Understanding and treating malignant glioma

1. Malignant Glioma
Robert Miller MD
www.aboutcancer.com

2. Brain primary: a normal
brain cell (glial cell)
becomes malignant and is
called a glioma
Brain metastases: cancer
that started elsewhere in the
body (e.g. lung or breast)
and spread to the brain

3. Malignant Gliomas
Glioblastomas 60 to 70%
Anaplastic Astrocytomas for 10 to 15%
Anaplastic Oligodendrogliomas 10%
Less common tumors such as anaplastic ependymomas
and anaplastic gangliogliomas account for the rest.

4. The incidence of these tumors has increased slightly over
the past two decades, especially in the elderly, primarily as
a result of improved diagnostic imaging.
Malignant gliomas are 40% more common in men than in
women and twice as common in whites as in blacks.
The median age of patients at the time of diagnosis is 64
years in the case of glioblastomas and 45 years in the case
of anaplastic gliomas.
Who Gets Brain Cancer?

5. Men
Cancer
Men
Brain
Woman
Cancer
Woman
Brain
Diagnose
d
44% 0.67% 37% 0.55%
Dying 24% 0.49% 20% 0.39%
Probability of getting or dying
of a brain cancer

6. Symptoms of Brain Tumor
 Headaches
 Seizures Visual changes,
 Changes in personality, mood, mental capacity, and
concentration
 Gastrointestinal symptoms such as nausea, loss of
appetite, and vomiting.
Seizures are a presenting symptom in approximately 20% of
patients
Among all patients with brain tumors, 70% with primary tumors
and 40% with metastatic brain tumors develop seizures at some
time during the clinical course

7. Brain Swelling – brain tumors often cause swelling or
edema which creates pressure on the brain, with headaches
and nausea, steroids like Decadron (dexamethasone) will
decrease this pressure

8. Symptom Grade III Grade IV
Symptoms by Grade

9. Types of Primary Brain
Tumors
Benign: meningioma, pituitary, pineal
Malignant: those that start with glial
cells (glue) astrocyte or
oligodendrocyte
Grade: low grade (I and II)
astrocytoma and high grade (III or IV,
more mutated and more rapid
growing)

10. Type Percent
Meningioma 33.4%
Glioblastoma 17.6%
Pituitary 12.2%
Nerve Sheath 8.7%
Astrocytoma 7.4%
Oligodendroglioma 2.1%
Medulloblastoma 1.0%
Types of Brain Tumors

11. Histologic Criteria of the World Health
Organization for the Classification of
Gliomas.
Fibrillary astrocytoma
Anaplastic astrocytoma
Glioblastoma multiforme

12. The Grade of the Glioma is critical in
making estimates of prognosis

13. Malignant Glioma
Histology Percent Survival
Anaplastic
astrocytoma
7% 50% (1p/19q)
27%
Glioblastoma 54% < 5%

14. Some cells in the normal brain undergo
genetic alterations, which leads to a
population of tumor–initiating cells (TICs),
which can then further accumulate genetic
and epigenetic changes and become brain
cancer–propagating cells (BCPC).

15. The latter cells are responsible for the formation of
multiple subtypes of glioblastoma.

16. Age
Incidence by Age and Type of
Brain Tumor

17. Survival

18. Brain Imaging

19. Glioblastoma
Certain brain
tumors .e.g.
glioma have a
distinct
appearance on
MRI scan . With
irregular borders
and necrotic
center

20. Glioblastoma
cells in green,
spread diffusely
through the brain
and are hard to
target accurately
for radiosurgery
and hard to cut
out

21. Glioblastoma spreads diffusely
through the brain

22. Glioblastoma are rapid growing cancers

23. Glioblastoma are rapid growing cancers and
often outgrow their blood supply so the center of
the tumor is literally dead cells or necrotic

24. Malignant Glioma can appear as a
complex cystic structure

25. occasionally a glioblastoma may appear as
multiple separate tumors and look metastatic
disease (called a multicentric glioblastoma)

26. Brain Metastasis as seen on an MRI Scan, the
sharp margins may make this a better case for
highly targeted radiation

27. Brain Metastasis has sharp borders
and Is easier to surgically resect or
target with radiosurgery

28. www.nccn.org

29. The current standard of care is to treat glioblastoma patients
with surgical resection, followed by temozolomide (Temodar,
TMZ) concomitant with external beam radiation (XRT), and then
subsequently with additional TMZ cycles.
Despite this treatment, patients have a median survival of 14.6
months and an overall survival of 27% at 2 years, that drops to
under 10% at 5 years.
Analysis of treatment failure patterns has revealed that up to
80% of recurrences occurred within 2 cm of the tumor
margins. This was the basis for inclusion of a margin from the
residual tumor and resection cavity, typically of 2–3 cm, when
radiation treatment portals were designed. More recent
data have demonstrated that now the majority of treatment
failures are within the irradiated field

30. Brain Surgery
Regardless of tumor type, the best
outcome if the surgeon removes as much
tumor as possible, keeps the surgical
morbidity (complications) low and an
ensures an accurate diagnosis

31. (C) An intraoperative microscopic view (white light) of the tumor resection
cavity is shown. (D) An intraoperative microscopic view of tumor
fluorescence (indicated by arrows) using “blue light” is shown.
Fluorescence-Guided Resection
of a Glioblastoma

32. High Grade Glioma

33. High Grade Glioma

34. High Grade Glioma

35. High Grade Glioma

36. High Grade Glioma

37. High Grade Glioma

38. High Grade Glioma

39. 100% – normal, no complaints, no signs of disease
90% – capable of normal activity, few symptoms or signs of disease
80% – normal activity with some difficulty, some symptoms or signs
70% – caring for self, not capable of normal activity or work
60% – requiring some help, can take care of most personal
requirements
50% – requires help often, requires frequent medical care
40% – disabled, requires special care and help
30% – severely disabled, hospital admission indicated but no risk
of death
20% – very ill, urgently requiring admission, requires supportive
measures or treatment
10% – moribund, rapidly progressive fatal disease processes
0% – death.
Karnofsky scoring

40. Glioblastoma

41. Glioblastoma

42. Glioblastoma

43. Benefit to PostOp Radiation for
Glioblastoma
Trial by Walker (J NeuroSurg 1978:49:333)
S only 14 weeks
S + BCNU 18.5 weeks
S + XRT 35 weeks
S + XRT/BCNU 34.5 weeks
Trial (Kristiansen Cancer 1981:47:649)
S only 5.2 months
S + XRT 10.8 months

44. Radiation Dose

45. Brain Radiation
In general radiation should start as soon as
possible after surgery and combined with
Temodar.
Radiation is daily, Monday through Friday for
6 weeks

46. Side Effects of Whole Brain
Radiation
1. Hair loss (usually takes two or three weeks to happen)
2. Mild skin itching or irritation
3. Short term more fatigue or slightly more confusion or
memory problems
4. Mild headache or nausea is uncommon but may require
medication (Decadron)
5. Occasionally hearing problems (fluid behind the ear
drums)

47. Long Term Effects of Radiation on the Brain
This patient had no symptoms, but radiation may effect
memory

48. Risk of white matter changes (leukoencephalopathy) 1
year after whole brain radiation for brain mets
U Pitt Study E Monaco (AANS 2012, Medscape Med News 2012-05-01)
WB+SRS SRS
1 year 97.3% 3.2%
So by one year 97% has some changes and
by 2 years 70% had grade 3 changes on the
MRI (but no symptoms)

49. Radiosurgery for Brain Tumors

50. Radiosurgery for
GBM
A total of 203 patients with supratentorial GBM were randomly
assigned either to postoperative SRS followed by EBRT (60 Gy)
plus BCNU (80 mg/m(2) Days 1-3 every 8 weeks for six cycles) or
to EBRT with BCNU alone.
RESULTS:
At a median follow-up time of 61 months, the median survival in the
radiosurgery group was 13.5 months as compared with 13.6 months
for the standard treatment group
Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.
Radiation Therapy Oncology Group 93-05

51. Treatment for Recurrent Glioma
The median survival for patients undergoing surgery
for recurrent GBM ranges from 3 to 8 months and
ranges from 13 to 20 months for patients with AA.
In a series of 114 consecutive patients with recurrent
malignant gliomas treated with SRS, the median
progression-free survival for patients with grade 3 and
grade 4 tumors was 8.6 and 4.6 months, respectively.
Radiation-induced necrosis was observed in 24
percent of cases.
Series with fractionated stereotactic radiotherapy
(FSRT) Median survival after reirradiation was 8
months for patients with GBM, 16 months for patients
with grade 3 tumors

52. Brain MRI before surgery (a) shows a periventricular contrast-enhancing mass, Postoperative
MRI (b) shows gross total resection. The patient underwent XRT and concomitant TMZ. Two
months after adjuvant therapy, follow-up MRI (c) shows a small recurrent nodule outside the
tumor cavity. This was targeted with SRS. Isodose lines around the lesion (d) treated with 20 Gy
at the 85% isodose line (e). Follow-up MRI (f) shows radiographic control up to 19 months later
Radiosurgery for Recurrent GBM

53. Comparison of stereotactic radiosurgery and
brachytherapy in the treatment of recurrent
glioblastoma multiforme.
Shrieve DC, Loeffler JS. Neurosurgery 1995 Feb;36(2):275-82;
Brain Tumor Center, Brigham and Women's Hospital, Boston,
Massachusetts, USA.
Twenty-one patients (24%) treated with SRS were alive, with a median
follow-up of 17.5 months.
Median actuarial survival, measured from the time of treatment for
recurrence, for all patients treated with SRS was 10.2 months, with
survivals of 12 and 24 months being 45 and 19%, respectively.

54. 1. There is evidence of no benefit when given
as part of the original therapy as a boost to
conventional radiation
2. Not enough evidence to determine benefit
when given for recurrent cases
3. Not enough evidence to determine a benefit
when given as primary therapy
data up to 2004

55. 0 5 10 15 20 25 30
Time (months)
Overall survival after SRS (72% at 6 mos, 38% at 12 mos)
Combs. Cancer 2005;104:2168)
Median survival 10 months
Thirty-two patients with recurrent glioblastoma multiforme
(GBM) were treated for 36 lesions with SRS from 1993 to
2001

56. Efficacy of stereotactic radiosurgery as a salvage
treatment for recurrent malignant gliomas
Compared with this historic control group, SRS significantly prolonged
survival as a salvage treatment in patients with recurrent glioblastomas (23
months vs 12 months)
Doo-Sik Kong, Cancer 2008;112:2046

57. Hypofractionated Stereotactic Radiation
Therapy: An Effective Therapy for Recurrent
High-Grade Gliomas
JCO June 20, 2010 vol. 28 no. 18 3048-3053
The median time from diagnosis to H-SRT was
11 months for grade 3 patients, and 8 months for
grade 4 patients.

58. Studies of stereotactic radiosurgery as
adjunct treatment for recurrent high-grade
gliomas

59. Studies of stereotactic radiosurgery +
molecular targeting agent as adjunct
treatment for recurrent high-grade
gliomas

60. Gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumab
combined with chemotherapy in 11 patients with recurrent glioblastoma
multiforme who experienced tumor progression despite aggressive initial
multi-modality treatment.
median margin dose of GKSR was 16 Gy (range 13-18 Gy). Following
GKSR, bevacizumab was administrated with irinotecan in nine patients and
with temozolomide in one patient. One patient was treated with
bevacizumab monotherapy.
The treatment outcomes were compared to 44 case-matched controls who
underwent GKSR without additional bevacizumab.
The median overall survival (OS) from GKSR was 18 months and 1-year OS
rate was 73%. the patients who received bevacizumab had significantly
prolonged and (18 months vs. 12 months)
Park KJ. J Neurooncol. 2012 Apr;107(2):323-33

61. Clinical Outcomes of Gamma Knife Radiosurgery in the Salvage
Treatment of Patients with Recurrent High-Grade Glioma.
World Neurosurg. 2013 Feb 9. pii: S1878-8750
Gamma knife radiosurgery has become increasingly popular as a salvage
treatment modality for patients diagnosed with recurrent high-grade glioma.
The purpose of this article is to review the efficacy of gamma knife
radiosurgery for patients who suffer from this malignancy.
Retrospective, prospective, and randomized clinical studies published
between the years 2000 and 2012 analyzing gamma knife radiosurgery for
patients with high-grade glioma were reviewed.
evidence suggests that gamma knife radiosurgery provides patients with a
high local tumor control rate and a median survival after tumor recurrence
ranging from 13 to 26 months. Gamma knife radiosurgery followed by
chemotherapy for recurrent high-grade glioma may provide select patients
with increased levels of survival.

62. Complications of
Radiosurgery
 Short term side effects are uncommon
(2%) with worsening symptoms or new
seizures
 About one third mild swelling
(headaches, nausea)
 Radionecrosis in 5% to 10% in primary
cases but may be 24% or higher in
retreat cases

63. Sometimes the MRI
will look worse after
radiosurgery due to
radionecrosis of the
cancer this may
slowly go away but
may require repeat
surgery

64. Chemotherapy

65. Chemotherapy
EORTC Trial: Randomized trial of 573 GBM
(<70y)
Temodar + XRT XRT
median survival 14.6 mos 12.1 mos
surv/2y 26.5% 10.4%
surv/5y 10% 2%
Lancet Oncology 2009;10:459

66. Lancet Oncology 2009;10:459
EORTC Trial GBM

67. Chemotherapy
MGMT hypermethylation will
respond better to Temodar (survival
9.7 months versus 6.8 months)

68. Molecular Predictors of Progression-Free and Overall Survival in
Patients With Newly Diagnosed Glioblastoma: A Prospective
Translational Study of the German Glioma Network
JCO December 1,
2009 vol. 27no.
34 5743-5750

69. Molecular
changes
found in
GBM are
all
potential
targets for
new
targeted
therapies

70. Abnormal
cell cycle
pathways
in GBM all
targets for
new
modern
targeted
therapy

71. Chemotherapy/Targeted
Therapy

72. Multiple
factors that
effect survival
and most of
this data is
older data
and may not
apply to a
newly
diagnosed
patients

73. RTOG Data showed survival was related to age,
type of malignant glioma and performance score
and mental status

74. Group Median survival Survival at 2 years
I 58 – 68 months 64 – 76%
II 37 – 57 months 67 – 68%
III 17 – 22 months 35 – 45%
IV 11 – 13 months 8 – 15%
V 8 – 9 months 3 – 6%
VI 4 - 5 months 3 – 4 %
Data from Curran JNCI 1993;85:704 and Kleinberg IJROBP 1997;38:31
Survival by RTOG Group

75. Group 1: Age ≤40, frontal tumor.
Group 2: Age ≤40, other tumor sites.
Group 3: Age >40 and <65; KPS >70 and gross or subtotal
resection.
Group 4: Age ≥65 or age <40; or KPS ≤70; or biopsy only.
GBM Survival

76. Group Criteria Survival
Best No steroids, KPS > 90, not
GBM
20.2 months
Medium Everything not in worst 7.4 months
Worst On steroids, age > 50, GBM 4.7 months
Survival with Recurrent
Malignant Glioma

77. www.cancer.gov/clinicaltrials

78. Malignant Glioma
Robert Miller MD
www.aboutcancer.com