ABSTRACT
Introduction: Zoledronic acid (ZOL) is a third-generation bisphosphonate with a higher affinity for bone resorption areas than earlier bisphosphonates (i.e., pamidronate, PAM). In human medicine, ZOL provides improved bone pain relief and prolonged time to skeletal-related events compared to its older generational counterparts. Preclinical studies have investigated its role as an anti-neoplastic agent, both independently and synergistically, with radiation therapy (RT). ZOL and RT act synergistically in several neoplastic human cell lines: prostate, breast, osteosarcoma, and fibrosarcoma. However, the exact mechanism of ZOL's radiosensitization has not been fully elucidated. Methods: We investigated ZOL's ability to induce apoptosis in canine osteosarcoma cell lines treated with various doses of megavoltage external beam radiotherapy. Second, we evaluated cell cycle arrest in ZOL-treated cells to assess several neo-adjuvant time points. Finally, we treated 20 dogs with naturally occurring appendicular OS with 0.1 mg/kg ZOL IV 24 h before receiving 8 Gy of RT (once weekly fraction x 4 weeks). Results: We found that apoptosis was increased in all ZOL-treated cell lines compared to controls, and the combination of ZOL and RT resulted in dissimilar apoptosis between Abrams and D-17 and HMPOS cell lines. Cell cycle arrest (G2/M phase) was minimal and variable between cell lines but perhaps greatest at 48 h post-ZOL treatment. Only 10% of dogs treated with ZOL and RT developed pathologic fractures, compared to 44% of dogs historically treated with PAM and RT (p = 0.027). Discussion: ZOL and RT appear to be a well-tolerated combination treatment scheme for non-surgical candidates; future studies must elucidate the ideal timing of ZOL.
ABSTRACT
BACKGROUND: Radiation therapy (RT) is used for local pain alleviation in dogs with appendicular osteosarcoma (OS), especially among dogs that are poor surgical candidates for amputation. However, many historical reports of fractionated protocols lack time to fracture and fracture rates. OBJECTIVES: The primary objectives of this retrospective study were to determine fracture rate and time to fracture of dogs receiving RT (coarse or fine fractionated) for appendicular OS. Secondary objectives were to evaluate tolerability and disease outcome measures. METHODS: Fifty-one dogs that received RT as part of treatment for appendicular OS were available for evaluation. Forty-five received coarse fractionation (C-RT, 8 or 6 Gy per fraction protocols [C-RT8 or C-RT6]) while the remaining six received fine fractionation (F-RT). RESULTS: The overall pathologic fracture rate was 37%. Pathologic fracture rate was significantly higher for dogs that received F-RT (5/6, 83%) compared to dogs that received C-RT (12/40, 30%, p = 0.021). In the 17 dogs that fractured, the overall median time to fracture was 57 days. For all dogs, the median progression free interval (PFI) and median overall survival time (OST) were 90 and 140 days, respectively. In a very small cohort of dogs (n = 7) treated with zoledronate and RT, fracture rate was 0% and extended survival times were noted. CONCLUSIONS: In conclusion, C-RT is recommended over F-RT due to lower risk of pathologic fracture and similar PFI. Prospective evaluation of combined C-RT and zoledronate, especially for dogs with poor surgical candidacy, is warranted for the treatment of canine appendicular osteosarcoma.
