Zoledronate ‘Not Recommended’ For Newly Diagnosed Osteosarcoma

The addition of zoledronate to preoperative chemotherapy fails to boost treatment-naïve osteosarcoma survival

medwireNews: Phase III trial investigators recommend against the use of the bisphosphonate agent zoledronate in adult and paediatric patients undergoing preoperative chemotherapy for newly diagnosed osteosarcoma.

The open-label OS2006 study was halted for futility at the second interim analysis after a median of 3.9 years, at which time 3-year event-free survival was achieved by 57.1% of the 160 patients given chemotherapy plus zoledronate versus 63.4% of the 158 patients given chemotherapy alone.

“The risk of failure was not reduced and was even marginally higher in the zoledronate groups than in the control group”, say the authors in The Lancet Oncology, citing a nonsignificant hazard ratio of 1.36.

They therefore conclude that, “from the results observed in this study, zoledronate cannot be recommended in patients with osteosarcoma.”

The study included 318 French patients aged 5.8 to 50.9 years old who were beginning age-appropriate chemotherapy, defined as a high-dose methotrexate-based regimen for those aged less than 18 years, doxorubicin, ifosfamide plus cisplatin for patients aged over 25 years and physician’s choice of the two regimens for patients aged 18 to 25 years.

Zoledronate-treated patients were given 10 infusions of the bisphosphonate and dose also differed by age. Patients aged less than 18 years were given 0.05 mg/kg up to a maximum of 4 mg, those aged over 25 years received 4 mg per infusion, and patients aged 18 to 25 years received two infusions at 0.05 mg/kg followed by 4 mg per infusion thereafter.

Lead author Sophie Piperno-Neumann, from Institut Curie in Paris, France, and co-workers say that hypocalcaemia and hypophosphataemia were the only excess acute toxicities in the zoledronate-treated patients versus controls. And the patient groups did not differ with regard to risk of fracture during treatment or wound healing complications after surgery.

Nevertheless, they emphasise that zoledronate receipt did not improve event-free survival even after excluding patients with metastases outside of the lung, and there was no significant heterogeneity of the treatment effect across age, chemotherapy regimen, risk group or tumour size subgroups.

Nor was 3-year overall survival better with zoledronate treatment, at 73.4% versus 84.4% for those given chemotherapy alone.

“Zoledronate seemed to be a good candidate in the treatment of osteosarcoma, because several preclinical studies have suggested that it exerts pleiotropic antitumour effects (eg, antiproliferative, anti-angiogenic, and immunomodulatory effects) against osteosarcoma cells in vitro and in animal models”, the investigators write.

They suggest that inadequate zoledronate dose or patient hormonal factors may explain the discrepancy between preclinical and OS2006 results. Alternatively, zoledronate’s immunological effect may have a negative impact in osteosarcoma patients, who have previously been shown to benefit from high numbers of tumour-infiltrating macrophages.

Ongoing translational studies associated with the OS2006 trial, assessing zoledronate impact on factors such as immune response and macrophage polarisation, may shed light on the mechanism of zoledronate in osteosarcoma, Sophie Piperno-Neumann et al conclude. 

Reference

Piperno-Neumann S, Le Deley M-C, Rédini F, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2016; Advance online publication 17 June. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30096-1

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