Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

Abstract

AimPatients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS. Patients and MethodsPatients with a histological diagnosis of OS were eligible if they were <40years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36weeks. Three dose levels of ZA were tested: 1.2mg/m2 [max 2mg], 2.3mg/m2 [max 4mg] and 3.5mg/m2 [max 6mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility. ResultsTwenty-four patients (median age 13.5years [range, 7–22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5mg/m2. DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3mg/m2 (max 4mg). ConclusionsZA can be safely combined with conventional chemotherapy with an MTD of 2.3mg/m2 (max 4mg) for patients with metastatic osteosarcoma.