Elsevier

The Lancet Oncology

Volume 18, Issue 2, February 2017, Pages e91-e100
The Lancet Oncology

Review
Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques

https://doi.org/10.1016/S1470-2045(17)30030-XGet rights and content

Summary

Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of paediatric brain tumours. Radiotherapy is one of the main contributors to neurocognitive sequelae. Current approaches for prevention and reduction of neurocognitive dysfunction include avoidance of radiotherapy in young children and reduction of the radiotherapy dose and volume of brain irradiated. Substantial advances have been made in brain imaging, especially with functional imaging and fibre tracking with the use of diffusion tensor imaging. Radiotherapy techniques for photon therapy have also evolved, with widespread use of techniques such as image-guided radiotherapy, volumetric modulated arc therapy, helical tomotherapy, and adaptive radiotherapy. The number of proton beam and heavy ion therapy facilities is increasing worldwide and there is great enthusiasm for clinical use of advanced MRI-guided radiotherapy systems. Here, we review the potential role of modern imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae in children with brain tumours, and discuss various strategies to integrate these advances to drive further research.

Introduction

Brain tumours, the most common solid tumours in children, account for more than 20% of paediatric cancers.1 With current advances in treatment, more than 70% of children who develop brain tumours are long-term survivors. Almost 50% of these paediatric patients will develop progressive neurological deficits later in life,2 leading to impaired academic performance and diminished career prospects as adults.3 Neurocognitive dysfunction can substantially affect daily life. These effects include difficulties in gaining or sustaining employment, unaffordable independent living, increased psychosocial problems and vulnerability, and increased likelihood of being a potential victim of theft, fraud, or assault.4, 5

Various disease-related, treatment-related, and host-related factors contribute to the development of neurocognitive dysfunction, including the location and size of the tumour, age at diagnosis, surgery, radiotherapy, chemotherapy, concomitant medications, disease-related or treatment-related endocrine dysfunction, and premorbid intellectual and neurological function.6 Studies also suggest that genetic effects, such as genetic and enzyme polymorphisms, could influence various elements of cognitive function, including general, verbal, and non-verbal intelligence, and processing efficiency and memory.7

Radiotherapy is one of the major factors contributing to neurocognitive dysfunction, which is typically progressive in nature.3, 8 Cognitive dysfunction can affect global cognitive functioning (intelligence quotient [IQ]), memory and attention, executive function, and psychomotor skills.6, 9 Prevention or minimisation of radiotherapy-induced cognitive dysfunction has been a topic of intense research for a long time. The only measures that have achieved some success so far are avoidance of radiotherapy in young children, especially those younger than 3 years of age, and reduction of the total radiation dose and brain volume irradiated.10, 11 The use of memantine (an N-methyl-D-aspartate [NMDA] receptor antagonist used in the treatment of dementia) with whole brain radiotherapy in adults reduced the decline in the primary endpoint of delayed recall in the Hopkins Verbal Learning Test-Revised (HVLT-R), although these findings were not statistically significant.12 Nonetheless, addition of the drug to radiotherapy delayed the onset of cognitive decline and reduced the rate of neurocognitive decline. However, this drug has not yet been studied in children who are receiving radiotherapy.

Substantial advances have been made in brain imaging, especially with functional mapping and fibre tracking with the use of diffusion tensor imaging.13 Some of these advances are being exploited in the surgical management of brain tumours and radiosurgery.14, 15, 16 However, integration of these technologies to improve planning of radiotherapy is occurring at a slow pace. In this Review, we summarise the role of modern imaging in our understanding of neurocognitive dysfunction, discuss the potential role of imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae, and propose promising strategies to integrate these advances to drive further research.

Section snippets

Mechanisms of radiotherapy-induced neurocognitive dysfunction

Radiotherapy can damage progenitor cells, inflammatory and stromal cells, and the vasculature.17 Inflammation, angiogenesis, and cell death induced by radiotherapy can cause damage to white and grey matter.9 Another potential mechanism of neurocognitive dysfunction is the radiation-induced depletion of oligodendrocytes, which could lead to inadequate myelination and white matter necrosis.18 Development of both white and grey matter depends on the age of the individual, and full myelination of

Effect of radiotherapy parameters

The risk and severity of neurocognitive dysfunction depends on several patient-related factors, disease-related factors, and radiotherapy parameters, such as total dose, dose per fraction, and volume of brain irradiated.9 Studies suggest that a higher dose of radiotherapy increases the risk of neurocognitive dysfunction, with a progressive deterioration over time.22, 23 Radiotherapy prevents children from acquiring new skills and knowledge, leading to gradual worsening of the deficit over time.3

Role of eloquent areas and domains of the brain in neurocognition

Various areas of the brain are important in neurocognition, but the relative contribution of individual areas to overall cognition is still not fully understood. Neurons and glial cells are produced from neurogenic stem cells located in the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal gyrus.25 These areas form part of the limbic system, and continuous renewal of neurons from neurogenic stem cells is important for memory.26 The limbic system consists

Conventional imaging in neurocognitive dysfunction

Conventional anatomical changes detected by MRI include changes to white matter, mild enhancement, and oedema in the distribution of the radiation field.17 Diffuse white matter changes (often referred to as leukoencephalopathy) develop in 16% of children treated with cranioradiotherapy for medulloblastoma or a primary neuroectodermal tumour after a median interval of 7·8 months (range 1·9–13·0 months).36 These lesions were most commonly seen in the pons and cerebellum, and 73% resolved fully

Importance of white matter structures in neurocognitive decline

Studies that measure changes in white matter volume have shown that a decrease in white matter volume following radiotherapy is associated with a decline in IQ and neurocognition.41, 42, 43 Voxel-based morphometry approaches show that frontal white matter (especially right-sided white matter) is more sensitive to volume loss than other parts of the brain.42 Increased loss of white matter volume is associated with intensity of CNS treatment (ie, treatment for brain tumours has a greater effect

Functional MRI with blood oxygen level-dependent imaging

Functional MRI (fMRI) is a well-established technique to identify cortical areas that are activated while undertaking a specific task. During cortical activation, a transient, focal increase in blood flow occurs that can be measured by differences in the magnetic properties of haemoglobin, depending on its oxygenation status. Deoxyhaemoglobin is paramagnetic and therefore shortens the T2* signal of the blood and its surroundings. (T2 is defined as the time constant for transverse magnetisation

Advanced radiotherapy techniques

No prospective studies have assessed the role of selective sparing of various eloquent areas and domains of the brain that are associated with different elements of cognitive function. A retrospective study31 has assessed the effect of the radiotherapy dose on potential functional targets of cognitive function, and shown that radiotherapy targeted to the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum affects global

The potential to integrate modern imaging with novel radiotherapy techniques

Strategies to prevent or minimise radiation-induced neurocognitive dysfunction include avoidance of radiotherapy in children younger than 3 years, optimal integration with chemotherapy to minimise the total dose of radiotherapy or volume of brain treated (or both), optimal target delineation with better imaging, and the use of conformal radiotherapy techniques.

Modern radiotherapy planning is based on co-registration of a conventional MRI scan with a planning CT scan. The clinical benefit of

Challenges of integration of functional imaging for radiotherapy planning

Most preclinical studies investigating the association of radiotherapy-induced changes with cognitive dysfunction focus on the hippocampus, with few data showing a link between changes in the non-hippocampal brain and neurocognitive function.84 Additionally, no long-term longitudinal clinical studies have been done to ascertain whether or not tolerance of various brain domains to radiotherapy is associated with neurocognitive dysfunction. One of the prerequisites for the use of functional

Future directions

Radiotherapy techniques, when combined with optimal imaging, are now able to avoid potential areas of the brain involved in neurocognitive function. This approach needs to be assessed prospectively in children with brain tumours, with neurocognitive function and tumour control as the primary outcomes. However, without proper knowledge of the patterns of failure of different brain tumours, avoidance of radiotherapy to areas of the brain that might harbour a tumour would be an unsafe approach.

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the search terms “brain tumours”, “radiotherapy”, “imaging”, “functional mapping”, “diffuse tensor imaging”, “fibre tracking”, “intensity-modulated”, “proton beam”, “MRI-Linac”, “IGRT”, “VMAT”, and “tomotherapy” from Jan 1, 1990, to June 15, 2016. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review. Isolated

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      An additional slice-by-slice illustration of the anatomical landmarks of the thalamus is provided on an axial plane (Fig. 7). Sparing the hippocampus, which is an important structure of LC, has proven its positive effect on the preservation of the cognitive function (Jacob et al., 2018; Raber et al., 2004; Ajithkumar et al., 2017; Hutchinson et al., 2017; Lee et al., 2002; Gondi et al., 2010a, 2013). However, even without hippocampal damage, the injury of other limbic structures, with their afferent and efferent WM pathways, results in post-RT cognitive dysfunction (Connor et al., 2017; Chapman et al., 2013; Nazem-Zadeh et al., 2012b; Chapman et al., 2012).

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