Not all PN require intervention and there is no single treatment pathway for patients with NF1-PN; watchful waiting, surgery, medical treatment, or a combination of these modalities are all possible options [
30]. Treatment should be individualized based on recommendations from the MDT, including consideration of the size and location of the PN, growth trajectory, effects on adjacent tissues, and current or potential complications while taking into account patient and family preferences [
29,
30]. Many factors influence treatment decisions, such as the age of the patient, the severity of symptoms and the presence of NF1-related comorbidities, and the possibility of developing severe and irreversible complications if PN continue to grow [
30]. These factors affect decisions regarding the suitability and preference for observation versus treatment and, when treatment is preferred, for surgical versus medical treatment [
30]. In addition, it may be beneficial for patients to travel to specialist facilities for diagnosis and treatment; however, we recognize that frequent, long-distance travel is not always feasible. Therefore, a combination of local toxicity evaluations, such as blood tests, telemedicine visits, and attempts to collaborate with local providers could be used once a care plan has been determined. This co-management of patients may improve as awareness of the diagnosis and management of NF1 increases [
29].
Surgery
As described above, complete resection and debulking surgery are important treatment strategies for PN, having the advantage of providing immediate relief from large and/or painful PN, whereas medical therapy typically takes longer to provide relief [
73].
Debulking surgery, when complete resection is not feasible, is typically directed at large PN that may be impinging on vital structures including the airway or spinal cord or at improving PN-related disfigurement or organ function, such as renal function when there is obstructive hydronephrosis. As such, PN location and structural characteristics are important considerations prior to surgical resection. Surgery is inherently more challenging when a PN involves structures located in the head or neck, mediastinum, or deep pelvis. PN that involve the brachial or lumbar plexus often affect motor function, cause pain, and require specialized expertise for surgical debulking or excision. Common indications for surgical resection include neurologic dysfunction, pain, airway difficulties, disfigurement, orthopedic issues, the need for diagnostic biopsies, or pre-malignancy [
24,
36,
74]. NF1-PN are typically highly vascular and blood loss may limit the surgical procedure; hence, in our experience, debulking of large superficial NF1-PN is often staged with multiple surgeries [
42,
75]. Pre-operative embolization can be used to mitigate the inherent risk of hemorrhage due to the vascularity of NF1-PN, which is more frequent with large neurofibromas located in anatomic regions where a tourniquet cannot be applied, which can lead to major surgical morbidity [
41,
42]. Furthermore, once there is a suggestion of malignant or pre-malignant degeneration in a PN (evaluated by pre-operative biopsy or imaging),
18FDG PET MRI or CT combined with regional MRI may be advised and timely surgical resection of the targeted area is warranted [
76‐
78]. NF1-PN debulking requires the surgeon to constantly balance the risks of neurologic deficit, bleeding, and potential compromise of adjacent structures with the benefit of resection. Intra-operative clinical decision making is critical to achieve this balance.
Because the primary goal of treatment is to improve or prevent PN-associated morbidity, predicted outcome is an important consideration when selecting a surgical treatment option. Surgical outcomes can be variable and a proportion of patients who undergo surgery may experience either no change in PN-related symptoms or only partial resolution [
75]. In addition, PN regrowth after surgery is not uncommon, especially in patients younger than 21 years of age [
24,
74,
75]. Indeed, rates of PN regrowth after partial resection have been reported to range from 29 to 68% depending on the extent of resection and can be 20% after complete excision, although confirming complete resection can be challenging [
24,
74]. Younger age in addition to tumor type, location (tumors of facial area or trunk), depth, and diffuse growth type are associated with tumor recurrence [
75]. Postoperative PN regrowth has historically been a cause for concern, which led to a cautious approach regarding the surgical management of NF1-PN; however, postoperative progression of PN may not be significantly different from the natural growth behavior, suggesting that postoperative tumor growth could be unrelated to and not promoted by surgery [
75].
Medical therapy
In addition to surgery, medical therapy is now an available treatment option for NF1-PN. Data from recent MEK inhibitor clinical trials are available to guide clinical treatment decision making. However, much remains to be learned about optimal use of medical therapy and ways in which we can combine medical and surgical treatment to optimize outcomes for individual patients.
Currently, the only approved medical therapy for NF1-PN is selumetinib, which is indicated for the treatment of pediatric patients (aged ≥ 2 years in the US and aged ≥ 3 years in Europe) with NF1 who have symptomatic, inoperable PN [
56,
57]. An inoperable PN was defined as a PN that could not be removed completely by surgery without risk of substantial morbidity, or if the patient or family refused a surgical approach [
79]. Examples of symptomatic PN include those with associated pain, disfigurement, and functional impairment. In contrast, another population to consider are those with PN that although not currently associated with morbidity pose a risk of future tumor-related complications [
49,
50]. Examples include head and neck PN that could compromise the airway or great vessels or brachial or lumbar plexus PN that could cause nerve compression and loss of function [
58].
Although treatment with a MEK inhibitor is indicated in patients with inoperable, symptomatic NF1-PN, there are data to suggest that treatment of patients with inoperable PN not currently causing clinically significant morbidity but deemed at risk for developing serious PN-related complications may be effective in preventing PN growth and PN-related morbidity [
80,
81]. Indeed, in SPRINT, patients with no significant PN-related morbidity at enrollment but the potential for development of PN morbidity (stratum 2) demonstrated a PR rate similar to patients with PN-related morbidity at enrollment (stratum 1) (68% vs. 71%) [
50,
58]. Therefore, further research is warranted to determine whether it is beneficial to initiate treatment prior to the onset of symptoms, thereby showing the effectiveness of reducing PN volume and preventing PN from becoming symptomatic, particularly in selected at-risk patients with rapidly progressing PN.
Treatment with targeted therapy also has the potential to facilitate multimodal therapy for large inoperable PN and to achieve better clinical response or time to progression [
46]. A case report describes an 11-year-old girl with NF1 in whom extensive growth of cervical PN masses rendered the cervical column inaccessible to recommended surgical intervention to prevent paraplegia. Treatment with trametinib initiated with a single 0.05 mg (0.015 mg/kg) dose, increased after 1 week to 0.5 mg (0.03 mg/kg) twice daily for 6 months, resulted in a 22% reduction in tumor volume, which was sufficient to enable surgery [
82]. Prospective studies of pre- and post-operative MEK inhibition are required to develop and validate a multimodal treatment algorithm and to more comprehensively understand how medical therapy and surgical approaches may augment each other in the treatment of NF1-PN. Furthermore, it has been proposed that by understanding the mechanism of response for NF1-PN, the development of rational combinations of MEK inhibitors with other targeted or cytotoxic therapies may be possible [
83].
Medical therapy may also play a role in patients with PN that are associated with more severe symptoms and/or causing substantial morbidity; for example, organ dysfunction such as hydronephrosis, airway compression, or sensory dysfunction from a head or neck PN [
18,
30,
84]. Among pediatric and adult patients with NF1-PN and spinal neurofibromas (associated with pain numbness, paresthesia, motor weakness, or gait abnormalities), treatment with selumetinib (12 cycles at the recommended dose of 25 mg/m
2 twice daily) was associated with a reduction in spinal neurofibroma burden and associated improvements in spinal canal distortion, circumferential cerebrospinal fluid disruption, and spinal cord deformity [
85].
Another key consideration in clinical decision making is that younger patients appear to be more likely to benefit from early initiation of a MEK inhibitor. Rapidly growing PN tend to be observed in younger children (i.e., aged ≤ 5 years), and progressive PN (those that grow by ≥ 20% per year) are unusual after adolescence [
17,
19,
86]. An analysis of data from the SPRINT trial showed that children who achieved a PR were slightly younger (median age 9.5 years) than those who did not (median age 13.3 years); however, age did not correlate with maximal PN shrinkage in patients who achieved a PR [
80]. Clinical experience suggests that younger patients tolerate medical therapy better and have better medication adherence than adolescents [
80]. However, it is important to note that selumetinib is currently dosed in a fasted state, which may be considered a limitation for some [
56]. These potential advantages of early initiation of medical therapy must be balanced against a lack of long-term data regarding the effect of MEK inhibition on growth and development and whether medical therapy changes the natural history of PN.
The optimal duration of therapy with a MEK inhibitor is still unknown. In the SPRINT trial, a median of eight cycles or 6.9 months of treatment with selumetinib was required before evidence of a PR became apparent [
80]. This is similar to the time to response observed with other MEK inhibitors such as binimetinib (12 cycles) [
55]. However, in SPRINT, symptomatic benefit often occurred before or in the absence of radiological benefit [
50]. It is as yet unclear how long treatment must be continued to sustain clinical benefit for these patients. The results of natural history studies of the growth of PN suggest that extended treatment may be required [
73]. The median duration of response was not reached in the phase II part of SPRINT; however, 82% of patients with a confirmed PR had a duration of response of at least 12 months, and the 3-year PFS was 84% [
50]. Prospective studies are required to determine whether it is possible to discontinue MEK inhibitor treatment once growth of PN has slowed or stopped in late adolescence or in young adulthood [
73]. It is also important to consider the safety profile of MEK inhibitors when considering longer-term treatment; careful monitoring and management of AEs is critical (Table
4).
Table 4
Monitoring and management of significant adverse events associated with selumetinib therapy [
56]
Rash | 91% | Monitor for rash at each encounter | Withhold treatment, reduce dose, or discontinue selumetinib |
Diarrhea | 77% | Monitor for diarrhea at each encounter | Loperamide Increase fluid intake Withhold treatment, reduce dose, or discontinue selumetinib |
Increased CPK | 76% | Measure CPK at baseline | Evaluate patients for rhabdomyolysis if CPK is increased Withhold treatment, reduce dose, or discontinue selumetinib |
LVEF ≥ 10% below baseline (and below institutional lower limit) | 23% | Echocardiogram at baseline, q3 months during the first year, and q6 months thereafter | Perform echocardiogram Withhold treatment, reduce dose, or discontinue selumetinib |
Ocular toxicity (blurred vision, photophobia, cataracts, and ocular hypertension) | 15% | Ophthalmic exam at baseline, and at regular intervals thereafter Optical coherence tomography q3 weeks until resolution in patients with RPED | Perform ophthalmic exam Withhold treatment, reduce dose, or discontinue selumetinib depending on severity Withhold selumetinib in patients with RPED, resume once resolved Discontinue selumetinib in patients with RVO |
It is important to note that clinical trials use sophisticated volumetric analysis that may not be available at all institutions. In a real-world clinical setting, radiologic progression may be monitored with standard MRI techniques; moreover, symptomatic improvement may be preferred to radiologic measurements to monitor the efficacy of treatment. Indeed, radiologic responses alone are not considered to be sufficient evidence of efficacy by the US Food and Drug Administration (FDA). The SPRINT trial was designed to show that reductions in PN volume (objective responses) were accompanied by detectable clinical improvements in PN as reflected by reductions in functional impairment, symptoms, or disfigurement, and improvement in QoL [
87]. It is also important to understand and not be discouraged when there is no measurable PN shrinkage using standard MRI, which can be less sensitive at detecting changes in PN volume compared with volumetric MRI.