CyberKnife stereotactic radiotherapy for treatment of primary intracranial tumors in dogs

Abstract Background Limited data exist about the use, efficacy, and prognostic factors influencing outcome when CyberKnife is used to treat dogs with intracranial neoplasia. Objectives To determine the prognosis and associated prognostic factors for dogs that were imaged, determined to have primary intracranial tumors, and treated with CyberKnife radiotherapy. Animals Fifty‐nine dogs treated with CyberKnife radiotherapy for primary intracranial tumors. Methods Retrospective medical record review of cases from January 2010 to June 2016. Data extracted from medical records included signalment, weight, seizure history, tumor location, tumor type (based on imaging), gross tumor volume, planned tumor volume, treatment dates, radiation dose, recurrence, date of death, and cause of death. Results The median progression‐free interval (PFI) was 347 days (range 47 to 1529 days), and the median survival time (MST) was 738 days (range 4 to 2079 days). Tumor location was significantly associated with PFI when comparing cerebrum (median PFI 357 days; range 47‐1529 days) versus cerebellum (median PFI 97 days; range 97‐168 days) versus brainstem (median PFI 266 days; range 30‐1484 days), P = .03. Additionally, the presumed tumor type was significantly associated with MST (P < .001). Conclusions and Clinical Importance Use of Cyberknife and SRT might improve MST, compared with RT, in dogs with intracranial neoplasia.


| MATERIALS AND METHODS
Medical records were retrospectively reviewed for all dogs receiving CyberKnife radiation for the treatment of primary intracranial tumors from January 2010 to June 2016. Fifty-nine dogs were included.
Complete data for presenting clinical signs were not available in all cases. Seizure activity was reported, before treatment, for 36 of the dogs.

| Pretreatment evaluation
Each dog underwent a physical exam and staging of disease before treatment. Most dogs were staged using complete blood count, biochemistry panel, thoracic radiographs, and abdominal ultrasound. Some dogs were staged using thoracic and abdominal computed tomography (CT) rather than radiographs and ultrasound. Presumptive diagnosed were made via advanced imaging (either magnetic resonance image [MRI] or CT) by a board-certified veterinary radiologist based on accepted imaging criteria for intracranial neoplasms. [14][15][16] Each dog had a CT examination of the head before treatment for radiation planning purposes.

| Treatment planning, regimen, and monitoring
Noncontrast CT images were used as primary CT set for dose calculation. Computed tomography slice thickness was 1.25 mm to allow accurate distinction between tumor and normal tissues. Contrast CT and MRI images were aligned with the noncontrast primary CT set.
Fifty-four of the 59 dogs had both CT and MRI. The remaining 5 dogs had CT only. Clinical target volume was defined as the gross tumor volume (GTV) delineated on the contrast CT and/or MRI images plus 2 to 2 and a half millimeters. This variation was based on clinician experience considering tumor margins, presumed tumor type, location, and peri-tumoral structures for each dog. No additional expansion was made for planning tumor volume (PTV). Critical structures, including eyes, optic nerves, optic chiasm, and normal brain, were also contoured. Inverse planning was performed using the Accuray CyberKnife treatment planning system. The dosing goal was 100% of the radiation prescription to 95% of the PTV when achievable. Eyes were normally blocked from beams and the dose constraints to the optic nerves, optic chiasm, healthy brain tissue, and tuning structures were established based on recommendations by the American Association of Physicists in Medicine Task Group 101 Report for human dosing. Tuning structures, which reduce uncontrolled dose diffusion, 17 were generated during planning to allow for increased conformity to PTV and avoidance of critical structures. Maximum dose to the optic chiasm was limited to less than 0.1 cc receiving greater than 2300 centigray (cGy). Maximum dose to the optic chiasm was limited to less than 500 cGy. In most cases, the best conformality was generally achieved using a single collimator with an isocentric technique although variable collimator iris dimensions were often used. The CyberKnife machine used in our study is equipped with an iris variable aperture collimator (apertures range from 5 to 60 mm) which allows the treatment field to vary within a single treatment. All radiation plans were reviewed and approved by an American College of Veterinary Radiology (ACVR) board-certified veterinary radiation oncologist.
Treatments were administered via 3 equal doses of 700 to 850 cGy per dose. The total dose per dog ranged from 2100 to 2550 cGy (1 dog received 2100 cGy, 3 dogs received 2250 cGy,   52 dogs received 2400 cGy, and 3  Anesthetic protocols were determined based on a dog's overall health. However, dogs were generally induced with propofol (5.5 mg/kg IV to effect) and maintained on isoflurane/O 2 . All dogs received mannitol (0.5-1 g/kg IV) before or during treatment. All dogs were mechanically ventilated with an electronic table-top ventilator (Engler). Anesthetic monitoring during treatment was conducted via live video monitoring. Anesthetic variables (heart rate, breaths per minute, end-tidal CO 2 , and blood pressure) were monitored via a Cardell 9500HD veterinary monitor and a separate pulse oximetry unit.

| Assessment of response to treatment
Repeat physical examinations were performed 2-and 4-weeks after treatment. In some cases, distance from the primary hospital precluded an in-hospital re-examination. In these cases, repeat physical

| Assessment of clinical status and treatment satisfaction
Owners were instructed to continue to follow-up with either our oncology service or their referring veterinarian after having the 4-week reexamination. Reexamination intervals were determined by individual clinicians. Owners were advised to monitor dogs for seizures, abnormal mentation, lethargy, and anorexia. Numerical/continuous variables evaluated include age, weight, GTV, PTV, dose per treatment, total dose, PFI, days from recurrence to date of death, and MST. Dogs were censored from PFI analysis if they had no recurrence of clinical signs, no evidence of progression on imaging, or were lost to follow-up. Dogs were censored from survival time analysis if they were alive, death was due to another cause, or were lost to follow-up. Because of the retrospective nature of this study, there were variations in treatment protocols before dogs undergoing CyberKnife.

| Dog sample
These were generally concerning the administration of antiepileptics and corticosteroids. One dog with a presumed meningioma received a dose of palliative radiation (4 Gy) before CyberKnife treatment. Concurrent or subsequent disease seen in this sample included: 1 dog with a thyroid mass at the time of treatment, 1 dog with a splenic stromal sarcoma (treated with splenectomy and carboplatin) after treatment, 1 dog with a histiocytoma of the body wall after treatment, 1 dog with a heart-base mass (treated with palliative radiation therapy) after treatment, and 1 dog with a hepatocellular carcinoma (surgically removed) after treatment. Additionally, 1 dog was euthanized due to the owner's death with no reported health concerns for the dog.

| Treatment course and response
All dogs received 3 fractions of radiation. Generally, treatments were given over 3 consecutive days. Eleven dogs received fractions on nonconsecutive days due to scheduling. One of these delays was due to hospital closure over a holiday. The remaining delays were due to owner preference. Of these dogs, the longest delay involved 2 dogs which received 3 treatments over 8 days. Imaging studies were compared using RECIST criteria. 18 One study was excluded as initial images were not available for review. Imaging findings included 1 complete response (mass was resolved on repeat MRI performed 218 days after treatment), 11 partial responses, 6 stable disease, and 3 progressive disease.

| Prognostic indicators
Mixed breed dogs (n = 15) and golden retrievers (n = 8) were the most common breeds in our sample. Golden retrievers represented 13% of dogs in our study; of these, 7 were diagnosed with a suspect meningioma, and 1 was diagnosed with a suspect glioma. To determine the prognostic influence of age, dogs were divided into 2 groups: those over 9.5 years of age and those less than or equal to 9.

| Adverse events
No adverse events were observed during treatment. Imaging was performed due to recurrence of clinical signs in 13 cases.
When clinical signs recurred, and imaging was not performed, we presumed the intracranial disease was progressive. However, without follow-up imaging we cannot exclude the possibility that these clinical signs were secondary to late radiation effects. Moving forward, standardization of follow-up and further investigation into management and treatment of recurrent clinical signs is warranted. Perhaps, longterm medical management or even prophylactic medical management is appropriate in these cases to extend PFIs.
Only 1 adverse event was reported in our study. Although CyberKnife protocols have been shown to have an improved adverse effect profile when compared to fractionated radiation protocols, our findings are lower than anticipated. 10 These findings may reflect lack of follow-up data rather than a truly lower risk of adverse effects.
Our study has several limitations because of its retrospective nature. These include variation in medical management (before and after CyberKnife treatment), nonstandardized follow-up, lack of definitive diagnoses, and inability to make comparisons between dogs treated with CyberKnife vs other SRT options.

ACKNOWLEDGMENT
No funding was received for this study. Abstract presented at the Veterinary Cancer Society October 2018 Conference.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.