Christine Noordhoek

In this thesis, we investigated plexiform neurofibromas (PNs) in adults with (mosaic) neurofibromatosis type 1 (NF1), focusing on clinical characteristics, diagnostic modalities and treatment. In Part I, we described the clinical characteristics and management of PNs. In order to improve clinical care, it is important to better understand the natural history of PNs. Chapter 2 reports on the clinical characteristics and management of PNs and malignant peripheral nerve sheath tumors (MPNSTs) in our adult NF1 population. We collected data from more than 1000 adult patients at the Dutch national expertise center for NF1. PNs were present in half of the patients of this cohort, even without routine use of whole body-MRI. The most common symptoms were pain, neurological deficits and cosmetic concerns. In the majority of the patients, only partial resection of the PN was possible, consequently, regrowth after resection was common. Postoperative complications occurred in 10% of the PN surgeries. These limitations of surgical treatment underscore the need to develop new systemic therapies. PNs can develop into MPNSTs, mainly in the proximal body regions such as the trunk. Four percent of the patients in our cohort had an MPNST. Furthermore, MPNSTs were the leading cause of death and prognosis was poor, with a five-year survival of 54.5%. Presence of nodular PNs and 17q11.2 microdeletion were associated with a higher MPNST risk. Regular follow-up is essential for all patients with NF1, and high risk subgroups should be monitored more frequently. Part II explores a promising additional imaging modality for PNs: high resolution nerve ultrasound (HRUS). Patients with NF1 and PNs often require imaging, either regional or whole body-MRIs. In Chapter 3, we evaluated the potential value of HRUS and nerve conduction studies (NCS) in screening for PNs. Sixty adult patients with NF1, with and without peripheral nervous system symptoms, were invited for a study visit that included neurological examination, one-sided NCS and two-sided HRUS. Nerve enlargements were found in 87% of the patients, and they were often asymptomatic. We reported that patients with no or few PNs could be easily distinguished from patients with continuous PNs (high tumor load) by using HRUS. Identifying patients with high PN tumor load can help deciding on frequency of surveillance, as tumor load is associated with a higher risk of developing MPNST. NCS did not have added value for PN screening. Chapter 4 presents data from the follow-up visits in the same cohort, two years after the baseline visit. HRUS and NCS were repeated and additionally we evaluated the interobserver variability of the cross-sectional area (CSA) measurements in the median nerve. Patients identified with high tumor load at baseline remained the same at follow-up. Comparing CSA measurements over time, we observed that PNs can both increase and decrease in size within two years. There was no correlation between age and PN growth. The spontaneous decrease of PN size within two years limits the use of tumor volume as a sole marker of treatment response in uncontrolled studies. Interobserver agreement of CSA measurements in the median nerve was excellent between our observers. In Part III, we investigated the efficacy and safety of trametinib as a treatment for PNs. In the past years, MEK inhibitors have emerged as the first effective systemic therapy for inoperable PNs. Chapter 5 contains the main findings of the TRAIN trial: trametinib in adults with NF1-related symptomatic PNs. The TRAIN trial was a single-center phase 2 trial in which 30 adult patients with either generalized or mosaic NF1 and a symptomatic, inoperable PN were treated with 2 mg trametinib per day in cycles of 4 weeks. The primary outcome measure was partial response rate on tumor volume defined as at least 20% volume decrease. Tumor volume response was assessed with 3-dimensional volumetric measurements on MRI after every 6th cycle. We reported an overall partial response rate of 50%, with a median time until best response of 12 cycles. None of the patients reached progressive disease (>20% tumor volume increase) on treatment. Patient-reported outcome measures on pain and pain interference reduced significantly after one year of treatment, but quality of life remained unchanged. Adverse events were common, especially acneiform rash and fatigue. The rate of treatment discontinuation because of adverse events was 40%. In conclusion, trametinib is effective in the treatment of PNs but management of adverse events remains a challenge. Chapter 6 reported the results of the TRAIN trial on cardiotoxicity of trametinib monotherapy in adults with NF1, and provided recommendations for monitoring. In the TRAIN trial, patients were monitored for cardiotoxicity every 3rd cycle with transthoracic echocardiography, electrocardiography, blood pressure measurement and N-terminal pro-B type Natriuretic Peptide (NT-proBNP) analysis. Cancer therapy-related cardiac dysfunction (CTRCD) occurred in 7 out of 30 patients. Only one case was classified as severe CTRCD, this was also the only patient with NT-proBNP increase. Ultimately, this patient required permanent treatment discontinuation, after which the left ventricular ejection fraction recovered. A cardiac MRI did not reveal any abnormalities. In the remaining CTRCD cases, the left ventricular ejection fraction recovered spontaneously or after initiation of an ACE-inhibitor and trametinib could be continued. All cardiotoxicity occurred within the first year of treatment. We therefore recommend to perform routine monitoring for cardiotoxicity only during the first year of MEK inhibitor treatment and afterwards only when clinically warranted. In Chapter 7, the findings of this thesis were discussed in the light of other international research and recommendations were given for future studies and clinical implementation.