Retrospective Analysis of Axial Skeleton Osteosarcoma in 22 Large-Breed Dogs

J Vet Intern Med 2001;15:120–124 Retrospective Analysis of Axial Skeleton Osteosarcoma in 22 Large-Breed Dogs Margaret E. Dickerson, Rodney L. Page, Tracy A. LaDue, Marlene L. Hauck, Donald E. Thrall, Martha E. Stebbins, and G. Sylvester Price Medical records of 22 large-breed dogs (⬎15 kg) with osteosarcoma (OSA) of the axial skeleton were reviewed to determine prevalence of metastasis and survival associated with this neoplasm. All dogs were treated with more than 1 mode of therapy including palliative radiation (n ⫽ 12), definitive radiation (n ⫽ 8), surgery (n ⫽ 7), chemotherapy (n ⫽ 12), or some combination of these therapies. Metastasis was documented in 10 of 22 dogs (46%), and the median survival for all dogs was 137 days. Primary cause of death was local tumor recurrence (54%). Breed (retriever versus purebred versus mixed-breed survival was 100, 182, and 264 days, respectively) and radiation therapy protocol (survival in dogs treated with palliative radiation therapy versus those treated with definitive radiation therapy was 79 and 265 days, respectively) were significantly related to survival (P ⬍ .05) Prevalence of metastasis and median survival for large-breed dogs with axial skeleton OSA seems to be similar to that reported for large-breed dogs with appendicular skeleton OSA. Definitive radiation therapy may have a role in the treatment of axial skeleton osteosarcoma. Key words: Canine; Metastasis; Radiation therapy; Retriever. T he available information on canine axial skeleton osteosarcoma (OSA) focuses on the apparent variance in clinical behavior with skeletal location of this tumor.1–7 For example, OSA of the ribs occurs in young dogs (4.5– 5.4 years) and is associated with a higher metastatic rate than OSA of other locations in the axial skeleton.1,2,5 Alternatively, patients with OSA of the mandible have a lower incidence of metastasis and longer survival than patients with OSA of all other areas of the axial skeleton.1,2,6 These few reports offer information from populations of both small- and large-breed dogs with axial skeleton OSA but provide no clear, consistent treatment recommendations for axial skeleton OSA. One report that thoroughly analyzed skeletal neoplasms in small-breed dogs (⬍15 kg) and compared them a similar population of large-breed dogs (⬎15 kg) found significant differences between these 2 populations in regard to survival, histologic type of neoplasm, age at diagnosis, and skeletal distribution of tumor.8 Small-breed dogs with axial skeleton OSA may have a better prognosis than large-breed dogs.7 Medium- and large-breed dogs are more commonly diagnosed with axial skeleton OSA than are small-breed dogs.2 However, a homogenous population of large-breed dogs with axial skeleton OSA has not been examined. Because of the deficiency of data concerning the behavior of axial skeleton OSA in large-breed dogs and treatment recommendations for this neoplasm, we chose to evaluate a group of large-breed dogs that had OSA of the axial skeleton. Our purpose was to define the prevalence of metastasis and survival associated with axial skeleton OSA in From the Departments of Companion Animal and Special Species Medicine and Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC. Previously presented as an abstract at the 18th annual meeting of the Veterinary Cancer Society in Estes Park, CO, October 1998. Reprint requests: Margaret E. Dickerson, RVT, Rollins Animal Disease Diagnostic Laboratory, 2101 Blue Ridge Road, Raleigh, NC 27607; e-mail: maggie.dickerson@ncmail.net. Submitted August 9, 1999; Revised February 29, July 13, 2000; Accepted September 22, 2000. Copyright 䉷 2001 by the American College of Veterinary Internal Medicine 0891-6640/01/1502-0006/$3.00/0 large-breed dogs. We also sought to offer reasonable treatment recommendations for dogs with this neoplasm. Additionally, any similarities between appendicular skeleton OSA and axial skeleton OSA in large-breed dogs have not been described. For this reason, we compared the prevalence of metastasis and survival associated with axial and appendicular skeleton OSA in large-breed dogs. Materials and Methods A retrospective review was conducted of medical records of dogs that presented to the North Carolina State University Veterinary Teaching Hospital (NCSU VTH) from May 1986 to May 1997. Age, sex, breed, body weight, duration of clinical signs, presence of metastasis at presentation, treatment received, date of detectable metastasis, and date and cause of death were recorded for all dogs. Only dogs ⬎15 kg with histologic confirmation of OSA of the maxilla, mandible, skull, rib, vertebrae, or pelvis that received radiation therapy, surgery, chemotherapy, or some combination of these therapies were included. Clinical staging at the time of presentation included physical exam, thoracic radiographs, CBC, chemistry panel, and imaging of the primary tumor via radiographs or computed tomography scan in all dogs. Cobalt 60 photons with either a palliative or definitive fractionation scheme were used to deliver radiation therapy. Dogs treated palliatively received 20–30 Gy, delivered in fractions of 10 Gy on a 0-, 7-, or 0-, 7-, 21-day schedule. Treatment fields were planned manually in 10 of these dogs and were computer-generated in 2. Dogs treated definitively received 45–57 Gy in 15–19 fractions of 3 Gy each. Treatment fields were planned manually in 2 of these dogs, and were computer-generated in 6. One dog was treated on a Monday-WednesdayFriday schedule with 48 Gy in 4-Gy fractions; all other dogs that received definitive therapy were treated daily, Monday through Friday. Heterogeneity of the radiation dose was calculated to be ⬍15% of the prescribed radiation dose. Surgical therapy was intended to provide complete excision of the tumor. Biopsy procedures or cytoreductive surgery were not considered definitive surgical therapy. Number of chemotherapy treatments, frequency of treatment, and agents used were recorded. Pulmonary metastases were confirmed with radiographs or postmortem examination. Soft tissue and bone metastases were confirmed with aspiration cytology or postmortem examination. Time to metastasis was defined as date of diagnosis to date of 1st detectable metastasis. Follow-up information was obtained from medical records and by telephone contact with referring veterinarians. Survival time was calculated from the date of diagnosis to the date of death. For the purpose of survival analysis by breed, Golden Retrievers and Labrador Retrievers were analyzed as 1 group. These similar breeds were combined because of the small sample size and previous jvim 15 Canine Axial Skeleton OSA reports that Golden Retrievers and Labrador Retrievers are frequently diagnosed with axial skeleton OSA.1,2 Estimates of probability for survival were determined by means of Kaplan-Meier survival curve analysis. Animals not dying by the end of the study, dying from other reasons than osteosarcoma, or lost to follow-up were censored. The log-rank statistic was used to test differences as a function of age, sex and weight (below versus above median), breed (retriever, other purebred, versus mongrels), metastasis at presentation, tumor location, type of radiation therapy (20–30 Gy versus 45–57 Gy), number of chemotherapy treatments (below versus above the median), the platinum drugs used (carboplatin versus cisplatin), and surgery and surgical margins (contained versus did not contain tumor cells). A 95% confidence interval (CI) was also calculated around the median survival time in days with censoring. A Pvalue ⬍.05 was considered significant. The statistical software package, SAS, Version 7.0,a was used for all statistical analyses. The initial metastasis prevalence, overall metastasis prevalence, and survival in dogs with axial skeleton OSA that received palliative radiation were compared to the same end points in dogs with appendicular skeleton OSA that received palliative radiation at NCSU VTH (n ⫽ 64). These 64 dogs with appendicular skeleton OSA represent a subset of 95 dogs that have been reported previously.9 Only dogs ⬎15 kg with histologic confirmation of OSA were selected for comparison. Dogs receiving palliative radiation therapy were chosen for comparison because it was a large treatment group, and palliative radiation therapy is a reasonable treatment for OSA when definitive surgery is not possible. To compare the signalment of dogs with axial skeleton OSA to dogs with appendicular skeleton OSA, Fisher’s exact test was used to compare size and age, and the Kruskal-Wallis test was used to compare age and body weight. Fisher’s exact test was used to test whether initial metastasis prevalence and overall metastasis prevalence in dogs with axial skeleton OSA differed from dogs with appendicular skeleton OSA. Kaplan-Meier estimates of survival probability and the log-rank test were used to compare survival in dogs with axial skeleton OSA to dogs with appendicular skeleton OSA. For results that were not significant but had enough animals within each comparison group, estimated sample sizes were calculated. These sample sizes estimate the number of dogs for a like data set required to demonstrate significance. This was done for critical variables only. Results Twenty-two dogs (10 males and 12 females) meeting the entrance criteria were identified. The median weight was 30 kg (range, 16.2–52.5 kg) and the median age was 9 years (range, 6.8–14 years), which was not different from those previously reported dogs with appendicular skeleton OSA. Median duration of clinical signs before presentation was 4 weeks (range, 4 days to 104 weeks). Seventeen (77%) of the dogs were purebreds, including 4 Labrador Retrievers, 3 Golden Retrievers, 3 German Shepherd Dogs, 3 Doberman Pinschers, 2 Rottweilers, 1 Afghan Hound, and 1 Bulldog. The remaining 5 (23%) were mixed-breed dogs. The majority of tumors (14/22, 64%) were located in the head and neck region. Four tumors were located in the maxilla, 3 in the mandible, 3 in the nasal cavity, 3 in the frontal sinuses, and 1 in the zygomatic arch. The remaining 8 tumors were located in the pelvis (3), vertebra (3), and rib (2). Twenty (91%) dogs received radiation therapy. Twelve dogs (60%), all with gross disease at the time of radiation therapy, were treated palliatively. Eight dogs (40%) were treated definitively; 5 of these dogs had gross disease at the time of radiation therapy. No difference was found in tumor location between dogs receiving palliative compared to de- 210 Mp 121 File # 10em 121 Fig 1. Median survival according to radiation therapy protocol: dogs treated palliatively (20–30 Gy in 10-Gy fractions), 79 days; dogs treated definitively (45–57 Gy in 3-Gy daily fractions), 265 days (P ⬍ .05). finitive radiation therapy. Twelve dogs that received palliative radiation therapy had a median survival of 79 days (95% CI ⫽ 54–144 days). The median survival for the 8 dogs that received definitive radiation therapy was 265 days (95% CI ⫽ 125–990 days). This difference in survival between palliative and definitive radiation therapy in this population was statistically significant (P ⫽ .015) (Fig 1). No difference was found between these 2 populations in regard to presence of metastasis, tumor location, or other treatment they received. Seven dogs (32%) had surgical therapy. One had evidence of complete excision, and 5 had histologic evidence of neoplastic cells at 1 or more of the surgical margins. Surgical margins for 1 dog could not be determined because the pathologist did not examine all of the surgical margins. Twelve dogs (56%) received chemotherapy. The number of treatments varied from 1 to 5 (median ⫽ 3). Chemotherapy was administered every 3 weeks, independent of surgery or radiation therapy schedules, and dosage was calculated from body weight (kg) to body surface area (m2). Seven dogs received carboplatin (200–250 mg/m2). Four dogs received cisplatin (40–70 mg/m2). One dog received both carboplatin (250 mg/m2) and adriamycin (30 mg/m2). Neither administration of chemotherapy, number of treatments administered, nor specific chemotherapeutic agent was related to survival or development of metastasis. The overall metastasis prevalence was 10 of 22 (46%). Four of the 22 dogs (18%) had radiographic or cytologic evidence of metastasis at the time of presentation. Six of the remaining 18 dogs developed metastasis after presentation. Metastases were found in the lungs (n ⫽ 5); bone (n ⫽ 3); lungs, myocardium, and lymph nodes (n ⫽ 1); and lungs and mediastinum (n ⫽ 1). Median time to metastasis, including the 4 dogs that had evidence of metastasis at presentation, was 49 days (95% CI ⫽ 0–103 days). For the 6 dogs that developed metastases after presentation, the median time to detectable metastasis was 91 days (range, 36–100 days). Median survival was 137 days (95% CI ⫽ 91–264 days). The cause of death for 12 of 22 dogs (55%) was local tumor 122 Dickerson et al Fig 2. Median survival according to breed: retriever breeds, 264 days; other purebred dogs, 182 days; mixed-breed dogs, 100 days (P ⬍ .05). recurrence. Of these 12 dogs, 5 had metastases at the time of death. Nine of the 12 dogs that died of local tumor recurrence had gross disease at the time of treatment. Four (18%) of the dogs were euthanized or died because of metastatic disease. Four (18%) of the dogs died because of nonspecific tumor-related causes. Because the description in the record was incomplete for these 4 dogs, cause of death could not be attributed to the primary tumor or metastasis. One dog died because of non–tumor-related causes; however, the OSA was stable at the time of death. One dog was still alive at last follow-up, although the current tumor status for this case is unknown. These 2 dogs were censored for the purpose of survival analysis. A relationship was found between breed and survival (P ⫽ .038). Golden Retrievers and Labrador Retrievers (n ⫽ 7) had a median survival of 100 days (95% CI ⫽ 16–130 days); whereas median survival for other purebred dogs (n ⫽ 10) and mixed-breed dogs (n ⫽ 5) was 182 days (95% CI ⫽ 91–527 days) and 264 days (95% CI ⫽ 66–990 days), respectively (Fig 2). No difference was found among these 3 populations in regard to presence of metastasis, treatment received, or location of tumor. The prevalence of metastasis at presentation for the 64 dogs with appendicular skeleton OSA treated with palliative radiation therapy at our institution was 13% (8/64) (P ⫽ .65). The overall prevalence of metastasis for this population was 26 of 64 (41%) (P ⫽ 1.00) and median survival was 130 days (95% CI ⫽ 107–178 days) (P ⫽ .25). In the 12 dogs with axial skeleton OSA treated with palliative radiation therapy, the prevalence of metastasis at presentation was 17% (2/12). The overall prevalence of metastasis for this population was 42% (5/12). The median survival was 79 days (95% CI ⫽ 54–144 days). No statistically significant difference was detected among initial metastatic prevalence, overall metastasis prevalence, and survival between the dogs with appendicular and axial skeleton OSA treated with palliative radiation therapy. Discussion These findings reveal similarities in prevalence of metastasis and survival between OSA of the axial and appen- dicular skeleton in large-breed dogs with gross disease that have not been previously reported. However, the metastatic prevalence we observed is lower than the reported metastatic prevalence for appendicular skeleton OSA.10–17 Analysis of the results of this study also suggests that definitive radiation therapy may be effective in controlling axial skeleton OSA. The only factors prognostic for outcome in dogs with axial skeleton OSA were definitive radiation therapy and breed. However, the small sample size limits the power of the comparative analyses in this study, and some prognostic factors not found to be significant in this study may prove to have prognostic importance when a larger population is examined. An example of this would be the effect on survival for chemotherapy used in conjunction with definitive radiation therapy. Unfortunately, only 8 dogs received definitive radiation therapy and 2 of these were censored, meaning only 1 of these 6 received no chemotherapy and 1 received carboplatin and the other 4 received cisplatin. No statistical analysis could be performed. The same is true for assessing the effect of surgery with definitive radiation therapy, where the statistical analysis would be comparing 2 noncensored dogs to 4 noncensored dogs. The median survival of dogs ⬎15 kg with axial skeleton OSA treated with palliative radiation therapy was similar to survival in dogs with appendicular skeleton OSA that received palliative radiation therapy. In addition, both the metastatic prevalence at presentation and the overall metastatic prevalence for both of these populations were similar. The metastatic prevalence in these dogs is lower than the 68–87% metastatic prevalence reported in dogs with appendicular skeleton OSA.10–17 This apparent disparity may be attributed to the fact that all of the dogs with axial and appendicular skeleton OSA reported here were treated palliatively, and, therefore, the cause of death was local disease.9 In contrast, the primary cause of death in dogs with appendicular skeleton OSA treated definitively with amputation and systemic chemotherapy is metastasis.10–17 Another possible explanation for the difference between the reported metastatic prevalence for appendicular skeleton OSA and the lower metastatic prevalence of the dogs reported here is attributable to the impact of primary tumor excision on metastasis. Primary tumor removal has been demonstrated to possibly increase tumor cell proliferation and therefore alter the metastatic behavior of the cancer.18 Because the number of dogs with axial skeleton OSA receiving definitive local and systemic therapy was small, we were unable to compare metastasis in these dogs to a population of dogs with appendicular skeleton OSA receiving definitive local and systemic therapy. It is encouraging that survival in large-breed dogs with axial skeleton OSA receiving definitive radiation therapy is longer than in dogs receiving palliative radiation therapy. This finding, combined with the observation of a lower metastatic prevalence in large-breed dogs with axial skeleton OSA, suggests that it may be reasonable to consider using definitive radiation therapy and systemic chemotherapy in these dogs. It may also be reasonable to speculate that such definitive treatment protocols for axial skeleton OSA in large-breed dogs may yield similar metastatic prevalence and survival to definitive treatment protocols for appendicular skeleton OSA. jvim 15 Canine Axial Skeleton OSA Only a few reports describe the use of definitive radiation therapy to treat dogs with OSA of any skeletal location.6,19–23 In these reports, less than optimal radiation sources and fractionation schemes were used. In a report published in 1975,19 18 dogs with OSA were treated with 2 fractions a week for 4 weeks. The dose per fraction was 4.57–5.67 Gy, with the use of either cobalt 60 or X rays. This protocol was based on information reported in 1972.20 Results were poor, and the authors assumed OSA to be nonresponsive to radiation therapy. However, this report does not clearly state how clinical response was measured. Also, the tumor location, disease-free interval, median survival time, and other treatment modalities were not specified. Therefore, it is somewhat speculative to conclude that this report provides adequate argument that OSA of the axial skeleton is not responsive to current definitive radiation therapy protocols. The only report found describing daily fractions of radiation therapy to treat OSA of the axial skeleton involved the use of surgery, definitive radiation therapy (total 45 Gy), and chemotherapy for 4 dogs with mandibular OSA.6 Survival data were not reported for all 4 dogs. Thirty-one dogs with appendicular skeleton OSA received 55 Gy in 3 or 4 fractions at 10- to 14-day intervals. Only a partial remission was achieved, and no dog survived more than 1 year.21 Twenty-three dogs with appendicular skeleton OSA with gross disease were treated with radiation only (36–52 Gy on a Monday-Wednesday-Friday schedule), and no influence on survival was apparent.22 The use of radiation therapy and intra-arterial cisplatin in place of amputation or limb-sparing procedures in dogs with appendicular skeleton OSA with radiation dose ranging from 24 to 40 Gy on a Monday-Wednesday-Friday schedule yielded survival comparable to that achieved from other treatments for OSA of the appendicular skeleton.23 In current clinical therapy, dogs with appendicular skeleton OSA are usually not treated definitively with radiation because of the ability to completely resect these tumors with amputation or limb sparing procedures. However, because of the obvious limitations of aggressive surgical resection of tumors of the axial skeleton, other localized therapy may be necessary to further control axial skeleton OSA. Our results are in agreement with previous reports concluding that surgery alone does not provide adequate local control for axial skeleton OSA because of the difficulty of obtaining complete excision.2,8 Five of the 7 dogs in our study had incomplete excision of their tumor, and 1 dog in which surgical margins could not be determined at the time of surgery was later documented to have tumor recurrence, confirming the suspicion that that dog’s surgical resection was also incomplete. Our results also agree with those of previous reports regarding the primary cause of death for dogs with OSA of the axial skeleton being local tumor recurrence.1–3,5,8 Most dogs with axial skeleton OSA are treated with surgery or palliative radiation therapy, with or without chemotherapy. In order to provide definitive control of the primary tumor, surgery and definitive radiation therapy should be considered. Dogs with axial skeleton OSA are often in pain at the time of presentation. Thus, cytoreductive surgery before radiation therapy may be warranted. Surgically removing the tumor before beginning definitive radiation therapy would 210 Mp 123 File # 10em 123 serve 2 purposes. First, it reduces the tumor volume to microscopic disease, and, second, it provides pain relief. The majority of dogs in our study that received definitive radiation had gross disease, yet the median survival was 265 days. Radiation therapy is thought to be more effective against microscopic disease than against bulky tumors.24,25 The median survival for dogs with axial skeleton OSA that have only microscopic disease at the time of definitive radiation therapy might be increased, but sample size limitations precluded this analysis (n ⫽ 4). Dogs in this study were not randomized to receive palliative or definitive radiation therapy. Although these treatment protocols may have been chosen with clinical bias, other potential prognostic factors such as presence of metastases, tumor location, and other treatment received did not seem to affect whether the dog received definitive or palliative radiation therapy. Based on previous reports, the specific location of the tumor in the axial skeleton may influence prognosis, response to treatment, outcome, and metastatic potential.1–3 We were unable to confirm or dispute these findings. The apparently better prognosis associated with tumors of the mandible may be attributed to their amenability to early detection and aggressive surgery. Because only 3 dogs in our study had mandibular tumors, we did not perform survival analysis based on tumor location. Similarly, only 2 dogs had rib OSA; therefore, we were unable to confirm results of previous reports concerning the metastatic potential or survival associated with OSA of the rib. In our study, mixed-breed dogs had a significantly longer median survival than purebred dogs, and the Golden Retrievers and Labrador Retrievers had the shortest median survival. Golden Retrievers and Labrador Retrievers are breeds commonly diagnosed with axial skeleton OSA,1,2 yet they have not been previously reported to have a decreased survival time relative to other breeds. This significance may represent statistical artifact; however, additional work is warranted to confirm the indication that breed may be a prognostic factor for dogs with axial skeleton OSA. Much of the analysis discussed to this point is limited by the size of the sample, especially when the axial OSA group is divided into subsets of the different treatment modalities. This is a common statistical difficulty, because this type of cancer is generally treated with a variety of multiple therapies. The available pool of patients also is limited. Most statistical tests will assume a power of 80% with an alpha of 5%, which reduce the possibility of making a conclusion of statistical significance from spurious or random results. Unfortunately, these tests require a certain sample size, which was frequently not to be found in these data. This is demonstrated in the large confidence intervals for survival times. Although it would be of clinical interest to use these data to predict what size study would need to be collected, this was not possible, both because of censoring of 2 dogs and because of the resultant size of each selected subset of dogs. Ten of 22 dogs in our study developed metastatic disease, which is similar to other reports of canine axial skeleton OSA.1–8 Therefore, chemotherapy is a rational part of any definitive treatment protocol for dogs with axial skeleton OSA. In our study, use of chemotherapy was not related to 124 Dickerson et al survival or the development of metastatic disease. This may be attributed to the inconsistency in drug administered, dose used, and treatment schedule. For dogs with appendicular skeleton OSA, chemotherapy has been shown to have a significant impact on survival after amputation of the affected limb.10–16 Based on the apparent similarities between axial and appendicular skeleton OSA, it is reasonable to expect that chemotherapy administered in accordance with standard doses and schedules would increase survival for dogs with OSA of the axial skeleton if the primary tumor is adequately controlled with surgery, definitive radiation therapy, or both. Definitive radiation therapy may have a role in the management of axial skeleton OSA where surgery alone seems to be inadequate for local tumor control. Because of the prevalence of metastasis associated with this disease, we believe chemotherapy should be included in a definitive treatment plan for axial skeleton OSA. Based on the observed similarities in behavior and response to therapy between axial and appendicular skeleton OSA in large-breed dogs, treatment of axial skeleton OSA including both aggressive local and systemic therapy may yield survival times comparable to those reported for appendicular skeleton OSA. Footnote a SAS, Version 7.0, SAS Institute, Cary, NC References 1. Hammer AS, Weeren FR, Weisbrode SE, et al. Prognostic factors in dogs with osteosarcomas of the flat or irregular bones. J Am Anim Hosp Assoc 1995;31:321–326. 2. Heyman SJ, Diefenderfer DL, Goldschmidt MH, et al. Canine axial skeleton osteosarcoma: A retrospective study of 116 cases. Vet Surg 1992;21:304–310. 3. Pirkey-Ehrhart N, Withrow SJ, Straw RC, et al. Primary rib tumors in 54 dogs. J Am Anim Hosp Assoc 1995;31:65–69. 4. Patnaik AK, Lieberman PH, Erlandson RA, et al. Canine sinonasal skeletal neoplasms: Chondrosarcomas and osteosarcomas. Vet Pathol 1984;21:475–482. 5. Feeney DA, Johnston GR, Grindem CB, et al. Malignant neoplasia of canine ribs: Clinical, radiographic, and pathologic findings. J Am Vet Med Assoc 1982;180:927–933. 6. Straw RC, Powers BE, Klausner J, et al. Canine mandibular osteosarcoma: 51 cases (1980–1992). J Am Anim Hosp Assoc 1996;32: 257–262. 7. Veterinary Cooperative Oncology Group. Retrospective study of 26 primary tumors of the osseous thoracic wall in dogs. J Am Anim Hosp Assoc 1993;29:68–72. 8. Cooley DM, Waters DJ. Skeletal neoplasms of small dogs: A retrospective study and literature review. J Am Anim Hosp Assoc 1997;33:11–23. 9. Ramirez O III, Dodge RK, Page RL, et al. 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Powers BE, Withrow SJ, Thrall DT, et al. Percent tumor necrosis as a predictor of treatment response in canine osteosarcoma. Cancer 1991;67:26–134. 23. Heidner GL, Page RL, McEntee MC, et al. Treatment of canine appendicular osteosarcoma using cobalt 60 radiation and intraarterial cisplatin. J Vet Intern Med 1991;5:313–316. 24. Fletcher GH. Basic principles of radiotherapy: Combination of irradiation and surgery. In: Fletcher GH, ed. Textbook of Radiotherapy, 3rd ed. Philadelphia, PA: Lea & Febiger; 1980:219–224. 25. Withers HR, Peters LJ. Basic principles of radiotherapy: Biologic aspects of radiation therapy. In: Fletcher GH, ed. Textbook of Radiotherapy, 3rd ed. Philadelphia, PA: Lea & Febiger; 1980:105–219.