A retrospective analysis of stereotactic body radiation therapy for canine heart base tumors: 26 cases.

INTRODUCTION: This study retrospectively evaluated outcomes and adverse radiation effects (AREs) associated with stereotactic body radiation therapy (SBRT) for canine heart base tumors (HBTs). A secondary aim was to identify any demographic or echocardiographic factors that might determine which dogs would most benefit from SBRT. ANIMALS: Twenty-six dogs that received SBRT for an imaging-based diagnosis of a HBT were evaluated. METHODS: Twenty-three dogs were treated with three fractions of 10 Gy delivered daily or every other day. The remaining 3 dogs received variable protocols of one to five fractions. Demographic, echocardiographic, and radiographic information, AREs, and treatment responses were collected. Correlations of these data with survival time were evaluated. RESULTS: The median overall survival time was 404 days (95% confidence interval: 239-554 days). The majority of dogs experienced a partial response (25%) or stable disease (60%) for a median duration of 333 days (95% confidence interval: 94-526 days). Three dogs had progressive disease within six months of SBRT. Radiographic pneumonitis was identified in 7 of 23 dogs, and clinical pneumonitis was identified in 4 dogs. No other AREs were noted. The rate of distant metastasis was 13%. On multivariate analysis, it was found that vena caval obstruction, supraventricular and ventricular arrhythmias, clinical signs, and enlarged locoregional lymph nodes at presentation were negatively associated with survival time. CONCLUSIONS: Stereotactic body radiation therapy was delivered with a low rate and degree of normal tissue complications. Asymptomatic dogs with confirmed, progressive growth of a HBT may most likely benefit from SBRT.

Outcome of 9 dogs treated with stereotactic radiation therapy for primary or metastatic vertebral osteosarcoma.

Primary and metastatic vertebral osteosarcoma (OSA) in the dog carries an overall guarded prognosis. Previously reported definitive treatments in dogs with vertebral OSA have included surgery, radiotherapy, chemotherapy or a combination of those therapies. This retrospective study was completed to determine patterns of failure, duration of local control and survival time in dogs with vertebral OSA treated with stereotactic radiation therapy (SRT). Nine dogs were treated with SRT for vertebral OSA. Protocols ranged from 1 to 5 fractions with total prescription ranging from 13.5 to 36 Gy. Six dogs had primary lesions and 3 had metastatic lesions. Neurologic score improved in 4 patients, remained the same in 4 and worsened in 1. Five of the 6 dogs that presented with assessable spinal pain had reported improvement in pain. Overall median survival time was 139 days and median duration of pain control was 77 days. There was not a statistically significant survival difference between dogs presenting with primary or metastatic disease, or dogs that had improvement in neurologic score following SRT. The data suggests similar survival times to the previously reported definitive treatments in dogs with vertebral OSA and displays continued difficulty in controlling this tumour. The dose limiting structure is the late responding spinal cord, but many of the patients herein died prior to the expected time to development of late radiation side effects.

Predicting clinical outcome in feline oral squamous cell carcinoma: tumour initiating cells, telomeres and telomerase.

Feline oral squamous cell carcinoma (SCC) has very poor prognosis. Here, a retrospective pilot study was conducted on 20 feline oral SCC patients who underwent stereotactic radiation therapy (SRT), to evaluate: (1) the value of putative tumour initiating cell (TIC) markers of human head and neck SCC (CD44, Bmi-1); (2) telomere length (TL) specifically in putative TICs; and (3) tumour relative telomerase activity (TA). Significant inverse correlations were found between treatment outcomes and Bmi-1 expression, supporting the predictive value of Bmi-1 as a negative prognostic indicator. While TL exhibited a wide range of variability, particularly in very short fractions, many tumours possessed high levels of TA, which correlated with high levels of Bmi-1, Ki67 and EGFR. Taken together, our results imply that Bmi-1 and telomerase may represent novel therapeutic targets in feline oral SCC, as their inhibition - in combination with SRT - would be expected to have beneficial treatment outcome.

Evaluation of 18F-FDG PET/CT as a diagnostic imaging and staging tool for feline oral squamous cell carcinoma.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (18FDG-PET/CT) has been shown to be effective for staging human oral squamous cell carcinoma (SCC) but its application for cats with oral SCC is unknown. Twelve cats with biopsy-proven oral SCC were imaged with whole body 18FDG-PET/CT to determine its value as a diagnostic imaging and staging tool and fine needle aspirates were obtained of accessible regional lymph nodes. All tumors were FDG avid and conspicuous on 18FDG-PET/CT images, with an average of the maximum standardized uptake value 9.88 ± 5.33 SD (range 2.9-24.9). Soft tissue infiltrative tumors that were subtle and ill defined on CT were highly visible and more extensive on FDG-PET/CT. Tumors invading the osseous structures were more similar in extent on 18FDG-PET/CT and CT although they were more conspicuous on PET images. Three cytologically confirmed metastases were hypermetabolic on PET, while two of those metastases were equivocal on CT.

Assessment of predictive molecular variables in feline oral squamous cell carcinoma treated with stereotactic radiation therapy.

This study evaluated molecular characteristics that are potentially prognostic in cats with oral squamous cell carcinoma (SCC) that underwent stereotactic radiation therapy (SRT). Survival time (ST) and progression-free interval (PFI) were correlated with mitotic index, histopathological grades, Ki67 and epidermal growth factor receptor expressions, tumour microvascular density (MVD), and tumour oxygen tension (pO(2)). Median ST and PFI were 106 and 87 days, respectively (n = 20). Overall response rate was 38.5% with rapid improvement of clinical symptoms in many cases. Patients with higher MVD or more keratinized SCC had significantly shorter ST or PFI than patients with lower MVD or less keratinized SCC (P = 0.041 and 0.049, respectively). Females had significantly longer PFI and ST than males (P ≤ 0.016). Acute toxicities were minimal. However, treatment-related complications such as fractured mandible impacted quality of life. In conclusion, SRT alone should be considered as a palliative treatment. MVD and degree of keratinization may be useful prognostic markers.

Intensity-modulated and image-guided radiation therapy for treatment of genitourinary carcinomas in dogs.

BACKGROUND: External beam radiation therapy can be used to treat pelvic tumors in dogs, but its utility is limited by lack of efficacy data and associated late complications. HYPOTHESIS/OBJECTIVES: The objective of this study was to assess local tumor control, overall survival, and toxicosis after intensity-modulated and image-guided radiation therapy (IM/IGRT) for treatment of genitourinary carcinomas (CGUC) in dogs. ANIMALS: 21 client-owned dogs. METHODS: A retrospective study was performed. Medical records of dogs for which there was intent to treat with a course of definitive-intent IM/IGRT for CGUC between 2008 and 2011 were reviewed. Descriptive and actuarial statistics comprised the data analysis. RESULTS: Primary tumors were located in the prostate (10), urinary bladder (9), or urethra (2). The total radiation dose ranged from 54-58 Gy, delivered in 20 daily fractions. Grade 1 and 2 acute gastrointestinal toxicoses developed in 33 and 5% of dogs, respectively. Grade 1 and 2 acute genitourinary and grade 1 acute integumentary toxicoses were documented in 5, 5, and 20% of dogs, respectively. Four dogs experienced late grade 3 gastrointestinal or genitourinary toxicosis. The subjective response rate was 60%. The median event-free survival was 317 days; the overall median survival time was 654 days. Neither local tumor control nor overall survival was statistically dependent upon location of the primary tumor. CONCLUSIONS AND CLINICAL IMPORTANCE: IM/IGRT is generally well-tolerated and provides an effective option for locoregional control of CGUC. As compared with previous reports in the veterinary literature, inclusion of IM/IGRT in multimodal treatment protocols for CGUC can result in superior survival times; controlled prospective evaluation is warranted.

Correlations between numerical chromosomal aberrations in the tumor and peripheral blood in canine lymphoma.

Lymphoma is the most frequently diagnosed hematopoietic malignancy in dogs. Untreated, the survival times are approximately one month. Chemotherapy is the current standard of care and can initiate and temporarily maintain remission, with average remission times of one year. Canine lymphoma is an established model of human non-Hodgkin's lymphoma, and studying this disease in dogs can provide insight to both human and canine disease. Cytogenetic abnormalities can aid in diagnosing tumors as well as in giving a more accurate prognosis for the specific mutations present. Evaluating peripheral lymphocytes instead of tumor cells is less invasive for the affected dog and technically easier. This study was designed to investigate a correspondence between numerical aberrations detected in the tumor and the peripheral blood in dogs with lymphoma. Twenty-five dogs with lymphoma had one lymph node excised, a peripheral blood sample drawn, and a bone marrow aspirate performed. Portions of the lymph node were submitted for immunophenotyping and cytogenetic analysis. The peripheral blood sample was cultured for cytogenetic analysis and the bone marrow aspirate was used for staging purposes. A significant correspondence between the numerical aberrations in the tumor and the peripheral blood was found. The findings in this study pave the way toward an alternative method for evaluating lymphoma. When tumor analysis is not possible, the peripheral blood offers a viable option for cytogenetic assessment. Additionally, this may provide a method to evaluate the efficacy of the treatment protocol during the course of treatment.

Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas.

Tumour oxygenation was measured in seven canine soft tissue sarcomas being treated with a fractionated course of radiation and hyperthermia. Measurements obtained during treatment were compared to pre-treatment measurements. The most important finding was an increase in oxygenation in tumours with low pre-treatment oxygenation that persisted throughout treatment. This is an advantageous hyperthermia effect as it may lead to increased radiation cell killing at each fraction. In other tumours, potentially less advantageous changes in oxygenation may be hyperthermia fractionation related and this deserves further investigation.

Curative-intent radiation therapy as a treatment modality for appendicular and axial osteosarcoma: a preliminary retrospective evaluation of 14 dogs with the disease.

Canine osteosarcoma is a common bone malignancy associated with aggressive local disease and rapid metastasis. Current local therapeutic modalities do not provide curative-intent options for dogs with significant orthopaedic or neurologic disease, dogs which are denied amputation or dogs with non-resectable lesions. The goals of this retrospective study included the evaluation of local control, survival, and time to the development of metastases in 14 dogs treated with curative-intent radiation therapy and chemotherapy. Median local disease control was 202 days (79-777). Median survival was 209 days (79-781). Median time to metastasis was 314 days (7-645). No significant correlation was found between the outcome and pre-treatment alkaline phosphatase levels, radiographic appearance, tumour site, radiation dose or chemotherapeutics administered. In these dogs, full-course radiation therapy in conjunction with chemotherapy was not found to yield equivalent results to the standard of care options.

Effect of calcitonin gene related peptide vs sodium nitroprusside to increase temperature in spontaneous canine tumours during local hyperthermia.

The objectives of this study were to compare the effects of two vasodilators, sodium nitroprusside (SNP) and calcitonin gene-related peptide (CGRP) on mean arterial pressure (MAP), heart rate (HR) and temperatures in tumour and surrounding normal tissue during local hyperthermia treatment. Eleven tumour-bearing pet dogs with spontaneous soft tissue sarcomas were given SNP intravenously during local hyperthermia. The drug infusion rate was adjusted to maintain a 20% decrease in MAP. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.2 degrees C (0.0-0.4 degrees C, p = 0.02) and 0.4 degrees C (0.1-0.7 degrees C, p = 0.02), respectively, in tumour. Normal subcutaneous tissue temperatures were mildly increased but remained below the threshold for thermal injury. The effects of CGRP were investigated in six tumour-bearing dogs following a protocol similar to that used for SNP. The median (interquartile (IQ) range) decrease in mean arterial pressure was 19% (15-26%) after CGRP administration and a significant increase was seen in tumour but not normal subcutaneous tissue temperatures. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.5 degrees C (0.1-1.6 degrees C, p = 0.03) and 0.8 degrees C (0.1-1.6 degrees C, p = 0.13), respectively. Administration of SNP or CGRP did not result in local or systemic toxicity in tumour-bearing dogs. However, the magnitude of increase in tumour temperatures was not sufficient to improve the likelihood of increased response rates. Therefore, there is little justification for translation of this approach to human trials using conventional local hyperthermia.

A preliminary assessment of whole-body radiotherapy interposed within a chemotherapy protocol for canine lymphoma.

Six dogs with spontaneously occurring, previously untreated lymphoma were treated with half-body radiation therapy (RT) doses interposed in a CHOP-based 25-week chemotherapy regimen. Chemotherapy-related toxicities were as expected and were mildly increased in severity post-RT compared with pre-RT. Treatment was delayed by 1-2 weeks per delay in four dogs due to chemotherapy-related neutropenia. Radiation therapy was administered in two consecutive day fractions of 4 Gray to the cranial and caudal halves of the body 4 weeks apart. Radiation-related toxicities consisted of lethargy, alopecia, diarrhoea of less than 2-day duration and average decreases in neutrophil counts of 50%. Late effects from RT were not evident. Median remission and survival times for the six dogs were 455 and 560 days, respectively. The protocol was well tolerated and should be studied further to evaluate the potential therapeutic gain of the addition of RT to chemotherapy for the treatment of canine lymphoma.

Radiation therapy in the treatment of canine and feline thymomas: a retrospective study (1985-1999).

A retrospective study was performed of 17 dogs and seven cats with various stages of thymoma treated with radiation alone or as an adjunctive therapy. Analysis revealed an overall response rate of 75% (15/20 evaluable cases). Partial (i.e., >50% reduction in tumor size) and complete (i.e., no detectable tumor) responses were included. Complete responses were rare (4/20). Three of five animals with stable disease (i.e., <50% change in tumor size) had improvements in clinical signs, despite lack of measurable response. A median survival time of 248 days (range, 93 to 1,657+ days) was achieved in dogs, and a median survival time of 720 days (range, 485 to 1,825+ days) was achieved in cats. Radiation therapy appears to be useful in the management of invasive thymomas in dogs and cats.

Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000).

OBJECTIVE: To compare use of doxorubicin, surgery, and radiation versus surgery and radiation alone for treatment of cats with vaccine-associated sarcoma. DESIGN: Retrospective study. ANIMALS: 25 cats with vaccine-associated sarcomas. PROCEDURE: Time to first recurrence and survival time were compared between the 2 treatment groups. The number of surgeries (1 or > 1) were compared with respect to time to first recurrence and survival time. RESULTS: Median time to first recurrence was 661 days for the group that received doxorubicin, surgery, and radiation. Median time to first recurrence has not yet been attained for the group treated with surgery and radiation alone. Median survival time was 674 days for the group treated with doxorubicin, surgery, and radiation and 842 days for the group treated with surgery and radiation alone. For time to first recurrence and survival time, significant differences were not detected between cats that had 1 surgery and those that had > 1 surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Significant differences between the 2 treatment groups were not detected. The efficacy of doxorubicin in the treatment of vaccine-associated sarcomas is uncertain.

Response of feline oral squamous cell carcinoma to palliative radiation therapy.

Seven cats with advanced oral squamous cell carcinoma were treated with palliative radiotherapy. Megavoltage radiation in 8 Gray (Gy) fractions was delivered on days 0, 7, and 21 for a total dose of 24 Gy. Treatment field included the mandible, oropharynx, retropharyngeal lymph nodes, and tonsils. Adjuvant treatment with chemotherapy was variable. Age ranged from 13 to 18 years old with a median age of 15 years. Three of the seven cats (43%) did not complete treatment. Six cats were euthanized due to tumor growth and/or radiation side effects with a median survival time of 60 days (range = 42 to 97 days, mean = 63 +/- 8.4 days). Radiotherapy complications or progression of disease occurred in 6 of 7 (85.7 %) cats and included adverse clinical signs, such as mucositis, serosanguinous oral discharge, pain, and dysphagia. These data suggest that coarse fractionation radiotherapy did not result in palliation in cats with inoperable oral squamous cell carcinoma.

Using units of CEM 43 degrees C T90, local hyperthermia thermal dose can be delivered as prescribed.

A randomized study was designed in dogs with spontaneous soft tissue sarcomas to gain information about the relationship between hyperthermia dose and outcome. The study compared two levels of thermal dose applied to dogs with heatable tumours, so it was necessary to deliver either a low (2-5 CEM 43 degrees C T90) or high (20-50 CEM 43 degrees C T90) thermal dose as precisely as possible. It was also desirable to have similar numbers of hyperthermia treatments in each thermal dose group. Identification of heatable tumours and randomization to high or low heat dose group was done during the first hyperthermia treatment. This was readily accomplished using mapping of temperatures in thermometry catheters, manual recording of thermal data, and visual inspection of raw thermal data with subsequent adjustment of the duration of the hyperthermia treatment. An analysis of precision of thermal dose delivery was conducted after approximately 50% of projected accrual had been met in a randomized phase III assessment of thermal dose effect. Fifty-four dogs were eligible for randomization; in 48 dogs the tumour was deemed heatable according to predetermined temperature criteria applied during the first heat treatment. Twenty-four dogs were randomized to the high heat dose group, and 24 to the low heat dose group. Median (range) total thermal dose for dogs in the high dose group was 43.5 CEM 43 degrees C T90 (16.4-66.6) compared to 3.2 CEM 43 degrees C T90 (2.1-4.6) for dogs in the low dose group. There was no overlap of thermal doses between groups. Thus, thermal dose could be delivered accurately, being within the predetermined range in 47 of the 48 dogs. Thermal dose quantified as CEM 43 degrees C T50, however, did overlap between groups and the clinical significance of this finding will not be known until outcome data are analysed. Most dogs in both groups received five hyperthermia treatments. Median (range) treatment duration for dogs in the high dose group was 300 min (147-692) compared to III min (51-381) for dogs in the low dose group. Relatively simple but accurate methods of delivering prescribed thermal dose as described herein will aid the translation of clinical hyperthermia from the research setting into more general practice once the characteristics of the relationship between hyperthermia dose and outcome are understood.

Outcome following treatment of vertebral tumors in 20 dogs (1986-1995).

Twenty dogs with histopathologically confirmed primary (n=15) or metastatic (n=5) osteosarcoma (n=14) or fibrosarcoma (n=6) of the vertebral column were treated with surgery (n=4), radiation therapy and chemotherapy (n=6), surgery and chemotherapy (n=2), or surgery, radiation, and chemotherapy (n=8). All dogs died due to their disease; 15 died due to local failure, and five died due to nonvertebral metastasis. Overall median survival time was 135 days, with a range of 15 to 600 days. Of the factors evaluated, only postoperative neurological status had a significant influence on outcome by multivariate analysis. This study supports the overall guarded prognosis for dogs with vertebral neoplasia. Better combinations of surgery, chemotherapy, and radiation therapy remain to be defined for this difficult subset of animal cancer.

Tumour cell kinetics as predictors of response in canine lymphoma treated with chemotherapy alone or combined with whole body hyperthermia.

Kinetic parameters including potential doubling time (Tpot), duration of S phase (Ts), labelling index (LI), and DNA index (DI) were obtained from 42 dogs with previously untreated lymphoma. Standard flow cytometric techniques using BrdUrd were employed. All dogs were treated with L-asparaginase and remission was induced in 26 dogs, which were then randomized to receive chemotherapy only (doxorubicin [DOX] alone or with lonidamine) or chemotherapy plus whole body hyperthermia (WBH). Dogs were treated every 3 weeks for up to five treatments and evaluated every 3 weeks for evidence of tumour recurrence. Within this subset of animals there was no difference in outcome based on treatment group. Median values for Tpot, Ts and LI were 3.4 days, 7.23 h and 12.49%, respectively. Dogs that had tumours with LI > or = 20% had a shorter time until recurrence than dogs with tumours characterized by LI < 20%. In dogs treated only with chemotherapy, dogs bearing tumours with longer than median Tpot and Ts values and lower than median LI had significantly longer remission duration than dogs with more rapidly proliferating tumours. Dogs treated only with chemotherapy, which had longer than median Tpot and Ts values and lower than median LI, had significantly longer remission duration than all other dogs in the study. The mechanisms in which kinetics are associated with response to chemotherapy are not clear and vary depending on tumour type and treatment regimen. More work is needed to understand factors involved in cell killing during in vivo hyperthermia.

Use of whole body hyperthermia as a method to heat inaccessible tumours uniformly: a phase III trial in canine brain masses.

In this study, whole body hyperthermia (WBH) was assessed as a means of heating intracranial tumours uniformly. Twenty-five dogs received radiation therapy and 20 the combination of radiation and WBH. Total radiation dose was randomly assigned and was either 44, 48, 52, 56 or 60 Gy. Because of WBH toxicity, intercurrent disease or tumour progression, seven of the 45 dogs received less than the prescribed radiation dose. For WBH, the target rectal temperature was 42 degrees C for 2h and three treatments were planned. In five of the 20 dogs randomized to receive WBH, only one WBH treatment was given because of toxicity. WBH toxicity was severe in six dogs, and resulted in death or interruption in treatment. Most tumours did not undergo a complete response, making it impossible to differentiate tumour recurrence from brain necrosis as a cause of progressive neuropathy. Therefore, survival was the major study endpoint. There was no survival difference between groups. One-year survival probability (95% CI) for dogs receiving radiation therapy alone was 0.44 (0.25, 0.63) versus 0.40 (0.19, 0.63) for dogs receiving radiation and WBH. There was no difference in the incidence of brain necrosis in the two treatment groups. Results suggest that use of WBH alone to increase the temperature of intracranial tumours as a means to improve radiation therapy outcome is not a successful strategy.

Effects of volume irradiated on the function of the canine ureter.

This study was designed to investigate the influence of the volume irradiated on the probability of ureteral complications and to provide data for volume modeling. One hundred thirty-four purpose-bred beagle dogs received single intraoperative doses of 6 MeV electrons ranging from 12 to 54 Gy to three lengths of ureter: 2, 4 or 8 cm. The response was evaluated by excretory urography. The ED50 was 21.9 Gy (95% CI 13.3-30 Gy) for 8 cm 3 years after treatment. The estimated ED50's were greater than 43 Gy for 4 cm and 85 Gy for 2 cm. Reducing the length of ureter irradiated from 8 cm to 4 cm increased the ED50 for ureteral dilation by at least a factor of 2, while reduction from 8 cm to 2 cm increased the ED50 by at least a factor of 4. The ED50 for renal injury secondary to stenosis was 30.5 Gy (95% CI 17.2-232 Gy) when an 8-cm field was irradiated. There was a significant effect of volume irradiated on the frequency of ureteral stenosis. Reducing the length of ureter included in the treatment field should allow delivery of higher doses to tumors without increased complications.

Principles of adjunctive radiation therapy.

Radiation therapy is becoming increasingly available to the practicing veterinarian. It is important that veterinarians be familiar with mechanisms and biologic effects of radiation used as a therapeutic modality in the treatment of cancer. It is also important that the veterinarian understand oncologic decision making and indications for various modalities including radiation therapy, surgery, and chemotherapy. Surgery and radiation therapy can be particularly complementary in combined therapy to achieve a functional and cosmetic result. This review introduces basic radiation therapy concepts, particularly regarding combination of radiation and surgery in the treatment of cancer in animals.