Introduction

Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are insidious, debilitating tumours that account for 3–5% of all paediatric brain tumours. They are a subtype of low-grade glioma (LGG), most often World Health Organization (WHO) grade 1 juvenile pilocytic astrocytomas (JPAs), with a smaller proportion being pilomyxoid astrocytomas (PXAs) [1]. They are common in patients with neurofibromatosis type 1 (NF1), with up to 20% developing an OPG at a mean age of 4.5–5 years old [2]. OPGs most commonly arise at the chiasmatic-hypothalamic region but can arise anywhere along the optic pathway [3]. Their intimate relationship to the optic apparatus, hypothalamus, ventricular system and brain parenchyma can result in a variety of clinical sequelae including visual loss, endocrinopathies and hypothalamic dysfunction, developmental/neuropsychological disorders, hydrocephalus and focal neurological deficits. This complexity of symptomatology, and the close relationship to key structures make the treatment of OPG challenging. Unlike other JPAs, the location typically precludes complete surgical resection or optimum radiation dosing without incurring an often-unacceptable neurological cost. Furthermore, key aspects of their behaviour including their natural history and optimal management are incompletely understood. Tumour stabilisation, progression or regression can all occur unpredictably. OPG management is highly individualised. Many undergo a period of observation with serial imaging unless there is progressive growth or visual symptoms. Chemotherapy with a carboplatin/vincristine ‘Packer’ regimen is often the first line, although alternatives such as the TPCV (thioguanine, procarbazine, lomustine, vincristine) are sometimes used, except in NF1 patients due to the risk of secondary leukaemia [4]. Radiotherapy is typically avoided in younger children due to risks of toxicity wherever possible [5], although it remains an option in the setting of refractory, progressive disease or where visual loss is occurring despite systemic therapy [6, 7]. The role of surgical biopsy and debulking surgery remains controversial [8, 9]. OPGs require multidisciplinary care by neurosurgeons, neuro-oncologists, radiation oncologists, endocrinologists, ophthalmologists, pathology, neuropsychology, paediatricians, geneticists and a host of allied health professionals. This multifaceted care underlies the complexity of the disease. Advances in the understanding and treatment of OPG could come from a variety of sources, including novel or repurposed pharmacological agents, emerging biological agents and tumour vaccines, refinement of surgical approaches, diagnostic and therapeutic radiological developments or quality of life–focussed research [10,11,12,13,14,15,16]. The aim of this systematic review was to formulate a comprehensive list of all current ongoing clinical trials that were specifically looking at a clinical care of OPGs in order to identify trends in current research and provide an overview of the field to guide future research efforts. This review includes trials that are registered, and in any stage of recruitment or analysis, but not yet published. A summary of each of the ongoing clinical trials will be presented to facilitate a rapid review of the field.

Methods

This systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines on April 10th, 2020 [17, 18]. Two clinical trial databases, the Cochrane Controlled Register of Trials (CENTRAL) and ClinicalTrials.gov, were searched. The search terms used to identify clinical trials were as follows: ‘(optic OR pathway OR visual OR opg OR chiasm OR midline OR hypothalamic OR hypothalamus OR neurofibromatosis OR NF1 OR pediatric OR paediatric) AND (glioma OR pilocytic OR astrocytoma OR pilomyxoid)’. Trials older than 2010 were excluded. Trial titles and abstracts were reviewed by two of the authors. Titles with no English language translation available, and duplicates, were removed. Exclusion criteria were applied; these included titles that were not related to OPG or to trials that would not include OPG as a subgroup based on their inclusion/exclusion criteria. Already-published studies were excluded; these articles were reviewed to ensure that the publications were final and complete, and not an interim analysis or partial publication, with further publication of trial results expected. Studies that had been withdrawn, abandoned or not updated in 3 years or more were also excluded. For identified trials where there had been no recent clinical trial update (in print or online) for > 3 years, contact was made with the principal investigator of the trial to establish progress and assess if the trial was still running. Two authors (CSH and AB) performed the search strategy independently and reviewed the final papers separately. Any conflicting findings were reviewed (by CSH, AB and WI) and a consensus agreed.

Results

Five hundred one clinical trials were identified with the search strategy described. After initial exclusions, 292 were screened. Thirty-six eligible studies were included in the final analysis. The identification, screening, eligibility and inclusion were conducted according to PRISMA guidelines. The strategy is summarised in Fig. 1.

Fig. 1
figure 1

PRISMA process summary. This figure demonstrates article inclusion and exclusion across the various stages of review

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After application of the PRISMA search strategy, we included 36 clinical trials in our final analysis.

A detailed summary of the stratified clinical trials included in the review is presented in Table 1.

Table 1 Clinical trials involving optic pathway glioma that are currently in progress
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Out of the 36 clinical trials assessed, 27 were pharmacological studies. There was one phase 0 trial, 8 phase 0/I drug trials, 7 mixed phase I and phase II, 9 phase II, and 2 phase III trials. There were 2 trials focussed on biological agents, 2 based on optimising radiation therapy, 2 on diagnostic neuroimaging, one on imaging-guided thermotherapy, one on genetic testing and one on social functioning.

Discussion

Systematically reviewing the ongoing clinical trials is important to update clinicians on potential new therapies, avoid duplication of research and identify research trends and developing areas of study to stimulate new investigation. As might be expected, the main focus of ongoing research studies in OPG is related to pharmacological agents. Twenty-seven out of the 36 identified research trials were drug trials. Such investigations are necessary to establish safety and efficacy of all new drugs and are essential to determine if these agents should be adopted or discarded. Many of the new agents were related to the BRAF/MEK/ERK or RAS pathways. A summary of the pharmacological agents under investigation is presented in Table 2.

Table 2 Pharmacological agents under investigation as potential therapies in optic pathway gliomas
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There were 5 ongoing trials into the same pharmacological agent selumetinib, and 2 looking at trametinib; this raises a question as to whether a collaborative approach would allow data sharing and ensure a common data element and consensus reporting. The included trials were dominated by North American centres and pharmaceutical companies. We did not identify any trials run from a low- or middle-income country (LMIC) despite reports that up to 80% of all paediatric cancer patients occur in these countries. Potential reasons for the lack of clinical trials in LMIC include a lack of specialised centres, equipment and staff, and a lower priority of cancer for healthcare planning strategies [19,20,21]. There were a small number of trials looking at non-pharmacological diagnostics, therapeutics and assessment social functioning relating to OPG. These are summarised in Table 3.

Table 3 Ongoing non-pharmacological trials related to optic pathway glioma
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Pending trials

The authors are aware of a further relevant clinical trial that is yet to start, the LOw Grade Glioma In Children (LOGGIC) study. LOGGIC will compare the effect of standard chemotherapy versus MEK inhibitor (trametinib) as first-line agents in paediatric low-grade glioma. The outcome measures will include a child’s quality of life, including visual and neurological function. The LOGGIC trial will be run by the European Society for Paediatric Oncology (SIOPE). As with any emerging field, this is likely to be just one of several trials not yet registered on public databases.

Unanswered questions

This systematic review highlights the dominant pharmacologic-centric nature of current OPG clinical trial research. There are several important areas of OPG care that remain clouded in uncertainty and controversy and are not currently being addressed by the ongoing clinical trials we identified in this study. A key outstanding question is regarding the natural history of OPG and how we can predict outcomes. We have a paucity of understanding of the natural history of OPGs, and we lack tools to predict their clinical course and long-term outcomes. Furthermore, it is controversial which outcome measure should be used. Commonly used oncological outcome measures such as overall survival and (radiological) progression-free survival may not be the most appropriate for the study of OPGs; alternatives include visual function, endocrine/hypothalamic dysfunction and quality-of-life measures. While one trial identified in this review relates to social functioning, this remains a poorly examined area. Hypothalamic dysfunction is a key component of the OPG disease that is often neglected in clinical studies and can be challenging to quantify. The hypothalamic consequences of existing and emerging therapies need examination. Questions remain regarding the optimal therapeutic management. Although general consensus statements exist, there remains uncertainty around the optimal surgical strategy. The timing and nature of the surgical approaches to OPGs have not been subjected to rigorous trial data. Surgical options include biopsy, partial/subtotal resection and radical resection [13]. Furthermore, the optimal timing of chemotherapy/radiotherapy initiation and the influence this has on overall outcomes are not fully known. The focus of current research, including all trials identified in this study, is on recurrent/refractory OPGs rather than new diagnosis. The long-term efficacy of various treatments for newly diagnosed OPGs is unknown. Optic pathway gliomas are typically treated as a single disease. However, it may be important to stratify and subclassify based on factors such as age (infantile versus juvenile) and based on molecular/genetic subtyping. An example of this is stratification into syndromic/NF1-related and non-syndromic/non-NF1-related OPGs. These patients have different anatomical predilections, their natural histories can vary and the optimal therapies may be different [22,23,24].

Limitations

We found few trials that were specifically focussed on OPGs as a distinct tumour subtype. As OPGs are a subset of LGG, they may be bundled into trials under umbrella terms like ‘LGG’ or ‘glioma’ or ‘JPA/PXA’. We not only developed a search strategy aimed at capturing trials that had specific reference to OPG (with the search terms; optic/visual/pathway/chiasm/midline/hypothalamus/hypothalamic) but also included terms to capture trials that may include OPGs without specific reference to them, e.g. by using terms (Neurofibromatosis/NF1/paediatric/paediatric) combined with generic blanket terms (glioma/astrocytoma/pilocytic/pilomyxoid). Where appropriate, we screened the trial protocols and inclusion/exclusion criteria to determine if OPGs might be included in the trials. As with any systematic review, there is always a risk that our search strategy missed a relevant trial. This risk is higher with a disease like OPG that is a subcategory of a wider disease. In order to try and minimise this danger, we used a reproducible search strategy that conformed to PRISMA guidelines. We elected to include all trials that could recruit OPGs; however, the vast majority are not focussed on OPGs but on LGG in general. We ensured that all included trials would allow OPGs as part of their criteria, but we cannot be sure that they will eventually recruit patients with this pathology in representative numbers, or if they will examine the data adequately to allow subgroup analysis of this pathology.

Conclusion

OPG are a debilitating childhood cancer that causes a significant burden of suffering. Our understanding of this disease is limited and we lack effective treatments and clear management consensus [1, 25]. This manuscript details a systematic review of current ongoing trials in OPG. We find that from an initial yield of 501 hits, 36 ongoing trials fulfilled criteria for inclusion. The majority of these are studies or pharmacological agents, mostly phase I or II. OPG is a complex multifaceted disease, and advances in care are likely to require ongoing research efforts across a spectrum of different research fields [26]. Studies investigating surgical interventions and quality of life were notably absent. This review provides an update on the current state of research in OPG and highlights the main agents under investigation. We hope that this updates and stimulates clinicians and research scientists to engage with this important topic.