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

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Fig 1.

Treatment schema. G-CSF, granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2; IV, intravenous.

Fig 2.

Survival by human epidermal growth factor receptor 2 (HER2) status and sites of metastasis. (A) Event-free survival (EFS) for all patients. (B) Overall survival for all patients. (C) EFS for lung only metastases. (D) EFS for combined lung and bone metastases.

Fig 3.

Changes in myocardial function during treatment: Solid lines represent best prediction of changes in myocardial function over time during protocol therapy. The standardized left ventricular fractional shortening (z score) decreases slightly as time from enrollment increases in both treatment arms. Neither downward trend nor the difference in slope between the two treatment arms is statistically significant.

Fig 4.

Serum measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiomyopathy. Changes in NT-proBNP levels in human epidermal growth factor receptor 2 (HER2) –negative patients treated without trastuzumab and HER2-positive patients treated with trastuzumab.