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.

Intensity-modulated radiation therapy dose prescription and reporting: Sum and substance of the International Commission on Radiation Units and Measurements Report 83 for veterinary medicine.

Institutions' adherence to protocol, quality assurance, and radiation parameter reporting are key to adequately interpret and compare treatment outcomes in radiation oncology. In 2017, the editorial board for Veterinary Radiology & Ultrasound adapted author guidelines on "technical information for radiation therapy (RT)". These guidelines provide a framework to report the RT treatment process in manuscripts resulting from veterinary clinical trials. In spite of this framework, however, in implementing IMRT, we have identified different "interpretations" of the extended prescription and reporting recommendations of the International Commission on Radiation Units and Measurements (ICRU 83), even within our small team. In the following commentary review, we provide a short summary of various detailed aspects of the ICRU 83 recommended (IMRT) prescription and reporting, including (a) absorbed target dose specification and prescription, (b) homogeneity and conformity, and (c) reporting of absorbed dose in organs at risk. In particular, we want to share our thoughts on possible dangers of noncompliance in adhering to protocol, prescription, and reporting. As veterinary IMRT publications still sparsely adhere to the recommendations of the ICRU, we were motivated to summarize the recommendations to facilitate appropriate reporting for IMRT in future veterinary studies.

Computed tomographic-lymphography as a complementary technique for lymph node staging in dogs with malignant tumors of various sites.

Locoregional lymph nodes are routinely examined in order to define the spatial extent of neoplastic disease. As draining patterns of certain tumor types can be divergent from expected anatomical distribution, it is critical to sample the lymph nodes truly representing the draining area. The aim of this bicenter prospective pilot study was to describe the technique of computed tomographic (CT)-lymphography for primary draining lymph node mapping in tumor staging in dogs. Forty-five dogs with macro- or microscopic tumors in specified localizations were evaluated. Depending on body weight, 0.8-2 ml contrast agent (iohexol) was injected into four quadrants around the tumor, and CT-images were obtained at 1, 3, 6, 9, and 12 minutes post-injection. Attenuation of chosen regions of interest (Hounsfield units (HU)) and patterns of enhancement were assessed for 284 lymph nodes in the precontrast study with median HUs of 31.1 (Interquartile range (IQR) = 18.4) and for 275 in the intravenous postcontrast study with 104.3 HU (IQR = 31.2) (paired Wilcoxon test, P < 0.001). In the CT-lymphography study, 45 primary draining lymph nodes with a significantly higher median HU value of 348.5 (IQR = 591.4) (one-sample t-test, P < 0.001) were identified. Primary draining lymph nodes were found to be clearly visible after 1-3 minutes after local injection, often concurrent with a good visibility of the lymphatic vessel system. The herein described technique of peritumorally injected CT-contrast agent followed by subsequent CT-lymphography for primary draining lymph node mapping works well in a majority of cases in all investigated sites and warrants further validation for different tumor entities.

Risk adaptive planning with biology-based constraints may lead to higher tumor control probability in tumors of the canine brain: A planning study.

BACKGROUND: Classical radiation protocols are guided by physical dose delivered homogeneously over the target. Protocols are chosen to keep normal tissue complication probability (NTCP) at an acceptable level. Organs at risk (OAR) adjacent to the target volume could lead to underdosage of the tumor and a decrease of tumor control probability (TCP). The intent of our study was to explore a biology-based dose escalation: by keeping NTCP for OAR constant, radiation dose was to be maximized, allowing to result in heterogeneous dose distributions. METHODS: We used computed tomography datasets of 25 dogs with brain tumors, previously treated with 10x4 Gy (40 Gy to PTV D50). We generated 3 plans for each patient: A) original treatment plan with homogeneous dose distribution, B) heterogeneous dose distribution with strict adherence to the same NTCPs as in A), and C) heterogeneous dose distribution with adherence to NTCP <5%. For plan comparison, TCPs and TCP equivalent doses (homogenous target dose which results in the same TCP) were calculated. To enable the use of the generalized equivalent uniform dose (gEUD) metric of the tumor target in plan optimization, the calculated TCP values were used to obtain the volume effect parameter a. RESULTS: As intended, NTCPs for all OARs did not differ from plan A) to B). In plan C), however, NTCPs were significantly higher for brain (mean 2.5% (SD±1.9, 95%CI: 1.7,3.3), p<0.001), optic chiasm (mean 2.0% (SD±2.2, 95%CI: 1.0,2.8), p=0.010) compared to plan A), but no significant increase was found for the brainstem. For 24 of 25 of the evaluated patients, the heterogenous plans B) and C) led to an increase in target dose and projected increase in TCP compared to the homogenous plan A). Furthermore, the distribution of the projected individual TCP values as a function of the dose was found to be in good agreement with the population TCP model. CONCLUSION: Our study is a first step towards risk-adaptive radiation dose optimization. This strategy utilizes a biologic objective function based on TCP and NTCP instead of an objective function based on physical dose constraints.

Indocyanine-based near-infrared lymphography for real-time detection of lymphatics in a cat with multiple mast cell tumours.

CASE SUMMARY: An 11-year-old female domestic shorthair cat was presented with cutaneous mast cell tumours (MCTs) localised at the right temporal region, the left buccal region and on the third digit of the right thoracic limb. Staging was negative and locoregional lymph nodes appeared normal, based on clinical findings. During surgery, real-time indocyanine green (ICG)-based lymphography was performed to detect the cutaneous draining pattern of all the primary MCTs. ICG was injected intracutaneously in four quadrants around each tumour, and a clear lymphogram was visible shortly after injection. Using near-infrared lymphography (NIR-L) for guidance, all lymphadenectomies were performed in 12 mins or less, with a maximal incision length of 3.5 cm. The smallest resected node was 0.9 cm in diameter. All MCTs were classified as low-grade cutaneous MCT. All four ICG-positive lymph nodes were considered premetastatic or metastatic. The only ICG-negative resected node was also negative for tumour cells. No complications related to NIR-L were recorded. RELEVANCE AND NOVEL INFORMATION: This is the first description of NIR-L in a cat with MCT. Application was straightforward and ICG enrichment only occurred in the metastatic nodes, suggesting correct identification of lymphatic draining patterns. Of note, as previously described in dogs, we did detect nodal metastasis, despite low-grade primary tumours. The clinical relevance should be evaluated in future studies.

Definitive-intent radiotherapy for sinonasal carcinoma in cats: A multicenter retrospective assessment.

Treatment of epithelial sinonasal tumours in cats is not commonly reported. In the newer reports, palliative radiation protocols have been described more often than definitive-intent protocols. In this multi-institutional retrospective study, we included 27 cats treated with single-modality radiotherapy. Cats were irradiated using 10 daily fractions of 4.2 Gy. Three cats (11.1%) experienced a complete clinical response and 17 (63%) had a partial clinical response. Stable clinical disease was noted in three cats (11.1%). Four cats (14.8%) showed progression within 3 months following treatment. The median time to progression for all cases was 269 days (95 % confidence intervals [CI]: 225; 314). The proportion of cats free of progression at 1 and 2 years was 24% (95% CI: 22%; 26%) and 5% (95% CI: 5%; 6%), respectively. None of the prognostic factors evaluated were predictive of outcome (anaemia, tumour volume at the time of staging, modified Adams stage, intracranial involvement, facial deformity, epistaxis, inappetence or weight loss). Median overall survival (OS) for all deaths was 452 days (95% CI: 334; 571). The proportion of cats alive at 1 and 2 years was 57% (95% CI: 37%; 77%) and 27% (95% CI: 25%; 29%), respectively. Surprisingly, cats with epistaxis had a longer median OS of 828 days (95% CI: 356; 1301) compared to 296 days (95% CI: 85; 508) in cats without epistaxis, (P = .04, Breslow). Radiation therapy used as a single modality for the treatment of feline sinonasal carcinoma improved clinical signs and was well tolerated but progression within a year was common.

Radiation therapy for intracranial tumours in cats with neurological signs.

OBJECTIVES: The aim of this study was to evaluate the outcome of cats with intracranial tumours presenting with neurological signs treated with radiation therapy. METHODS: This study comprised a retrospective multicentre case series. Medical records of a total of 22 cats with intracranial space-occupying lesions, presenting with neurological signs and/or epileptic seizures and treated with external beam radiation therapy, were reviewed. In the treated cats, patient-, tumour- and treatment-related variables were investigated, including age, sex, tumour location, tumour volume, total radiation dose, equivalent dose in 2 Gy fractions (EQD2), corticosteroid dose, overall treatment time and institution for influence on local tumour control and survival. RESULTS: Based on advanced imaging characteristics, the 22 treated cats presented with meningioma (n = 11), pituitary tumour (n = 8), choroid plexus tumour (n = 2) or glioma (n = 1). Allocated to the neuraxis, 11 lesions were extra-axial, three were intra-axial and eight were located in the pituitary region. At diagnosis, 21 cats exhibited altered neurological status. One cat presented with epileptic seizures and another cat had both seizures and altered neurological status. The mean total physical dose of radiation was 41.63 Gy (± 4.33), range 24-45 Gy. In all but one cat (95.5%), neurological signs improved after radiation therapy. The median progression-free survival was 510 days (95% confidence interval [CI]: 51-969). The proportion free of progression at 1 year was 55.7% (95% CI: 33-78). Fourteen cats died (only in five cases was death related to the intracranial tumour) and eight cats were still alive or lost to follow-up. The median overall survival time was 515 days (95% CI: 66-964). None of the tested variables influenced outcome. CONCLUSIONS AND RELEVANCE: Radiation therapy seems to represent a viable treatment option in cats with intracranial tumours, relieving neurological signs and improving local tumour control. Radiation therapy may be considered for cats with tumours in complicated/inoperable localisations or for cases with a high peri- and postoperative risk.

Outcome and failure patterns of localized sinonasal lymphoma in cats treated with first-line single-modality radiation therapy: A retrospective study.

Failure rate and site are not well defined in localized sinonasal lymphoma in cats treated with radiotherapy. In this study, we describe (a) failure pattern, (b) outcome, (c) influence of previously reported prognostic variables on the outcome in cats with suspected localized sinonasal lymphoma. In this multi-institutional retrospective study, we included 51 cats treated with single-modality radiotherapy. Cats were irradiated using 10x4.2Gy (n = 32), 12x3Gy (n = 11) or 5x6Gy (n = 8). Regional lymph nodes were prophylactically irradiated in 24/51 cats (47.1%). Twenty-five cats (49.0%) developed progressive disease: progression was local (nasal) in five (9.8%), locoregional (nodal) in two (3.9%), local and locoregional in three (5.9%), systemic in nine (17.6%) and both local and systemic in six cats (11.8%). No cat receiving prophylactic nodal irradiation had progression in the locoregional lymph nodes. The median time to progression was 974 days (95%CI: 283;1666), with 58% and 53% of cats free of progression at 1 and 2 years, respectively. Median overall survival was 922 days (95%CI: 66;1779) with 61% and 49% alive at 1 and 2 years, respectively. Half of the cats that died of relapse/progression (13/26) died within 6 months of treatment, suggesting possible shortcomings of staging, rapid dissemination of disease or sequential lymphomagenesis. None of the prognostic factors evaluated were predictive of outcome (prednisolone use, anaemia, nasopharyngeal involvement, modified canine Adams tumour stage, protocol, total dose). Radiotherapy is an effective treatment for localized sinonasal lymphoma with a long time to progression. However, in one-third of the cats, systemic disease progression occurs soon after radiotherapy.