CNS Flashcards
Describe the epidemiology and risk factors for high grade glioma.
Incidence (Australian statistics)
- 1900 cases annually (all brain malignancies)
- Glioblastoma has an incidence of 6.9 per 100 000 people
M>F (1.4:1)
Peak incidence 65-75 years
o Note median survival inversely proportional to age (elderly = worse prognosis)
Aetiology
Predominantly sporadic (no known cause)
1. Previous ionising radiation = causative (small absolute risk) a. e.g. scalp irradiation for tinea capitis 2. Cellular phone use --> hypothesis only (nil causal association) 3. Nitrosamines (cured meats) --> correlation (no proven causation) 4. Genetic syndromes (<5% of glioblastoma) a. Turcot’s syndrome (constitutional mismatch repair deficiency - biallelic OR APC mutation) i. Also results in intestinal polyps/malignancy b. Lynch syndrome or HNPCC (MMR deficiency – monoallelic) i. Associated with multiple malignancies (GI, endometrial, ovarian, etc.) c. Li-Fraumeni syndrome (TP53 mutation) d. NF1 Also associated with neurofibromas, café-au-lait spots, schwannoma
Describe the WHO pathological classification for Gliomas
A number of genes play key roles
- IDH1 & IDH2 –> oncometabolite accumulation
- 1p/19q co-deletion
- ATRX
- TERT promoter
- EGFR
The combination of these mutations leads to a specific integrated pathological diagnosis
Glioblastoma
Can occur either primarily (usually older patients) or secondarily (younger)
- Primary = de novo tumour (no precursor) and thus IDH is wildtype 90%
- Secondary = occurs within the background of a lower grade glioma and thus IDH is mutant 10%
○ Younger 40-50yo
Pathology Classification (Based WHO Classification of CNS Tumours, 5th ed 2021)
Integrated histological and molecular diagnosis approach
- Note that molecular diagnosis takes precedence over histological diagnosis
Key Categories (diffuse glioma)
Updated WHO classification has only 3 types:
- Astrocytoma (IDH-mutant)
- Oligodendroglioma (IDH-mutant & 1p/19q co-deleted)
- Glioblastoma (IDH-wildtype)
Grade then allows further grouping
WHO II
○ Astrocytoma (IDH-mutant)
○ Oligodendroglioma (IDH-mutant & 1p/19q co-deleted)
WHO III
○ Astrocytoma (IDH-mutant)
○ Oligodendroglioma (IDH-mutant & 1p/19q co-deleted)
WHO IV
○ Glioblastoma (IDH-wildtype)
○ Astrocytoma (IDH-mutant, CDKN2A/B deletion)
○ Diffuse midline glioma (H3K27M-altered)
Note that any IDH-wildtype tumour is generally classified as a glioblastoma
- Need to prove one of 3 other molecular factors (see below)
- If this fails, then WHO G4 astrocytoma IDHwt
Note that a IDH-mutant histological glioblastoma is a G4 astrocytoma
NOS (not otherwise specified) suffix is applied if no further molecular/genetic analysis performed (i.e. histological diagnosis only)
- E.g. oligodendroglioma NOS
What histopathological features define HG from LG gliomas?
The AMEN criteria describe the histological features that separate low and high grade gliomas
A- cellular Atypia
M- high Mitotic index
E- Endothelial proliferation
N- Necrosis
Describe the pathology for WHO II and III Astrocytoma
Diffuse astrocytoma, IDHmut (WHO II)
- More common in younger adults (mid 30s), younger than GBM
○ Grade 4 often 50
○ Male predominance
- Median OS = 10 years for grade 2, 8 years for grade 3
- Frontal lobe is most common location, but can occur anywhere
○ Often presents seizures, headache or ICP
○ MRI findings:
▪ T1 hypodense (black)
▪ T2 hyperintense (white)
▪ T2/FLAIR mismatch signal considered highly specific radio genomic signature for astrocytoma’s IDH mutant. High T2 intensity (bright) with relatively hypointense (dark) signal on FLAIR
▪ Contrast enhancement = higher grade
▪ Ring like enhancement and necrosis in grade 4
- High chance of progression to higher grade disease (70%)
Prognosis
Younger better
Resection/residual
Mitotic count/KI67 -no clear prognosis if grade 2-3
Grade 4 = worse. CDKN2a/2b even worse prognosis
Treatment: surgery, chemo or RT
Grading: mitotic activity, nuclear atypia, pleomorphism, necrosis, microvascular proliferation (AMEN) or CDKN2A / CDKN2B homozygous deletion (Grade 4 feature)
- Macroscopic ○ May be large, diffuse and infiltrative (without destruction) § False appearance of being able to enucleate ○ Variable cut surface (firm --> soft and gelatinous) - Microscopic ○ Diffusely infiltrative astrocytic glioma with increased cellularity and atypia § No mitoses, microvascular proliferation or necrosis ○ Cells with elongated and irregular hyperchromatic nuclei, eosinophilic GFAP-positive cytoplasm ○ Gemistocytic variant --> gemistocytes (large, densely packed and globoid cells) - Immunohistochemistry ○ POS = IDH R132H, GFAP, Olig2 ○ NEG = ATRX loss - Molecular ○ IDH mutant ○ 1p/19q preserved
Astrocytoma, IDHmut (WHO III)
- Median age = 38 years
- Median OS = 8 years
- Microscopic ○ As per diffuse astrocytoma, with: § Increased nuclear atypia, mitosis and hyperchromasia ○ Still avoids microvascular proliferation or necrosis (these make it grade 4) ○ CDKN2a/2b deletion = grade 4
Describe the pathology for WHO II and WHO III Oligodendroglioma.
Oligodendroglioma, IDHmut & 1p/19q co-deleted (WHO II)
- Peak incidence in late 30s-50
- 0.23/100,000 slight male predominance (less common then astrocytoma’s)
- Prognostic: slow growing. Best with complete resection, grade 2
○ Unfavourable –contrast enhancement. CDKN2a/2b homozyous deletion.
- Median OS = 20 years grade 2,
○ 15 years grade 3
-
- Most commonly occur in the fronto-temporal lobes –white and grey matter, occasional leptomeningeal
- Often present with seizure
- Heterogenous T1/T2, poorly circumscribed. Grade 3 more contrast enhance. No DWI change. Cystic changes
- Calcifications in oligodendroglioma
-
- Grading
○ Grade 2: well differentiated without anaplastic features (AMEN)
○ Grade 3 prominent anaplastic –brisk mitotic, microvascular proliferation, necrosis
§ No strict mitotic criteria. ?6/10hpf
§ CDKN2A deletion ?may also be a molecular marker for Grade 3
Treat: surgery, adjuvant CRT
- Macroscopic ○ Grey gelatinous masses ○ Cut surface commonly shows cystic change, focal haemorrhage and calcification - Microscopic FRIED EGG ○ Diffusely infiltrating tumours § No mitoses, microvascular proliferation or necrosis ○ Cellular appearance § Round nuclei with peri-nuclear halo (fried-egg appearance) § Delicate branching capillary pattern (chicken-wire appearance) ○ Calcification is present in 90% of cases - Immunohistochemistry ○ POS = IDH R132H, ATRX retained, GFAP, Olig2 ○ NEG = - Molecular ○ IDH mutant ○ 1p/19q co-deleted
Oligodendroglioma, IDHmut & 1p/19q co-deleted (WHO III)
- Median age = 49 years
- Median OS = up to 15 years
- Microscopic ○ As per oligodendroglioma, with: § increased cellularity, pleomorphism, mitotic rate and microvascular proliferation § only occasional necrosis § Or CDKN2A/2B deletion
Describe the pathology for Glioblastoma.
Glioblastoma, IDHwt (WHO IV)
- 45% of all malignant brain tumours (70% of all gliomas)
- Median age = 65 years
- Median OS = 14 months
- May occur anywhere in brain, prefers temporal lobe, subcortical white matter/deep grey matter
- 20% multifocality
- Macroscopic ○ Very infiltrative, friable and vascularised tumour ○ Heterogenous cut surface § Peripherally grey, with central yellow necrosis § Thrombosed vessels and haemorrhage common § May have cystic degeneration, surrounding oedema - Microscopic ○ Often appears like astrocytoma rather than olidodendroglioma ○ CAMEN § Increasing Cellularity, Atypia and Mitoses § Microvascular proliferation (Endovascualar) § Also has pseudopalisading necrosis = tumour cells on edge of necrotic regions, serpentine necrosis is similar § Variants include § Gliosarcoma (worse prognosis) -areas have atypical spindle cells, less glial stains § Giant Cell Glioblastoma § Epithelioid Glioblastoma - Immunohistochemistry ○ POS = GFAP, ATRX retained, Olig2, S100, CK, Ki67 ○ NEG = - IHC for primary: ○ IDH wildtype, ○ Any of: § TERT promoter mutation § EGFR amplification § Chromosome 7 gain and chromosome 10 loss (7+/10-) - IHC for secondary ○ IDH mutation, p53 amplified, MDM2
Beside GBM describe other IDH wild type gliomas
Other bad IDH wildtype tumours:
Diffuse midline glioma -g4
H3K27 altered, me3
EZIP,
EGFR
Diffuse hemispheric glioma H3G34 mutant
G34 R and G34 V mutations most common -IHC stain or methylation
ATRX negative
Diffuse pediatric type high grade glioma
Generally in children, Wildtype IDH and H3
Molecular diagnosis on methylation 3 groups
RTK1
RTK2
MYCN
Anaplastic
Discuss molecular markers: IDH and 1p/19q co-deletion in gliomas.
Molecular markers (NOTE: molecular diagnosis takes precedence over histological)
IDH (DIAGNOSTIC)
- Mutation implies G1-3 origin (or secondary glioblastoma –> WHO IV astrocytoma)
○ IDH-wildtype diffuse astrocytomas (WHO II) are rare
○ IDH-wildtype anaplastic astrocytomas (WHO III) make up 20%
○ Virtually no IDH-wildtype oligodendrogliomas (WHO II & III)
- Wild-type implies primary G4 glioblastoma (90% of glioblastomas)
- IDH mutant have better prognosis (both WHO III & IV)
- IDH1 R132H marker via IHC is positive in 90% of cases (NGS required if IHC is negative)
○ NGS done if pt <55yo
- IDH1 inhibitors and vaccines are in development
Oncologic mechanism:
Involved in KREB cycle. Fromation of oncogenic metabolite 2HG
Induction of HIF1 hypoxia pathway
1p/19q co-deletion (DIAGNOSTIC)
- Co-deletion indicates oligodendroglioma (highly accurate)
○ Preservation indicates astrocytic origin
- Co-deletion occurs almost always with IDH mutation
- predictive (PCV chemo improves OS by 7yrs in co-deleted pts) and prognostic factor (regardless of what treatment these patients do better).
In regard to gliomas, discuss ATRX, TP53, TERT and EGFR mutations.
ATRX (indicative)
- Chromatin remodelling protein important in DNA replication, telomere stability, gene transcription, chromosome congression and cohesion during cell division
- Loss of expression/mutation generally indicates astrocytic origin (non-diagnostic)
○ Mutually exclusive of 1p/19q co-deletion and TERT-p mutations
- Associated with IDH mutation
TP53 mutation (indicative)
- Nuclear staining correlates with most IDH-mutant astrocytomas
- Not as specific as ATRX loss
TERT promoter mutation (indicative)
- Mutation more common in IDH-wildtype primary glioblastoma and oligodendroglioma
Chromosome 7 gain & Chromosome 10 loss
- Occurs commonly with primary glioblastoma IDHwt
EGFR (prognostic only)
- Overexpression associated with shorter OS
Discuss MGMT methylation in glioma.
MGMT methylation
- Methylation is both prognostic (independent predictor of better OS) and predictive (better response to temozolamide)
- MGMT removes akyl groups from DNA =repairs TMZ damage. Methylation = silencing = less repair.
- MGMT hypermethylation is frequently seen in IDH mutant astrocytomas (> 75%; associated with G CIMP), IDH wild type glioblastomas (40 - 50%), oligodendrogliomas (majority), high grade astrocytoma with piloid features (46%), diffuse hemispheric glioma H3G34 mutant and primary diffuse large B cell lymphoma of the CNS (52%)
- Still has better prognosis even without chemo ○ Seen in 40-50% of GBM ○ But not prognostic in low grade
Describe the normal glial cells of the CNS
Glial Cells of the CNS
- Astrocyte: supporting star shape glial cell with feet processes supporting neuron axons synapse to help regulate extracellular electrolyte eg K and recycling of neurotransmitter, and wrapping blood vessels to provide BBB and regulate vasoconstriction/vasodilation
- Oligodendrocytes: supporting glial cells with processed wrapping around aonx to provide myelin to allow saltatory action potentials
- ependymal cells: lining cells along the ventricular system to support/ and secrete CSF, promote circulation of CSf via microcilias, form the blood/CSF barrier, and serve as glial stem cells
- microglia- serve as CNA dnefense system as macrophages, remove plaque, foregin bodies, damage neurons
Describe the prognostic factors for glioma.
Patient Factors
- Age
- Duration of symptoms >3months worse
- Performance Status (typically as Karnofsky)
- Functional status (as per original RPA score)
- Neurological function
Tumour Factors
- Pathological subtype (integrated histological/molecular features)
○ IDH1
○ 1p/19q co-deletion
§ 1p19q is also BOTH prognostic - these pt do better regardless of the Tx- and predictive - respond to PCV chemo, improves OS by 7yrs in co-deleted pts)
- Tumour size
- MGMT methylation (predictive and prognostic)
○ Unmethylated do worse –the MGMT protein removes alkylating damage (TMZ)
○ Also more response to TMZ
○ Also more pseudoprogression in methylated patients
- EGFR mutation (prognostic only),
- tert promoter (prognostic)
- Tumour multiplicity
Treatment Factors
- Degree of resection (complete macroscopic resection vs biopsy alone)
- Longer wait for treatment
- Lower dose
- Addition of chemotherapy to radiotherapy
Describe the history, examination and work up for glioma
Consultation
- History ○ Presenting symptoms (mass effect and oedema) § Headache § Nausea § Focal neurology (motor, sensory, speech, balance) § Seizure ○ PMHx § Previous radiotherapy ○ Medications § Radiosensitisers ○ FHx: § Li Fraumeni § Lynch (dMMR) § Turcot's (APC/FAP or constitutional dMMR) ○ Social § Support to progress through treatment § Performance status - Examination ○ Performance status ○ Orientation ○ UL, LL and CN neurological examinations
Investigations
- Imaging ○ CT Brain in first instance (exclude haemorrhage if acute neurology) ○ MR brain with GAD § T2 § FLAIR § Post contrast T1 - enhancement § DWI/ADC § Supratentorial white matter § Heterogenous and infiltrative appearance § Thick, irregular margins - post contrast enhancement § Restricted diffusion ○ MR Spectroscopy - Histopathological confirmation ○ Surgical Biopsy ○ Must include molecular typing (IDH1, TERT, p53, MGMT, etc.) ○ Send for Next generation sequencing (NGS) if indicated
Discuss surgical management of gliomas.
Goals of surgery:
Reduce mass effect and oedema -can improve symptoms/QOL
Tissue
Survival benefit esp RANO class 1 (supramaximal = enhancing and nonenhancing disease) and class 2 (gross resection of enhancing)
Surgical technique Stereotactic -brands: brainlab, stealth Enbloc (mets, low grade) vs piecemeal (CUSA =ultrasound and sucked up) Advanced techniques Intraoperative MRI, US 5 ALA -tumour fluoresces Awake surgery May need fMRI preop if near eloquent area
Describe management of GBM
Definitive Glioblastoma
- This is relevant for IDHwt glioblastoma as well as IDHmut astrocytoma G4 1. Maximal safe resection a. Degree of resection predicts survival -retrospective data: 8 months vs 24 months 50% overall survival 2. Adjuvant chemoradiotherapy a. 60Gy/30F with concurrent temozolamide (75mg/m2) i. 10% surival benefit of concurrent TMZ 3. Adjuvant chemotherapy a. 6 months of temozolamide (150-200mg/m2) - NOTE ○ Chemoradiotherapy to commence within 4-6 weeks of surgery ○ MGMT methylation is predictive for outcome with this therapy
Palliative & Elderly Glioblastoma
- Multiple trials have explored treatment in elderly or poor performance status ○ Variably defined as age >70 and KPS <70 - In general, any treatment is superior to no treatment ○ That said, BSC may be appropriate in some cases - Options (in decreasing order of toxicity) ○ 40Gy/15F with concurrent TMZ (only if excellent PS) ○ 40Gy/15F alone ○ 25Gy/5F alone - If MGMT methylated: ○ TMZ alone is a reasonable alternative ○ Addition of concurrent TMZ with RT will preferentially benefit this population
Discuss pseudoprogression after GBM treatment.
- Pseudoprogression:
○ Enhancement of the tumour cavity after treatment which appears like recurrence, captured on serial MRI.
○ Peak at 1-3 months post CRT in 30-50% of pts and disperses over the next few months in half of pts.
○ MGMT meth increases the incidence of pseudoprogression
○ difficult to differentiate from recurrence/ MR spectroscopy unreliable, potential use for MRI Perfusion
○ MECH: Transient increased permeability of tumour vasculature secondary to RT and TMZ. Also transient interruption of myelin synthesis secondary to RT injury to oligodendrocytes.
○ Management:
○ If symptomatic, Start on 4 mg Dex, ↑ if needed or ↓ by 2mg every 2 weeks if responding. Can settle over 6/52.
○ If Asymptomatic, can omit steroids, but have script.
○ If good PS/clinically stable continue TMZ
○ Repeat imaging at 3/12
○ Consider surgery if past 3/12 to exclude recurrence
Discuss management of WHO G3 Astrocytoma
WHO G3 astrocytoma
○ Tx Paradigm: Max safe resection—> Adj RT 59.4Gy/33F—> adj chemo TMZ
- Should receive sequential radiotherapy and chemotherapy
○ Upfront radiotherapy is associated with improved time to failure only
- Adjuvant radiotherapy = 59.4Gy/33F - ESK 60Gy/30Fx Adjuvant chemotherapy = 12 months of TMZ at 150-200mg/m2
Discuss management of WHO G3 Oligodendroglioma
WHO G3 oligodendroglioma
- Tx Paradigm: Max safe resection—> Adj RT 59.4Gy/33F—> adj chemo (PCV EORTC or TMZ extrapolate CATNON)
- Should receive sequential radiotherapy and chemotherapy
○ Upfront radiotherapy is associated with improved time to failure only
○ If young patient, consider delay RT until salvage (French POLCA trial)
- Adjuvant radiotherapy = 59.4Gy/33F Adjuvant chemotherapy = PCV (or TMZ as more tolerable -extrapolation from CATNON)
Discuss the assessment of progression/recurrence in GBM
- Progression/Recurrence
○ Recurrence are aggressive, and decision is based on patient PS and extend of dz.
○ RANO criteria- within the first 12 weeks post RT: progression can only be determined if the majority of the new enhancement is outside the 80% isodose line or with pathological confirmation
○ Previously, McDonald Criteria was used but there were limitation hence RANO was developed
§ McDonald criteria (90’s) - looking at size, contrast enhancement, steroid use, clinical status.
□ Complete response: Complete disappearance of all tumour on consecutive CT or MRI scans at least one month apart, off steroids
□ Partial response: >=50% decrease in area of enhancing tumour on consecutive imaging studies of at least one month apart. Doses of steroids must be stable or decreased and the patient must be neurologically stable
□ Progressive disease: >=25% increase in size of enhancing tumour or any new tumour on CT or MRI
□ Stable disease: all other situations
Limitations:
□ Difficulty measuring irregular lesions
□ Lack of assessment of non-enhancing component
□ Lack of guidance for multiple lesions
□ Relies on enhancement- which can be affected by multiple things- e.g. steroids, seizures, inflammn, surgical changes to BBB, ischaemia, RT necrosis.
□ Pseudoprogression
□ High radiographic RR (loss of enhancement) of anti-angiogenic agents may not be true response
Discuss non-radiotherapy management options for GBM recurrence after resection + chemoRT
§ Re-resection +/- chemotherapy with carmustine
□ surgery best for large + well circumscribed symptomatic tumours amenable to GTR or near-GTR.
□ Retrospective data –complete resection prolongs overall survival
□ Not durable tumour control and typically followed by chemotherapy. (Ph3 trial showed carmustine prolong mOS post Sx.)
□ Bx may be necessary to distinguish tumour vs pseudoprogression
□ no evidence to suggest Sx is better than RT +/- chemo alone
□ Caution: risk of wound-healing complications in pt who had prior Avastin
§ Chemo- TMZ metronomic, CCNU-procarbazine, Avastin+lomustine
□ no Single agent has been shown to be superior.
□ Regimen cased in Tx hx, Perf, side effect profile, tumour factors
□ TMZ re-challenge most suitable for MGMT methylated and long- disease interval (as per the Perry trial- 12mo OS 24%)
□ RCT showed lomustine+ Avastin is better than Lomustine alone, but high toxicity.
§ Avastin (bevacizumab) - anti-angiogenesis with response within days. only improves mPFS but not OS.
□ (? is the effect secondary to anti-tumour effect or just reducing pseudoprogression?)
□ Cannot have surgery once avasatin onboard
§ Tumour Treating Fields (TTF):
□ Use of alternating electrical fields applied to the head through electrodes worn for 18hrs per day.
□ No RCT, not available in Aus, expensive,
□ Non-RCT Evidence showed is similar to chemotherapy, no OS or QoL.
§ Clinical trials
Discuss re-irradiation in GBM recurrence.
§ Re-irradiation:
□ Suitable for pt not suitable for GTR or near GTR.
□ Feasible in >6mo interval, improve 6m PFS by 20-30%, and decrease steroid requirement
□ Several retro studies showed RE-RT showed mOS 8-11mo
□ Low risk of radionecrosis if Cummulative NTD <100Gy (a/b2), no clear volume effect if fractionated
□ VITAL pt selection:
® ECOG 0-1
® Unifocal lesion
® Age 50-60, DFS > 6-12m
® low steroid requirement
® no severe late effects
® in or out of field recurrence
□ No Benefit for concurrent TMZ, do sequential
□ Fractionation: 30Gy/10F [ESK 35Gy/10F is quite tolerable, alternatively 40Gy/15F ]
® RTOG 1205 Ph2, 2019. Re-RT (35Gy/10F, GTV+5mm= PTV) + Avastin vs Avastin alone. Median OS unchanged 12.5mo. Improved 6 mo PFS 54 vs 29%, HR 0.42, p=0.001. Treatment was well tolerated: 5% acute and 0% delayed grade 3+ treatment-related AE
® Bevacizumab 10mg/m2 every 2 weeks, first dose prior to re-RT, continue until progression
Radiotherapy (FSRT) 35Gy/10#. GTV=enhancing disease on MRI,
CTV (optional)=GTV+0-5mm, PTV=CTV+3-5mm.
◊ OARs (RTOG 1205 for 35Gy/10#)
} Brainstem: Dmax<20Gy (up to 25Gy acceptable)
} Optic nerve/chaism PRV: Dmax<24Gy (up to 30Gy acceptable)
**Consider: Interval since TMZ, MGMT status, expected marrow reserve.
□ Fractionated SRS 35Gy/10F, allow higher dose and lower margin
® Fogn et al- Large series-> Decreased steroid requirement, med OS 11mo, well tolerated. > 50% RR. Technique: 35Gy/10F, GTV = T1+C lesion, PTV=GTV + <5mm
□ Brachytherapy using intro inflatable balloon catheter with I-125 radioisotope- decreasing in exp. mOS 12mo with low acute toxicity but high radio necrosis ~40%
Discuss temozolomide for GBM
GBM:
Concurrent TMZ -7 days/week
Adjuvant TMZ (STUPP phase 2 protocol)
TMZ is an Oral alkylating agent, which causes DNA damage by adding an alkyl group to. guanine, which when unrepaired in the cells, trigger cell apoptosis. This is effective in MGMT methylated GBM as MGMT (DNA repair enzyme) is deficient due to methylation hence alkyl addition is unrepaired resulting in cell death.
Good bioavailibility, crosses BBB
TMZ is used as an adjuvant treatment concurrent with RT and following RT as monotherapy
- It improves mOS and mPFS for MGMT methylated and unmethylated patient, stronger benefit for methylated.
Unmethylated MGMT -neutralises TMZ,
MGMT removes akyl DNA damage to guanine bas
TMZ toxicity:
- Acute: fatigue, hypersomnolence, N+V, lymphopaenia, Anaenia or neutropaenia, thrombocytopaenia (can occur early, sudden, or idiosyncratic), mild aceniform rash, Steven’s Johnson Syndrome (rare), PJP infection
- Subacute: Aplastic anaemia (rare)
- Latent: Teratogenic potential (assumed), hepatotoxicity (rare)
New systemic trials overseas:
TTF -improved survival
Lomustine +TMZ in methylated GBM -improved survival but poor quality study
Temzolomide
- Toxicities: cytopenias
○ Need weekly blood tests
○ Temporary raise in LFTs
○ Constipation
○ Emetogenic
Increases risk for encapsulated gram negative sepsis
Discuss non-temozolomide systemic therapy used in GBM
- Any role for other chemo in the GBM
○ NOA-9 -> MGMT meth GBM-> Adj RT+TMZ -> Adj TMZ alone vs Adj TMZ+lomustine
§ improved mOS 48mo vs 31mo (SS).
§ However 60% vs 50% G3 toxicity
§ Caveat: small trial, significant additional toxicity, ? consider in very fit pts - Role of Avastin?
- Avastin= VEGF inhibitor, monoclonal antibody which binds to the VEGF to block angiogenesis -> decrease cerebral oedema + radionecrosis-> extends PFS but NOT OS
- Potent anti-edema effects that can improve clinical function and reduce glucocorticoid requirements in selected patients
- Two phase III RCTs did not confirm a benefit for bevacizumab in the upfront setting for GBM (no OS improvement and increased risk of toxicity)
- Bevacizumab is therefore not recommended for routine use in patients with newly diagnosed GBM
- Used in recurrent GBM as monotherapy (single arm nonrandomised studies)
- Avastin toxicity: bowel perforation (1%), wound dehiscence, renal failure, ATE/DVT, GI bleed, Posterior Reversible Encephalopathy Syndrome (PRES), increase risk of intracranial bleed by 2-3x
Recurrence:
Multiple failed studies
RCT ph3: Lomustine + bevacizumab -PFS benefit but not OS
Relatively tolerable
Trials:
Latrectinib for TRK mutations
Lots of ph1
Discuss the evidence for radiotherapy in GBM for fit patients
Definitive Glioblastoma
Stupp trial (Stupp, 2005) ○ 573 patients with glioblastoma (age < 70 and ECOG <2) § 60Gy/30F with concurrent TMZ & adjuvant TMZ § Randomised RT + TMZ vs RT alone ○ Median OS benefit (14.6mo vs 12.1mo; p <0.001) ○ ↑ acute morbidity + late morbidity, esp. leukoencephalopathy. Need steroids during concurrent phase. Need antiemetic and PCP prophylaxis with Bactrim DS. ○ Note that no patients >70yo included (median age of diagnosis = 65-70 years) § Post-hoc cohort analysis demonstrated only minor benefit from addition of TMZ in 65-70yo group
Key points about radiotherapy delivery:
○ Dose § Pooled analysis of three trials demonstrated a stepwise improvement in OS with increasing doses between <45Gy to 60Gy (Walker, 1979) § Dose escalation trials comparing 60Gy vs 70Gy has demonstrated no OS or local control benefit (Chang, 1983) ○ Hyperfractionation § RTOG 90-06 demonstrated no OS benefit for 72Gy/60F (1.2Gy/F BD) vs 60Gy/30F (Curran, 1996) ○ CTV margin § It has been shown that 90% of GBM recurrences occur within 2cm of the primary tumour (Hochberg and Pruitt, 1980) § This finding persists even despite high dose RT (Phase 1 trial for 80Gy partial brain irradiation – Lee, 1999)
Delays to radiotherapy worsens survival (Australian retrospective data)
Aim to treat 4-6 weeks postop
Discuss the evidence for MGMT as a prognostic marker
MGMT as prognostic marker
* RTOG 0525 –sequential treatment assigned according to MGMT status.
○ RTx/TMZ+ TMZ (concurrent with 12mo maintenance TMZ 150-200 x5d– control arm)
○ RTx/TMZ + TMZ intense (dose intensification 75-100 x21d q4w x6-12c for 12 months) -> no change in OS/PFS with dose intensification of Adj TMZ
○ However, this was the 1st trial showing MGMT as a prognostic marker – pts do better with methylated MGMT.
§ mOS ~15 mo. MPFS ~6 mo. Efficacy did not differ by methylation status.
§ mOS for UnMe’d / Me’d of 14→ 21 mo, PFS for UnMe’d / Me’d of 6→ 9 mo.
§ G3+ toxicity (mostly fatigue and lymphopenia) 34→ 53%.
Discuss the evidence for management of GBM in older patients.
Elderly & Palliative Glioblastoma
NORDIC, IAEA, CE6, NOA8
* French RCT→ RT> BSC (NEJM Keime-Guilbert, 2007) - Some treatment is better than BSC alone ○ 50.4Gy/28F + BSC is superior to BSC alone (median OS 29.1wks vs 16.9wks; p = 0.002) ○ Trial discontinued early due to obvious OS benefit ○ Inclusion = ≥70yo and KPS ≥70 * Multiple approaches have been trialled ○ Hypofractionation § 40Gy/15F alone (Roa, 2004) □ 40Gy/15F non-inferior to 60Gy/30F (median OS 5.6mo vs 5.1mo; p = 0.57) □ Inclusion = ≥60yo with KPS ≥ 50 § 25Gy/5F alone (Roa, 2015) □ 25Gy/5F non-inferior to 40Gy/15F (median OS 7.9mo vs 6.4mo; p = 0.988) □ Inclusion = ≥60yo OR KPS = 50-70 ○ Combined modality § 40Gy/15F with concurrent TMZ (Perry, 2017) □ 40Gy/15F + TMZ superior to 40Gy/15F alone (median OS 9.3mo vs 7.6mo; p < 0.001) □ Concurrent + adjuvant TMZ □ Inclusion = ≥65yo with ECOG ≤2 □ Outcomes: Median OS improved with TMZ (9.3 months vs. 7.6 months, p<0.001), Increased PFS 5.3mo vs 3.9mo ® Benefit greatest for MGMT methylated: 13.5 months vs. 7.7 months ® Smaller benefit for un-methylated: 10.0 months vs. 7.9 months ◊ *Not all patients had MGMT methylation status available* ® Conclusion: Addition of TMZ to short course RT improved survival in elderly patients with GBM ○ TMZ alone § Nordic randomised phase III trial (Malhstrom, 2012) - RT 60Gy/30F vs RT 34Gy/10F vs TMZ alone ? □ Inclusion = ≥60yo and ECOG 0-2 □ Median OS 6 mos vs. 7.5 mos vs. 8.3 mos □ TMZ superior to standard RT 60Gy/30Gy alone (median OS 8.3mo vs 6.0mo; p = 0.01) □ No significant difference between TMZ alone and hypofractionated RT 34Gy/10F (median OS 8.3mo vs 7.5mo; p = 0.24) □ If >70yo, both TMZ alone and hypofractionated RT superior to standard RT (OS HR 0.35 and 0.59 respectively) □ Greater survival advantage with TMZ alone if MGMT methylated vs unmethylated (median OS 9.7mo vs 6.8mo; p = 0.02) § NOA-08 randomised phase III trial (Wick, 2012) - ddTMZ alone vs RT alone 54-60Gy ? □ Inclusion = ≥65yo and KPS ≥60 □ TMZ alone is non-inferior to 60Gy/30F alone (median OS 8.6mo vs 9.6mo; p = 0.033) ® Note large non-inferiority margin (25%) □ In MGMT methylated patients, median EFS benefit seen with TMZ vs RT (8.4mo vs 4.6mo) □ With no MGMT methylation, outcomes poor but RT better: 4.6 vs. 3.3 mo □ Conclusion: ® OS with TMZ was noninferior to RT in elderly or poor KPS GBM. TMZ is ideal for methylated MGMT and RT is ideal for unmethylated MGMT
Discuss the evidence for management of WHO Grade 3 Astrocytoma.
WHO G3 astrocytoma
* NOT for concurrent chemoradiotherapy ○ CATNON study (2nd interim analysis, 2019) § Prospective randomised trial of WHO III glioma without 1p/19q co-deletion (ie molecular diagnosis of anaplastic astrocytomas) § 4 arms = randomised to 59.4Gy/33F alone, with concurrent TMZ, with adjuvant TMZ or with both concurrent and adjuvant TMZ § 59.4Gy/33F with concurrent TMZ vs without TMZ (5yr OS 50.2% vs 52.7%; not sig) § Interim analysis (further reports to be released) § 2021 update: □ Adjuvant chemo improved median OS 82 vs 47 months HR 0.6 P <0.0001 * FOR adjuvant chemotherapy (NON 1p/19q co-deleted patients – anaplastic astrocytoma) ○ CATNON study (1st interim analysis, 2017) § Adjuvant TMZ provides OS benefit (5yr OS 55.9% vs 44.1%) ○ CATNON study (3nd interim analysis, 2021) § Adjuvant TMZ has OS benefit in IDH mutant but NOT wildtype patients Median OS 82 vs 47 months HR 0·64
WHO G3 glioma (all)
* Sequencing ○ Post-operative radiotherapy should precede adjuvant chemotherapy ○ NOA-04 trial (Wick, 2009) § Newly diagnosed WHO III gliomas (all subtypes included) were randomised to post-operative: 1) RT, 2) PCV, or 3) TMZ § Upon recurrence, patients would proceed to the therapy not initially received § No significant differences between arms with respect to PFS or OS Potential trend towards TTF benefit for upfront RT (need for salvage treatment at 54mo = 77.8% [chemo] vs 48% [RT])
Discuss the evidence for Avastin in GBM
Role of Avastin:
* Not recommended for upfront use in ppt with GBM.
○ Concurrent use with Avastin only showed mild PFS benefit but no OS improvement, and increased serious adverse effects with worse sx burden, QoL, and more decline in neurocognitive function
* AVAglio (NEJM 2014). (n=921): GBM treated with Sx -> RT+TMZ OR concurrent TMZ + bevacizumab -> adj TMZ + bevacizumab -> maintenance bevacizumab to progression ○ Outcomes § Median PFS improved with bevacizumab (10.6 v.s 6.2 months) § Baseline health-related QOL and performance status maintained longer in bevacizumab group § No significant difference in OS § Increased rate of serious adverse events with bevacizumab (67% vs. 51%) * RTOG 0825 (NEJM 2014). (n=637): GBM treated with Stupp protocol VS Bevacizumab added at week 4 of standard chemoradiation; followed by 6-12 cycles of maintenance TMZ+bevacizumab ○ Outcomes: § Median PFS improved with bevacizumab (10.7 vs. 7.3 months, p=0.007) – did not meet pre-defined significance threshold of p<0.004 § No difference in median OS § Increased serious adverse events with bevacizumab – neutropenia, hypertension, thromboembolism § Bevacizumab group experienced increased symptom burden, worse QOL, more frequent decline in neurocognitive function cf. placebo
Discuss the evidence for management of WHO grade 3 oligodendroglioma.
WHO G3 oligodendroglioma
* FOR adjuvant chemotherapy ○ RTOG 94-02 (Cairncross, 2013) § Randomised to RT alone (59.4Gy/33F) vs PCV followed by RT § Overall Cohort □ No unadjusted median OS benefit (4.7yr vs 4.6yr; not significant) □ Adjusted analysis found OS benefit favouring PCV + RT (HR 0.67, p = 0.01) § Molecular Oligodendrogliomas (1p/19q co-deletion) □ Median OS benefit for PCV + RT (7.3yr vs 14.7yr; p = 0.03) □ Median PFS benefit for PCV + RT (2.9yr vs 8.4yrs; p < 0.001) § Histological Oligodendrogliomas □ Median OS unchanged (2.7yr vs 2.6yr; p = 0.39) ○ EORTC 26951 (Van den Bent, 2013) § Randomised to RT alone (59.4Gy/33F) vs RT followed by PCV § Overall cohort □ Median OS benefit for RT + PCV (30.6mo vs 42.3mo; CI sig) □ Median PFS benefit for RT + PCV (13.2mo vs 24.3mo; CI sig) § Molecular Oligodendrogliomas (1p/19q co-deletion) □ Trend to median OS benefit for RT + PCV (112mo vs not reached; CI 0.31-1.03) □ Median PFS benefit for RT + PCV (50mo vs 157mo; CI sig) § Histological Oligodendrogliomas □ No median OS benefit for RT + PCV (21mo vs 25mo reached; CI 0.62-1.10) □ Median PFS benefit for RT + PCV (9mo vs 15mo; CI sig) ○ Summary of these studies § OS benefit for addition of adjuvant sequential chemotherapy □ Sequencing does not matter (trials were opposite), however tolerability is likely better with RT first § Larger benefit for co-deleted tumours § NOTE: PCV was used, rather than TMZ (uncertain applicability) □ Ongoing CODEL trial ® Randomise WHO II + III 1p/19q co-deleted oligodendrogliomas to [RT/conTMZ + adjTMZ] vs [RT + adjPCV] * Potential role for delaying RT until relapse o Rationale § 1p/19q tumours have been seen to be very chemo-sensitive § Given long-term survival, avoiding late toxicity of high-dose cerebral radiotherapy is beneficial o Currently no prospective evidence to support this approach § Ongoing French POLCA trial · Randomise 1p/19q co-deleted anaplastic oligodendroglioma to PCV alone vs RT followed by PCV o Issues § NOA-04 trial (including an unsegregated group of WHO III anaplastic gliomas) demonstrated a trend towards reduced TTF with upfront chemotherapy alone § It remains to be seen if the co-deleted group are an exception to this
Discuss the evidence for tumour treating fields in GBM
Tumour treating fields (TTF) for GBM: Current Advances and Future Directions [Rominiyi BJC ‘20].
* Worn > 18h per day. Impairment of microtubule assembly/disassembly. Adds ~4-5 mo to MS!
* EF-14 Maintenance TTF [Stupp JAMA ‘15, ‘17]: Stupp→ TMZ ± TTF.
TTF adds 5 mo to OS! But, need to wear it for 18h/d.
Take-home: OS HR 0.63 for addition of TTF, same as for addition of TMZ to Stupp.
Critique: Not double-blinded as placebo didn’t have a helmet. Randomization occurred after completion of CCRT. Increased support of TTF patients. Financial support to many study investigators.
○ 695 pts, newly dx. Supratentorial. Interim of 310 pts. Primary MPFS.
○ MS 16→ 20.9 mo, MPFS 4→ 6.7 mo. 2y OS 31→ 43%, 3y OS 16→ 26%, 5y OS 5→ 13%.
§ Even more impressively, survival times measured from completion of Stupp.
§ Me’d subgroup: MS 21.2→ 31.6 mo.
§ Non-me’d subgroup: MS 14.7→ 16.9 mo.
2y OS 31→ 43%, 3y OS 16→ 26%, 5y OS
Describe the long course radiotherapy technique for GBM
Long-Course Glioblastoma
Patients
IDHwt glioblastoma, with
- Age < 70, AND
- ECOG <2
Pre-simulation
MDT discussion
Ideally know MGMT status prior
Discuss driving limitation
Post-op MR brain should be performed
- Immediately post-op, OR
- After 3-4 weeks
Simulation
Supine with arms by sides
- Handgrips
Immobilisation mask
Generous CT (2mm)
- Vertex to mid neck
Fusion
MR brain fusion
- T1 GAD + T2-FLAIR
- Preop and postop imaging
Dose prescription
Single Dose Level
- 60Gy/30F prescribed to PTV as per ICRU 83
Concurrent chemotherapy
- TMZ 75mg/m2 daily
VMAT technique
10 days per fortnight
Volumes
* GTV
○ Enhancing gross disease on CT + MRI
○ Tumour cavity
○ Mass component of T2/FLAIR abnormality
* CTV
○ GTV + 15-20mm
○ Incorporate surrounding FLAIR (especially if IDHmut)
○ Respect anatomical margins (cross 5mm over at falx and tentorium)
* PTV
○ CTV + 3-5mm
Target Verification
Daily CBCT
OARs
Brain
- D1/3 < 60Gy
- D2/3 < 50Gy
- D3/3 < 45Gy
Brainstem
- Dmax < 54Gy
Hippocampus (spare contralateral)
- D40% < 7.3Gy
Optic nerves
- Dmax < 54Gy
Spinal Cord
- Dmax < 45Gy
Cochlear
- Mean < 45Gy
Lens
- Dmax < 7Gy
Orbit
- Mean < 35Gy
Describe the hypofractionated radiotherapy technique for GBM
Hypofractionated Glioblastoma
Patients
IDHwt glioblastoma, with
- Age > 70, OR
- ECOG >=2
Pre-simulation
MDT discussion
Ideally know MGMT status prior
Discuss driving limitation
Post-op MR brain should be performed
- Immediately post-op, OR
- After 3-4 weeks
Simulation
Supine with arms by sides
- Handgrips
Immobilisation mask
Generous CT (2mm)
- Vertex to mid neck
Fusion
MR brain fusion
- T1 GAD + T2-FLAIR
Dose prescription
Single Dose Level
- 40Gy/15F prescribed to PTV as per ICRU 83
Alternative dose prescriptions
- 34Gy/10F
- 25Gy/5F
Consider concurrent chemotherapy
- TMZ 75mg/m2 daily
VMAT technique
10 days per fortnight
Volumes
* GTV
○ Enhancing gross disease on CT + MRI
○ Tumour cavity
* CTV
○ GTV + 15-20mm
○ Incorporate surrounding FLAIR (especially if IDHmut)
○ Respect anatomical margins (cross 5mm over at falx and tentorium)
* PTV
○ CTV + 3-5mm
Target Verification
Daily CBCT
OARs
Lens
- Dmax < 7Gy
All other OARs
- Dmax < prescribed dose
Describe the radiotherapy technique for G3 Glioma.
WHO G3 Glioma
Patients
1) IDHmut G3 astrocytoma
2) IDHmut 1p/19q co-deleted G3 oligodendroglioma
Pre-simulation
MDT discussion
Ideally know MGMT status prior
Discuss driving limitation
Post-op MR brain should be performed
- Immediately post-op, OR
- After 3-4 weeks
Simulation
Supine with arms by sides
- Handgrips
Immobilisation mask
Generous CT (2mm)
- Vertex to mid neck
Fusion
MR brain fusion
- T1 GAD + T2-FLAIR
Dose prescription
Single Dose Level
- 59.4Gy/33F prescribed to PTV as per ICRU 83
VMAT technique
10 days per fortnight
Volumes
* GTV
○ Enhancing gross disease on CT + MRI
○ Tumour cavity
○ All T2/FLAIR signal
* CTV
○ GTV + 15-20mm
○ Incorporate surrounding FLAIR (especially if IDHmut)
○ Respect anatomical margins (cross 5mm over at falx and tentorium)
* PTV
○ CTV + 3-5mm
Target Verification
Daily CBCT
OARs
Brain
- D1/3 < 60Gy
- D2/3 < 50Gy
- D3/3 < 45Gy
Brainstem
- Dmax < 54Gy
Hippocampus (spare contralateral)
- D40% < 7.3Gy
Optic nerves
- Dmax < 54Gy
Spinal Cord
- Dmax < 45Gy
Cochlear
- Mean < 45Gy
Lens
- Dmax < 7Gy
Orbit
- Mean < 35Gy
Describe the prognosis and follow up for GBM and HG Glioma.
Follow-Up
- First MR brain 4-6 weeks after radiotherapy (baseline) ○ Pseudoprogression: usually occurs weeks to 3 months after treatment, § Worse in methylated - Clinical review every three months for the first three years ○ MR Brain at each visit - Clinical review every six months ongoing ○ MR Brain at each visit
Radionecrosis
Mineralised necrosis (calcification)
RT vascular changes -hyalinization of small vessels
Describe the RANO assessment for GBM recurrence.
Pattern of failure
78% recur in field/marginal
22% remote -especially in methylated, at average 14months.
Describe the epidemiology and risk factors for LG Glioma
Incidence (Australian statistics)
- 1900 cases annually (all brain malignancies)
- Low-grade glioma has an incidence of 0.50 per 100 000 people
- 6% of all CNS tumours
Incidence shifts since adopting 2016 WHO classification among
- Astrocytoma’s more common the oligodenodrogliomas
M>F (1.4:1)
Peak incidence 30-40 years
o Probability decreases with increasing age
Aetiology
Predominantly sporadic (no known cause and development poorly udnerstoof)
1. Previous ionising radiation = causative (small absolute risk) a. e.g. scalp irradiation for tinea capitis b. Craniospinal radiation 2. Genetic syndromes (<5% of glioblastoma) a. Li-Fraumeni syndrome (TP53 mutation) i. Pediatric, H3 wildtype, IDH wildtype b. NF1 i. Also associated with neurofibromas, café-au-lait spots, meningioma, schwannoma c. Turcot’s syndrome (constitutional mismatch repair deficiency - biallelic OR APC mutation) i. Also results in intestinal polyps/malignancy d. Lynch syndrome or HNPCC (MMR deficiency – monoallelic) i. Associated with multiple malignancies (GI, endometrial, ovarian, etc.) GBM Noonan syndeome (pilocytic astrocyt
Describe the differentiation of Astrocytoma from Oligodendroglioma.
Astrocytoma vs Oligodendroglioma
1st step: IDH mutant both (If wild-type, GBM)
Loss of ATRX is typical of diffuse astrocytoma’s, not oligodendrogliomas
2nd step: 1p/19 co deletion (If present–> oligodendroglioma, If absent astrocytoma)
3rd step: CDK2a/B (If retained- low grade astrocytoma (2 or 3), If deleted G4 astrocytoma)
Describe pilocytic astrocytoma.
Pilocytic astrocytoma –most common
- Circumscribed, well differentiated astrocytic neoplasm with piloid (hair-like) processes, most commonly occurring in children and young adults, WHO grade 1
- Most common in cerebellum, supratentorial. Can get anywhere eg optic pathaway
- Pathophysiology MAPK pathway. Or NF1 - Treatment: gross total surgical resection
Describe the prognostic factors for LG Gliomas.
Patient Factors
- Age > 40 years (worse)
- Performance status
- Absence of neurological deficits is better
○ Presence of seizure is favourable (early detection)
Tumour Factors
- Histology
○ Oligodendrogliomas have better survival compared with astrocytoma
- Anaplastic features (AMEN)
- IDH status
○ IDHwt G2 astrocytoma has similar prognosis to glioblastoma
- CDKN2A/b deletion
- TERT promoter (worse prognosis- tumour replicative immortality)
- Size (>4cm is worse)
- Multifocal
- Crossing midline
- Frontal/temporal worse
- Unmethylated MGMT worse
Treatment Factors
- Maximal safe resection
- Addition of chemotherapy to radiotherapy
Describe the history, examination and investigation for LG Gliomas.
Consultation
- History ○ Presenting symptoms § Frequently present with seizure § Headache § Nausea § Focal neurology (motor, sensory, speech, balance) ○ PMHx § Previous radiotherapy ○ Medications § Radiosensitisers ○ FHx: § Li Fraumeni § NF1 § Lynch (dMMR) § Turcot's (APC/FAP or constitutional dMMR) ○ Social § Support to progress through treatment § Performance status § Fertility - Examination ○ Performance status ○ Orientation ○ UL, LL and CN neurological examinations
Investigations
- Imaging ○ CT Brain in first instance (exclude haemorrhage if acute neurology) § Oligodendroglioma tends to have calcifications ○ MR brain with GAD § T1 post GAD (Hypointense, don't take up contrast) § T2-FLAIR mismatch = astrocytoma ddx DNET (Bright on T2, relative hypointense of T2 Flair) § Low grade more circumscribed (less infiltrative), no contrast uptake - Histopathological confirmation ○ Surgical Biopsy ○ Must include molecular typing (IDH1, TERT, p53, MGMT, etc.)
Describe the general management for low risk LG gliomas.
General measures
* Prohibited driving/machinery/swimming
* Anticonvulsants
○ Do not use prophylactically
○ Start if single general/partial seizure as risk of 2nd seizure is 40%, lifelong tx, as if another seizure- affects driving, work etc.
○ Keppra- well tolerated, good dosing spectrum, does not induce cytochrome p450
○ Older anticonvulsants like Phenytoin- narrow therapeutic window + needs close monitoring, causes liver abnormalities, neurological abnormalities (e.g. ataxia), skin reaction, interacts with other drugs
* Dexamethasone presurgery- decide on individual basis, depending on sx, extent of oedema, comorbidities e.g. DM. Do not use if suspect PCNSL as would affect diagnosis.
G2 Astrocytoma (IDHmut) & G2 Oligodendroglioma (IDHmut)
* No clear difference to management approach ○ More likely to favour post-operative observation in oligodendroglioma group (slower progression) § 3-4 monthly MRI for the first 2 years then 6 monthly for several years and then yearly. * Surgery is the mainstay definitive therapy ○ Ensures good surgical staging (eliminate sampling error for high-grade disease) ○ Improved survival with macroscopic resection ○ preservation of function as per observational studies * Not truly curative given infiltrative nature of disease ○ Recurrence is a question of when, not if * * Indications for observation ○ GTR ○ <40yrs ○ Present with seizures only ○ No mass effect ○ No neurologic deficit ○ No enhancement on CT/MRI ○ Favorable molecular features: 1p19q co-deletion or IDH1 mutation Pure oligodendroglioma Supportive care * Fertility preservation * Everything disrupted: Financial and social, life interrupted, relationships, roles ○ Family diagnosis, caregiver role change ○ Will * Fatigue management * Cognitive decline * Rehabilitation services, physical, cognitive, return to work/driving
Diagnosis disclosure very important event.
Ongoing supportive care team and communication
Intervention timepoints
-key post initial treatment
Living with brain cancer, survivorship
Scan anxiety
Describe the high risk features and the adjuvant management of high risk LG Gliomas.
- Indications for upfront adjuvant therapy are:
○ Macroscopic residual disease/STR
○ Age > 40 years
○ Poor ECOG, KPS<70
○ Unfavourable molecular features: IDH WT, No 1p19q codeletion, ki67 >3%
○ Neurological deficits
○ astrocytoma
○ size > 4cm
○ crosses midline- Adjuvant therapy would be the same as therapy for progression
“Crumbling 40yo ASTROphysicist with 6cm dick with limping leg crossing the middle of the road”
○ >40yo
○ Midline
○ Astrocytoma
○ Neuro deficit
○ >6cm in size
OR
“SATAN”
○ Size > 6cm
○ Age >40yo
○ Tumour crossing midline
○ Astrocytoma
○ Neuro deficitsRationale for Adj RT: Improve mPFS (5.5yr vs 3.5yr). NO effect on mOS [EORTC 22845]
* Adjuvant therapy would be the same as therapy for progression
* Otherwise, delayed radiotherapy is reasonable (at time of recurrence/progression)
* Adjuvant regimen= Adj RT followed by Adj Chemo
○ Radiotherapy to a dose of 45-54Gy in 1.8Gy/F
§ Dose choice is dependent on tumour bulk and volume
○ Adjuvant chemotherapy :
§ 6x PCV - improve mPFS and OS but very toxic, greatest benefit for Oligo, less degree in astrocytoma (RTOG 9802)
§ 6x TMZ is an alternative, easier to administer and better tolerated.* Up-to-date recommendation: § delay in young pts, fully resected, favourable molecular features § immediate in older pts with residual disease or unfavourable molecular features § individualise otherwise – more unfavourable features -> more likely upfront treatment * Re-resection only indicated if large/rapid recurrence with symptomatology ○ Consider surgery if there is concern of transformation to high grade disease
Describe the management of Pilocytic astrocytomas.
Pilocytic Astrocytoma
* JPA’s commonly occur in children and young adults with common locations being the cerebellum, optic pathways, hypothalamus, 3rd ventricle and cerebral hemispheres.
* It is the most common tumour occurring with NF1
* They are distinguished from diffuse astrocytomas + oligodendroglial tumours because of their lack of invasiveness, and favourable prognosis in many patients
* However, multicentric spread can occur, especially with hypothalamic tumours
Management
* Surgical resection is the standard initial approach in patients with JPAs.
* Even if resection incomplete, RT + CT usually withheld until evidence of tumour growth.
* RT- not shown to have a favourable impact on survival or prevention of tumour progression in JPAs. Therefore, avoid RT in initial management of these pts
* Indications for RT:
○ At time of diagnosis if surgery is not feasible.
○ Progressive disease following surgical resection.
* When RT is recommended, an involved field fractionated course to 54Gy is most commonly used
Outcomes
* The overall 10 year survival is 80%
* In patients undergoing GTR, 10 year DFS and OS approaches 100%
List differentials for low grade gliomas, besides astrocytoma and oligodendroglioma.
Low grade favourable glioma include:
○ Pilocytic astrocytoma
○ Pleomorphic astrocytoma
○ Subependymal giant cell astrocytoma
○ Subependymoma
○ Ganglioglioma
○ Central neurocytoma
○ Dysembryoplastic neuroepithelial tumours
Managed like JPA
Discuss the evidence for radiotherapy in LG Glioma.
Radiotherapy:
- All pts should receive XRT at some point
- Observe initial for best prognostic category dt significance of late effects (neurocognitive, radn necrosis)
- Moderate dose XRT 50-54Gy is adequate. Usually 54Gy for Grade 2 and 59.4Gy for Grade 3
EORTC 22845 (van den Bent, 2005) Non Believers trial
- 314 patients with low-grade gliomas were randomised to
○ Early RT (54Gy/30F) vs delayed/salvage RT
- Improved median PFS with early RT (5.3yrs vs 3.4yrs)
- Better seizure control at one year with early RT
- No change to median OS (7.4yrs vs 7.2yrs)
Dose
Dose escalation is not associated with improved outcomes
- 45Gy can be used (EORTC trial)
- 54Gy can be used (standard in RTOG 9802)
- EORTC 22844 "Believers trial" , Karim IJROBP 96 ○ 300+ pts, incompletely excised LGG, XRT 45 vs. 59.4Gy. RT modalities – EBRT, SRS, IORT, brachy ○ No diff in PFS (49%) or OS (59%) ○ Prognostic variables: "SATAN" Size > 6cm, Age >40yo, Tumour crossing the midline, Astrocytoma, Neuro deficits. 3-5 risk factors = high risk ○ No benefit to dose escalation - NCCTG, Shaw JCO 02 ○ 200+ pts, post op XRT 50.4Gy vs. 64.8Gy ○ No diff in PFS or OS, more radiation necrosis with high dose (NS). ○ Increased G3-5 toxicity - RTOG/Intergroup trial (Breen, 2020) ○ 203 opatients were randomised to § 50.4Gy vs 64.8Gy ○ No difference in OS or PFS with higher dose RT ○ Size < 5cm was predictive for outcome
Discuss the evidence for concurrent chemotherapy in LG Glioma.
RTOG 9802 (Shaw, 2012) Standard of Care for LGG
- 251 patients with G2 glioma were included
○ 18-39 years with subtotal resection
○ >40 years with any resection
- Randomised to
○ RT alone (54Gy/30F)
○ RT with adjuvant chemotherapy (6x PCV)
- Long-term analysis
○ Improved median OS with RT + chemo (13 years vs 8 years)
○ Magnitude of benefit from addition of PCV was greatest for oligodendroglioma
Key take away: Survival benefit and PFS of RT + Chemo vs RT alone
Classification of ‘high risk’ patients based on the above
As per RTOG 9802, high risk features
Age >40
Sub-total resection
EORTC Criteria (3+ of the following)
Age >40
Sub-total resection
Astrocytoma
>6 cm
Tumour crosses midline
Patient has neurological deficits (excluding seizures) at presentation
Chemotherapy
* RT-> PCV vs RT alone–showed PCV improved mOS, 10yrOS and PFS ONLY in IDH mut.
w NO benefit in IDH-WT
* Evidence for PCV but TMZ better tolerated and easier to administer
* Pts selected for immediate post-op therapy should receive sequential CTx as part of their management
w RTOG 98-02. * Unfavourable prognosis pts (age >40, debulking surgery only) randomized to RT +/- PCV. PCV= procarbazine, CCNU (lomustine)/ vincristine * Benefit with CT but very toxic Rx. * Post-RT 6xPCV survival advantage over RT alone 54Gy/30F w Improved mOS 13.3 vs 7.8 years, HR 0.59, p=0.03 w improved PFS 10 vs 4 years. w Improved 10yr OS 60 vs 40% and 10yr PFS 51% vs 21% w mOS by type: ® IDH mut/codel not reached vs 13.9yrs ® IDH mut/noncodel 11.4yr vs 4.3yr ® IDH WT 0.7-1.9yrs, not different w On subanalysis, benefit only in IDH-mutant (noncodel or codeleted). There is no benefit to chemo in IDH-WT * Toxic: grade 3 and 4 haematological toxicity 51% and 15% with PCV * Effect greatest for Oligodendroglioma and OA but astrocytomas also benefited * Concurrent ChemoRT using Stupp protocol 54Gy/30F+TMZ followed by 12mo of TMZ w RTOG 0424 (2009) [Fisher IJROBP '15, NeurOnc '18, MGMT, '20, Fleming JCO '21]: * Ph2. Historic vs. Stupp 54/30 * 129 pts with 3/5 Pignatti [Pignatti JCO '02]. RoR "WHO II" with 55% astrocytomas. * Stupp 54 Gy regimen feasible for LGG, with better 3y OS than historical controls. * Molecular analysis: IDHmt-1p19q codel (33%), IDHmt-1p19qnoncodel (35%), IDHwt (33%). * MGMT Me'd in 75%, more likely if ODG (95%), less likely if AA (64%). * IDHmt in 80%, more likely MGMT Me'd. If not Me'd, then over half are non-IDHmt. * Median OS 8.2yrs, median PFS 4.5yrs □ Outcome better than historical RT alone * 3y OS for historical controls / 04-24 of 54→ 73%. □ Codeleted oligo MS 7.3→ 14.7y. * 3y PFS 59%. mPFS 4.5y. Inferior to 98-02 in large part likely due to larger degree of AA (>50% vs. ~25%) * [cf 98-02-> 0424] 10y PFS 26→ 51%. PFS is negatively influenced by delayed RT. * [cf 98-02-> 0424] 10y OS 37→ 60%. * Non-methylated MGMT OS HR 3.52. * mOS for IDHmt-1p19q codel / IDHmt-1p19qnoncodel / IDHwt of 9.4→ 8.8→ 2.3y. □ mOS for IDHwt ± MGMT Me'd of 2.6→ 3.8y (n=11, 5). □ G3 toxicity 43%. * CONCLUSION: □ Long-term results support TMZ with radiation for high-risk low-grade glioma. □ IDH and 1p19q were much more prognostic than MGMT, except MGMT did give some prognostic value in IDHwt. ® As of WHO 2021, IDH-wt is now by definition glioblastoma, regardless of histologic appearance. However observe that these glioblastomas-of-sorts receiving TMZ, if methylated, have longer survival times than those in the GBM EORTC studies (Stupp 2009 and 2017). However there is a possibility of low power here. □ On subanalysis, TMZ seemed to work better for 3/5 risk factors than 4-5/5 compared to EORTC, but the trial was not powered for this analysis. ® 69% with 3 risk factors, 25% with 4, and 6% with 5. This trial uses "SATAN" criteria established from EORTC "Believers" trial (Karim 1996). TBL QS: Among historically grade 2 gliomas treated with modern high-risk treatment strategies, IDH-WT tumors do poorly, slightly mitigated by MGMT-methylation, supporting the current paradigm shift to lumping these in with glioblastomas, preferably treated on a clinical trial. * In Summary: STUPP protocol using 54Gy vs Historical (RT -> PCV) □ STUPP improved mOS and 3yr OS □ STUPP decreased mPFS and 3yr PFS at 3yr, but improved 10yr PFS ® mOS improved IF IDH mut and IDH WT and IF Co-deletion > non Co-deleted ® MGMT methylation improved mOS ® IDH WT without MGMT do poorly □ IDH and 1p19q codeletion is more prognostic than MGMT
Discuss the evidence for temozolomide monotherapy in oligodendroglioma.
- Role of TMZ monotherapy vs RT alone
w EORTC 22033 trial, (TROG 06-01).
* LGG stratified for 1p19q LOH, after resection
* TMZ CT alone (75mg/m2 for 1 yr) vs. XRT alone, Trying to avoid long-term XRT sequelae
* TMZ use extrapolated from high grade glioma, but treating for 1yr (HGG have 6m Rx)
* PFS 46 mos with RT vs. 39 mos TMZ, p=0.22
* There is no significant difference in PFS between radiation and TMZ, though RT is favored.
□ If IDHmt/non-codel, RT had longer PFS.
□ No different in PFS with IDHmt/codel and IDHwt tumors [IDHwt now = GBM]
□ Median OS not reached
□ No differences in HRQOL or global cognitive function between groups
* Overall, no difference in PFS between arms for IDH WT and Oligo except for Astrocytoma IDH mut/non-codel (TMZ inferior to RTx)
* Furthermore, for 1p19q codeleted, PFS inferior to PCV (55 months, versus 120 months in RTOG 9802)
* In Summary:
□ TMZ vs RT alone
® Astrocytoma – RT > TMZ
Oligo and IDH WT -> TMZ = RT
Discuss the evidence for IDH inhibitors in LG Glioma.
IDH inhibitors (As Low grade gliomas are IDH mutant by definition)
INDIGO Trial 2023
-Vorasidenib oral brain penetrator IDH inhibitor or IDH 1 and IDH 2
-Double blinded, phase 3 study looks at oral vorasidenib vs placebo in residual or recurrent Grade 2 IDH mutant glioma (patients had not received any other treatment besides upfront surgery)
-N=331
-PFS 27.7 months vs 11.1 months improved (HR 0.26) and delayed time to next intervention
-Vorasidenib group higher side effects, most commonly Grade 3 ALT level
-OS not reported
-Of note, PFS in this trial was much worse than RTOG9802 (2.3yrs vs >12yrs). Unclear role for Vorasidenib. Might have role in delaying RT (by median of 2 years)
Describe the radiotherapy technique for LG Glioma.
WHO G2 Glioma
Patients 1) IDHmut G2 astrocytoma
2) IDHmut 1p/19q co-deleted G2 oligodendroglioma
Pre-simulation
MDT discussion
Confirm risk group and decision to proceed with RT
Discuss driving limitation
Fertility discussion (more relevant for chemotherapy)
Post-op MR brain should be performed
- Immediately post-op, OR
- After 3-4 weeks
Simulation
Supine with arms by sides
- Handgrips
Immobilisation mask
Generous CT (2mm)
- Vertex to mid neck
-IV contrast (Evaluate the cavity/any residual disease)
Fusion
MR brain fusion
- T1 GAD + T2-FLAIR
Dose prescription
Single Dose Level
- 54Gy/30F prescribed to PTV as per ICRU 83
- Dose reduce to 50.4Gy or 45Gy if large brain volume
VMAT technique
10 days per fortnight
Volumes
* GTV
○ Tumour cavity
○ All T2/FLAIR signal
○ Any enhancing gross disease on CT + MRI (uncommon)
* CTV
○ GTV + 10mm
○ Incorporate surrounding FLAIR (especially if IDHmut)
○ Respect anatomical margins (cross 5mm over at falx and tentorium)
* PTV
○ CTV + 3-5mm
Target Verification
Daily CBCT
OARs
Brain
- D1/3 < 60Gy
- D2/3 < 50Gy
- D3/3 < 45Gy
Brainstem
- Dmax < 54Gy
Hippocampus (spare contralateral)
- D40% < 7.3Gy
Optic nerves
- Dmax < 54Gy
Spinal Cord
- Dmax < 45Gy
Cochlear
- Mean < 45Gy
Lens
- Dmax < 7Gy
Orbit
- Mean < 35Gy
Describe the prognosis and follow up in LG Glioma.
Follow-Up
- First MR brain 4-6 weeks after radiotherapy (baseline) - Clinical review every three months for the first three years ○ MR Brain at each visit - Clinical review every six months ongoing MR Brain at each visit
Describe the epidemiology and risk factors for brain metastasis.
Incidence
Metastases form the most common type of brain tumours (>50%)
- 10-20% of patients w/ cancer develop brain mets
- 1/2 solitary
- 10x more likely than a primary brain tumour
Most common primary sites (incidence per tumour site)
- Lung (30-60%)
- Melanoma (10%)
- Renal cell (10%)
- Breast cancer (5%) -esp HER2+
- Colorectal (2%)
Incidence is increasing
- Partially due to longer survival with systemic therapy
- MRI better detected smaller, asymptomatic lesions
- Brain represents a sanctuary site, so should develop metastases given enough time
Anatomy
Location
- Frequency of metastasis to common locations is primarily related to volume of brain
- Supratentorium (80% of metastases)
- Cerebellum (15%)
- Brainstem (5%)
Tend to occur at the grey-white matter interfaces
- Smaller vessel sizes at junctions act as a filter
- Result of arterial haematogenous spread and areas receiving greater supply
Despite these patterns, certain histologies have predilections for location (unexplained)
- Breast –> cerebellum
- NSCLC –> parieto-occipital lobes
Describe the location and function of Brocas area, wernickes area, pre-motor strip and sensory strip
Broca’s area (inferior frontal gyrus)
-Often in the left hemisphere
-Bounded by the sylvian fissure inferiorly and the pre central sulcus/primary motor cortex posteriorly
- lesion expressive aphasia (loss of ability to produce speech, still able to comprehend)
Broca’s area 44 and 45
Wernicke’s area (superior temporal gyrus)
-Area 22
-Beneath the sylvian fissure
- lesion if in dominant hemisphere = loss of ability to understand speech, still produce speech but often doesn’t make sense
Post central gyrus: Primary SENSORY cortex
Areas 1, 2 and 3
-Opposite half of the body is re-presented in the same up-side down/inverted homunculus as above
-Lesion loss of sensory levels opposite side of body, often crude pain/temp/touch can return dur to the thalmus
Both bounded inferiorly by the Sylvian fissure
Pre motor area (strip anterior to the motor cortex)
-Lesions result in difficulty to perform learned skills e.g. apraxia and agraphia
Describe the prognostic factors in brain metastasis.
Prognostic factors (Yamamoto, 2013)
* Age<=65
* KPS>= 80
* Extracranial disease
* Emerging: tumour volume ie. <10cm^3
* Number of lesions -> but may be more of a function of tumour burden/volume
* Female
* Controlled 1o, no extra-cerebral mets
* neuroasymptomatic
RTOG Recursive Partitioning Analysis (RPA) Score
* From 3 randomised RTOG brain met trials
* 4 PFs: KPS, age, control of primary, extracranial mets
* Doesn’t account for histology
* Very old data (pts treated 1979-1993); improvements in imaging, SRS, surgery, systemic therapy since
Site-specific GPA Scores
Caveats -retrospective database data, a bit old
Lung: KPS, age, presence of extra-cranial mets, # brain mets
Melanoma, RCC: KPS, number brain mets
Breast Cancer: Tumor subtype, KPS, age
GI cancers: KPS
Describe the history, investigation and work up for brain metastasis.
Consultation
- History ○ HPI § Raised ICP □ Headache □ Nausea □ Confusion □ Ataxia □ Seizure § Focal neurology □ Weakness □ Sensory change □ Incoordination § Haemorrhage ○ PMHx: § Previous malignancy ○ If no previous malignant history § Systems evaluation for cancer § Risk factors □ Smoking □ Alcohol □ PMHx and syndromes - Examination ○ Full neurological examination
Work-Up
- CT with contrast ○ Assess haemorrhage (non-con scan) ○ Assess ICP +/- hydrocephalus ○ Identify metastases - MR Brain with contrast ○ Establish number and location of lesions ○ Mets often have circumscribed margins, , large amounts of vasogenic edema compared with the size of the lesion, grey-white matter location ○ Distinguish from non-cancer diagnoses § Infection, inflammation (sarcoid), benign tumours - If no previous diagnosis ○ CT CAP (staging) ○ +- PET ○ Tumour markers ○ Biopsy (if easily accessible) § Craniotomy is a reasonable alternative § If diagnosis in doubt or unknown primary tumour
Describe the differential diagnosis for a brain lesion.
DDx
- Malignant:
○ Primary brain tumour
§ Glial: astrocytoma, oligo, GBM, ependymoma
§ Primary CNS lymphoma, secondary CNS
§ Benign CNS tumour
□ Schwannoma (acoustic neuroma)
□ Pituitary adenoma
□ meningioma
○ Paraneoplastic phenomena
○ Brain met
§
- Non-malignant ○ Infectious processes (e.g. abscess) ○ Progressive multifocal leukoencephalopathy ○ Demyelination ○ Stroke § Infarction § Bleeding ○ Treatment effects, esp. radiation necrosis ○ Foreign body
Discuss management of brain metastasis with surgery
Craniotomy + Resection
Surgical management is most appropriate if:
- No previous diagnosis (need for histological diagnosis)
- Single intra-cranial lesion
○ Especially if large tumour (>3-4cm) where SRS alone is unlikely to provide control
○ Accessible surgically
- Minimal/no extracranial disease
- RPA class I or II/ good KPS
- Urgent decompression required (e.g. symptomatic; hydrocephalus with 4th ventricular compression)
- Tumours with long natural histories (e.g. breast cancer)
Indications for surgery
- Large lesions
- Symptomatic
- Possible non-maligant differential
Eloquent areas
Post-op cavity SRS
- Without any further management, 50% risk of local cavity recurrence within the next 6mo
- Better LC vs. surgery alone, less neurocog decline vs. WBRT
This does not address the risk of distant intra-cranial progression
- 25-50% risk within 12 months
What are the options for management of brain metastasis?
Initial
- Any symptoms of hydrocephalus or raised ICP need to be managed urgently ○ Dexamethasone 8-16mg per day ○ If seizures, levetiracetam (Keppra) loading dose --> maintenance dose ○ Allied health, pal care, stop driving - Urgent imaging to establish diagnosis ○ If no previous oncological diagnosis, consider delaying steroids until diagnosis (lymphoma)
Lin X, DeAngelis LM. Treatment of brain metastases. J Clin Oncol 2015; 33: 3475-84.
- Chemo: can consider as 1st line for: germ cell, SCLC
○ For asymp mets in pts slated to receive chemo may be reasonable to monitor
○ Met has identified molecular alteration amenable to targeted therapy
- Consider WBRT: CNS & systemic progression, few systemic options, poor KPS
○ Multiple (>3-10) mets, esp if primary disease not chemo-sensitive
○ Large (>4cm) met not amenable to SRS
○ Post-sx of dominant met with multiple remaining mets
○ Salvage after SRS or WBRT failure
- Consider SRS: 1-3 mets, esp if radio-resistant
○ Post-sx of single met, esp if >3cm and in the posterior fossa
○ Local relapse after sx resection of single met
○ Salvage of 1-3 mets after WBRT
- Consider sx resection: uncertain dx
○ 1-2 mets, esp when assoc with extensive edema
○ Dominant met in critical location
- No tmt is reasonable: systemic progression, few/no tmt options, poor KPS
○ steroids
If prognosis >3-6 months
- Consider neurocognitive decline from WBRT
SRS good local control with minimal toxicity
Discuss management of brain metastasis with SRS, including the advantages and disadvantages
SRS Alone
Preferred to WBRT due to improved neurocognitive outcomes
- High local control in treated lesions
Should be considered if:
- 1-5 metastases (ideally < 3cm in size)
○ Can consider for 6-10 metastases in highly select populations
○ Not involving brain stem or chiasm
- Known diagnosis and no uncertainty
- Willing to have surveillance MR brain
- Anticipated lifespan >3 months
○ Most randomised studies support SRS selected pt with anticipated survival of >=6 months
Patients all require surveillance MRs every 3 months
- Risk of distant intra-cranial recurrence (25-50% within 12 months)
Consolidation WBRT should not be routinely recommended
- Data demonstrates reduction in risk of intracranial progression only
- No OS advantage and marked increase in neurocognitive toxicity
Can consider WBRT if patients decline subsequent MR follow-up
Relative contraindications
* Involving brain stem
* <= 5-10mm from chiasm
* Systemic disease uncontrolled/not being treated
* Low PS
* >=4cm (surgery should be considered)
* Small cell lung ca (although approach individualised, emerging)
Contraindications
* Presence of leptomeningeal disease
* Disseminated intracranial disease
* Uncontrolled raised intracranial pressure on steroids
* Lymhoma/leukemia
* Poor KPS or short survival interval
Discuss pseudoprogression after radiotherapy
Pseudoprogression
The risk of radionecrosis is about 10% following SRS
Risk factors
- Prior RT (WBRT or SRS)
- EQD2 dose of >72Gy
- Single fraction SRS
- Larger primary (i.e. single fraction for lesions >2cm)
- Concurrent immunotherapy
Ways to clinically identify necrosis vs progression
- Most radionecrosis is asymptomatic (tumours will progressively be symptomatic)
- Serial MR imaging +- perfusion
- MR spectroscopy
- FET PET/CT (if availabe)
If asymptomatic, patients should be followed closely (MR every 6-8 weeks)
- Do not intervene (unlikely to be true progression)
If develop symptoms, consider management
- Dexamethasone
- Consider surgical resection (therapeutic + confirm necrosis vs progression)
- Bevacizumab (steroid sparing)
Discuss whole brain radiotherapy for brain metastasis, including hippocampal avoidance.
Whole Brain RT
WBRT has been used much less frequently in recent years due to neurocognitive concerns
Still remains a good treatment if
- Good performance status
- Too many metastases for SRS approach
Hippocampal Avoidance + Memantine
Should be considered standard of care in most patients receiving WBRT
- Exceptions are CNS lymphoma +/- small cell lung cancer
Deliver 30Gy/10F with a “hippocampus + 5mm” avoidance structure
- Keep hippocampal doses to –> D100% < 9Gy and Dmax < 16Gy
Use concurrent memantine (escalating dose protocol)
- 5mg mane for 1 week
- 5mg BD for 1 week
- 10/5mg for 1 week
- 10mg BD ongoing for 6mo
Poor Performance Status
Establish if acute performance status issue
- Decompressive surgery may improve this
Patients with more chronic (or irreversible) poor performance status should not receive WBRT
- QUARTZ trial –>
○ Randomised phase III trial
○ No advantage compared with BSC (dexamethasone) over WBRT
○ In OS and QoL
Discuss the use of systemic therapy for brain metastasis.
Discuss the evidence to support SRS alone for management of brain metastasis.
SRS
Summary:
- Key factors influencing local control from SRS are
○ Dose and fractionation
○ Tumour size
○ Cystic or necrotic tumours (worse LC)
- No clear relationship to histology
HYTEC tumour control probability (Redmond, 2021) ○ Extensive review of multiple trials regarding SRS for intact brain metastases § Multiple fractionations § Multiple clinical scenarios ○ Modelling applied to interpolate data points ○ Outcomes § 2 year local control data
JROSG 99-1 - Aoyama et al, JAMA 2006, 2015
○ RCT of 132pts with 1-4 brain mets <3cm
○ SRS +/- WBRT 30Gy/10#
○ The addition of WBRT to SRS did not improve OS in patients with 1-4 brain mets, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT.
EORTC 22952 – Kocher et al, JCO 2011, JAMA 2018
○ 359pts with 1-3 brain mets <3.5cm in size, stable systemic disease and PS 0-2
○ RCT
○ Surgery or SRS +/- WBRT
▪ 71% LINAC based SRS
○ Overall adjusted risk of local failure not different between surgery and SRS
▪ Surgery patients more likely to fail early (0-3 months) and SRS more likely to fail late (>9 months)
○ Decreased neurological death in WBRT group
○ Quality of life improved when WBRT not given.
MDACC SRS vs WBRT for patients with 4-15 brain metastasis – Li et al, ASTRO 2020
○ Phase III RCT of adult patients with 4-15 untreated non-melanoma brain mets
○ Even when treating >3 brain metastasis, SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT; without compromising LC or OS.
Discuss the evidence to support consolidation SRS after surgery.
SRS as Consolidation Following Surgery
Summary
- SRS improves local control compared with surgery alone
- Fractionated courses are likely superior to single fraction
Meta-analysis (Akanda, 2020) ○ 3458 patients across 50 studies were included § All studies investigated SRS as consolidation following surgical resection ○ Outcomes § Overall, local control at 12 months was 83.7% □ Distant brain control was 53% at 12 months § Fractionated SRS was associated with better local control than single fraction § Addition of a margin did not improve local control § Necrosis is uncommon (7%)
NCCTG N107C/CEC.3 trial randomised 194 patients with one resected BM to post-operative SRS or WBRT.2 Post-operative SRS showed a longer cognitive deterioration free survival (median 3.7 months, 95%CI: 3.45-5.06) compared to WBRT (median 3 months, 95%CI: 2.86-3.25). Sixty percent of patients in the SRS arm had a cavity ≤3 cms (i.e. would have received 1–20 Gy SRS).
Mahajan et al. 2017 randomised 132 patients with one to three BMs to post-operative SRS or observation alone.19 Post-operative SRS showed an improved 12-month local tumour recurrence free rate (72%, 95%CI: 60%-87%) compared to observation (43%, 95%CI: 31%-59%)
Discuss the evidence to support whole brain radiotherapy.
WBRT
Neurocognitive Prevention
Both HA-WBRT and memantine individually improve neurocognitive outcomes
CC001 RCT for HA-WBRT (Brown, 2020) ○ 518 patients receiving whole brain radiotherapy + memantine were randomised to § HA-WBRT vs normal § Dose-escalation memantine protocol (6mo duration) ○ Outcomes § Significant reduction in risk of cognitive decline overall □ Improvement in executive function and learning/memory domains § Improved PROs (including fatigue and memory) § No detriment to OS or intracranial PFS identified Memantine trial (Brown, 2013) ○ 508 patients receiving whole brain radiotherapy § Randomised to 20mg/day of memantine for 6mo ○ Outcomes § Reduction in risk of cognitive decline overall □ Improvement in executive function, processing speed and delayed recognition domains § Longer time to cognitive decline
Whole Brain RT as Consolidation
Cochrane meta-analysis (Soon, 2014) ○ 663 patients across 5 RCTs § Patients with brain metastases who received surgery or SRS § Randomised to consolidation WBRT ○ Outcomes § WBRT was associated with decreased risk of intracranial progression (RR 0.47%; p<0.0001) § No OS benefit seen (HR 1.11) § QoL and neurocognitive toxicities are uncertain
Omission for Poor Performance Status
QUARTZ trial (Mulvenna, 2016) ○ 538 patients with metastatic NSCLC (brain mets) were randomised to § WBRT 20Gy/5F + BSC § BSC (dexamethasone) ○ Non-inferiority design ○ Outcomes § WBRT was not associated with improved OS □ No improvement in QoL or reduced dexamethasone use § Increase in toxicity associated with WBRT § Slight improvement in QALYs with RT (4.7 days --> no clinically significant) ○ Patients where poor performance status § If ECOG 0-1 consider alternative options
Describe the radiotherapy technique for intact brain met SRS
Intact SRS
Patients
Ideally
- 1-4 brain metastases
- Not larger than 3-4cm
- Minimal symptoms
- Control of extra-cranial disease
ECOG 0-2
Pre-simulation
Dex > usually only if symptomaric
Consults: Neurosurg r/o candidate
MDT Discussion
- Review imaging
- Discuss management options
- Discuss extra-cranial disease and prognosis/therapeutic options
Consider suitability to drive
Simulation
Supine with immobilisation mask
Arms by side
CT from vertex to mid-neck (C7)
- SRS protocol (<=1mm slices)
Fusion
MRI brain (T1 + GAD)
- Stereotactic protocol (1mm slices)
- <=7 days prior to start
- Rigid anatomical fusion of whole brain, landmarks sulci, ventricles, BV, brain stem
- MRI with distortion correction on and 1mm slice thickness
Dose prescription
<20mm in size
- 18-20Gy in 1F (or one of below)
- Astro 20-24Gy/1Fx
20-30mm
- 27Gy in 3F
- 18Gy/1 Fx (Astro/RTOG)
>30mm
- 30Gy/5F
>40-60mm
- 25Gy/5F
Single fx feasible for up to 3-4cm depending on location, extent of oedema and cumulative volume
Hypofractionation allows for improved therapeutic ratio for larger lesions to achieve higher dose
Dexamethasone 4mg day of treatment
- If single fraction
VMAT-based SRS technique
Daily
(≥ 96% PTV & 100% CTV covered by prescribed dose)
Volumes
GTV = tumour on MR
CTV= GTV
PTV = GTV + 2mm
(dependent on departmental setup; some 2-5mm, can be 0 for Gamma knife)
PTV=GTV if invasive frame immbolisation
Target Verification
Daily CBCT
OARs
Brainstem –> Dmax (0.1cc)
- <12Gy/1F
- <24Gy/3F
- <30Gy/5F
Optic Nerve/Chiasm –> Dmax (0.1cc)
- <10Gy/1F
- <18Gy/3F
- <25Gy/5F
Brain
V15Gy<15cc for single fraction–radionecrosis risk <10%
Objectives
GTV
- D100 ≥100% of prescribed dose (PD)
- Dmax (0.03cc) <135% linac
PTV
- Ideal D98 ≥100% of PD
Quality Indices
Conformity Index (Vol 100% / Vol PTV)
- <1.5
Gradient Index (Vol 50% / Vol 100%)
- <5
Dmax
- 125-143%
Describe the epidemiology and risk factors for meningioma.
Incidence (USA statistics)
- 29000 cases annually
- 2 per 100000 people annually
Most common primary brain tumour (30%)
Female predominance (2:1)
Tend to occur in adults (50+ years), risk increases with age
Aetiology
1) Ionising radiation (reasonably long latent period) a. Childhood therapy (CSI, TBI) b. Tinea capitis 2) Genetic causes a. Neurofibromatosis Type 2 (NF2) 75% lifetime risk b. MEN 1 (parathyroid, pancreas net, pituitary adenoma) 8% risk meningioma 3) Hormonal factors a. Postulated due to: i. Female predominance ii. Associated with pregnancy (more often a flare in symptoms if present during pregnancy) iii. Association with OCP or HRT use iv. Progesterone receptor on meningioma 4) Obesity
Inconclusive
- Cell phones
- Head trauma
Common sites
-Cerebral convexity
-Falx, tentorium cerebelli
-BOS
Describe the pathogenesis and locations for meningioma.
Pathogenesis
Primarily benign tumours arising from the meningothelial cells of the arachnoid mater
- Can be found anywhere along the meningeal surface (brain, spine)
Most common cytogenetic abnormality is chromosome 22
- Most common is 22q12 deletion (involving NF2 gene)
- Multiple meningiomas should raise concern for germline NF2 mutation
Higher grade meningiomas often harbor mutations in:
- TERT-promoter
- CDKN2A deletion
Describe the pathology for meningioma.
Meningioma (WHO G1)
- Macroscopic
○ Extra-axial dural based lesion on imaging
Rounded and well circumscribed nodules which are attached to dura
○ Generally peels away from brain surface easily (G2/3 exception)
○ May cause adjacent bone reaction
○ Cut surface
§ Rubbery
§ May be gritty (psammomatous calcification)
§ Grade 2/3 regions of necrosis/brain invasion
- Microscopic
○ Typically exists in lobulated architecture with whorls
○ Syncytial cells with indistinct cell membranes
○ May contain psammoma bodies or rarely necrosis/haemorrhage
○ Key subtypes
§ Meningothelial (WHO G1) –> most common; lobules of epithelial cells, syncytial cells with whorls
§ Fibroblastic –> firm tumours with fascicles of spindle cells (resemble schwannoma or solitary fibrous tumour)
§ Transitional -> Whols, features in between meningothelial and fibrous
§ Angiomatous –> vascular component is >50% of tumour; meningothelial cells wrapped around vessels
§ Psammomatous –> extensive psammoma bodies -found in spine
§ Rhabdoid
§ Papillary
Grade 1 but cause oedema++: angiomatous, microcystic, secretory and lymphoplasmacyte rich
- Immunohistochemistry ○ POS = SSTR2a, vimentin, EMA, S100, PR -EMA positive (schwannoma negative) SSTR2A positive- most sensitive and specific for meningioma ○ NEG = GFAP, OCT4 (germ cell markers) -GFAP - stains for brain parenchyma/glial cells. Stain used to assess for brain invasion
Describe the grading of meningioma.
Most common:
Meningiothelial: Epithelioid cells,
Fibrous: Spindle cells with collagen
Transitional: Features in between meningothelial and fibrous, can has psammoma bodies
Rhabdoids and Papillary
-In the past were included in Grade 3 criteria, now can be Grade 1 unless they meet G2 or G3 meningioma
-Based on meta-analysis evidence that patient outcomes independent of rhabdoid and papillary features
Grade is based on
-Histological subtype (Can be any, except clear cell or chordoid=auto G2)
-Mitotic activity or brain invasion (<4 MPHPF G1, 4-19 MPHPF G2, >20 MPHPF G3. Brain invasion G2)
-Minor criteria: Increased cellularity, prominent nucleoli, necrosis, sheeting architecture, small cell change (3/5=G2)
-Anaplasia
-TERT promoter or CDKN2A/B homozygous deletion (Auto Grade 3 )
Describe the Simpsons criteria for resection of meningiomas.
Describe the upfront management of meningioma
Meningiomas
- Surgical resection, standard treatment with Simpson Grade
- Simpson Grade (Multiple by 10% G1-4 to give the 10 year recurrence rate)
- Radiotherapy
o If no amenable for surgery e.g. skull base venous sinuses, elderly, patient preference
- Post-op role in high risk cases
- EANO guidelines
Small & Asymptomatic
- Observation is appropriate in the first instance for most patients ○ MR surveillance § Frequency □ 3-6 months after first study □ Then annually for 5 years □ Then bi annually ongoing § Observe rate of growth (most important factor) § 40% progression at 5 years § If lost to follow-up may progress to unresectable - Consider intervention if: ○ Rate of growth increases ○ Symptomatic ○ Patient preference
Large & Symptomatic
- Upfront management should be considered if: ○ Large (typically more than 3-4cm) ○ Symptomatic from lesion ○ Adverse imaging characteristics suggestive of higher grade § Heterogeneously enhancing § Local brain invasion, mushroom effect § Mass effect, oedema and midline shift § Trans-cranial extension § Hyperostosis or bone destruction § Absence of CSF cleft § Lack of calcifications - Surgical resection is typically the mainstay of upfront therapy ○ Provides immediate debulking ○ Consider preop angiogram and embolisation for large high grade tumours ○ Provides prognostic histopathology ○ Gr 1 resection 10% recurrence ○ G2 (coagulate tail) 20% recur ○ G3 (tail left) 30% recur ○ G4 subtotal 40% recur
Discuss the adjuvant management of grade 1 meningioma
Grade I meningioma
- If completely resected, no adjuvant therapy is required and can observe - If partial resection, adjuvant therapy is controversial (RT or observation is reasonable depending on patient/treatment/tumour factors) ○ Adjuvant radiotherapy will certainly improve local control ○ However, the rate of progression is slow and only half of patients will progress by 10 years - It is reasonably to delay adjuvant radiotherapy until progression ○ Consider upfront adjuvant radiotherapy only if in an unresectable location - If multiply recurrent, will need to proceed to adjuvant radiotherapy - RT dose for WHO G1 meningioma ○ 50.4Gy/28F If bulky residual, consider 54Gy/30F
Describe the adjuvant management of grade II and III meningioma
Grade II meningioma
- If completely resected, role of adjuvant radiotherapy is controversial (RT or observation is reasonable depending on patient/treatment/tumour factors) ○ Adjuvant RT will improve local control ○ However, presence of OS benefit is controversial § Likelihood is that salvage is achievable at time of recurrence (with close observation) - Reasonable to consider upfront adjuvant RT if: ○ If difficult surgical location ○ Patient unlikely to comply with close surveillance protocol - If partial resection, all patients need adjuvant radiotherapy ○ Typically at a dose of 54Gy/30F ○ 95% pfs 3 years
Grade III meningioma (+ recurrent grade II)
- All patients require adjuvant radiotherapy, regardless of degree of resection ○ Without treatment, are associated with a considerable OS deficit ○ Adj RT improve both LC and OS - Adjuvant radiotherapy doses should be 60Gy/30F - 60% PFS
Discuss definitive radiotherapy for unresectable meningioma and management of recurrence/salvage.
Definitive Radiotherapy (unresectable)
- Typically most relevant for base of skull tumours ○ Surgery remains the gold-standard treatment preference - Note, you will have no definitive evidence of histological grade ○ Use imaging signs to guide dosage - Radiotherapy dose ○ Presume grade I § Stereotactic --> 12-16Gy/1F (most trial dose to 50% isodose line) □ 5yr LC 94-98% □ Brainstem tolerance is 12Gy (use lower doses if adjacent) § Fractionated stereotactic --> 25Gy/5F or 25Gy/5F can be used for larger tumours, and less likelihood of oedema compared to SRS § Fractionated --> 50.4Gy/28F ○ If higher-grade § Fractionated --> 54Gy/30F § Fractionated --> 60 Gy/30F
Criteria for SRS:
○ >3mm from optic apparatus and brainstem
○ <3-4cm
○ <10cc volume
○ distinct margins
○ little/ no oedema
○ Grade 1
○ Recurrence
Special sites:
- Optic sheath -> Def RT 50.4Gy/28F
OR Surgery, Surg+Adj RT, or observation-> all likely to result in worse vision
Outcome: LC >90%, stabilization of vision in 90%
- Cavernous sinus-> Def or Adj RT
Outcome: 5yr PFS > 90%. (30% improved neurological function, 60% reduced progression and 10% continued to progress)
Discuss the advantages and disadvantages of managing meningioma with surgery, radiotherapy or observation.
Describe the prognosis and follow up for meningioma.
MRI 3 monthly for 1st year, 6 monthly year 2-5 then yearly after 5 years
Response pattern SRS:
80% stable disease
Partial 15%
Transient enlargement/Pseudoprogression in 5% in first 1-2 years -up to 4x volume
Less pseudoprogression for conventional
Describe the pathophysiology and subgroups of ependymoma.
Pathophysiology
Arise from the ependymal cells which line the ventricular system
Anatomical location as well as molecular status imparts prognostic value
- Supratentorial is better than posterior fossa
- Spinal is best location (due to ease of resection)
Describe the general management for ependymoma in children and adolescents.
Intracranial Ependymoma
- Gold standard therapy is maximal safe resection ○ Also the most rapid way to improve symptomatology - Adjuvant therapy to follow depends on the age, grade, extent of disease and degree of resection - Most will get rt to tumour bed
Adjuvant Therapy for Infants (<12 months)
- Concerns about early radiotherapy exist (developmental toxicity) - Upfront adjuvant chemotherapy (as bridge to delay radiotherapy) ○ Methotrexate, cyclophosphamide, vincristine and cisplatin/etoposide - Radiotherapy to follow thereafter - Avoid craniospinal irradiation in children < 3 years old (concerns about developmental issues) - Radiation doses for children: ○ 54Gy/30F to the post-operative bed § Consider boost of any macroscopic disease (59.4Gy/33F) ○ Less common 36Gy/20F to the craniospinal axis (when disseminated)
Describe the radiotherapy technique for ependymoma in the head, spine and disseminated.
Describe the prognosis for ependymoma.
Describe the WHO subtypes for Intracranial germ cell tumours
WHO Subgroups
1) Germinoma 2) Non-germinoma a. Embryonal Carcinoma b. Yolk sac tumour c. Choriocarcinoma d. Teratoma (mature or immature) e. Mixed
Histopathology
Entirely unchanged from testis/ovary
Tumours are grouped on the basis of:
1) Serum + CSF markers (b-HCG & AFP)
a. Any AFP elevation implies non-germinoma
b. Mild b-HCG elevation can be seen in germinoma
2) Immunohistochemistry (PLAP & c-KIT)
Describe the prognosis for intracranial germ cell tumour
List the differential diagnosis for a supracellar tumour
Differential Diagnosis for Suprasellar mass
Malignant
- Pituitary adenoma/PitNET
- Pituitary carcinoma (very rare)
- Germ cell tumour
- Meningioma
- Metastasis from another primary Glioma
- Craniopharyngioma
- Chordoma
- Optic nerve glioma
- Ependymoma
- paraneuronal tumour- neuroblastoma, paraganglioma
- CNS lymphoma
Benign:
- AVM
- Sarcoid
- Aneurysm
- TB
- Cleft Cyst
- Granuloma
DDx pituitary mass = “SATCHMO”
S = Sarcoid
A = Aneurysm
T = Teratoma or Tuberculosis (and other granulomatous dx)
C = Craniopharyngioma, Cleft cyst (Rathke), Chordoma
H = Hypothalamic glioma, Histiocytosis
M = Meningioma, Mets
O = Optic nerve glioma
Describe the pathology for pituitary adenoma, carcinoma, pituitary neuroendocrine tumours
Pituitary Adenoma/PitNET
- Macroscopic
○ Typically soft and well circumscribed red-brown tumours
○ Macroadenomas may be invasive and have foci of haemorrhage or necrosis
○ 30% of cases are non-encapsulated and invade adjacent structures (aggressive adenoma)
- Microscopic
○ Uniform/Bland monomorphic polygonal cells arrayed in sheets
○ Nested architecture with stippled regular distributed chromatin (salt and pepper chromatin)
§ Does not have the variability of normal pituitary (cell lines intermixed)
§ Higher density than normal pituitary
○ Sparse/disrupted reticulin network distinguishes from normal pituitary
○ Ki67 and mitotic activity are associated with behaviour
§ Aggressive adenomas typically express more division
○ Crook cell -aggressive variant –pink glassy cytoplasm with crooked nucleus.
- Immunohistochemistry
○ POS = synaptophysin, reticulin (delineates normal architecture vs disrupted adenoma)
○ NEG = CK7, CK20, TTF1, GFAP (glioma)
○ The use of hormone stains (prolactin, ACTH, GH, etc.) or transcription factors (PIT1, SF1, T-PIT) can assist in delineating a cell line § T-PIT = ACTH = corticotroph § PIT 1 = TSH, GH, prolactin § SF1 = LH, FSH - High risk for recurrence ○ Lactotrophs in men ○ Crook cell ○ Silent corticotrophs ○ Pluri-hormonal PIT1 positive tumours
Histopathology (Malignant)
Pituitary Carcinoma
- Exceedingly rare (<1% of all pituitary tumours)
- Diagnosed on the basis of identifying systemic metastasis or CSF spread(craniospinal or extracranial)
○ No different on histopathology
- Can be secretory or non-secretory
○ Most carcinomas secrete prolactin or ACTH
- Highly aggressive disease course
○ Multiple local recurrences prior to metastasis
- Microscopic ○ As above § May have increased nuclear pleomorphism and mitotic activity ○ Cannot identify malignant carcinoma histologically - Molecular –HRAS, P53, RB, cyclinD2
Describe the anatomy and hormones produced by the pituitary gland.
Anatomy
Embryology:
* Ant: derived from Rathke’s pouch – evagination of ectodermal primitive pharyngeal cavity
* Post: diencephalon – neuroectodermal origin
* Anterior lobe (derived from Rathke’s pouch) secretes 6 hormones: (FLAT.GP)🡪 FSH, LH, ACTH, TSH, GH, PRL under the influence of the hypothalamus. ○ 3 sections § Pars anterior: Largest, hormone secretion § Pars inetrmedia: thin layer that separates pars anterior from posterior lobes § Pars tuberalis * Posterior lobe (nervous tissue) secretes: ○ Oxytocin. ○ ADH § Both oxytocin and ADH are made in the hypothalamus and stored in the posterior pituitary ready to be released * Anterior and posterior lobes ○ Same venous drainage (anterior and posterior hypophyseal veins) ○ Anterior arterial supply: superior hypophyseal artery (From the ICA) ○ Posterior arterial supply: Superior hypophyseal aretru, infundibular aretery and inferior hyophyseal artery * Sella turcica relations ○ Lat- cavernous sinus (containing CN3,4,6,5a,5b + ICA) ○ Sup: Hypothalamus, optic chiasm, ant cerebral arts ○ Inf: sphenoidal sinus + nasopx ○ Anterior: Sphenoid sinus (surgical access- trans-sphenoidal) ○ Posterior: Dorsum sellae, basilar artery, pons
What is the general management for pituitary microadenoma and macroadenoma
Microadenoma (asymptomatic, non-functioning)
- Observation alone
- Incidental finding in 10% of population, very common
Macroadenoma (symptomatic with mass effect, nonfunctioning)
* Patient: Performance status, co morbidities, surgical risk
* Tumour: Functional/non functional, size, local symptoms, mass effect, location
(cavernous sinus)
- Treatment: Residual tumour post-op, experienced surgeon, resectability, response to medical management, side effects
- Surgery preferred: Trans-sphenoidal resection ○ Post-operative radiotherapy § 50.4Gy/28F or 18Gy/1F if non-secretory § Indicated if □ Suboptimal resection - R2 (alternative is observation) □ High-risk pathology (atypical features, local invasion) □ Following resection of recurrent disease - Medical management can result in a reduction in size- depends on the histology ○ Cabergoline or bromocriptine (dopamine agonist) if prolactinoma ○ octreotide or lanreotide ○ ketoconazole - Definitive radiotherapy ○ Indication: § surgical resection is not feasible (medical or technical) § Symptomatic or growing macroadenoma, or functional adenoma ○ PROs: control growth ○ CONs: slow response of hypersecretion, slow relief of visual impairment ○ SRS vs EBRT/fractionated SRS- equivalent efficacy in endocrine control but SRS slightly faster dec hormone (case series data only)with time to normalising hormonal levels
Pituitary Carcinoma
- very rare, 0.2%, very poor prognosis mOS 21mo
- By definition, always have metastatic disease at diagnosis
- First line therapy is TMZ
- Consider concurrent RT+TMZ to the primary, 59.4Gy/33F +/- Avastin
Describe the management of the different types of functioning pituitary adenoma.
Functioning adenoma:
- Treatment of choice depends on histology
○ Prolactinoma/Lactotroph
§ Trial dopamine agonist first (very effective 90% in decrease in size +hormone secretion)–> resection if fails
○ All other functional adenomas
§ Resection first (medical as bridging while awaiting for Surg/RT)
- Referral to endocrinologist ○ Non-functioning --> replacement of hormonal deficits ○ Functioning --> suppression of excessive hormone levels ○ Medical Management § Prolactinoma: Dopamine agonist (before surgery) □ Hyperprolactinemia interferes with pulsatile GnRH secretion and decreases FSH and LH □ Dopamine agonists normalise prolactin levels= CABERGOLINE □ Only pituiatry type in which medicla management first line, then surgery as can decrease size in >90% of patients § Somatostatin analogues ○ GH adenoma/residual disease post surgery - Ocretotide/lanreotide ○ Often just whilst awaiting surgery § ACTH/Cushingoid ○ Surgery/RT first line ○ Some studies suggest cabergoline. Can be effective in suppressing ACTH, alsoketaconazole - If sub-optimal effect, consider trans-sphenoidal resection - Radiotherapy is reserved for third-line therapy in all cases ○ 54Gy/30F or 20-22Gy/1F if secretory ○ Note considerable delay to endocrine effect ○ Indications § Recurrence following resection (after failure of medical therapy) § Ineligibility for medical/surgical management
Describe the fractionated radiotherapy technique for pituitary adenomas.
Fractionated
Patients
Typically after failure (or ineligibility) of medical and surgical management
Pre-simulation
Endocrinology review
- Ensure maximal medical management trialled
MDT review
Baseline endocrine markers
Baseline ophthalmological review
Simulation
Supine with thermoplastic immobilisation mask
Fusion
MR Brain (thin slices of pituitary fossa)
- 1mm T1-GAD
Dose prescription
If non-secretory
- 50.4Gy/28F prescribed to the PTV (as per ICRU 83)
If secretory
- 54Gy/30F
VMAT technique
10 days per fortnight
Volumes
GTV = visible macroscopic disease
CTV = in general 0 mm,
- consider 2-3mm if marked extra-sellar invasion (e.g. cavernous sinus) or aggressive/ invasive disease
PTV = 5mm
Target Verification
Daily CBCT
OARs
Brainstem
- Dmax < 54Gy
Optic chiasm
- Dmax < 54Gy
Retina
- Dmax < 45Gy
Describe the SRS radiotherapy technique for pituitary adenomas.
SRS
Patients Typically after failure (or ineligibility) of medical and surgical management
Ensure optic chiasm is >2mm from target
Size<3cm
Pre-simulation
Endocrinology review
- Ensure maximal medical management trialled
MDT review
Baseline endocrine markers
Baseline ophthalmological review
Simulation
Supine with thermoplastic immobilisation mask
Fusion
MR Brain (thin slices of pituitary fossa)
- 1mm T1-GAD
Dose prescription
If non-secretory
- 18/1F prescribed to the PTV
If secretory
- 22/1F
VMAT-based SRS technique
10 days per fortnight
Volumes
GTV = visible macroscopic disease
CTV = in general, 0mm
- consider 2-3 mm if marked extra-sellar invasion (e.g. cavernous sinus) or aggressive/ invasive disease
PTV = 2mm
Target Verification
Daily CBCT
OARs
Brainstem
- Dmax < 8-10Gy
Optic chiasm
- Dmax < 8-10Gy (2% neuropathy)
Discuss outcomes and follow up for pituitary tumours.
Follow up:
* Endocrine Bloods every 4 months for 2 years 🡪 then every 6 months
* History, exam and hormonal assessment at review
* Surveillance MRI 12 monthly
* Consider annual visual field checks
RT Response
80% reduced function in 6 weeks
90% reduced size in 6 weeks to 6 months, ongoing reduction over years
SRS 20% transient enlargement 2mm @ 6 months
Hypopituitism
Prolactin deficiency
* Not unable to lactate after delivery
ACTH
* Cortisol replacement, hydrocrotisone
* Specific timing to reflect bodies natural production of cortisol and stress dosing needed
* Diabetes insipidus through correction of cortisol deficiency
TSH
* TSH deficiency results in lack of T4
* Treat with exogenous T4 (Thyroxine)
LH/FSH deficiencies
* Males: Testosterone replacement based on serum testosterone levels. If wishing to remain fertile treat with Gonadotropins
* Females: Estrogen-progesterone replacement therapy. If wishing to remain fertile, gonadotropins for ovulation induction
GH
Not routinely recommended in all patients due to weak clinical benefit/high cost
Describe the pathogenesis and pathology for vestibular schwannoma
Pathogenesis
- Inactivating mutation of the NF2 gene ○ NF2 produces schwannomin (membrane-based tumour suppressor protein) - Sporadic schwannomas arise after biallelic inactivation of NF2 ○ Germline NF2 mutation therefore increases probability of a second hit - 90% of all schwannomas occur on CN VIII (vestibulocochlear) (inferior vestibular nerve) ○ Others include CN V and VII - 95% sporadic and unilateral
Pathology
Vestibular schwannoma
- Most commonly impact CN VIII
○ Of this, most impact vestibular divisions of nerve
- Bilateral schwannoma is pathognomonic of NF2 syndrome
- Macroscopic ○ Solid, globoid mass with a tan cut surface ○ Firm grey mass loosely attached to nerve (can be separated - no invasion) ○ May have cystic or haemorrhagic components - Microscopic ○ Well circumscribed and encapsulated tumour ○ Often hyper and hypocellular areas ○ Uniform/bland spindled Schwann cells with varying density § Alternating dense and sparse regions within tumour ○ Verrocay bodies (nuclear palisading) ○ Swan neck spindle cells ○ Degenerative changes is common (nuclear pleomorphism, vascular hyalinisation, cystic change) ○ No mitoses ○ Uniformly spindled Schwann cells with Antoni A (Hypercellular) and Antoni B (Hypocellular: myxoid, vacuolated) regions - IHC ○ POS = S100, Sox10, type IV collagen, CD34 (endothelial marker) ○ NEG = keratin negative. EMA, CK, ER/PR, SSTR2a
Describe the history, examination and work up for vestibular schwannoma.
Consultation
- History ○ Age 30-50yrs ○ Common presentation (Cranial nerve VIII) § Gradual sensorineural hearing loss □ Preferential loss of high-frequencies □ Usually unilateral □ May occasionally be sudden (assume obstructive ischaemia) § Tinnitis § Impaired balance § Incidental finding ○ Ear pain ○ Uncommon presentations (CN V and VII symptoms) § Facial weakness § Facial numbness § Taste disturbance ○ PMHx: § NF2 syndrome □ Previous schwannoma □ Meningioma □ Neurofibromatous findings (neurofibroma, café-au-lait spot) § Previous radiotherapy ○ Family Hx: § NF2 syndrome (associated with malignant Schannoma) □ Can be bilateral - Examination ○ General appearance ○ Detailed cranial nerve examination § CN VIII □ Weber & Rinne's tests (assess sensorineural vs conductive hearing) □ Formal audiometry □ Balance assessment § Include all other CN (esp facial nerve) □ House Brackmann score - Speech discrimination ○ Hearing and able to exclude background noise
Investigations
- MRI Brain/Base of Skull ○ Enhancing mass at the internal auditory canal ○ May extend into the CPA +/- contact brainstem - Formal audiometry ○ Non-serviceable hearing
Biopsy is not necessary
Describe the staging for vestibular schwannoma
Describe the evidence for radiotherapy in vestibular schwannoma
- Sherry 2019
○ 11 year follow up of RT for benign CNS pathologies
No cases of radiation secondary malignancy
Prognostic features:
Tumour>10cc worse
Dose >12gy better
Describe the prognosis for vestibular schwannoma.
Transient Swelling 20-60% in first 6 months (rarely at 3-4 years, up to 6 years)
Decrease over years
Follow up with annual MRI
Describe the WHO classification and the molecular grouping for medulloblastoma.
All tumours are WHO G4 regardless of grade/subgroup
1) Classical a. Midline location 2) Desmoplastic/nodular a. Presents in the hemispheres b. Associated with PTCH1 gene (Gorlin syndrome) c. Favourable prognosis 3) Extensive nodularity a. Excellent prognosis 4) Large Cell Anaplastic a. Poor prognosis and aggressive disease course b. High risk of CSF dissemination
Describe the staging and risk grouping for medulloblastoma.
Risk Grouping
Standard Risk
- Age >3 years
- Low residual disease (<1.5cm3)
- Localised disease –> Chang stage M0 (no evidence of dissemination on MR Brain/Spine and LP)
- Classical or nodular/desmoplastic histopathology
High Risk
If does not meet the above criteria
Discuss the management of medulloblastoma
General Principles
- Patients often present with raised ICP ○ Surgical resection is an emergent procedure for decompression - As with other CNS tumours, gross total resection is highly prognostic - Due to the high-risk of CSF seeding, craniospinal irradiation is standard of care
Chemotherapy involves alternating cycles of:
1) Cisplatin/lomustine/vincristine
2) Cyclophosphamide vincristine
Concurrent vincristine with RT (weekly)
The approach to adults is essentially unchanged
- Even standard risk patients receive the higher CSI dose of 30-36Gy
Describe the prognosis and follow up for medulloblastoma.
Post-Treatment Surveillance
- Clinical review every three months for the first two years ○ History and Examination ○ MR Brain + Whole Spine - Clinical review every six months for years 2-5 ○ History and Examination ○ MR Brain + Whole Spine - Clinical review annually thereafter ○ History and Examination ○ MR Brain + Whole Spine - Late Effects ○ Endocrine monitoring § Pituitary dysfunction § Thyroid dysfunction § Gonadal dysfunction ○ Cataracts ○ Intelligence ○ Cerebrovascular disease ○ Second malignancy
Describe the pathogenesis and pathology for CNS embryonal tumours
Histogenesis
Poorly differentiated neuroepithelial tumours originating from the germinal matrix of the neural tube
May differentiate along multiple cell lines
- Pure neuronal –> neuroblastoma
- Mixed neuronal and ganglion –> ganglioneuroblastoma
- Retina –> retinoblastoma
WHO CNS Tumours (5th Ed, 2021)
Note that CNS Embryonal Tumour, NOS is a catch-all for those which do not meet other classifications
Molecularly defined:
- Embryonal tumour with multilayered rosettes –> C19MC-altered
- Neuroblastoma –> FOXR2-activated
- CNS Tumour with BCOR duplication
Histopathology
All embryonal tumours are WHO G4 by definition
CNS Embryonal NOS | Supratentorial PNET
- As per medulloblastoma
○ Only distinction is the supratentorial location
- Cannot have molecular features of another category
Atypical Teratoid/Rhabdoid Tumour (AT/RT)
- Microscopic
○ Small blue round cell tumour with appearances similar to rhabdoid cells
○ Necrosis and mitoses are common
- Immunohistochemistry
○ POS = vimentin, CK, CD99
○ NEG = germ cell markers, loss of INI1
- Molecular
○ SMARCB1 inactivation
Embryonal tumour with multilayered rosettes
- Microscopic
○ Multilayered small round blue cells with pseudostratified neuroepithelium around a central lumen
○ Nuclei are positioned away from the lumen
○ High Ki67
- Immunohistochemistry
○ POS = vimentin, CK, CD99, INI1
○ NEG = germ cell markers, synaptophysin
- Molecular
○ Amplification of C19MC
Neuroblastoma
- Microscopic
○ Highly cellular tumour
○ Small cells with hyperchromatic nuclei and a clear halo
○ Vascular pseuodorosettes and Homer Wright rosettes are seen
- Immunohistochemistry
○ POS = GFAP, synaptophysin
○ NEG = CD99
- Molecular
○ FOXR2 activation
Describe the clinical presentation and work up for an AVM
Clinical presentation:
* Intracerebral haemorrhage (most common)
* Seizure
* Headache
* Focal neurological deficit
* Incidental
Work-up
* CT brain to rule out cerebral bleeding
* Angiography
○ CT angiography for vasculature and Spetzler-Martin score
MRI angiography for relationship to normal brain structures and functional MRI to determine eloquent areas
Describe the side effects from radiotherapy for AVMs
Toxicities from SRS
* Early side effects includes seizures, nausea, vomiting and headache
* Delayed side effects include seizures, radio necrosis, oedema, venous congestion, cyst formation
* Risk of symptomatic adverse effects are 7% and 3% for permanent late effects (relationship to dose and location)
* Dose (V12) and Higher PIE associated with higher likelihood of injury
The risk of intracranial tumors or malignancies resulting from SRS is controversial; reported risks for radiation-induced tumorigenesis range from 0.0% to 2.6% at 15-year follow-up, and 0.9% for malignant transformation of benign tumors.
