Natural History and Disease Burden of Neurofibromatosis Type 1 with Plexiform Neurofibromas: A Systematic Literature Review

Figures & data

Figure 1 PRISMA diagram.

Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Criteria for Study Inclusion

	Inclusion Criteria
Populations	Patients with NF1 with PN
	Patients with NF1 without PN
Outcomes	Disease overview
	Demographics
	Clinical characteristics
	Disease progression/natural history
	Disease complications
	Impact on patient functioning and health-related quality of life
	Mortality/survival
	Treatment
	Practice patterns/treatment patterns
	Medications
	Surgery
	Resource-use estimates
	Drug utilization
	Outpatient and emergency department visits
	Imaging costs (eg, MRI, CT, PET)
	Number of hospitalizations and length of stay
	Management of drug-related adverse events
	Direct costs
	Medication costs
	Outpatient visit costs
	Hospitalization costs
	Emergency department visits
	Laboratory costs
	Diagnostic costs
	Physician costs
	Costs of managing drug-related adverse events
	Indirect or other costs of interest, including the following
	Productivity loss of patient (wages lost from absences)
	Out-of-pocket expenses
	Travel costs for patient
	Caregiver burden
Time	The database searches will be performed for the past 10 years, except for disease overview, which will be for the past 5 years
Study design	Prospective (including clinical trials), retrospective, cross-sectional, or other studies
	Systematic literature reviews
Other	Electronic database searches will be limited to articles published in the English language

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; NF1, neurofibromatosis type 1; PET, positron emission tomography; PN, plexiform neurofibroma.

Table 2 Summaries of Plexiform Neurofibromas Growth

Reference	Study Details	Population	Follow-Up Period	Key Findings
Dombi et al^Citation25	US longitudinal study to analyze changes in PN volume in relation to age and body growth in children and young adults with NF1 and inoperable, symptomatic, or progressive PNs, using a sensitive, automated method of volumetric MRI analysis	N = 49 Median age: 8.3 years	Median: 34 months	Included patients had a total of 61 PNs 69% of patients experienced an increase of ≥20% of PN volume PN volume increased more rapidly than body weight over time (P = 0.026) Younger patients had the most rapid PN growth rate
Nguyen et al^Citation26	German retrospective study to assess internal PNs using volumetric WBMRI	N = 171 Median age: 28.6 years	Median 2.2 years	71 of the 171 included patients had a total of 200 PNs Median growth rate in whole-body tumor volume was 3.7% per year This growth rate correlated with larger whole-body tumor volume (P < 0.001) and younger age (P = 0.004) 13.5% of individual tumors increased in size by >20% per year, on average; these were significantly more frequent among children than among adults (P < 0.001) 70% of these tumors were found in pediatric patients, representing 29% of tumors found in the pediatric age group 30% of these tumors were found in those aged >18 years, representing 6.0% of tumors found in this age group
Gross et al^Citation11	Retrospective review of patients enrolled in the National Cancer Institute Natural History Study of Patients with Neurofibromatosis Type 1 (NCT00924196) using volumetric MRI analysis	N = 41 Median age: 8 years	At least yearly until age 18, then every 1–3 years	Included patients had a total of 57 PNs 86% of PNs had >20% increase in tumor volume from baseline to maximum assessment Median 108.9% change in PN volume between baseline and maximum assessment Observed 15.9% per year median PN growth rate Median PN growth rate was 35.1% per year in patients aged 3–5 years and 13.1% per year for patients aged 11–25 years Patients with NF1 and PN who reported increased use of pain medication experienced 21% growth in PNs per year (vs 13% growth in PNs per year in patients with NF1 and PN who did not report increased use of pain medication)
Tucker et al^Citation27	German study to characterize the growth of PNs in patients with NF1 between 1990 and 2006 using serial MRIs	N = 34 Mean age: 10 years	Median: 6.0 years	Included patients had a total of 44 PNs 14 PNs were symptomatic (4 were superficial and displacing, 3 were superficial and invasive, 2 were deep and displacing, and 5 were deep and invasive) Superficial tumors grew significantly more quickly than deep tumors (P = 0.034) The growth rate of tumors was significantly greater in patients aged <10 years at initial examination than in patients aged >10 years at initial examination (0.7 cm^2/year vs 0.03 cm^2/year; P = 0.014) 30% of the PNs identified in patients aged <10 years (n = 18) were symptomatic, which included 4 of 9 (44%) rapidly progressing tumors
Dagalakis et al^Citation28	Retrospective study using data from the National Cancer Institute NF1 Natural History Study to evaluate the relationship between pubertal progression and change in PN burden over time in pediatric and young adult patients with NF1 and PN	N = 41 Actively progressing through puberty (n = 16); age range: 7–20 years Peripubertal (n = 25); age range: 6–11 years and 17–33 years	Mean: 20 months	The number of PNs was not stated No statistically significant differences in tumor burden change over time between the groups (P = 0.31) No statistically significant differences in peripubertal and pubertal PN growth rates (P = 0.90)

Abbreviations: MRI, magnetic resonance imaging; NF1, neurofibromatosis type 1; PN, plexiform neurofibroma; WBMRI, whole-body magnetic resonance imaging.

Table 3 Summary of Quality of Life Burden Data

Reference	Study Design	Population	PRO Instrument(s)	Key Findings
Lai et al^Citation29	Concept elicitation interviews to develop a conceptual model of NF1 with PN experience	Adults with NF1 with PN (n=16) Children and adolescents with NF1 with PN (n=15) Parents of children with NF1 with PN (n=17)	None	Five domains were identified: pain, social functioning, physical function impact, stigma, and emotional distress
Lai et al^Citation30	Qualitative study	Children with NF1 with PN n =140	PROMIS; Neuro-QOL	Children with NF1 with PN reported worse scores than population norms for all domains except fatigue and pain Boys reported significantly worse pain interference, stigma, meaning and purpose, mobility function, and upper extremity function than girls
Rosser^Citation32	Prospective study of patients who enrolled in NF Clinical Trials Consortium PN treatment trials	Adolescents with NF1 with PN n=38	Numeric Rating Scale; Brief Pain Inventory; Pain Interference Scale; NF1 PedsQL Scale	Patients reported considerable pain, with 42% of patients taking pain medication regularly Most affected QOL domains were physical functioning, worry, pain/hurt, and fatigue
Wolters et al^Citation31	Prospective natural history study	Children and adolescents with NF1 with PN n=41	Impact of Pediatric Illness Scale	Pain was found to interfere with daily functioning in most youths, even when they used pain medication Total tumor volume and social-emotional problems predict pain interference, while disease complications, pain interference, and social-emotional problems predict overall QOL

Abbreviations: Neuro-QOL, Quality of Life in Neurological Disorders; NF1, neurofibromatosis type 1; PedsQL, Pediatric Quality of Life Inventory; PN, plexiform neurofibroma; PRO, patient-reported outcome; PROMIS, Patient-Reported Outcomes Measurement Information System; QOL, quality of life.

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