Enrico Martin

160 Chapter 7 Introduction Malignant peripheral nerve sheath tumors (MPNSTs) are rare, but aggressive soft tissue sarcomas (STS) with high rates of recurrence and metastasis. 1–3 Almost half of all cases are related to neurofibromatosis type I (NF1), while others occur sporadically or after radiation exposure. 1,4 The NF1 gene is commonly affected in MPNSTs causing the loss of neurofibromin, a Ras inhibiting enzyme. 5 Ras activation results in the downstream activation of Ras pathways, leading to upregulation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). 6 However, loss of neurofibromin alone is not enough to cause an MPNST. 7 Research over the last three decades has implicated multiple factors in the pathogenesis of MPNSTs, including loss of function in TP53 , CDKN2A , SUZ12 , and PTEN genes, as well as amplification of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and MET. 8–12 Despite our increased understanding of the complex biology underlying MPNSTs, prognosis has remained poor, with 5-year survival rates ranging from 30-60% in patients who have undergone curative surgery of their tumor, and even lower rates in those with advanced and metastatic disease. 1–3,13 Surgery with wide negative margins remains the mainstay treatment for MPNST. 1,3 Radiotherapy is commonly used either postoperatively or in a neoadjuvant setting as it improves local control, but does not affect overall survival. 1,14,15 In a study investigating neoadjuvant chemotherapy, histotype-guided treatment of four STS types, including MPNST (this cohort was treated with etoposide-ifosfamide), has not shown any benefit compared to standard anthracycline based chemotherapy. 16 Therefore, there has thus far been no rationale for treating MPNST differently from other STS. Neoadjuvant chemotherapy could be considered for high-grade, large, and deep MPNST, 16,17 and may allow initially inoperable patients to become operable. 2,18 However, over 10% of MPNST patients present with unresectable or metastatic disease. 2,3,19 Additionally, 40-60% of patients receiving treatment with curative intent will develop metastatic disease. 19–21 For the whole group of STS, first line palliative chemotherapy consists of an anthracycline (doxorubicin or epirubicin) containing schedule. This might be combined doxorubicin and ifosfamide or doxorubicin monotherapy. Overall, a clinical response rate of approximately 21% has been reported for MPNST treated with combined doxorubicin and ifosfamide. 18 Adding ifosfamide to doxorubicin has improved progression-free survival (PFS), but not overall survival (OS), and comes at the cost of increased toxicity. 22 The high rates of advanced and metastatic disease and poor response to standard chemotherapy highlight the need for novel therapies in the treatment of MPNST. Targeted therapy and immunotherapy has brought new options to many other cancer types, but is not yet established in STS in general or MPNST specifically. Especially target specific, non-cytotoxic treatments are of interest as they may specifically