Stephen J. Withrow

Comparative aspects of osteosarcoma : dog versus man

Canine osteosarcoma bears striking resemblance to osteosarcoma in humans. Similarities include the following: male sex predilection, large patient size, 75% or more affecting the appendicular site, metaphyseal location, generally unknown etiology, less than 10% of patients have documented metastasis at presentation, over 90% of tumors show high-grade histology, 75% of tumors show aneuploidy, the metastatic rate is 80% or more with amputation alone, the lung is the most common site of metastasis, and there is improved survival with adjuvant chemotherapy. The major differences are age of onset, with dogs being affected in middle age; greater frequency in the dog, with over 8000 new cases per year; and time to metastasis being faster in the dog than man. Canine osteosarcoma is a readily available and highly comparable spontaneously occurring cancer that should be useful in a better understanding of the same disease in humans.

Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression

BackgroundPulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone.ResultsUsing parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8) and solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively). Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways.ConclusionsCollectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies.

Improved survival associated with postoperative wound infection in dogs treated with limb-salvage surgery for osteosarcoma.

BackgroundLimb-salvage surgery and adjuvant chemotherapy are performed as a treatment of appendicular osteosarcoma in dogs. Approximately 50% of dogs that undergo limb-salvage surgery develop postoperative surgical wound infections. Postoperative surgical infections may affect survival in cancer patients. The purposes of this study were to examine the effect of surgical wound infection on survival, local recurrence, and metastasis in relation to other prognostic factors for dogs with spontaneous osteosarcoma treated with limb-salvage surgery.MethodsForty-seven client-owned dogs with osteosarcoma of the distal radius were treated with limb-salvage surgery and adjuvant chemotherapy—either carboplatin or carboplatin and doxorubicin. Hazard ratios were estimated by using the Cox proportional hazard model, and survival functions were estimated by using the Kaplan-Meier product-limit life-table method.ResultsOf the 47 dogs in this study, 32 (68%) developed a postoperative wound infection. Infection, dog weight, and extent of the primary tumor (percentage of length) significantly affected survival, and infection and percentage of length significantly affected time to metastasis. None of the variables considered in this study affected local recurrence. Dogs that were diagnosed with an infection were less likely to die (hazard ratio, .446), and dogs with greater body weight and greater percentage length involvement were more likely to die (hazard ratios of 3.37 and 3.66, respectively).ConclusionsIn dogs with osteosarcoma treated with limb-salvage surgery, infection has a positive influence on survival, as does a smaller initial length of radius involved and lower body weight.

Response of aorta and branch arteries to experimental intraoperative irradiation

Injury to the aorta was evaluated in dogs 2 and 5 years after fractionated irradiation (EBRT), intraoperative irradiation (IORT) or a combination. Doses greater than 20 Gy IORT combined with 50 Gy EBRT given in 2 Gy fractions or 30 Gy IORT alone were accompanied by a significant risk of aneurysms or large thrombi as determined at necropsy 4 to 5 years following irradiation. Narrowing of the aorta as detected by aortography occurred at 5 years but was not detected earlier. The ED50 for aortic narrowing was 38.8 Gy IORT and 31 Gy IORT plus 50 Gy EBRT. The ED50 for branch artery injury was 24.8 Gy IORT alone and 19.4 Gy IORT plus 50 Gy EBRT. The difference in ED50s for IORT alone and IORT plus EBRT indicates that the contribution of the EBRT dose in terms of an IORT dose for aortic narrowing was 7.8 Gy and for branch artery injury was 5.4 Gy. The ED50 for incidence of small thrombi in the aorta was about 29 Gy for IORT alone and 23.5 Gy for IORT combined with EBRT. Fibrous thickening of the adventitia was measured and the effect of the 50 Gy EBRT component of a combination of EBRT and IORT was determined to be equivalent to 10 to 12 Gy IORT. Based on the various estimates, IORT doses of 10-15 Gy have an effect of 5 times or greater the amount given in 2 Gy fractions. At all EBRT doses and at lower IORT doses the intima was greatly thickened. At IORT doses of 20 Gy or above there was a dose related decrease in intimal thickness to near normal values. This was probably due to cell killing or inhibition of intimal proliferation that predominated at higher doses. Although the risk of serious vascular complications appears low following IORT of humans, this may be due to short observation times and the fact that IORT doses currently used are usually 20 Gy or less; this may be near the tolerance for late response of larger arteries. Only one dog in this study had complete rupture of the aorta causing death. Five other dogs at high IORT doses had near ruptures of the aorta but were clinically normal.

Intra-arterial cisplatin with or without radiation in limb-sparing for canine osteosarcoma

Methods. Forty‐nine dogs with spontaneously occurring osteosarcoma underwent limb‐sparing surgery after preoperative therapy consisting of intra‐arterial cisplatin alone or intra‐arterial cisplatin in combination with doses of radiation from 20–40 Gy in 10 fractions. All resections were marginal, and the defect was repaired with a cortical allograft.

Intraoperative irradiation of the canine abdominal aorta and vena cava

The canine abdominal aorta and vena cava were examined 6 months after single doses of intraoperatively delivered electrons (IORT), fractionated external beam X rays, or a combination. The predominant pathologic change in aortas given fractionated doses was a segmental thickening of the subendothelial region of the tunica intima which was due to fibroelastic proliferation. In severe cases, the intimal proliferation caused significant narrowing of the aortic lumen. The greatest proliferation and lumen narrowing resulted from 80 Gy given in 30 fractions, whereas 60 Gy produced little response. In contrast, IORT alone or combined with fractionated doses resulted in mild subendothelial intimal proliferation at all doses. In some aortas there was focal aortic wall thinning after IORT alone or combined with fractionated doses. This response may be explained by increased intimal cell death and lost or delayed proliferative capability caused by large single doses. These studies suggest that large single doses produce structural alterations in the walls of large blood vessels that are clinically undetectable at early post-irradiation times. If these changes progress in severity they could lead to late effects such as rupture, fissure, or aneurysm that are clinically more significant than the marked intimal proliferation and lumen narrowing changes seen after fractionated doses. The aortic cell responsible for intimal fibroelastic proliferation appears to be a pluripotential stem cell capable of producing fibrous, elastic, and possibly smooth muscle tissue. There were no significant alterations in any of the irradiated vena cavas.

Biodegradable Cisplatin Polymer in Limb-Sparing Surgery for Canine Osteosarcoma

Background: The rate of local recurrence of osteosarcoma after limb-sparing surgery in dogs and humans has been reported up to 28%. The primary purpose of this study was to determine whether a biodegradable cisplatin-containing implant (OPLA-Pt), inserted into the limb-sparing surgery site at the time of surgery, would decrease the rate of local recurrence. Secondary aims included evaluation of systemic toxicity associated with the release of cisplatin from the implant and identification of prognostic factors associated with limb-sparing surgery for osteosarcoma in dogs.Methods: Eighty dogs with spontaneously occurring osteosarcoma were treated with limb-sparing surgery. They were randomized to receive the biodegradable implant either without cisplatin (control group) or with cisplatin (OPLA-Pt group) and were targeted to receive four doses of an adjuvant cisplatin chemotherapy protocol.Results: Although this was not statistically significant (P = .071), dogs in the OPLA-Pt group were 53.5% less likely to develop local recurrence than dogs in the control group. There were no significant differences in systemic toxicity between treatment arms. Incomplete surgical resection, absence of infection, and fewer than four doses of adjuvant chemotherapy had a significant correlation with local recurrence and survival according to univariate analyses, although only incomplete surgical resection remained significant for local recurrence after multivariate analysis.Conclusions: Local tumor recurrence may be decreased after limb-sparing surgery by use of biodegradable implants impregnated with chemotherapeutic agents.

Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999–2006)

OBJECTIVE To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis. DESIGN Retrospective case series. ANIMALS 50 client-owned dogs. PROCEDURES Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications. RESULTS Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy. CONCLUSIONS AND CLINICAL RELEVANCE Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.

Multilobular Osteochondrosarcoma in 39 Dogs: 1979-1993

Thirty-nine, older, large-breed dogs with multilobular osteochondrosarcoma (MLO) each presented primarily with a fixed mass involving the flat bones of the skull. Twenty-five dogs were treated with surgical resection alone, nine were treated with adjuvant therapy, and five were not treated. Forty-seven percent of dogs treated had local tumor recurrence, and 56% had metastasis. Median time to recurrence, median time to metastasis, and median survival time were 797, 542, and 797 days, respectively. Histological grade, surgical margins, and tumor location affected outcome. Long-term remission can be obtained with aggressive treatment of MLO, although it is locally invasive and moderately metastatic.

Percent tumor necrosis as a predictor of treatment response in canine osteosarcoma

The percent tumor necrosis was determined in 200 dogs with spontaneously occurring osteosarcoma. One hundred dogs had no treatment before amputation or death. One hundred other dogs were treated with either radiation therapy alone (n = 23), intraarterial (IA) cisplatin alone (n = 16), intravenous (IV) cisplatin alone (n = 6), radiation therapy plus IA cisplatin (n = 47), or radiation therapy plus IV cisplatin (n = 8). Eighty‐nine of these 100 dogs had their tumors resected 3 weeks after the end of therapy (6 weeks after the initiation of therapy) and replaced with a cortical bone allograft. Dogs with preoperative treatment were evaluated for local tumor control and time to metastasis. The mean percent tumor necrosis in untreated osteosarcoma was 26.8%. The mean percent tumor necrosis for dogs receiving radiation only, IA cisplatin only, and IV cisplatin only was 81.6%, 49.1% and 23.8%, respectively. The mean percent tumor necrosis for dogs receiving radiation therapy plus IA cisplatin or radiation therapy plus IV cisplatin was 83.7% and 78.2%, respectively. There was no significant difference between percent tumor necrosis in untreated osteosarcoma compared with those receiving IV cisplatin, but there was a significant increase in percent tumor necrosis with all other treatments. A mathematic model for the effect of cisplatin and radiation dose was developed using multiple regression analysis. The radiation dose calculated to cause at least 80% tumor necrosis was 42.2 Gy (95% confidence interval [CI], 38.0 to 47.6 Gy) when radiation was given alone and 28.1 Gy (95% CI, 21.3 to 36.6 Gy) when radiation was combined with IA cisplatin. Areas of viable tumor tended to be most frequent adjacent to the articular cartilage and in the joint capsule. Percent tumor necrosis was strongly predictive for local tumor control; 28 of 32 dogs with greater than 80% tumor necrosis had local control, and only eight of 29 dogs with less than 79% tumor necrosis had local control (P = 0.0047). There was no correlation between percent tumor necrosis and time to metastasis.