Medical Treatment for High Grade Gliomas – An Overview

1. Medical Treatment for High Grade Gliomas – An Overview Dr Daphne Tsoi MBBS MSc FRACP Medical Oncologist Royal Perth Hospital SJOG Hospitals Subiaco, Murdoch

2. 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)

3. 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)

4. Glial cells http://ovidsp.com/spb/ovidweb.cgi Chamberlain MC et al. West J Med. 1998;168:114-120.

5. Glioma: Grading Chamberlain MC, et al. West J Med. 1998;168:114-120.

6. Median Survival: Importance of Histologic Grading • Pathologic diagnosis is crucial in determining treatment and prognosis 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.

7. 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)

8. Presentation • Headache • Seizure • Motor weakness/speech deficit • Altered personality • Loss of memory/cognition • Dizziness

9. MRI Biopsy Investigations

10. Features of Glioblastoma Multiforme • Rapid progression • Enhancing tumor • Surrounding edema • Contains tumour • ~ 5% multifocal

11. Treatment • Surgery • Radiotherapy • Chemotherapy

12. 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)

13. Temozolomide – Side Effects • Tiredness / fatigue • Nausea • Constipation (from anti-emetics) • Low blood counts – red/white/platelets • Particularly lymphocytes (risk of Pneumocystis carinii pneumonia) • Rash

14. Standard Treatment for GBM • Radiotherapy concurrently with Temozolomide followed by 6 months of Temozolomide

15. Phase III Study: New GBM Radiation ± Temozolomide Concomitant TMZ + RT* Adjuvant TMZ R 0 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.

16. Phase III Study: New GBM Radiation ± Temozolomide 100 Median Survival 90 RT + temozolomide: 14.6 months 80 RT alone: 12.1 months 70 60 50 Probability of OS (%) 40 30 20 10 0 0 6 12 18 24 30 36 42 Months • 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.

17. Temozolomide - indications • Recurrence of anaplastic astrocytoma and glioblastoma multiforme

18. 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.

19. 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

20. 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

21. Further Treatment for Progression • Surgery • Radiation (stereotactic radio-surgery) • 2nd line chemotherapy

22. 2nd line Chemotherapy • No consensus • Low dose temozolomide (+/- procarbazine) • Carboplatin • BCNU/CCNU • Bevacizumab (+/- Irinotecan) • Clinical trials if possible

23. Glioblastoma: A Highly Vascular Tumour • The vascular network formed in GBM is abnormal • vessels are dilated, tortuous, disorganised, highly leaky

24. Angiogenesis

25. Avastin (Bevacizumab) – mechanism of action

26. Bevacizumab: Anti-VEGF Antibody • After 4 cycles bev/irinotecan • Recurrent GBM at baseline • Vredenburgh JJ, et al. J Clin Oncol. 2007;25:4722-4729. • National Comprehensive Cancer Network guideline: CNS cancers (V.1.2008)

27. 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

28. New drugs that failed to impress • Erlotinib • Enzastaurin • Edotecarin • Cediranib

29. 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

30. 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

31. Approach to Patients • Financial / income source • Family / dependents • Transfers to frequent clinic visits • Home modifications / hire equipments • Carers • burn-out, financial source

32. 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

33. 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