Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review
Background Osteosarcoma mostly occurs during the period of rapid bone growth in children and adolescents as high-grade osteosarcomas. Current treatment recommended for high-grade non-metastatic and metastatic and/or relapsed osteosarcoma involves neoadjuvant multiagent conventional chemotherapy, followed by surgical resection of macroscopically detected tumour and postoperative adjuvant chemotherapy. However, residual micrometastatic deposits that develop following surgery have shown resistance to postoperative/adjuvant chemotherapy. Therefore, there is a critical need for more effective and innovative therapeutic approaches such as immune stimulatory agents. The most extensively studied immune stimulatory agent in the treatment of osteosarcoma is mifamurtide. The aim of this systematic review was to identify and synthesise the evidence on the effectiveness of mifamurtide in addition to standard chemotherapy on survival outcomes. Objectives To present the best available evidence related to the treatment of high-grade non-metastatic and metastatic osteosarcoma with mifamurtide in addition to standard chemotherapy. Inclusion criteria Types of participants All populations of patients, regardless of age, gender or ethnicity with high-grade, resectable, non-metastatic and metastatic osteosarcoma based on histological diagnosis. Types of interventions and comparators This review focused on intravenous infusion of either of the pharmaceutical formulations of mifamurtide (MTP-PE or L-MTP-PE) in addition to standard chemotherapy, and the comparator was chemotherapy alone. Types of studies This review considered any experimental study design including randomised controlled trials, non-randomised trials and quasi-experimental studies. Types of outcomes The primary outcomes of interest were event-free survival, overall survival and recurrence of osteosarcoma. Secondary outcomes that were considered included health-related quality of life and any mifamurtide-related adverse events. Search strategy A search for published and unpublished literature in the English language was undertaken (seven published literature databases, four unpublished literature databases, and three government agency and organisational websites). Studies published between 1990 to June 2016 were considered. A three-step strategy was developed using MeSH (Medical Subject Headings) terminology and keywords to ensure that all relevant studies related to this review were included. Methodological quality The methodological quality of included studies was assessed by two reviewers, who appraised each study independently, using a standardised Joanna Briggs Institute (JBI) critical appraisal tool. Data extraction Data was extracted from the studies that were identified as meeting the criteria for methodological quality using the standard JBI data extraction tool. Data synthesis Due to the heterogeneity of populations and interventions and available studies, meta-analyses were not possible and results are presented in narrative form. Results Three papers outlining two studies involving 802 patients evaluated the effectiveness of mifamurtide in addition to chemotherapy. Results indicated no significant difference in event-free survival between the addition of mifamurtide to standard chemotherapy regimens and chemotherapy alone, both in non-metastatic and metastatic osteosarcoma patients. There was a significant difference in progression-free survival favouring the addition of mifamurtide in pulmonary metastatic and/or relapsed osteosarcoma. There was no significant difference in overall survival between the addition of mifamurtide and chemotherapy alone in metastatic osteosarcoma; however there was a significant difference favouring the addition of mifamurtide in non-metastatic osteosarcoma patients. The addition of mifamurtide resulted in a significant difference in survival after relapse in pulmonary metastatic and/or relapsed osteosarcoma patients. Both studies reported on mifamurtide-related adverse events – the first was reported as toxicity which included haematological, hepatic, renal, gastrointestinal disorders, cardiac rhythm, nervous system disorders, ear disorders and others (infection, fever and performance status) in metastatic osteosarcoma patients. Results were similar across all combined treatment regimens. Although no statistical analysis was undertaken, the figures suggest there were no significant differences between the treatment regimens. In the other study, mifamurtide-related adverse events were reported as clinical toxic effects of mifamurtide in relapsed osteosarcoma, which included chills, fever and headache for the initial dose of mifamurtide, while for the subsequent doses of mifamurtide all patients reported toxicity as delayed fatigue. Conclusions The available evidence on the effectiveness of mifamurtide in addition to a standard chemotherapy regimen for the treatment of high-grade osteosarcoma is limited and therefore no definitive conclusions can be made. Implication for practice There is currently limited evidence to recommend or refute the addition of mifamurtide to the standard chemotherapy regimen for the treatment of high-grade osteosarcoma. Implication for research Additional high quality studies such as randomised controlled trials or quasi-experimental studies involving a larger sample size are required. Consistency in outcome measures is critical to facilitate comparison. Cost-effectiveness studies of mifamurtide are required to inform choice from a societal perspective.
osteosarcoma, osteogenic sarcoma, mifamurtide, muramyl tripeptide
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