Ultrasonography of Osteosarcoma in Dogs
Sonography Atlas of Dogs

Osteosarcoma was diagnosed in 38 dogs. Thirty-six tumors originated from the appendicular skeleton
and two from the axial skeleton. Nineteen of the dogs were treated with amputation alone, and 19 were
treated with amputation and adjuvant chemotherapy consisting of doxorubicin and cisplatin. The 36
dogs with appendicular osteosarcoma had complete amputation of the affected limb, whereas the two
dogs with osteosarcoma of the axial skeleton had an en bloc resection.
The mean survival of the 19 dogs treated with amputation alone was 218 days (median, 175 days). Ten
dogs were alive at 6 months and four survived 1 year. None of the dogs survived longer than 16 months.
Radiographic lesions consistent with metastatic osteosarcoma were seen after surgery in the nine dogs
in which radiographs were taken.
The mean survival of the 19 dogs treated with amputation and chemotherapy was 415 days (median,
300 days). Drug toxicity was not observed. Fifteen dogs were alive at6months, seven dogs were alive at
1 year, 5 dogs were alive at 2 years, and two dogs were alive at 3 years or longer. One dog is alive and
well at 25 months. Radiographic lesions suggestive of metastatic osteosarcoma developed in the other
18 dogs. The 19 dogs treated with amputation and chemotherapy had significantly longer survival times
than the dogs treated with amputation alone. (Journal of Veterinary Internal Medicine 1988;
2: 177-1801

OSTEOSARCOMA is a malignant bone tumor that has been described in humans, dogs, and cats.'-3 The biologic behavior of osteosarcoma in dogs and humans appears to be similar, and the dog has been suggested as a model for the disease in human Osteosarcoma is reported to be the most common primary bone tumor in dogs, accounting for 50%to 80%
of all malignant neoplasms of bone in this A presumptive diagnosis is frequently made from clinical and radiographic signs, although surgical biopsy is necessary for a definitive diagnosis. A report of 183 dogs with osteosarcoma lists the sites of origin and frequency of occurrence as follows: femur, 37 (20.4%); humerus, 35 ( 19.5%); radius, 32 ( 19.2%);tibia, 17 (9.3%);skull, 14 (7.6%); vertebrae, 12 (6.5%); ribs, 9 (4.9%); scapula, 8 (4.4%);ulna, 8 (4.4%); coxae, 6 (3.3%);and metacarpus,
The primary treatment for osteosarcoma in the dog has been amputation of the affected limb or body part. A report of 65 historic control dogs treated with amputation alone showed that seven (10.7%)were alive 1 year after amputation. Of 46 dogs that underwent necropsy, 40 (87%)had metastatic disease, involving the lungs pnmarily. Two dogs (3%)were alive 2 years or longer after amputation.6 The high rate ofmetastasis, coupled with a poor prognosis of survival for 1 year, demonstrates the need to evaluate the use ofadjuvant chemotherapy to treat dogs with osteosarcoma after amputation. In preliminary reports, radiation therapy, chemotherapy, immunotherapy, and combinations thereof have been described.
The results of these studies have been disappointing, although interpreting the results is difficult in part, because ofsmall sample size. Thepurpose ofthis study was to evaluate the results of a clinical trial involving two groups of dogs with osteosarcoma. In one group, doxorubicin and cisplatin were used as adjuvant chemotherapy after amputation. In the other group, surgical amputation alone was performed.


Materials and Methods
From February 1982 to February 1987, osteosarcoma was identified in 38 dogs. Thirty-six had tumors of the appendicular skeleton and two had tumors of the axial skeleton. Thirty-two of the dogs were diagnosed at The Animal Medical Center and six were diagnosed at Colorado State University. Nineteen ofthe dogs were treated with amputation alone, and 19 were treated with amputation and adjuvant chemotherapy consisting of doxorubicin and cisplatin. The 36 dogs with osteosarcoma of the appendicular skeleton had a complete amputation of the affected limb. The two dogs with osteosarcoma of the axial skeleton had an en bloc resection of their tumor. Diagnosis was made by surgical biopsy in all
dogs. Tissue specimens were processed routinely, decalcified,* fixed in buffered 10% formalin, embedded in paraffin, cut at 6 pm, and stained with hematoxylin and eosin (H&E). All specimens were reviewed by one of us (A.K.P.).
Complete blood and differential counts, serum biochemical analysis, urine analysis, and modified Knott's tests for microfilaria of Dirofrlaria immitis were performed in all 38 dogs. Thoracic radiographs were taken in all 38 dogs, and radiographs ofthe affected limb were taken in the 36 dogs with osteosarcoma ofthe appendicular skeleton. A cardiac evaluation, including auscultation and pretreatment electrocardiogram (ECG), was performed in all 38 dogs.
Nineteen dogs received adjuvant chemotherapy 2 weeks after surgical removal of tumor. Doxorubicinf (30 mg/m2, intravenously [IV]) was administered on day 1 and cisplatin$ (60 mg/m2, IV) was administered on day 21. This treatment cycle was repeated in 21 days. The total cumulative dose of doxorubicin administered over the 8-week period was 60 mg/m2 in combination with a total cisplatin dose of 120 mg/m2. An ECG and complete blood count were performed before each doxorubicin treatment. Complete blood and differential counts, determination of serum urea nitrogen and creatinine concentrations, and urine analysiswere performed before each cisplatin treatment. One dog was evaluated by means of an endogenous creatinine clearance.
Doxorubicin was diluted 1:l with normal saline to achieve a final concentration of 1 mg/ml, and was administered IV over a 5-minute to 10-minuteperiod. All dogs received the antihistamine drug diphenhydramine (30 mg/m2, IV) before each administration.
Cisplatin was added to normal saline and infused IV over an 8-hour period. All dogs underwent saline diuresisg (30 ml/kg) for at least 8 hours and received mannitol (500 mg/kg, IV) as a slow infusion before each administration. Dexamethasone 1) (0.025 mg/kg, IV) and prochlorperazinelI (0.1 mg/kg, IV) also were given before cisplatin administration to prevent drug-induced emesis (Matus RE, personal observation, 1982).j 2 Saline diuresis was continued for another 8 hours after cisplatin administration.
Survival times were evaluated in 38 dogs. The disease-free interval was evaluated in 27 dogs. The diseasefree interval was measured as the time ofamputation or tumor resection to the time that radiographic evidence of metastatic disease was demonstrated. There was poor owner compliance for follow-up radiographs in the 19 dogs receiving amputation alone. Survival was measured from the time ofsurgery to the time ofdeath in all dogs. Five dogs, all treated with adjuvant chemotherapy, underwent necropsy.
Analysis of variance (ANOVA) was used to evaluate the significance of the differencebetween the mean survival times of the two groups. The distribution of data did not vary significantly from a normal distribution (P< 0.0 I), as evidenced by the Kolmogorov-Smirnov one-sample test for normality. The P test is considered robust for a one-way ANOVA in comparing differences between the means of groups of independent observations. Confidence limits were determined at 95% (P
< 0.05). Standard regression analysiswas used to evaluate the relationship between disease-free interval and survival in all dogs.

Results
The mean age of the 38 dogs was 8.9 years (median, 9 years; range, 3 to 14 years). There were 17 male dogs and 21 female dogs (56%)in the study. Thirty-five of the dogs (92%) weighed 20 kg or more. The most commonly represented breeds were Irish Setter (n = lo), Labrador Retriever (n = 4), Golden Retriever (n = 3), Old English Sheepdog (n = 2), German Shepherd (n = 2), Bull Mastiff (n = 2), Doberman Pinscher (n= 2), and Collie (n = 2). There were three mixed-breed dogs and one each of the breeds of Weimaraner, Viszla, Saint Bernard, Great Dane, Bouvier des Flandres, Standard Poodle, Cocker Spaniel, and Springer Spaniel. Six of the 32 dogs (19%) diagnosed at The Animal Medical Center were Irish Setters. In contrast, The Animal Medical Center hospital population of Irish Setters over the same time period was only 1.3%
                       Nineteen dogs (50%) had osteosarcoma involving the thoracic limb, 17 dogs (45%)had osteosarcoma involving the pelvic limb, and two dogs(5%)had osteosarcoma of a single rib. The sites oforigin and frequency ofoccurrence of osteosarcoma in the 38 dogs were as follows: femur, 9 (24%);humerus, 8 (21%);radius, 8 (21%); tibia, 7 (19%);scapula, 2 (5%); ribs, 2 (5%);ulna, 1 (2.5%);and fibula, 1 (2.5%).
Serum biochemical analysis was unremarkable except in one dog with mild azotemia (serum creatinine concentration, 2.2 mg/dl; urine specific gravity, 1.021). The results of an endogenous creatinine clearance test performed in this dog before amputation were within the normal range (endogenous creatinine concentration; 3.0k 0.5 mg/kg body weight/min). Results of hematologic testing and urinalysis were normal in all dogs before and after surgery. No cardiac abnormalities were detected. None of the 38 dogs had clinical or radiographic evidence of metastatic disease at the time of surgery.
Nineteen dogs were treated with amputation alone. All of these dogs had osteosarcoma of the appendicular skeleton. The mean survival was 218 days (median, 175 days; range, 30 to 480 days). Ten dogs (52%)were alive at 6 months and four dogs (21%)survived 1 year. None of the dogs in this group survived more than 16 months. Radiographic lesions consistent with metastatic osteosarcoma were seen after surgery in nine dogs of this group. Radiographs were not taken after surgery in the other ten dogs. Pulmonary lesions were seen in seven of the nine dogs (78%). The other two dogs (23%)had osteolytic lesions of bone compatible with metastatic osteosarcoma-in the contralateral forelimb in one dog and in the ipsilateral acetabulum and pelvis in the other dog. These two dogs did not have radiographic evidence of pulmonary metastases. The mean disease-free interval for the nine dogs was 183 days (median, 160 days; range, 30 to 360 days). Five of the nine were euthanatized at the time that the diagnosis of metastatic disease was made. Three of the four remaining dogs were euthanatized within 60 days, and one dog died of progressive disease 270 days after the diagnosis of metastatic
osteosarcoma.
Nineteen dogs were treated with a combination of doxorubicin and cisplatin after amputation or tumor resection. Seventeen of these dogs had osteosarcoma of the appendicular skeleton and two had osteosarcoma of a rib. The mean survival ofthe 19dogs in this group was 415 days (median, 300 days; range, 65 to 1320 days). Fifteen dogs (79%) were alive at 6 months, seven dogs (37%)were alive at 1 year, five dogs (26%)were alive at 2 years, and two dogs (10%) lived 3 years or longer (38 and 44 months, respectively).One dog is alive and well at 25 months, with no evidence of metastatic disease. Radiographic lesions suggestive of metastatic osteosarcoma developed in the other 18dogs in this group. Pulmonary
lesions only developed in ten dogs (56%),lesions of the bone and lungs developed in six dogs (33%),and lesions of the bone only developed in two dogs (1 1%). Hypertrophic osteopathy developed in two dogs with pulmonary lesions. The mean disease-free interval for these dogs was 330 days (median, 2 10 days; range, 60 to 1320 days). Five dogs were euthanatized at the time of diagnosis because of metastatic disease. Eight of the dogs were euthanatized within 60 days, and six of the dogs died or were euthanatized 120 to 260 days after confirmation of metastatic lesions. All deaths were directly related to progression of osteosarcoma. Metastatic pulmonary lesions developed in two of the dogs before
completion of treatment. Survival time for these two dogs was 65 and 350 days, respectively. Drug toxicities were not observed in any of the 19 dogs treated with adjuvant chemotherapy.
Necropsy was performed in five ofthe dogs that were treated with adjuvant chemotherapy. Of the five dogs, two had only pulmonary lesions, two had metastasis to the bone and lungs, and one had metastasis to the bone, lungs, kidney, and myocardium.
Results of statistical analysis indicated that the dogs treated with chemotherapy and amputation lived significantly longer (P= 0.04) than the dogs treated with amputation alone (Fig, 1). Disease-free interval, determined in 27 of the 38 dogs, was significantly related to long-term survival (P= 0.003). The disease-free intervals of the two groups could not be correlated because only nine ofthe 19 dogs not treated with chemotherapy had radiographs taken after surgery.

Discussion
The 38 dogs ofthis study had a slightly higher mean age than that reported by other investigator. This may be due, in part, to the small number ofgiant breed dogs in this study, in which osteosarcoma tends to develop at a younger age than other breeds6 The small number of giant breed dogs in our study may reflect our reluctance, and that of the owners, to accept the inherent risk of amputation in such animals. Reportedly, osteosarcoma develops more commonly in Irish Setters than in other breeds, and a disproportionately high number (19%)was seen in this study, indicating a possible breed predispo-sition.2 The male to female ratio of 0.8:1 is lower than that reported by other investigator.  The sites of tumor occurrence did not differ from those of studies reported previously.
Doxorubicin is a potent antineoplastic agent belonging to the anthracycline antibiotic class of chemotherapeutic agents. Cisplatin is a heavy metal complex containing two chloride atoms and two ammonia molecules surrounding a central platinum atom. Reviews of the actions, indications, and toxicities of these drugs in the dog are Studies in humans have demonstrated a more favorable response of patients with osteosarcoma to doxorubicin and cisplatin than to other
drugs.15 A report from the human literature on the treatment of advanced, unresectable, or metastatic osteosarcoma disclosed more responses in patients treated with combination doxorubicin/cisplatin than those treated with cisplatin alone.
The 19 dogstreated with amputation alone had longer survival times than the dogs of the classic study by Brodey.6 However, none of these dogs survived longer than 16 months, whereas 3% ofthe historic control dogs lived
2 years or longer.6 It is difficult to comment on metastatic patterns, as only nine of these 19 dogs had radiographs taken after surgery. Of interest are the two dogs in which bone lesions w'ith no radiographic evidence of pulmonary metastasis developed. Osteosarcoma in the dog has a low prevalence ofbone metastasis, and multicentric osteosarcoma is exceedingly rare. 17.18 Necropsies were not performed, so pulmonary metastases not visible radiographically could not be evaluated. Radiographic bone surveys or nuclear scans have been advocated as a more reliable way to identify metastatic osteosarcoma than thoracic radiographs alone.

The 19 dogs treated with amputation and adjuvant doxorubicin/cisplatin lived significantly longer than the 19 dogs treated with amputation alone. The long-term survival in some of the dogs treated with adjuvant chemotherapy did not change the final outcome of the disease, i.e., 18 of 19 dogs (94%) have died of metastatic osteosarcoma. However, the biologic behavior of the tumor may have been altered, as evidenced by the extremely high prevalence ofmetastasis to the bone (44%). In 65 dogs treated by amputation alone, bone metastases were seen in only 5%.6 Combination doxorubicin/
cisplatin adjuvant chemotherapy might inhibit or delay progressive pulmonary metastasis, which may allow the
expression ofbone lesions.
In a report of 14 dogs treated with amputation and single-agent chemotherapy (doxorubicin, 30 mg/m2, every 3 weeks for five treatments), results were disappointing, possibly because ofinadequate drug dosaging.' Results of preliminary studies in dogs with osteosarcoma treated with amputation or limb salvage and single-agent chemotherapy (cisplatin, 40 to 50 mg/m2 every 4 weeks for two to six treatments) are being evaluated." The results of the present study demonstrate a
synergistic response between doxorubicin and cisplatin when used as adjuvant chemotherapy following amputation for the treatment of osteosarcoma in the dog. No drug toxicity was observed. However, the methods used to monitor toxicities were probably inadequate to detect early effects, although the total cumulative doses of doxorubicin and cisplatin used in this study were probably insufficientto cause toxicity in dogs. The majority of the dogs treated with adjuvant chemotherapy have died of metastatic osteosarcoma, despite length of survival. The effect on survival and toxicity caused by more aggressive treatment protocols using higher cumulative drug dosages needs to be evaluated.

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