Rowan J. Milner, BVSc (Hons), MMedVet (Med), DECVIM,
Neoplasia of the skeleton occurs in all species, although the dog has a higher incidence (6.5 in 100,000) than other domestic species and man. Primary skeletal neoplasia makes up 80% of these cases in the dog and is rarely cured. A biphasic incidence of osteosarcoma occurs in large breeds of dogs with a peak at 18 to 24 months and in older dogs a median of 7 years. Osteosarcoma in the dog has a predilection for the appendicular skeleton with the majority of tumors occurring in the metaphyseal area (75%). Treatment of osteosarcoma in the dog involves a multi-modality approach. Amputation of the effected limb has been reported to give a mean survival time of 19.8 weeks with 11.5% alive at one year and 2% at 2 years. Currently the gold standard appears to be amputation or limb-sparing together with chemotherapy. This review will discuss non-surgical treatment of canine osteosarcoma.
Osteosarcoma was previously thought to be a radiation-resistant tumor, however a recent report indicates that together with chemotherapy radiation can be used as an effective method for local control. The first reports explored the use of cobalt 60 radiation and intra-arterial cisplatin without amputation. Their reported survival times were a median of 34.3 weeks. When dogs with metastases were excluded, median survival was 46.9 weeks. This is comparable with amputation and chemotherapy. A more recent report using palliative (fractionated) radiation therapy (RT) and chemotherapy, give a median survival time of 17 weeks, however the radiation dose was less (10 Gy on days 0, 7 and 21). In a more recent report, improved survivals were found when the number of fractionated doses (10 Gy) was increased from 3 to 4 treatments. A more intense fractionation protocol has been tried using between 18 and 22 treatments (18-22 anesthetics) to achieve a total dose of 48-57 Gy, but results were equivocal.
A newer development is stereotactic radiosurgery (SRS). SRS has the advantage of being able to deliver a single, large fraction of radiation via multiple stereotactically targeted, arced fields. Radiosurgery relies on extreme accuracy of dose delivery to the tumor, delivering only a small fraction of the dose to normal tissues just millimeters away, thus reducing side effects in normal tissue but delivering a significant radiation dose. The next speaker, Dr Farese, will discuss this form of radiation delivery in the limbs of dogs and will not be discussed in detail in this review. Apart from the appendicular skeleton, SRS has also been used to treat nasal osteosarcomas at the University of Florida. Unfortunately the median survival times were shorter compared to other tumors treated with this modality. The efficacy of SRS for nasal osteosarcoma is limited by the radiation dose that can be given safely to the nose and surrounding structures when compared to other areas. This restricts its application to smaller osteosarcomas in the center of the nasal cavity.
Targeted Radiotherapy with Radiopharmaceuticals
Radioisotopes offer a unique method of radiation delivery when combined with ligands. Ligands function as targeting agents which allow selective targeting of cancers for radiation dose delivery by the radioisotope. Collectively these agents are then known as radiopharmaceuticals. One the most commonly reported therapeutic radiopharmaceutical is Samarium (Sm)-153-lexidronam (EDTMP).6 Samarium153 is the radioisotope which delivers a radiation dose to the target by beta decay (beta-emitter) and has the added property of gamma decay, i.e., the distribution of the radioisotope can be monitored using a gamma camera. The ligand lexidronam (EDTMP) is an amino-bisphosphonate which like the bone scan agent MDP (labeled with Tc-99m) localizes in areas of increased bone metabolism. This agent is not only selective for the cancer but will localize in areas with red marrow activity.
The first report of the radioisotope, Samarium-153-lexidronam (EDTMP), to treat canine bone tumors was by Latimer et al.7,8 He treated forty dogs with naturally occurring osteosarcoma. Dogs were randomized to receive either a single dose of 37 MBq/kg or two doses a week apart. No significant differences were found between the two groups and early tumors and metastatic lesions appeared to show some response.
In a report by Moe et al9 Sm-153-EDTMP was used to treat an osteosarcoma of the maxilla together with surgical debulking, results were considered good. Straw et al10 reported the use of Sm-153-EDTMP in two dogs with mandibular osteosarcoma, one dog was lost to follow up at 41 months and the other dog died of renal failure at 6.9 months with recurrence of the tumor at the primary local site. In a larger study Milner et al.11 treated 10 dogs with osteosarcoma. A single dog had a dramatic response to therapy, but all the other cases showed progression of the osteosarcoma. In 1999, Aas et al12 treated fifteen dogs with Sm-153-EDTMP. Dogs were given between one and four doses of Sm-153-EDTMP at 36-57 MBq/kg. Their conclusions were that a favorable high tumor dose, was achieved in the tumor compared to surrounding tissue and that pain relief and in some cases, tumor growth was delayed. At necropsy a number were found to have metastases. No serious side effects were observed. A report comparing Sm-153-EDTMP and Strontium (Sr)-89 distribution in canine osteosarcoma bone found a more uniform distribution for Sr-89 in the cancer and a lower radiation dose to bone marrow.13
More recently, Barnard et al reported 35 dogs receiving Sm-153-EDTMP.14 Of the 32 dogs with appendicular tumors, 20 (63%) had an improvement in the severity of lameness 2 weeks after administration of the first dose of radioactive samarium, 8 (25%) had no change in the severity of lameness, and 4 (12%) had a worsening. Overall median survival time was 100 days, with 3 dogs (8.6%) alive after 1 year. Median survival time for the 32 dogs with appendicular tumors was 93 days, with 3 (9.4%) alive after 1 year. This was not significantly different from the median survival time of 134 days for a historical cohort of 162 dogs with appendicular osteosarcoma that underwent amputation as the only treatment.
Not surprisingly, because of red marrow localization, the primary complication of Sm-153-EDTMP treatment is myelotoxicity.7,11 Myelotoxicity occurs approximately 2 week after treatment and remains hematologically evident for 2 to 3 weeks. Renal toxicity appears not to be significant even though Sm-153-EDTMP, in common with other bisphosphonates, is cleared by the kidneys.15 Acute radiation nephritis is thought to occur only after exposure to radiation of more than 1,000 cGy.16 Lattimer et al 7 did not report renal toxicity.
Cisplatin, used either alone or in combination with doxorubicin (Adriamycin), has improved survival of dogs with osteosarcoma.17 It is recommended that adjuvant chemotherapy be administered as close to the time of surgery as possible, however it is still unknown if chemotherapy given early has any benefit on survival.18 On average, five doses of cisplatin at 70mg/m2 is administered every 3 weeks together with amputation or limb sparing. This protocol gives a median survival of 392 days, with a 1-year survival rate of 52 percent and a 2-year survival of 31 percent. Saline diuresis is vital in preventing nephrotoxicity with cisplatin. Nephrotoxicity is the dose-limiting toxicity in dogs. Carboplatin a less nephrotoxic drug than cisplatin; when used with appendicular OSA and amputation four doses of carboplatin gave a median survival of 321 days, and 35.4 percent of dogs alive at 1 year.19,20 The advantage with carboplatin is that it can be given intravenously without the saline diuresis. Carboplatin is given at 300mg/m2 together with amputation every 21 days. Toxicity is associated with myelosuppression however, the maximum tolerated cumulative dose has not been described. A number of reports using cisplatin combined with doxorubicin seem to have improved results.17 The most effective protocol seems to be cisplatin on day 1 at 50 mg/m2 followed by doxorubicin on day 2 at 15mg/m2 for up to 4 cycles.21 However in 2005, Chun et al found the median survival time of 300 days was not improved over previously reported single-agent protocols, but the 10 dogs that survived to a year lived a median of 510 days.22
Combination carboplatin and doxorubicin has also been recently reported.23 Thirty-two osteosarcoma dogs were treated by amputation or limb sparing and had adjuvant chemotherapy with alternating doses of carboplatin (300 mg/m2 IV) and doxorubicin (30 mg/m2 IV) every 21 days for a total of 3 cycles. Efficacy, toxicity, and previously identified prognostic factors for osteosarcoma were evaluated. The median progression free survival was 227 days (range 180-274), and the median overall survival was 320 days (range 153-487). The 1-year survival rate was 48%, and the 2-year survival rate was 18%. These results are also not significantly longer than single agent chemotherapy protocols.
Bisphosphonates (BP) form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and are pharmacokinetically similar in their intestinal absorption, skeletal distribution and renal elimination.24 Two groups of bisphosphonates exist chemically, non amino-bisphosphonates and the amino-bisphosphonates. The amino-bisphosphonates have greater antiresorptive capabilities and represent a newer generation of bisphosphonates, e.g., alendronate, pamidronate, zoledronate and ibandronate.24 The primary of mechanism of action of BP is inhibition of osteoclastic activity. Non amino-bisphosphonates are incorporated into the energy pathways of the osteoclast resulting in disrupted cellular energy metabolism leading to apoptosis. Amino-bisphosphonates exert their effect on osteoclasts via their inhibition of the mevalonate pathways resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonates also inhibit cancer cell proliferation and induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase, have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapy for hypercalcemia of malignancy, inhibition of bone metastasis and bone pain. While BP's are regarded as metabolically inert in the body, side affects do occur and include esophagitis, gastritis, suppression of bone repair, and allergic reactions. Some literature exists on the use of BP's in canine osteosarcoma cell lines and dogs with OSA.25-27 Clinically Fan et al25 published a study to evaluate the clinical safety of pamidronate when administered at a mean dosage of 1.0 mg/kg IV q28d in 33 tumor-bearing dogs. They evaluated renal function before each successive pamidronate treatment. They found that of thirty-three dogs treated with pamidronate, only one developed clinically relevant increases in serum creatinine and blood urea nitrogen concentrations. The biologic activity was assessed prospectively in 10 dogs with appendicular osteosarcoma by assessing reductions in urine N-telopeptide excretion and bone mineral density of the primary tumor using dual-energy x-ray absorptiometry. Pain control was also assessed. They found that i.v. pamidronate appeared to be clinically safe in tumor-bearing dogs and may possess modest biologic activity for managing neoplastic complications associated with pathologic bone resorption.25 In a newer prospective study, Fan et al26 evaluated single-agent pamidronate as palliative therapy for bone pain in canine appendicular osteosarcoma. The therapeutic responses in dogs were monitored by using a numerical cumulative pain index score (CPIS) and by quantifying urine N-telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x-ray absorptiometry. They also monitored pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx and rBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy. They found that of the forty-three dogs, twelve (28%) had pain relief for >4 months, lasting a median of 231 days. Changes in CPIS and rBMD during treatment were statistically different between responders and nonresponders. From this study Fan et al,26 concluded that i.v. pamidronate reduced CPIS and increased rBMD, relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs.26 Thus it appears that bisphosphonates may become a standard component of medical therapy for canine osteosarcoma.
Miscellaneous Therapy--Anti-angiogenic therapy or "Metronomic therapy", Anti-MMP
Other therapies that have and are being investigated as adjuncts to chemotherapy included, anti-MMP therapies,28 immune modulators,29,30 and NSAIDS.26,31
1. Green EM, et al. J Am Anim Hosp Assoc 2002;38(5):445.
2. Heidner GL, et al. 1991;5(6):313.
3. Cooke K, et al. In: Anonymous. 16 ed. 2002;367.
4. Friedman WA, et al. Linac Radiosurgery. A Practical Guide. Berlin: Springer, 1998.
5. Farese JP, et al. J Am Vet Med Assoc 2004;225(10):1567,1548.
6. Ketring AR. 1987;14(3):223.
7. Lattimer JC, et al. 1990;31(8):1316.
8. Lattimer JC, et al. 1990;31:586.
9. Moe L, et al. 1996;37(5):241.
10. Straw RC, et al. 1996;32(3):257.
11. Milner RJ, et al. 1998;69(1):12.
12. Aas M, et al. 1999;5(10 Suppl):3148s.
13. Kvinnsland Y, et al. 2002;29(2):191.
14. Barnard SM, et al. 2007;230(12):1877.
15. Lin JH. 1996;18(2):75.
16. Madrazo A, et al. 1975;114:822.
17. Chun R, et al. 2000;14(5):495.
18. Berg J, et al. 1997;79(7):1343.
19. Khanna C, et al. 2002;8(7):2406.
20. Bergman PJ, et al. 1996;10(2):76.
21. Dernell WS, et al. In: Withrow SJ, MacEwen EG, eds. Small Animal Clinical Oncology. 3rd ed. Philadelphia: W. B. Saunders Company, 2001;378.
22. Chun R, et al. J Am Anim Hosp Assoc 2005;41(6):382.
23. Kent MS, et al. J Vet Intern Med 2004;18(4):540.
24. Milner RJ, et al. J Vet Intern Med 2004;18(5):597.
25. Fan TM, et al. J Vet Intern Med 2005;19(1):74.
26. Fan TM, et al. J Vet Intern Med 2007;21(3):431.
27. Farese JP, et al. In Vitro Cell Dev Biol Anim 2004;40(3-4):113.
28. Moore AS, et al. J Vet Intern Med 2007;21(4):783.
29. Kurzman ID, et al. 1995;1(12):1595.
30. Vail DM, et al. Clin Cancer Res 1995;1(10):1165.
31. Royals SR, et al. Am J Vet Res 2005;66(11):1961.