ACVR and ECVDI consensus statement: Reporting elements for toxicity criteria of the veterinary radiation therapy oncology group v2.0.

The toxicity criteria of the veterinary radiation therapy oncology group (VRTOG) version 2 guidelines are a substantial update to reflect significant advances in radiation oncology over the last three decades. Radiation therapy techniques provide precise and spatially accurate radiation delivery, which facilitates treating tumors in more anatomic locations and incorporating hypofractionated protocols. The purpose of this update is to aid radiation oncology teams in capturing and grading clinically relevant data that impacts the decision-making process in everyday practice and the assessment of clinical trials involving radiation therapy. A dedicated committee initially updated the criteria to include more anatomical sites and grades to characterize a broad spectrum of possible radiation-induced acute and late tissue changes. Through the revision process, which solicited and incorporated feedback from all radiation oncologists within the American College of Veterinary Radiology (ACVR) and specialists outside the ACVR, the authors endeavored to create a grading structure reflective of clinical decision-making in daily radiation oncology. The updated VRTOG v2 toxicity criteria guideline complements the updated Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) guidelines. Because radiation oncology continues to progress rapidly, the VRTOG toxicity criteria should be regularly updated as adverse event data that will be collected following this update further informs the practice of radiation oncology.

Contouring in the optic plane improves the accuracy of computed tomography-based segmentation of the optic pathway.

Canine optic pathway structures are often contoured on CT images, despite the difficulty of visualizing the optic pathway with CT using standard planes. The purpose of this prospective, analytical, diagnostic accuracy study was to examine the accuracy of optic pathway contouring by veterinary radiation oncologists (ROs) before and after training on optic plane contouring. Optic pathway contours used as the gold standard for comparison were created based on expert consensus from registered CT and MRI for eight dogs. Twenty-one ROs contoured the optic pathway on CT using their preferred method, and again following atlas and video training demonstrating contouring on the optic plane. The Dice similarity coefficient (DSC) was used to assess contour accuracy. A multilevel mixed model with random effects to account for repeated measures was used to examine DSC differences. The median DSC (5th and 95th percentile) before and after training was 0.31 (0.06, 0.48) and 0.41 (0.18, 0.53), respectively. The mean DSC was significantly higher after training compared with before training (mean difference = 0.10; 95% CI, 0.08-0.12; P < 0.001) across all observers and patients. DSC values were comparable to those reported (0.4-0.5) for segmentation of the optic chiasm and nerves in human patients. Contour accuracy improved after training but remained low, potentially due to the small optic pathway volumes. When registered CT-MRI images are not available, our study supports routine addition of an optic plane with specific window settings to improve segmentation accuracy in mesaticephalic dogs ≥11 kg.

Pilot study evaluating the tolerability of a 3 Gy × 10 daily fraction 3D-conformal palliative radiation therapy protocol plus toceranib for the treatment of measurable carcinomas in the dog.

The use of radiation therapy in conjunction with small molecule inhibitors is an appealing treatment combination for non-resectable carcinomas, which tend to be locally invasive with variable risk of locoregional metastasis. This prospective, pilot study aimed to evaluate the tolerability and adverse event profile of concurrent toceranib and palliative-intent radiation therapy (PRT) in dogs with measurable carcinoma and to secondarily evaluate short-term measurable tumor response. Fifteen dogs with measurable carcinoma received toceranib and 3D-conformal PRT in 3 Gy/fraction for 10 daily fractions. Adverse events were graded using standard schemes and tolerability was followed via quality-of-life questionnaires during the 12-week treatment period. Thirteen dogs (87%) experienced acute radiation toxicity, graded as severe in three dogs. All dogs experienced toceranib toxicity, graded as severe in one dog. Seven dogs (47%) completed the 12-week study protocol; four were withdrawn due to toxicity and/or associated poor quality of life and four developed progressive disease. Based on these preliminary results, this 3D-conformal chemoradiation protocol should be considered with caution and only with proper owner education on potential toxicity. More conformal treatment planning techniques or alternative protocols should be investigated for improved tolerability.

Use of MRI increases interobserver agreement on gross tumor volume for imaging-diagnosed canine intracranial meningioma.

There is a lack of information regarding interobserver agreement on canine meningioma gross tumor volume (GTV) delineation, and on the impact of MRI on this agreement. The objectives of this retrospective, secondary analysis, observer agreement study were to describe agreement between veterinary radiation oncologists on GTV for canine intracranial meningioma, and to compare interobserver agreement between delineation based on CT alone and delineation based on fused CT-MRI. Eighteen radiation oncologists delineated GTV for 13 dogs with an imaging diagnosis of meningioma on pre- and postcontrast CT, pre- and postcontrast T1-weighted magnetic resonance, and T2-weighted magnetic resonance images. Dice similarity coefficient (DSC), concordance index (CI), and center of volume (COV) were used to quantify interobserver agreement. Multilevel mixed models were used to examine the difference in volume, DSC, CI and COV 3D distance between CT and CT-MR imaging. The mean volume for GTV contours delineated using fused CT-MRI was larger than when CT alone was used for delineation (mean difference CT-MR - CT = 0.89 cm3, 95% CI 0.66 to 1.12, P < .001). Interobserver agreement on GTV was improved when MRI was used; the mean DSC and CI were higher, and the mean COV 3D distance was lower, when fused CT-MRI was used than when CT alone was used (P < .001 for all differences). Based on our results, fused CT-MRI is recommended for radiation therapy planning of canine intracranial meningioma.

Response and outcome following radiation therapy of macroscopic canine plasma cell tumours.

Thirty dogs with macroscopic plasma cell tumours (PCTs) were treated with radiation therapy (RT). Twelve patients were treated with palliative-intent prescriptions (range, 4-10 Gy/fraction (median, 7 Gy/fraction) for a total dose of 20 to 35 Gy (median total dose 30 Gy). Eighteen patients received definitive-intent prescriptions (range, 3.0-4.2 Gy/fraction (median, 3 Gy/fraction) for a total dose of 42 to 54 Gy (median total dose 48 Gy). Involved sites included the oral cavity, skin, multiple myeloma (MM)-associated lytic bone lesions, bone (solitary osseous plasmacytoma; SOP), nasal cavity, larynx, retrobulbar space, lymph node and rectum. Ninety-five percent of evaluable dogs had a complete (CR; 16/22) or partial response (PR; 5/22). Patients with MM experienced significant analgesia. The median progression-free survival (PFS) was 611 days (range: 36-2001 days). Events in the non-MM cases included in-field progression (5/26, 19%) and disseminated disease (5/26, 19%). The median survival time (MST) for all dogs was 697 days (range: 71-2075 days), and when only non-MM cases were considered, MST was 771 days (range: 71-2075 days). Fourteen patients were alive without disease progression or had died of unrelated causes. Achievement of a PR was associated with an inferior PFS and MST as compared with CR. Palliative-intent RT was associated with inferior MST as compared with definitive-intent RT. RT is a useful therapeutic modality for PCTs and tumour responses are often complete and durable, with protracted survivals. The optimal radiation dose and schedule are yet to be defined.

Multimodality treatment including ONCEPT for canine oral melanoma: A retrospective analysis of 131 dogs.

Canine oral melanoma (OM) is an aggressive cancer with a high rate of metastasis. Surgery and/or radiotherapy (RT) are effective local treatments, yet many dogs succumb to distant metastasis. Immunotherapy represents an attractive strategy for this potentially immunogenic tumor. The objective of this multi-institutional retrospective study was to examine the clinical outcome of dogs with OM treated with ONCEPT melanoma vaccine. Most dogs also underwent surgery and/or RT (8 Gy × four weekly fractions). Dogs with distant metastasis at diagnosis and those receiving concurrent chemotherapy were excluded. One hundred thirty-one dogs treated with ONCEPT were included: 62 had adequate local tumor control defined as complete tumor excision or irradiation of residual microscopic disease; 15 were treated in the microscopic disease setting following an incomplete excision without adjuvant RT; and 54 had gross disease. Median time to progression, median progression-free survival, and median tumor-specific overall survival were 304, 260, and 510 days, respectively. In multivariable analysis, presence of gross disease correlated negatively with all measures of clinical outcome. Other negative prognostic indicators were primary tumor ≥2 cm, higher clinical stage (stages 2 and 3), presence of lymph node metastasis at diagnosis, and caudal location in the oral cavity. Radiotherapy had a protective effect against tumor progression. To date, this is the largest reported series of dogs with OM treated with ONCEPT. Several previously reported prognostic indicators were confirmed.

Prolonged survival after craniectomy with skull reconstruction and adjuvant definitive radiation therapy in three dogs with multilobular osteochondrosarcoma.

Multilobular osteochondrosarcoma is an uncommon canine tumor but presents a treatment challenge when arising on the skull. This retrospective case series study aimed to describe outcome of a multimodality treatment approach involving aggressive surgical resection and adjuvant definitive radiation therapy in a group of dogs with multilobular osteochondrosarcoma of the calvarium. Clinical, imaging, treatment, and outcome data were collected from retrospective review of medical records. Three dogs met inclusion criteria. The presenting clinical complaint was the presence of a mass effect of the skull in all three dogs and concurrent neurologic abnormalities in one dog. Advanced imaging revealed aggressive lytic and proliferative tumors arising from the calvarium in all three dogs. All dogs were treated surgically with a modified craniectomy, repaired with a titanium mesh-polymethyl methacrylate bone cement implant or a low prolife titanium mesh plate and followed by adjuvant definitive radiation therapy with 2.5 Gy per fraction for 22 daily fractions. There were no major immediate surgical complications and radiation was well tolerated overall. Neurologic improvement was seen in the patient that presented with neurologic disease. Survival times from surgery were 387, 422, and 730 days and from the time of radiation were 358, 397, and 677 days. Findings in this sample of three dogs supported the use of aggressive therapy with a combination of surgical craniectomy and cranioplasty utilizing a titanium mesh implant and high dose definitive radiation therapy for local control and prolonged survival times in dogs with multilobular osteochondrosarcoma of the skull.

Effect of prophylactic cefalexin treatment on the development of bacterial infection in acute radiation-induced dermatitis in dogs: a blinded randomized controlled prospective clinical trial.

BACKGROUND: Acute radiation-induced dermatitis (ARID) is a common sequela of radiation therapy and carries the risk of secondary bacterial skin infection. No standard of care exists for managing canine ARID and evidence-based guidelines are lacking; however, prophylactic use of antibiotics is common. HYPOTHESIS/OBJECTIVES: To evaluate the impact of prophylactic cefalexin on the prevalence and severity of bacterial infection in canine ARID. ANIMALS: Seventeen dogs treated with definitive-intent radiotherapy. METHODS: All dogs were treated with definitive-intent radiation therapy (48-57.5 gray) targeted to the skin surface. Dogs were randomized to receive either prophylactic cefalexin (22 mg/kg twice daily) beginning halfway through the prescribed radiotherapy course (cohort A) or to serve as controls (cohort B). Aerobic skin cultures and surface cytological evaluation were performed at first onset of moist desquamation and one week following completion of radiation therapy. Skin toxicity grading and owner quality of life (QoL) questionnaires were performed weekly. The rate of infection, multidrug resistance status, toxicity severity and QoL between cohorts were compared. RESULTS: Staphylococcus schleiferi and S. pseudintermedius were the most frequent bacterial agents isolated in both cohorts. There was no significant difference in prevalence of bacterial infection or overall QoL between cohorts at either time point; however, multidrug-resistant infections were significantly increased in cohort A versus cohort B. Clinician- and client-perceived severity of toxicity was significantly greater and median duration of moist desquamation was significantly longer in cohort A than cohort B. CONCLUSIONS AND CLINICAL IMPORTANCE: Prophylactic use of cefalexin for management of canine ARID is not recommended.

OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES.

Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi-institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy ± chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation ± chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation.

Computed tomographic findings in 57 cats with primary pulmonary neoplasia.

Primary pulmonary neoplasia is relatively uncommon in cats and generally has a poor prognosis. In this multicenter, retrospective study of 57 cats with pulmonary neoplasia, the most frequent presenting signs were anorexia/inappetence (39%) and cough (37%). The pulmonary tumors were considered to be incidental findings in 9% cats. In computed tomographic (CT) images, primary pulmonary tumors appeared as a pulmonary mass in 55 (96%) cats and as a disseminated pulmonary lesion without a defined mass in two (4%) cats. Most pulmonary tumors were in the caudal lobes, with 28 (49%) in the right caudal lobe and 17 (30%) in the left caudal lobe. CT features associated with pulmonary tumors included mass in contact with visceral pleura (96%), irregular margins (83%), well-defined borders (79%), bronchial compression (74%), gas-containing cavities (63%), foci of mineral attenuation (56%), and bronchial invasion (19%). The mean (range) maximal dimension of the pulmonary masses was 3.5 cm (1.1-11.5 cm). Additional foci of pulmonary disease compatible with metastasis were observed in 53% cats. Pleural fluid was evident in 30% cats and pulmonary thrombosis in 12% cats. The histologic diagnoses were 47 (82%) adenocarcinomas, six (11%) tumors of bronchial origin, three (5%) adenosquamous cell carcinomas, and one (2%) squamous cell carcinoma. In this series, adenocarcinoma was the predominant tumor type, but shared many features with less common tumor types. No associations were identified between tumor type and CT features. Prevalence of suspected intrapulmonary metastasis was higher than in previous radiographic studies of cats with lung tumors.

Survival times for canine intranasal sarcomas treated with radiation therapy: 86 cases (1996-2011).

Sarcomas comprise approximately one-third of canine intranasal tumors, however few veterinary studies have described survival times of dogs with histologic subtypes of sarcomas separately from other intranasal tumors. One objective of this study was to describe median survival times for dogs treated with radiation therapy for intranasal sarcomas. A second objective was to compare survival times for dogs treated with three radiation therapy protocols: daily-fractionated radiation therapy; Monday, Wednesday, and Friday fractionated radiation therapy; and palliative radiation therapy. Medical records were retrospectively reviewed for dogs that had been treated with radiation therapy for confirmed intranasal sarcoma. A total of 86 dogs met inclusion criteria. Overall median survival time for included dogs was 444 days. Median survival time for dogs with chondrosarcoma (n = 42) was 463 days, fibrosarcoma (n = 12) 379 days, osteosarcoma (n = 6) 624 days, and undifferentiated sarcoma (n = 22) 344 days. Dogs treated with daily-fractionated radiation therapy protocols; Monday, Wednesday and Friday fractionated radiation therapy protocols; and palliative radiation therapy protocols had median survival times of 641, 347, and 305 days, respectively. A significant difference in survival time was found for dogs receiving curative intent radiation therapy vs. palliative radiation therapy (P = 0.032). A significant difference in survival time was also found for dogs receiving daily-fractionated radiation therapy vs. Monday, Wednesday and Friday fractionated radiation therapy (P = 0.0134). Findings from this study support the use of curative intent radiation therapy for dogs with intranasal sarcoma. Future prospective, randomized trials are needed for confirmation of treatment benefits.

Completeness of reporting of radiation therapy planning, dose, and delivery in veterinary radiation oncology manuscripts from 2005 to 2010.

Surrounding a shift toward evidence-based medicine and widespread adoption of reporting guidelines such as the Consolidated Standards of Reporting Trials (CONSORT) statement, there has been a growing body of literature evaluating the quality of reporting in human and veterinary medicine. These reviews have consistently demonstrated the presence of substantive deficiencies in completeness of reporting. The purpose of this study was to assess the current status of reporting in veterinary radiation oncology manuscripts in regards to treatment planning methods, dose, and delivery and to introduce a set of reporting guidelines to serve as a standard for future reporting. Forty-six veterinary radiation oncology manuscripts published between 2005 and 2010 were evaluated for reporting of 50 items pertaining to patient data, treatment planning, radiation dose, delivery of therapy, quality assurance, and adjunctive therapy. A mean of 40% of checklist items were reported in a given manuscript (range = 8-75%). Only 9/50 (18%) checklist items were reported in > or = 80% manuscripts. The completeness of reporting was best in regards to a statement of prescription radiation protocol (91-98% reported) and worst in regards to specification of absorbed dose within target volumes and surrounding normal tissues (0-6% reported). No manuscripts met the current International Commission of Radiation Units and Measurements (ICRU) dose specification recommendations. Incomplete reporting may stem from the predominance of retrospective manuscripts and the variability of protocols and equipment in veterinary radiation oncology. Adoption of reporting guidelines as outlined in this study is recommended to improve the quality of reporting in veterinary radiation oncology.

Cyclization/hydrosilylation of functionalized 1,6-diynes catalyzed by cationic platinum complexes containing bidentate nitrogen ligands.

A 1:1 mixture of the platinum dimethyl diimine complex [PhN[double bond]C(Me)C(Me)[double bond]NPh]PtMe(2) (4a) and B(C(6)F(5))(3) catalyzed the cyclization/hydrosilylation of dimethyl dipropargylmalonate (1) and HSiEt(3) to form 1,1-dicarbomethoxy-3-methylene-4-(triethylsilylmethylene)cyclopentane (3) in 82% isolated yield with 26:1 Z:E selectivity. Platinum-catalyzed diyne cyclization/hydrosilylation tolerated a range of functional groups including esters, sulfones, acetals, silyl ethers, amides, and hindered ketones. Diynes that possessed propargylic substitution underwent facile cyclization/hydrosilylation to form silylated 1,2-dialkylidene cyclopentanes as mixtures of regioisomers. Diynes that possessed an electron-deficient internal alkyne underwent cyclization/hydrosilylation in moderate yield to form products resulting from silyl transfer to the less substituted alkyne. The silylated 1,2-dialkylidenecyclopentanes formed via diyne cyclization/hydrosilylation underwent a range of transformations including protodesilylation, Z/E isomerization, and [4 + 2] cycloaddition with dieneophiles.