4th Annual NCCTG Patient Advocate Symposium Neuro-Oncology

1. 4th Annual NCCTGPatient Advocate SymposiumNeuro-Oncology Paul Brown, MD Associate Professor of Oncology Department of Radiation Oncology Mayo Clinic Rochester, MN

2. �Intermediate� Gratification in My Practice Direct Patient Care Education Research

5. WHY DO RESEARCH MOTIVATION Money Fame Cure Cancer Crazy? Initial Reason� Improve Patient Care Sustaining � Intellectual Curiosity and Larger Impact Patient Care

6. Brain Cancers: Frequency Total new primary 17,500 (1.35%) Total deaths primary 14,000 (2.35%) Total metastatic tumors 300,000 ~30% of patients with cancer develop brain metastases eventually

7. Types of Primary Adult Brain Tumors Gliomas Low Grade Pilocytic Oligodendroglioma Mixed tumors Astrocytomas High Grade Anaplastic Glioblastoma Multiforme Other Primary CNS lymphomas Germ cell tumors Ependymomas Medulloblastoma Pituitary adenomas Meningiomas Chordomas

8. Glioblastoma Multiforme

11. High Grade GliomaBackground Time period 1 Yr Surv 5 Yr Surv McGill Univ 1939-1958 44% 7% Mayo Clinic 1990-1994 47% 10%* Jean Bouchard (McGill Univ. Montreal), Radiation therapy of tumors and diseases of the nervous system, Lea & Febinger 1966. Buckner et al. "A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma." Cancer 92(2): 420-33, 2001. *Values taken from curves

13. Rationale for TMZ Treatment Ease oral administration Favorable toxicity profile Metabolism not significantly influenced by anti-seizure medication Crosses the blood-brain barrier Active agent glioblastoma Synergistic with XRT

15. EORTC/NCIC Phase III GBM Trial: Overall Survival

16. Phase III EORTC/NCIC MGMT Status

17. 0525 Protocol Schema

18. Oligodendroglioma Classified as low-grade or anaplastic Very responsive to treatment: chemotherapy and radiation Prognosis and treatment response strongly correlated with 1p & 19q LOH

19. Impact of 1p 19q LOH

20.

21. Intergroup-9402

22. Intergroup-9402: Results

24. Intergroup-9402: Results 2/3 grade III or IV toxicity with PCV 46% 1p 19q deletion 57% Oligodendrogliomas (p<0.001) 14% Mixed Oligoastrocytoma

26. NCCTG/RTOG N0577 Phase III 1p/19q Co-deleted Anaplastic Oligo Following this theme, NCCTG recently received CTEP approval to lead N0577, a new Phase III Intergroup trial for1p/19q codeleted newly diagnosed anaplastic oligodendroglioma patients. This study was developed in conjunction with ECOG, RTOG, NCIC, EORTC and NCI. This study addresses a potentially practice-changing question, namely whether there is a survival advantage of combined TMZ and RT over RT alone or TMZ alone. Translational correlates include 1p/19q translocation status, MGMT gene promotor hypermethylation, and serial QOL and neurocognitive assessments. Following this theme, NCCTG recently received CTEP approval to lead N0577, a new Phase III Intergroup trial for1p/19q codeleted newly diagnosed anaplastic oligodendroglioma patients. This study was developed in conjunction with ECOG, RTOG, NCIC, EORTC and NCI. This study addresses a potentially practice-changing question, namely whether there is a survival advantage of combined TMZ and RT over RT alone or TMZ alone. Translational correlates include 1p/19q translocation status, MGMT gene promotor hypermethylation, and serial QOL and neurocognitive assessments.

27. Low-Grade Gliomas

28. Low Grade Astrocytomas Types Pilocytic astrocytoma Oligodendroglioma Oligoastrocytoma Low grade astroctyoma Occur in younger patients (20-50 years) Diffuse in nature Slow growing Typically in cerebral hemispheres More likely to present with seizure Responsive to radiation

29. Intergroup 86-72-5250.4 Gy vs 64.8 Gy

31. RTOG 98-02 Intergroup Trial

32. RTOG 98-02 Intergroup Trial 251 high risk patients No benefit progression free or overall survival Toxicity Gr 3+4 67% vs 9%

34. Neurocognitive ToxicityBrain Necrosis

35. Etiology Neurocognitive Deficits Radiation Chemotherapy Surgery Tumor location and progression Medications Nutritional deficiency states Trauma Infections Vascular disease Intrinsic neurologic diseases Metabolic Hydrocephalus

36. Neurocognitive Toxicity Retrospective trials neurocognitive decline in adults Outdated, primitive technique (whole brain RT) Large fraction sizes Unknown denominator Most important- LACK OF BASELINE TESTING

37. Neurocognitive Toxicity NCCTG 86-72-51 corollary study 20 patients (10 Arm 50.4 Gy,10 Arm 64.8 Gy) Underwent extensive battery of neurocognitive tests at baseline (after surgery, before RT), and q18 months up to 5 years

38. Neurocognitive Toxicity No differences in neurocognitive function between the two arms or compared to baseline Results consistent with other prospective trials; tumor progression most important cause of deterioration

39. Brain Metastases

40. Management of Brain Metastases Therapeutic Choices WBRT alone Surgical resection +/- WBRT Single brain metastasis Stereotactic radiosurgery +/- WBRT

42. Gamma Knife

43. Rationale for Radiosurgery Spherical/pseudospherical Most mets <4 cm Generally noninfiltrative Improved local control single lesions--better survival Need higher doses for local control than can be achieved with WBRT

44. JRSOG 9901 Phase III Trial GK 1-4 Brain Mets n=132 � GK + WBRT No neurocognitive or QOL testing

46. N0574 As of 3/1 enrolled 37 pts over 15 months.As of 3/1 enrolled 37 pts over 15 months.