In this interview, Dr João Passos shares his views on various issues concerning Neurofibromatosis and its treatment options.
João Passos, MD is a neurologist doctor graduated from the University of Lisbon who, since 2011, has been seeing patients at the Portuguese Institute of Oncology Francisco Gentil of Lisbon (IPO), Portugal. APNF interviewed Dr. Passos since we recognize his great merit and dedication in the follow-up and treatment of many cases of Neurofibromatosis (NF) both from Portugal and Portuguese-speaking African countries (PALOP).
Q1. When did you realize that you wanted to become a neurologist?
During medical school, we are exposed to different medical and surgical specialties. This was the time when I formed my first opinion about what I wanted to be as a doctor. Neurology was one of the options I considered when, years later, I was faced with the need to choose a specialty. The commitment to this specialty grew during my internship and only recently I began to focus on cancer patients and patients with Neurofibromatosis type 1.
Q2. Do you only follow children with NF associated oncological problems or a preventive surveillance is also a concern for IPO?
At IPO, I follow children with oncological problems (plexiform neurofibromas and optic pathway gliomas) and adults with or without established oncological diagnoses. Nonetheless, patients with the mutation presenting no oncological disease are also followed as part of our oncological surveillance program.
Q3. Recently you felt that it would be necessary to start follow-up appointments for adults with NF. Why?
The IPO is an oncological centre that has a high technical capacity for cancer treatment. Individuals with the type 1 NF mutation in adulthood may have extremely variable clinical manifestations and most are unaware of the risks associated with their genetic condition.
This age-based risk stratification should be further individualized for each patient and for each family.
Serious complications of NF vary throughout life and are related to the development of benign tumours in children, malignant tumours in young adults and vascular problems in adults and the elderly. This age-based risk stratification should be further individualized for each patient and for each family. The need to establish a protocol for patient follow-up and early identification and treatment of patients at risk for developing serious complications was the main reason for the establishment of this medical appointment, which is still under development, and extends to different medical specialties focusing on the evaluation of the results from the current protocol that has been implemented.
Q4. The conventional therapy for the treatment of inoperable oncological features associated with NF is chemotherapy. Has it been effective in the long run?
Optic pathway gliomas are the tumours most often treated with conventional chemotherapy. Most patients do not need more than one treatment protocol. For inoperable plexiform neurofibromas, conventional chemotherapy is not effective. There are malignant brain tumours that can respond to a combination of radiotherapy and conventional chemotherapy.
Q5. More recently other drugs for other oncological cases have been developed which have also been very effective in patients with NF1, namely Selumetinib (from AstraZeneca) and Trametinib (from Novartis). Currently, these drugs are available in Portugal but are still under some restrictions. What are the criteria for prescribing each one of these therapeutics? Are they prescribed only in a hospital / outpatient setting?
Selumetinib is currently used to treat inoperable plexiform neurofibromas that are associated with significant morbidity. Growing neurofibromas at critical sites are also indicated for treatment. The use of Selumetinib is individualized and each patient gets independent approval from the IPO Pharmacy and Therapeutics Commission, the Infarmed (National Authority for Medicines and Health Products, I. P.) and the Pharmaceutical Company. Trametinib is also used to treat inoperable plexiform neurofibromas and low-grade gliomas. At IPO, its use is limited to the treatment of patients with refractory benign brain tumours (optic pathway gliomas or pilocytic astrocytomas) who have progressed despite prior multiple lines of conventional chemotherapy.
The use of Selumetinib in each country depends on the rules running there.
Q6. Recently, the use of Selumetinib has been approved in a Portuguese adult with NF1 who has an inoperable plexiform neurofibroma with associated or progressive morbidity. Why just now? Is this the case in other countries too?
This drug is at an early stage of use, and preliminary studies supporting its use have been performed in the paediatric population only. Studies are currently underway in the adult population, but the results are not yet available. The use of Selumetinib in each country depends on the rules running there. In the United States, the Food and Drug Administration has given the Selumetinib a breakthrough therapy designation status, but its use is not yet approved. Similarly, the European Medicines Agency has not yet approved the use of Selumetinib. It follows that the use of Selumetinib is conditional on individual patient assessment and after the approval by various entities, particularly in adulthood, for which there are no published studies.
Q7. Does Trametinib have the same beneficial effects on plexiform neurofibromas?
The benefit that patients with NF1 and plexiform neurofibromas may have with MEK inhibitors has been demonstrated in several phase 2 studies. All studies demonstrated benefits, and a level of 40% are responders. With respect to Trametinib, there are case series that demonstrate its benefits. There are no trials comparing treatments (Selumetinib versus Trametinib).
Q8. Why is the bureaucratic process for providing these drugs by pharmaceutical companies so complex and time consuming?
The bureaucratic process is complex due to the characteristics of the drug. The fact that it is at an early stage of its development justifies the special care adopted in its authorization and use. Once treatment is started, rigorous pharmacovigilance and evaluation of results by the responsible clinician and the institution where it is being used is necessary, which takes time and technical resources.
Q9. How are these drugs better than conventional chemotherapy?
For plexiform neurofibromas, Selumetinib is the best treatment because the rate of responding patients is 70%, taking into account the results of the SPRINT phase 2 study. Conventional chemotherapy has no effect on treating such tumours. For low-grade gliomas, clinical trials comparing MEK inhibitors with conventional chemotherapy are underway and will answer the question – What is the best treatment.
Q10. Do you receive people from all over the country or does IPO restrict consultations only to southern Portuguese, islands and PALOP citizens?
We get patients from all over the country.
Q11. Can we expect something similar for NF such as the announced genetic treatment for Spinal Muscular Atrophy, the drug Zolgensma (given via a single injection), recently approved in the US, but still unavailable in Europe?
Being a genetic disease, treatment with this methodology would theoretically be possible, but most serious complications related to type 1 NF are already treatable at this time, unlike what happens with Spinal Muscular Atrophy. However, there are neurological changes within NF1 that would probably not be reversed with eventual gene therapy, such as autism spectrum disorders or attention deficit hyperactivity disorder, as they may be related to neuronal organization at an early stage of development.
Q12. What is the second hit on NF1 (it also happens in NFs patients)? And how does this phenomenon render ineffective a cure such as we have seen for Spinal Muscular Atrophy (which is also a monogenic / single gene disease)?
An important difference from Spinal Muscular Atrophy (SMA) is that SMA is an autosomal recessive disorder. Affected children do not produce a protein important for the survival of motor neurons, and so the neurons responsible for muscle control are gradually destroyed, invariably causing death to infants. With respect to NF1, mutation carriers generally have only one healthy copy of the NF1 gene (heterozygous). If during the process of cell division, a mutation occurs in the second (healthy) copy of the gene, we consider it to be a second hit. This means that the cell no longer produces a protein important for regulating cell proliferation and the tissue acquires the ability to divide and to originate a tumour. In this conceptual model on the origin of tumours in the NF1 mutation carriers, gene therapy would continue to be effective because by increasing the expression of the missing protein, it would (positively) interfere with the molecular pathway that regulates cell proliferation and which is implicated in the origin of the tumours.
Q13. Are you in contact with any laboratory working to develop gene therapy for NFs?
Q14. Are any other promising therapies being developed?
Several MEK inhibitors are currently being explored in the treatment of plexiform neurofibromas in NF1 patients. Regarding new therapies (with different classes of drugs) I am not aware of any under development.
Q15. NF patients, given the variability of their symptoms, would expect to be seen at a specialized centre with several medical specialties. For when can we expect such a centre in Portugal?
It is unlikely that there will be a specialized centre solely to treat/follow NF1 mutation carriers. In Portugal, estimations point to approximately 3,000 people with this genetic condition, 600 of which are under 18 years old. A small percentage of these will have severe NF-related complications, which means that a specialized centre would not have enough volume to justify an appropriate level of proficiency in treating NF1-related complications. I believe that a consultation of Neurofibromatosis integrated in an oncology centre in conjunction with other referenced medical specialties (which may be located in other hospitals) is the best way to care for patients with severe NF-related complications. This integrated model already exists for the paediatric population at Dona Estefânia Hospital (Children Hospital Lisbon), for example.
In Portugal, estimations point to approximately 3,000 people with this genetic condition, 600 of which are under 18 years old.
Q16. How can an adult with NF schedule an appointment with you at IPO? Should you be referred by any General Practitioner or the patient can contact directly with this institution?
Just send the medical appointment request to firstname.lastname@example.org
This interview is published with the kind permission of APNF and Dr João Passos. It was originally made in Portuguese and kindly translated by APNF.