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Medical Treatment for High Grade Gliomas – An Overview
Dr Daphne TsoiMBBS MSc FRACP
Medical OncologistRoyal Perth HospitalSJOG Hospitals Subiaco, Murdoch
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Incidence
~ 1400 cases of primary brain tumour diagnosed in Australia each year
Primary CNS cancers – 7/100,000/year (Colon cancer – 60/100,000/year) 14th most common cancer in Australia Highest in terms of average year lost (12
years per patient)
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Average years of life lost for patients in Australia and the UK, 2001, by cancer type Sources: Burnet et al , Australian Institute of Health and Welfare (AIHW)
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Glial cells
http://ovidsp.com/spb/ovidweb.cgi
Classification Characteristics
Astrocytes Star-shaped cells
Astrocytomas
Oligodendrocytes Possess few dendrites
Oligodendrogliomas
Ependymal cells Line the ventricles
Ependymomas
Chamberlain MC et al. West J Med. 1998;168:114-120.
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Glioma: Grading
Grade Tumor Type Glioma %
I/II Well-differentiated (low-grade) astrocytoma
15 to 20
III Anaplastic astrocytoma 30 to 35
IV Glioblastoma multiforme 40 to 50
Chamberlain MC, et al. West J Med. 1998;168:114-120.
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Median Survival: Importance of Histologic Grading
Pathologic diagnosis is crucial in determining treatment and prognosis
Tumor TypeMedian
Survival, years
Low-grade oligodendroglioma 4-10
Low-grade astrocytoma 5
Anaplastic oligodendroglioma 3-4
Anaplastic astrocytoma 3
Glioblastoma multiforme <1
1Bruce J. Available at: http://www.emedicine.com.2Hariharan S. Available at: http://www.emedicine.com.3DeAngelis LM. N Engl J Med. 2001;344:114-123.
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Primary vs Secondary GBM
Primary GBM Develops de novo from
glial cells Accounts for > 90% of
biopsied or resected cases Clinical history of 6 months Occurs in older patients
(median age: 60 years)
Secondary GBM Develops from low-grade or
anaplastic astrocytoma ~ 70% of lower grade
gliomas develop into advanced disease within 5-10 years of diagnosis
Comprises < 5% of GBM cases Occurs in younger patients
(median age: 45 years)
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Presentation
Headache Seizure Motor weakness/speech deficit Altered personality Loss of memory/cognition Dizziness
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Investigations
MRI Biopsy
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Features of Glioblastoma Multiforme Rapid progression Enhancing tumor Surrounding edema
Contains tumour
~ 5% multifocal
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Treatment
Surgery
Radiotherapy
Chemotherapy
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Temozolomide(Temodal)
Methylating agent
Principal mechanism is causing damage to DNA of tumour cell, leading to cell death
Taken orally, rapidly absorbed Penetrates the blood-brain barrier Dose according to ‘body surface area’
(height/weight)
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Temozolomide – Side Effects
Tiredness / fatigue Nausea Constipation (from anti-emetics) Low blood counts – red/white/platelets
Particularly lymphocytes (risk of Pneumocystis carinii pneumonia)
Rash
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Standard Treatment for GBM
Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide
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Focal RT daily—30 x 200 cGy;total dose: 60 Gy
TMZ 75 mg/m2 PO QD for 6 weeks, then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles
Concomitant TMZ + RT*
Adjuvant TMZ
Wks6 10 14 18 22 26 30
RT Alone
R0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Phase III Study: New GBM Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996.
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Phase III Study: New GBM Radiation ± Temozolomide
Phase III study (N = 573): 2-year OS rate improved from 10.4% with RT alone to 26.5% with temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996.
100908070605040302010
00 6 12 18 24 30 36 42
Pro
bab
ility
of
OS
(%
)
Months
Median SurvivalRT + temozolomide: 14.6 monthsRT alone: 12.1 months
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Temozolomide - indications
Recurrence of anaplastic astrocytoma and glioblastoma multiforme
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Surgical Implantation of Chemotherapy Wafers: Gliadel®
Gliadel is a trademark of Guilford Pharmaceuticals.
BCNU-infused wafers implanted to tumour
bed at time of surgery chemotherapy released
to surrounding brain tissue over a period of 2 to 3 weeks
Clinical trials showed survival benefit
PBS difficulties
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Progressive Disease
Challenges of diagnosing progressive disease Pseudo-progression increase in enhancement without tumor progression Especially after chemo-radiation First post-RT MR scan should not be used for treatment
decisions ‘Treat the patient not the scan’
Techniques to help distinguish - MRS (spectroscopy), PET scans, SPECT scans
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Pseudoprogression: The Index Case
Male, gross total resection for anaplastic ependymoma in August ’97, no neurological deficits, pre-RT MRI:
Deterioration during/after radiation therapy (10/97-12/97, 65 Gy)
Thereafter slight clinical improvement for more than 1 year
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Further Treatment for Progression Surgery
Radiation (stereotactic radio-surgery)
2nd line chemotherapy
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2nd line Chemotherapy
No consensus Low dose temozolomide (+/- procarbazine) Carboplatin BCNU/CCNU Bevacizumab (+/- Irinotecan) Clinical trials if possible
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Glioblastoma: A Highly Vascular Tumour The vascular network formed in GBM is
abnormal
vessels are dilated, tortuous, disorganised, highly leaky
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Angiogenesis
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Avastin (Bevacizumab) – mechanism of action
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Bevacizumab: Anti-VEGF Antibody
1. Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729.2. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)
Recurrent GBM at baseline
After 4 cycles bev/irinotecan
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Bevacizumab for recurrent glioblastoma Unanswered questions Phase II results only ?changes on MRI reflect tumour shrinkage,
or reduced swelling from stopping leaking blood vessels
Concerns about rapid progression upon stopping treatment
Phase III trials underway
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New drugs that failed to impress Erlotinib Enzastaurin Edotecarin Cediranib
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Approach to Patients
Complex challenges specific to brain tumour patients
Disease Physical impairment – weakness, poor mobility,
speech, vision Cognitive impairment – memory, insight,
judgment, personality, disinhibition Depression Seizures
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Approach to Patients
Polypharmacy Steroids
weight gain, elevated BSL, proximal myopathy, emotional lability, reversal of sleep/wake cycle
Anticonvulsants Antiemetics / aperients / antibiotics Anticoagulants Medications for other medical conditions ?compliance
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Approach to Patients
Financial / income source Family / dependents Transfers to frequent clinic visits Home modifications / hire equipments Carers
burn-out, financial source
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Approach to Patients Multidisciplinary approach
Neurosurgeon Radiation Oncologist Medical Oncologist Rehabilitation team Clinical specialist nurse Neurologist Endocrinologist OT/physio/dietitian/speech pathologist Community/palliative care/hospice Social worker Inpatient team GP
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Conclusions
Management of GBM remains challenging with median survival at 9-15 months
Survival improved by Resection Adjuvant radiotherapy plus concurrent chemotherapy
Temozolomide is component of standard of care Promising investigational directions – the use of targeted therapy Individually tailored therapy based on genetic profile Clinical trials participation should be considered Multidisciplinary team approach is paramount