Oncological Management of Brain Tumours Anna Maria Shiarli SpR in Clinical Oncology 15 th July 2013
Outline General considerations of Primary Brain Tumours: epidemiology, pathology, presentation. Diagnosis Treatment of Low Grade Gliomas Treatment of High Grade Gliomas Radiotherapy How is it done? Radiotherapy toxicity Brain Metastases
Epidemiology Incidence of 9000 per annum in the UK all CNS tumours ; 58% of which are intracranial tumours 14 new cases per 100 000 each year ( UK) 445 000 new cases worldwide Lifetime risk 1/77 Brain tumours are 1.6% of all cancers On average each GP diagnoses one patient with brain tumour every 7 years. Peak disease incidence 70 80 years
Mortality
Risk Factors Increasing age Higher socio economic status Mostly sporadic AIDS / immunocompromised cerebral lymphoma Ionising radiation (gliomas, meningiomas) Inherited cancer syndromes (neurofibromatosis type 1, von Hippel Lindau symdrome, tuberous sclerosis, Li Faumeni)
Gliomas
Pathology Gliomas most common WHO I low proliferative potential, discrete WHO II Infiltrating, can progress to high grade WHO III High mitotic activity, infiltration, anaplastic WHO IV tumour necrosis, rapid pre/ post operative growth Molecular tests Deletions of 1p and 19q O6 Methylguanine DNA methyltransferase (MGMT) silencing by promoter methylation. Ki 67 proliferative potential Highly infiltrative spread along white matter to other parts of the brain Rarely metastasise outside the CNS CSF spread medulloblastoma, ependymoma Haematogeneous medulloblastoma ( lung, liver, bone)
Clinical presentation Symptoms/signs of increased intracranial pressure : Headache, nausea, vomiting 70% of patients have headache at presentation Principal presenting symptoms: Headache 50% Seizures 20% Cognitive disturbance 12% Motor deficit 8% Speech disturbance 5% Visual disturbance 4% Sensory disturbance 2% Collateral History is important
Investigations/ Diagnosis History ( including from friends and family) Examination MRI location, oedema, necrosis, haemorrhage, mass effect T1 pre and post gadolinium T2 oedema, Fluid attenuated inversion recovery (FLAIR), removes CSF signal. CT contrast if MRI not possible lower sensitivity (temporal, posterior fossa) Magnetic resonance spectroscopy High grade Vs Low grade, primary Vs metastatic Dynamic contrast enhanced perfusion MRI assesses blood flow, increased gliomas (blood brain barrier) PET increased FDG uptake with increased grade Biopsy/ histological diagnosis when possible stereotactic/needle/ Open/ image guided
Treatment General Considerations Acute management Control Symptoms Steroids (8mg Dexamethasone BD) Anti epileptic medication reach therapeutic levels! ( phenytoin, carbamazepine, levetiracetam) Analgesia Psychological support to pt and family clear and honest discussion of poor prognosis. Early involvement of Palliative care and community teams. MDT discussion Neurosurgery, Neuroradiologist, Neuropathologist, Oncology, Clinical Nurse Specialists, Physiotherapy, Rehabilitation
Low Grade Gliomas Prognostic evaluation: EORTC criteria (Pignatti et al. JCO 2002) > 40 years Astrocytoma histology Tumour > 6cm Crossing midline Neurological deficit
Low grade Gliomas No clear consensus for treatment. Usually resection complete histopathologic evaluation, potentially curative, relief of symptoms. Gross tumour resection Vs Subtotal resection Maximal safe resection attempted. With GTR reduced rates of recurrence (Claus EB et al 2005 Cancer). Needs to be balanced against QOL and morbidity from extent of resection.
Low Grade Gliomas Radiotherapy Watch and Wait Vs immediate post op radiotherapy EORTC 22845 trial (van den Bent MJ et al 2005, Lancet) randomised to observation vs post op RT RT improved median progression free survival (5.3 vs 3.4 years) (5yr PFS 55% vs 35%) No significant difference in Overall Survival (68% vs 66%). QOL gained by delaying recurrence needs to be weighted against QOL lost due to potential neurotoxicity of Radiotherapy. Studies show progressive deterioration in some patients from baseline cognitive function after RT (with no tumour progression). Advancing neuroimaging techniques and radiotherapy techniques may limit RT induced neurotoxicity.
Low Grade Gliomas RT or not? Balance risk of recurrence Vs potential toxicity Factors to consider: < 40 years Histology GTR Vs STR How symptomatic is the patient Standard Regime 54 Gy / 30 fractions higher doses tested in RCTs showed increased neurotoxicity with no difference in Overall Survival ( Shaw et al JCO 2002)
High Grade Gliomas Anaplastic types (Anaplastic Astrocytoma) and GBM 85% are GBM late presentation Median age of presentation 64 years Prognostic factors: Age > 50 years Performance status Histology ( Grade III Vs IV) Symptoms/ mental status Resection Gross Total Resection Vs Partial Resection Median Survival Ranges from 60 months in better prognostic groups to 5 months in worst prognostic groups
High Grade Gliomas Treatment Symptoms control Steroids, Anti epileptics, Surgical decompression if increased ICP MDT discussion patient PS, co morbidities, extent and location of tumour. Maximum feasible neurosurgical resection. RT benefits established in late 1970s in patients with anaplastic gliomas increase in MS from 14 weeks to 35 weeks in arms receiving WBRT compared to chemotherapy or observation (Walker MD et al J. Neurosurg 1978) Better MS with increased WBRT doses (Walker et al IJOP 1979). RT regime established to 60Gy in 30 fraction no benefit in OS with higher RT doses)
High Grade Gliomas Treatment EORTC/ NCIC (Stupp et al, NEJM 2005). Phase III trial, 573 glioblastoma patients 84% GTR/ PR, randomised to RT alone Vs RT + Temozolamide (Concurrently + Adjuvant 6 months / 5 days/ every 4 weeks). Improved MS 12.1 mo 14.6 mo Improved 2 yr OS 10.4% 26.5% Improved median PFS 5.0 mo 6.9 mo Only 7% Grade 3 or 4 haematologic toxicity RT with Temozolamide standard of care post op or first line if inoperable, with pts with good PS.
High Grade Gliomas Treatment The STUPP regime : RT in 30 sessions/ fractions 60Gy = Mon Fri 6 weeks Temozolamide concurrent (75mg/m 2 /d) Temozolamide adjuvant 150 200mg/m 2 /d for 5 days every 4 weeks, for 6 months. Temozolamide: Alkylating agent Alkylates/ methylates DNA DNA damage promotes cancer cell death Main side effects Bone marrow suppression Low WBC, Hb/ platelets/ Risk of Neutropenic Sepsis /Nausea/ vomiting/ Fatigue/Constipation
High Grade Gliomas Treatment O6 Methylguanine DNA methyltransferase (MGMT) DNA repair gene encodes for DNA repair protein Methylation of its promoter makes the gene inactive Decreased ability to repair DNA. Tumours with inactive gene more susceptible to chemotherapy. Patients with methylated MGMT promoter in tumour benefit from Temozolamide ( Hegi et al 2004 Clin. Cancer Res)
HGG Treatment / Elderly patients Mean age of HGG 61 years 60% of HGG occuring in patients > 60 years With an ageing population incidence expected to increase. Age is a prognostic factor and survival decreases for each decade > 50 years. Elderly patients under represented in clinical trials. The EORTC/ NCIC 2004 trial recruitment was up to 70 years. Elderly patients may be frail and in view of poorer prognosis in this group treatment of 6 weeks of RT with TMZ may not be justifiable.
HGG Treatment/ Elderly patients Shorter RT regimes can be currently considered some studies 40 Gy in 15 fractions showed equivalence (Roa W et al 2004 JCO) 40 Gy/ 15 fractions; 30 Gy in 10 fractions can be considered depending on PS/ co morbidities. Nordic randomised phase III trial (Malmstrom A et al 2012 Lancet Oncol) compared: TMZ alone Vs 34Gy / 10 fractions Vs 60 Gy/ 30 fractions Similar OS in TMZ and short course RT group > 70 yrs longer survival in TMZ/ short course RT than long course RT high number of patients unable to complete long course RT treatment Patients treated with TMZ and had MGMT methylation had improved OS (9.7 months Vs 6.8 months), good toxicity profile.
HGG Treatment / Elderly patients Short course RT treatment or treatment with TMZ alone can be considered in elderly patients as an alternative to standard treatment. MGMT status assessment important in the elderly to decide treatment. MGMT not routinely available in most centres in the UK Cost 1 000 000 to test 2500 cases in the UK.
HGG Anaplastic oligodendrogliomas Have sensitivity to chemotherapy PVC procarbazine, lomustine, and vincristine Loss of chromosomal arms 1p and 19q in 50% 70% of tumors. 1p deletion is a statistically significant predictor of chemosensitivity ( Cairncross JG 1998. J Natl Cancer Inst) Combined loss 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence free survival after chemotherapy. 1p and 19q loss strongly associated with longer overall survival. Adjuvant PCV chemotherapy after RT increase PFS (23 Vs 13.2 months; P = 0.0018). no change in OS (Van den Bent MJ et al 2006 JCO).
HGG Treatment / Relapse Steroids/ Maximise symptom control If local recurrence consider surgery and chemo. If inoperable and no RT previously RT If diffuse relapse chemotherapy if good performance status If poor performance status best supportive care.
Brain Radiotherapy How is it done? CT scanning with contrast 3 mm slices CT scan images fused/ co registered with T2 MRI images. CT scan allows planning of RT/ MRI allows better identification of tumour.
Brain RT Patient immobilisation at planning CT. Thermoplastic shell/ Perspex shell
Brain RT Reference points marked on shell. Patient placed in position using with laser beams. Opaque markers placed on reference points so that they are seen on the planning CT scan.
Linear Accelerator
Brain RT Contours: GTV : Gross Tumour volume CTV: Clinical Tumour volume (GTV + 15 25 mm) PTV: Planned Tumour volume (CTV + 5mm) OAR: Organs at Risk Lenses, Optic Nerve, Optic Chiasm, Brain Stem Avoid bone Clinical decision about relative risks and benefits if PTV volumes and OAR overlap
Beam arrangement to encompass PTV conformal, tailored to avoid treating normal tissue and OAR reduce toxicity Shielding (Green areas)
-ICRU 50/62 Recommendations PTV 95%- 107% of dose no structures outside PT > 95%
Brain RT Verification by portal images to check whether actual treatment delivered matches what is planned. IMRT Intensity Modulated Radiotherapy Treatment Multiple beams used with variable shielding to improve geometric shape of treatment delivered, achieve more uniformity of dose, reduce toxicity to critical structures.
Brain RT Toxicity Acute: alopecia radiation dermatitis / erythema fatigue increase in oedema with side effects of headache, nausea, vomiting, seizures, increased neurological deficit Impaired short term memory and concentration Increase steroids, anti emetics, anti epileptics Regular on treat review (doctor, MacMillan Radiographer Subside 4 6 weeks post treatment
Brain RT Practical issues Shells can be claustrophobic cutting out part of shells. Shells can increase erythema cutting out parts of shell Transport an every day treatment. Regular blood tests if concurrent Temozolamide Acute deterioration may necessitate stopping RT. Psychological support to patient and family
Brain RT Toxicity Late (3 months 3 years post RT) Memory impairment Increased risk of stroke Visual Loss/ retinopathy/ cataracts Impaired hormone production (hypothalamus, pituitary) Fatigue Hair Loss
Stereotactic radiotherapy Stereotactic radiotherapy (SRt) is used to deliver focused, relatively large doses of radiation to a small, precisely defined target. Gammaknife Cyberknife The role of SRT in the management of patients with HGG is not well established. Addition of an SRT boost prior to standard XRT provides no survival benefit. Possible survival benefit when SRS is performed after XRT
Brain Metastases Occur in 20% 40% of patients with other cancer. Most common lung, breast, melanoma, renal, GI. Solitary tumours should be considered for neurosurgical resection if operable. Post op Radiotherapy may reduce intracranial relapse. SRS may be appropriate in small lesions ( < 3cm) Palliative Whole Brain Radiotherapy Treatment (WBRT) in multiple lesions. RT planning is simpler covers the whole skull, two lateral beams used. Common regimes: 12Gy in 2 fractions; 20Gy in 5 fractions; 30Gy in 10 fractions.
Current Challenges/ Summary Most Primary brain tumours are Gliomas, most of which present at Grades III/ IV and carry a poor prognosis. Age, histology and performance status are prognostic factors for both LGG and HGG. Careful MDT assessment needed as there is a fine line between increasing life expectancy and improving QOL in these patients. Early involvement of palliative care / community support/ honest discussion regarding prognosis/ family support. Acute oncological management to improve symptoms as much as possible. RT +/ chemotherapy as standard treatment STUPP for HGG. Careful assessment in elderly patients and treatment decision. RT induced Toxicity/ Chemo Toxicity Vs Performance status and prognosis. Steroid Use side effects/ patient education/ access for advice.
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