Management of patients with neurofibromatosis type 1 and studies of pirfenidone

Aim: Neurofibromatosis type I (NF₁) is a common tumour predisposing disease in humans. Plexiform neurofibromas are a major cause of morbidity in these patients. Unfortunately, effective medical therapy for these tumours is lacking. The histopathology of neurofibroma is complex, with diverse cellular content and large amount of fibrous tissue. We hypothesised that events connected with fibrogenesis might constitute a point of molecular vulnerability of plexiform neurofibromas. Methods: Pirfenidone is a novel, small molecule agent that exhibits potent activity against fibroblasts in vitro and in vivo. We developed an animal model for neurofibroma [human neurofibroma xenotransplants into severe combined immunodeficiency (SCID) mice] and evaluated effects of pirfenidone on neural tumour implants. Results: Survival of neurofibroma xenografts in SCID mice treated with oral pirfenidone was significantly lower when compared with survival of xenografts in non-treated animals. Based on encouraging preclinical studies, human studies for patients with plexiform neurofibromas have been initiated. Clinical trial on 24 adults was recently completed at Mayo Clinic and most patients remained stable for 2 years of treatment, not experiencing major toxicity. Paediatric phase I study has been completed and phase II study is still ongoing. Conclusion: Pirfenidone is a well-tolerated oral agent. Results from completed trials to date are promising, indicating its potential role in treatment of NF1. Because of the variable and incompletely understood natural history of neurofibromas, interpretation of outcome from clinical trials is difficult and will require longer follow-up of larger population of treated patients and placebo-controlled trials to determine the role of pirfenidone in the therapy of NF1-related tumours.