Enrico Martin

279 General discussion and future perspectives not know what the impact of radiotherapy is on recurrence rates in this population specifically, as radiation exposure more commonly may cause secondary malignancies in NF1 and MPNSTs commonly arise within plexiform neurofibromas. 11 The ideal timing of radiotherapy is not entirely clear either. Although neoadjuvant administration is gaining popularity in STS generally, surgeons other than surgical oncologists are still more likely to prefer postoperative administration in MPNST ( Chapter 5 ). Chapter 2-4 demonstrated that adjuvant radiotherapy is still more commonly the treatment of choice. Radiation dosage is smaller in neoadjuvant administration, but careful dissection may be more difficult in an irradiated field if one is planning to perform epineural dissection (peeling off epineurium) and nerve or tendon reconstructions require well vascularized wound beds. In vulnerable patient groups it has yet to be shown that radiotherapy is of additional value when an R0 resection can be performed. Chemotherapy The use of chemotherapy in localized adult MPNST is controversial, which is highlighted in Chapter 5 . Ideally, doxorubicin and ifosfamide are used as chemotherapeutic regimen in MPNST. 12,13 But there is currently a lack of solid evidence to define the role of perioperative chemotherapy in any STS. 13–17 MPNSTs are known to be relatively chemoresistant STS, possibly even more so in NF1. 12,18 Administration of chemotherapy in adult localized disease is currently not widely employed ( Chapter 2, 3, and 5 ). In pediatric MPNST however, a larger proportion of patients with localized disease receives perioperative chemotherapy with no difference between sporadic and NF1 patients ( Chapter 4 ). The use of chemotherapy has been incorporated for pediatric NRSTS in the EpSSG and Children’s Oncology Group (COG) guidelines and since 2005 doxorubicin and ifosfamide have become standard regimens. Survival has ameliorated after 2005 for pediatric MPNST in contrast to adult MPNST ( Chapter 3 and 4 ), which begs to differ if incorporating chemotherapy in a selected group of adult patients would also be beneficial nonetheless. The increasing centralization of pediatric cancer healthcare in the Netherlands may have been an additional factor contributing to increasing survival prognosis in children. Recently, their treatment is further centralized in a single center, the Princess Máxima Center for pediatric oncology. In adult STS it has been shown that centralization ameliorates outcomes as well, 19 which would advocate further centralization of adult MPNST healthcare. Unfortunately, chemotherapy yields unsatisfactory response rates in metastasized MPNST, warranting new systemic therapies. Chapter 7 highlighted that the search for these new therapies is arduous, but ongoing. So far no targeted therapy has yet proven effective in MPNST patients, despite compelling preclinical in vivo evidence. Ever since the publication of Chapter 7 , the SARC023 trial has been published, investigating the addition of ganetespib (Hsp90 inhibitor) to sirolimus (mTOR inhibitor). 20 Alas, no responses were found. 12