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High Grade Gliomas : Case Presentation and Summary of Evidence for Radiation Therapy Management

High Grade Gliomas : Case Presentation and Summary of Evidence for Radiation Therapy Management. Jonathan Klein PGY3, Radiation Oncology University of Toronto. Case #1. Mr. A 64M presents to ER with two weeks of dizziness and “things on my left side look funny”.

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High Grade Gliomas : Case Presentation and Summary of Evidence for Radiation Therapy Management

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  1. High Grade Gliomas: Case Presentation and Summary of Evidence for Radiation Therapy Management Jonathan Klein PGY3, Radiation Oncology University of Toronto

  2. Case #1 • Mr. A • 64M presents to ER with two weeks of dizziness and “things on my left side look funny”. • Feels he veers to the left side when walking.

  3. Workup • History • Physical

  4. Workup • History • Characterize symptoms: OPQRST • General: headache, seizures, N/V, syncope, cognitive Δ • Focal: weakness, sensory loss, aphasia, visual Δ • Family history • PMHx/Meds/allergies • Physical

  5. Workup • History • Characterize symptoms - OPQRST • General: headache, seizures, N/V, syncope, cognitive Δ • Focal: weakness, sensory loss, aphasia, visual Δ • Family history • PMHx/Meds/allergies • Physical • CNS: GCS, CNII-XII, gait, strength, DTRs, Babinski • Screening CVS, lung, abdomen exam

  6. Imaging • MRI with gadolinium is preferred modality Relevant imaging findings for contouring • T1 with gadolinium: enhancing cavity • T2/FLAIR: edema and enhancement

  7. Workup

  8. Imaging

  9. Histology • 4 criteria (AMEN) : • nuclear Atypia • Mitosis • Endothelial proliferation • Necrosis # Criteria 0 1* 2 3-4 Grade I II III IV *1 criterion = atypia for Grade II

  10. Staging • AJCC TNM Staging System not used

  11. Staging • GBM can be primary or secondary (10%)

  12. Prognosis • Prognosis by classification • Oligodendroglial component is positive prognostic factor

  13. Prognosis • Curran, JNCI, 1993 • Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma • 3 RTOG studies testing RT +/- Chemo • Results • <50yo: histology most important prognostic factor • >50yo: KPS most important prognostic factor • Mental status differentitated poor KPS group • Conclusion: Older and poor KPS do worse Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.

  14. Lamont ED, Christakis NA. Survival estimates in advanced cancer. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013.

  15. Prognosis • By recursive partitioning analysis (RPA) Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.

  16. Management • Referred to Neurosurgery • What should they do?

  17. Surgery • NORCTs have studied • Surgery vs not • Total vs subtotal resection • Standard: Attempt at gross resection • Not always possible • Location • Critical structures

  18. Surgery • Simpson, Int J RadiatOncolBiol Phys, 1993 • Review of 3 RTOG trials: 643 patients with GBM • Improved survival with more resection Surgery: Biopsy Partial Total % of patients: 17% 64% 19% MS (months): 6.6 10.4 11.3 Simpson JR et al. Int J RadiatOncolBiol Phys. 1993 May 20;26(2):239-44.

  19. Surgery • Lacroix, J Neurosurg, 2001 • Retrospective review, 416 patients with GBM • Improved survival with total resection (>98%) Surgery Partial (<98%) Total (>98%) MS (months) 8.8 13 • Predictors of survival • Age, KPS, extent of resection, degree of necrosis, pre-op MRI enhancement Lacroix M, et al. J Neurosurg. 2001 Aug;95(2):190-8.

  20. Back to Case • Patient taken to OR • Resection attempted, but 2.4cm segment of tumour remains

  21. Management • Referred to Radiation Oncology • What should we do?

  22. Radiation • Walker, J Neurosurg, 1978 • Phase III, 303 patients with anaplasticglioma • Surgery then randomized to: RT vs BCNU vsRT+BCNU vsObs MS (mo) 8.1 4.2 8 3.2 • Showed no benefit from chemo • RT = 50Gy WBRT + 10 Gy boost • BCNU = carmustine 80mg/m2 x days 1-3 every 6-8 weeks Walker MD et al. J Neurosurg. 1978 Sep;49(3):333-43.

  23. Radiation • Walker, Int J RadiatOncolBiol Phys, 1979 • Meta-analysis of 3 RCTs • 621 patients with Gr. III/IV glioma • Surgery then: Obsvs45Gy vs 50Gy vs55Gyvs60Gy MS (mo) 4 3 7 9 10 • Showed benefit for RT and dose-response relationship Walker MD, et al.Int J RadiatOncolBiol Phys. 1979 Oct;5(10):1725-31.

  24. Radiation • Walker, NEJM, 1980 • Phase III, 358 patients with anaplasticglioma • Surgery then randomized to RT vs RT+BCNU vsRT+SemusvsSemus • Results • No arm significant difference between arms • Conclusion: RT alone remains standard Walker MD et al. N Engl J Med. 1980 Dec 4;303(23):1323-9.

  25. Radiation • Kristiansen, Cancer, 1981 • Phase III, 118 patients with Gr III/IV astrocytoma • Surgery then randomized to: RT vsRT+BleomycinvsObs MS (mo) 10.810.8 5.2 • Showed no benefit from chemo • RT = 45Gy WBRT • Bleomycin = carmustine 180mg 3/week, 1hr prior to RT, weeks 1,2,4,5 Kristiansen K et al. Cancer. 1981 Feb 15;47(4):649-52.

  26. Radiation • Laperriere, Radiotherapy + Oncology, 2002 • Systematic review of 6 RCTs • Confirmed benefit from post-op RT • Recommended: • Young (< 70 yo) • Treat enhancing tumour + margin (e.g. 2 cm) • Dose: 50-60 Gy in 1.8-2Gy per fraction • Older with good KPS • Can use short course RT • Older with poor KPS • Can consider supportive care alone • This review did not recommend addition of chemo Laperierre N et al. RadiotherOncol. 2002 Sep;64(3):259-73.

  27. Radiation • So RT is good… • What dose should we give?

  28. Radiation • Nelson, NCI Monog., 1988  RTOG 74-01 • 626 patients with Gr III/IV astrocytoma • Randomized to: 60Gy* vs 60+10 vs 60+B** vs60+C+D*** • Median survival: 60Gy: 9.3 months vs 60+10Gy: 8.2 months • Subsets: >60 yo: RT+chemodid not improve survival 40-60 yo: RT+BCNU = 23% 2 year survival vs RT alone =8% *60 Gy WBRT **60 Gy + carmustine (=BCNU) ***60 Gy + semustine + dacarbazine Nelson DF et al. NCI Monogr. 1988;(6):279-84.

  29. Radiation • Bleehen, BJC, 1991 • 474 patients with Gr III/IV astrocytoma • Surgery, no chemo, then randomized to: 45/20* vs 40/20+20/10** MS (mo) 9 12 • 60/30 improved survival with similar toxicity *=45/20 to “all known and potential tumour” **=40/20 as above, then 20/10 to “defined tumour volume together with a 1 cm margin around it.” Bleehen NM, Stenning SP. Br J Cancer. 1991 Oct;64(4):769-74.

  30. Radiation • Scott, Int J RadiatOncolBiol Phys, 1998 RTOG 9006 • 712 patients with Gr III/IV glioma • Randomized to carmustine+ : 60/30 vs 72/60 (1.2 Gy/# BID) MS (mo) 13.2 11.2 • 72/60 not better for any subgroup • 60/30 was better for all patients < 50 yo Scott CB et al. Int J RadiatOncolBiol Phys. 1998 Jan 1;40(1):51-5.

  31. Radiation • Should we use SRS?

  32. ?SRS? • Early series showed promising survival w/SRS • Buatti et al., 1995 • Int J RadiatOncolBiol Phys. 1995 Apr 30;32(1):205-10. • Int J RadiatOncolBiol Phys. 1995 Jul 15;32(4):1161-6. • Gannett et al., 1995 • Int J RadiatOncolBiol Phys. 1995 Sep 30;33(2):461-8. • Masciopinto et al., 1995 • J Neurosurg. 1995 Apr;82(4):530-5.

  33. ?SRS? • RTOG 9305 Souhami, Int J RadiatOncolBiol Phys, 2004 • RCT, 203 GBM pts all received 60Gy EBRT +carmustine • Randomized to upfront SRS vsno SRS (15-24Gy) • Median survival not different: 13.5 v 13.6 months • SRS not currently standard for GBM Souhami et al. Int J RadiatOncolBiol Phys 2004;60:853-860.

  34. Management • Referred to Medical Oncology • Should the patient have chemotherapy?

  35. Chemotherapy • Stewart, Lancet, 2002 • Metanalysis, 12 RCTs, 3004 patients • Hazard ratio for death = 0.85 • Chemotherapy group did better Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.

  36. Chemotherapy Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.

  37. Chemotherapy • Stupp, JCO, 2002 • Phase II, 64 patients with primary GBM • RT + Temozolomide RT: 60Gy/30 TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cycles • Median survival = 16 months • OS: 1 yr = 58% ; 2 yr = 31% • Grade ≥3 toxicity = 6% • Good prognosis subsets: • ≤50 years old • patients who had debulking surgery Stupp R et al. ClinOncol. 2002 Mar 1;20(5):1375-82.

  38. WAKE UP!!!! Important Study Alert

  39. EORTC 26981 • Stupp, NEJM, 2005 (2009 Lancet Oncology update) • Phase III, 573 patients <70 yo with primary GBM • Randomized to • RT alone vsStuppPhase II protocol: • RT: 60Gy/30 • TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cycles Stupp R et al. N Engl J Med. 2005 Mar 10;352(10):987-96.

  40. EORTC 26981 • 88% of patients received full course ChemoRT • 40% of patients completed adjuvant Chemo • Grade ≥3 toxicity = 4%

  41. EORTC 26981 RT ChemoRT MS (med) 12.1 mo 14.6 mo PFS (med) 5 mo 6.9 mo OS: 2 yr 10% 26% 4 yr 3% 12% 5 yr 2% 10%

  42. EORTC 26981 • Overall survival curve Stupp R et al. N Engl J Med. 2005 Mar 10;352(10):987-96.

  43. EORTC 26981 Subgroups: Methylated MGMT Unmethylated Stupp R et al. N Engl J Med. 2005 Mar 10;352(10):987-96.

  44. EORTC 26981 • Improved response for patients with methylated MGMT gene • Epigenetic silencing of MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.

  45. MGMT Methylation • Hegi, NEJM, 2005 • 206 patients from EORTC 26891 trial assessed for MGMT methylation status • MethylMGMT found in 45% • Results • MethylMGMT was a favorable prognostic factor: HR =0.45 • For methylMGMT TMZ better than RT: 21.7 vs 15.3 months • For unmethylMGMT, no statistically significant difference • Conclusions • GBM with methylMGMT benefited from TMZ, but unmethylMGMT promoter did not benefit Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.

  46. Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.

  47. RTOG 0525 • Gilbert, ASCO, 2011 • RCT, 833 pts > 60 yo with GBM/Gliosarcoma • Test dose-dense TMZ regimen • Randomized to EORTC 26981 RT+TMZ protocol vs 60Gy/30 + daily TMZ followed by 21d adjuvant chemo Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

  48. RTOG 0525 Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

  49. RTOG 0525 Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

  50. RTOG 0525 • Improved response for patients with methylated MGMT continued • No difference in PFS or OS between study arms for either methylated or non-methylated subgroups

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