For which manifestations of neurofibromatosis should we most urgently find medicines, according to NF experts and patient representatives?  

This question was answered in the manuscript “Identifying challenges in neurofibromatosis: a modified Delphi procedure”, which was published in the European Journal of Human Genetics on April 26th 2021. Britt A. E. Dhaenens, Rosalie E. Ferner, Annette Bakker, Marco Nievo, D. Gareth Evans, Pierre Wolkenstein, Cornelia Potratz, Scott R. Plotkin, Guenter Heimann, Eric Legius and Rianne Oostenbrink co-authored this manuscript of which we offer here a lay summary.

The different types of NF and their manifestations

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis are genetic disorders that predispose to the development of tumours on nerves. These tumours are mostly not cancerous with a relatively low chance of turning into cancer. However, these benign tumours can cause serious challenges, such as blindness, deafness, impaired mobility and pain. In addition to the nervous system tumours, some NF1 patients suffer from bone abnormalities, cognitive and behavioural challenges, psychological distress and other forms of cancer including breast cancer.

In NF1, the benign tumours are called neurofibromas, while in NF2 and schwannomatosis patients suffer from different tumours, called schwannomas. Just like neurofibromas, the schwannomas form in different parts of the body and cause many problems.

When NF2 patients suffer from vestibular schwannomas – benign tumours that form in the nerve that goes from the brain to the ear- these tumours cause hearing loss and a feeling of imbalance. Some NF2 patients also suffer from cataracts, pain, etc.

Schwannomatosis (SWN) patients develop schwannomas all over the body except within the skin. Patients often suffer from excruciating pain, and available medication does not always alleviate the pain.

The appearance of these manifestations is highly variable among patients with NF. Some patients have almost no manifestations, while other patients have multiple severe manifestations that greatly impact their daily life. This­­­ wide range of manifestations complicates the development of a framework for clinical trials. In clinical drug trials, we test whether a drug is effective for a manifestation of NF. For example, does a drug shrink the tumour, or does it relieve pain?

The study and the Delphi procedure explained

The aim of this study was to reach agreement on the most important manifestations of NF to select for clinical drug trials, based on the opinions of both NF experts and patient representatives.

To do so, we performed a five-staged modified Delphi procedure. A Delphi consists of multiple rounds of questionnaires which are completed by a panel of experts. After each questionnaire, participants receive a summary of the results of the previous round. Through this summary, experts can rethink their earlier answers in light of the replies of other experts, making it possible to reach agreement. Our modified Delphi consisted of two questionnaires and a consensus meeting for 40 NF experts and a survey for 63 patient representatives.

In the questionnaires for NF experts, manifestations were scored on the “need for a new drug treatment” on a 4-point scale. A higher score indicates a higher need for a new drug treatment. In the second questionnaire, the highest average scores were assigned to the manifestations MPNST (a cancerous nerve tumour) (4,0) and high grade glioma (aggressive cancer of the brain) (3,9) for NF1; meningioma (benign tumour of the brain)(3,9) for NF2 and pain (3,9) for SWN. In a similar survey, the patient representatives assigned high scores to all manifestations. In NF1 the manifestation plexiform neurofibroma was scored highest (benign nerve tumour) (4,0), for NF2 this was vestibular schwannoma (4,0), and for SWN this was seen in pain (3,9).

We also asked both NF experts and patient representatives to rank the groups of manifestations by priority to be included in clinical dug trials. The experts ranked MPNST as highest priority for NF1, followed by plexiform neurofibromas. Tumour manifestations, like the vestibular schwannoma and meningioma, received highest ranking in NF2, and pain was the most important problem for SWN. Patient representative rankings for NF1 were similar to the experts’ opinions, except that they ranked the high grade (aggressive) gliomas as the most important manifestation. This high priority as seen by patients later resulted in the inclusion of high grade gliomas in our final selection. For NF2 and SWN, the patient representatives agreed with the experts.

Conclusions and implications for clinical research

After this study, we conclude that NF experts and patient representatives prioritise the development of clinical drug trials for MPNST, plexiform neurofibromas, cutaneous neurofibromas and high grade gliomas for NF1; tumours for NF2; and pain for SWN. The findings of this study are mostly important and relevant to EU-PEARL, to aid the creation of the platform trial framework. However, this study may also serve as a guideline on which manifestation may have highest priority for future clinical trials.

Read the full article here.

More about platform trials here.

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