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Key Points in the Management of Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

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Miriam Bornhorst, MD

Clinical Director, Gilbert Neurofibromatosis Institute
Children’s National Hospital
Washington, DC

Miriam Bornhorst, MD, has no relevant financial relationships to disclose.

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Carlos Romo, MD

Assistant Professor of Neurology, Oncology and Medicine Director of Clinical Research
The Neurofibromatosis Therapeutic Acceleration Program
Department of Neurology
Johns Hopkins University School of Medicine
Baltimore, Maryland

Carlos Romo, MD, has no relevant financial relationships to disclose.

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Released: July 18, 2022

Key Takeaways

  • Asymptomatic patients may be monitored without intervention unless there is cause for concern of impending symptoms or malignancy.
  • Selumetinib is an oral targeted agent approved for patients 2 years of age or older with neurofibromatosis type 1 and inoperable plexiform neurofibromas but is not indicated for the treatment of malignant peripheral nerve sheath tumors.
  • In addition to routine labs, completion of an echocardiogram, serum creatine phosphokinase, and ophthalmology evaluation is recommended prior to initiating selumetinib.

The treatment of neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs) requires a specialized and multidisciplinary team. Various treatment modalities may be used for patients ranging in age from children to adults. It is important to recognize the presentation of NF1, as well as clinical changes throughout the course of the patient’s lifetime. The decision to treat is dependent on many factors and may include tumor location, patient symptoms, morbidity or concern for mobility, tumor growth rate, and tumor features. In this commentary based on a live symposium, Miriam Bornhorst, MD, and Carlos Romo, MD, highlight key points on treatment and clinical considerations in the management of NF1.

Treatment Options
When to Observe
Patients eligible for close monitoring without intervention are those who are asymptomatic, who do not have any signs concerning for malignant transformation of their plexiform neurofibromas; those without mass effect from the plexiform tumor to surrounding structures in a critical location, such as the mediastinum around major vessels or the trachea; and those without concern that the plexiform tumor is increasing in size with impending symptoms or neurologic deficits.

Surgery is still considered the standard of care for PNs. This modality works best for small tumors that are completely resectable. Surgery is usually considered in symptomatic patients. Establishing the goal of surgery is very important; an oncologic resection of a histologically proven high-grade malignant peripheral nerve sheath tumor (MPNST) from a biopsy should aim to excise the entire tumor en bloc and obtain wide negative margins, whereas partial resection of a benign plexiform neurofibroma for pain control might be acceptable. Surgical resection is not without potential complications, which may include new or worsening neurologic deficits, cerebrospinal fluid leak in the case of spinal tumors, and wound infections, among others. Complications are highest with spinal tumors and are more commonly associated with those located in the cervical and lumbosacral rather than the thoracic regions. When surgical resection is necessary, a comprehensive multidisciplinary team including a neurosurgeon and other surgical subspecialist should be available.

One question encountered in practice is whether surgery will make the tumor grow faster. Studies evaluating tumor progression and the rate of tumor progression following surgery have shown that although surgery does not necessarily alter the rate of tumor growth, you can see regrowth of the tumor after surgery if it is not completely resected. Based on available literature, we anticipate about 20% to 40% of patients will have tumor progression following surgery to the extent that they need to have additional intervention. Tumors of the head, neck, and face and those with less extensive resection are more likely to progress, as well as tumors resected in those younger than 10 years of age. Is it notable as well that postoperative growth rates tend to mirror those observed in the preoperative setting.

Symptom Management
We often initiate treatment for symptom management, which can include pain, edema, and neurologic deficits. Pain is a significant morbidity associated with PNs and may require therapeutic management. A referral for physical and occupational therapy should be considered when appropriate. Gabapentinoids, tricyclic antidepressants, or serotonin–norepinephrine reuptake inhibitors such as duloxetine may be initiated for the treatment of neuropathic pain. Other third-line and fourth-line agents, such as tramadol, can be considered, although these are rarely used in our practice. There are nonpharmacologic options such as alpha-lipoic acid and vitamin B12, and psychological and social support is critical when caring for patients with PNs.

When to Consider Targeted Therapy
At present, the MEK1/2 inhibitor selumetinib is the only FDA-approved medication for patients 2 years of age or older with NF1 and a symptomatic and inoperable PNs. The approval was based on the results of preclinical and clinical studies, including the phase II SPRINT trial, which demonstrated a partial response (defined as a ≥20% reduction in the target tumor) in 68% of pediatric patients with improvement in both pain and function. In an open-label phase II study in adults, selumetinib led to partial responses in 69% of patients.

Targeted therapy is considered in symptomatic patients with pain, airway compression, or neurologic deficits such as weakness, vision problems, or myelopathy. We think about targeted therapies in patients with inoperable and progressive tumors with no clinical, radiographic, or histologic evidence of malignancy. It is important to understand that oral targeted therapy is used for benign PNs and is not indicated as a single therapy for the treatment of MPNST. Additional considerations with selumetinib include the ability to swallow capsules, as this is the only available formulation and they must be swallowed whole. Patient compliance and close monitoring for adverse events is very important.

Finally, available data suggest that tumor progression may occur after discontinuation of therapy. Therefore, we generally continue the MEK inhibition until there is disease progression, intolerable toxicity, or patient characteristics that suggest the tumor will stop growing (eg, patient age).

Adverse Events and Monitoring With Selumetinib
The most common adverse events that we see with selumetinib are gastrointestinal-related symptoms (ie, nausea, vomiting, constipation, diarrhea), fatigue, and a range of skin toxicities Acneiform rash is common, particularly in older patients, as is paronychia. Eczema or eczematous-like rash is more prevalent in younger patients. Constipation is commonly encountered in practice in younger patients, and a stool softener can be initiated concomitantly with selumetinib. An increase in creatine phosphokinase (CPK) occurs commonly as well and should be monitored, although most patients remain asymptomatic and do not require dose reductions.

Due to the risk of cardiomyopathy, increased CPK, and ocular toxicity, an echocardiogram, serum CPK, and ophthalmology evaluation are recommended before initiating selumetinib. Changes in echocardiogram can occur at any time during treatment and may be seen after the patient has been receiving therapy for many years. It is important to monitor with routine physical exams and to obtain periodic echocardiograms to monitor for changes in left ventricular ejection fraction.

The is little to no role for radiation in benign PNs. The efficacy of this modality is not understood, and it increases the risk of secondary malignancy, particularly in NF1. Radiation in NF1 may be considered in the treatment of patients with MPNST, usually when the tumor is high grade and its size is ≥5 cm.

When to Consider Clinical Trials
We should always consider clinical trial enrollment. Unfortunately, there is a lack of access to clinical studies in many cases. Even if patients are unable to participate in treatment studies, there are opportunities for natural history, imaging, and biomarker development studies, as well as tissue sample donation.

Malignant Transformation
Currently, there is no ideal or standardized method for identifying which patients are at risk of malignant transformation. However, some factors are thought to contribute to an increased risk, including:

  • Deeper tumors, as opposed to those that are more superficial and involving the skin
  • Large number of tumors and large volume of tumor burden
  • Family or personal history of MPNST
  • Atypical neurofibromas or atypical neurofibromatosis neoplasms of uncertain biological potential
  • Having a distinct nodular lesion, typically approximately ≥3 cm in size
  • NF1 gene microdeletion syndrome (typically characterized by a more severe phenotype)
  • Prior exposure to radiation

How do we monitor these tumors? We obtain MRIs at baseline to evaluate anatomic extent and relation to other structures in the area, as well as for future comparison to demonstrate objective measurement of tumor growth. However, there is no clear consensus on surveillance, and generally routine MRIs of the neuroaxis are not recommended in patients who are asymptomatic. Although PET/CT scans may be helpful for monitoring, there is no guidance on how frequently or in which specific patient populations they should be used.

Serial PET and CT scans have been explored for surveillance in pediatric patients; we do not use these imaging modalities in our clinical practice to minimize exposure to radiation, especially when data support good sensitivity and specificity of MRI. We use whole-body MRI with diffusion-weighted sequences and apparent diffusion coefficient mapping in those considered to be at high risk—patients with the risk factors mentioned before. Based on imaging characteristics, the neurofibromas are then categorized as being either likely benign, suspicious but uncertain, or highly suspicious for malignancy. This approach requires prospective validation, and research is underway to better understand its benefits and limitations.

Clinical causes for concern that may prompt imaging include palpable or visual tumor growth and new report of pain or change in its semiology (quality, intensity, and frequency).

Your Thoughts?
What challenges have you encountered when managing patients with NF1 and inoperable PNs? Answer the polling question and join the conversation by posting a comment in the discussion section below.

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