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Medical Treatment for High Grade Gliomas – An Overview Dr Daphne Tsoi MBBS MSc FRACP Medical Oncologist Royal Perth Hospital SJOG Hospitals Subiaco, Murdoch 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) 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) Glial cells Classification Characteristics Astrocytes Star-shaped cells Astrocytomas Oligodendrocytes Possess few dendrites Oligodendrogliomas Ependymal cells Line the ventricles Ependymomas http://ovidsp.com/spb/ovidweb.cgi Chamberlain MC et al. West J Med. 1998;168:114-120. 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. Median Survival: Importance of Histologic Grading Pathologic diagnosis is crucial in determining treatment and prognosis Tumor Type Low-grade oligodendroglioma Low-grade astrocytoma Anaplastic oligodendroglioma Median Survival, years 4-10 5 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. 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 510 years of diagnosis Comprises < 5% of GBM cases Occurs in younger patients (median age: 45 years) Presentation Headache Seizure Motor weakness/speech deficit Altered personality Loss of memory/cognition Dizziness Investigations MRI Biopsy Features of Glioblastoma Multiforme Rapid progression Enhancing tumor Surrounding edema Contains tumour ~ 5% multifocal Treatment Surgery Radiotherapy Chemotherapy 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) Temozolomide – Side Effects Tiredness / fatigue Nausea Constipation (from anti-emetics) Low blood counts – red/white/platelets Particularly lymphocytes (risk of Pneumocystis carinii pneumonia) Rash Standard Treatment for GBM Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide Phase III Study: New GBM Radiation ± Temozolomide Concomitant TMZ + RT* R 0 Adjuvant TMZ 6 10 14 18 22 26 30 Wks RT Alone 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 Focal RT daily—30 x 200 cGy; total dose: 60 Gy *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase. Stupp R, et al. N Engl J Med. 2005;352:987-996. 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 Probability of OS (%) 100 90 80 70 60 50 40 30 20 10 0 Median Survival RT + temozolomide: 14.6 months RT alone: 12.1 months 0 6 12 Stupp R, et al. N Engl J Med. 2005;352:987-996. 18 24 Months 30 36 42 Temozolomide - indications Recurrence of anaplastic astrocytoma and glioblastoma multiforme Surgical Implantation of Chemotherapy Wafers: Gliadel® 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 Gliadel is a trademark of Guilford Pharmaceuticals. 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 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 (10/9712/97, 65 Gy) Thereafter slight clinical improvement for more than 1 year Further Treatment for Progression Surgery Radiation (stereotactic radio-surgery) 2nd line chemotherapy nd 2 line Chemotherapy No consensus Low dose temozolomide (+/- procarbazine) Carboplatin BCNU/CCNU Bevacizumab (+/- Irinotecan) Clinical trials if possible Glioblastoma: A Highly Vascular Tumour The vascular network formed in GBM is abnormal vessels are dilated, tortuous, disorganised, highly leaky Angiogenesis Avastin (Bevacizumab) – mechanism of action Bevacizumab: Anti-VEGF Antibody Recurrent GBM at baseline After 4 cycles bev/irinotecan 1. Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729. 2. National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008) 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 New drugs that failed to impress Erlotinib Enzastaurin Edotecarin Cediranib 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 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 Approach to Patients Financial / income source Family / dependents Transfers to frequent clinic visits Home modifications / hire equipments Carers burn-out, financial source 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 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