This presentation provides an overview of the standard of care and new advances in the treatment of high-grade glioma, specifically glioblastoma multiforme (GBM) and anaplastic astrocytoma. The key points discussed include: - The current standard of care for GBM is maximal safe surgical resection followed by concurrent radiation therapy and temozolomide chemotherapy, then adjuvant temozolomide. - The landmark EORTC/NCIC trial established temozolomide combined with radiation as the standard of care, improving median survival from 12 to 14.6 months. - MGMT promoter methylation status is the strongest predictor of outcome, with methylated tumors responding better

1. By
Osama Elzaafarany
Assistant lecturer of clinical oncology
Medical Research Institute-Alexandria University
High-grade glioma..
Standard of care & new advances…
March 2014

2. Contents:
 Introduction: 2 slides.
 GBM:
 Epidemiology: 1 slide.
 Molecular biology & New trends: 5 slides
 EORTC/NCIC trial: 10 slides.
 MGMT: 1 slide.
 Evidence-based medicine: 6 slides.
 Avastin in GBM: 2 slides.
 Novocure (TTF): 2 slides.
 Gliadel (BCNU) wafers: 1 slide.
 Anaplastic astrocytoma: 7 slides
 Take home message.
Aim of this presentation:
• To understand the standard of care for both
GBM and anaplastic glioma.
• What is the new advances and modifications
to the standard of care?

3. WHO
grade III grade IV
What is high-
grade glioma?
GBM
• Anaplastic astrocytoma
• Anaplastic oligodendroglioma
• Anaplastic mixed glioma
“oligo-astrocytoma”
Anaplastic
gliomas

4. Glioblastoma Multiforme:
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
 Most common 1ry malignant brain
tumor in adult.
 About 50 % of all gliomas.
 1 year survival about 30 %.
 Men > females.
 Peak incidence: 65-75 ys.
 Age median survival.
 Malign CNS = 1.4% of all cancers.
 1ry CNS tumors ~ 66.000 new
cases/year: (USA, 2012):
=> glioma = 32 %
=> GBM = 16% of 1ry CNS Ts.
~10.000 new cases of GBM/year
Established risk factor:
previous exposure to ionizing radiation:
Pre-natal diagnostic X-rays.
Cranial RTx for ALL: (risk 0.5% at 10ys).
• Hereditary syndromes: 5%
of GBM cases:
• Suspected when you have
multiple brain tumors.
• P53, NF1, Turcot’s.

5. Molecular Biology:
 GBM characterized by extensive heterogeneity at the cellular and
molecular levels.
 Develops either de novo (primary GBM), or as the result of the
malignant progression from a lower-grade glioma (secondary
GBM).
 4 molecular sub-types: (classical, mesenchymal, proneural and neural)
 The true cellular origin of gliomas, including GBM, is still a
debatable question => Two different hypotheses for the origin:
 accumulation of alterations that occur in differentiated mature
cells (glial cells).
 most recent hypothesis assumes that cancer cells arise from
the accumulation of alterations that occur directly in stem
cells: CD133 +ve.
treatment resistance
treatment resistance

6. Molecular Biology:
Growth factor
receptors
Signaling pathways
 RB pathway.
 P53 pathway.
 Tyrosine Kinases pathways:
RAS-RAF.
PI3K

7. Molecular Biology “promising agents”
EGFR
1) Over-expressed: 50% of GBM.
2) Del of exon 2-7 “loss of extra-cell domain”: (mutant EGFRvIII)
• 30 % of patients
• Poor prognosis.
• Celldex intradermal vaccine (Rindo pepi mut).
• Phase II study, ACT III trial, SNO 2010, 65 pts with newly diagn GBM,
• Taken for 3 months with adjuv TMZ.
• Median survival ~ 22 ms (compared with 15 m in EORTC/NCIC study)
Now ongoing:
Phase III Study of Rindopepimut/GM-CSF in newly Diagnosed GBM; (ACT IV).
ClinicalTrials.gov Identifier: NCT01480479

8. Cilengitide:
• Anti-integrins: which is important for angiogenesis.
• I.V. drug.
• Newly diagnosed GBM:
 Phase II trial, (Burt Nabors, Cancer2012;118:5601-7, Nov 2012)
 Combined with RT + TMZ.
 OS was ~20 months.
 Patients with MGMT promoter methylation tend to show a higher PFS and OS (~30 ms).
• Now ongoing:
 CORE study, phase II (NCT00813943)
 Clinical trial testing the efficacy of cilengitide with TMZ + RT in patients with or without
MGMT methylation.

9. Cediranib:
• Oral pan-VGEFR TKI
• Recurrent GBM:
 As a single agent (phase II): showed a PFS ~ 4 ms and OS was ~
7.5 ms
 A phase III trial with cediranib + lomustine for the treatment of
recurrent GBM in currently ongoing (NCT00777153).
• Newly diagnosed GBM:
 All clinical trials are currently ongoing or recruiting:
 Phase I/II cediranib + RT + TMZ (NCT01062425 and NCT00662506);
 Phase I combination with BVZ (NCT00458731);

10. What is the standard of care for GBM?
adjuv.
ConcurrentSurgery
RTx
TMZ
TMZ
Age ≤ 70
PS ≤ 2
Surgery: max safe resection.
RTX: 60 Gy, fractionated, partial brain.
TMZ: Temodar.

11. EORTC/NCIC

12. EORTC/NCIC
RAND
After Surgery
• 573 pts.
• GBM.
• Age ≤ 70
• PS ≤ 2
RTX alone
RTx+TMZ
then adjuv TMZ

13. EORTC/NCIC methodology:
 Radiotherapy :fractionated focal irradiation ,2 Gy per fraction
given once daily 5 days per week over 6 weeks; (total dose of 60 Gy).
 Concomitant chemotherapy: temozolomide 75 mg /m2 daily.
from the first day of radiotherapy until the last day, (no longer than
49 days).
 Adjuvant temozolomide: 6 cycles of 5-day schedule every 28
days; 150 mg /m2 for the first cycle and was increased to 200 mg
/m2 beginning with the second cycle.
 patients in the radiotherapy plus temozolomide group were to
receive prophylaxis against Pneumocystis carinii pneumonia,
consisting of either inhaled pentamidine or oral trimethoprim–
sulfamethoxazole

14. •At least 2 weeks of Cortz.
Before randomization.
•About 70% were on Cortz.
About 16% had just Biopsy..
About 70% were ≥ 50 years
subgroup with no
survival benefit

16. EORTC/NCIC Results:
2-year survival rate
27 % with
RTx + TMZ
10 % with
RTx alone.
5-years: 10.9 %
5-years: 1.9 %
Median survival benefit=2.5 m;
From 12.1 m to 14.6 m with RTx-TMZ

17. TMZ did not increase risk
of treatment delay or
interruption
Median time from diagnosis to the
start of treatment was 5 weeks
85 % completed concurrent
RTx-TMZ
78% started adjuv TMZ
47% completed 6 cycles
Main reason was
disease progression

18. EORTC/NCIC Results:
 Grade 3 or 4 hematologic toxic effects:
• Concomitant RTx + TMZ: 7 % of patients.
• RTx alone: 0 %
• Adjuvant TMZ: 14 %
 A benefit of combined therapy was recorded in
all clinical prognostic subgroups, including
patients aged 60–70 years.
 Methylation of the MGMT promoter was the
strongest predictor for outcome and benefit
from temozolomide chemotherapy

19. Critic:
Benefit from
Concomitant RTx-TMZ
Adjuvant TMZ
OR

20. MGMT
 O-6-methylguanine-DNA methyltransferase.
 DNA repair enzyme.
 Function: repair the damage of DNA caused by
alkayting agents e.g TMZ.
 When methylated: it dose not work.
 Methylated cases: better response to TMZ, better PFS
and OS.
 This was illustrated in the update of EORTC/NCIC trial
in 2009, and both NOA-08 and the Nordic trial of TMZ
in elderly GBM pts.

21. Evidence- based medicine:
ConcurrentSurgery
TMZ
RTx
TMZ

22. ConcurrentSurgery
TMZ
RTx
TMZ
Benefit of RTx :
Dose of RTx :
Fx of RTx :
Stereo. boost:
Dose-dense
TMZ
Avastin
BTSG
MRC
RTOG9006
RTOG9305
RTOG0825
AVAglio
GLARIUS
RTOG0525
Old age
Nordic
NOA-08
Canadian
Frensh
Evidence- based
medicine:
BCNU-wafer
Neuro-onc J
2003, Phase III

23. BTSG, 1978:
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
MRC, 1991:
474 pts randomized to 45 Gy vs 60 Gy increase surv from
( no chemo) 9 to 12 ms. With 60 Gy
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
RTOG9006, 1998:
222 pts.
90% GBM
RAND
• Observ.
• BCNU.
• RTx alone.
• RTx +BCNU. Increase surv: 3-6 ms
712
pts.
RAND
• 60 Gy:
(2Gy/Fx)
• 72 Gy:
(1.2Gy BID)
Better survival

24. RTOG0525, 2011-JCO:
823pts.
KPS≥60
RAND
• Standard TMZ dose
• Dose-dense TMZ.
No difference in both OS &
PFS.
Increase toxicity with dose-
dense
After
RTx

25. Canadian trial, 2004-JCO:
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
French trial, 2007-NEJM:
100 pts.
GBM
age≥ 60
KPS≥ 50
RAND
•RTx 60 Gy.
• 40 Gy/ 15 Fx (3 Ws)
Same OS ;
5.5 ms.
decrease need
to inc Cortz dose
with 40 Gy
85 pts.
G III & IV
age≥ 70
KPS≥ 70
RAND
• RTx
(50 Gy/ 1.8 Gy)
•BSC
Significant
inc of
survival
Critic: underpowered statisticaly
GBM in elderly
more than 44% of GBM
occcur in pts > 65 ys.

26. Nordic (NCBTSG), 2012-Lancet onc:
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
German (NOA-08), 2012-Lancet onc :
“non-inferiority study”
342 pts.
GBM
Age > 60
Good PS
RAND
TMZ alone; 6 ms
vs
RTx 34 Gy/ 2Ws
vs
RTx 60 Gy.
412 pts.
GBM (89%)
Age > 65
KPS≥ 60
RAND
• RTx
(60Gy/ 30 Fx)
•TMZ:
Week on / week off
100 mg / m2
No
Significant
differences in
OS (~9 ms)
GBM in elderly
> Neutopenia in TMZ arm
Better
survival
when
compared to
60 Gy

27. Avastin in GBM
FDA approval in recurrent cases in 2009 based on 2 phase II
studies:
BRAIN trial, JCO 2009:
 Phase II.
 167 pts with Recurrent disease.
 Avastin alone or with Irinotecan.
 Avastin decreases the need to escalade the cortz dosage.
 Intra-cranial Hge 4% with Avastin + Irino.
 Grade ≥ 3: HTN (8%), convulsion (6%), fatigue (90%).
6ms PFS OS RR
Avastin 43 % 9 % 28 %
Avastin+Irinotecan 50 % 9 % 38 %

28. Avastin in newly
diagnosed GBM
Adding to standard
of care
Compared with
standard of care
GLARIUS trial
• JCO, 2013, Abstract
• Phase III
• ~ 170 pts.
• Non-methyl MGMT
Significant inc
In PFS with
Avastin + Irinotecan+RTx
vs
Standard of care
AVAglio trial
• JCO, 2013, Abstract
• Phase III
• ~900 pts.
Significant inc
In PFS with
addition of
Avastin to
Standard of care
RTOG 0825
• JCO, 2013, Abstract
• Phase III
• 637 pts.
Significant inc
In PFS with addition
of Avastin to
Standard of care
Inc GIII toxicity with
Avastin.

29. Novocure (TTF):
• Uses electric fields within the human
body that disrupt the rapid cell division
exhibited by cancer cells.
• Disrupt mitotic spindle microtubule
assembly and to lead to dielectrophoretic
dislocation of intracellular
macromolecules and organelles during
cytokinesis.
•Affect only one cell type at a time; The
frequency used for a particular treatment
is specific to the cell type being treated.
• TTF therapy has not been shown to
affect cells that are not undergoing
division.

30. Novocure (TTF):
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
 FDA approval in 2011 for recurrent cases of GBM based on
phase III study:
 Stupp et al, Eur J cancer, 2012
 237 pts with recurrent disease.
 Rand to TTF vs Chemo.
 Result was same survival.
 Low toxicity with TTF + imroved QOL.
 Now ongoing trial for adding TTF to standard of care in newly
diagnosed cases. (NCT00916409)

31. Gliadel wafers:
• Implantation of BCNU-wafers in the surgical cavity
intraoperatively.
• Significantly improve survival in recurrent cases
(Brem et al, Lancet 1995).
• In a phase III trial from Germany, which was
published at the neuro-oncology journal in 2003, 240
newly diagnosed pts showed significant improvement
in median survival from 12 m to 14 ms after
implantation of BCNU-wafers then RTx ( no adjuv
systemic chemo).
• FDA approved in new cases.
•Toxicity:
 CSF leak 5%
 I.C.HTN 9 %. .
Which is not the standard of care

32. Anaplastic Gliomas
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas.
Would you
treat it typically
as the GBM ??

33.  Resection appears to improve survival relative to biopsy, as it does for
GBM.
 Addition of chemo to Rtx. failed to improve survival in 2 phase III
trials: (unlike GBM)
 Co-deletion of 1p 19 q correlates with better response to chemo.
 Adjuvant temozolomide was as effective and less toxic than PCV in
anaplastic astrocytoma, based on one retrospective study. (?)
Rationale for the ongoing CODEL trial.
RTOG 9402 and EORTC 26951
Rationale for the ongoing RTOG 9813 trial.
Should be investigated in pts with poor prognosis ( non co-deleted):
Rationale for the ongoing CANTON trial.
What bout using CTx. alone as adjuvant ?

34. RTOG9402, 2006-JCO :
after surgery
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
EORTC26951, 2006-JCO:
after surgery
289 pts.
Anaplastic
oligodendr.
RAND
PCV X 4 then Rtx.
RTx alone (60Gy)
Same OS
PCV
increase PFS
Benefit with
co-deleted pts.
368 pts.
Anaplastic
oligodendr.
RAND
• RTx then PCV X 6
•RTx alone (60Gy)
No diffr. in OS
Increase PFS

35. NOA-04, 2009-JCO:
• Survival rates were equivalent whether chemotherapy or radiotherapy was used
first among patients with anaplastic astrocytomas, oligodendrogliomas, and mixed
tumors.
• Time to progression following RT was longer than after chemotherapy.
• Initial radiation therapy achieved more complete and partial responses than initial
chemotherapy.
318 pts.
Anaplastic
glioma
RAND
• RTx
•PCV
•TMZ
Progression
• Chemo.
•RTx
•RTx
Suggesting the superiority of radiotherapy.

36. The ongoing CATNON (Concurrent vs. Adjuvant Temozolomide for
NON 1p19q co-deleted anaplastic gliomas)
It will answer 2 questions:
• Benefit of add CTx in non co-del anaplastic glioma.
• Concurrent vs adjuv TMZ (? In EORTC/NCIC trial).

37.  CODEL; (for 1p/19q CO-DELeted tumors):
Randomizes patients to:
 RT alone.
 RT with concurrent and adjuvant temozolomide.
 Temozolomide alone.
To prospectively address the issue of CTx alone in co-deleted
patients.
 RTOG 9813 :
Randomized patients with anaplastic astrocytomas (or
oligoastrocytomas) to:
 Radiotherapy with concurrent nitrosourea; (carmustine or lomustine).
 Radiotherapy with concurrent temozolomide.

38. What is the standard of care for
anaplastic glioma ?
Surgery RTx
TMZ
PCV
Surgery: max safe resection.
RTX: 60 Gy, fractionated, partial brain.
PCV: Procarbazine+CCNU+Vincristine
If co-deleted
or
concurrent
Good PS
Before or
after RTx.

40.  The standard of care of newly diagnosed GBM cases is
Surgery then concurrent RTX/TMZ then adjuvant 6 cycles
TMZ.
 Some new and promising trends will be based on
molecular targets.
 The standard of care of newly diagnosed anaplastic
glioma cases is surgery followed by adjuvant RTx, and if
co-deleted you can add adjuvant chemo.