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

Review question/objective 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 post‐radiation.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 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, high‐dose 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)‐kB pathway, leading to an increased production of proinflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐&agr;), 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‐&agr; 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 liposomal‐encapsulated 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/m2 infused intravenously over a one‐hour period twice a week for 12 weeks, then once a week for 12‐24 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 study23 reported potential infusion‐related adverse events (IRAEs) and AEs. Another study13 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.