This presentation provides an introduction to brain cancer and major treatment options. An overview of current imaging methods is given, including approaches to diagnosis, characterisation and response assessment. The major MR methods available are briefly described, as an introduction to the following more detailed presentations on specific MR imaging Methods. Current approaches to objective imaging based response assessment are discussed.
1. Brain Cancer
Brain cancer can be primary disease, derived from cell types found in the brain, or may result from non brain tissues that have spread from extra-cranial primary cancer, and so represent disease emanating from non-brain cell types. Tumours may be malignant, or benign. Distinguishing these groups is important in diagnosis. Brain tumours present significant challenges to diagnosis and treatment, due to their inaccessibility and the considerable complexity and importance of neighbouring or surrounding tissues. As a consequence obtaining tissue is a greater challenge than at many locations, and this is particularly the case in follow-up, response assessment and in children. The intact blood brain barrier, with much tighter control of molecular than occurs outside of the central nervous system (CNS), restricts access to many drugs as well as limiting access of some diagnostic agents.
Classification of CNS tumours is based on the WHO scheme, which was updated in 2006 (1). This builds on previous classification, based primarily in histology, to incorporate genetic and molecular features, improving the biological basis of identification. Radiological assessment will therefore need to relate to this revised classification scheme (2). A recent review summarises many of the more important mutations and molecular features found in adult brain tumours (3). A minority of glioma result from genetic predisposition, resulting, for example, from NF1/2, TP53, CDKN2, TSC1/2 and PTEN mutations. IDH1mutations are common in low grade and anaplastic gliomas, conferring improved outcome. EGFR amplification is common in primary glioblastoma. Genetic instability can lead to molecular evolution during development and under the selective pressure of treatment and spread. Childhood brain cancer is often superficially similar to adult brain cancer, but generally differs in grade distribution, likelihood of transformation and anatomical location. Molecular profiling has now shown key biological differences underpinning different behaviour and response (4,5).
2. Treatment
The primary treatment for glioma is surgery, although complete resection may not be possible, and a characteristic of glioma is diffuse infiltration within the blood brain barrier, requiring methods of wide area treatment in the brain. Treatment usually includes radiotherapy together with temozolomide as first line, with treatments addressing molecular susceptibilities considered for subsequent phases and trials. Surgery followed by radiotherapy is common in anaplastic glioma with variable evidence regarding best chemotherapeutic approach. Low grade glioma generally progress slowly, but eventually transform to higher grade glioma. Surgery is generally employed, but subsequent more intensive radiotherapy and/or chemotherapy may be delayed until progression. Further evaluation of small molecule inhibitors and a range of immunological approaches, together with selective opening of the blood brain barrier, are likely over the next few years (1).3. Imaging of brain cancer
3.1 Detection and diagnosis
Imaging has a critical role in identifying the presence of CNS disease following symptomatic presentation. CT may often be employed at this stage, and can readily identify disease with blood brain barrier (BBB) breakdown, via the use of contrast, but may be less helpful where the BBB is intact, although MRI is more informative, and can better support diagnosis and grading. MRI provides a range of contrasts and information (see below) that can inform on the likely type of disease and the extent. It provides the approach of choice for initial diagnosis and planning of interventions such as surgery. It is better able to identify areas of oedema and extended disease that will help guide subsequent interventions. Definitive diagnosis will generally rest on tissue sampling via biopsy or surgery, although in some tumours such as paediatric diffuse intrinsic pontine glioma, tissue sampling may not be indicated. Metabolic status, assessed via MR spectroscopy, can identify key metabolites that can enable discrimination of some tumour types, complementing imaging information (6-11).3.2 Treatment planning
MRI enables evaluation of bulk disease, together with evaluation of its nature, and of areas of likely necrosis, together with functional information relating to perfusion and cellularity. It can provide information that can aid assessment of extent, infiltration and associated reactive responses in the brain, which may be indicative of microscopic extension. Magnetic resonance spectroscopy (MRS) can support assessment of grade, as well as distinguishing some tumour types. PET also provides a valuable resource to evaluate extent of disease, having in principle, higher sensitivity for small deposits of disease, whilst also providing information on metabolic features, depending on the tracer employed (10). Increasingly, in planning either surgery or radiotherapy, identification of the function and location of adjacent critical structures can be of great value, enabling sparing of critical functions and improved assessment of local involvement. Here BOLD assessment of neural function, and tractography to enable identification of neural pathways, as well as vascular and tissue perfusion evaluation can be helpful.3.3 Response assessment
Imaging is the primary means of assessing early response, incomplete excision and local recurrence or intracranial spread of disease. In some cases symptomatic response, and other markers, may also be important, but they will not localise any disease. For many indications, MRI is likely to be the most useful method, but there are important roles for PET in identifying small areas of disease and identifying recurrence or active residual disease from treatment related effects where MRS may also have a role. In some cases CT may be employed, or combined modality imaging. Formal response assessment for trial reporting is considered separately below.
Evaluation of CNS response can also be confounded by both pseudoprogression, where disease is apparently worsening, but longer term follow up indicates this is not the case, and pseudoresponse, where disease appears to be resolving, but in fact is progressing (12,13). The former is often attributed to the effects of treatment causing breakdown of the BBB, together with increased vascularisation related to repair processes, leading to increased contrast uptake; while the latter may be caused by healing of the BBB, whilst tumour continues to develop within the BBB without increased vascularisation, so there is a reduction in contrast uptake. This can particularly be an issue with anti-VEGF directed treatments, which are likely to reduce BBB breakdown. New guidelines on response assessment (revised RANO criteria) now also take account of the period since treatment. These will be discussed further below.
A particularly important area for imaging is in helping guide further treatment decisions. At this stage, there may be reluctance to perform further biopsy and surgery may not be indicated. Imaging may help identify transformation or evolution of phenotype, as well as extent and behaviour of disease. It will also provide a new baseline for subsequent response assessment.
4. Overview of imaging approaches
Detailed descriptions of the different imaging techniques are given in subsequent talks, and so here the main approaches will be mentioned, to provide some indication of their application.
Morphological imaging is usually based on T1w, T2w and FLAIR. T1w imaging provides good anatomical detail, with tumour often having low signal intensity. T2w images generally provide greater sensitivity for tumours, which often have high signal, and also show fluid as high signal. Fluid attenuated inversion recovery images are T2w but reduce the signal from fluids, improving the conspicuity of tumours, and also enabling separation of oedema from cerebro-spinal fluid (6). However the bulk of tumour can be difficult to separate from oedema and similar affects (6-11).
Functional information is added with a range of further approaches. Contrast enhanced T1w imaging often improves the visualisation of the tumour, while providing information on BBB breakdown and further local features of tissues such as necrosis. However, low grade glioma generally do not enhance, and brain tumours can also develop diffuse infiltration inside an intact BBB. Dynamic contrast enhanced measurements (14) enable assessment of vascular permeability and several other parameters. Dynamic susceptibility imaging also uses contrast agent, but samples rapidly during passage of the initial bolus to obtain cerebral blood volume (CBV) and cerebral blood flow (CBF). Further techniques such as arterial spin labelling, are also being developed to measure perfusion.
Diffusion weighted MRI can identify regions of high cellularity based on the restricted water diffusion in such areas. This is a valuable approach to identify areas of functional tumour. The technique can also provide quantitative assessment of apparent diffusion coefficient (ADC) of value in characterising tissues and assessing response. Diffusion tensor imaging (DTI) enables tractography, providing a means of identifying critical connective pathways to support planning of surgery and radiotherapy. Blood oxygen level dependent (BOLD) MRI, utilising T2*w sequences, can identify specific areas of brain function, again supporting planning and identifying relocation of function due to distortion and functional plasticity. DTI has also been reported as contributing to differentiation of different types of tumour, and of different tumour associated tissues.
Proton MRS enables measurement of a number of important metabolites, including choline containing molecules (Cho) which report on lipid synthesis and breakdown, N-acetyl aspartate (NAA) considered to be a neuronal marker, creatine containing molecules (Cre)(15) . Lipids are present particularly in higher grade tumours and in areas of necrosis. Lactate can also be seen but resonates at a similar frequency to some lipids, so more advanced techniques are required to distinguish it clearly. MRS can aid identification of tumour type and grade, identification of areas of more aggressive disease, and can be helpful in identifying some post treatment effects, such as pseudo progression. Pattern recognition methods have been shown to help in identifying different tumour types (16,17). Measurements of other nuclei, such as 31P, 19F and 13C are also possible, with recent advances in hyperpolarisation enabling direct measurements of 13C pyruvate to lactate exchange (18,19). These approaches require broad band MR systems, and a dynamic nuclear polarisation (DNP) system for hyperpolarised 13C studies.
PET also provides a means of exploring specific metabolic process in the brain, as well as the possibility of identifying uptake and binding of specific cellular receptors. The most common PET radiopharmaceutical, fluorodeoxyglucose (18FDG), provides limited contrast for brain tumours due to the high uptake of glucose in the normal brain. Fluorinated thymidine (18FLT) measures amino acid uptake, as does fluoroethylthymidine (18FET), although uptake rates are lower than for 18FDG. 11C labelled substrates can also be employed, such as 11C methionine and 11C acetate. Due to the short half life, these require an on site cyclotron and chemistry, as well as rapid measurements (11). A number of hypoxia markers are under investigation, including 18F misonidazole (18F-MISO), and fluoroazomycin-arabinofuranoside (18FAZA) (20).
5. Response assessment
Routine assessment is usually based on radiological reporting based onT1w, T2w, contrast uptake, and possibly DWI. More complex methods may be included at some centres. For trials, it is usual to have a standardised assessment, which is likely to use the guidelines recommended by the Response Assessment for Neuro-Oncology (RANO) working group (20-26). This provides (and is developing) specific guidelines for different tumour types. These currently include high grade glioma (27,28) and metastases (29-31). Further guidelines are available for neurological response and immunological therapies (32).
While a detailed description of these guidelines is beyond the scope of this syllabus, more information can be found in several recent reports. The major assessment is based on the product of maximal cross sectional diameters of enhancing tumours. There are also criteria for changes in non-enhancing tumour and additional trial entry criteria to reduce the impact of pseudo progression following radiotherapy.
6. Conclusions
MRI provides the core imaging modality for detection, diagnosis, staging, treatment planning and evaluation of treatment response. The ability to manipulate contrast, together with the range of functional parameters available, provide powerful tools to better classify and assess the function of brain tissues and disease. Advances in instrumentation, with MR/PET systems, enable addition of specific metabolic and receptor probes to be evaluated in the same study. Developments in dynamic nuclear polarisation may further extend metabolic evaluation of brain tumours.1: Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20. doi: 10.1007/s00401-016-1545-1
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