5 cc | 26.5 Gy | 35 Gy | Ulceration/fistula | [16] | |
| 5 | <10 cc | 28 Gy | 32 Gy | Ulceration/fistula | [18] | |
| 3 | <5cc | 15 Gy | 24 Gy | Ulceration | [18] | |
| 3 | <5cc | 16.5 Gy | 22.2 Gy | Ulceration | [15] | |
| 3 | <5 cc | 22.5 Gy | 30 Gy | Ulceration | [16] | |
| 5 | <5cc | 18 Gy | 32 Gy | Ulceration | [15, 18] | |
| 5 | <5 cc | 26.5 Gy | 35 Gy | Ulceration | [16] | |
| 3 | <5cc | 17.7 Gy | 25.2 Gy | Enteritis/obstruction | [15] | |
| 3 | <30 cc | 20.7 Gy | 28.5 Gy | Enteritis/obstruction | [16] | |
| 3 | <5 cc | 16.2 Gy | 27 Gy | Enteritis/obstruction | [18] | |
| 5 | <5 cc | 19.5 Gy | 35 Gy | Enteritis/obstruction | [15, 18] | |
| 5 | <30 cc | 24 Gy | 34.5Gy | Enteritis/obstruction | [16] | |
| 3 | <5cc | 21 Gy | Ulceration | [17] | ||
| 3 | 200 cc | 16 Gy | NA | Basic renal function | [15] | |
| 3 | 200 cc | 14.7 Gy | NA | Basic renal function | [16] | |
| 3 | 200 cc | 14.4 Gy | NA | Basic renal function | [18] | |
| 5 | 200 cc | 17.5 Gy | NA | Basic renal function | [15, 18] | |
| 5 | 200 cc | 17.5 Gy | NA | Basic renal function | [16] |
with large and invasive tumours in which surgery is deemed too risky.
An important observation of this study was the high rate of se- vere AEs from SBRT. Three dogs developed acute grade III GI AEs, and two other dogs developed acute grade IV GI AEs that required up to 3 days of hospitalisation. An additional 5 dogs died from either severe pancreatitis or GI perforation. In total, 47% of patients developed grade ≥ III, 33% grade ≥IV, and 24% grade V AEs. The impact in survival rates was noticeable, such as that by excluding the five radiation-related deaths, PFS was 22.7 months and OST 23.1 months (Figure 2). It is difficult to ex- plain the contrast from prior studies using similar SBRT proto- cols, but we suspect that it may be related to the population size and/or variation in treatment planning and delivery. However, it is important to note that all dogs that experienced grade ≥IV AEs received a total dose greater than 30 Gy, suggesting that this may be a cutoff for what is tolerated by the pancreas and small intestine. Table 2 shows the protocols that each patient that ex- perienced AEs received. A total dose of > 30 Gy does appear to be associated with a higher risk of death due to side effects but was not associated with a worse outcome in terms of death due to disease progression, at least in this study. This highlights the
need to determine dose constraints for normal tissue when treat- ing with SBRT to avoid severe side effects.
Veterinary medicine is still lacking in data of dose constraints for abdominal organs, so human literature is often used as a reference. If considering the constraints reported for human SBRT (Table 4), it is possible that for many of these protocols, the dose limits suggested in the literature for critical organs were not met due to their proximity, especially for large target volumes. Figure 3 demonstrates the proximity of the target vol- umes to GI organs to which we have seen the most severe AEs. Reconsidering dose fractionation schemes and selecting cases with tumour dimensions amenable for SBRT is warranted to produce a safer treatment. In addition, visualisation of proper positioning of abdominal organs is poor to none on daily cone beam CT images, and the cases reported here lacked strategies to account for organ motion during treatment.
Implementing tactics for motion management in a systematic way could help decrease the rate of AEs. Controlled ventila- tion, breath holding techniques, and respiratory gating, the latter less accessible in veterinary medicine, are methods used to minimise respiration-induced organ motion [19, 20].
CBCT
Dose Color Wash [%]
112.4
K
112.4
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
A
25:1
10.0
108.5 %
Patient positioning for treatment has also shown to affect ab- dominal organs’ movement. Ventral recumbency, commonly used in veterinary medicine, was reported to have the largest range of movement for kidneys, adrenal glands and stomach [21]. Bilateral organs had the least movement when the organ was in a downward position. For instance, right lateral recum- bency gave the smallest right-left movement to the right ad- renal gland [21]. In addition, Meier et al. showed that small reductions of PTV margins (by 1-2 mm) have led to significant normal tissue sparing while maintaining dose coverage to the target [22].
SBRT for human adrenal malignancies has been associated with mostly grade I or II adverse events [23]. One study of 35 patients with adrenal metastases treated with a median dose of 40 Gy in five fractions described a 17% rate of grade 2 (nausea, diarrhoea and fatigue), and no case of grade ≥3 AEs. A more in-depth meta-analyses reported an overall rate of grade ≥ 3 of 1.8% [24]. Primary adrenal insufficiency was observed in 13.8% of patients at a median time of 4.3 months, associated with prior contralat- eral adrenalectomy and bilateral metastases [25].
A lot of the limitations from this study originate from its ret- rospective and multi-institutional nature, and the small sample size. Many factors that could affect outcome were not uniform across the patient population including tumour type, tumour size/extension, planning techniques, dose fractionation, fre- quency of treatment, total prescription dose, and adjuvant che- motherapy. Some medical records were incomplete and lacked clarity. Follow-up visits and staging tests varied in frequency and diagnostic technique. Retrospectively graded tumour re- sponse and AEs likely lack accuracy. Due to so many variations among the patients from this study, statistical analysis to evalu- ate risk factors of severe AEs or outcome was not plausible.
In conclusion, results from this study suggest that SBRT for the treatment of canine adrenal tumours could be a promising treatment alternative in cases that carry a high surgical risk. However, the high rate of morbidity and mortality reported here
is worrisome; therefore, re-evaluating protocols, planning/treat- ment strategies, and case selection is necessary in maintaining patient safety and improving survival expectancy.
Acknowledgements
The authors have nothing to report.
Funding
The authors have nothing to report.
Ethics Statement
The dogs reported in this study were client-owned pets with naturally occurring cancer that received treatment under consent obtained from the clients to treat their pets. All dogs were treated according to the principles and practices of specialty medicine prevailing at the time of their treatment.
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.
References
1. J. S. Barrera, F. Bernard, E. J. Ehrhart, S. J. Withrow, and E. Mon- net, “Evaluation of Risk Factors for Outcome Associated With Ad- renal Gland Tumors With or Without Invasion of the Caudal Vena Cava and Treated via Adrenalectomy in Dogs: 86 Cases (1993-2009),” Journal of the American Veterinary Medical Association 242 (2013): 1715-1721.
2. A. E. Kyles, E. C. Feldman, H. E. De Cock, et al., “Surgical Manage- ment of Adrenal Gland Tumors With and Without Associated Tumor Thrombi in Dogs: 40 Cases (1994-2001),” Journal of the American Veter- inary Medical Association 223 (2003): 654-662.
3. S. J. Withrow, D. M. Vail, and R. L. Page, Withrow and MacEwen’s Small Animal Clinical Oncology, 5th ed. (Elsevier/Saunders, 2013).
4. J. V. J. Cavalcanti, O. T. Skinner, P. D. Mayhew, J. C. Colee, and S. E. Boston, “Outcome in Dogs Undergoing Adrenalectomy for Small Adre- nal Gland Tumours Without Vascular Invasion,” Veterinary and Com- parative Oncology 18 (2020): 599-606.
5. F. Massari, S. Nicoli, G. Romanelli, P. Buracco, and E. Zini, “Adrenal- ectomy in Dogs With Adrenal Gland Tumors: 52 Cases (2002-2008),” Journal of the American Veterinary Medical Association 239 (2011): 216-221.
6. D. Enright, V. M. Dickerson, J. A. Grimes, S. Townsend, and K. M. Thieman Mankin, “Short- and Long-Term Survival After Adrenalec- tomy in 53 Dogs With Pheochromocytomas With or Without Alpha- Blocker Therapy,” Veterinary Surgery 51 (2022): 438-446.
7. P. D. Mayhew, S. E. Boston, A. L. Zwingenberger, et al., “Perioper- ative Morbidity and Mortality in Dogs With Invasive Adrenal Neo- plasms Treated by Adrenalectomy and Cavotomy,” Veterinary Surgery 48 (2019): 742-750.
8. M. Dolera, L. Malfassi, S. Pavesi, et al., “Volumetric-Modulated Arc Stereotactic Radiotherapy for Canine Adrenocortical Tumours With Vascular Invasion,” Journal of Small Animal Practice 57 (2016): 710-717.
9. T. Linder, C. Wakamatsu, J. Jacovino, Y. H. Hsieh, and M. Mueller, “Stereotactic Body Radiation Therapy as an Alternative to Adrenalec- tomy for the Treatment of Pheochromocytomas in 8 Dogs,” Veterinary and Comparative Oncology 21 (2023): 45-53.
10. S. M. Nguyen, D. H. Thamm, D. M. Vail, and C. A. London, “Re- sponse Evaluation Criteria for Solid Tumours in Dogs (v1.0): A Veter- inary Cooperative Oncology Group (VCOG) Consensus Document,” Veterinary and Comparative Oncology 13 (2015): 176-183.
11. V. J. Poirier, M. Keyerleber, I. K. Gordon, et al., “ACVR and ECVDI Consensus Statement: Reporting Elements for Toxicity Criteria of the Veterinary Radiation Therapy Oncology Group v2.0,” Veterinary Ra- diology & Ultrasound 64 (2023): 789-797.
12. S. Palladino, M. A. Keyerleber, R. G. King, and K. E. Burgess, “Util- ity of Computed Tomography Versus Abdominal Ultrasound Examina- tion to Identify Iliosacral Lymphadenomegaly in Dogs With Apocrine Gland Adenocarcinoma of the Anal Sac,” Journal of Veterinary Internal Medicine 30 (2016): 1858-1863.
13. M. Zuercher, F. Vilaplana Grosso, and A. Lejeune, “Comparison of the Clinical, Ultrasound, and CT Findings in 13 Dogs With Gastric Neo- plasia,” Veterinary Radiology & Ultrasound 62 (2021): 525-532.
14. O. Taeymans, K. Peremans, and J. H. Saunders, “Thyroid Imaging in the Dog: Current Status and Future Directions,” Journal of Veterinary Internal Medicine 21 (2007): 673-684.
15. S. H. Benedict, K. M. Yenice, D. Followill, et al., “Stereotactic Body Radiation Therapy: The Report of AAPM Task Group 101,” Medical Physics 37 (2010): 4078-4101.
16. R. Timmerman, “A Story of Hypofractionation and the Table on the Wall,” International Journal of Radiation Oncology, Biology, Physics 112 (2022): 4-21.
17. S. Molinelli, J. de Pooter, A. Mendez Romero, et al., “Simultaneous Tumour Dose Escalation and Liver Sparing in Stereotactic Body Radi- ation Therapy (SBRT) for Liver Tumours due to CTV-To-PTV Margin Reduction,” Radiotherapy and Oncology 87 (2008): 432-438.
18. B. Emami, “Tolerance of Normal Tissue to Therapeutic Radi- ation,” Reports of Practical Oncology and Radiotherapy 1 (2013): 123-127.
19. K. L. Kelsey, L. N. Kubicek, N. J. Bacon, T. Torres, and S. A. Rob- ertson, “Neuromuscular Blockade and Inspiratory Breath Hold During Stereotactic Body Radiation Therapy for Treatment of Heart Base
Tumors in Four Dogs,” Journal of the American Veterinary Medical As- sociation 250 (2017): 199-204.
20. N. Van Asselt and N. Christensen, “Initial Treatment Experience Obtained With the Real-Time Predictive Motion Tracking Radiotherapy Platform Synchrony: A Pilot Study,” Veterinary Radiology & Ultrasound 65 (2024): 745-749.
21. A. R. Kim, S. An, G. Hwang, M. Choi, T. S. Hwang, and H. C. Lee, “Assessment of Abdominal Organs Movement by Respiration Using Computed Tomography in Dogs: A Pitfall for Radiation Therapy,” Jour- nal of Veterinary Clinics 40 (2023): 104-112.
22. V. Meier, C. Staudinger, S. Radonic, et al., “Reducing Margins for Abdominopelvic Tumours in Dogs: Impact on Dose-Coverage and Nor- mal Tissue Complication Probability,” Veterinary and Comparative On- cology 19 (2021): 266-274.
23. D. A. S. Toesca, A. J. Koong, R. von Eyben, A. C. Koong, and D. T. Chang, “Stereotactic Body Radiation Therapy for Adrenal Gland Me- tastases: Outcomes and Toxicity,” Advances in Radiation Oncology 3 (2018): 621-629.
24. W. C. Chen, J. D. Baal, U. Baal, et al., “Stereotactic Body Radiation Therapy of Adrenal Metastases: A Pooled Meta-Analysis and System- atic Review of 39 Studies With 1006 Patients,” International Journal of Radiation Oncology, Biology, Physics 107 (2020): 48-61.
25. O. Hamidi, M. Miljanic, G. Tumyan, et al., “Adrenal Insufficiency Following Stereotactic Ablative Radiotherapy (SAbR) of Adrenal Gland Metastases,” Cancers (Basel) 16 (2024): 3140.
Supporting Information
Additional supporting information can be found online in the Supporting Information section. Table S1: Radiation morbidity scoring scheme [1].