Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children's oncology group.
OBJECTIVE
Despite efforts to intensify chemotherapy, survival for patients with metastatic osteosarcoma remains poor. Overexpression of human epidermal growth factor receptor 2 (HER2) in osteosarcoma has been shown to predict poor therapeutic response and decreased survival. This study tests the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 overexpression.


METHODS
Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry. All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide. Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline. Only patients with HER2 overexpression received concurrent therapy with trastuzumab given for 34 consecutive weeks.


RESULTS
The 30-month event-free and overall survival rates for patients with HER2 overexpression treated with chemotherapy and trastuzumab were 32% and 59%, respectively. For patients without HER2 overexpression, treated with chemotherapy alone, the 30-month event-free and overall survival rates were 32% and 50%, respectively. There was no clinically significant short-term cardiotoxicity in patients treated with trastuzumab and doxorubicin.


CONCLUSIONS
Despite intensive chemotherapy plus trastuzumab for patients with HER2-positive disease, the outcome for all patients was poor, with no significant difference between the HER2-positive and HER2-negative groups. Although our findings suggest that trastuzumab can be safely delivered in combination with anthracycline-based chemotherapy and dexrazoxane, its therapeutic benefit remains uncertain. Definitive assessment of trastuzumab's potential role in treating osteosarcoma would require a randomized study of patients with HER2-positive disease.
Massachusetts General Hospital, Boston, MA, USA. debb@partners.org
David
D
Ebb
Paul
P
Meyers
Holcombe
H
Grier
Mark
M
Bernstein
Richard
R
Gorlick
Steven E
SE
Lipshultz
Mark
M
Krailo
Meenakshi
M
Devidas
Donald A
DA
Barkauskas
Gene P
GP
Siegal
William Shay
WS
Ferguson
George Douglas
GD
Letson
Karen
K
Marcus
Allen
A
Goorin
Peter
P
Beardsley
Neyssa
N
Marina
D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab