REIRRADIATION OF RECURRENT CANINE NASAL TUMORS

Canine nasal tumors are typically treated with radiation therapy but most patients develop local recurrence. Our purpose was to evaluate tumor and normal tissue response to reirradiation in nine dogs. The median dose delivered with the first protocol was 50 Gy (range 44–55 Gy) and the median fraction number was 18 (range 15–20). For the second protocol, the median dose was lower intentionally, median of 36 Gy (range 23–44 Gy), without changing the median fraction number of 18 (range 14–20) to avoid late effects. The median time between protocols was 539 days (range 258–1652 days). Median survival was 927 days (95% confidence interval [CI] 423–1767 days). Median time to progression following the first and second courses was 513 days (95% CI 234–1180 days) and 282 days (95% CI 130–453 days), respectively. These were not significantly different (P=0.086). The qualitative response assessment was better for the first course compared with the second (P=0.018). Severity and timing of skin, mucous membrane, and ocular effects were similar for early side effects between the two courses (P>0.05 for all comparisons). All dogs experienced some late side effects, with two out of nine being classified as severe. These severe effects were blindness in each dog, possibly related to tumor recurrence. Reirradiation of canine nasal tumors resulted in a second clinical remission in eight of nine dogs, although the second response was less complete. Acute and late effects for seven of nine patients were not life threatening, indicating that reirradiation of canine nasal tumors may be a viable treatment option after recurrence.     

A COMPARISON OF RADIOGRAPHIC AND COMPUTED TOMOGRAPHIC FINDINGS IN 31 DOGS WITH MALIGNANT NASAL CAVITY TUMORS

Nasal cavity radiographs and CT images from 31 dogs with nasal cavity cancer were compared. All dogs had abnormal clinical signs relating to -nasal cancer and histologic confirmation of malignant nasal cavity neoplasia. No dog had cyto reductive surgery prior to imaging. All radiographic and CT examinations were abnormal. CT was more accurate than radiographs in identifying unilateral versus bilateral nasal cavity disease and tumor extension into adjacent structures such as the cranial cavity, hard palate, and pterygopala-tine fossa. The improved accuracy of CT in these respects was not of benefit in the confirmation of nasal cavity disease because radiographs were abnormal in every instance. However, CT may be useful for more accurate tumor staging, predicting possible treatment-related complications, and planning of surgery and radiation therapy. It was also determined that one dorsally located radiation therapy portal bounded laterally by the medial ocular canthi, as described in previous reports, would not have been adequate for encompassing all abnormal tissue in 28 of the 31 dogs evaluated.     

FACTORS INFLUENCING SURVIVAL AFTER RADIOTHERAPY OF NASAL TUMORS IN 130 DOGS

Improvements in survival of dogs with nasal tumors have been slow to develop throughout the past three decades. Despite multiple studies examining various radiation time-dose schema, the advancement of CT-based computerized treatment planning, and the evaluation of detailed staging systems, the optimal treatment regimen, and most important prognostic factors regarding survival remain unclear. In this study, data from four previous studies were combined with data from 44 additional dogs, and this population of 130 dogs was evaluated for factors which influenced survival. Twenty-one dogs were treated with orthovoltage at the University of Pennsylvania. One hundred nine dogs were treated with cobalt photons at North Carolina State University. Sixty-five of these 109 dogs had been previously described. Of the 44 dogs not previously described, 35 were treated with a shrinking field technique. Survival was determined from the medical record, or from information derived by telephone or mail survey. The univariate Cox regression model was used to examine for relationship between various patient, tumor, and treatment variables and survival. Significant relationships identified in the univariate analysis were further analyzed using the multivariate Cox regression model. Median survival of the 130 dogs was 8.9 months (95% C.I., 8-11 months). In the univariate analysis, the following variables were associated with decreased survival: 1) age >10 years old, 2) regional lymph node metastasis, 3) advanced tumor stage, 4) use of megavoltage radiation, 5) overall total dose >55 Gray, and 6) boost technique performed. In a multivariate analysis of 125 dogs with complete data for age, radiation type, and radiation dose, age (p < .001) and radiation type (p = .02) were identified as joint predictors of survival. After adjusting for age, the staging system lost prognostic significance (p = .06). In a subset of dogs that received cobalt radiation, after adjusting for age, dogs treated with a boost technique had decreased survival (p = .001). In general, local control of canine nasal tumors following aggressive radiation therapy is poor. Early diagnosis and selection of appropriate patients is warranted and palliative types of treatment should be considered in dogs with a poor chance of long term survival.     

A COMPARISON OF NORMAL TISSUE COMPLICATION PROBABILITY OF BRAIN FOR PROTON AND PHOTON THERAPY OF CANINE NASAL TUMORS

This study compared the calculated normal tissue complication probability of brain in dogs with a nasal tumor, which had both photon and proton treatment planning. Nine dogs diagnosed with a variety of histologies, but all with large, caudally located nasal tumors were studied. Three-dimensional (3-D) photon dose distribution, and a proton dose distribution was calculated for each dog. To calculate the normal tissue complication probability (NTCP) for brain, the partial brain volume irradiated with the prescribed dose was determined, then a mathematic model relating complications to partial volume and radiation dose was used. The NTCP was always smaller for proton plans as compared to photon plans, indicating conformation of the dose to the target allows a higher dose to be given. If a 5% NTCP were accepted, the mean applicable dose for this group of dogs was 50.2 Gy for photons, but 58.3 Gy for protons. Not all dogs would benefit the same from proton irradiation. If a large partial brain volume has to be irradiated, the advantage becomes minimal. There is also a minimal advantage if the planning target volume (PTV) includes a small, superficial brain volume. However, for a complex PTV shape the degree of conformation is clearly superior for protons and results in smaller calculated NTCPs.     

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.     

USE OF RADIATION AND A SLOW-RELEASE CISPLATIN FORMULATION FOR TREATMENT OF CANINE NASAL TUMORS

The purpose of this study was to evaluate the combined use of radiation and a slow-release cisplatin chemotherapy formulation for treatment of malignant nasal tumors in dogs. In this retrospective analysis, 51 dogs were evaluated with respect to treatment toxicity, tumor type, stage of disease, cribriform plate involvement, and overall survival. In general, treatment was well tolerated. Mean and median survival as assessed by the Kaplan-Meier product limit method was 570 and 474 days, respectively. No other factors, including tumor type, stage of disease, or cribriform plate invasion had a significant impact on survival. In conclusion, a combination of slow release cisplatin chemotherapy and radiation for the treatment of canine nasal tumors is well tolerated. Results of this analysis warrant further study to elucidate possible other beneficial radiation potentiating drugs and dosing schedules.     

SLOW RELEASE CISPLATIN COMBINED WITH RADIATION FOR THE TREATMENT OF CANINE NASAL TUMORS

Thirteen dogs with malignant tumors of the nasal cavity were treated with a combination of slow release cisplatin and megavoltage radiation. Radiation was delivered on a Monday through Friday schedule using a 6 MV linear accelerator. The median total dose was 49.5 Gy (range 49.5-56 Gy). Cisplatin was given using an open-cell polylactic acid polymer, impregnated with the drug and implanted intramus-cularly at a distant site, as a slow release delivery system (OPLAn-Pt [THM Biomedical, Inc]). The median dose used was 60 mg/m2 (range 60–100 mg/m2). When combined with radiation, this delivery system caused no systemic drug toxicity, and a local tissue reaction was seen in only two dogs. Acute side effects to normal tissue from radiation were not enhanced, as measured by subjective assessment. When compared to a group of historical controls that received radiation without OPLA-Pt, the dogs that received combined radiation and cisplatin had longer overall survival times, with a median of 580 days. The control group had a median survival of 325 days. Previously reported median survival times for comparable megavoltage radiation treatment range from 6 to 13 months. Some dogs in both groups also received adjubant chemotherapy but this did not influence survival time. By multivariate analysis, only the use of OPLA-Pt was found to significantly influence survival, with a p value of p = 0.023. Mega-voltage radiation and slow release cisplatin appears to be a well tolerated combination that may favorably affect survival of dogs with nasal tumors.     

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.     

DOSIMETRIC IMPACT OF DAILY SETUP VARIATIONS DURING TREATMENT OF CANINE NASAL TUMORS USING INTENSITY-MODULATED RADIATION THERAPY

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0–10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9±3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain.     

ORTHOVOLTAGE RADIOTHERAPY OF CANINE TRANSMISSIBLE VENEREAL TUMORS

Eighteen dogs with transmissible venereal tumors were treated with orthovoltage radiotherapy. Total radiation doses ranged from 10 to 30 Gy, given during periods of one to 34 days. Tumor cure, defined as lack of recurrence within one year after completion of radiotherapy, was observed in all 18 dogs. In seven of eight dogs, tumors were cured with a single dose of 10 Gy. The tumor that recurred after the single 10 Gy dose had been treated with chemotherapy prior to radiotherapy and was subsequently cured with additional radiotherapy. Data presented indicate that transmissible venereal tumors are radiocurable and that a single dose of 10 Gy is sufficient for cure in most dogs.     

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.     

RADIOTHERAPY OF SQUAMOUS CELL CARCINOMAS OF THE CANINE NASAL PLANE

Squamous cell carcinoma of the nasal plane in eight dogs was treated with radiotherapy. Radiotherapy failed to control the tumor in each dog. Mean time until treatment failure was apparent was 2.9 months. Squamous cell carcinoma of the nasal plane in dogs appears to respond more poorly to radiotherapy than does squamous cell carcinoma of the gingiva.     

MR, CT AND CLINICAL FEATURES FROM FOUR DOGS WITH NASAL TUMORS INVOLVING THE ROSTRAL CEREBRUM

The clinical findings and computed tomographic and magnetic resonance images from four dogs with nasal tumors that invaded the central nervous system were revlewed. There were minimal or no clinical signs related to nasal disease. Brain imaging with magnetic resonance or computed tomography demonstrated antemortem involvement of brain and nasal structures. Magnetic resonance imaging was optimal for demonstrating this involvement and showed more detailed anatomic features of the mass and secondary pathologies attributed to the mass.     

COMPUTED TOMOGRAPHY OF THE NORMAL FELINE NASAL CAVITY AND PARANASAL SINUSES

Computed tomography (CT) images of the feline nasal cavity and paranasal were acquiredfrom noraml adult cats. Good resolutin and amatomic detail were obtained from the CT images using soft tissue formatting. A desciption of normal feline nasal cavity and paranasal sinus anatomy using CT is presented.     

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 NINE-DAY ACCELERATED RADIATION PROTOCOL FOR FELINE SQUAMOUS CELL CARCINOMA

Nine cats with oral squamous cell carcinoma were treated with an accelerated radiation protocol (14 fractions of 3.5 Gy in 9 days). Radiation was administered twice daily with a 6hour break between treatments. Median overall survival was 86 +/- 110 days. Median survival for cats with a partial response (n=6) was 60 +/- 7 days, while median survival for cats with a complete response (n=3) was 298 +/- 187 days (P = 0.0639). The accelerated protocol was well tolerated and toxicity in the early and late period was manageable in all cats. Further modification of the protocol is warranted to extend survival.     

AN ACCELERATED TECHNIQUE FOR IRRADIATION OF MALIGNANT CANINE NASAL AND PARANASAL SINUS TUMORS

Tumor and normal tissue response was assessed in 21 dogs with malignant nasal tumors given 42 Gy cobalt radiation in 9 or 10 fractions over 11 to 13 days. Local tumor/clinical relapse recurred in 68% of dogs, with a median relapse free interval (RFI) of 270 days. Median survival was 428 days. One year survival for all dogs was 60%. RFI and survival times are better than, or similar to, previous reports of dogs treated with radiotherapy only. Acute radiation effects were severe in one dog. Late effects were severe in six of 15 dogs (40%) with durable tumor control. Late effects included bilateral blindness (3), osteoradionecrosis (3), and seizures (1). These six dogs had a median survival of 705 days. Loss of vision occurred in at least one eye in nine dogs (47%). Tumor staging based on CT findings were predictive for survival duration. Tumor histology was not predictive of outcome. Labrador Retrievers were significantly over-represented. Despite comparable or improved tumor control and survival times provided by this accelerated protocol, relative to other radiotherapy reports, local failure remains the major cause of death, and late radiation effects can be severe in dogs with durable tumor control.     

COMPUTED TOMOGRAPHIC EVALUATION OF ANATOMIC AND PATHOLOGIC VARIATIONS IN THE FELINE NASAL SEPTUM AND PARANASAL SINUSES

The purpose of this study was to compare the prevalence of nasal septal deviation and variations of the paranasal sinuses in normal and diseased cats. Prevalence of nasal septal deviation was 86.7%, 68.4%, and 71.4% in cats with rhinitis, neoplasia, and normal cats, respectively, with no statistically significant difference (P = 0.244). There was a statistically significant difference (P = 0.01) in the magnitude of nasal septal deviation between cats with and cats without nasal disease, using a cutoff value of 1 mm for maximum distance of deviation from midline. There was a statistically significant difference (P = 0.019) between cats with rhinitis and neoplasia when comparing the presence of a mass (7.7% and 53.8%, respectively), but not when comparing for lysis of the septum. Deviation of the frontal sinus septum occurred in 27.7% of all cats, while the sphenoid septum was oblique and eccentric in 96.6% of all cats. The mean length of the frontal sinus was longer in male cats than female cats. The presence of nasal septal deviation alone cannot be used as a criterion to diagnose nasal disease, but cats with rhinitis or neoplasia have more marked deviation than normal cats. The presence of a mass and lysis of the septum were only seen in cats with nasal disease and a mass is more likely to be seen with neoplasia than rhinitis. Male cats have a longer frontal sinus than female cats. Almost all cats have an oblique, eccentric sphenoid septum.