A multidisciplinary NF1 clinic is essential for early diagnosis, treatment and prevention of complications for NF1 patients. No previous reports have been published regarding multidisciplinary healthcare for NF1 patients in China. In this study, we summarized NF1 patients’ data from 2013 to 2021 and elucidated the patients’ characteristics in China’s first NF1-specialty clinic.
Patients were primarily adolescents during their first admission. This suggests that some pediatric patients may initially seek for medical care in other pediatric oncological hospitals, while others only consult in outpatient departments without having surgery until adolescence when symptoms become more severe during puberty. In general, there is no gender preference in NF1 patients, but our report indicated that more male adolescents were admitted than female adolescents. The geographic location of Shanghai can explain the distribution of patients' origins, as Zhejiang, Jiangsu, Anhui and Jiangxi provinces are all neighboring provinces of Shanghai. Our report indicates that NF1 may affect marriage as over 40% of the 30-39 age group is unmarried, considering the average age of first marriage is 28.67 years old for Chinese people6. The disease also has a negative impact on occupational status, as no less than 20% of unemployment was observed in each age group. The COVID-19 pandemic has had little effect on the admission of NF1 patients in this hospital, which decreased slightly in 2020 and bounced back quickly in 2021. Since PRS, Ophthalmology and Head and Neck Oncology contributed a large part to patients’ admission, neurofibromas of head and neck region are undoubtedly the most encountered type of tumors. Lastly, approximately a quarter of patients were admitted more than once, which strongly suggests that surgical excision alone is insufficient to treat NF1in long-term management. Therefore, clinical trials and basic research for novel therapeutic strategies are necessary for NF1 healthcare.
Current challenges in China’s NF1 healthcare
Despite the progress achieved throughout the years, NF1 healthcare development in China is still in a preliminary stage as several challenges remain. According to the Chinese Neurofibroma survey report (2020), there are estimated 550,000 NF patients in China5. However, most hospitals do not have adequate resources to set up NF1-specialty clinics and to meet NF1 patients’ care needs. General neuro-oncologists or dermatologists may not be fully familiar with this rare genetic disorder, especially in rural areas. The lack of access to appropriate NF1 medical care may result in delayed and inaccurate diagnosis and treatment, causing a substantial burden on social welfare. Another challenge is the absence of systemic platform for NF1 clinical and basic research. Currently, NF1 institutes in China work independently without having an NF1 hospital network or joint research platform to collaborate and share information with each other. Dispersion of institute resources leads to inefficient research development and innovation. This can be shown by the small amount of NF1-related publications and clinical trials from Chinese institutes over the years. As of 2021, only 14 NF-related studies were funded by the National Natural Science Foundation of China (NSFC). In addition, there are still limited NF1-specific reference books in Chinese language available. Clinicians and researchers study NF1 only in NF1 chapters within either Neurology or PRS reference books, or through online resources. The lack of original Chinese NF1 textbooks hinders the exploration of up-to-date knowledge and new concepts in Chinese NF1 research community. This series of challenges keep China's NF1 medical care and research lagging behind.
International experience
Having a comprehensive NF1 center network is of the utmost importance in NF1 healthcare. In the U.S. and Europe, NF1 healthcare systems have been well developed with NFCN clinics in the US and CTF Europe member clinics providing NF1 specialized medical care. Every NF1 clinic has experts in different core specialties and sub-specialties to offer patients a comprehensive multidisciplinary management approach. In general, a thorough physical examination is performed on patients’ first visit, especially neurological and ophthalmic assessments. Depending on the diagnosis, additional tests such as imaging and genetic tests may also be required. Once the diagnosis is established, specialized treatment plan is developed with the involvement of other experts including dermatologist, plastic surgeons, orthopedic surgeons or otolaryngologists. NF1-related medical problems are monitored in long-term follow-up care with the assistance of endocrinologists, cardiologists and behavioral specialists. Genetic consultation is also an essential part of most NF1 clinics with genetic specialists explaining the hereditary implications for affected individuals. Recently, there was a report of the first Japan NF1 center7, in which patients under 15 years old were arranged with mandatory evaluations in core departments such as pediatrics, ophthalmology, neurosurgery, and orthopedics. Some major items to be evaluated include developmental retardation, intraocular pressure, brain tumor, scoliosis, and limb dysplasia. The well-established clinical practice model of these NF1 clinics truly provides better medical care and options to NF1 patients. This ideal model also provides an insight for Chinese hospitals to improve.
Apart from providing specialized clinical services, an NF clinical network of hospitals also provides the environment for NF1 clinical trials. The Neurofibromatosis Clinical Trials Consortium (NFCTC), established under the U.S. Department of Defense Neurofibromatosis Research Program (NFRP), comprises 25 clinical and collaborating sites committed to developing clinical trials for NF medications8. Their NF1-related clinical trials include the Cabo Study (XL184)9, the STOPN trial (Sirolimus)10-13, the STARS trial (Lovastatin)14-17, the RAD001 trial (Everolimus)18,19, the MEK Study (Mirdametinib)20, the BMP2 INFUSE Study21, the BINI Study (Binimetinib)22 and the Poly-ICLC Study23. Over the past decade, the Consortium has completed studies in patients with NF1-related plexiform neurofibromas, MPNSTs, low-grade gliomas, neurocognitive challenges and learning disabilities. In Europe, the EU Patient-Centric Clinical Trial Platforms project (EU-PEARL), a public-private-sector partnership funded by the Innovative Medicines Initiative (IMI), works on developing integrated clinical trial platforms and creates a more efficient and patient-centric way of drug development in Europe24. These effective platform trials will benefit all forms of NF1 individuals with better allocation of promising treatments. To improve clinical trial response criteria, an international collaborative group called REINS was formed in 2011 dedicated to developing new standardized consensuses for clinical trials of neurofibromatosis25-27. This collaboration works on different specific areas and makes recommendations on disease biomarkers, cutaneous neurofibromas, imaging of tumor response, and functional, neurocognitive and patient-reported outcomes. In addition, CTF built the NF Registry to connect NF1 individuals through online patient registration. Patients also need to fill out a medical questionnaire regarding their clinical features and experience28. To date, NF Registry has more than 10000 registered participants28. Patient enrollment and NF surveys enable a more efficient way to expand the NF community and invite NF1 individuals to participate in relevant clinical trials. International experience in clinical trials will undoubtedly benefit clinical trial development in China.
A network of NF1 centers also facilitates the collaboration and development of basic science research. The traditional scientific research model is relatively linear and inefficient due to competition and data hoarding. In 2014, CTF established the Synodos models that encourage collaboration among scientific researchers and institutes29. This research approach allows researchers, clinicians and other experts from different disciplines and institutes to cooperate by sharing unpublished data and research advancements, thereby producing clinical benefits with a more efficient translation of research findings. CTF formed three Synodos teams from eight institutes and two companies over the years for NF1 treatment29. The first two teams are the Synodos for NF1 Preclinical Acceleration that mainly investigate in NF1-relevant swine models with the studies of tumors biology, correlation with humans and drug testing30-34. The third Synodos works on two studies developing treatments for NF1 gliomas. The first study, led by Dr. David Gutmann of the Washington University School of Medicine and Dr. Michael Fisher of the Children’s Hospital of Philadelphia, is focused on pediatric NF1 patients with LGG. Dr. Antonio Iavarone of Columbia University led the second study on all grades of gliomas from affected individuals of all ages and eventually published the work in 2018 regarding the molecular landscape of glioma in NF1 patients35. The Synodos research model emphasizes data sharing and research collaboration which can vastly improve research efficiency and development in China.
Social support and patient engagement are essential for the sustainability of the NF1 healthcare system and clinical network. As one of the driving forces in global NF healthcare, CTF collaborates with multiple non-profit organizations such as the National Organization for Rare Disease (NORD) and the Health Research Alliance (HRA), and healthcare companies such as AstraZeneca and SpringWorks, to raise NF1 awareness in social policies and innovative researches. CTF also holds an NF conference annually that allows clinicians, researchers, patients and health companies to gather around to share and summarize the up-to-date research findings and development in the NF1 community36. Since patient engagement is an essential component in clinical care, CTF also makes great efforts in patient support. NF workshops that include patient’s sharing session are held so that clinicians and scientists can understand more from the patients’ perspectives37. NF Camp provides a community and opportunity for teenage patients with NF1 to spend time with those facing the same challenge and make friendship with each other38. To raise social awareness of NF1, CTF also holds a series of online lectures, the INFER masterclass, to allow more medical professionals and patients to know more about the scientific development of such disease39. The role of CTF in building social support and awareness of NF1 contributes significantly to the global NF1 community.
Endeavors From Chinese Collaborative NF1 Model
The establishment of a full-fledged NF clinic network is still in the exploratory stage in China but some significant progress has been made in recent two years. In 2020, China's first NF1 multi-centered treatment collaboration group for neurofibromatosis was established by Professor Qingfeng Li's team from Shanghai Ninth People's Hospital dedicated to standardizing diagnosis and treatment of neurofibromatosis. The collaborative group was joined by eight hospitals initially and will gradually be expanded to over 30 hospitals once standardized management of NF patients is achieved. Approved by the National Health Commission, Professor Qingfeng Li's team established the first NF1 center for the compassionate use of Selumetinib, the first FDA-approved drug for pediatric plexiform neurofibromas. This orphan drug application not only provides a chance for some of the most urgent patients, but also allows the team to collect clinical case data in order to apply for the approval of drug use in China. In 2021, the collaborative group presented the Expert consensus on Diagnosis and Management of Neurofibromatosis Type 1 (2021 edition) that incorporates a comprehensive understanding of NF1 clinical features, diagnosis, treatment and genetic counselling40. Regarding patient support, China’s first non-governmental organization for NF1 patient support, the Neurofibromatosis Shenzhen Care Center (NSCC), was established in 2019. NSCC aims to build a communication and mutual assistance platform for NF patients by conducting psychological care and social integration work41. They also work on raising public awareness of NF to eliminate social discrimination, and promote clinical and biomedical research development in medical institutions.
Future directions
Continued refinement is necessary to meet the growing needs of the NF1 population. Hospitals should develop large cohorts based on NF1 patients, systematically register their clinical manifestations and family history and establish corresponding NF1 patients’ biobanks. Meanwhile, institutes should work on the development of biomarkers identification pipeline for translational research based on the NF1 cohort data. It is also important to consolidate the integration of clinical research and drug development by establishing strategic partnership models with Chinese and International pharmaceutical companies for NF1 research and development. With better access to patient data based on a larger cohort and a more established clinic network, a better version of NF1 expert consensus or clinical guideline will become possible. This will eliminate the substantial heterogeneity in NF1 management and eventually bring better medical care to NF1 patients.