Identifying risk factors for recurrence/relapse in NF1 optic pathway gliomas: Moving forward by looking back

Neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (NF1-OPG) is the chief medical problem of patients with NF1 during childhood. These low-grade gliomas tend to occur in approximately 15%-20% of NF1 patients, with approximately half needing to receive tumor-directed treatment.1–3 Unfortunately one-third of patients relapse after this initial therapy.1 If all young children with NF1 had routine magnetic resonance imaging (MRI) screening, this incidence may be even higher, but the current standard of care solely requires surveillance ophthalmologic examinations. A critical knowledge gap of NF1-OPGs lies with determining which patients will experience treatment-refractory or relapsed disease.4 To date, only characteristics of patient age, posterior tumor location, and residual tumor volume have been correlated with poor visual outcomes and tumor progression.1 In this study, Kotch et al detail their findings from a retrospective review of 103 patients diagnosed with NF1-OPG across seven institutions, from 2005 to 2014.5 A majority of these patients received carboplatin-based therapies and 44% exhibited refractory/relapsed disease with a median time to progression of 21.5 months. Treatment-refractory/relapsed NF1-OPG was defined as two or more treatment regimens needed due to relapsed disease or lack of treatment response. The primary outcomes were centered on 2 and 5 years from initiation of chemotherapy and the secondary objective was evaluation of long-term visual acuity. They concluded that risk factors for treatment-refractory and relapsed disease included patients less than 24 months of age, gliomas localized posterior to the chiasm, familial NF1 inheritance, and optic pathway abnormalities by 2 years of age. Interestingly, neither the size of the OPG nor the severity of visual acuity at initial diagnosis correlated with the risk for treatment failure or relapsed disease. Due to a lack of NF1-OPG studies centered on treatment-refractory and relapsed disease performed to date, this retrospective review was definitely warranted, so as to assist with optimal design of prospective trials.4 Yet, it would be interesting to know how the authors collected 111 subjects for this study, as the denominator could provide information regarding true NF1-OPG disease incidence and treatment response. Moreover, prior studies have identified approximately one-third of patients fail frontline chemotherapy, while this cohort exhibited a higher percentage (44%) of refractory/relapsed cases.1 The total patient evaluation and higher treatment failure numbers may be secondary to the inclusion of academic centers that have expertise in NF1 clinical care and thus see more complicated cases. Specifics of orbital MRI of OPGs have become more sophisticated over the last decade. The most recent Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria detailed essential MRI sequences at baseline and suspected disease progression.6 While Kotch et al utilized a central review for neuro-ophthalmologists, there was no central review performed by neuroradiologists to further characterize these OPGs via RAPNO criteria.5 Additionally, there was no central review by neuro-oncologists to confirm NF1 diagnosis, and/or link clinical history (eg, neurologic symptoms, proptosis, endocrinologic symptoms, etc.) with relative risk factors.4 All of these patients had a diagnosis of NF1 but genotyping was not reported nor performed in each. Previous studies have demonstrated localization of the NF1 gene mutation (specifically at the 5′ third of the gene) appears to be a true feature of the mutations in NF1 patients with OPGs when compared with NF1 patients without OPGs (OR = 6.05, P = .003). These findings demonstrate the possibility of linking genotype features with phenotypes of visual deterioration pre- or post-therapy.7 Worsening visual acuity distinguished them as progressive disease candidates warranting change of therapy. Yet past studies have demonstrated visual changes may have occurred prior to therapy initiation; meaning initial therapy may not have needed to be terminated or changed completely.1,8 Furthermore, this retrospective review does not account for such rare cases of NF1-OPG patients with spontaneous visual improvement sans therapy that may have never needed treatment with longer observation windows; yet seemingly clinically unsafe if left untreated for more than 18 months from diagnosis.1,4 Collectively, these results further obviate the need for future prospective studies to better outline disease prognostication. NF1-associated OPGs are mostly indolent but may cause severe visual impairment which requires treatment. Sadly, it is a complex condition without clear indications for who, when, and how best to treat. These findings by Kotch et al are useful because if age and tumor location are validated risk factors, then earlier identification of high-risk patients can impact treatment recommendations. Studies like these improve our understanding of chemotherapy options and anticipated response to therapy. While the widely accepted gold standard of therapy for low-grade gliomas is carboplatin with vincristine, its use is associated with a high incidence of allergies, myelosuppression, alopecia, nausea, neuropathy, abdominal pain, and hearing loss.9 In comparison, the Canadian Pediatric Brain Tumor Consortium demonstrated similar survival outcomes and a lower toxicity profile with vinblastine monotherapy for progressive low-grade gliomas; again underscoring the need to standardize prospective trials to directly compare therapeutic options.10 This study is additionally valuable for validating Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) endpoints for visual outcomes, which interestingly may be discordant from radiographic measurements. Future studies should follow RAPNO imaging guidelines to enhance the identification of tumor progression, along with functional outcomes. Furthermore, genotype-phenotype correlations should be explored in this tumor predisposition syndrome, where germline and somatic mutations ultimately drive tumorigenesis which has the potential to benefit from tumor-targeted novel therapeutics.11 Overall, prospective data on the natural history of NF1-OPGs can help stratify which patients are at high risk and thus potentially provide justification for additional and/or alternative tumor-directed therapy for a subset of patients with the intent of overall vision preservation. This research/work/investigator was supported (in part) by the Division of Intramural Research of the National Institutes of Health, National Institute on Neurologic Disorders and Stroke. Conflict of interest statement. N/A.

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