Gliomas are the commonest primary, malignant tumour of the brain and account for more average years of life lost than all other cancers (Burnet NG et al Br J Cancer. 2005; 92(2):241-245). Glioblastomas are the commonest malignant tumour and encompass a spectrum of genetic subtypes characterised by rapid invasion causing deterioration in quality of life before death from progressive disease. Low grade gliomas comprise of a group of slow growing but malignant tumours that slowly progress before transforming into glioblastomas. Patients describe this as ‘living with a time-bomb in their brain”. The lack of new therapies makes optimising current treatments a priority.
Surgery plays a major role in managing gliomas – especially where adjuvant therapies are ineffective (Ewelt C et al, J Neurooncol. 2011; 103(3):611-618). Complete resection improves outcome and delays progression (Stummer W et al Acta Neurochir (Wien). 2011; 153(6):1211-1218.; Stummer W, et al Journal of Neuro-Oncology. 2012:1-9; Brown TJ et al. JAMA Oncol. 2016) if it is possible to identify all of the tumour (Roberts DW et al. J Neurosurg. 2011; 114(3):595-603). Radiotherapy is limited by the sensitivity of the brain to radiation induced injury – our lack of understanding the mechanisms and factors that determine normal tissue response (Burnet NG et al. Int.J.Cancer. 1998; 79(6):606-613) is a major limitation to improving radiotherapy delivery to optimise brain tumour control.
Brain injury from tumours is two-fold:
- Injury due to tumour invasion
- Injury caused by treatment of tumours
The impact of such injury is not well understood. It impacts quality of life and cognitive functioning, yet neuro-oncology research focuses on survival and fails to routinely record these outcome measures.
Aims and specific short (1 year), medium (2-3 years) and long (4-5 years) objectives
Short term (1 year):
- develop and validate new technology approaches to measuring quality of life and cognitive function as well as determining the true extent of tumours
Medium-term (2-3 years):
- study the effect of treatments on normal brain functioning and validate methods to assess treatment response
- develop methods that integrate new imaging methods into surgical and radiotherapy treatment planning
Long term (4-5 years):
- translate these technologies into clinical practice to personalise surgery, radiotherapy and rehabilitation
The theme aims to develop technology to improve quality of life and functional outcome in brain tumour patients. It will do so by focusing on four sub-themes:
- Identification of full extent of tumour
- Monitoring therapy
- Effect of tumour and treatment on the normal brain
- Developing a pathway for evaluating new technologies in surgical oncology
SUBTHEME 1: Identifying the true extent of tumour
Local invasion is a cardinal feature of gliomas and a major cause of failure of local control. Virtually all patients will die of progressive disease adjacent to the surgical cavity. Imaging used to plan treatment and determine treatment outcome is non-specific and insensitive to tumour extent (Price S et al. American Journal of Neuroradiology. 2006; 27(9):1969-1974). Identification of ‘residual disease’ will allow individualisation of tumour volumes for surgery and radiotherapy planning.
The CRUK-funded PRaM-GBM study (Price, Waldman and Jena) is a multicentre imaging biomarker validation study that aims to see if novel imaging using diffusion tensor MRI can predict the sites where tumours will progress. Our short- to medium-term plan is to deliver this study that should open in February 2017. Once we can identify where tumours progress, our medium- to long-term aim is to develop trials to change surgical and radiotherapy planning to improve local control.
To use advanced imaging methods to direct surgery we need to overcome issues with brain shift in neuronavigation. Neuronavigation is a major advance in neuro-oncology, but brain shift intra-operatively prevents it detecting tumour margins. This project will use intra-operative ultrasound to identify and correct for this brain shift (Giannarou and Price) and develop the methods over the medium-term to direct surgery using advanced imaging.
Differentiating normal brain from low grade gliomas can be extremely difficult as these tumours can appear normal. We know that a common mutation of isocitrate (IDH-1 and -2) early in the development of these tumours leads to large accumulation of the oncometabolite 2-hydroxyglutarate (2-HG) in tumour cells. Our short-term aim is to develop an assay to rapidly detect 2-HG intra-operatively (Price and Hutter). Our medium-term plan is then to correlate 2-HG concentration from this assay with tumour cellularity (immunohistochemistry can identify individual tumour cells to measure tumour cellularity) and then determine a threshold between tumour and normal brain. In the long-term we aim to see if this method allows more extensive resection of tumours.
SUBTHEME 2: Assessing response to therapy
Diffusion MRI methodology for detecting early response to therapy (Waldman) – diffusion MRI is sensitive to tumour cellularity. Changes in the apparent diffusion coefficient (ADC) reflect changes in cellularity. Several metrics have been described, this project (funded by the Brain Tumour Charity) will compare different methodologies to determine which is most sensitive to detecting early response in patients with brain tumours.
Use of circulating cell-free DNA techniques to monitor tumour response (Brindle and Mair) – by identifying DNA fragments with tumour specific mutations allows early detection of tumours and is a method of studying tumour genetic evolution with treatment to monitor treatment response as well as treatment escape due to new mutations. This project will use this new technology to understand changes due to treatment.
MR Spectroscopy for 2-Hydroxyglutarate to monitor response to treatment of low grade gliomas (Ansorge) – the oncometabolite, 2- hydroxyglutarate (2-HG), can be detected with proton spectroscopy, although the concentrations are low and the spectra overlaps other substances. This project plans to utilise the 7-Tesla MR imaging facilities in Oxford, Cambridge and Nottingham to optimise detection of 2-HG (short-term) before translating it back to 3-Tesla (medium term). We will then use this to monitor treatment response in these tumours (medium- to long-term).
SUBTHEME 3: Effect of tumour and treatment on normal brain function
Recording patient reported outcome measures and quality of life (DAMSEL Project) (Joannides, Price and Brodbelt) – for treatments that are essentially palliative, the aim of treatment must be to improve quality of life. The DAMSEL Project (funded by InnovateUK) aims to develop a cloud-based tool that can record quality of life and patient symptoms.
Screening for neurocognitive deficits in neuro-oncology patients (Rohit Sinha, Neurosurgery from Cambridge and Tom Manley from the MRC Cognitive Brain Sciences Unit, Cambridge) – neurocognitive deficits are common, but full neuropsychological assessment is difficult. The CogENT Study will assess cognitive function before and after surgery in patients with brain tumours (short-term). It will use the OCS-Bridge screening tool developed for screening neurocognitive function following stroke.
These outcome measures (QoL and neurocognitive function) will be used to:
- Identify patient issues for holistic needs assessment(short-term);
- Select suitable patients for targeted rehabilitation (medium-term; see c below)
- Record as outcome measures for trials and the National Brain Tumour Registry
Targeted Rehabilitation in Neuro-Oncology – there are virtually no services for neuro-oncology rehabilitation. The progressive brain injury from the tumour and frequent poor prognosis limits the time for patients to achieve their rehabilitation potential. There are two areas of interest:
- Targeted pre-habilitation in neuro-oncology – pre-habilitation (i.e. rehabilitation started pre-operatively) has been shown very effective in other surgical fields. Pre-operative neuro-oncology patients frequently have deficits that, even if they are made no worse, will delay discharge from hospital. This study aims to use DAMSEL to identify suitable patients and then get them assessed pre-operatively by physiotherapy and occupational therapy and targeted rehabilitation started pre-operatively (short-term).
- Targeted tools for rehabilitation – this will use products from other themes designed for brain injury rehabilitation and assess them in this specific setting (short- to medium-term).
Effect of surgery on normal brain function (Price and Sinha) – we understand the impact of surgically induced motor and, to some extent, language deficits. We don’t know the impact of surgically induced deficits of visual function or cognition. This project aims to understand the impact of surgery on patient functioning and quality of life (short-term). We will also look at the disruption of individual white matter tracts and brain networks to understand brain regions that impact on functioning and quality of life (medium-term).
Effect of radiotherapy on normal brain function (Price, Jena, Burnet and Jenkinson) – advanced imaging can identify subtle changes in brain structure and function. In this project, we aim to study changes in white matter (diffusion tensor imaging), perfusion and brain networks (resting state fMRI) in the normal brain and correlate changes in different anatomical structures and radiation dose with changes in cognitive function (short-term). We will use this data to change planning of radiotherapy (medium- to long-term).
SUBTHEME 4: Developing a pathway for evaluating technology in surgical oncology
Stephen Price led a workshop on technology trials in surgical oncology that was part of the NCRI Future of Surgery series. Following on from this we will work on developing a pathway for trialling new technologies in surgical oncology. This work will be performed in collaboration with the IDEAL collaboration and the NCRI.