Overview of glioblastoma multiformae

1. Case Based Panel Discussion:
GBM

2. Initial Presentation
• A 73-year-old man presented to emergency department after experiencing a
generalized seizure.
• He had moderate left-sided weakness in the initial postictal period which
quickly resolved.
• In retrospect, the patient had noted subjective left-hand clumsiness for a
month prior to the seizure but had not reported it to his family or physician.
• A CT scan was obtained in the emergency room and was followed shortly by an
MRI.

3. Clinical Case
• The patient was started on antiepileptic therapy at the time of his emergency
department visit. He had no further seizures.
• His exam was pertinent for a Karnofsky Performance Score of 90, and subtle
left-sided pronator drift and slowing of rapid hand and foot movements on the
left side were his only findings on physical exam.
• Dexamethasone was not initiated as he did not have symptoms of elevated
intracranial pressure, such as headache or papilledema.

4. What would your Initial work up be?

5. Initial Workup – CT & MRI
Both of these images, and
the MRI in particular,
were concerning for
glioblastoma, and
metastasis and non-
neuroplastic entities such
as infection or
demyelination were
thought to be significantly
less likely.

6. Pathology
• Pathology revealed glioblastoma, MGMT methylated.
• The MGMT methylation status is prognostic of better survival, relative to
patients with unmethylated MGMT.

7. What would your Initial plan of
management be?

10. Clinical Case
• The patient underwent resection of his tumor without use of awake craniotomy
or intraoperative MRI.
• Following surgery, his left-sided weakness was transiently worse but it then
improved back to the pre-surgical baseline.
• His extensive resection placed him in a more favorable prognostic group than
biopsy alone would have.

11. Preoperative and postoperative MRI images

12. Feasibility of Supramaximal
Resection (SMR) in GBM?

13. Dimou J, Beland B, Kelly J. Supramaximal resection: A systematic review of its safety, efficacy and feasibility in glioblastoma. Journal of Clinical Neuroscience. 2020 Feb 1;72:328-34.

14. Dimou J, Beland B, Kelly J. Supramaximal resection: A systematic review of its safety, efficacy and feasibility in glioblastoma. Journal of Clinical Neuroscience. 2020 Feb 1;72:328-34.

15. Dimou J, Beland B, Kelly J. Supramaximal resection: A systematic review of its safety, efficacy and feasibility in glioblastoma. Journal of Clinical Neuroscience. 2020 Feb 1;72:328-34.

16. Conclusion – Systemic Review
• These studies highlight that feasibility of SMR is restricted to a modest percentage of
resectable glioblastoma patients, even with the instruments available to perform such
resections competently.
• This data re-affirms the importance of achieving GTR (gross total resection), whenever it can
be safely accomplished, as the minimum standard of surgical care for all glioblastoma
patients.

17. Post Surgery what would your plan
of management be?

18. RT Alone
TMZ 75 mg/m2 PO QD for 6 weeks,
then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles
Focal RT daily—30 x 200 cGy;
total dose: 60 Gy
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Concomitant
TMZ + RT*
Adjuvant TMZ
6 10 14 18 22 26 30 Wks
R 0
Phase III Study: New GBM: Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996.

19. Phase III Study: New GBM. Radiation ± Temozolomide
Stupp R, et al. N Engl J Med. 2005;352:987-996. Stupp et al. Lancet Oncol, 10:559-66, 2009
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42
Probability
of
OS
(%)
Months
Median Survival
RT + temozolomide: 14.6 months
RT alone: 12.1 months

20. Clinical Case
• The patient had excellent performance status and was felt to be a candidate for
standard chemoradiotherapy, despite his age of 73.
• He developed mild nausea and moderate fatigue during chemoradiotherapy,
but no life-threatening toxicities.
• He likewise tolerated adjuvant TMZ well from a symptomatic standpoint,
though several cycles had to be briefly delayed due to mild thrombocytopenia.
• He discontinued TMZ therapy and moved to an observational phase following
the sixth adjuvant cycle.
• Had he not been judged a good candidate for standard therapy, a TMZ-only
approach, sparing radiation, would have been an acceptable alternative for an
elderly man with an MGMT-methylated tumor.

21. Clinical Case
• Patient remained clinically and radiographically stable for nearly 2 years until he
had tumor progression along the medial margin of his resection cavity.
• His KPS at the time of progression was 80, due to increased left-sided
weakness, but he was still able to live independently with his wife.
• After discussing options, patient chose to pursue salvage chemotherapy.

22. Clinical Case - MRI
• The first MRI following the
completion of chemoradiotherapy,
shown in Fig. A, demonstrated a rim
of contrast enhancement around
the resection cavity that had not
been visible on the initial
postoperative imaging.
• Tumor progression after 2 yrs along
the medial margin of his resection
cavity, as shown in Fig. B.

23. Views regarding surgery on Eloquent areas in the brain….

24. Classification of Eloquent locations
1) Sawaya R, Hammoud M, Schoppa D, Hess KR, Wu SZ, Shi WM, et al. Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 1998;42:1044-56. 2) González-Darder JM, González-López P, Talamantes F, Quilis V, Cortés V, García-March G,
Roldán P. Multimodal navigation in the functional microsurgical resection of intrinsic brain tumors located in eloquent motor areas: role of tractography. Neurosurg Focus. 2010 Feb;28(2):E5. doi: 10.3171/2009.11.FOCUS09234. PubMed PMID: 20121440. 3) Ening G, Osterheld F, Capper D, Schmieder K,
Brenke C. Risk factors for glioblastoma therapy associated complications. Clin Neurol Neurosurg. 2015 Jan 9;134:55-59. doi: 10.1016/j.clineuro.2015.01.006. [Epub ahead of print] PubMed PMID: 25942630

25. • Pseudo-progression
• Psuedo-response
Clinical Dilemma….

26. Recurrent Glioblastoma
• Recurrence in GBM is a rule rather than exception
• Diagnosis of recurrence:
• Pseudo-Progression (5-30%): Transient increase of contrast enhancing
tumour within 3 months of completion of CTRT
• Pseudo-responses: Divergent effects on T1 contrast vs. FLAIR images
[Anti-angiogenic therapies]
• Updated RANO criteria: Restrictive parameters within 3 months,
corticosteroids use, T2 FLAIR changes
• Advanced imaging: Perfusion imaging, Dynamic susceptibility contrast,
Apparent diffusion coefficient and MR spectroscopy, 18F-FET-PET

27. What is your plan of management in case of
recurrence?
• Surgery
• Radiation
• 2nd line chemotherapy/targeted therapy/ Immunotherapy

29. Surgery for recurrent/progressive GBM
• Select group of patients may benefit from surgery:
• Confirmed progression and PFI (longer is better)
• Good performance status (KPS ≥ 80), tumour in non-eloquent area,
non-ependymal involvement, small tumour volume, GTR possible
• ? MGMT methylation status
• Other benefits of surgery:
• Diagnosis of recurrent disease (vs. radiation necrosis)
• Confirmation of initial histology
• Determination of molecular markers for biomarker-based decision
making

30. Surgery for recurrent/progressive GBM

31. Re-irradiation for recurrent GBM
• Role less defined: Lack of prospective RCT
• Stereotactic Radiosurgery: 30-36 Gray in 2-3.5 Gray per fraction
• Young age, good KPS, small volume disease (Ryu et al 2014; Combs et
al 2007)
• Interval less than 6 months (Fogh et al 2010) or >6-12 months (Combs
et al 2013)
• Stereotactic Radiosurgery with BEV:
• Ionizing radiation up regulates VEGF, stimulating angiogenesis
• BEV could counteract angiogenesis
• BEV could also mitigate radiation induced inflammation, edema and
necrosis

33. Brachytherapy for recurrent GBM
• Resection plus placement of I-125 seeds (Patel et al 2000; Larson et al): Median survival 52 weeks
• Resection->I-125 seeds-> Resurgery (Mayr et al 2002; Boisserie et al 1996): Median survival 35-56 weeks
• Resection plus Gliasite brachytherapy (Chan et al 2005): Median survival 36 months
• HDR interstitial brachytherapy sole (Tselis et al; 2007): Median survival 37 months

35. Chemotherapy for recurrent GBM
• Sparse number of trials
• Older trials before 2005, TMZ-naïve patients
• Different endpoints and response criteria impede comparability
• Varied treatment options without
• Treatment options:
• Nitrosoureas
• TMZ
• Bevacizumab/ Combination BEV
• Immunotherapy/experimental therapy/clinical trial

36. The combination of bevacizumab and lomustine met pre-specified criteria & should be evaluated further
The study do not support a role for single-agent bevacizumab in the treatment of recurrent glioblastoma

37. N Engl J Med 2017;377:1954-63.
EORTC - 26101
2:1 ratio
Primary end point - overall survival

38. Bev + Lom vs Lom alone:
Similar OS but significant improvement with PFS
N Engl J Med 2017;377:1954-63.

39. Conclusions of EORTC - 26101
• Adding bevacizumab to lomustine did not confer a survival advantage over
lomustine alone but prolonged progression-free survival.
• There were no unexpected findings from assessments of toxic effects.
• Addition of bevacizumab in the current trial did not result in reduced use of
glucocorticoids
• MGMT status was not predictive of benefit from the combined therapy.
• This trial led to the full approval of Bevacizumab in recurrent GBM by USFDA
in Dec 2017.

40. Bevacizumab monotherapy and combination

41. BRAIN Study: Survival Data Comparing Bevacizumab versus
Bevacizumab plus Irinotecan in Recurrent GBM
Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
Single-agent Bevacizumab demonstrated an objective response for a clinically meaningful duration
J Clin Oncol 27:4733-4740. © 2009
Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and
radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab
plus irinotecan† (n=82) for up to 104 weeks

42. BRAIN Study: Survival Data Comparing Bevacizumab versus
Bevacizumab plus Irinotecan in Recurrent GBM
Bevacizumab
(n = 85)
Bevacizumab +
Irinotecan
(n = 82)
ORR 28.2% 37.8%
6month PFS 42.6% 50.3%
12-months survival 38% 38%
18-months survival 24% 18%
24-months survival 16% 17%
30-months survival 11% 16%
Cloughesy T et al. Proc ASCO 2010;Abstract 2008. Henry S. Friedman etal. J Clin Oncol 27:4733-4740. © 2009
Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and
radiotherapy (RT). Patients were randomized to receive either Bevacizumab alone 10mg/kg/ 2wkly (n=85) or Bevacizumab
plus irinotecan† (n=82) for up to 104 weeks

43. Treatment Algorithm: Recurrent GBM

44. Role of Immune-Checkpoint
inhibitors in Recurrent GBM in
your practice?

45. CheckMate 143: Nivolumab vs Bevacizumab in
Recurrent GBM (Cohort 2)—Study Design
Endpoints:
 Primary: OS in all randomized patients
 Secondary: investigator-assessed ORR
and PFS; 12-mo OS rate
 Other key endpoints: safety; biomarkers
Assessments:
 Tumor: contrast-enhanced MRI Q6W
until Wk 13, then Q8W
 Safety: CTCAE v4.0
Treatment until:
 Confirmed progression
 Unacceptable toxicity
 Discontinuation for
other reasons
Follow-up:
 Safety for ≥ 100 days
 Progression
 OS (every 3 mos)
Patients with GBM in first
recurrence after first-line
treatment with at least RT and
temozolomide
(N = 369)
Nivolumab 3 mg/kg Q2W
n = 184
Bevacizumab 10 mg/kg Q2W
n = 185
Randomized 1:1
Stratified by measurable
disease at baseline
(yes/no)
Median follow-up: nivolumab, 9.8 mos (range: 1.3-26.3);
bevacizumab, 9.4 mos (range: 0-26.8)
Reardon. WFNOS 2017. NCT02017717.

46. CheckMate 143: Nivolumab vs Bevacizumab in Recurrent
GBM—OS, PFS
Events, n
Median OS, Mos
(95% CI)
12-Mo OS Rate, %
(95% CI)
Nivolumab 154 9.8 (8.2-11.8) 41.8 (34.7-48.8)
Bevacizumab 147 10.0 (9.0-11.8) 42.0 (34.6-49.3)
Events, n
Median PFS, Mos
(95% CI)
12-Mo PFS Rate, %
(95% CI)
Nivolumab 171 1.5 (1.5-1.6) 10.5 (6.5-15.5)
Bevacizumab 146 3.5 (2.9-4.6) 17.4 (11.9-23.7)
Mos
184 41 27 19 18 12 10
185 88 46 32 27 19 12
Nivolumab
Bevacizumab
Patients at Risk, n
Mos
184 168 133 96 77 59 39 24 9 0
185 169 135 99 72 48 37 14 5 0
Nivolumab
Bevacizumab
Patients at Risk, n
PFS
HR: 1.97 (95% CI: 1.57-2.48;
P < .0001)
0 3 6 9 12 15 18 21 24 27
Probability
of
PFS
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS
HR: 1.04 (95% CI: 0.83-1.30;
P = .76)
Probability
of
OS
0 3 6 9 12 15 18 21 24 27
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nivolumab
Bevacizumab
Censored
Reardon. WFNOS 2017. NCT02017717.
7 1 0
3 1 0
Nivolumab
Bevacizumab
Censored

47. CheckMate 143: Nivolumab vs Bevacizumab in Recurrent
GBM—Corticosteroid Use
 Patients treated with nivolumab required higher doses of corticosteroids to manage their
disease than those treated with bevacizumab
*The number of patients who received corticosteroids and proportion of on-treatment patients who received corticosteroids are indicated at each data point.
Corticosteroid Use*
0
1
2
3
4
Wks
Baseline 6 12 18 24
73
(40%)
76
(46%)
97
(53%)
83
(50%)
75
(56%)
68
(50%)
46
(56%)
43
(45%)
20
(41%)
24
(32%)
Median
Dose
(mg/day)
Nivolumab
Bevacizumab
Reardon. WFNOS 2017. NCT02017717.

48. Conclusion
• Multidisciplinary care is necessary to maximize survival time and preserve quality of life.
• In appropriately selected patients, aggressive surgery may relieve symptoms and prolong
survival.
• Pathologists, Medical oncologists, Radiation oncologists, and Neurosurgeons and
Neurologists work as a team to design and deliver the treatment plan.

49. THANK YOU