Elsevier

The Lancet Oncology

Volume 21, Issue 6, June 2020, Pages e305-e316
The Lancet Oncology

Series
Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group

https://doi.org/10.1016/S1470-2045(20)30064-4Get rights and content

Summary

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

Introduction

Paediatric low-grade gliomas are the most common brain tumours in children, representing 40–50% of all paediatric CNS tumours.1 Although overall survival for children with these tumours is excellent, event-free survival remains low, with many children requiring multiple therapies throughout childhood.2 In addition, many children have functional deficits (such as visual dysfunction and sensorimotor deficits) as a consequence of their tumour, its treatments, or both. Because the majority of patients survive, a paradigm shift has occurred among paediatric low-grade glioma treatment experts, with a new focus on preserving functional outcomes and maintaining a good quality of life (QOL).1, 3, 4

Several molecularly targeted agents are being investigated in clinical trials, with early data showing their efficacy.5 Comparing outcomes of these new agents with outcomes of previous therapies is crucial. However, historical studies used varied measures of outcome (with the majority based on imaging response assessment alone) so using standardised imaging sequences is of the utmost importance. The comparability of outcomes is complicated further, because the radiographic response of the tumour to therapy does not always correlate with functional outcome, especially in optic pathway gliomas associated with neurofibromatosis type 1.6 It is essential to better standardise the response definitions for paediatric low-grade glioma clinical trials, not only to make comparisons of response outcome across multiple international studies more feasible, but also to incorporate functional outcomes when appropriate. We, therefore, established an international subcommittee of the Radiologic Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group to develop consensus recommendations for response assessment in paediatric low-grade gliomas. The committee consisted of 25 international experts in the areas of paediatric neuro-oncology, neuroradiology, and neurosurgery.

The committee first met and developed a set of agreed assignments—ie, questions they deemed necessary to understand the controversies of imaging assessment in paediatric low-grade gliomas (panel 1). These assignments were then divided among the committee members, who researched, and then presented, all available literature to the entire RAPNO committee, who then discussed these data. The committee then developed consensus statements and recommendations, on the basis of available literature, committee expertise, and clinical experience. Each topic assignment was discussed until a consensus was reached.

Section snippets

Disease classification

The term paediatric low-grade glioma refers to paediatric WHO grade I and II tumours of glial origin, with pilocytic astrocytoma being the most frequent diagnosis.3 It is now generally accepted that most paediatric low-grade gliomas are a single-pathway disease affecting the MAPK signal transduction pathway, despite varying histological appearances, with BRAF–KIAA1549 fusion and BRAFV6000E (ie, Val600Glu) mutation events comprising the most frequent somatic molecular alterations (whereas

Defining baseline scans

Classically, whether in or outside of a clinical trial, MRI scans are done before surgical resection or biopsy, and are typically repeated within 24–72 h postoperatively to assess the amount of residual disease before initiating a medical therapy, such as chemotherapy or radiotherapy. Paediatric low-grade glioma can present as a clinical emergency with symptoms of acute increased intracranial pressure due to obstructive hydrocephalus. Such clinical emergencies can lead to patients not being

Baseline brain or spine imaging and frequency of surveillance

If feasible and safe, all patients with paediatric low-grade glioma receiving treatment as an adjunct to surgery should have a presurgical baseline MRI scan to assess the tumour, and a postoperative MRI scan within 24–72 h after surgery to assess the amount of residual tumour. In situations for which surgery is not indicated, or only a small biopsy sample is taken, a postoperative MRI scan might not be clinically indicated or necessary to assess residual tumour, and the diagnostic or prebiopsy

Role of T1-weighted contrast-enhanced imaging, T2-weighted, and T2-fluid attenuated inversion recovery imaging and image acquisition

Although contrast-enhanced T1-weighted (T1) imaging is a mainstay for assessment of brain tumours, in general the use of contrast agents in paediatric low-grade glioma is controversial, given the spontaneous change in contrast uptake behaviour in residual tumours without clinical progression, and data concerning potential long-term toxic effects of contrast agents.22, 23 The literature does not have a substantial amount of data discussing the specific use of T1 and postcontrast imaging for

Advanced imaging, histology, and molecular subgroups

Preliminary literature on perfusion MRI, PET, and magnetic resonance spectroscopy indicates that these modalities and techniques can help to distinguish high-grade from low-grade gliomas, but these modalities are still considered exploratory at this point, are not standardised, and available data are insufficient to consider them in standard assessment of response in paediatric low-grade gliomas.31, 32, 33, 34 In addition, although there has been a great increase in the histological and

Neurofibromatosis type 1-associated paediatric low-grade gliomas

Current data do not suggest that different imaging techniques or sequences should be used for neurofibromatosis type 1-associated paediatric low-grade gliomas versus non-neurofibromatosis type 1-associated paediatric low-grade gliomas. However, experts from the RAPNO working group agree that specific imaging should be part of any optic pathway or hypothalamic lesion, as discussed later in this Series paper. Currently, standard MRI sequences are the best way to determine focal areas of signal

Assessment of cysts

There are minimal prospective data evaluating how a cyst should be incorporated into paediatric low-grade glioma tumour measurement and response. Clinical experiences and guidelines from historical and ongoing protocols from the COG, Pediatric Brain Tumor Consortium, and SIOPE, as well as some guidance for adult imaging from Response Assessment in Neuro-Oncology, help to inform this topic.40 The following recommendations are based on the RAPNO international expert consensus and require further

Visual outcomes

A substantial proportion of sporadic and neurofibromatosis type 1-related paediatric low-grade gliomas arises in the optic pathway and hypothalamic region affecting visual function and QOL of patients with paediatric low-grade gliomas. The prospect of stopping or potentially slowing a decline in visual acuity is an indication to initiate treatment in patients with paediatric low-grade gliomas.41, 42 There is consensus in the RAPNO group that assessment of visual function should be done in any

Motor, neuropsychological, and patient-reported outcomes

In addition to impairment of visual function, a substantial proportion of patients with paediatric low-grade glioma have motor, cognitive, behavioural, and other neurological function deficits (such as epilepsy), resulting in reduced quality of survival.44 Pilot studies that evaluated various domains of neurological function in patients with paediatric low-grade gliomas using the Vineland Adaptive Behavioral Scale show substantial deficits in scores for various subdomains, including motor

Defining radiological response

Clinical trial consortia (including COG, Pediatric Brain Tumor Consortium, and SIOPE) have generated a large number of response datasets in paediatric low-grade gliomas, using measurements in two or three perpendicular planes. Although prospective data comparing endpoints for measurements in two or three perpendicular planes are missing, there is wide experience of using both measures for clinical trials internationally. The RAPNO low grade glioma committee therefore proposes using both

Conclusions

Paediatric low-grade glioma tumours have unique characteristics compared with adult low-grade gliomas, which must be taken into consideration when defining radiological response. Also, given that most children with paediatric low-grade gliomas will not succumb to their disease, a focus on functional outcomes has moved to the forefront of the goals of treatment for these patients.53 Although late effects are crucially important for these patients, these parameters are difficult to interpret in

Search strategy and selection criteria

References for this Series paper were identified through searches of PubMed using the search terms “low-grade glioma”, “pediatric”, “radiologic assessment”, “pilocytic astrocytoma”, “response”, “neurofibromatosis”, “functional outcomes”, “visual outcomes”, “REiNS”, and “RANO”, for articles published from Jan 1, 2000, until June 30, 2019. Articles were also identified through searches of our own files. Only papers published in English were reviewed. The final reference list was generated on the

References (53)

  • RJ Packer et al.

    Pediatric low-grade gliomas: implications of the biologic era

    Neuro Oncol

    (2017)
  • DTW Jones et al.

    Pediatric low-grade gliomas: next biologically driven steps

    Neuro Oncol

    (2018)
  • MJ Fisher et al.

    Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis

    Neuro Oncol

    (2012)
  • A Chalil et al.

    Low grade gliomas in children

    J Child Neurol

    (2016)
  • DT Jones et al.

    Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

    Nat Genet

    (2013)
  • A Lassaletta et al.

    Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

    J Clin Oncol

    (2017)
  • JL Ater et al.

    Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children's Oncology Group

    Cancer

    (2016)
  • JO Blakeley et al.

    The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis

    Am J Med Genet A

    (2017)
  • DR Weidman et al.

    Dose-level response rates of mTor inhibition in tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA)

    Pediatr Blood Cancer

    (2015)
  • MJ Fisher et al.

    2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

    Am J Med Genet A

    (2018)
  • D Sturm et al.

    Pediatric gliomas: current concepts on diagnosis, biology, and clinical management

    J Clin Oncol

    (2017)
  • M Tosur et al.

    Diencephalic syndrome: a rare cause of failure to thrive

    BMJ Case Rep

    (2017)
  • BC Widemann et al.

    Conclusions and future directions for the REiNS International Collaboration

    Neurology

    (2013)
  • SR Plotkin et al.

    Achieving consensus for clinical trials: the REiNS International Collaboration

    Neurology

    (2013)
  • RSV de Lande et al.

    Adaptive behavior impaired in children with low-grade glioma

    Pediatr Blood Cancer

    (2019)
  • S Avula et al.

    JTaPB. Comparison of final intra-operative MR scan and post-operative MRI performed 24 to 72 hours after brain tumour resection

    Neuro Oncol

    (2016)
    • †

    Joint first authors

    View full text
    © 2020 Elsevier Ltd. All rights reserved.