CNS II General Management & GBMs Flashcards
how is cerebral oedema managed
glucocorticoids such as dexamethasone, considered the ‘gold standard’.
-> side effects of glucocorticoids, such as dexamethasone, include Cushing’s syndrome, increased risk of pneumonitis, long term osteoporosis and compression fractures.
- Pitter et al (2016) reported that corticosteroid use during RT with or without chemotherapy is an independent predictor of poor outcome in GBM (if you have to continue corticosteroid use during RT it is usually a poor prognostic outcome)
- suggest replace dexamethasone with short term VEGF antagonists instead. this is not the gold standard
problems with using corticosteroids in RT practice?
swelling - causes problems with masks
in working environment, when booking patients, pre-empt the swelling that the patient might have and CT re-scan that they may need
seizure control
- risk of seizures varies between 60-100% in LGGs and between 40% and 60% in GBMs
- seizures as a symptom are a favourable prognostic factor for survival ( a seizure is showing that where the patient has a tumour, they still have some functioning brain parenchyma )
- recurrence or worsening of seizures during the disease trajectory may indicate tumour progression
- one third of patients with brain tumour-related epilepsy show pharmacoresistance to antiepileptic drugs
- levetiracetam is the drug of choice, followed by valproic acid, based on the evidence ( these drugs can be very nauseating )
- if seizures are recurring, these can be combined
- other options are: lacosamide, lamotrigine or zonisamide if the others are not tolerable to the patient
- valproic acid is of interest as it may prolong survival in patients with GBM (EORTC study, 2011)
surgical management
best prognosis with maximal safe surgery typically using a craniotomy
- CNS tissue is intolerant of trauma ( if a brain surgeon removes some neurones, they are gone and can no longer function. you cannot come in with the margins that you would in other sites)
- CNS tissue is not capable of regeneration
- CNS tissue is critical to normal body functioning
- surgical debulking is most frequent procedure, maximising brain function
medical oncology management
- chemotherapy drugs as radiosensitisers for treatment of gliomas
- BCNU (Carmustine) can be directly implanted into the brain (Glial wafer) and CCNU (Lomustine) ( this negates any issues with blood brain barrier. work best at rest phase of cell cycle, therefore cell cycle non-specific )
- procarbazine
- vincristine ( inhibit microtubule formation and hence prevent cell division, cell cycle specific )
- temezolomide
- lipid soluble drugs so can cross blood-brain barrier
general guidelines for target volumes
- in general the GTV is individualised for each tumour volume based on the likelihood of the tumour to infiltrate ( grade 1 tumour a lot less likely to infiltrate surrounding brain parenchyma than a grade 4. you must follow the disease and know the disease tract of the tumour )
- the disease must be followed along with the white matter tracts and a non-uniform (isotropic) margin used
- volumes should pay respect to anatomical borders ( strange shapes. awkward for tx planning )
field arrangements CNS tumours
- mainly modulated techniques especially for hippocampal sparing in whole brain treatments ( hippocampus is responsible for memory. QoL of patients. you must be able to taper the dose –> modulated techniques )
- be careful of exit doses, vertex fields are problematic in some scenarios with photons
-> high dose to thyroid, carotid artery and jugular vein
( vertex fields means you are shooting straight through the patient. couch is turned and gantry is turned to either 90deg or 270deg. vertex field goes through the head of the patient and hits everything through the patient on exit dose. if you raise the couch and turn the gantry slightly - this is called a superior anterior oblique - the gantry is at 60deg and the couch is at 90deg or the gantry is at 300deg and the couch is at 90deg. **juvenile patients - you don’t want to cause any issues to thyroid / carotid artery / jugular vein ) - location of hot spots critical, remember ‘double trouble’
( ‘double trouble’ - if you are treating a patient’s brain to 60Gy/30# but there is a hot spot of 110% near the optic chiasm. This would mean that this hot spot is getting 2Gy x 110% = 2.2Gy/# and it is also getting 60Gy x 110% = 66Gy. something like this would render the patient blind )
OARs CNS tumours
when contouring target volume and OARs, fuse planning CT and pre- and post-op MRIs
OARs:
- brainstem
- hippocampus
- hypothalamus
- lens
- orbits
- pituitary gland
- lacrimal glands
- middle and inner ear
- optic apparatus (optic nerve & optic chiasm)
- spinal cord
- cochlea
( there is a hierarchy of OARs. Lens is always bottom of the list - we would never compromise target coverage to spare the lens / optic apparatus )
(Tolerance of normal tissues: dependence on TD and fractionation, in context of histology, site, PS and expected OS.
Brain parenchyma: 54-60 Gy in 30 fractions
Risk of necrosis 5% with a dose of 60 Gy in 30 but volume dependant.
A volume effect also exists for intellectual damage., in theory ok with doses up to 54Gy in 30 fractions but not well understood.
Brain stem: 54Gy in 30 or 55GY in 33 (same)
Optic nerves/chiasm: 45-50 Gy in 1.67 or 1.8 Gy fractions
Pituitary and hypothalamus: Little long term effect for doses under 20-24 Gy. In children, doses of 40-60Gy damage hormone secretion. Adults who receive 50-60Gy have significant long-term pituitart-hypothalamus dysfunction.
Middle and inner ears: doses up to 60Gy recover function
Lacrimal glands: 20Gy
Lens: 5-6Gy over 30 fractions no cataracts.
Permanent alopecia: Depends on dose to hair follicles in the dermis however 50% of patients can experience alopecia with a dose of 43Gy. )
GBM
- ** GBMs are derived form neural stem cells, neural stem cell-derived astrocytes and oligodendrocytes precursor cells
- ** GBM is extremely challenging to treat with 5-year overall survival being 7.2%, according to US data
- ** almost all GBMs recur even after aggressive management due to:
-> incomplete resection and high infiltrative nature of GBMs ( maximal safe surgery. can cross cerebral hemispheres )
-> high degree of genetic heterogeneity within the tumour ( one part of the GBM could be completely different to the other parts )
-> immunosuppressive tumour microenvironment ( unless you have a hot tumour microenvironment you won’t be suitable for immunotherapy) - GBMs are highly hypoxic and permit the development of glioma initiating cells, which are self-renewing ( for RT to work, it must be in a highly oxygenated environment to create the free radicals that will damage the cells. There is also a highly necrotic cell volume with GBM, RT will not work in necrotic environment )
-> this can lead to potentially more aggressive recurrent tumours that are radio and chemo resistant - genetic heterogeneity makes target therapy development problematic as there are 4 genomic subtypes of GBM known:
-> Mesenchymal (Neurofibromatosis (NF1, PTEN TP53 gene mutation)
-> Classical (EGFR amplication, no TP53 mutation)
-> Proneural (TP53, IDH1, PDGFRA mutations)
-> neural (contamination of original tumour with non-tumour cells) - issue is that all of these subtypes can vary spatially and temporally within the same tumour, according to RNA analysis
- immunosuppressive microenvironment of GBMs is inhospitable as the tumours lack pre-existing tumour T cell infiltration, making them resistant to immune checkpoint inhibitors (known as ‘cold’ tumours). RT can modulate this microenvironment and turn these ‘cold’ tumours to ‘hot’.
presentation of GBM
- majority of the malignant gliomas are GBMs ( stage 3 and 4. most are stage 4 )
- arise in adults, with a peak incidence at 45-65 years
- usually found in frontal and temporal lobes
- extremely necrotic and haemorrhagic
- may be multi-focal ( could arise in more than one location )
- main presentation is headaches, followed by seizures
surgical oncology management of GBM
- extent of surgical resection is positively correlated with survival time
- aim for gross total resection but problematic:
-> successful identification of tumour margins, microscopic finger-like projectile growth of GBMs
-> avoiding eloquent areas ( pt typically awake during procedure )
-> ‘brain shift’ - movement of brain during surgery relative to pre-operative imaging (gravity, pt position, tissue/fluid loss during surgery, drugs used to manage intracranial pressure)
medical oncology management GBM
standard is the Stupp protocol post-operatively
- 6 weeks of concomitant Temezolomide with RT (75mg/m^2), followed by adjuvant Temezolomide (150-200mg/m^2) for 5 days every 28 days for 6 cycles. ( = Temadol / Tremadol. Pts can be very nauseous with Temezolomide. Taken in tablet form chemo )
- Temexolomide is a small molecular alkylating agent that methylates the purine bases of DNA and thereby damages its structure
- Its main cytotoxic action is via O^6-methyguanine lesions that lead to cellular senescence, apoptosis and autophagy ( cellular senescence = cells getting old. apoptosis = cell death by cell suicide. autophagy = cells consuming themselves )
- used with RT to increase the likelihood of double strand breaks
- side effects of Temezolomide are haematologic primarily
-> thrombocytopaenia presents in 10-20% of patients
- non haematologic side effects are less common and include nausea, fatigue, anorexia and hepatotoxicity
- BCNU in the form of Gliadel wafters can also be considered for GBM as can CCNU but Temezolomide is the current gold standard
Methyl Guanine Methyl Transferase (MGMT)
- Temezolomide kills tumour cells by transferring methyl groups to DNA - it alters the DNA configuration by attaching a thymine rather than a cytosine during DNA replication
-> this damage can be reversed by the DNA repair enzyme MGMT, hence the methylation status of the MGMT gene promotor has very relevant clinical significance
-> MGMT inactivation or ‘silencing’ is associated with improved OS and PFS and is a very important prognostic biomarker in the Stupp protocol
-> MGMT status is determined using assays such as Methylation-Specific PCR, but there are others and consensus on which assay is optimal as yet.
medical oncology management GBM
Bevacizumab is used predominantly in the treatment of recurrent GBM ( recurrent - pts who started with a lower grade glioma that then changed into GBM )
-> monoclonal antibody administered intravenously
-> has anti-angiogenic properties and inhibits VEGF-A to stop angiogenesis
-> levels of VEGF-A are 30 times higher in GBM than in low grade glioma, hence its use mainly in GBM
-> can improve PFS in newly diagnosed GBM but not OS (unlike Temexolomide), therefore mainly used in recurrent disease
Indications for RT and systemic therapies (ASTRO Delphi methodology)
- RT improves OS compared with best supportive care or chemo alone
- use of fractionated RT and TMZ as standard of care in patients up to 70 years of age
- addition of Bevacizumab does not improve OS but may prolong PFS
- addition of other systemic therapies to RT and TMZ remains investigational
