Osteosarcoma is the most common malignant mesenchymal tumor of the bone in pediatric population. That can arise from any bone, but most often localization of tumor´s origin is in metafyseal area of long bones. Osteosarcoma is composed of malignant osteoblasts, which produce immature bone tissue and osteoid. In histological point of view osteosarcoma can be subdivided into high grade forms such as conventional, telangiectatic or chondroblastic and into more indolent forms like parosteal or periosteal osteosarcoma.
Incidence of that disease is very rare of 4.0 (3.5–4.6) for the range 0–14 years and 5.0 (4.6–5.6) for the range 0–19 years per year per million persons and it varies with age (1). There are well known two incidence peaks. First during skeletal growth spurt in age of 15–19 years and second one is during elderly age. (1)Known environmental and genetic risk factors are previous irradiation of the bone, Pagets disease or heritable syndromes such as Li-Fraumeni or germline mutation in RB1 tumor suppressor gene.
Clinical presentation of osteosarcoma is predominantly pain in affected area which initially appears after physical activities and afterwards typically during sleep in “on/off” mode. In general, further symptoms are swelling, palpable mass or loss of function of the limb. Up to 20% of patients are diagnosed with apparent metastatic disease (lungs, bones), but majority of patients are diagnosed with localized disease. Despite that, they have already microscopic metastases in time of the diagnosis. (2)
Total resection of clinically detectable tumors is mainstay of long term survival, even if treatment approach for this disease needs to be multimodal. Though methods of surgical local control were improved and shifted more to limb salvage strategy than previously used amputations, relaps-free survival rates of localized extremity tumors are still approximately 15–17% in case of surgical treatment only. Combination of surgery with intensive neoadjuvant and adjuvant multiagent chemotherapy controls microscopic metastatic disease and improve free-survival rates to about 70%. Nevertheless, in cases of metastatic disease, local progression or nonresectable primary tumors the success rate is still very poor with less than 20% survival five years since diagnosis. (3) Since 70´s of previous century till nowadays only four chemotherapeutic agents have been routinely used in systemic therapy. Backbone of conventional chemotherapy treatment is built by doxorubicin, cisplatine and methotrexate with leucovorin rescue. An alkylation agent ifosfamide is also effective in treatment of osteosarcoma but addition of ifosfamide to other agents is too toxic and did not improve treatment results. Up to date no any new chemotherapy agents with proven efficacy have been added to standard chemotherapy regimen and overall survival rates are stagnating. Thus, treatment strategy for locoregional disease is still based on former schedules. Other additional and experimental treatments in metastatic or progressive disease consist also of targeting the bone microenvironment (bisfosfonates), tyrosin kinase receptors (e.g. sorafenib, pazopanib), intracellular signaling molecules (dasatinib) and of unspecific immune therapy (interferon).
Mifamurtide (Mepact) is synthetic lipophilic analog of muramyl dipeptid, peptidoglycan contained in bacterial wall, which can activate innate immune system. Its tumoricidal effect on microscopic metastases is probably caused by stimulation of monocytes and macrophages associated with increasing level of proinflammatory cytokines. The rationale behind the use of mifamurtide in osteosarcoma treatment is to mimic a kind of infection that can help to eradicate residual micrometastases that are not eliminated by systemic chemotherapy.(2) View of clinical community on regular administration of mifamurtide with standard adjuvant chemotherapy is still not endorsed despite registration study which showed benefit of mifamurtide addition to adjuvant chemotherapy and significantly improved 6-year overall survival from 70% to 78%, event free survival was 61%.(4)