James T. Custis

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.

Stereotactic radiation therapy for treatment of canine intracranial meningiomas.

The objective of this study is to determine the rate of toxicity, median survival time (MST) and prognostic factors in dogs with presumed intracranial meningiomas that were treated with stereotactic radiation therapy (SRT). Patient demographics, neurological history, details of SRT plans and response to treatment (including toxicity and survival times) were examined for potential prognostic factors. Overall MST (MST) due to death for any cause was 561 days. There was a mild to moderate exacerbation of neurological symptoms 3-16 weeks following SRT treatments in 11/30 (36.7%) of dogs. This presumed adverse event was treated with corticosteroids, and improvement was seen in most of these dogs. Death within 6 months of treatment as a result of worsening neurologic signs was seen in 4/30 (13.3%) of dogs. Volume of normal brain that received full dose at a prescription of 8Gy × 3 fractions was predictive of death due to neurological problems within this 6-month period.

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.

Stereotactic body radiation therapy for treatment of injection-site sarcomas in cats: 11 cases (2008–2012)

OBJECTIVE To evaluate outcomes of stereotactic body radiation therapy (SBRT) in cats with injection-site sarcomas (ISS) via assessment of local responses and recurrences, survival times, and complications. DESIGN Retrospective case series. ANIMALS 11 cats with ISS. PROCEDURES Medical records of cats that were treated with SBRT for ISS between June 2008 and July 2012 were reviewed; information on patient demographics (age, sex, and breed), oncological histories (including prior treatment and histologic grade), details of SBRT plans (tumor volume, treatment field sizes, and prescription), response to treatment (including toxicoses), progression-free intervals, and survival times were extracted. RESULTS Acute radiation-associated toxicoses were infrequent and limited to mild, self-limiting dermatitis and colitis in 2 and 1 of the 11 cats, respectively. No late radiation-associated toxicoses were observed. The objective response rate was 8 of 11 cats; these patients either had a partial or complete response as determined on the basis of CT or physical examination findings. The median progression-free interval was 242 days, and the median overall survival time was 301 days; median follow-up time of censored subjects was 173 days. CONCLUSIONS AND CLINICAL RELEVANCE SBRT was completed in 3 to 5 days and was well tolerated when used to treat cats with ISS. Measurable tumor responses were achieved in most cats in this study. Stereotactic body radiation therapy provided a means for palliation of ISS; further investigation is required to determine whether SBRT is a valid treatment option for downstaging disease prior to definitive surgery.

EVALUATION OF CANINE PROSTATE INTRAFRACTIONAL MOTION USING SERIAL CONE BEAM COMPUTED TOMOGRAPHY IMAGING

This study used kilovoltage (kV) cone beam computed tomography (CBCT) imaging to characterize canine intrafractional prostate motion during hypofractionated stereotactic radiotherapy treatment. Serial CBCT images taken just prior to initiating treatment, and at several times during the treatment session, were acquired throughout the course of treatment for canine patients. All patients were immobilized in dorsal recumbency while using an air-inflated rectal balloon. For each treatment session, rigid registration of intrafraction CBCT images with the interfraction CBCT used for setup verification was performed. Contours of the prostate and urethra were drawn on each CBCT image set and the center of mass for each structure was evaluated as a function of time. A total of seven canine patients was included in the study, resulting in 41 CBCT images collected during a total of 12 treatment sessions. Over 70% of our data were collected for CBCTs taken between 20 and 51 min after final patient setup was complete. The mean intrafraction movement in a single direction for the prostate and urethra was ≤0.14 mm and ≤0.22 mm, respectively. The maximum intrafraction movement for the prostate and urethra was ≤ 1.60 mm and ≤ 2.00 mm, respectively. The maximum variability in intrafraction movement for the prostate and urethra, as defined by two standard deviations, was ≤1.40 mm and ≤1.50 mm, respectively. Minimal intrafraction variability using appropriate patient positioning and rectal balloon, combined with kV CBCT image-guided radiation therapy tools to account for interfraction changes, permit accurate and precise targeting of structures of interest.

Advances in Veterinary Radiation Therapy Targeting Tumors and Improving Patient Comfort

Newer technology, such as intensity-modulated radiation therapy, can dramatically decrease acute radiation side effects, making patients more comfortable during and after treatment. Stereotactic radiation therapy for definitive treatment can be delivered in 1 to 5 fractions, with minimal radiation-associated effects. Image-guided radiation therapy can be used to direct treatment in locations previously not amenable to radiation therapy. Traditional fractionated radiation therapy remains the most commonly available type in veterinary medicine and is the standard of care for many tumors. This article discusses the role of advancements in the treatment of veterinary cancer patients and reviews more traditional radiation treatment.

Orthotopic model of canine osteosarcoma in athymic rats for evaluation of stereotactic radiotherapy

OBJECTIVE To develop an orthotopic model of canine osteosarcoma in athymic rats as a model for evaluating the effects of stereotactic radiotherapy (SRT) on osteosarcoma cells. ANIMALS 26 athymic nude rats. PROCEDURES 3 experiments were performed. In the first 2 experiments, rats were injected with 1 × 10(6) Abrams canine osteosarcoma cells into the proximal aspect of the tibia (n = 12) or distal aspect of the femur (6). Tumor engraftment and progression were monitored weekly via radiography, luciferase imaging, and measurement of urine pyridinoline concentration for 5 weeks and histologic evaluation after euthanasia. In the third experiment, 8 rats underwent canine osteosarcoma cell injection into the distal aspect of the femur and SRT was administered to the affected area in three 12-Gy fractions delivered on consecutive days (total radiation dose, 36 Gy). Percentage tumor necrosis and urinary pyridinoline concentrations were used to assess local tumor control. The short-term effect of SRT on skin was also evaluated. RESULTS Tumors developed in 10 of 12 tibial sites and all 14 femoral sites. Administration of SRT to rats with femoral osteosarcoma was feasible and successful. Mean tumor necrosis of 95% was achieved histologically, and minimal adverse skin effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE The orthotopic model of canine osteosarcoma in rats developed in this study was suitable for evaluating the effects of local tumor control and can be used in future studies to evaluate optimization of SRT duration, dose, and fractionation schemes. The model could also allow evaluation of other treatments in combination with SRT, such as chemotherapy or bisphosphonate, radioprotectant, or parathyroid hormone treatment.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

Abstract A22: The impact of dose reduction upon local tumor control for stereotactic radiation therapy in an orthotopic rat model of osteosarcoma

Purpose: Primary bone tumors such as osteosarcoma (OSA) are rare but devastating tumors that most commonly affect young people. For adolescents and dogs with OSA, local tumor control can be difficult to achieve with finely fractionated radiation therapy. Stereotactic radiation therapy (SRT) is a promising treatment modality that results in the delivery of ablative radiation dose to the tumor, while preferentially minimizing dose to the surrounding normal tissues. In our clinical experience with SRT in dogs, a total dose of 36Gy delivered in three fractions has been associated with excellent local tumor control based upon clinical response and histopathology of the irradiated tumor. The risk of post radiation fracture is related to pre-existing tumor associated osteolysis and the effect of irradiation upon normal bone. A previously established orthotopic rat model was used to perform a dose reduction study in an effort to optimize the SRT protocol. Methods & Materials: Twenty-four nude rats were injected with 1 x 10^6 canine osteosarcoma cells into the distal femoral metaphyses. Two weeks after tumor inoculation, rats were treated with SRT delivered once daily in three equal fractions. The tumor affected bone of six rats each were treated to a total dose of 36Gy (12Gy/fx), 33Gy (11Gy/fx), 30Gy (10Gy/fx), or 27Gy (9Gy/fx). Tumor viability and response to SRT were evaluated once weekly for six weeks via bioluminescence imaging, radiographs of the femur, and urine pyridinoline levels (PYD). Acute radiation effects of the skin were evaluated by Veterinary Radiation Therapy Oncology Group (VROTG) normal tissue toxicity scoring rubric. Post mortem histology provided an objective measure of tumor necrosis. Results: In all treatment groups, PYD levels were significantly increased two weeks after tumor inoculation (p Conclusions: All four protocols were well tolerated and associated with mild, transient skin toxicity. In canine and human osteosarcoma data, improved duration of local tumor control is correlated with tumor necrosis of 80% or higher. While there was no statistical significance between treatment groups, only the 36Gy group achieved that benchmark of tumor control. Consideration of SRT as a therapeutic option for adolescents with OSA requires further evaluation via orthotopic models. Future dose reduction studies evaluating the clinically relevant concurrent administration of carboplatin and SRT are warranted. Citation Format: James T. Custis, Anthony L. Schwartz, Joseph F. Harmon, Barbara E. Powers, Laura S. Chubb, Susan M. LaRue, Nicole P. Ehrhart, Stewart D. Ryan. The impact of dose reduction upon local tumor control for stereotactic radiation therapy in an orthotopic rat model of osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A22.