Typically diagnosed in early childhood, neurofibromatosis type 1 (NF1) is a rare, progressive, genetic condition characterized by benign tumors called plexiform neurofibromas (PN) that develop along nerve sheaths throughout the body.1-4 Though benign, PN are highly variable and, depending on their size and location, have the potential to cause serious clinical complications, including pain, disfigurement, loss of function, spinal compression, and airway obstruction.5,6

The unpredictability and complexity of NF1 PN make this a particularly challenging disease to treat.1,5,6

NF1 PN

NF1 PN: A progressive disease that may have a big impact on patients

NF1 is caused by mutations in the NF1 gene that codes for neurofibromin.6

  • Changes in the function of neurofibromin, a natural tumor suppressor protein, are associated with overactivation of RAS, leading to cellular proliferation and, ultimately, tumor formation6-8

PN are one of the most prevalent morbidities associated with NF1

  • NF1 occurs in 1 out of every 3000 individuals2

  • 30% to 50% of patients with NF1 will develop PN2

  • These tumors are highly variable in terms of size, shape, and growth rate, making it impossible to predict disease severity for any individual patient1,5

Because they can grow along any peripheral nerve in the body, PN have the potential to affect multiple organs, causing major clinical complications.2,6

PN are often progressive when left untreated

Plexiform neurofibromas typically manifest at birth, with rapid growth usually occurring during the first decade of life.2,9

The National Cancer Institute (NCI) conducted a long-term Natural History study of patients with NF1, which highlighted the progressive nature of plexiform neurofibromas and the development of PN-related morbidities.10

Out of 92 patients in the
Natural History study,
76% had
≥20% increase in PN volume
over a 2.8-year period
 10

Percentage Change in Target PN Volume
Percentage Change in Target PN Volume

*The Natural History study began enrollment in 2008 and is ongoing. As of October 2018, 111 patients were enrolled who had NF-related PN. 92 patients with NF1-related PN between the ages of 3 and 18 years who had at least 2 volumetric scans during the Natural History study are presented above.10

Of the 111 patients enrolled in the Natural History study by October 2018, a subset of 41 patients was selected for inclusion in a retrospective analysis based on the following eligibility criteria11:

  • Patients had comprehensive evaluations at least yearly until age 18 and thereafter at least every 3 years to characterize NF1-related manifestations

  • Patients were required to have at least one PN, with MRI evaluation performed at 2 or more timepoints

  • PN-related symptoms (pain, motor, vision, bowel, bladder, and airway morbidities) were assessed

  • Patients had at least 7 years of clinical data

Consistent with previous studies, patients had PN that were widely distributed throughout the body11:

PN Widely Distributed Throughout Body

Conclusions from this retrospective subset analysis of 41 patients (with 57 PN) included11:

  • Median PN growth rate per year was 15.9%

  • 86% of PN had >20% increase in tumor volume from baseline to maximum assessment

  • Median PN volume change between baseline and maximum assessments was 108.9%

  • >52% of PN had an increase in the number of associated functional morbidities between baseline and maximum PN volume assessment

  • The majority of PN had already resulted in morbidities at baseline (median age at baseline was 8 years) and even smaller tumors could result in morbidity depending on their location

Because untreated PN tend
to be
progressive and often result in
increasing morbidities,
early evaluation
and intervention are critical
 11,12

MRI=magnetic resonance imaging; RAS=rat sarcoma viral oncogene homolog.

Learn about a treatment option for NF1 PN

CLINICAL COMPLICATIONS

NF1-related PN can lead to major clinical complications

Plexiform tumors are typically present at birth.2 During a child’s early years, the only visible sign may be areas of discoloration or subtle soft-tissue overgrowth.5 Some plexiform tumors may be located so deeply within the body that they go unnoticed until pain or other symptoms become present.5

However, plexiform tumors can rapidly grow to much larger sizes.5,12

One study found that nearly 77%
of PN are invasive or displacing,

meaning that they infiltrate multiple
planes of tissue or put pressure on
nearby
structures in the body, which
can result in significant morbidity
 13

PN Scan

Although benign, plexiform neurofibromas represent a major source of morbidity, with the potential to cause2,11:

Pain

Chronic PN-related pain may require ongoing
management with pain medication14

Disfigurement

PN tumors located in the head,
neck, and face can
result in highly visible deformities5

Spinal cord compression

PN can compress nerves, resulting in pain,
weakness, numbness, and loss of motor function,
as well as bladder or bowel dysfunction5

Vision impairment

When located near the orbital area,
PN can result in loss of vision15

Airway compromise

PN that grow within the chest
can compromise breathing ability5

Even small tumors may cause
significant morbidity
depending
on their location
 11

In the previously mentioned retrospective analysis of the NCI Natural History study, a subset of 41 patients were evaluated. Collectively, these patients reported 57 distinct PN (with some patients reporting multiple tumors). These PN were evaluated at baseline and at their individual maximum volume assessment. Conclusions from this analysis included11:

PN tended to develop early 11

  • 70% of the PN evaluated had at least 1 associated morbidity at baseline (median baseline patient age was 8 years) 11

    • At baseline, the most common morbidity was pain (associated with 37% of PN)

Functional morbidities tended to increase over time 11

  • Between baseline and maximum PN volume assessment:

    • >52% of the PN evaluated had an increase in the number of associated functional morbidities 11

    • The number of PN with motor-related morbidities doubled 11

    • 8 PN, which had zero associated functional morbidities at baseline, developed 1 or more 11

Faster-growing PN were associated with increased use of pain medication 11

  • 27 PN required an increase in the number of pain medications between baseline and maximum PN volume assessment 11

  • PN requiring an increase in pain medication generally grew faster than those PN that did not result in increased pain medication (median annual PN growth of 21% vs 13%) 11

PN are frequently associated
with clinically significant
morbidities,
making early detection
and intervention critical
 11

NCI=National Cancer Institute.

Learn about a treatment option for NF1 PN

TREATMENT CHALLENGES

NF1-related PN surgical challenges

Surgical removal may be an option and should be considered in the case of aesthetic disfigurement, pain, or functional deficits.1

However, the nature and structure of plexiform neurofibromas make complete resection challenging, and many of these tumors are deemed inoperable for reasons that include5,6:

Infiltrative quality

PN can be large and irregularly shaped, with a tendency to infiltrate beyond the nerve sheath into surrounding layers of tissue.5,6

  • Even partial removal can be difficult if the tumor has intertwined itself with vital tissue or nerves 5

Challenging locations

PN are often located in surgically challenging areas such as the head, neck, chest, or spine.5

  • PN located within the brachial plexus, the network of nerves that connect the arm and hands to the spinal cord, may be difficult to completely remove without sacrificing function or causing serious disability 5

High vascularity

PN tend to be overvascularized, which increases the risk of bleeding and the need for transfusion during surgery.5

  • Hematoma and delayed wound healing are also common complications 5

For patients with inoperable PN, treatment may focus on symptomatic management and a careful “watch and wait” approach in which tumors are routinely reassessed.5,6

NF1 PN is a difficult-to-treat condition due to its unpredictability, progressive nature, and potential for serious clinical complications. 1,5,6 Disease management is complex and requires a multidisciplinary approach to manage the physical symptoms and challenges that affect pediatric patients and their parents or caregivers. 5,16

Maintaining an open dialogue and engaging patients and caregivers throughout their journey can help them better manage treatment decisions as they cope with this debilitating condition. 5

Learn about a treatment option for NF1 PN

NF1 with PNs:
A rare disease with enormous impact on patients and caregivers

Neurofibromatosis (NF) is a rare, progressive neurogenetic condition characterized by diverse and progressive manifestations that can include cutaneous, neurologic, skeletal, and neoplastic features3,4

  • NF1 is caused by mutations in the NF1 gene that code for neurofibromin5
    • Depletion of neurofibromin, a natural tumor suppressor, is associated with elevated RAS activity and cellular proliferation, which can result in the formation of tumors
  • NF1 is typically diagnosed in early childhood and occurs in an estimated 1 out of every 3000 live births6-8

RAS=rat sarcoma viral oncogene homolog.

PNs are a significant challenge for patients with NF1

  • 30% to 50% of patients with NF1 can develop PNs, which are tumors that grow along the nerve. Five to 10 percent of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNSTs)7
  • Many PNs are considered inoperable for reasons that include:
    • Their complexity, invasive nature, and tendency to grow within and throughout the nerve sheath, all of which compromise the ability to achieve clear margins7,9
    • Common locations, such as the head, neck, spine, and trunk, which may be surgically challenging1,9
    • The risk of neurological damage and functional impairment as a result of surgery6
    • The tumors’ vascularity and high propensity to bleed during surgery4,10
  • NF1 with PNs is usually treated with a clinical team approach including geneticists, neurologists, oncologists, surgeons, as well as other health care professionals from relevant disciplines11,12

Consider the disease burden of NF1 with PNs

The pain, disfigurement, and functional impairment associated with NF1 has a significant impact on patients’ and caregivers’ quality of life and emotional well-being

  • NF1 has a high burden of illness, particularly in patients with inoperable PNs2
  • Individuals with NF1 are prone to developing both benign and malignant tumors of the CNS and peripheral nervous system2
  • Tumors growing >20% per year have been shown to be significantly more frequent in children than adults13
  • Patients may have better results when PNs are detected and addressed early14

CNS=central nervous system.

The pain that PNs inflict goes beyond physical impairment into psychosocial issues

  • The lifelong consequences of NF1 include patients’ social alienation due to the visible nature of the disease and caregivers’ psychosocial and stress-related issues10
  • The complex and unpredictable nature of the disease leads to a strong likelihood of psychological issues for patients, which can diminish their ability to experience a happy and fully engaged childhood6

NF1 with PNs can also emotionally impact caregivers

  • Caregivers can experience significant emotional turmoil, including feelings of fear, anger, sadness, grief, and guilt2
  • Symptoms of anxiety and depression are common for both patients and their caregivers, and psychiatrists and counselors can play an important role in managing psychological complications2

Current treatment for NF1 with PNs

Treatment for NF1 can be complex due to the lifelong impact of the disease, the need to surgically address the lesions, and the complications that may affect multiple organ systems2,11,15

  • Surgical removal or debulking of PNs has been a mainstay of NF1 treatment; in some cases, surgical outcomes are favorable and lead to symptomatic improvement. Unfortunately, many PNs are deemed inoperable due to their2,11,15
    • Size
    • Location
    • Involvement with nerves and organs
  • For these patients, treatment may focus on symptomatic management and a careful monitoring approach in which tumors are routinely reassessed2
  • Prognosis is poor for MPNSTs in patients with NF1. Treatment often requires off-label chemotherapy regimens that may include the use of doxorubicin and ifosfamide4,11
    • There is currently no effective chemotherapy treatment regimen for PNs in NF12,7
  • Currently there are no FDA-approved pharmacological treatments for PNs2,7

Therapy for other complications of NF1

  • Treatment for mobility issues related to NF1 include surgery, supplements for bones (such as calcium and vitamin D), and lifestyle modifications (such as wearing a brace and/or receiving physical therapy)2,7
  • Treatment for pain can include analgesics, including opioids and neuropathic pain remedies, and surgical debulking2,6
    • Data suggest that 12% of children with PNs take narcotics and more than 70% of children and adults with NF1 use prescription pain medications16
  • For NF1-related neurobehavioral issues such as cognitive deficits, patients may receive lovastatin and ADHD medications, while psychosocial treatments may involve antidepressants7

ADHD=Attention-deficit/hyperactivity disorder.

NF1 with PNs is a particularly difficult disease state due to its unpredictability, potential for disfigurement, and the emotional burden placed on children and their caregivers. Treatment is complex and requires a multidisciplinary approach to manage the physical symptoms and complications of PNs, as well as the psychosocial challenges.2,7

Maintaining an open dialogue, promptly discussing health-related changes, and engaging patients and caregivers as much as possible throughout their journey can help them cope with this rare and devastating condition.2

References:

1. Tonsgard JH. Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006;13(1):2-7. 2. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: A multidisciplinary approach to care. Lancet Neurol. 2014;13(8):834-843. 3. Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016;18(5):624-638. 4. Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, et al. Recommendations for imaging tumor response in neurofibromatosis clinical trials. Neurology. 2013;81(21 Suppl 1):S33-S40. 5. Korf BR, Rubenstein AE. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. New York, NY: Thieme Medical Publishers; 2005. 6. Hersh JH. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121(3):633-642. 7. Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited—from bench to bedside. Oncotarget. 2014;5(15):5873-5892. 8. Adil A, Singh A. Neurofibromatosis Type 1 (Von Recklinghausen). https://www.ncbi.nlm.nih.gov/books/NBK459358/?report=printable. Updated June 3, 2019. Accessed May 20, 2020. 9. Anderson JL, Gutmann DH. Neurofibromatosis type 1. In: Islam MP, Roach SE, eds. Neurocutaneous Syndromes. Waltham, MA: Elsevier B.V.; 2015:75-86. Handbook of Clinical Neurology. 3rd series; vol 132. 10. Data on File, REF-75729, AstraZeneca Pharmaceuticals LP. 11. Gross AM, Singh G, Akshintala S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018;20(12):1643-1651. 12. Friedrich RE, Schmelzle R, Hartmann M, Fünsterer C, Mautner V-F. Resection of small plexiform neurofibromas in neurofibromatosis type 1 children. World J Surg Oncol. 2005;3(1):6. 13. Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Fünsterer C. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology. 2006;48(3):160-165. 14. Wolters PL, Burns KM, Martin S, et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet A. 2015;167A(9):2103-2113. 15. Avery RA, Katowitz JA, Fisher MJ, et al. Orbital/peri-orbital plexiform neurofibromas in children with neurofibromatosis type 1: multi-disciplinary recommendations for care. Ophthalmology. 2017;124(1):123-132. 16. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44:81-88.