title: 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: OBJECTIVE
  Patients 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.
  
  
  METHODS
  Patients with a histological diagnosis of OS were eligible if they were <40 years 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 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. 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.
  
  
  RESULTS
  Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). 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 2.3 mg/m(2) (max 4 mg).
  
  
  CONCLUSIONS
  ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma.
authors.affiliation: University of California San Francisco, Benioff Children's Hospital, San Francisco, CA, United States. goldsbyr@peds.ucsf.edu
authors.forename: Robert E
authors.initials: RE
authors.lastname: Goldsby
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.forename: Doojduen
authors.initials: D
authors.lastname: Villaluna
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.forename: Michael S
authors.initials: MS
authors.lastname: Isakoff
authors.forename: James
authors.initials: J
authors.lastname: Meyer
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Neyssa
authors.initials: N
authors.lastname: Marina
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004487:Edema / Q000139:chemically induced; D005121:Extremities / Q000503:physiopathology; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D007010:Hyponatremia / Q000139:chemically induced; D017674:Hypophosphatemia / Q000139:chemically induced; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D052016:Mucositis / Q000139:chemically induced; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010146:Pain / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid