Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review protocol

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1 Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review protocol Rincy Jimmy, BSc (Hons), MSc (Hons) 1 Sarahlouise White, BSc (Hons), MClinSci, PhD 1 Karolina Lisy, BSc (Hons), PhD 1 1. School of Translational Health Science, Joanna Briggs Institute, Faculty of Health Sciences, the University of Adelaide, Adelaide, South Australia Review question/objective Corresponding author: Rincy Jimmy rincyjimmy@adelaide.edu.au The objective of this review is to present the best available evidence related to the treatment of osteosarcoma with mifamurtide in addition to standard chemotherapy. The specific review question to be addressed is: What effect does mifamurtide have on event-free survival, overall survival, and quality of life as an adjunct to chemotherapy for high-grade non-metastatic and metastatic osteosarcoma patients? Background Osteosarcoma (also called osteogenic sarcoma) is the most common primary malignant tumor of osteoid tissues in bone. 1-3 Osteosarcoma is microscopically different to normal bone tissue. This tissue is derived from mesenchymal cells which exhibit osteoblastic differentiation and produce malignant osteoid and immature bone. 1 The Enneking Staging System classifies osteosarcoma into high grade, intermediate grade, or low grade based on histological characteristics. 4 In addition, there are different histological subtypes of high-grade osteosarcoma such as osteoblastic, chondroblastic, fibroblastic, small cell, teleangiectatic, high-grade surface, pagetoid, extra-skeletal and postradiation. 4,5 High-grade osteosarcomas are the fastest growing type of osteosarcoma. This review will focus on the most common of the three types of high-grade osteosarcoma (osteoblastic, chondroblastic and fibroblastic) which account for 80-90% of osteosarcoma diagnoses. 4-6 Osteosarcoma is diagnosed in about 1000 individuals in both Europe and the United States of America each year. 7,8 Osteosarcoma usually develops during periods of rapid bone growth. As such, most cases of osteosarcoma that occur in children and young adults are high-grade. 4 Adults aged over 60 years who develop osteosarcoma often have other predisposing factors such as a history of radiation exposure, hereditary disorders including retinoblastoma, Li-Fraumeni syndrome, Rothmund Thomas syndrome, Werner syndrome and Bloom syndrome, or Paget s disease (a benign condition doi: /jbisrir Page 61

2 characterized by abnormal development of new bone cells). 9,10 In children and young adults osteosarcoma usually develops in areas of rapid bone growth such as near the ends of the long bones. 11 Osteosarcoma begins with a pain and is often mistaken for growing pains. 10 Many patients present to a doctor with pain following an injury to the affected area or when a pathological fracture occurs. 4 When diagnosed, 70-80% of patients present with localized disease (non-metastatic), while 20-25% of patients present with metastatic osteosarcoma which most commonly occurs in lungs, lymph nodes or other bones. 6 Currently, high-grade non-metastatic and metastatic osteosarcoma treatment involves neoadjuvant multiagent conventional chemotherapy (cisplatin, doxorubicin, highdose methotrexate, and ifosfamide), surgical resection of macroscopically detected tumor and postoperative adjuvant chemotherapy. 1,5 The preoperative chemotherapeutic treatment offers the time to achieve tumor shrinkage and induces tumor necrosis in primary tumor to facilitate tumor resection. It also offers time to study the histological effect of preoperative chemotherapy on primary tumor to possibly alter postoperative chemotherapy. 12 The degree of tumor necrosis is a prognostic marker used to validate the effectiveness of neoadjuvant chemotherapy treatment. 12 Current treatment for osteosarcoma achieves 60-70% event-free survival for patients without metastases and approximately 20% event-free survival for patients with metastases. 8,13 Innovative therapeutic approaches, such as the use of immune activators (stimulants) used in combination with existing multiagent chemotherapy, are needed to aid in preventing tumor recurrence and improvement of survival rates in patients with high-grade osteosarcoma. 14 Novel target-selective treatment strategies are necessary for high-grade osteosarcoma targeting the residual micrometastases. Mifamurtide (also known as muramyl tripeptide [MTP] and muramyl tripeptide phosphatidylethanolamine [MTP-PE]), is a fully synthetic lipophilic analogue of muramyl dipeptide (MDP), the smallest naturally-occurring immune stimulatory component of bacterial cell walls. 6-8,15 Both mifamurtide and MDP stimulate immune responses via binding to nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor expressed primarily in monocytes, macrophages and dendritic cells. 2 By binding to NOD2, mifamurtide activates the nuclear factor (NF)- B pathway, leading to an increased production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), interferon gamma (IFN-gamma), and immune stimulation markers plasma neopterin and serum C-reactive protein. 13,16 Activation of tumoricidal macrophages and monocytes may potentially help to eradicate residual micrometastases that are resistant to postoperative adjuvant chemotherapy. 2,8,17 The immunostimulatory effects of mifamurtide are similar to MDP with the advantage of a longer half-life in plasma and with less pyrogenic effects. Stimulation of the innate immune defense by mifamurtide can be measured by: (1) analysis of blood plasma cytokine levels such as rapid induction of circulating TNF-α and IL-6 (one to two hours postinfusion); (2) prolonged elevations in plasma neopterin (24 hours postinfusion) and serum C-reactive protein (72 hours postinfusion); and (3) fibrosis of the area from where the tumor was removed, inflammatory macrophage infiltration into the lesions, and change in the malignant characteristic (e.g. morphology) of tumor. 16,18-20 There are two formulations of mifamurtide in use, the free-drug form (MTP-PE) and the liposomalencapsulated form liposomal MTP-PE (L-MTP-PE). Liposomal MTP-PE is specifically designed to deliver the drug to macrophages and monocytes and is ten times less toxic than MTP-PE. 2,16,21,22 The standard protocol of delivery of both forms of mifamurtide is 2 mg/m 2 infused intravenously over a doi: /jbisrir Page 62

3 one-hour period twice a week for 12 weeks, then once a week for weeks. 2,6,7,23 One study found that the addition of mifamurtide to standard chemotherapy in 662 eligible patients improved six year overall survival from 70% to 78%, and reduced the risk of death from osteosarcoma by one third. 7 Potential adverse effects (AEs) of mifamurtide in patients undergoing standard chemotherapy also require clarification. There is some suggestion that there may be minor adverse events; however the evidence has yet to be systematically examined. One study 23 reported potential infusion-related adverse events (IRAEs) and AEs. Another study 13 also reported short-term side effects such as fever, headache, flu-like symptoms and rigors. Participants in a separate study experienced significant serious AEs; however they were not systematically recorded. 24 A preliminary search of The Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports and PubMed revealed no systematic reviews either published or underway on this topic. Hence a systematic review is required to identify and synthesize the best available evidence on the effectiveness of mifamurtide as an adjunct to chemotherapy for high-grade, resectable, non-metastatic and metastatic osteosarcoma. Keywords Osteosarcoma; Mifamurtide; Chemotherapy Inclusion criteria Types of participants This review will consider any quantitative studies that include patients with high-grade, resectable, non-metastatic and metastatic osteosarcoma based on histological diagnosis. Patients with other types of bone cancer such as Ewing s sarcoma and Chondrosarcoma will be excluded from this review. Types of interventions This review will consider studies that evaluate intravenous infusion of either of the pharmaceutical formulations of mifamurtide (MTP-PE or L-MTP-PE) in addition to standard multi-drug chemotherapy (such as combinations of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide) after macroscopically complete surgical resection. The standard protocol for delivery of mifamurtide is 2 mg/m 2 infused during a one-hour period twice a week for 12 weeks, then once a week for weeks. Types of comparator(s) The comparison group for this review will be patients with high-grade, resectable, non-metastatic and metastatic osteosarcoma, who have received standard chemotherapy alone. Types of outcomes Primary outcomes to be considered for this review include: Event-free survival (EFS) measured in years post-intervention from the time of study commencement until any recurrence or tumor progression of osteosarcoma. doi: /jbisrir Page 63

4 Overall survival of patients measured in percentage of patients surviving post-intervention with the time to follow-up after the treatment up to 10 years post-intervention. Recurrence of osteosarcoma, detected by X-ray, computed tomography (CT) scans and magnetic resonance imaging (MRI) scans, tumor markers (such as blood plasma levels for any changes: (1) variation in cytokine levels with circulating TNF-α and IL-6; (2) elevation of serum C-reactive proteins and plasma neopterin; and (3) any histological reappearance of malignant characteristic of tumor. Secondary outcomes include: Health-related quality of life as measured using any validated, standardized tools and any mifamurtide-related adverse events. Types of studies This review will consider any experimental study designs including randomized controlled trials, nonrandomized trials and quasi-experimental studies that examine the effect of mifamurtide on osteosarcomas as an adjunct therapy to chemotherapy in the treatment of high-grade, resectable, non-metastatic and metastatic osteosarcoma. In the absence of experimental studies, observational studies (such as cohort studies and case control studies) will be considered. Search strategy The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in the English language from 1990-to date (August 2014) will be considered for inclusion in this review. Even though mifamurtide was invented in the 1980s, it was not investigated in clinical trials as a treatment of osteosarcoma until 1990s. 14,16 The databases to be searched include: PubMed CINAHL Embase Cochrane Library (CENTRAL) Scopus Web of Science Cancerlit The search for unpublished studies will include: Grey Literature: Google advance search, MedNar Clinical trial gov doi: /jbisrir Page 64

5 National Library of Medicine National Comprehensive Cancer Network (NCCN), NCCN Web site ( National Cancer Institute (NCI) and its web site ( CureSearch is a combined effort of the National Childhood Cancer Foundation and the Children s Oncology Group (COG), and its website Initial keywords to be used will be: Osteosarcoma; Mifamurtide; Chemotherapy Initial logic grids have been developed for PubMed and Embase (Appendix I) Assessment of methodological quality Quantitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI- MAStARI) (Appendix II). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Data collection Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix III). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data synthesis Quantitative papers, where possible, will be pooled in statistical meta-analysis using the JBI-MAStARI software. All results will be subjected to double data entry to minimize the risk of error during the data entry. Where appropriate, Relative Risks and/or Odds Ratios and their associated 95% confidence interval will be calculated for analysis of categorical data. For continuous data collected using the same scale, the weighted mean differences (WMD) and standard deviation will be calculated; for data collected using different scales, the standardized mean differences (SMD) will be calculated. Heterogeneity will be assessed using standard Chi square test and if found will be investigated prior to any further analysis. Where statistical pooling is not possible, the findings will be presented in narrative form. Conflicts of interest None Acknowledgements As this systematic review forms partial submission for the degree award of Masters in Clinical Science, a secondary reviewer (Arisara Patthum BA Nursing Science, PG Certificate Critical Care) will be utilized for critical appraisal only. doi: /jbisrir Page 65

6 References 1. Gill J, Ahluwalia MK, Geller D, Gorlick R. New targets and approaches in osteosarcoma. Pharmacol Ther. 2013; 137: Kager L, Potschger U, Bielack S. Review of mifamurtide in the treatment of patients with osteosarcoma. Ther Clin Risk Manag. 2010; 6: Mori K, Ando K, Heymann D. Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases. Expert Rev Anticancer Ther. 2008; 8: Redondo A, Cruz J, Lopez-Pousa A, Baron F. SEOM clinical guidelines for the treatment of osteosarcoma in adults Clin Transl Oncol. 2013; 15: Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment - Where do we stand? A state of the art review. Cancer Treat Rev. 2014; 40: Frampton JE. Mifamurtide: a review of its use in the treatment of osteosarcoma. Paediatr Drugs. 2010; 12: Ando K, Mori K, Corradini N, Redini F, Heymann D. Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin Pharmacother. 2011; 12: Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther. 2009; 9: Katonis P, Datsis G, Karantanas A, et al. Spinal osteosarcoma. Clinical Medicine Insights: Oncology. 2013; 7: Majo J, Cubedo R, Pardo N. Treatment of osteosarcoma. A review: Revista Española de Cirugía Ortopédica y Traumatología (English Edition). 2010;54(5): Anderson P, Kopp L, Anderson N, et al. Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma). Expert Opin Investig Drugs. 2008; 17: Ando K, Heymann MF, Stresing V, Mori K, Redini F, Heymann D. Current therapeutic strategies and novel approaches in osteosarcoma. Cancers. 2013; 5: Nardin A, Lefebvre ML, Labroquere K, Faure O, Abastado JP. Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Curr Cancer Drug Targets. 2006; 6: Johal S, Ralston S, Knight C. Mifamurtide for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection: a cost-effectiveness analysis. Value Health. 2013; 16: Anderson PM, Tomaras M, McConnell K. Mifamurtide in osteosarcoma--a practical review. Drugs Today (Barc). 2010; 46: Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol. 1992; 10: Kleinerman ES, Snyder JS, Jaffe N. Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide phosphatidylethanolamine in children with osteosarcoma. J Clin Oncol. 1991; 9: Kleinerman ES, Gano JB, Johnston DA, Benjamin RS, Jaffe N. Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol. 1995; 18: Bramwell V. Metastatic osteosarcoma: a review of current issues in systemic treatment. Sarcoma. 1997; 1: Kleinerman ES, Raymond AK, Bucana CD, et al. Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid). Cancer Immunol Immunother. 1992; 34: Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005; 23: Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol. 2008; 26: doi: /jbisrir Page 66

7 23. Anderson PM, Meyers P, Kleinerman E, et al. Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr Blood Cancer. 2014; 61: Mifamurtide: osteosarcoma: ineffective and harmful. Prescrire Int. 2011; 20: 89. doi: /jbisrir Page 67

8 Appendix I: logic grid for initial database search Logic grid for Embase Osteosarcoma Experimental drug Conventional Treatments Outcomes Osteosarcoma/syn mifamurtide /syn OR muramyl tripeptide /exp OR muramyl tripeptide :ab Chemotherapy /exp survival/syn OR event free survival :ti,ab OR quality of life :ti,ab OR adverse events :ti,ab OR recurrence:ti,ab Logic grid for PubMed Osteosarcoma Experimental drug Conventional Treatments osteosarcoma[mh:n mifamurtide Chemotherapy[tw] oexp] OR [Supplementary Concept] osteosarcoma, OR mifamurtide[tw] OR juxtacortical[mh] OR Acetylmuramyl-Alanylosteosarcoma*[tw] Isoglutamine[mh] OR OR osteogenic mepact[tw] OR L-MTPsarcoma[tw] OR PE[tw] OR MTP PE bone sarcoma*[tw] [tw]or OR osteoid muramyl tripeptide[tw] sarcoma[tw] OR muramyltripeptide[tw] OR cgp [tw] OR cgp 19835a [tw] OR mf 59 [tw] OR mf59 [tw] OR mlv [tw] Outcomes survival/syn OR event free survival [tw] OR quality of life [tw] OR adverse events [tw] OR recurrence[tw] doi: /jbisrir Page 68

9 Appendix II: Appraisal instruments MAStARI appraisal instruments doi: /jbisrir Page 69

10 doi: /jbisrir Page 70

11 nsert page brea doi: /jbisrir Page 71

12 Appendix III: Data extraction instruments MAStARI data extraction instrument doi: /jbisrir Page 72

13 t page break doi: /jbisrir Page 73