GBM – Oncological Management

1. GBM – Oncological Management Dr H Lord Consultant Clinical Oncologist

2. Aetiology • Primary: arise de novo, associated with p53 mutation, in elderly. “Part of growing old” • Secondary: arise from pre-existing lower grade glioma. Occur in younger pts

3. Pathways to a GBM

4. GBM - Incidence • 2-3 / 100,000 population in Europe • 50% of parenchymal brain tumours

5. GBM - Presentation • Depends on location – first seizure, dysphasia, cognitive decline, personality change, headache and n&v

6. Ix - MRI

7. MRI features • Solitary • Heterogenous – necrotic centre • Ring enhancing • Surrounding oedema • Midline shift

8. Surgery • Usually performed to gain histology or to debulk maximally – never curative

9. Pathology • Pleomorphic • High mitotic rate • Vascular proliferation • Necrosis

10. Pathology • All histological features present here • Stains positively for GFAP • In future test for MGMT methylation status – positive prognostic and predictive indicator

11. Oncology Management • Depends on fitness - RPA EORTC Class III <50yo KPS > 90 Class IV <50, KPS <90 ≥50, KPS ≥ 90, complete or partial resection and working Class V ≥ 50, KPS ≥ 90, partial resection and not working ≥ 50, KPS ≥ 90, biopsy only ≥ 50, KPS < 70

12. Oncology Mx • Overall Survival Rates depend on fitness and age - RPA Class Median Survival(months) 1 Year Survival(%) RPA Class III 17 70 IV 11 46 V 7 28 Reference:Shawl, EG, Seiferheld, W, Scott, C, et al. (2003). "Re-examining the radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) for glioblastoma multiforme (GBM) patients". International Journal of Radiation Oncology*Biology*Physics 57 (2): S135–6. doi:10.1016/S0360-3016(03)00843-5

13. Radiation + chemo • In RPA Class III pts: Combined Chemo XRT 60Gy in 30# over 6 weeks, daily treatment Mon - Fri TMZ 75mg/m2po daily throughout 1 month off – MRI - if no PD and well, to continue to adjuvant: TMZ 150mg/m2po d1-5 q28d cycle 1 increasing to TMZ 200mg/m2d1-5 q28d cycle 2-6 if tolerated

14. Requirements and Toxicities • Planning CT • Visit to simulator takes 2 weeks • Start treatment • Fatigue • Hair loss • Nausea • Hepatotoxicity • Mild skin reaction

15. Stupp Trial • Randomised controlled Phase III trial • Newly Dx GBM • 60Gy in 30# vs 60Gy in 30# plus oral Temozolamide (75 mg /m2 per day, 7 days per week from the first to the last day of radiotherapy, followed by six cycles of adjuvant temozolomide 150 to 200 mg /m2 for 5 days during each 28-day cycle.) • The primary end point was overall survival.

16. Trial • 573 patients from 85 centres • The median age 56 years • 84 % patients undergone debulking surgery. Results: • At median follow-up of 28 months: • median survival 14.6 months with radiotherapy plus temozolomide 12.1 months with radiotherapy alone. • Unadjusted HR for death in the radiotherapy-plus-temozolomide group 0.63 (95% CI 0.52 to 0.75; P<0.001 by the log-rank test) • 2 y survival rate 26.5% with radiotherapy plus temozolomide and 10.4% with radiotherapy alone. • Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7% patients

17. Kaplan–Meier Estimates of Overall Survival According to Treatment Group. The hazard ratio for death among patients treated with radiotherapy plus temozolomide, as compared with those who received radiotherapy alone, was 0.63 (95 % CI 0.52 to 0.75; P<0.001).

18. Kaplan–Meier Estimates of Progression-free Survival According to Treatment Group. The hazard ratio for death or disease progression among patients treated with radiotherapy plus temozolomide,as compared with those treated with radiotherapy alone, was 0.54 (95% CI, 0.45 to 0.64; P<0.001).

19. Conclusion • The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit, with minimal additional toxicity. • Rapidly changed practice!

20. 5 year survival data

21. RPA Class IV and V • Consider 60Gy in 30# over 6 weeks alone, without chemo • Or 30Gy in 6 # over 2 weeks, given on alternate days • Or palliative care only

22. Alternatives • Gliadel wafers at time of surgery – carmustine soaked • 2007 NICE recommended Gliadel wafers can be used after removal of ≥90% of a newly diagnosed high grade glioma, and for relapsed GBM. • 2005 Scottish Medicines Consortium approved Gliadel wafers for newly diagnosed high grade glioma, so grade 3 or 4 glioma, alongside surgery and radiotherapy.

23. Future • MGMT status –predictive for efficacy of treatment and is prognostic for overall survival • Methylation of MGMT leads to less DNA repair occurring – so damage caused by radiation and chemo is not repaired and treatment is more effective • Methylated in 44% GBMs – no rationale yet to test, as no proof that unmethylated tumours do not repsond to TMZ.

24. Future • BR14 trial – 4 arm study, Gd 3 tumours; • XRT vs. • XRT + concurrent TMZ vs. • XRT + adjuvant TMZ vs. • XRT + concurrent and adjuvant TMZ • Ideal design, how Stupp should have been done.

25. TMZ • Also being researched as an alternative to XRT in low grade tumours ( BR13) • As an alternative to XRT in elderly pt (>65yo) not fit for concurrent 6 weeks chemo XRT – Elderly Trial EORTC • 40Gy in 15# +/- TMX

26. More Research!!

27. Thank you