This is a PDF of a presentation given to the Radiation Oncology department at the University of Minnesota in October 2015. This PDF focuses on evaluation, management, and state-of-the-art approach to gliomas from a medical neuro-oncology perspective.

1. Neuro-Oncology for the
Radiation Oncologist
Emil Lou, MD, PhD
Medical Oncology/Neuro-Oncology
Department of Medicine, University of Minnesota
October 7, 2015

2. • In this PDF:
– Focus on Gliomas (see separate PDF for overview
of non-glioma neuro-oncology).

3. General principles of the field of Neuro-Oncology
• Multidisciplinary (neurology, neurosurgery,
radiation oncology, medical oncology,
neuropathology)
• Different radiologic criteria: RANO Criteria (not
RECIST) – primary CNS tumors and CNS
metastases
• Separate pathologic grading criteria: WHO
• Society of Neuro-Oncology (SNO)
• …but research and clinical trials are actively
presented at ASCO and ASTRO meetings as well.

4. Topics in Neuro-Oncology
• Primary tumors of the brain and spinal cord
(adult and pediatric)
• Solid tumor metastases to the brain and spinal
cord
• CNS lymphomas
• Leptomeningeal disease
• Paraneoplastic disorders
• Neurologic complications of cancer and of
cancer-directed therapies

5. Malignant Gliomas
• Annual incidence of malignant brain tumors
– 7.3 cases per 100,000 people
• Glioblastoma multiforme (GBM)
– 54% of all gliomas
– 17% of all brain tumors
– ~ 9500 cases per year in 2004-2007
• GBM incidence
– 1.6-fold higher in men than women
– 4-fold higher when age > 65 compared to those < 55
• GBM survival rates 1995-2007
– 2-year 12.6%, 5-year 4.75%
Available at: http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-3-2011.pdf. Accessed April 12, 2011;
Kohler BA, et al. J Natl Cancer Inst. Published online March 31, 2011. (Slide adapted from CME presentation from Educationl Concepts Group)

6. Clinical Presentation
Glioma Outcome
Project;
Chang, et al.
French Brain Tumor
Database;
Bauchet, et al.
Seizures 32% 26%
Headache 56% 28%
Raised ICP -- 18%
Mental status disorders -- 42%
Memory loss 36% --
Cognitive change 34% --
Personality change 23% --
Sensory-motor deficit -- 50%
Sensory deficit 13% --
Motor deficit 33% --
Visual problems 22% --
Chang SM, et al. JAMA. 2005;293:557-564; Bauchet L, et al. Neuro Oncol. Published online April 2, 2010.

7. • The following slides were downloaded from
NEJM.org and adapted from the case “Case
17-2012 — A 54-Year-Old Man with
Visual-Field Loss and a Mass in the
Brain” published May 31, 2012.

8. Case Records of the
Massachusetts General
Hospital
Case 17-2012 — A 54-Year-Old
Man with Visual-Field Loss and
a Mass in the Brain
Tracy T. Batchelor, M.D., A. Gregory Sorensen, M.D., and David N. Louis, M.D.
N Engl J Med
Volume 366(22):2112-2120
May 31, 2012

9. Summary
• A 54-year-old man had transient
then persistent partial loss of
vision.
• Images of the brain showed two
adjacent masses in the left occipital
and posterior parietal regions.
• A diagnostic procedure was
performed.

10. Initial Imaging Studies and Biopsy Specimen.
Batchelor TT et al. N Engl J Med 2012;366:2112-2120

11. Final Diagnosis
• Glioblastoma, WHO grade IV
of IV, with methylation of the
MGMT promoter.

12. Pathogenesis of GBM Subtypes
Cells of origin Primary GBM subtypes
Classical
Mesenchymal
Neural
Pro-neural
Cancer
stem cell
Sequential genetic
alterations & clonal
evolution
Grade 2/3
Astrocytoma
Secondary GBM

13. Follow-up Imaging Studies and Biopsy Specimen.
Batchelor TT et al. N Engl J Med 2012;366:2112-2120

14. • Glioblastoma is a highly
malignant tumor, with a
median survival of 9 to 14
months and 5-year survival in
less than 10% of patients.

15. Clinical Pearls
• What is the benefit of resection in a suspected case of
glioblastoma?
• Resection of a suspected malignant brain tumor confers
several benefits. A resection specimen provides
representative tumor tissue for histologic diagnosis,
including molecular genetic tests.
• A debulking resection may also reduce mass effect and
intracranial pressure, leading to clinical improvement and
decreased need for medications to reduce brain edema,
e.g., glucocorticoids.
• A prospective, randomized trial showed that, in a subset of
patients with glioblastoma, gross total resection conferred
a survival benefit as compared with subtotal resection.

16. Prospective Trials and Clinical Outcomes by
Resection Status
Stummer W, et al. Neurosurg. 2008;62:564-576; Gorlia T, et al. Lancet Oncol. 2008;9:29-36.
Study Post-surg
Treatment
Median Survival by Extent of
Resection
Hazard Ratio
Complete
(C)
Subtotal
(S)
Biopsy
(B)
Stummer* RT
(n = 243)
16.7 mo 11.8 mo -- 0.54 (0.041-0.71)
(C vs S)
Gorlia† RT
(n = 286)
14.2 mo 11.7 mo 7.9 mo 1.45 (1.22-1.73)
(S vs C)
Gorlia† RT + TMZ
(n = 287)
18.8 mo 13.5 mo 9.4 mo 1.46 (1.22-1.74)
(S vs C)
*Utilized fluorescing agent 5-aminolevulinic acid (5-ALA) with surgery.
†EORTC / NCIC study of adjuvant TMZ.

17. NEJM Morning Report Questions
• Q. What is the standard of care for patients
with newly diagnosed glioblastoma?
• A. Radiation was shown in the 1970s and
1980s to be superior to supportive care or
chemotherapy alone in prolonging survival and
is a critical component of the management of
glioblastoma. Radiation is delivered as focal,
fractionated, external-beam treatments.

18. Standard Therapy for Newly Diagnosed GBM
• Maximal safe surgical resection
• A role for TTF (Optune)? FDA approved this for 1st-line
setting on October 5, 2015
• Radiotherapy
– 60-65 Gy in 30-35 fractions over 6 weeks
– Involved field plus a 2-3 cm margin
• Chemotherapy
– Temozolomide
Concurrent TMZ: 75 mg/m2 daily for 6 weeks
• Adjuvant TMZ: 150-200 mg/m2/day x 5 days, every 28 days for 6-12
months

19. Temozolomide
• Temozolomide is an oral methylating agent that
improves progression-free and overall survival as
compared with radiation alone.
• It is administered concurrently with radiation for
6 weeks (chemoradiation) and then without
radiation for 6 months.
• This regimen is now considered the standard of
care for patients with newly diagnosed
glioblastoma, regardless of the methylation
status of MGMT.

20. Temozolomide (TMZ)
• Imidazotetrazine derivative
– 2nd generation alkylating agent
• 100% oral bioavailability
– No dietary restrictions; food lessens absorption by 9%
– Taking on empty stomach may decrease nausea
• Spontaneous hydrolysis to active agent, MTIC
• Rare cumulative toxicity
– PCP prophylaxis required for 42-day regimen w/RT
• Concentration in high grade glioma tissue 20% that of
blood
Friedman HS, et al. Clin Cancer Res. 2000;6:2585-2597; Temodar prescribing information. Available at:
http://www.spfiles.com/pitemodar.pdf, accessed April 24, 2011; Pitz MW, et al. J Neurooncol. Published
online ahead of print March 12, 2011.

21. Overall Survival With RT + TMZ in Newly
Diagnosed Patients < 70 Years
EORTC / NCIC Trial
Stupp R, et al. Lancet Oncol. 2009;10:459-466.
Radiotherapy plus temozolomide
Radiotherapy
P < 0.0001
n = 287
n = 286
RT + TMZ
RT
P < 0.0001

22. Subset analysis – Stupp et al, NEJM
2005

23. Clinical Pearls
• How does the status of methylguanine–DNA
methyltransferase (MGMT) methylation affect
the prognosis of glioblastoma?
• MGMT is a DNA-repair protein; the methylation
status of the MGMT promoter has prognostic
and potentially predictive significance in
glioblastoma.

24. MGMT
• Studies of the methylation status of the
MGMT promoter in primary and recurrent
glioblastomas have shown that recurrent
tumors may change their methylation status,
particularly if the primary tumor had a
methylated MGMT promoter; however,
methylation status of the MGMT promoter at
recurrence does not appear to be predictive of
subsequent outcome.

25. Methylation
(TMZ)
Chloroethylation
(BCNU)
Guanine
(DNA)
O6-methylguanine O6-Chloroethyl guanine
O6-methylguanine:
Thymine mismatch
N1-O6-ethanol guanine
Survival
(resistance, carcinogenesis)
Cell Death
DNA ds break DNA ds break
Mutation
Transformation
DNA interstrand
crosslink
MGMTMGMT
MGMT
MGMT-DNA
crosslink
Methylguanine Methyltransferase (MGMT)
Verbeek B, et al. Br Med Bull. 2008;85:17-33.

26. Clinical Pearls
• In one study, patients with glioblastoma
whose tumors were positive for MGMT
methylation had a median survival of 21.7
months and 2-year survival of 46%;
• as compared with patients whose tumors
were negative for MGMT methylation, who
had a median survival of 12.7 months and 2-
year survival of 13.8%.

27. NEJM Morning Report Questions
• Q. What is tumor pseudoprogression?
• A. Tumor pseudoprogression is a reaction of the
tumor and tumor microenvironment to
radiation and chemotherapy. In one case series
of glioblastoma, patients with tumors that
showed pseudoprogression had improved
survival relative to patients with tumors that did
not develop pseudoprogression.

28. Pseudoprogression
• Tumor pseudoprogression usually occurs within 3
months after completion of radiation and
chemotherapy.
• Pseudoprogression occurs in approximately 20 to
40% of patients with glioblastoma after
chemoradiation.
• Pseudoprogression may be associated with
cerebral edema and increased intracranial
pressure and can result in neurologic symptoms
and signs.

29. • MGMT has been implicated in tumor resistance to
alkylating drugs
– Removes the alkyl group from the O6 guanine
• Inactivation by promoter methylation of the MGMT
gene is associated with superior outcomes in
malignant glioma in a retrospective analysis
– Of 206 EORTC / NCIC trial patients, 45% had MGMT
promoter methylation
Hegi ME, et al. N Engl J Med. 2005;352:997-1003.
Methylguanine Methyltransferase
(MGMT) and Prognosis

30. Effect of MGMT Promoter Methylation
Status on Survival
Hegi ME, et al. N Engl J Med. 2005;352:997-1003.
Months
0 6 12 18 24 30 36 42
Methylated
MGMT
promoter
Unmethylated
MGMT
promoter
Hazard ratio 0.45
95% CI 0.32-0.61
P < 0.001
ProbabilityofOverallSurvival
EORTC / NCIC Trial

31. Effect of MGMT Promoter Methylation
Status on Survival by Treatment
EORTC / NCIC Trial
Unmethylated MGMT Methylated MGMT
RT + TMZ
n = 60
RT alone
n = 54
RT + TMZ
n = 46
RT alone
N = 46
Median OS 12.6 months 11.8 months 23.4 months 15.3 months
2-year OS 14.8% 1.8% 48.9% 23.9%
3-year OS 11.1% 0% 27.6% 7.8%
4-year OS 11.1% 0% 23.1% 7.8%
5-year OS 8.35 0% 13.8% 5.2%
Stupp R, et al. Lancet Oncol. 2009;10:459-466.

32. NEJM Morning Report Questions
• Q. What is tumor pseudoprogression?
• A. Tumor pseudoprogression is a reaction of the
tumor and tumor microenvironment to
radiation and chemotherapy.
• In one case series of glioblastoma, patients with
tumors that showed pseudoprogression had
improved survival relative to patients with
tumors that did not develop pseudoprogression.

33. Pseudoprogression
• Tumor pseudoprogression usually occurs within 3
months after completion of radiation and
chemotherapy.
• Pseudoprogression occurs in approximately 20 to
40% of patients with glioblastoma after
chemoradiation.
• Pseudoprogression may be associated with
cerebral edema and increased intracranial
pressure and can result in neurologic symptoms
and signs.

34. Pseudoprogression
• Subacute treatment-related reaction occurring shortly after therapy, with or
without clinical deterioration, and subsequent improvement
– Difficult to distinguish from progression on MRI
• Studies suggest it occurs in 10%-45% of patients
– Approximately 30% of those are clinically symptomatic
• More frequent in patients with
– MGMT methylation
– RT / TMZ or lomustine, high-dose RT
• May be a positive prognostic marker
• Management
– Asymptomatic: continue with planned post-RT therapy
– Symptomatic: consider re-resection or steroids with planned post-RT
therapy or short-course bevacizumab with planned
post-RT therapy
Chamberlain MC, et al. J Neurooncol. 2007;82:81-83; Taal W, et al. Cancer. 2008113:405-410; Brandes AA, et al. J Clin Oncol.
2008;26:2192-2197; Brandsma D, et al. Lancet Oncol. 2008;9:435-461.

35. • The following question is from ASCO SEP, Second Edition:
• A 55 year old man presented with syncope, a history of lightheadedness which
had worsened over several months, and mild personality changes. Imaging
revealed a right frontal mass measuring 7.3 by 6.3 cm which was associated with
a 1.9 cm midline shift. He underwent resection followed by standard
temozolomide/radiation. Four weeks after the conclusion of combined therapy
he is being seen in the office with a repeat MRI, just prior to the start of cycle
one of temozolomide at 150 mg/m2, 5/28 days. Clinically the patient is doing
well. His energy has returned. He has no complaints of lightheadedness and his
wife is relieved to report that he seems like himself. The MRI, however, shows an
increase in enhancement surrounding the surgical cavity as well as at the inferior
aspect of that cavity. The next step in his treatment should be:
•
• Bevacizumab 10 mg/kg every 14 days.
•
• Participation in a clinical trial.
•
• A discussion of hospice.
•
• Continue with temozolomide 5/28 as planned.

36. • Answer: Continue with temozolomide 5/28 as planned.
• Rationale :
• Pseudoprogression describes the frequently observed, non-tumor related
increase in enhancement on MRI following initial radiation or chemoradiation
to the brain. These radiologic changes, appearing in the first 12 weeks
following the completion of chemo/radiation, do not prompt a change in the
therapeutic plan and resolve with time. Persistent increases in enhancement
may prompt a biopsy to determine the presence of viable tumor.
• Suggested Readings:
• Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment
criteria for high-grade gliomas: response assessment in neuro-oncology
working group. J Clin Oncol 2010;28:1963.
• http://university.asco.org/sites/university.asco.org/files/wen_cnsreview.pdf
• Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA,
van Es CA, van den Bent MJ. Incidence of early pseudoo-progression in a
cohort of malignant glioma patients treated with chemoirradiation with
temozolomide. Cancer 2008:113(2):405.
• http://onlinelibrary.wiley.com/doi/10.1002/cncr.23562/pdf

37. Pseudoprogression and Correlation to MGMT
Status in Newly Diagnosed GBM
Brandes AA, et al. J Clin Oncol. 2008;26:2192-2197.
Enlarged Lesion
(n = 50)
Stable or No Lesion
(n = 53)
Continue TMZ
2nd MRI (3 months)
Continue TMZ
Stable or Reduced PsPD (n
= 32)
Further progression
ePD (n = 18)
Methylated MGMT (n = 36) 13 (25%) 21 (66%) 2 (11%)
Unmethylated MGMT (n = 67) 40 (75%) 11 (34%) 16 (89%)
1st MRI after concomitant
therapy
Continue TMZ Stop TMZ
P = 0.0002
PsPD = pseudoprogression
ePD = early disease progression

38. Pseudoprogression Example
Before
RT
4 wks after
RT (TMZ
begun)
8 wks
after RT
6 months
later

39. Survival and Prognostic Features With
Radiochemotherapy in Newly Diagnosed GBM
Brandes AA, et al. J Clin Oncol. 2008;26:2192-2197.
Methylated
Unmethylated
With PsPD
With ePD
Neither
PsPD = pseudoprogression
ePD = early disease progression

40. Response Assessment in
Neuro-Oncology (RANO) Criteria
*Progression occurs when any of the criteria is/are present.
CR PR SD PD
T1-Gd + None ≥ 50% ↓ < 50% ↓ to
< 25% ↑
≥ 25% ↑*
T2 / FLAIR Stable or ↓ Stable or ↓ Stable or ↓ Stable or ↑*
New Lesion None None None Present*
Corticosteroids None Stable or ↓ Stable or ↓ NA
Clinical status Stable or ↑ Stable or ↑ Stable or ↑ ↓*
Requirement for
response
All x 4 wks All x 4 wks All Any*
Wen PY, et al. J Clin Oncol. 2010;28(11):1963-1972.

41. Recurrence
• Nearly all glioblastomas will recur
• FDA-approved therapies
– Novo-TTF (Optune) – see later slides
– Carmustine wafer indication
• For “recurrent glioblastoma multiforme patients as an adjunct to surgery”
– Bevacizumab indication
• For “progressive disease in adult patients following prior therapy as a single agent”
• Based on “improvement in objective response rate”
• Median TTP from initiation of first-line therapy
– 6.9 months
Wen PY and Kesari S. N Engl J Med. 2008;359(5):492-507; Stupp R, et al. J Clin Oncol. 2007;25:4127-4136;
Gliadel prescribing information. Available at: http://www.gliadel.com/Docs/Pdf/201241R1_Gliadel_PI.pdf and Avastin prescribing
information. Available at: http://www.gliadel.com/Docs/Pdf/201241R1_Gliadel_PI.pdf. Accessed April 11, 2011.

42. Radiographic Patterns
of Relapse in GBM
Chamberlain MC, et al. J Neuro Oncol. 2011;101:319-323.
Presentation
(n = 80)
First
recurrence:
post-TMZ + RT,
onset BE
(n = 80)
Second
recurrence:
progression on
BEV only (n =
80)
Third
recurrence:
progression on
BEV + or
alternative (n
= 57)
Pattern
Local 70 (87.5%) 64(80%) 57 (71.3%) 41(71.9%)
Local to other 6 (8.5%) 8 (12.5%) 1 (1.75%)
Distant 5 (6.25%) 6 (7.5%) 7 (8.75%) 4 (7.0%)
Multifocal 3 (3.75%) 5 (6.25%) 7 (8.75%) 4 (7.0%)
Diffuse 2 (2.55) 5 (6.25%) 9 (11.25%) 8 (14.0%)
Other = distant, multifocal, or diffuse.

43. Imaging Studies and Biopsy Specimen 19 Months after Surgery.
Batchelor TT et al. N Engl J Med 2012;366:2112-2120

44. Imaging Studies Performed before and after the Administration of Bevacizumab.
Batchelor TT et al. N Engl J Med 2012;366:2112-2120

45. Re-Irradiation
• At recurrence, the majority of patients have undergone a
full course of external beam irradiation
• Currently used in a minority of patients
– Select patients with focal disease and good KPS
• Reports suggest fractionated stereotactic re-irradiation and
radiosurgery may be beneficial
– Controversial questions regarding selection bias
• Salvage therapy should be highly individualized
• Lack of prospective randomized trials
Butowski NA, et al. J Clin Oncol. 2006;24:1273-1280. Combs SE, et al. J Clin Oncol. 2005;23:8863-8869. Brandes AA, et al. Crit Rev in
Oncol/Hematol. 2008;67:139-152.

46. Hypofractionated Stereotactic Radiation
Therapy at Recurrence
• 147 patients with recurrent high-grade glioma
– H-SRT: median dose = 35 Gy in 3.5 Gy fractions
• Younger age (P = 0.001), smaller GTV (P = 0.025), and shorter time between
diagnosis and recurrence (P = 0.034) were associated with improvement in
survival
• Doses of radiation 35 Gy approached significance (P = 0.07)
• No significant benefit of surgical resection or chemotherapy when
controlled for other prognostic factors
Recurrence > or < after 6 months of initial treatment H-SRT > 35 Gy or < 35 Gy
Fogh SE, et al. J Clin Oncol. 2010;28(18):3048-3053.

47. Hypofractionated Stereotactic
Radiation and Bevacizumab
• Toxicity
– 3 pts discontinued therapy due to grade 3 CNS hemorrhage,
wound dehiscence, and bowel perforation
GBM cohort
N = 20
ORR 50%
PFS-6 65%
1-year OS 54%
Median OS 12.5 months
Recurrent malignant glioma
Prior RT
N = 25
Bevacizumab
10 mg/k q 2 wks/28 d cycle
30 Gy HFSRT
Gutin PH, et al. Int J Radiat Oncol Biol Phys. 2009 Sep 1;75(1):156-163.

48. Low-grade gliomas
(LGG)

49. Pathology
• Grade 1 gliomas- Pilocytic astrocytomas
• Grade 2 gliomas- oligodendrogliomas,
astrocytomas and mixed oligoastrocytomas
• Pleomorphic Xanthrochromic Astrocytomas

50. Pathology
• Molecular profiling has changed the
understanding and treatment of low grade
gliomas
• The important genetic mutations are IDH-1,
1p and/or 19q deletions and P53

51. Features of high-risk LGG
• Size > 6 cm
• Tumor crossing the midline
• Unresectable or incomplete tumor resection
• Age > 40
• Contrast enhancement
• Increasing attention to molecular profiles in neuro-
oncology: may need to add absence of 1p/19q co-
deletion; absence of IDH mutation (IDH 1 or 2)
• Pignatti et al., JCO 20(8), April 2002

52. Rational Approaches
• Delay radiation therapy to limit neurotoxicity
• Delay chemotherapy until the patient has symptoms
that interfere with quality of life and progressive MRI
changes
• If the patient requires treatment, consider a clinical
trial, and if none exists, treat with temozolomide
• The optimal schedule of temozolomide is unknown

53. Presentation
• Seizures are the most common presenting
symptoms
• Focal neurologic symptoms and aphasia are
the next most common symptoms
• Headache is far less common than in high
grade gliomas

54. Date of download: 10/16/2013
Copyright © 2012 American Medical
Association. All rights reserved.
From: Comparison of a Strategy Favoring Early Surgical Resection vs a Strategy Favoring Watchful Waiting in
Low-Grade Gliomas
JAMA. 2012;308(18):1881-1888. doi:10.1001/jama.2012.12807
Grade I tumors were included in the review process to ensure that tumors classified as “unspecified low-grade glioma” were
reassessed. After blinded review of histopathology, 153 patients were included in the analysis (91% of screened); 66 (43%) from
hospital A and 87 (57%) from hospital B. Zero patients were lost to follow-up at both hospitals. WHO indicates the World Health
Organization. aTwo cases from hospital A and 3 cases from hospital B were not reviewed due to lack of tissue specimen, and the
initial diagnosis was maintained.
Figure Legend:

55. Date of download: 10/16/2013
Copyright © 2012 American Medical
Association. All rights reserved.
From: Comparison of a Strategy Favoring Early Surgical Resection vs a Strategy Favoring Watchful Waiting in
Low-Grade Gliomas
JAMA. 2012;308(18):1881-1888. doi:10.1001/jama.2012.12807
This is a regional comparison of results of the 2 favored surgical strategies (but including patients at hospital A treated with resection
and patients at hospital B undergoing biopsy only). Biopsy preferred (hospital A): 29% initial resections. Resection preferred
(hospital B): 86% initial resections. There was a significant difference in survival between patients treated at the 2 hospitals
(P = .01). The shaded areas indicate 95% CIs. Median survival was 5.9 years (95% CI, 4.5-7.3) in the center in which biopsy and
watchful waiting was preferred. Median survival was not reached in the center in which early resection was the preferred strategy.
Figure Legend:

56. Date of download: 10/16/2013
Copyright © 2012 American Medical
Association. All rights reserved.
From: Comparison of a Strategy Favoring Early Surgical Resection vs a Strategy Favoring Watchful Waiting in
Low-Grade Gliomas
JAMA. 2012;308(18):1881-1888. doi:10.1001/jama.2012.12807
This analysis excludes patients who initially received treatment different from the local favored strategy (excluding the 19 patients
with initial resections at hospital A and the 12 patients who were only initially biopsied at hospital B). A survival benefit of resection
was seen with median survival of 5.8 years (95% CI, 3.0-8.7) at hospital A while median survival was not reached at hospital B
(P < .001). Shaded areas indicate 95% CIs.
Figure Legend:

57. Table 1 Frequencies of selected molecular abnormalities among low-grade
gliomas
Bourne, T. D. & Schiff, D. (2010) Update on molecular findings, management and outcome in low-grade
gliomas
Nat. Rev. Neurol. doi:10.1038/nrneurol.2010.159

58. Figure 1 A model for the development and progression of astrocytic and
oligodendroglial tumors
Bourne, T. D. & Schiff, D. (2010) Update on molecular findings, management and outcome in low-grade
gliomas
Nat. Rev. Neurol. doi:10.1038/nrneurol.2010.159
Permission obtained from Oxford University Press Ltd © Ichimura, K. et al. Neuro. Oncol. 11, 341–347 (2009)

59. IDH Mutations
• Early oncogenic event, found in the majority
of grade 2 diffuse astrocytomas,
oligodendrogliomas, and all of the mixed
oligoastrocytomas
• The vast majority of grade 3 anaplastic
astrocytomas, oligodendrogliomas, and
secondary grade 4 glioblastomas also have
IDH mutations

60. IDH Mutations
Tumor Type IDH1 mut IDH2 mut Combined
Pilocytic Astro 0 0 0
Diffuse Astro 82% 8% 90%
PXAs 14% 0 14%
An Astro 68% 5% 73%
Oligos 80% 4% 84%
An Oligos 86% 8% 94%
Primary GBM 5% 0 5%
Secondary
GBM
85% 0 85%

61. When Loss Means Gain.
Smeitink J. N Engl J Med 2010;362:1144-1145.

62. IDH Mutations
• IDH mutations result in the accumulation of D-
2-hydroxyglutarate, and reduced formation of
alpha-ketoglutarate
• As a result of less alpha-ketoglutarate, HIF-
1alpha levels increase
• Paradoxically, HIF-1alpha is important in the
biology of glioblastoma, but has not been
implicated in grade 2 or 3 gliomas

63. 1p, 19q deletions
• The majority of oligodendrogliomas have co-
deletion of 1p and 19q.
• Tumors with co-deletion of 1p and 19q have a
better prognosis and respond better to
chemotherapy, particularly PCV and
temozolomide.
• Tumors with deletion of one allele have an
intermediate prognosis.

64. New paradigms for molecular
classifications – 2015 updates
• Cancer Genome Atlas Research network,
“Comprehensive, Integrative Genomic Analysis of
Diffuse Lower-Grade Gliomas”, NEJM June 10, 2015.
• Genome-wide analysis of 293 LGG (adults) – exome
sequencing, miRNA, targeted protein expression.
• Defined 3 molecular subclasses predictive of prognosis:
– Mutations in IDH and co-deletion of 1p/q19q: “most
favorable clinical outcomes.”
– IDH mutations, no codeletions of 1p/19q: 94% had
mutations in TP53.
– LGG without IDH Mutation: “molecularly and clinically
similar to glioblastoma.”

65. Summary of Major Findings.
The Cancer Genome Atlas Research Network. N Engl J Med 2015;372:2481-2498

66. Clinical Outcomes.
The Cancer Genome Atlas Research
Network. N Engl J Med 2015;372:2481-2498

67. Conclusions
• The integration of genomewide data from multiple platforms delineated
three molecular classes of lower-grade gliomas that were more
concordant with IDH, 1p/19q, and TP53 status than with histologic
class.
• Lower-grade gliomas with an IDH mutation either had 1p/19q
codeletion or carried a TP53 mutation.
• Most lower-grade gliomas without an IDH mutation were molecularly
and clinically similar to glioblastoma.

68. Differential Diagnosis
• The key is to do the MRI
• The most common other diagnoses include
stroke, multiple sclerosis, sarcoidosis and
acute demyelinating encephalomyelitis
• Other CNS tumors can present in an identic

69. Natural History
• Median survival is 5-13 years
• The majority, approximately 80%, evolve to a
higher grade glioma

70. Surgery
• Surgical resection is the primary treatment for
low grade gliomas
• Surgery establishes a definitive diagnosis
• Delicate balance between extent of surgery
and post-operative symptoms, particularly
with the prolonged survival

71. Should All Low Grade Gliomas Receive
Treatment Post-operatively?
• The patients symptoms determine the need
for therapeutic intervention
• Quality of life is paramount
• No study has shown that a therapy resulted in
an improved overall survival, many studies
report an improved progression-free survival

72. EORTC 22845
• Randomized 311 LGG patients from 1986-
1997 to observation or radiation therapy to 54
Gy
• 5 year PFS 37% observation vs 44% XRT
(p=0.02)
• 5 year OS 66% observation vs 63% XRT

73. EORTC 22844
• 379 LGG patients randomized between 1986-
1997 between 45 Gy post-operative XRT vs
59.4 Gy
• 5 year PFS 47% low dose XRT vs 50% with high
dose XRT
• 5 year OS 58% low dose XRT vs 59% with high
dose XRT

74. NCCTG/RTOG/ECOG/SWOG Intergroup
Study
• 211 LGG patients randomized between 1986-
1994 to low dose XRT 50.4 Gy vs high dose
XRT 64.8Gy
• 5 year PFS was 55% in the low dose XRT group
vs 52% in the high dose XRT group
• 5 year OS was 72% in the low dose XRT group
vs 65% in the high dose XRT group

75. RTOG Study in high risk LGG
• 251 LGG glioma patients were randomized
between 1998-2002 between XRT alone (54
Gy) vs XRT plus PCV chemotherapy
• 5 year PFS 48% XRT alone vs 61% XRT plus PCV
(p=0.18)
• 5year OS 62% XRT alone vs 73% XRT plus PCV
(p=0.40)

76. RTOG 0424: Phase II trial for high-risk LGG
• 129 patients (75 male, 54 female)
• 2005 to 2009
• Median age 49; 3 or more high-risk factors
• RT (54 Gy in 30 fractions) with concurrent +
adjuvant TMZ
• 3-yr OS 73.1% was higher than for reported
historical controls (p<0.001).

77. EORTC 22033-26033
• Randomizes LGG patients to XRT alone vs
temozolomide alone
• Patients are stratified by the presence of the
1p deletion

78. ECOG E3F05
• Randomizes LGG patients to XRT alone vs
XRT/daily temozolomide followed by adjuvant
temozolomide
• Tumor will be analyzed for 1p and 19q
deletions

79. Future Directions
• Understand the growth factor pathways that
stimulate low grade gliomas and use TKIs to
inhibit the pathways
• Is PDGF the primary growth factor for low
grade gliomas?
• Vaccines with glioma associated antigens may
be an effective strategy

80. LGG Summary
• Low grade gliomas are more common in
younger patients and they live for many years
• On MRI, low grade gliomas usually do not
enhance, but in patients > 50 years of age, the
low grade usually enhances
• Try to avoid radiation therapy
• Treat with chemotherapy when the patient is
symptomatic

81. Anaplastic Gliomas
• The key is the pathology, anaplastic
oligodendrogliomas vs astrocytomas and
mixed oligoastrocytomas
• Co-deletion of 1p/19q defines an
oligodendroglioma
• The degree of enhancement correlates with
tumor angiogenesis and VEGF levels

82. Treatment of anaplastic
oligodendogliomas: EORTC 26951
• Long-term randomized phase III study; patients
received 6 cycles PCV (procarbazine, lomustine,
vincristine) following RT, vs RT alone. Long-term
follow-up reported in 2013 (van den Bent et al,
JCO January 20 2013).
• 368 patients; median follow-up 140 months
• Median OS in RT/PCV = 42.3 months vs 30.6
months in RT Arm (HR 0.75).
• Trend toward more benefit in the 80 patients
with co-deleted 1p19q.
• IDH mutation associated with better prognosis.

83. Anaplastic Gliomas
• Pure anaplastic oligodendrogliomas with co-
deletion of 1p/19q have a better prognosis,
and temozolomide is the treatment of choice
• Other grade 3 anaplastic gliomas should be
treated with combine chemo-radiotherapy,
followed by 6-12 months of temozolomide

84. Anaplastic Gliomas
• Clinical trials are needed for recurrent grade 3
gliomas
• Gliomatosis cerebri is a unique entity, with
different pathophysiology
• For enhancing grade 3 gliomas, bevacizumab
is efficacious, similar to glioblastoma, but less
active in non-enhancing tumors

85. Conclusions
• Grade 3 anaplastic gliomas are a stepping
stone away from a grade 2 and glioblastoma
• The presence of the 1p/19q co-deletion is
important in determing prognosis and therapy
• Tumor biomarker studies are needed as part
of clinical trials to improve treatment results

86. Elderly Patients
• Age is the single most powerful predictor of
outcome
• Elderly GBM is characterized by genetic
differences and intrinsic aggressiveness
• TMZ + concurrent RT is standard for patients <
70 years
– Less well defined for patients > 70 years
• Is sequential therapy better for older patients
– If so, what sequence?
Brandes AA and Franceshi E. J Clin Oncol. 2010 Education Book.

87. Considerations for Challenging Patient Groups
• Elderly (age 70 and up): 20% or more of all GBM
– No standard of therapy; no consensus
– Usually excluded from trials1
• Compromised patients: 10% or more of all GBM
– Defined as moderate-severe impairment in performance
(Karnofsky Performance Status < 70) and inability to perform
activities of daily living
– No standard of therapy; no consensus
– Usually excluded from trials2
• MGMT-expressing: > 50% of all GBM
– Prospective evaluation is ongoing1,3
1. Roa W, et al. J Clin Oncol. 2004;22:1583-1588; 2. Keime-Guibert F, et al. N Engl J Med. 2007;356:1527-1535; 3. Hegi ME, et al. N
Engl J Med. 2005;352:997-1003.

88. Adverse Prognostic Factors
Recursive Partitioning Analysis
• Reviewed survival of patients with high-
grade gliomas in the RTOG database
• 5 variables stratify patients into 6
subgroups
Age
Performance status
Histology
Neurologic function
Duration of symptoms
Curran WJ Jr, et al. J Natl Cancer Inst. 1993;85:704-710; Pichimeier U, et al. Neuro-oncol. 2008;6:10225-2034.
Class Median
Survival
(mo)
2-year
Survival
(%)
I 59 76
II 37 68
III 18 35
IV 11 15
V 9 6
VI 4.5 4
 Validated in subsequent studies; extent of resection associated
with survival in classes IV and V
 Underscores the importance of prognostic factors on outcome
and may be used to compare trials

89. Rationale for Anti-VEGF Therapy of
Glioblastoma
• Glioblastomas are highly vascularized
• The degree of vascularization has been linked to
prognosis
• After recurrence, tumor dynamics change
– Growth rate
– Histology
– Increased angiogenesis
– VEGF expression
de Groot JF, Gilbert MR. Curr Opin Neurol. 2007;20:712-718. Furnari FB, et al. Genes Dev. 2007;21:2683-2710.
Wen PY, Kesari S. N Engl J Med. 2008;359:492-507.

90. Bevacizumab in recurrent GBM - NCI
study 1,2
Avastin Prescribing
Information. Genentech, Inc.
December 2011.
Data on file. Genentech, Inc.
Friedman HS, Prados MD,
Wen PY, et al. J Clin Oncol.
2009;27:4733-4740.
Kreisl TN, Kim L, Moore K, et
al. J Clin Oncol. 2009;27:740-
745.
The BRAIN study was an open-label, multicenter, randomized, noncomparative Phase II study of patients (N=167)
with previously treated GBM 1-3
Dosing: Avastin 10 mg/kg as a solution for intravenous (IV) infusion every 2 weeks (q2w) until disease
progression or unacceptable toxicity 1
Inclusion criteria: Prior radiotherapy (RT; completed >8 weeks prior) and previous treatment with
temozolomide (TMZ); >4 weeks postsurgery; a Karnofsky performance status (KPS) >70 was required 1-3
Exclusion criterion: Active brain hemorrhage 1
Median age, 54 years; 32% female; 81% in first relapse; KPS >90 in 45% of patients and between 70 and 80 in
55% of patients 1,3

91. Adverse Events (Grade > 3) with Bevacizumab in
Recurrent GBM
Cloughesy T, et al. J Clin Oncol. 2010;28(15S). Abstract 2008; Kreisl T, et al. J Clin Oncol. 2009;7(5):740-745.
Adverse Event BRAIN Trial NCI Trial
Bev alone
(n = 84)
Bev + Irinotecan
(n = 79)
Bev alone
(n = 48)
Hypertension 10.7% 3.8% 4.2%
Cerebral hemorrhage 0% 1.3% NR
Venous thromboembolism 3.6% 10.1% *
Proteinuria 1.2% 3.8% 0%
Wound healing complications 2.4% 1.3% NR
Arterial thromboembolism 3.6% 2.5% *
Hypophosphatemia NR NR 2.1%
Hepatic dysfunction NR NR 2.1%
GI perforation 0% 2.5% 2.1%
*Overall thromboembolic event rate 12.5%. NR = not reported.

92. Phase III trials– first-line Bevacizumab
• RTOG 0825 - Phase III Double-Blind Placebo-
Controlled Trial of Conventional Concurrent
Chemoradiation and Adjuvant Temozolomide Plus
Bevacizumab versus Conventional Concurrent
Chemoradiation and Adjuvant Temozolomide in
Patients with Newly Diagnosed Glioblastoma
• 637 randomized patients
• TMZ/XRT vs TMZ/XRT with
Bevacizumab
• Median OS 15.7 vs 16.1 months,
p=0.11
– MGMT methylated promoters:
14.3 vs 23.2 months, p<0.001)
• PFS 7.3 vs 10.7 months, p=0.004
• Gilbert et al. ASCO Annual Meeting Plenary Session,
2013
• AVAglio
921 randomized patients
TMZ/XRT vs TMZ/XRT with
Bevacizumab
Median OS, 16.7 vs 16.8
months, p=0.0.0987, HR 0.88
• PFS 6.2 vs 10.6 months,
p<0.001, HR 0.64
• Chinot O, Wick W, Mason W, et al.
Phase III trial of bevacizumab added to
standard radiotherapy and
temozolomide for newly-diagnosed
glioblastoma: mature progression-free
survival and preliminary overall
survival results in AVAglio. Neuro
Oncol. 2012; 14:vi101-vi105. Abstract
OT-3. -

93. AVAglio
Characteristic
RT/TMZ/Pib
(n = 463)
%
RT/TMZ/BEV
(n = 458)
%
Median age, yr (range) 56.0 (18-79) 57.0 (20-84)
Gender, male 64 62
WHO PS
0 52 50
1-2 48 50
RPA class
III 16 17
IV 60 57
V 23 26
Surgical status
Biopsy 10 13
Partial resection 48 46
Complete resection 42 41
KPS
50-80 30 33
90-100 70 67

94. Anticoagulation in Glioma Patients
Treated With Bevacizumab
• Retrospective analysis of 282 high-grade glioma patients
treated with bevacizumab
• 64 also received anticoagulation
– Grade > 3 hemorrhage rate 6.3%
• Intracranial, epistaxis, GI
• 218 patients did not receive anticoagulants
– Grade > 3 hemorrhage rate 0.9%
• Intracranial
• Serious hemorrhage rate higher in patients who received
anticoagulants (P = 0.025)
– Unresolved whether type of anticoagulation presents different
risks
Bartolomeo J, et al. J Clin Oncol. 2010;28(15s). Abstract 2043.

95. Future Questions Regarding
Anti-VEGF Therapy
• Optimal bevacizumab therapy
– Single-agent bevacizumab: dose, schedule, duration
– Bevacizumab plus chemotherapy
• Which chemotherapy
• Predictive biomarkers
• Imaging
– Prediction of response to bevacizumab-based therapy
– Identification of progression on bevacizumab
• Optimal treatment of patients progressing on bevacizumab
• Efficacy of other VEGF Inhibitors

96. Electrical Field Device
NovoTTF-100A System
• Portable device with electrodes on surface of scalp delivering
low-intensity, changing electrical fields known as “tumor-
treatment fields” (TTF)
• Thought to damage tumor cells based on their shape and
electrical characteristics; Kirson et al., PNAS 2007, “Alternating
electric fields arrest cell proliferation in animal tumor models
and human brain tumors.”
• Approved by FDA on April 15, 2011 for relapsed or refractory
GBM
– Based on single randomized trial of 237 patients
– OS similar in TTF and chemotherapy groups
– TTF produced suggestion of improved quality of life, slight increased
risk of headache and convulsion compared with chemotherapy
Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251669.htm. Accessed April 25, 2011.

97. Electrical Field Device
NovoTTF-100A System
• Follow-up analyses:
– Assessed tumor response and progression using Macdonald
criteria.
– Median duration of response: 7.3 months vs 5.6 months vs BPC
(Best Physician’s Choice) chemotherapy in 2nd-line setting.
– 5/14 Novo responders had prior low-grade histology.
– Median OS was longer in responders than in non-responders
(p<0.0001).
– Mean cumulative dexamethasone dosing << in responders (35.9
mg vs 485.6mg)
– Wong et al., “Response assessment of NovoTTF-100A versus
best physician’s choice chemotherapy in recurrent
glioblastoma,” Cancer Medicine, 2014.

98. Novo-TTF (Optune)
• Approved by the U.S. FDA for 1st-line treatment of GBM as of
October 5, 2015
• Based on EF-14 Phase III trial that was terminated at interim
analysis, presented at SNO Annual Mtg 2014.
• 315 patients, 1st-line GBM.
• TTF + TMZ median OS: 19.6 months, c/w 16.6 months TMZ alone
(HR 0.75; p=0.034).
• TTF+TMZ median PFS: 7.1 months, c/w 4.0 months TMZ alone (HR
0.63; p=0.001).
• Percentage alive at 2 yrs: 43% with combination, 29% with TMZ
alone.
• Stupp: “These results are spectacular – a lot better and much more
convincing than we ever would have dreamt of….” From Novocure
Press release, November 15, 2014.