Abstract
Introduction
Neurofibromatosis type 1 (NF1) is a neurogenetic condition present in approximately 1 in 3000 births. 1 Plexiform neurofibromas (pNFs) are present in about half of NF1 cases. 2 These are benign tumours that grow along deep nerves 3 and are thought to be present from birth. 4 They are frequently associated with functional and neurological deficits, disfigurement and substantial pain. 5 There is a lifetime risk of malignant transformation in pNFs and they may cause compression of the airways or vital organs. As a source of major morbidity in NF1, pNFs have a profound impact on an individual’s quality of life (QoL). 6
Currently, there is no cure for pNFs. Surgical resection is the best therapeutic option for symptomatic pNFs. However, surgery can be challenging and is not always technically possible. 7 Surgery is unlikely to result in permanent removal of the tumour and may cause further complications including nerve damage and functional impairment.8–10 There are multiple recent clinical trials designed to stop the growth, reduce the size and improve the symptoms of pNFs (e.g. NCT02177825, NCT03231306, NCT02407405, NCT03326388, NCT0239075 and NCT01362803). These trials used some form of tumour size measurement as the endpoint for the therapeutic study, as radiographic response is an important marker of drug activity. However, it is also important to demonstrate that treatment results in participants feeling better to add context and meaningful clinical impact to imaging improvement in clinical studies.
In addition to imaging tumour response, common outcomes employed in clinical trials include assessment of signs, symptoms and functions. 11 Such data are commonly collected via patient-reported outcome measures (PROMs). Most PROMs assess Health-related Quality of Life (HRQL). This construct consists of a variety of different impairments and functional limitations resulting from disease. 12
Several studies have looked at the impact of NF1 on HRQL.13–35 Most of these studies focused on children and adolescents.
QoL is a distinct outcome from HRQL. Rather than producing a profile of symptoms and functional limitations, QoL provides a holistic assessment of the value of an individual’s life in the context of their health status. The needs-based model 36 is a widely operationalised approach to QoL measurement in health research. The model was derived from research conducted with depressed and recently recovered depressed participants. 37 Qualitative interviews revealed that individuals’ experiences of depression were described in terms of the needs that they were unable to meet. The needs-based model postulates that life gains its quality from our ability to fulfil basic human needs. An individual is considered to have poor QoL when few needs are satisfied. 36 The impairments and functional limitations imposed by disease prevent needs from being fulfilled. Consequently, a needs-based approach allows the impacts of disease to be directly assessed rather than inferred. The needs-based model forms the theoretical basis for this study. In addition to providing insight into the impact of NF1-associated pNFs on the lives of patients, the study was also used to develop the content for a patient-reported outcome (PRO) measure suitable for use with this patient group. Such a measure would be used in conjunction with other outcome measures in therapeutic trials.
Methods
Ethics approval
In the United Kingdom, ethics committee approval was obtained from North West-Liverpool Central Research Ethics Committee (14/NW/0279). In the United States, approval was granted by the Johns Hopkins University School of Medicine (JHU-SOM) Institutional Review Board.
Participants
Individuals with NF1 (defined by meeting clinical criteria or positive genetic testing), >18 years, with at least one pNF in any location, were eligible for the study. A pNF was defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches; or a spinal neurofibroma that involves two or more levels with connection between the levels or extending laterally along the nerve; or a skin thickness neurofibroma that measures >3 cm on longest diameter by visual examination, palpation or two-dimensional (2D) magnetic resonance (MR) imaging; or >3 mL by volumetric MR imaging. Potential participants were identified through convenience sampling from the clinics they attended: Saint Mary’s Hospital, Manchester and Johns Hopkins Comprehensive Neurofibromatosis Centre, Baltimore. Patients were sent a letter in the post inviting them to participate in the study. Those interested were asked to contact the local researchers to arrange a convenient date and time for the interview. In the United Kingdom, interviewees were given the option of being interviewed in their own home, the offices of Galen Research or in a private room at Saint Mary’s Hospital. US interviews were conducted at Johns Hopkins Comprehensive Neurofibromatosis Centre. Individuals with cognitive difficulties who were unable to give consent were not enrolled. All participants provided written informed consent.
Patient interviews
One-to-one unstructured, qualitative interviews were conducted by three male and one female interviewers (aged 24–63 years), including S.P.M. and J.W. All interviewers have a degree in psychology and extensive experience in conducting qualitative interviews with patients. At the beginning of each interview, the interviewer introduced his/herself and explained their role and the purpose of the interview, which was to explore the ways in which pNFs and their treatment impacted the lives of patients. In instances where participants spoke of the symptoms or functional limitations caused by their pNFs, they were encouraged to explain how these affected their ability to meet their needs.
Previous qualitative research has demonstrated that saturation of information can be achieved with 30 participants.38,39 The aim was to recruit a combined total of 40 participants from the United Kingdom and United States, in case there were any major differences in outcome between countries.
Data analysis
The UK and US data were combined for analysis. Interviews were audio-recorded and transcribed verbatim with identifying information omitted from the transcripts to ensure participants’ anonymity. Theoretical thematic analysis, 40 guided by the needs-based model of QoL, was performed on the transcripts. Four members of the research team were involved in analysing and coding the data. Qualitative analysis software was not employed. Each transcript was analysed independently by two of these four researchers (who had not interviewed the respondent), to reduce the risk of missing important aspects of the interviews. Issues raised by patients were grouped into themes, derived from the current transcripts. The research team in the United Kingdom and a US NF clinician then worked together to refine the themes. For reporting purposes, relevant statements were grouped into themes that arose from the analyses of the interview transcripts.
Results
Participants
Demographic and disease information for the sample are presented in Table 1. The sample consisted of 42 participants with NF1-associated pNFs from the United Kingdom and United States. None of the interviews had to be terminated at the request of the interviewee. The duration of the interviews ranged from 10 to 90 min.
Interviewee demographic and disease information.
Interview findings
The interview transcripts revealed 696 statements related to the impact of pNFs on need fulfilment. These statements were grouped into specific issues and then merged into broad themes. For example, issues such as parenting, employment and responsibility were combined into the theme of ‘role fulfilment’. The five major themes derived from the analyses were appearance, relationships, independence, role fulfilment and pleasure. These themes covered all issues identified from the interviews. It should be noted that the themes do not describe needs themselves but are enablers of need fulfilment.
Comparison between outcomes of UK and US interviews
An analysis was undertaken to compare the outcome of interviews in the two countries. Only four examples were found where a specific issue was raised in one country only. UK interviewees commented on missing out on opportunities in life. In the United States, some participants expressed concerns about being asked by others about their condition, being unable to fill their time and being touched (physically) by other people. In all other respects, the interviewees in each country raised the same issues when describing the impact of their condition. The following sections report the main outcomes of the qualitative interviews.
Appearance
The way we look affects needs such as self-confidence and self-esteem, identity, approachability, relationship building and employability. Interviewees revealed that their pNFs attracted much attention from strangers, who stared at the disfigurement or made hurtful remarks about their appearance:
Feelings of insecurity and self-consciousness resulted from these reactions. Respondents expressed discomfort with the way they looked and felt unattractive because of their pNF. Some reported avoiding seeing themselves in a mirror:
Participants expressed that whenever possible, they tried to ensure that their pNFs were not visible to others by covering them with clothing. Where clothes could not achieve this, the fear of others’ reactions prevented participants from taking part in certain activities, such as swimming:
Some interviewees reported being reluctant to leave the house for fear of people reacting to their appearance. Since social situations were considered stressful, participants often opted to stay indoors:
On occasions where participants did socialise, they reported feeling uncomfortable and unable to enjoy themselves:
Relationships
Forming relationships is a fundamental enabler of need fulfilment. They can satisfy several needs such as physical contact, fun, love, intimacy, appreciation, respect and support in coping with problems.
Interviewees explained how their attitude towards their pNFs affected their relationships with partners, family and friends. It was common for participants to reveal that they took their frustration out on people to whom they were emotionally close:
Not being physically able to join in activities with family and friends was another factor affecting relationships. Interviewees recognised the effect that this had on others:
Participants revealed how their pNFs resulted in constantly staying home and having to decline invitations to social outings with family and friends. This placed great restrictions on their social life and ability to take part in activities they enjoyed:
People with NF1 reported feeling that they were letting people down on occasions when they were unable to spend time with their loved ones:
This frequently resulted in feelings of guilt. The impact of their condition on participants’ intimate relations was also discussed in the interviews:
For those without partners, interviewees reported that their condition interfered with dating, to the extent that they were hesitant or no longer willing to seek relationships:
Interviewees attributed the breakdown of past romantic relationships to the pNFs:
Interviewees revealed that they found meeting new people difficult because of a lack of confidence:
For some participants, their pNFs had such an impact that they reported being generally reluctant to establish any form of relationship with others.
Independence
This quality is fundamental to autonomy and is related to self-control, resolve, freedom and achievement. Due to the unpredictable nature of their pNFs, interviewees reported restrictions on their independence. The associated pain and reduced mobility limited patient’s ability to make plans and contributed to feelings of a lack of control over their situation:
Participants felt dependent on other people. Accepting that they needed assistance from others was difficult:
People with NF1-associated pNFs who experienced pain and discomfort found it difficult to devote attention to other issues. Feelings of preoccupation with their pNFs were commonly expressed in interviews:
Role fulfilment
Having roles and being able to meet others’ expectations are fundamental needs for our lives. Our roles guide how we behave and give us influence and status. Those participants unable to work explained that they missed being of value and giving something back to the world:
It was clear from the interviews that employment provides a means of fulfilling needs:
Interviewees stated that their pNFs prevented them from living life to the full:
Some participants had decided not to have children. After experiencing living with the condition, they felt it would be unfair to take the risk of inflicting pNFs on a child. Their decision prevented the role of a parent being fulfilled:
Others who did have children reported feeling that they were unable to fulfil their parental role:
For one parent, passing NF1 onto his daughter was something that he could not forgive himself for:
Interviewees revealed that their pNFs restricted them from fulfilling a variety of roles at home:
Pleasure
The pNFs had a considerable impact on the ability to meet needs for pleasure and relaxation. Participants expressed no longer being able to take part in hobbies that they once loved due to various problems:
Swimming was a favourite activity that interviewees generally avoided as they were unable to cover their pNFs:
Increasing pain and mobility problems also caused hobbies to be abandoned:
Socialising became less pleasurable due to discomfort and self-consciousness. Individuals often preferred to avoid these situations leading to a restricted social life. Figure 1 shows the percentage of interviewees who made at least one comment within each of the five themes identified.
Percentage of respondents raising each of the interview themes.
Discussion
Qualitative research can provide rich insight into the patient-perceived impact of illness and provide meaningful information about the effects of treatment on patients’ perceived QoL.38,39,41 People living with a condition are the best, and arguably the only, valid judges of how it impacts their QoL. The data gathered in this study identified the pertinent and specific concerns of interviewees with NF1-associated pNFs. Specifically, it identified how the condition influences need fulfilment.
The qualitative interviews conducted focused on how the symptoms and functional limitations resulting from pNFs impacted the ability of people to meet their needs. Consequently, the interviewees decided which of these impacts were most important for them. This is a unique perspective that adds depth and context to the information collected by existing HRQL measures. For example, one study asked clinical experts which issues were likely to be of importance to patients. 33 Interviewees were then asked to indicate which of these issues they considered most important. Adults included in the study (n = 16) selected pain, anxiety, disfigurement, stigma, body image and physical functioning most frequently from the options provided. This greater focus on the symptoms of the disease reflects the method by which the topics were selected.
In this study, interviews were conducted in the United Kingdom and the United States, allowing cross-cultural differences in the patient-perceived impact of pNFs to be explored. Data analysis revealed that the same needs were impeded in both sets of participants. This supports the tenet of the needs-based model which argues that human needs are universal.
All people with NF1 should be monitored by a specialist at least annually. However, adults with mild disease are far less likely to have complications and may elect not to attend a specialist NF1 clinic. 42 It is also possible that some children in the population, with mild disease, may not have been diagnosed. Consequently, our sample may have missed people with less severe disease, who would be unlikely to participate in clinical trials. The US sample was recruited from a major centre in Baltimore (Johns Hopkins Comprehensive Neurofibromatosis Centre). The research team in the United Kingdom recruited patients from a major centre treating this condition in England and included people from Manchester and the surrounding areas. However, every effort was made to include adults with a range of ages and perceived disease severities and a mix of males and females.
The disfigurement caused by the pNFs was variable in the current sample of patients. Some interviewees had few visible signs of the condition, while others had significant facial or other disfigurement. Great emphasis in the study was placed on the impact of pNFs rather than that of the common benign cutaneous neurofibromas. While these can also be disfiguring, clear distinctions were made throughout the interviews. Interviewers did report that there was considerable variability in the disfigurement experienced by interviewees. Some patients were able to cover up their pNFs, while others were unable to hide them because of their size or location (e.g. on the face or neck).
Appearance, relationships, independence, role fulfilment and pleasure were identified as particularly important issues for people with pNFs. These aspects of life are important to people because they are enablers of need fulfilment. For example, relationships allow people to identify as part of a group, to have status, to communicate, to work as part of a team and to form friendships and fall in love. It is interesting to relate these issues to those identified in similar qualitative work conducted with other patient groups. Appearance and relationships are commonly identified as important issues in chronic disease. However, additional factors are also identified, which are related to the specific condition. In depression, self-value and self-care were important additional areas of concern. 36 Crohn’s disease patients highlighted the importance of hygiene and nutrition. 43 Role fulfilment, self-image and emotional control were identified in interviews with patients with ankylosing spondylitis. 44 Interviews with psoriatic patients indicated that emotional stability and freedom were areas of concern. 45
This study differs from previous work in two main respects. First, it was not concerned with measuring impairments and functioning directly, but on determining their impact on the value of the lives of adult patients. 46 Application of the needs-based model of QoL worked well as a means of categorising the experiences of the interviewees. Second, an adult sample was employed. There remains scope for developing a needs-based measure for children with pNFs, to complement the HRQL measures.
Instruments developed from qualitative needs-based interviews have been widely used in international clinical trials to determine the value individuals gain from new interventions.47–49 Such information is necessary to complement assessments of safety and efficacy. Furthermore, as needs-based measures do not focus on symptoms or functions, they are also able to show the benefits to patients of non-clinical interventions.50–52
The findings from this study provided a pool of items that were used to develop the PlexiQoL, an 18-item needs-based PRO measure, specific to adults with NF1-associated pNFs. It is intended that the PlexiQoL will be used in studies designed to evaluate the benefits of interventions (both clinical and non-clinical) for this patient group. Without disease-specific, reliable and valid outcome measures, it is difficult to establish that such interventions are of value to patients. For example, surgical removal of pNFs is associated with a high risk of damage to surrounding vital structures and the risk of significant haemorrhage and can lead to extensive, disfiguring scarring. 53
Conclusion
This study provides insight into the impact of NF1-associated pNFs on the lives of patients. Analysis of qualitative interviews revealed that pNFs have a major effect on individuals’ ability to meet their basic human needs. The needs identified are the aspects of life most likely to be impaired in these patients. An understanding of need fulfilment will complement information generated from traditional health-related QoL measures, particularly in a multi-faceted syndrome such as NF1.
Footnotes
Declaration of conflicting interests
Ethical approval
Funding
Informed consent
ORCID iD
