This document summarizes results from a clinical trial evaluating the efficacy of adding temozolomide chemotherapy to radiation therapy for the treatment of glioblastoma. The trial involved 573 patients randomized to receive either radiation therapy alone or radiation therapy plus temozolomide. The addition of temozolomide resulted in a statistically significant improvement in median survival (14.6 months vs 12.1 months) and 2-year survival rates (26.5% vs 10.4%). Progression-free survival was also improved in the temozolomide group. Toxicity was found to be minimal. The results provide support for the standard of care now being radiation therapy plus temozolomide for newly diagnosed

1. Brain tumors
C
Dr Belal Elhawwari
Radiation Oncologist

2. The Hashemite Kingdom of
Jordan

3.  Population
 6,508,271 (July 2011 est.)
 Age structure
 0-14 years:
 35.3% (male 1,180,595/female 1,114,533)
15-64 years:

59.9% (male 1,977,075/female 1,921,504)
65 years and over
 : 4.8% (male 153,918/female 160,646) (2011 est.)

4. Trend of cancer in Jordan, 19802009

5. Ten most common cancers
among Jordanian Males, 2009
Rank
1
2
3
4
5
6
7
8
9
10
Cancer
No
%
Colorectal
290
12.7
Lung
256
11.2
Leukemia
189
8.3
U.Bladder
184
8.1
Prostate
179
7.9
Non- Hodgkin's Lymphoma
128
5.6
Brain & CNS
100
4.4
Larynx
88
3.9
Stomach
68
3.0
Hodgkin's Disease
68
3.0

6. Ten most common cancers among
Jordanian Females , 2009
Rank
Cancer
No
%
1
Breast
926
36.8
2
Colorectal
264
10.5
3
Thyroid
140
5.6
4
114
4.5
110
4.4
6
Leukemia
Non- Hodgkin's
Lymphoma
Corpus Uteri &
Unspecified
104
4.1
7
Hodgkin's Disease
79
3.1
8
Stomach
77
3.1
9
Ovary
75
3.0
10
Brain &CNS
72
2.9
5

7. Trend of cancer in Jordan, 19802010

8. Ten most common cancers
among Jordanian Males, 2010
Rank
1
2
3
4
5
6
7
8
9
10
Cancer
No
%
Colorectal
332
14.2
Lung
311
13.3
Prostate
218
9.4
U.Bladder
186
8
Leukemia
127
5.5
Non- Hodgkin's Lymphoma
120
5.2
Brain & CNS
Stomach
106
4.5
90
3.9
Larynx
74
3.2
Hodgkin's Disease
65
2,8

9. Ten most common cancers among
Jordanian Females , 2010
Rank
Cancer
No
%
1
Breast
941
37.4
2
Colorectal
226
9.0
3
136
5.4
4
Thyroid
Non-Hodgkin
lymphoma
130
5.2
5
Uterus
113
4.5
6
Leukemia
91
3.6
7
Ovary
84
3.3
8
Lung
68
2.7
9
Hodgkin disease
67
2.7
10
Stomach
62
2.5

10. Top ten cancers among
Jordanian both sexes, 2010

11. Age-Standardized Incidence Rate per (100,000 )population for Male
cancers ( all sites) , Jordan compared with other countries .

18. Radiotherapy plus Concomitant &
Adjuvant Temozolomide for
Glioblastoma
Roger Stupp, M.D., Warren P.
Mason, M.D., et al,
European Organisation for Research and
Treatment of Cancer Brain Tumor and
Radiotherapy Groups and the National Cancer
Institute of Canada Clinical Trials Group
Volume 352 Issue 10 , 10 March 2005, Pages 987996

19. Introduction
Treatment of Glioblastoma
Surgical resection
,safely feasible
Adjuvant
Radiotherapy
adjuvant carmustine,
(a nitrosourea drug )
used in the USA .
No survival benefit
Compared with RTX
alone
randomized phase 3 trial of nitrosourea -based adjuvant chemotherapy
Stupp R, et al . ASCO 2003 , American Society of Clinical Oncology, 2003:779-88.

20. Introduction
Treatment of recurrent gliomas
Temozolomide
as a single agent
Antitumor
activity
reduces the DNA-repair
enzyme (MGMT) in
tumor tissue
longer survival especially
patients with glioblastoma
Hegi ME, et al.. Clin Cancer Res 2004;10:1871-1874

21. Introduction
pilot phase 2 trial
in patients Glioblastoma
Concomitant:
temozolomide
+
fractionated
radiotherapy
adjuvant
Temozolomide
6 cycles
two-year survival rate,
31 %
promising clinical
activity
Stupp R et al.. J Clin Oncol 2002;20:1375-1382

22. therefore the (EORTC) & the (NCIC)
initiated this trial
Concomitant:
temozolomide
+
fractionated
radiotherapy
adjuvant
Temozolomide
6 cycles
phase 3 trial
in patients Glioblastoma
Comparing
Radiotherapy
alone

23. the (EORTC) & the (NCIC) trial
patients
The median age :
56 years
Eligibility criteria :
*newly diagnosed
glioblastoma
(grade IV astrocytoma)
*p/s 2 or less
*adequate renal ,
Hematologic & hepatic
function
baseline examination:
1.
CT-scan or MRI
2.
CBC & chemistry
3.
physical examination
4.
pathology review
84% underwent
debulking surgery
573 patients
from 85 institutions
in 15 Countries
pathological review
confirmed in 93 %
Histologic slides were
submitted for 85%

24. the (EORTC) & the (NCIC) trial
Methodology & Design
573 patients from 85
institutions in 15
Countries
From August 2000 until
March 2002
Radiotherapy
(286 patients)
Randomly
assigned to
receive
End point :
Overall survival
Radiotherapy
+temozolomide
(287 patients)

25. the (EORTC) & the (NCIC) trial
treatment - Radiotherapy alone
Radiotherapy
60 Gy/ 30 fractions /6 weeks
day 1
7
5
14
21
28
35
43
week 1
week 2
week 6
week 3
week 5
week 4
GTV (tumor without edema )
CTV (GTV+ 2-3 cm margins)
Planned with CT-scan
+ 3D planning system
Radiotherapy delivered
with 6MV linear & more

26. the (EORTC) & the (NCIC) trial
treatment - RTx+Temodal
Radiotherapy
60 Gy/ 30 fractions /6 weeks
day 1
7
5
14
21
28
35
43
week 1
week 2
week 6
week 3
week 5
week 4
GTV (tumor + edema )
CTV (GTV+ 2-3 cm margins)
Planned with CT-scan
+ 3D planning system
Radiotherapy delivered
with 6MV linear & more

27. the (EORTC) & the (NCIC) trial
treatment - RTx+Temodal
Radiotherapy
60 Gy/ 30 fractions /6 weeks
day 1
7
5
14
21
28
Break
35
43
week 1
Temodal
75 mg/m2
Daily 7 D
week 2
Temodal
75 mg/m2
Daily 7 D
week 6
week 3
Temodal
75 mg/m2
Daily 7 D
week 5
week 4
Temodal
75 mg/m2
Daily 7 D
Temodal
75 mg/m2
Daily 7 D
Temodal
75 mg/m2
Daily 7 D
4 week
Adjuvant
Temodal
Temodal
5 days every 28
days for 6 cycles
150 mg/m2 cycle 1
200 mg/m2 cycle 2
200 mg/m2 cycle 3
200 mg/m2 cycle 4
200 mg/m2 cycle 5
200 mg/m2 cycle 6
GTV (tumor without edema )
CTV (GTV+ 2-3 cm margins)
Planned with CT-scan
+ 3D planning system
Radiotherapy delivered
with 6MV linear & more

28. the (EORTC) & the (NCIC) trial
Results
At a median follow up 28 months
480 pts (84%) died
Median survival:
RTx alone :12.1 months
RTx+Temadal :14.6 months
The 2 yrs survival :
RTx alone :10.4%
RTx+Temadal :26.5%

30. the (EORTC) & the (NCIC) trial
Results
The median progressionfree survival was:
RTx alone : 5.0 months
RTx+Temadal : 6.9 months
The progression-free survival
at 12 months :
RTx alone :9.1%
RTx+Temadal :26.9%

32. adverse events
 No grade 3 or 4 hematologic
toxic effects were observed in
the radiotherapy group
 During adjuvant
 During concomitant
temozolomide therapy
temozolomide therapy

33. The effects of TEMODAL and MGMT on methylation status of DNA.
Adapted from MGMT and Objection Handling.ppt

34.  TEMODAL is an alkylating agent that kills
cells by adding a methyl group to DNA.
DNA damage caused by TEMODAL
culminates in cell death through
apoptosis. One enzyme that is known to
repair the DNA damage caused by
alkylating agents such as TEMODAL is O6methylguanine-DNA methyltransferase
(MGMT

35. MGMT is expressed in all cells. MGMT
repairs damaged DNA by removing methyl
groups from the O6 position of DNA
guanines. Once MGMT has removed one
methyl group, it is inactivated. It would seem
reasonable therefore that lower MGMT levels
in tumour cells might result in a higher
response following TEMODAL administration,
and conversely high MGMT levels might
translate into a lower response rate.

36. the (EORTC) & the (NCIC) trial
treatment - Conclusion
 the addition of temozolomide to radiotherapy provides
a statistically significant survival benefit
with minimal toxicity
 the regimen of radiotherapy plus temozolomide
should serve as :
the new platform from which we need to explore for
new regimens for treating malignant gliomas.
Thank you

37. ASCO 2013 data

38. A phase II trial of lithium, bevacizumab, temozolomide, and
radiation for newly diagnosed glioblastomas (GBM)
 . This phase II study evaluated the
safety and efficacy of using lithium
and bevacizumab (BEV) in newly
diagnosed GBM.
 Conclusions: The strategy of
targeting angiogenesis and invasion
simultaneously in newly diagnosed
GBM is effective and feasible. Clinical
trial information: NCT01105702.

39. Final results of a single-arm phase II study of
bevacizumab and temozolomide following
radiochemotherapy in newly dignosed adult
glioblastoma patients
 This study evaluated efficacy and
safety of bevacizumab (BEV) added
to the post-radiation treatment phase
for patients with newly diagnosed
glioblastoma (GBM).
 Participants received standard
radiation therapy (RT) within 6 weeks
of surgery, and concomitant
administration of temozolomide
(TMZ)

40. Four weeks after radiation, treatment
with TMZ (Days 1-5 of a 28 day cycle)
with BEV, (days 1 and 15 of a 28 day
cycle) was started, and continued until
disease progressed or adverse effects
indicated need to stop treatment.

41.  ). Results suggest that the addition of
bevacizumab to the post-RT phase of
treatment improves both PFS and OS
for persons with GBM despite the high
percentage of participants being
unable to progress to post-radiation
treatment. Clinical trial information:
NCT005906

42. Temozolomide plus bevacizumab in elderly patients
with newly diagnosed glioblastoma and poor
performance status: An Anocef phase II trial
 evaluated the efficacy and safety of the
combination of TMZ with bevacizumab
(BV) as an initial treatment for elderly
patients with GBM and KPS<70.
 Conclusions: This study confirms that
TMZ-based treatment is of help in
elderly GBM patients with poor KPS.
However, the addition of bevacizumab
does not appear to be of benefit in term
of PFS and OS.

43. Survival benefit from bevacizumab in newly
diagnosed glioblastoma (GBM) according to
transcriptional subclasses.
 Background: Genome-wide
transcriptional studies (TCGA and
others) have identified distinct GBM
molecular subtypes, but to date this
has not translated into prognostic or
therapeutic implications.
Bevacizumab has emerged as a new
treatment option for GBMs, although
a survival benefit has yet to be
demonstrated in unselected patients
(pts).

44.  We analyzed outcomes from a
prospective phase II trial in newly
diagnosed GBM treated with
hypofractionated stereotactic
radiotherapy (HFSRT) combined with
temozolomide and bevacizumab, and
correlated with GBM transcriptional
subclasses.

45.  Conclusions: We provide proof-ofprinciple that GBM transcriptional
classification is biologically and
therapeutically relevant, identifying
non pro-neural GBMs as the best
candidates for bevacizumab
treatment.

46.  Our findings imply that angiogenesis
and tumor invasion mechanisms in
proneural tumors may be distinct
from other subtypes, and we suggest
such pts should not be offered
bevacizumab treatment upfront.
Future randomized trials focusing on
non-proneural tumors may finally
demonstrate a survival advantage for
bevacizumab in GBM. Clinical trial
information: NCT01392209.

47. Progression-free survival (PFS) and health-related quality
of life (HRQoL) in AVAglio, a phase III study of bevacizumab
(Bv), temozolomide (T), and radiotherapy (RT) in newly
diagnosed glioblastoma (GBM).
 : GBM has a high disease burden and
poor prognosis, and impacts negatively
on HRQoL. Symptomatic therapies for
GBM, such as corticosteroids (CS), may
impact patient status negatively
Methods: AVAglio, a randomized,
double-blind, placebo (P)-controlled trial
in patients (pts) ≥18 yrs with newly
diagnosed GBM, evaluated the addition
of Bv or P

48. Bevacizumab in combination with TMZ in patients
with recurrent GBM: Final OS and PFS analysis
 BEV provides a consistent clinical benefit
in the treatment of relapsing GBM in
terms of a delayed progression and
increased median overall survival
compared to historical controls. The aim
of this study is to evaluate the efficacy
and toxicity profile of the combination of
BEV with dose dense TMZ, reporting the
final results of PFS, OS and the toxicity
experienced

49.  Conclusion: Although the
combination don’t met the previous
reported activity of BEV, 19% of
patients had longer survivals which
suggest the need to identify patients
that benefit for this treatment.
Clinical trial information:
NCT01115491

50. Tumor response based on adapted Macdonald criteria
and assessment of pseudoprogression (PsPD) in the
phase III AVAglio trial of bevacizumab (Bv) plus
temozolomide (T) plus radiotherapy (RT) in newly
diagnosed glioblastoma (GBM).
 Conclusion: Addition of Bv to 1stline T/RT significantly improves ORR.
The rate of confirmed PsPD was low
in both arms. Clinical trial
information: NCT00943826

51. Conclusion
Thank you