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

Robert E. Goldsby, Timothy M. Fan, Doojduen Villaluna, Lars M. Wagner, Michael S. Isakoff, James Meyer, R. Lor Randall, Sharon Lee, Grace Kim, Mark Bernstein, Richard Gorlick, Mark Krailo, Neyssa Marina

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Abstract

Aim 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. Patients and 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/m2 [max 2 mg], 2.3 mg/m 2 [max 4 mg] and 3.5 mg/m2 [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/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 2.3 mg/m 2 (max 4 mg). Conclusions ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m2 (max 4 mg) for patients with metastatic osteosarcoma.

Original languageEnglish (US)
Pages (from-to)2384-2391
Number of pages8
JournalEuropean Journal of Cancer
Volume49
Issue number10
DOIs
StatePublished - Jul 2013

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zoledronic acid
Osteosarcoma
Drug Therapy
Maximum Tolerated Dose
Therapeutics
Extremities
Hypophosphatemia
Mucositis
Osteonecrosis

Keywords

  • Chemotherapy
  • Metastatic osteosarcoma
  • Zoledronic acid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Goldsby, Robert E.; Fan, Timothy M.; Villaluna, Doojduen; Wagner, Lars M.; Isakoff, Michael S.; Meyer, James; Lor Randall, R.; Lee, Sharon; Kim, Grace; Bernstein, Mark; Gorlick, Richard; Krailo, Mark; Marina, Neyssa.

In: European Journal of Cancer, Vol. 49, No. 10, 07.2013, p. 2384-2391.

Research output: Contribution to journalArticle

Goldsby, RE, Fan, TM, Villaluna, D, Wagner, LM, Isakoff, MS, Meyer, J, Lor Randall, R, Lee, S, Kim, G, Bernstein, M, Gorlick, R, Krailo, M & Marina, N 2013, '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', European Journal of Cancer, vol. 49, no. 10, pp. 2384-2391. https://doi.org/10.1016/j.ejca.2013.03.018
Goldsby, Robert E. ; Fan, Timothy M. ; Villaluna, Doojduen ; Wagner, Lars M. ; Isakoff, Michael S. ; Meyer, James ; Lor Randall, R. ; Lee, Sharon ; Kim, Grace ; Bernstein, Mark ; Gorlick, Richard ; Krailo, Mark ; Marina, Neyssa. / 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. In: European Journal of Cancer. 2013 ; Vol. 49, No. 10. pp. 2384-2391.
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abstract = "Aim 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. Patients and 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/m2 [max 2 mg], 2.3 mg/m 2 [max 4 mg] and 3.5 mg/m2 [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/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 2.3 mg/m 2 (max 4 mg). Conclusions ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m2 (max 4 mg) for patients with metastatic osteosarcoma.",
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T1 - Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma

T2 - A report from the Children's Oncology Group

AU - Goldsby, Robert E.

AU - Fan, Timothy M.

AU - Villaluna, Doojduen

AU - Wagner, Lars M.

AU - Isakoff, Michael S.

AU - Meyer, James

AU - Lor Randall, R.

AU - Lee, Sharon

AU - Kim, Grace

AU - Bernstein, Mark

AU - Gorlick, Richard

AU - Krailo, Mark

AU - Marina, Neyssa

PY - 2013/7

Y1 - 2013/7

N2 - Aim 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. Patients and 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/m2 [max 2 mg], 2.3 mg/m 2 [max 4 mg] and 3.5 mg/m2 [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/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 2.3 mg/m 2 (max 4 mg). Conclusions ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m2 (max 4 mg) for patients with metastatic osteosarcoma.

AB - Aim 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. Patients and 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/m2 [max 2 mg], 2.3 mg/m 2 [max 4 mg] and 3.5 mg/m2 [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/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 2.3 mg/m 2 (max 4 mg). Conclusions ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m2 (max 4 mg) for patients with metastatic osteosarcoma.

KW - Chemotherapy

KW - Metastatic osteosarcoma

KW - Zoledronic acid

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