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

Massachusetts General Hospital, Boston, MA, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2012; 30(20):2545-51. DOI: 10.1200/JCO.2011.37.4546
Source: PubMed


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.
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.
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.
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.

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    • "Cediranib (AZD-2171), a specific VEGF receptor inhibitor, has been demonstrated to possess a growth inhibitory effect in solid tumor xenograft models, including those of OS (82). However, in a phase II trial of the HER2-targeted agent trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic OS patients, no significant difference was found between the HER2-positive and HER2-negative groups (83). Therefore, the therapeutic benefit of this HER2-targeted agent remains uncertain, and a definitive assessment of the potential role of trastuzumab in treating OS requires further studies of patients with HER2-positive disease. "
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    • "At the moment, there are few molecular elements that serve as effective therapeutic targets or as accurate prognosis for the outcome of chemotherapy.80,81 It is known that overexpression of alkaline phosphatase, lactate dehydrogenase, and human epidermal growth factor receptor 2 can predict poor outcome.82 Further research is required in order to produce efficacious targeted therapies. "
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    • "High frequencies of allelic loss have been detected at 3q and 18q (Yamaguchi et al., 1992), suggesting that other tumor suppressor genes may be important in OS. In one study conducted by Ebb et al. (2012) overexpression of human epidermal growth factor receptor 2 (HER2/neu, ErbB2) was suggested to be associated with early pulmonary metastases and decreased survival in approximately 40% of cases. Expression of bone morphogenetic protein type II receptor (BMPR2) was also found to correlate with metastasis (Guo et al., 1999). "
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