POTENTIAL FOR INTENSITY-MODULATED RADIATION THERAPY TO PERMIT DOSE ESCALATION FOR CANINE NASAL CANCER

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary     

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.     

USE OF PHOTON FIELDS WITH NONCOINCIDENT ISOCENTERS TO IMPROVE HOMOGENEITY OF DOSE DISTRIBUTION

To compare changes in dose distribution in irregularly shaped volumes treated using fields with noncoincident isocenters compared with fields with coincident isocenters. The hypothesis was that use of fields with noncoincident isocenters would result in improved homogeneity of dose distribution. We chose to test the hypothesis in canine nasal tumors because of the increased dorsoventral thickness of the caudal compared with the rostral nasal cavity. Computed tomography images from eight dogs with nasal tumors were selected. A tissue-contouring program was used to outline contours, including the mandible as a normal tissue structure and the planning target volume (PTV), divided into a rostral and caudal volume. A traditional computerized treatment plan consisting of two parallel-opposed fields was constructed for each dog. A second treatment plan using a third caudally located field having a different isocenter was constructed for comparison. Dose-volume histograms were generated and compared for each contoured structure in both plans. In all dogs the use of noncoincident fields resulted in increased dose to the ethmoid region through the caudal field. Minimum dose in the caudal tumor PTV increased as well. At the same time, dose delivered to the mandible, prone to develop significant side effects, was lower in all dogs with the use of noncoincident fields, as it was possible to reduce the dose delivered from the ventral field. Use of photon fields with noncoincident isocenters can improve the dose distribution in irregularly shaped volumes in comparison with fields with coincident isocenters. Improved tumor dose distribution was achieved with the addition of a smaller field having a different isocenter.     

RADIOBIOLOGICAL AND TREATMENT PLANNING STUDY OF A SIMULTANEOUSLY INTEGRATED BOOST FOR CANINE NASAL TUMORS USING HELICAL TOMOTHERAPY

Feasibility of delivering a simultaneously integrated boost to canine nasal tumors using helical tomotherapy to improve tumor control probability (TCP) via an increase in total biological equivalent uniform dose (EUD) was evaluated. Eight dogs with varying size nasal tumors (5.8-110.9 cc) were replanned to 42 Gy to the nasal cavity and integrated dose boosts to gross disease of 45.2, 48.3, and 51.3 Gy in 10 fractions. EUD values were calculated for tumors and mean normalized total doses (NTD(mean)) for organs at risk (OAR). Normal Tissue Complication Probability (NTCP) values were obtained for OARs, and estimated TCP values were computed using a logistic dose-response model and based on deliverable EUD boost doses. Significant increases in estimated TCP to 54%, 74%, and 86% can be achieved with 10%, 23%, and 37% mean relative EUD boosts to the gross disease, respectively. NTCP values for blindness of either eye and for brain necrosis were < 0.01% for all boosts. Values for cataract development were 31%, 42%, and 46% for studied boost schemas, respectively. Average NTD(mean) to eyes and brain for mean EUD boosts were 10.2, 11.3, and 12.1 Gy3, and 7.5, 7.2, and 7.9 Gy2, respectively. Using helical tomotherapy, simultaneously integrated dose boosts can be delivered to increase the estimated TCP at 1-year without significantly increasing the NTD(mean) to eyes and brain. Delivery of these treatments in a prospective trial may allow quantification of a dose-response relationship in canine nasal tumors.     

COMPARISON OF ISODOSE DISTRIBUTIONS IN CANINE BRAIN IN HETEROGENEITY-CORRECTED VERSUS UNCORRECTED TREATMENT PLANS USING 6 MV PHOTONS

Magnetic resonance (MR) images may be useful for radiation planning due to greater contrast resolution. One disadvantage of MR images for radiation planning is the inability to incorporate electron density information into the dose calculation algorithm. To assess the magnitude of this problem, we evaluated radiation dose distribution in canine brain by comparing computed tomography (CT)-based radiotherapy plans with and without electron density correction. Computerized radiotherapy plans were generated for 13 dogs with brain tumors using 6 MV photons. A tissue-contouring program was used to outline the gross tumor volume (GTV) and the planning target volume (PTV) for each patient. Two treatment plans were generated for each dog. First, the plan was optimized without heterogeneity correction. Then the heterogeneity correction was implemented without changing any other plan parameters. Isodose distributions and dose volume histograms (DVHs) were used to compare the two plans. The D95 (dose delivered to 95% of the volume) within the PTV was calculated for each treatment plan and differences in the D95s were compared. The mean D95s without and with heterogeneity correction were 49.1 +/- 0.7 and 48.9 +/- 1.0Gy, respectively. The absolute mean percent dose difference without and with heterogeneity correction was 1.0 - 0.9% (-1.3-3.2%) and was not considered to be clinically significant. We found no clinically significant difference between CT-based radiotherapy plans without and with heterogeneity correction for brain tumors in small animals, which supports the use of MR-based treatment planning for radiotherapy of small animal brain tumors.     

A comparison of two dose calculation algorithms—anisotropic analytical algorithm and Acuros XB—for radiation therapy planning of canine intranasal tumors

Although anisotropic analytical algorithm (AAA) and Acuros XB (AXB) are both radiation dose calculation algorithms that take into account the heterogeneity within the radiation field, Acuros XB is inherently more accurate. The purpose of this retrospective method comparison study was to compare them and evaluate the dose discrepancy within the planning target volume (PTV). Radiation therapy (RT) plans of 11 dogs with intranasal tumors treated by radiation therapy at the University of Georgia were evaluated. All dogs were planned for intensity‐modulated radiation therapy using nine coplanar X‐ray beams that were equally spaced, then dose calculated with anisotropic analytical algorithm. The same plan with the same monitor units was then recalculated using Acuros XB for comparisons. Each dog's planning target volume was separated into air, bone, and tissue and evaluated. The mean dose to the planning target volume estimated by Acuros XB was 1.3% lower. It was 1.4% higher for air, 3.7% lower for bone, and 0.9% lower for tissue. The volume of planning target volume covered by the prescribed dose decreased by 21% when Acuros XB was used due to increased dose heterogeneity within the planning target volume. Anisotropic analytical algorithm relatively underestimates the dose heterogeneity and relatively overestimates the dose to the bone and tissue within the planning target volume for the radiation therapy planning of canine intranasal tumors. This can be clinically significant especially if the tumor cells are present within the bone, because it may result in relative underdosing of the tumor.     

PROTON SPOT SCANNING RADIOTHERAPY OF SPONTANEOUS CANINE TUMORS

Thirty dogs with spontaneous tumors were irradiated with proton therapy using a novel spot scanning technique to evaluate the safety and efficacy of the system, and to study the acute and late radiation reactions. Nasal tumors, soft tissue sarcomas, and miscellaneous tumors of the head were treated with a median total dose of 52.5 Gy given in 3.5 Gy fractions. Acute effects, late effects, tumor response, and outcome were analyzed. No unexpected radiation reactions were seen, however two dogs did develop in-field osteosarcoma, and one dog developed in-field bone necrosis. Complete response to therapy was seen in 40% (12/30), partial response in 47% (14/30), and no response in 13% (4/30). Median survival for all dogs was 385 days (range of 14–4583 days). Dogs with nasal cavity tumors had a median survival of 385 days (range of 131–1851 days) and dogs with soft tissue sarcomas had a median survival time of 612 days (range of 65–4588 days). Treatment outcome was similar to historical controls. This new proton spot scanning technique proved to be safe and reliable.     

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.     

Irradiation of brain tumors in dogs with neurologic disease

Radiation therapy is the treatment of choice for many primary canine brain tumors. The radiation dose tolerated by surrounding healthy brain tissue can be a limiting factor for radiation treatment and total dose as well as fractionation schedules, and volume effects may play a role in the outcome of patients undergoing radiation therapy. The purpose of this retrospective study was to evaluate the efficacy of radiation therapy in dogs with brain tumors that showed signs of neurologic disease. Forty-six dogs with brain tumors were included in the analysis. In 34 dogs, computer-generated treatment plans were available, and dose-volume data could be obtained. The totally prescribed radiation therapy doses ranged from 35 to 52.5 Gy (mean = 40.9 [SD +/- 2.91) applied in 2.5- to 4-Gy fractions (mean = 3.2). The median overall survival time calculated for deaths attributable to worsening of neurologic signs was 1,174 days (95% confidence interval [CI], 693-1,655 days). Assuming that all deaths were due to disease or treatment consequences, the median survival time was 699 days (95% CI, 589-809 days). No prognostic clinical factors such as the location or size of the tumor or neurologic signs at presentation were identified. With computerized treatment planning and accurate positioning, high doses of radiation (> 80% of the total dose) could be limited to mean relative brain volumes of 35.3% (+/- 12.6). These small volumes may decrease the probability of severe late effects such as infarction or necrosis. In this study, very few immediate or early delayed adverse effects and no late effects were noted, and quality of life was good to excellent.     

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.     

PROTON IRRADIATION OF FELINE NASAL PLANUM SQUAMOUS CELL CARCINOMAS USING AN ACCELERATED PROTOCOL

Fifteen cats were treated for squamous cell carcinoma of the nasal planum using proton beam radiation. The protocol used was accelerated with eight equal fractions given on four consecutive days, with a minimum of six hours between fractions. Total dose of radiation delivered was escalated with nine cats receiving 40.4 CGE (60Co Gy equivalent), and three cats each receiving 42.4 and 44.8 CGE. Complete response to the protocol was 60% (9/15), partial response was 33% (5 of 15), and no response was seen in 6.6% (1 of 15). Tumor control rate at one year was 64% and no cat had tumor recurrence after one year. Median survival was 946 days (+/- 516 days). Side effects were minimal with no severe reactions noted in the early or late period. This protocol offers an effective treatment for squamous cell carcinoma of the feline nasal planum with minimal side effects and may be adaptable to conventional radiation sources particularly when the field size is very small.     

A BOOST TECHNIQUE FOR IRRADIATION OF MALIGNANT CANINE NASAL TUMORS

Eighteen dogs with malignant nasal cavity tumors were treated with radiation therapy, including a boost technique. Three 3:0 Gy boost doses were added to a treatment protocol consisting of sixteen 3.0 Gy daily fractions, bringing the total dose to 57 Gy. This boost technique was implemented without an associated increase in overall treatment time by giving the boost doses on a twice-a-day basis. Boost doses were given during the first half of the radiation therapy period. The treatment was completed as planned in 16 of the 18 dogs; two dogs received lower doses (51 and 54 Gy). Median survival was 177 days, poorer than in some other reported studies of nasal tumor irradiation. Acute effects were unacceptable, with 11 of the 18 dogs developing severe mucositis, desquamation, edema, swelling, and pruritus. The extensive nature of the acute reactions compromised assessment of the effect of the increased radiation dose on the tumor. Although there is justification for assessing more aggressive radiation protocols in canine nasal tumor patients, total doses approximating 60 Gy can not be given as described because of the inability of acutely responding normal tissues to compensate.     

DOSIMETRIC CONSEQUENCES OF USING CONTRAST‐ENHANCED COMPUTED TOMOGRAPHIC IMAGES FOR INTENSITY‐MODULATED STEREOTACTIC BODY RADIOTHERAPY PLANNING

Potential benefits of planning radiation therapy on a contrast‐enhanced computed tomography scan (ceCT) should be weighed against the possibility that this practice may be associated with an inadvertent risk of overdosing nearby normal tissues. This study investigated the influence of ceCT on intensity‐modulated stereotactic body radiotherapy (IM‐SBRT) planning. Dogs with head and neck, pelvic, or appendicular tumors were included in this retrospective cross‐sectional study. All IM‐SBRT plans were constructed on a pre‐ or ceCT. Contours for tumor and organs at risk (OAR) were manually constructed and copied onto both CT's; IM‐SBRT plans were calculated on each CT in a manner that resulted in equal radiation fluence. The maximum and mean doses for OAR, and minimum, maximum, and mean doses for targets were compared. Data were collected from 40 dogs per anatomic site (head and neck, pelvis, and limbs). The average dose difference between minimum, maximum, and mean doses as calculated on pre‐ and ceCT plans for the gross tumor volume was less than 1% for all anatomic sites. Similarly, the differences between mean and maximum doses for OAR were less than 1%. The difference in dose distribution between plans made on CTs with and without contrast enhancement was tolerable at all treatment sites. Therefore, although caution would be recommended when planning IM‐SBRT for tumors near “reservoirs” for contrast media (such as the heart and urinary bladder), findings supported the use of ceCT with this dose calculation algorithm for both target delineation and IM‐SBRT treatment planning.     

Conventional fractionated radiotherapy outcomes for young dogs with nephroblastoma of the spinal cord: 5 cases

Published radiotherapy results for spinal nephroblastomas in dogs are limited. In this retrospective longitudinal study (1/2007–1/2022), five dogs with a median age of 2.8 years received post-operative 3D conformal, conventional fractionated radiotherapy (CFRT) with 2–4 fields (parallel-opposed with or without two hinge-angle fields), for an incompletely resected nephroblastoma. Clinical findings prior to surgery included one or more of the following: pelvic limb paresis (5), faecal incontinence (2), flaccid tail (1), non-ambulatory (2) and deep pain loss (1). All masses were located between T11 and L3 and surgically removed via hemilaminectomy. Dogs received 45–50 Gray (Gy) in 18–20 fractions, and no dogs received chemotherapy post-radiation. At analysis, all dogs were deceased, with none lost to follow-up. The median overall survival (OS) from first treatment to death of any cause was 3.4 years (1234 days; 95% CI 68 days-upper limit not reached; range: 68–3607 days). The median planning target volume was 51.3 cc, with a median PTV dose of 51.4 Gy and median D98 = 48.3 Gy. Late complications or recurrence was difficult to fully determine in this small dataset; however, some degree of ataxia persisted throughout life in all dogs. This study provides preliminary evidence that post-operative radiotherapy may result in prolonged survival times dogs with spinal nephroblastomas.     

A complication probability study for a definitive‐intent,moderately hypofractionated image‐guided intensity‐modulated radiotherapy protocol for anal sac adenocarcinoma in dogs

Previous trials showed the importance of administering radiation therapy (RT) with small doses per fraction in canine pelvic tumours to maintain acceptable toxicity levels. With increased accuracy/precision of RT, namely intensity‐modulated RT (IMRT), this approach might be challenged. Theoretical toxicity calculations for a new definitive‐intent moderately hypofractionated RT protocol for canine anal sac adenocarcinomas (ASAC) were performed, focussing on the risk of toxicity in pelvic organs at risk (OAR). Computed tomography datasets of 18 dogs with stage 3b ASAC were included. Re‐planning with margins for daily image‐guidance/IMRT was performed and a new protocol isoeffective to previously described definitive‐intent protocols was computed. Dose‐volume information were derived from individual plans and used for normal tissue complication probability (NTCP) computations. A 12 × 3.8 Gy protocol was computed for risk estimation. Tumour volumes ranged from 27.9 to 820.4 cm³ (mean 221.3 cm³ ± 188.9). For late rectal toxicity/bleeding ≥grade 2, median risk probability was 2.3% inter quartile range (IQR: 5.9; 95% confidence interval (CI): 1.2, 8.4) (rho = 0.436) and 3.4% (IQR: 0.96; 95%CI: 3.1, 4.0) (rho = 0.565), respectively. Median late toxicities in urinary bladder, kidneys and small bowel were <1%, except in one kidney. Myelopathy/myelonecrosis had a median risk probability of 4.1% (IQR: 23.5; 95%CI: 2.1, 25.2) (rho = 0.366) and 5.6% (IQR: 13.5; 95%CI: 3.1, 14.1) (rho = 0.363), respectively. However, graded risk showed a probability estimate for late spinal cord toxicity of ≥5% in 8/18 patients. The daily‐imaging IMRT 12 × 3.8 Gy protocol for canine ASAC seems tolerable for most cases, even in advanced disease. Theoretical dose computations serve as estimate, but are safe measures before implementing new protocols into clinical use.     

UNEXPECTED TOXICITY FOLLOWING USE OF GEMCITABINE AS A RADIOSENSITIZER IN HEAD AND NECK CARCINOMAS: A VETERINARY RADIATION THERAPY ONCOLOGY GROUP PILOT STUDY

Gemcitabine (2',2'-difluorodeoxycytidine) was given intravenously twice weekly to 10 cats with oral squamous cell carcinoma and 15 dogs with nasal carcinoma undergoing radiotherapy as a radiosensitizing agent. The average total radiation dose was 50 Gy for dogs and 54 Gy for cats given Monday-Friday (planned dose of 54 and 57 Gy, respectively). Dogs received an average of five doses of gemcitabine beginning at 50 mg/m2, and cats received an average of five doses of gemcitabine beginning at 25 mg/m2. Twelve of 15 dogs and five of 10 cats required chemotherapy dose reduction or postponement because of hematologic or normal tissue toxicity. The results herein do not support the use of gemcitabine at the studied dose and schedule, as significant hematologic and local tissue toxicity was observed in the studied patients. Pharmacokinetic data are necessary to best define the efficacy and optimal dose and schedule of gemcitabine in combination with traditional radiotherapy.     

FAILURE PATTERNS FOLLOWING COBALT IRRADIATION IN DOGS WITH NASAL CARCINOMA

The pattern of tumor recurrence was assessed in 24 dogs receiving cobalt radiation therapy for nasal carcinoma. Dogs were evaluated using nasal cavity computed tomography prior to treatment, and at 1, 3, 6 and 12 months after treatment, and at 6-month intervals thereafter if still alive. Dogs were treated with various combinations of total dose, and fraction size. Total doses were normalized to equivalent doses given in 3.0 Gy fractions. The extent of tumor regression or duration of tumor control were not dependent on absolute total dose, normalized total dose, or tumor type. The median duration of local control in all dogs was 312 days. Marked tumor regression was observed in 11 of the 24 dogs. Median duration of local control was significantly longer in dogs with marked tumor regression in comparison to dogs without tumor regression; 389 vs. 161 days respectively. When tumor recurrence was documented in dogs having tumor regression, the location of the recurrence was in the nasal cavity. No tumor recurred in a sinus or periorbital region, and only one geographic miss was detected. Tumor recurrence in the irradiated volume, including dogs with and without marked regression, was documented in 13 of the 24 dogs. The high local failure rate, coupled with the recurrence pattern in these dogs, suggests there may be an opportunity for improvement in local control through use of shrinking field techniques.