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 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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ABSTRACT: Due to the emergence of adjuvant and neoadjuvant chemotherapy, the survival rate has been greatly improved in osteosarcoma (OS) patients with localized disease. However, this survival rate has remained unchanged over the past 30 years, and the long-term survival rate for OS patients with metastatic or recurrent disease remains poor. To a certain extent, the reason behind this may be ascribed to the chemoresistance to anti-OS therapy. Chemoresistance in OS appears to be mediated by numerous mechanisms, which include decreased intracellular drug accumulation, drug inactivation, enhanced DNA repair, perturbations in signal transduction pathways, apoptosis- and autophagy-related chemoresistance, microRNA (miRNA) dysregulation and cancer stem cell (CSC)-mediated drug resistance. In addition, methods employed to circumvent these resistance mechanism have been shown to be effective in the treatment of OS. However, almost all the current studies on the mechanisms of chemoresistance in OS are in their infancy. Further studies are required to focus on the following aspects: i) Improving the delivery of efficacy through novel delivery patterns; ii) improving the understanding of the signal transduction pathways that regulate the proliferation and growth of OS cells; iii) elucidating the signaling pathways of autophagy and its association with apoptosis in OS cells; iv) utilizing high-throughput miRNA expression analysis to identify miRNAs associated with chemoresistance in OS; and v) identifying the role that CSCs play in tumor metastasis and in-depth study of the mechanism of chemoresistance in the CSCs of OS.Oncology letters 05/2014; 7(5):1352-1362. · 0.99 Impact Factor
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ABSTRACT: In the US, children diagnosed with cancer are living longer, but not without consequences from the same drugs that cured their cancer. In these patients, cardiovascular disease is the leading cause of non-cancer-related morbidity and mortality. Although this review focuses on anthracycline-related cardiomyopathy in childhood cancer survivors, the global lifetime risk of other cardiovascular diseases such as atherosclerosis, arrhythmias and intracardiac conduction abnormalities, hypertension, and stroke also are increased. Besides anthracyclines, newer molecularly targeted agents, such as vascular endothelial growth factor receptor and tyrosine kinase inhibitors, also have been associated with acute hypertension, cardiomyopathy, and increased risk of ischemic cardiac events and arrhythmias, and are summarized here. This review also covers other risk factors for chemotherapy-related cardiotoxicity (including both modifiable and non-modifiable factors), monitoring strategies (including both blood and imaging-based biomarkers) during and following cancer treatment, and discusses the management of cardiotoxicity (including prevention strategies such as cardioprotection by use of dexrazoxane).Paediatric Drugs 08/2014; · 1.72 Impact Factor
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ABSTRACT: Pediatric sarcomas are relatively rare malignancies individually. As a group they are typically approached with combination chemotherapies in addition to local control. Fortunately, these malignancies have been approached through careful clinical trial collaboration to define risk groups and appropriately deliver local control measures and systemic therapies. Although local disease is typically approached with curative intent, therapy typically lasts over 6 months and has significant associated morbidities. It is more difficult to cure metastatic disease or induce sustained remissions. In this article, we discuss recent advances in the understanding of the disease process and highlight recent and future cooperative group trials in osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcomas, and desmoid tumor as well as discuss promising therapeutic approaches such as epigenetics and immunotherapy.Current Oncology Reports 08/2014; 16(8):395. · 2.87 Impact Factor