1. management of low grade gliomas robert r johnson, m.d. department of radiation oncology july 15, 2010

2. table of contents • background • pathological classification • molecular features • presentation • treatment • technique

3. background • slow-growing tumors • 10% of primary brain tumors in adults • 20-25% of gliomas • 2000 cases/year in u.s. • divided into: • pilocytic astrocytoma • diffusely infiltrating glioma

4. background • pilocytic astrocytoma • more common in children (jpa) • cerebellum • do occur in young adults • low grade • even after recurrence • cured by surgery • > 90% long-term survival after complete resection • 70-80% after incomplete resection

5. background • diffusely infiltrating glioma • 3rd-4th decade of life • 20 years earlier than high-grade gliomas • slow growing but eventually fatal • 80% transform to high-grade

6. histological subtypes • astrocytoma – 50% • fibrillary • protoplasmic • gemistocytic • behaves more like anaplastic astrocytoma • oligodendroglioma – 28% • oligoastrocytoma – 22%

7. prognosis • 42,688 patients diagnosed between 1995-2006 • astrocytoma • 5-year survival 47% • oligoastrocytoma • 5-year survival 57% • oligodendroglioma • 5-year survival 79% http://cbtrus.org/2010-NPCR-SEER/Table23.pdf

8. pathological classification • who grading • I: slow-growing, non-malignant • pilocytic astrocytoma • II: relatively slow-growing, can recur as higher-grade tumor • astrocytoma, oligodendroglioma, oligoastrocytoma

9. pathological classification • stanne-mayo classification • based on 4 criteria: • nuclear atypia • mitoses • endothelial proliferation • necrosis • grade I: 0/4 • pilocyticastrocytoma • grade II: 1/4 • astrocytoma, oligodendroglioma, oligoastrocytoma

10. molecular features • ploidy • better prognosis with diploid relative to aneuploid • proliferation • better prognosis with ki-67 index < 3% • co-deletion of 1p and 19q

11. co-deletion of 1p/19q • found in 70-75% oligodendroglioma • 35-40% oligoastrocytoma • rarely in pure astrocytoma • favorable prognosis • 139 samples of 80 patients with low-grade glioma • median survival: • 15 years with co-deletion • 5 years without • more likely to respond to chemotherapy

12. presentation

13. imaging • pilocytic astrocytoma • well-circumscribed • cystic • contrast-enhancing • vasogenic edema is rare

14. imaging • diffusely infiltrating glioma • ct • diffuse , non-enhancing • calcifications with oligodendroglioma

15. imaging • diffusely infiltrating glioma • mri • hypointense and non-enhancing on t1 • hyperintense on t2

16. treatment • pilocytic astrocytoma • more amenable to total resection • well-circumscribed • close follow-up after surgery • 70-80% long-term survival after subtotal resection • transformation to high-grade glioma very rare • adjuvant radiotherapy not typically offered • 50-55 gy for recurrent/unresectable disease

17. pilocytic astrocytoma • 20 adults from ncctg 86-72-51 followed prospectively • 3 patients irradiated after biopsy • 50.4 gy • 17 patients observed after subtotal or gross total resection brown et al. ijrobp 2004;58:1153-1160.

18. pilocytic astrocytoma

19. pilocytic astrocytoma

20. pilocytic astrocytoma • excellent prognosis irrespective of treatment modality • distinctly different behavior from diffusely infiltrating gliomas • 10-year survival 95% vs 17% in ncctg 86-72-51

21. diffusely infiltrating glioma • surgery • radiation • chemotherapy

22. surgery • usually performed first • establish diagnosis • tumor debulking • total resection uncommon due to diffuse infiltration • rarely curative • retrospective data suggests benefit for total/subtotal resection • most accurate pathological assessment

23. radiation • 3 randomized trials have assessed timing and dose of adjuvant radiotherapy • eortc 22485 • immediate vs delayed • eortc 22484 • 45 gy vs 59.4 gy • ncctg 86-72-51 • 50.4 gy vs 64.8 gy

24. eortc 22485 • 314 patients with resected or biopsied low-grade glioma • inclusion criteria • supratentorial low-grade glioma • 16-65 years • karnofsky > 60 • randomized to 54 gy/30 fractions vs observation and radiation at progression van den bent et al. lancet 2005;366:985-990.

25. eortc 22485

26. eortc 22485

27. eortc 22485 • 65% patients in observation group treated with radiation at recurrence • median survival after recurrence 3.4 years vs 1.0 years • favoring observation group • ~70% histologically confirmed recurrences high-grade • no quality of life study

28. eortc 22485 • conclusions • no difference in overall survival for early vs delayed radiotherapy • longer time to recurrence with early rt • unknown if rt or recurrence is worse for quality of life • seizures at 1 year • 25% with rt, 41% with observation • P = 0.03

29. eortc 22484 • 379 patients with resected or biopsied low-grade glioma • inclusion criteria • supratentorial low-grade glioma • incompletely resected pilocytic astrocytoma • 16-65 years • karnofsky > 60 • randomized to 45 gy/25 fractions vs 59.4 gy/33 fractions karim et al. ijrobp 1996; 36:549-556.

30. eortc 22484 5 year os 58% vs 59% 5 year pfs 47% vs 50%

31. eortc 22484 • interesting subgroup analyses • extent of resection • size of tumor

32. eortc 22484 • outcome analyzed by extent of resection • significant improvements in os and pfs with more extensive surgery • no dose response

33. eortc 22484

34. eortc 22484

35. eortc 22484 • acute toxicity more common in high-dose arm • 15% vs 8% required > 1 week break • no difference in late toxicity • no radionecrosis in either arm

36. eortc 22484 • conclusions • no dose response above 45 gy • prognostic importance of • extent of resection • tumor size • histology • astrocytoma worst • neurological deficits

37. eortc 22484/22485 • poor prognostic variables • age > 40 • tumor > 6 cm • tumor crossing midline • astrocytoma histology • neurological deficits • 0-2 = low risk, median survival 7.7 years • > 3 = high risk, median survival 3.2 years

38. ncctg 86-72-51 • 203 patients with resected or biopsied low-grade glioma • inclusion criteria • supratentorial low-grade glioma • pilocytic astrocytoma excluded • > 18 years • randomized to 50.4 gy/28 fractions vs 64.8 gy/36 fractions shaw et al. jco 2002;20:2267-2276.

39. ncctg 86-72-51

40. ncctg 86-72-51 • toxicity • grade 3-5 toxicity seen in 13% patients on both arms • grade 3-5 severe toxicity • radionecrosis and encephalitis • 5% vs 2.5% at 2 years • more common with high dose

41. ncctg-86-72-51 • conclusions • no dose response above 50.4 gy • higher severe toxicity with high dose • prognostic importance of • extent of resection • tumor size • histology • astrocytoma worst • age

42. radiation • conclusions • no difference in survival with post-op rt vs rt at progression • improved pfs • no dose response above 45-50 gy • increased toxicity with higher dose • age, histology, tumor size, extent of resection all predict outcome

43. chemotherapy • no established role • 2 trials reported encouraging results with ccnu • neither significant • pcv and temozolomide also been tested

44. ccnu • swog • randomized 60 patients with incompletely excised low-grade glioma to 55 gy +/- concurrent ccnu • median survival favored chemo arm • 7.4 years vs 4.5 years • not significant • prematurely closed due to slow accrual • possible benefit if adequately powered eyre et al. j neurosurg. 1993.

45. pcv • rtog 98-02 • 3 armed trial • arm 1: low risk (age < 40, gross total resection) • observe • arms 2 and 3: high risk (age > 40, subtotal resection or biopsy) • randomized to 54 gy +/- 6 cycles adjuvant pcv • procarbazine, ccnu, vincristine

46. pcv • rtog 98-02 cont’d • preliminary results presented at asco in 2006