A toxicity study of low‐dose rate half‐body irradiation and chemotherapy in dogs with lymphoma

Thirteen dogs with previously untreated multicentric lymphoma were enrolled in a prospective study investigating the effects of low‐dose rate total body irradiation (TBI) and chemotherapy. Dogs received either 6 or 8 Gy TBI in half‐body fractions, 2 weeks apart. Toxicity consisted of mild to moderate haematological and gastrointestinal (GI) signs. One dog died from treatment complications. Anorexia was noted independent of dose. Haematological toxicity was more common and more severe after 8 Gy treatment. GI toxicity was more likely postcaudal half‐body irradiation with 8 Gy. Other than leukotrichia, late effects from radiation were not observed. Results indicated that haematological and nonhaematological toxicity was dose dependent. However, the protocol was well tolerated and treatment intensification using a 2‐week inter‐radiation interval was possible in all dogs treated with 6 Gy. Preliminary survival data for these dogs were very encouraging, providing a strong rationale to analyse the efficacy of low‐dose rate irradiation (LDRI) in canine lymphoma.     

Using biologically based objectives to optimize boost intensity‐modulated radiation therapy planning for brainstem tumors in dogs

Irradiated brain tumors commonly progress at the primary site, generating interest in focal dose escalation. The aim of this retrospective observational study was to use biological optimization objectives for a modeling exercise with simultaneously‐integrated boost IMRT (SIB‐IMRT) to generate a dose‐escalated protocol with acceptable late radiation toxicity risk estimate and improve tumor control for brainstem tumors in dogs safely. We re‐planned 20 dog brainstem tumor datasets with SIB‐IMRT, prescribing 20 × 2.81 Gy to the gross tumor volume (GTV) and 20 × 2.5 Gy to the planning target volume. During the optimization process, we used biologically equivalent generalized equivalent uniform doses (gEUD) as planning aids. These were derived from human data, calculated to adhere to normal tissue complication probability (NTCP) ≤5%, and converted to the herein used fractionation schedule. We extracted the absolute organ at risk dose‐volume histograms to calculate NTCP of each individual plan. For planning optimization, gEUD_{(a = 4)} = 39.8 Gy for brain and gEUD_{(a = 6.3)} = 43.8 Gy for brainstem were applied. Mean brain NTCP was low with 0.43% (SD ±0.49%, range 0.01‐2.04%); mean brainstem NTCP was higher with 7.18% (SD ±4.29%, range 2.87‐20.72%). Nevertheless, NTCP of < 10% in brainstem was achievable in 80% (16/20) of dogs. Spearman's correlation between relative GTV and NTCP was high (ρ = 0.798, P < .001), emphasizing increased risk with relative size even with subvolume‐boost. Including biologically based gEUD values into optimization allowed estimating NTCP during the planning process. In conclusion, gEUD‐based SIB‐IMRT planning resulted in dose‐escalated treatment plans with acceptable risk estimate of NTCP < 10% in the majority of dogs with brainstem tumors. Risk was correlated with relative tumor size.     

Ocular and periocular radiation toxicity in dogs treated for sinonasal tumors: A critical review

Visual impairment from radiation‐induced damage can be painful, disabling, and reduces the patient's quality of life. Ocular tissue damage can result from the proximity of ocular organs at risk to irradiated sinonasal target volumes. As toxicity depends on the radiation dose delivered to a certain volume, dose‐volume constraints for organs at risk should ideally be known during treatment planning in order to reduce toxicity. Herein, we summarize published ocular toxicity data of dogs irradiated for sinonasal tumors from 36 publications (1976‐2018). In particular, we tried to extract a dose guideline for a clinically acceptable rate of ocular toxicity. The side effects to ocular and periocular tissues were reported in 26/36 studies (72%) and graded according to scoring systems (10/26; 39%). With most scoring systems, however, toxicities of different ocular and periocular tissues are summed into one score. Further, the scores were mostly applied in retrospect and lack volume‐ and dose‐data. This incomplete information reflects the crux of the matter for radiation dose tolerance in canine ocular tissues: The published information of the last three decades does not allow formulating dose‐volume guidelines. As a start, we can only state that a mean dose of 39 Gy (given in 10 x 4.2 Gy fractions) will lead to loss of vision by one or both eyes, while mean doses of <30 Gy seem to preserve functionality. With a future goal to define tolerated doses and volumes of ocular and periocular tissues at risk, we propose the use of combined ocular toxicity scoring systems.     

Hypofractionated radiation therapy in the treatment of canine thymoma: Retrospective study of eight cases

Thymomas are one of the most common tumors of the cranial mediastinum in dogs; however there is limited information available on the use of radiation therapy for treating this neoplasm. Objectives of the current retrospective observational study were to describe outcomes and side effects of a hypofractionated radiation therapy protocol in a group of dogs with confirmed thymoma. A total of eight dogs were included. To generate individualized treatment plans, we designed the planning target volume according to the limits on mean lung dose and the percentage of the total lung volume exceeding 20 Gy (V20). The total administered dose was 48–49 Gy, with one fraction per week for a total of six to seven fractions. After therapy, two dogs achieved complete responses, two achieved partial responses, and the disease remained stable in two. Two dogs died during the radiation therapy protocol and were not classified. The median mean lung dose and V20 were 6.0 Gy (range: 3.1–15.0 Gy) and 12.4% (range: 2.3–27.5%), respectively. The overall response rate was 50.0%, and the median time to response following treatment initiation was 22 days (range: 14–115 days). Acute and late side effects were common in the skin and/or lung and were self‐limiting or asymptomatic. The median survival time was not reached (range: 8–1128 days) and the 1 year survival rate was 75.0%. Hypofractionated radiation therapy was well tolerated in this sample of dogs with thymoma and may be considered when owners decline surgical treatment or the tumor is deemed unresectable.     

Single fraction stereotactic radiation therapy (stereotactic radiosurgery) is a feasible method for treating intracranial meningiomas in dogs

The aim of this retrospective, pilot study was to evaluate stereotactic radiosurgery as a method for treating intracranial meningiomas in dogs. Included dogs had an imaging diagnosis of presumed intracranial meningioma, were treated using a standardized stereotactic radiosurgery protocol, and had a follow‐up time of >6 months after stereotactic radiosurgery. A single fraction of 16 Gy stereotactic radiosurgery was delivered to the tumor, with an internal simultaneously integrated boost to a total dose of 20–24 Gy to the central portion of the tumor. Thirty‐two dogs were sampled. One dog was euthanized in the periprocedural period, and 10 of the remaining 31 dogs (31%) experienced an acute adverse event (defined as declining neurologic function due to tumor progression or treatment‐associated complication within the first 6 months after stereotactic radiosurgery), three of which were fatal. Too few subjects (n = 6) had cross‐sectional imaging after stereotactic radiosurgery to determine an objective response rate; however, 17/30 (57%) dogs assessed for response had a perceived clinical benefit from treatment. The overall median survival time was 519 days (95% confidence interval: 330–708 days); 64% and 24% of dogs were alive at 1 and 2 years after stereotactic radiosurgery, respectively. Dogs with infratentorial tumor location and high gradient indices had shorter survival. There were no factors identified which were predictive of acute adverse event. Survival times reported herein are similar to what has previously been reported for other stereotactic and traditional fractionated radiotherapy protocols. Findings therefore supported the use of stereotactic radiosurgery as an alternative method for treating dogs with presumed intracranial meningiomas.     

COMPARISON OF TWO COARSE FRACTIONATED RADIATION PROTOCOLS FOR THE MANAGEMENT OF CANINE PITUITARY MACROTUMOR: AN OBSERVATIONAL STUDY OF 24 DOGS

Radiotherapy is a commonly used treatment for pituitary macrotumors in dogs, but the optimum protocol has not been established. Twenty four dogs with MRI confirmed pituitary macrotumors were treated with one of two radiotherapy protocols. Twelve dogs were treated with 10 fractions of 3.8 Gy/fraction on a “Monday–Wednesday–Friday” schedule, the remaining 12 with five “once‐a‐week” protocols (1 × 5 Gy, followed by 4 × 8.25 Gy) to a total dose of 38 Gy. The overall median survival time for all dogs was 235 days (range 28–1,328), dogs treated with 10 fractions had a median survival time of 961 days (range 28–1,328) compared to 182 days (range 42–507) in the five‐fraction group (P = 0.006). Clinical improvement was found in both groups, and no significant side effects were noted in either group. These results suggest that a “Monday–Wednesday–Friday” schedule may improve survival times, as compared to a “once‐a‐week” protocol. As this study was of an observational nonrandomized nature, future work is necessary to establish whether more highly fractionated protocols or different total doses will further improve outcome.     

Changes in target volume during irradiation of canine intranasal tumors can significantly impact radiation dosimetry

Nasal tumor size can change during radiation therapy (RT). The amount of peritumoral fluid (eg, mucohemorrhagic effusions) can also fluctuate. How often this occurs and the magnitude of change are unknown. Likewise, there are no data which describe dosimetric effects of these changing volumes during a course of RT in veterinary medicine. This study addresses that gap in knowledge. Using pet dogs with nasal tumors, three CT image sets were created. Different Hounsfield units were applied to the gross tumor volume (GTV) of each image set: unchanged, –1000 (AIR), –1000 (to the portion of the GTV that actually underwent volume reduction during clinical RT; REAL). Two plans were created: 18‐fraction three‐dimensional conformal RT (3DCRT) and three‐fraction intensity‐modulated stereotactic RT (IM‐SRT). For nearby normal tissues and GTV, near‐maximum doses (D_2% and D_5%) and volumes receiving clinically significant doses were recorded. To verify “AIR” results, thermoluminescent dosimeters recorded dose in cadavers that were irradiated using both 3DCRT and IM‐SRT plans. “AIR” scenario had ≤1.5 Gray (Gy) increases in D_2% and ≤3.2 cc increases of volume. “REAL” scenario had ≤0.97 Gy increases in D_5% and ≤0.55 cc increases of volume at clinically relevant doses. Both were statistical significant. Results suggest that near‐complete resolution of GTV warrants plan revision.     

A complication probability planning study to predict the safety of a new protocol for intracranial tumour radiotherapy in dogs

Technical advances make it possible to deliver radiation therapy for canine intracranial tumours in fewer fractions, under the assumption of equivalent tumour control. With the aim of estimating the late toxicity risk profile for various tumour sizes and locations, the present paper evaluates the normal tissue complication probability (NTCP) values for the intracranial organs at risk. By making isoeffect calculations, a new 10‐fraction radiation protocol was developed with the same tumour control probability (TCP) as a currently used 20‐fraction standard protocol, and complication risk profiles for brain, brainstem and optic chiasm were modelled using a representative population of 64 dogs with brain tumours. For >59% of cases, the new 10‐fraction protocol yielded an acceptable, low risk estimate of late toxicity (<10%). Our calculations suggest that it may be safe to treat small to intermediate‐sized tumours that are neither located near the optic chiasm nor at the brainstem with 10 daily fractions of 4.35 Gy.     

Pharmacokinetics and bone resorption evaluation of a novel Cathepsin K inhibitor (VEL‐0230) in healthy adult horses

Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy‐terminal cross‐linking telopeptide of type I collagen (CTX‐1)] analyses were performed following single and multiple oral dose protocols of a Cathepsin K inhibitor (VEL‐0230) in horses. Outcomes included plasma and urine drug and CTX‐1 concentrations. In the dose range study, 2, 4, and 8 mg/kg body weight (b.w.) doses were administered in a Latin square design to three mares and evaluated for 1 week. Based on the PK characteristics of VEL‐0230, 4 mg/kg b.w. was selected for the dose interval study in which 3.25 days (d) and 7 days dose intervals were evaluated over three administrations using four exercising horses in a Latin square design. The 3.25 days and 7 days dose intervals provided a rapid inhibition of bone resorption based on plasma CTX‐1. CTX‐1 inhibition prior to next dose administration was not different from baseline in the 3.25 days and 7 days protocols, and for the first 3 days but the sustained CTX‐1 inhibition in the 7 days protocol along with the cost and logistic benefits for weekly administration made the 7 days protocol preferable. Weekly administration of VEL‐0230 may provide effective inhibition of bone resorption in young exercising horses that returns to baseline within 7 days after drug withdrawal even after multiple doses.     

Definitive‐intent intensity‐modulated radiation therapy provides similar outcomes to those previously published for definitive‐intent three‐dimensional conformal radiation therapy in dogs with primary brain tumors: A multi‐institutional retrospective study

Radiotherapy with or without surgery is a common choice for brain tumors in dogs. Although numerous studies have evaluated use of three‐dimensional conformal radiotherapy, reports of definitive‐intent, IMRT for canine intracranial tumors are lacking. Intensity‐modulated radiation therapy has the benefit of decreasing dose to nearby organs at risk and may aid in reducing toxicity. However, increasing dose conformity with IMRT calls for accurate target delineation and daily patient positioning, in order to decrease the risk of a geographic miss. To determine survival outcome and toxicity, we performed a multi‐institutional retrospective observational study evaluating dogs with brain tumors treated with IMRT. Fifty‐two dogs treated with fractionated, definitive‐intent IMRT at four academic radiotherapy facilities were included. All dogs presented with neurologic signs and were diagnosed via MRI. Presumed radiological diagnoses included 37 meningiomas, 12 gliomas, and one peripheral nerve sheath tumor. One dog had two presumed meningiomas and one dog had either a glioma or meningioma. All dogs were treated in the macroscopic disease setting and were prescribed a total dose of 45‐50 Gy (2.25‐2.5 Gy per fraction in 18‐20 daily fractions). Median survival time for all patients, including seven cases treated with a second course of therapy was 18.1 months (95% confidence of interval 12.3‐26.6 months). As previously described for brain tumors, increasing severity of neurologic signs at diagnosis was associated with a worse outcome. Intensity‐modulated radiation therapy was well tolerated with few reported acute, acute delayed, or late side effects.     

Palliative radiotherapy as treatment for non-resectable soft tissue sarcomas in the dog – a report of 15 cases

Fifteen dogs with various non‐resectable soft tissue sarcomas were treated with a palliative protocol of Cobalt⁶⁰ radiation. Twelve (80%) of the 15 tumours were fibrosarcomas and haemangiopericytomas. Total tumour radiation dose was 24 Gy, given in three 8 Gy fractions, on days 0, 7, 21 or weekly. Thirteen tumours (87%) responded with stable disease; median time to progression and median survival time were 263 and 332 days, respectively. Radiation toxicity was negligible. The survival and local control with this palliative protocol are almost comparable with curative intent primary radiotherapy.     

Definitive‐intent intensity‐modulated radiation therapy for treatment of canine prostatic carcinoma: A multi‐institutional retrospective study

No standard of care is currently recognized for treatment of canine prostatic carcinoma (PC). This retrospective study assesses outcome following definitive‐intent, intensity‐modulated radiation therapy (RT) in dogs with PC. Medical records review was performed, including 18 patients from four institutions undergoing definitive‐intent intensity‐modulated radiotherapy to treat PC. Diagnosis was incidental in 7/18 (39%) patients. Five dogs (28%) had evidence of metastasis to loco‐regional lymph nodes at diagnosis. Seventeen patients received concurrent non‐steroidal anti‐inflammatory drugs; 15/18 (83%) patients received maximally‐tolerated dose (MTD) chemotherapy, with variable drugs and protocols employed. Total prescribed radiation dose ranged from 48 to 54 Gy (median 50 Gy) delivered as daily doses of 2.5‐2.8 Gy. One patient was euthanized prior to completing radiotherapy. Acute toxicity was observed in nine patients; Grade 1‐2 diarrhoea was the most common toxicity observed. Suspected late toxicity (urethral stricture, ureteral stricture and hindlimb oedema) was observed in three patients. Median event‐free survival (EFS) following RT was 220 days, and median overall survival was 563 days. Local progression occurred in seven patients at a median of 241 days. Median overall survival was significantly longer in incidentally diagnosed dogs (581 vs 220 days in symptomatic dogs, P = .042). EFS was significantly longer in patients treated with MTD chemotherapy (241 vs 25 days, P < .001), and significantly shorter in patients presenting with evidence of metastatic disease (109 days) vs those without (388 days, P = .008). These findings suggest that definitive‐intent radiotherapy is a valuable treatment option for local control of canine PC with moderate risk of toxicity.     

Long‐term survival with stereotactic radiotherapy for imaging‐diagnosed pituitary tumors in dogs

Published studies on the use of stereotactic radiotherapy for dogs with pituitary tumors are limited. This retrospective observational study describes results of stereotactic radiotherapy for 45 dogs with imaging‐diagnosed pituitary tumors. All dogs were treated at a single hospital during the period of December 2009–2015. The stereotactic radiotherapy was delivered in one 15 Gray (Gy) fraction or in three 8 Gy fractions. At the time of analysis, 41 dogs were deceased. Four were alive and censored from all survival analyses; one dog received 8 Gy every other day and was removed from protocol analyses. The median overall survival from first treatment was 311 days (95% confidence interval 226–410 days [range 1–2134 days]). Thirty‐two dogs received 15 Gy (median overall survival 311 days; 95% confidence interval [range 221–427 days]), and 12 received 24 Gy on three consecutive days (median overall survival 245 days, 95% confidence interval [range 2–626 days]). Twenty‐nine dogs had hyperadrenocorticism (median overall survival 245 days), while 16 had nonfunctional masses (median overall survival 626 days). Clinical improvement was reported in 37/45 cases. Presumptive signs of acute adverse effects within 4 months of stereotactic radiotherapy were noted in 10/45, and most had improvement spontaneously or with steroids. Late effects versus tumor progression were not discernable, but posttreatment blindness (2), hypernatremia (2), and progressive neurological signs (31) were reported. There was no statistical difference in median overall survival for different protocols. Patients with nonfunctional masses had longer median overall survival than those with hyperadrenocorticism (P = 0.0003). Survival outcomes with stereotactic radiotherapy were shorter than those previously reported with definitive radiation, especially for dogs with hyperadrenocorticism.     

The pharmacokinetics of cytarabine administered at three distinct subcutaneous dosing protocols in dogs with meningoencephalomyelitis of unknown origin

The objective of this study was to evaluate the pharmacokinetics of the standard cytarabine (Ara‐C) protocol (50 mg/m² subcutaneously every 12 hr for 2 days) used for dogs with neuroinflammatory disease and compare it to two more practical protocols (a single 200 mg/m² subcutaneous dose and two 100 mg/m² subcutaneous doses every 12 hr). Four client‐owned dogs previously diagnosed with meningoencephalomyelitis of unknown origin were administered three distinct Ara‐C protocols with a 21‐day washout between each protocol. A complete blood count was performed seven days after each dosing protocol to assess for clinically relevant myelosuppression. No adverse events were observed. Plasma Ara‐C concentrations were measured using a validated liquid chromatography coupled to tandem mass spectrometry assay. The mean maximal concentrations in this study were 4,230, 9,293, and 16,675 ng/ml for a single dose of 50, 100, and 200 mg/m², respectively. There was a linear relationship between dose and drug exposure. Drug exposure was similar regardless of the dosing protocol when the total dose was analyzed, with an area under the concentration versus time curve of 37,026, 38,465, and 32,510 ng × hr/ml for 50, 100, and 200 mg/m², respectively.     

Anatomic and volumetric characterization of the cisterna chyli using CT lymphangiography and computer‐assisted design software in dogs with idiopathic chylothorax

The objectives of this retrospective, observational study were to characterize the anatomical features of the cisterna chyli (CC) in a cohort of dogs diagnosed with idiopathic chylothorax that underwent CT lymphangiography (CTLa), and to evaluate the feasibility of computer‐assisted design (CAD) software to quantify volumetric measurements of the CC. Twenty‐three client‐owned dogs with idiopathic chylothorax were included. Additionally, CTLa was performed in three canine cadavers to assess the ability of CAD software to accurately acquire volumetric measurements. Injection sites, attenuation values, anatomic location, dimensions, and aortic diameter to CC ratio (Ao:CC) were recorded. Video records of video‐assisted thoracic surgery (VATS) thoracic duct ligation (TDL) were reviewed in eight out of 23 dogs to compare operative and CTLa findings. The CC was dorsal and right‐sided in 18 out of 23 dogs, located between L1 and L4 in 21 dogs, and extended as far cranially as T11 in two dogs. The median measurements for length, height, and width were 150.0, 5.5, and 13.3 mm, respectively. Median total volume was 1.82 mL. Median volumes to the right and left of the aorta were 1.46 and 0.49 mL, respectively (P = .014). Median total CC volume to body weight ratio (CC:bw) was 0.07 mL/kg. The presence of an intrathoracic CC was observed intraoperatively in six out of eight cases that underwent VATS TDL. Findings supported the use of CTLa and CAD as feasible methods for characterizing the CC in dogs diagnosed with chylothorax. These methods may facilitate interventional planning involving the CC such as embolization.     

Fluoroquinolone levels in healthy dog urine following a 20‐mg/kg oral dose of enrofloxacin exceed mutant prevention concentration targets against Escherichia coli isolated from canine urinary tract infections

A 3‐day course of oral enrofloxacin is effective for treating uncomplicated urinary tract infection (UTI) in dogs when administered 20 mg/kg Q24H. However, emergence of fluoroquinolone‐resistant mutants of uropathogens is a concern. Urine concentrations of enrofloxacin and ciprofloxacin were measured in six healthy dogs following dose of enrofloxacin 20 mg/kg. Mutant prevention concentrations of Escherichia coli isolated from canine UTI were also determined against ciprofloxacin. Urine AUC(24)/MPC ratios considering ciprofloxacin concentrations ranged 3819–7767, indicating that selection of resistant E. coli mutants in dogs with uncomplicated UTIs is unlikely in the bladder given that an AUC(24)/MPC = 39 is considered to be protective against mutant selection for ciprofloxacin. However, additional studies are required to evaluate the effects of this enrofloxacin treatment protocol on bacteria that colonize anatomic sites where fluoroquinolones achieve lower concentrations compared to the urinary bladder.     

Pharmacokinetics of a low dose and FDA‐labeled dose of diclazuril administered orally as a pelleted topdressing in adult horses

The purpose of this study was to determine the pharmacokinetics of the FDA‐approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil^TM, Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady‐state. To determine the CSF concentration at steady‐state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA‐labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high‐pressure liquid chromatography. A one‐compartment pharmacokinetic model with first‐order oral absorption was fitted to the single administration data. Steady‐state pharmacokinetics was performed using noncompartmental analysis for steady‐state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA‐labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady‐state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady‐state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture.     

Hypofractionated radiation therapy for the treatment of microscopic canine soft tissue sarcoma

Soft tissue sarcomas (STSs) are locally invasive and surgery with or without radiation therapy is the current standard of care in dogs. Typical protocols for treating incompletely excised STSs involve curative intent radiation with total dose in excess of 50 Gy. Forty‐eight dogs with histologically confirmed incomplete or closely excised STSs were treated with a hypofractionated protocol that is typically reserved for palliative radiation therapy (RT) (6–8 Gy/weekly fractions to a total dose of 24–32 Gy). Ten dogs (21%) developed local recurrence, 11 dogs (23%) developed metastasis, and 3 dogs developed both (included in each group). The median progression free survival was 698 days. The local failure‐free probability at 1 and 3 years was 81 and 73%. The 1 and 3 years tumour‐specific overall survival was 81 and 61%. Long‐term local tumour control was achieved in the majority of dogs. This protocol is reasonable to prescribe in older patients or when financial limitations exist.