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Journal of the Egyptian Nat. Cancer Inst., Vol. 21, No. 2, June: 107-119, 2009
The Outcomes of Concomitant Radiation Plus Temozolomide
Followed by Adjuvant Temozolomide for Newly Diagnosed
High Grade Gliomas: The Preliminary Results of Single
Center Prospective Study
HANAN SHAWKY, M.D.; ABDEL HALIM ABO HAMAR, M.D.; SAMAR GALAL, M.D.;
FATMA ZAKARIA, M.D. and DALIA EL-SHORBAGY, M.D.
The Department of Clinical Oncology, Tanta University Hospital.
ABSTRACT
Purpose: Temozolomide (TMZ) is an oral alkylating
agent with demonstrated efficacy as second-line therapy
for patients with recurrent anaplastic astrocytoma and
glioblastoma multiforme (GBM). We reported the
preliminary results of the treatment with concomitant
radiation therapy (RT) plus TMZ followed by adjuvant
TMZ therapy in patients with newly diagnosed high grade
gliomas (HGG) to determine the safety, tolerability, and
efficacy.
Patients and Methods: Between January, 2006 and
December, 2007, a total of 27 patients over the age of 18
years with newly diagnosed, histologically confirmed
HGG were assigned to receive oral TMZ (75 mg/m 2 /d x
7 d/wk for 6 weeks, from the first to the last day of RT)
with fractionated RT (60 Gy total dose: 2 Gy x 5 d/wk for
6 weeks) followed by TMZ monotherapy (150 to 200
mg/m 2 /d x 5 days, every 28 days for six cycles) at Clinical
Oncology Department, Faculty of Medicine, Tanta
University Hospital. The primary end point was overall
survival; secondary end points were progression-free
survival, safety and tolerability.
Results: At a median follow-up period of 17 months
(range; 5-30 months), the median progression-free survival
(PFS) for all patients with HGG was 11 months, and the
one-year PFS rate was 43.14%. The median overall survival
(OS) was 19 months and the one-year OS rate was 81.2%.
Patients with GBM were analyzed separately from HGG,
and the median overall survival (OS) was 17 months, and
the one-year OS rate was 83.3%. The median PFS was 10
months, and the one-year PFS rate was 27.8%. The mean
age was 50.2 years (standard deviation ±9.7284), and
44.4% of patients had undergone biopsy only. There was
no mortality caused by drug toxicity. Patients younger
than 50 years old and patients who underwent debulking
Correspondence: Dr Hanan Shawky Gamal El-Deen, 37-
Ibn Sinna Street, kafr El Zayat, Gharbya, hannshawky@
yahoo.com
surgery had the best survival outcome.
Conclusion: The addition of TMZ to RT followed by
adjuvant TMZ was well tolerated, and has shown promising
activity in the treatment of newly diagnosed HGG. Further
investigation is warranted.
Key Words: Temozolomide – Radiotherapy – High grade
glioma.
INTRODUCTION
Primary brain tumors comprise only
approximately 2% of all malignant diseases [1].
However, with an incidence of 5 per 100,000
persons, more than 17,000 cases are diagnosed
every year in the United States, with
approximately 13,000 associated deaths [2]. In
adults, the most common histologies are grade
3 anaplastic astrocytoma (AA) and grade 4
glioblastoma multiforme (GBM) [1,3]. The
standard management of malignant gliomas
involves surgical resection to the extent that is
safely feasible [4], followed by radiotherapy
(RT) with or without adjuvant chemotherapy
[5-10]. Despite this multidisciplinary approach,
the prognosis for patients with GBM remains
poor. The median survival rates for GBM are
typically in the range of 9 to 12 months, with
2-year survival rates in the range of only 8%
to 12% [11-15].
In the United States, adjuvant carmustine,
a nitrosourea drug, is commonly prescribed
[16,17]. Nitrosoureas are the main
chemotherapeutic agents used in the treatment
of malignant brain tumors; however, they have
107

108
The Outcomes of Concomitant Radiation Plus Temozolomide
shown only modest antitumor activity [11,13].
Cooperative-group trials have investigated the
addition of various chemotherapeutic regimens
to radiotherapy [18-21], but no randomized phase
3 trial of nitrosourea-based adjuvant
chemotherapy has demonstrated a significant
survival benefit as compared with radiotherapy
alone, although there were more long-term
survivors in the chemotherapy groups in some
studies [22].
Temozolomide (TMZ) is a novel, oral,
second-generation, alkylating agent that has
demonstrated antitumor activity as a single
agent or in combination with other
chemotherapeutic agents in the treatment of
recurrent and newly diagnosed GBM [23-32].
After oral administration, temozolomide is
rapidly absorbed with almost 100%
bioavailability [33]. It readily crosses the bloodbrain
barrier and achieves effective
concentrations in the CNS with a reported
plasma-CSF ratio of approximately 30% to 40%
of those observed in the plasma [34,35]. The
approved conventional schedule is a daily dose
of 150 to 200 mg per square meter of bodysurface
area for 5 days of every 28-day cycle.
Daily therapy at a dose of 75 mg per square
meter for up to seven weeks is safe; this level
of exposure to temozolomide [36] depletes the
DNA-repair enzyme O6-methylguanine-DNA
methyltransferase (MGMT) [37]. This effect
may be important because low levels of MGMT
in tumor tissue are associated with longer
survival among patients with glioblastoma [38,39]
who are receiving nitrosourea-based adjuvant
chemotherapy [40,41].
The concurrent administration of TMZ and
radiation has been explored in vitro and in vivo
[42]. In vitro studies have shown that, depending
on the cell line, treatment of glioma cells with
TMZ and x-rays can have either an additive or
synergistic effect. In a phase II study by Stupp,
et al. [43], demonstrated that concomitant RT
plus continuous daily TMZ followed by adjuvant
TMZ is well tolerated and improves survival
in patients with newly diagnosed GBM. Another
completed phase III studies by the European
Organisation for Research and Treatment of
Cancer (EORTC) had confirmed this data [23,44].
On the basis of this evidence, we initiated
this study to investigate the safety, tolerability,
and survival of concomitant RT plus TMZ
therapy followed by adjuvant TMZ therapy in
patients with newly diagnosed HGG.
PATIENTS AND METHODS
Patients:
Between January, 2006 and December, 2007,
32 patients over the age of 18 years with newly
diagnosed, histologically confirmed HGG, were
the subjects of this study, of which 27 were
assessable for response at Clinical Oncology
Department, Faculty of Medicine, Tanta
University Hospital. Five patients were
ineligible, not treated, or incorrectly treated:
reasons included treatment refusal (n=2) and
hepatic insufficiency (n=3). Patients were
required to have a Karnofsky performance status
(KPS) of ≥70 and adequate hematologic, renal,
and hepatic functions, defined as absolute
neutrophil count 1.5x10 9 cells per liter; platelet
count 100x10 9 cells per liter; hemoglobin more
than 90 g/L; serum creatinine and total serum
bilirubin 1.5 times the upper limit of normal;
aspartate aminotransferase or alanine
aminotransferase less than 2.5 times the upper
limit of normal; and alkaline phosphatase less
than 2.5 times the upper limit of normal. Study
enrollment had to be within six weeks from
diagnostic biopsy or resection. Eligible patients
were also required to have no other severe
underlying disease (including chronic hepatitis
B or C infection). Exclusion criteria included
any medical condition that could interfere with
the oral administration of temozolomide or any
previous or concurrent malignancies at other
sites.
Study design and treatment:
Within six weeks after the histologic
diagnosis of HGG, we assigned eligible patients
to receive temozolomide (marketed as Temodal)
at a dose of 75 mg per square meter per day,
given 7 days per week from the first day of
radiotherapy until the last day of radiotherapy,
in a fasting state, 1 hour before RT, and in the
morning on days without RT. Concomitant focal
RT was delivered once daily at 2 Gy per fraction,
5 d/wk, for a total of 60 Gy. Adequate
immobilization masks were required to ensure
reproducibility. Treatment volumes were
determined on the basis of preoperative contrastenhanced
computed tomography (CT) or
gadolinium-enhanced magnetic resonance

Hanan Shawky, et al. 109
imaging (MRI) of the brain. Treatment volume
generally included the contrast-enhancing lesion
plus a 2- to 3-cm margin, depending on the
location. Radiation therapy was delivered with
60Co photons. After a 4-week break, patients
were then to receive up to six cycles of adjuvant
temozolomide according to the standard 5-day
schedule every 28 days. The dose was 150 mg
per square meter for the first cycle and was
increased to 200 mg per square meter beginning
with the second cycle, so long as there were no
hematologic toxic effects. Prophylactic
antiemetics were used only as required during
concomitant RT plus temozolomide therapy.
Prophylactic antiemetics, including
metoclopramide or 5-hydroxytryptamine-3
antagonists, were routinely prescribed once a
day before adjuvant temozolomide.
Anticonvulsants and corticosteroids were
administered as needed.
Surveillance and follow-up:
The baseline examination included a
complete medical history, physical examination,
determination of performance status,
hematology and clinical chemistry assessments,
and gadolinium-enhanced MRI or contrastenhanced
CT of the brain. During radiotherapy
with temozolomide, complete blood counts were
checked weekly, and blood chemistry was
checked monthly. During adjuvant
temozolomide therapy, patients underwent a
monthly clinical evaluation and a comprehensive
evaluation at the end of cycles 3 and 6. Tumor
progression was defined according to the
modified WHO criteria as an increase in tumor
size by 25 percent, the appearance of new
lesions, or an increased need for corticosteroids
[45]. When there was tumor progression, patients
were treated at the investigator's discretion, and
the type of second-line therapy was recorded.
Toxic effects were graded according to the
National Cancer Institute Common Toxicity
Criteria, version 2.0, with a score of 1 indicating
mild adverse effects, a score of 2 moderate
adverse effects, a score of 3 severe adverse
effects, and a score of 4 life-threatening adverse
effects.
Statistical analysis:
The primary end point was overall survival;
secondary end points were progression-free
survival, and safety. Toxicity was graded
according to the common toxicity criteria
(version 2.0). Safety and toxicity are reported
for all treated patients.
Toxic effects are reported separately for the
radiotherapy period, defined as extending from
day 1 of radiotherapy until 28 days after the
last day of radiotherapy, or until the first day
of adjuvant temozolomide therapy. The
adjuvant-therapy period was defined as
extending from the first day of adjuvant
temozolomide therapy until 35 days after day
1 of the last cycle of temozolomide. Findings
with respect to the quality of life are not reported
here.
Overall survival was calculated from the
time of study entry until death or last followup
according to the Kaplan-Meier method [46]
with SPSS [Statistical package] (version 9.0).
Mean and standard deviation were estimates of
quantitative data. Overall survival and
progression-free survival were compared by the
Kaplan-Meier method [46] with statistical
significance assessed by the log-rank test. All
p values were two-tailed; a value of ≤0.05 was
considered significant.
RESULTS
Patient characteristics:
Patients ≥18 years of age with newly
diagnosed and histologically proven HGG were
eligible for the study. Patient demographics and
baseline disease characteristics for the eligible
27 patients are listed in Table (1). The mean
age was 50.2±9.7 years old, (range; 21-71 years
old). The majority of patients had a Karnofsky
performance status (KPS) of ≥80. About 44%
of the patients underwent biopsy only, 22.2%
underwent gross total resection, and 18.5%
underwent subtotal resection, however,
immediate postoperative imaging was not
performed in all patients. Histopthological slide
revisions were confirmed the diagnosis of
glioblastoma in 66.7% of the reviewed cases;
25.9% had anaplastic astrocytoma (WHO grade
III), and in 7.4% of the patients the diagnosis
was oligodendroglioma (WHO grade III). The
mean time from diagnosis to the start of therapy
with RT plus temozolomide was 2.7 weeks,
standard deviation ±0.9842, (range, 1-5 weeks).
Table (2) summarizes the details of
treatment. Among the 27 patients who were
assigned to receive concomitant radiotherapy

110
The Outcomes of Concomitant Radiation Plus Temozolomide
plus temozolomide, 17 (63%) completed both
radiotherapy and temozolomide as planned. Ten
patients (37%) prematurely discontinued
adjuvant temozolomide because of toxic effects
(in 3 patients), disease progression (in 5), or
other reasons (in 2). The majority of patients
completed their RT within the prescribed 6
weeks (42±3 days). Unplanned interruptions in
RT were usually brief (median, four days) and
interruptions due to the toxicity of therapy
Table (1): Demographic characteristics of the 27 patients
with high grade gliomas at baseline.
Characteristic
Age (years):
Mean
Range

Hanan Shawky, et al. 111
was discontinued early because of progressive
disease in 5 patients (18.5%)]. Only 5 patients
discontinued adjuvant temozolomide because
of toxic effects. Beginning with cycle 2, the
dose of temozolomide was increased to 200 mg
per square meter in 70.4% of patients.
Seventeen patients (63%) received all
concomitant and adjuvant temozolomide as
planned in the protocol. The response rate,
including complete remission and partial
remission, was 55.6%.
Safety and tolerability:
We analyzed adverse events separately
during radiotherapy with concomitant
temozolomide, the adjuvant-therapy period, and
the entire study period (from study entry until
disease progression or last follow-up).
Hematologic toxicity and infection:
Concomitant phase of treatment. During the
concomitant RT plus temozolomide phase, grade
3 or 4 neutropenia occurred in 2 patients (7.4%)
(Table 3), and grade 3 or 4 thrombocytopenia
occurred in 2 patients (7.4%), with 1 patient
experiencing platelet counts of less than 10,000
cells per cubic millimeter. Grade 3 or 4
lymphocytopenia occurred in 3 patients (11.1%).
Two patients had infections that required
hospitalization and treatment interruption.
Analysis indicated that 1 of the 2 patients
developed pneumonia. This patient was
receiving corticosteroids and experienced grade
4 neutropenia and lymphocytopenia at the time
of infection. One patient required surgical
revision of a scar infection and osteomyelitis 3
weeks after start of RT. However, this patient's
blood counts were within normal limits during
treatment.
Adjuvant temozolomide: During the adjuvant
temozolomide phase, grade 3 or 4 neutropenia
or thrombocytopenia occurred in 7.4% and
18.5% of patients, respectively. Five patients
required a dose reduction or delay because of
grade 3 or 4 thrombocytopenia.
Non-hematologic toxicities:
Non-hematologic toxicities were mild to
moderate (Table 4). During the CCRT phase,
prophylactic antiemetics were required in 59.3%
of patients; however, only 7 patients (25.9%)
received antiemetics for longer than the first
Table (3): Hematologic toxicities and infection in the 27 patients with high grade
gliomas.
RT with concomitant TMZ
Adjuvant TMZ
Adverse Event
Grade 3
Grade 4
Grade 3
Grade 4
No. %
No. %
No.
%
No.
%
Anemia
Neutropenia
Thrombocytopenia
Lymphocytopenia
Infection
1
1
1
2
1
3.7
3.7
3.7
7.4
3.7
0
1
1
2
1
0
3.7
3.7
3.7
3.7
1
1
2
3
0
3.7
3.7
7.4
11.1
0
0
1
3
3
0
0
3.7
11.1
11.1
0
Table (4): Non-hematologic toxicities in the 27 patients with high grade gliomas.
Adverse Event
RT with concomitant TMZ
Grade 2 Grade 3 Grade 4 Grade 2
Adjuvant TMZ
Grade 3 Grade 4
No.
%
No.
%
No. % No. %
No. % No. %
Nausea/vomiting
Rash
Fatigue
6
0
4
22.2
0
14.8
1
1
1
3.7
3.7
3.7
0
0
0
0
0
0
7
0
4
25.9
0
14.8
2
0
1
7.4
0
3.7
0
0
0
0
0
0

112 The Outcomes of Concomitant Radiation Plus Temozolomide
week of the concomitant treatment. During the
adjuvant temozolomide phase, 33.3% of patients
required antiemetic therapy. One patient
experienced a treatment-induced rash that
resulted in early discontinuation of
temozolomide after 7 days of CCRT. Moderate
to severe fatigue was reported in 5 patients
during the CCRT phase (grade 3; one patient)
and in 5 patients during the adjuvant
temozolomide phase (grade 3; one patient).
The short duration of follow-up precludes
definitive assessment of late radiation toxicity;
only 9 patients were alive with a follow-up
longer than 24 months. However, signs of
leukoencephalopathy, without evident clinical
impairment, were apparent on MRI in all of
these patients. One patient developed
intracranial hypertension, refractory seizures,
and loss of vision 25 months after beginning
RT. The loss of vision may in part be due to
prior RT. Subsequent work-up indicated a spinal
dissemination of the disease with positive CSF
cytology and no evidence of local recurrence.
A second patient developed neurologic
deterioration with progressive short-term
memory loss and hemiplegia 17 months after
beginning RT. At 26 months, this patient was
still alive without evidence of tumor progression.
The remaining patients with follow-up longer
than 18 months are doing well without any
clinical signs of neurologic impairment.
Thromboembolic events occurred in 3
patients (11.1%). Two patients died of cerebral
hemorrhage in the absence of a coagulation
disorder or thrombocytopenia.
Survival:
At the time of this analysis, 19 patients had
died. The median duration of follow-up was 17
months, (range, 5-30 months). On the basis of
Kaplan-Meier estimates, the median overall
survival for the all patients with high grade
gliomas (n=27) was 19 months (95% confidence
interval, 13.58-24.42) (Table 5). About 33.3%
of our patients were alive at 2 years, (Table 5).
The median progression-free survival was
11 months (95% confidence interval, 8.56-
13.44) (Table 5). The two-year progression-free
survival rate was 26.1%.
The 18 patients with glioblastoma were
analyzed separately from the other patients with
high grade gliomas, and the median overall
survival was 17 months (95% confidence
interval, 13.9-20.1). The one-year and two-year
overall survival rate were 83.3% and 38.1%
respectively (Fig. 1).
The median progression-free survival for
the 18 patients with glioblastoma was 10 months
(95% confidence interval, 8.99-11.01) (Fig. 2).
The six-month progression-free survival rate
was 72.22%.
Prognostic factors:
We analyzed the median overall survival
and survival rates of the eligible patient
populations in relation to prognostic indicators.
In patients younger than 50 years old, the median
survival was not reached at 24 months, with
66.7% of these patients still alive at 24 months.
In patients 50 years old, the 24 months overall
survival was only 35.7% months (p=0.005),
(Fig. 3). The prognosis by surgical respectability
was also analyzed in these eligible patients.
Patients who underwent gross total resection,
near-total removal and subtotal resection had
24 months overall survival of 57%. However,
for patients who underwent partial removal or
biopsy, the 24 months overall survival was
26.8% (p=0.0017), (Fig. 4).
As regard to pathological type, the 24 months
overall survival for patients with glioblastoma
and anaplastic astrocytoma (WHO grade III),
was 38.1% and 77.8% respectively (p=0.0025),
(Fig. 5).
Survival according to other possible
prognostic factors were included, Karnofsky
Table (5): Overall Survival and progression-free survival
of all patients with high grade gliomas (n=27).
Variable
Overall Survival (months):
Median
95% confidence interval
12-month
24-month
Progression-free survival
(months):
Median
95% confidence interval
12-month
24-month
Survival
19.00 months
13.58-24.42 months
81.16%
33.3%
11.00
8.56-13.44 months
43.14%
26.14%

Hanan Shawky, et al. 113
Oveall Survival
1.0
0.8
0.6
0.4
0.2
Survival Function
Censored
Progrssion free Survival
1.0
0.8
0.6
0.4
0.2
Survival Function
Censored
0.0
0 6 12 18 24 30 36
Time (Months)
Fig. (1): Overall survival of patients with glioblastoma
(n =18).
1.0
0.8
0.0
0 6 12 18 24 30 36
Time (Months)
Fig. (2): Progression-free survival of patients with glioblastoma
(n =18).
1.0
0.8
Oveall Survival
0.6
0.4
0.2
Oveall Survival
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36
Time (Months)
Age

114 The Outcomes of Concomitant Radiation Plus Temozolomide
Oveall Survival
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36
Time (Months)
Sex
Female
Female-censored
Fig. (7): Overall Survival of patients with high grade gliomas
according to sex.
performance status (KPS) (p=

Hanan Shawky, et al. 115
In this study, lymphocytopenia is often
observed with TMZ treatment but may, in part,
be due to the frequent administration of
corticosteroids as was described in another
phase I trial [36]. Although lymphocytopenia
occurs frequently, it is not typically associated
with clinical sequelae. However, one of the 27
patients we treated with concomitant RT plus
TMZ therapy developed pneumonia. The
frequency of opportunistic infections in a similar
patient population treated with RT alone is
unknown.
Nausea and vomiting, the most frequently
reported non-hematologic adverse events, were
also mild to moderate and could be readily
controlled with the administration of standard
antiemetics. Non-hematologic toxicity observed
with temozolomide treatment was in agreement
with the report published by Stupp, et al. [43].
Late toxicity resulting from exposure to
alkylating agents or combined modality
treatment remains a concern. Concomitant RT
plus TMZ therapy did not increase late toxicities
associated with RT during our follow-up period;
however, follow-up remains too short to make
any conclusions with regard to late toxicities
resulting from treatment with TMZ.
Some reports of concomitant RT plus TMZ
followed by adjuvant TMZ therapy for GBM
were published. In 2005, the efficacy of
postoperative TMZ radiochemotherapy in
malignant glioma was reported in Germany [65].
According to that report, median PFS time was
7.3 months for primary glioblastoma, treated
with concomitant RT plus TMZ. That study also
reported that the median overall survival time
for patients with glioblastoma was 14.6 months.
Another randomized prospective study of
concomitant RT plus TMZ was reported in 2005
proving that this protocol is more effective than
RT alone in patients with newly diagnosed
glioblastoma [66]. This randomized study
compared concomitant RT plus TMZ with RT
alone in patients with newly diagnosed
glioblastoma. It reported that the median overall
survival time for patients with glioblastoma
was 14.6 months with RT plus TMZ and 12.1
months with RT alone. The 2-year overall
survival rate was 26.5% with RT plus TMZ and
10.4% with RT alone. That study confirmed the
effectiveness of concomitant RT plus TMZ for
glioblastoma patients.
Survival results in our study are encouraging.
Indeed, the median PFS time of 10 months, the
median overall survival of 17 months and the
2-year overall survival rate of 38.1% for the 18
patients with glioblastoma in our series treated
with concomitant RT plus TMZ followed by
adjuvant TMZ therapy compares favorably with
the other previous reported protocols. At present
concomitant RT plus TMZ followed by adjuvant
TMZ therapy is widely accepted as the current
standard care for patients with glioblastoma
[23,32,42,44,67-72].
Unlike glioblastoma, there is no definite
consensus about the standard regimen for WHO
grade III gliomas, such as anaplastic astrocytoma
and anaplastic oligodendroglioma. For example,
a phase III trial of RT plus chemotherapy using
procarbazine, lomustine and vincristine (PCV)
to treat anaplastic oligodendroglioma was
published in 2006 [73]. This study concluded
that PCV plus RT did not prolong the survival
of patients with anaplastic oligodendroglioma
and the longer PFS was associated with
significant toxicity. Therefore, it is essential to
verify the role of TMZ in the treatment WHO
grade III glioma. Since the above-mentioned
landmark study of Stupp, et al. [66] in 2005,
there have been many phase II and III clinical
studies of the treatment of HGG with TMZ in
adults [67,68,74-77]. These trials have reported
good outcomes, and our present results for
patients with WHO grade III and IV gliomas
are also favorable, with tolerable toxicity. In
our study the median PFS time was 11 months,
and the median overall survival was 19 months
for the 27 patients with HGG treated with
concomitant RT plus TMZ followed by adjuvant
TMZ therapy. Our results are consistent with
most of these reports, confirming that
concomitant RT plus TMZ followed by adjuvant
TMZ therapy offers good clinical outcomes in
the treatment of HGG.
Subanalyses performed to determine the
existence of prognostic factors in the patient
population under evaluation revealed that
baseline KPS was an important prognostic factor
that correlated meaningfully with median
survival (p=

116
The Outcomes of Concomitant Radiation Plus Temozolomide
substantially better survival rates than patients
who had a biopsy only. These prognostic factors
observed in our patient population under
evaluation were in agreement with the report
published by Stupp, et al. [43].
In conclusion, this is the first report of results
of concomitant RT plus TMZ followed by
adjuvant TMZ therapy in the treatment of HGG
in Clinical Oncology Department, Tanta
University Hospital, Faculty of Medicine, Tanta
University, Egypt. This study demonstrated
concomitant RT plus TMZ followed by adjuvant
TMZ therapy, is a promising regimen for
patients with HGG and we propose concomitant
RT plus TMZ followed by adjuvant TMZ
therapy as an alternative approach with tolerable
toxicities for patients with WHO grade III
gliomas, as well as for those with glioblastoma,
nevertheless, the challenge remains to improve
clinical outcomes further. To confirm this, a
multicenter, meta-analysis and a randomized
trial with a large number of patients are required
in the near future. Many questions remain
unanswered regarding the applications of this
regimen to lower grade gliomas and the optimal
combination of radiotherapy and temozolomide.
REFERENCES
1- Wen PY, Kesari S. Malignant Gliomas in Adults.
NEJM. 2008, 359: 492-507.
2- Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller
BA, Clegg LX, et al. (eds). SEER Cancer Statistics.
2001, 1973-1998. Bethesda, MD, National Cancer
Institute.
3- Kleihues P, Burger PC, Scheithauer BW. The new
WHO classification of brain tumours. Brain Pathol.
1993, 3: 255-68.
4- Pichlmeier U, Bink A, Schackert G, Stummer W, the
ALA Glioma Study Group. Resection and survival in
glioblastoma multiforme: An RTOG recursive
partitioning analysis of ALA study patients. Neurooncol.
2008, 10(6): 1025-34.
5- Sigmond J, Honeywell RJ, Postma TJ, Dirven CMF,
de Lange SM, van der Born K, et al. Gemcitabine
uptake in glioblastoma multiforme: potential as a
radiosensitizer. Ann Oncol. 2009, 20: 182- 7.
6- Vredenburgh JJ, Desjardins A, Reardon DA, Friedman
HS. Experience with irinotecan for the treatment of
malignant glioma. Neuro Oncol. 2009, 11: 80-91.
7- Stupp R, Hegi ME, van den Bent MJ, Mason WP,
Weller M, Mirimanoff RO, et al. Changing paradigmsan
update on the multidisciplinary management of
malignant glioma. Oncologist. 2006, 11(2): 165-80.
8- Gilbert MR. New treatments for malignant gliomas:
careful evaluation and cautious optimism required.
Ann Intern Med. 2006, 144 (5): 371-3.
9- ReardonDA, Rich JN, Friedman HS, Bigner DD.
Recent Advances in the Treatment of Malignant
Astrocytoma. J. Clin. Oncol. 2006, 24 (8): 1253-65.
10- Attenello FJ, Mukherjee D, Datoo G, McGirt MJ,
Bohan E, Weingart JD, et al. Use of Gliadel (BCNU)
Wafer in the Surgical Treatment of Malignant Glioma:
A 10-Year Institutional Experience. Ann. Surg. Oncol.
2008, 15: 2887-93.
11- Galanis E, Buckner J. Chemotherapy for high-grade
gliomas. Br J Cancer. 2000, 82: 1371-80.
12- Levin V, Leibel S, Gutin P. Neoplasms of the central
nervous system, in DeVita V Jr, Hellman S, Rosenberg
S (eds): Cancer: Principles and Practice of Oncology.
Philadelphia, PA, Lippincott-Raven. 1997, pp 2022-82.
13- DeAngelis LM. Brain tumors. N Engl J Med. 2001,
344: 114-23.
14- Buckner JC. Factors influencing survival in highgrade
gliomas. Semin Oncol. 2003, 30 (19): 10-14.
15- Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein
AS, Fischbach AJ, et al. Recursive partitioning analysis
of prognostic factors in three Radiation Therapy
Oncology Group malignant glioma trials. J Natl Cancer
Inst. 1993, 85: 704-10.
16- Walker MD, Alexander E Jr, Hunt WE, MacCarty CS,
Mahaley MS Jr, Mealey J Jr, et al. Evaluation of
BCNU and/or radiotherapy in the treatment of
anaplastic gliomas: a cooperative clinical trial. J
Neurosurg. 1978, 49: 333-43.
17- Walker MD, Green SB, Byar DP, Alexander E,
Batzdorf U, Brooks WH, et al. Randomized
comparisons of radiotherapy and nitrosoureas for the
treatment of malignant glioma after surgery. N Engl
J Med. 1980, 303 (23): 1323-29.
18- Medical Research Council Brain Tumor Working
Party. Randomized trial of procarbazine, lomustine,
and vincristine in the adjuvant treatment of high-grade
astrocytoma: a Medical Research Council trial. J Clin
Oncol. 2001, 19: 509-18.
19- Shapiro WR, Green SB, Burger PC, Mahaley MS Jr,
Selker RG, VanGilder JC, et al. Randomized trial of
three chemotherapy regimens and two radiotherapy
regimens and two radiotherapy regimens in postoperative
treatment of malignant glioma: Brain Tumor Cooperative
Group trial 8001. J Neurosurg. 1989, 71: 1-9.
20- Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-
Tamayo R, Kramer S, et al. Comparison of
postoperative radiotherapy and combined postoperative
radiotherapy and chemotherapy in the multidisciplinary
management of malignant gliomas: a joint Radiation
Therapy Oncology Group and Eastern Cooperative
Oncology Group study. Cancer. 1983, 52 (6): 997-
1007.
21- Green SB, Byar DP, Walker MD, Pistenmaa DA,
Alexander E Jr, Batzdorf U, et al. Comparisons of

Hanan Shawky, et al. 117
carmustine, procarbazine, and high-dose
methylprednisolone as additions to surgery and
radiotherapy for the treatment of malignant glioma.
Cancer Treat Rep. 1983, 67: 121-32.
22- Stupp R, Hegi ME. Recent developments in the
management of malignant glioma. In: Perry MC, ed.
ASCO 2003 educational book. Alexandria, Va.:
American Society of Clinical Oncology. 2003, 779-
88.
23- Stupp R, Hegi ME, Mason WP, van den Bent MJ,
Taphoorn MJ, Janzer RC, et al. Effects of Radiotherapy
with Concomitant and Adjuvant Temozolomide versus
Radiotherapy alone on survival in Glioblastoma in
a Randomized Phase III study: 5-year Analysis of the
EORTC-NCIC trial. The Lancet Oncology. 2009, 10
(5): 459-66.
24- Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke
B, Kortmann R-D, et al. Phase II Trial of Lomustine
Plus Temozolomide Chemotherapy in Addition to
Radiotherapy in Newly Diagnosed Glioblastoma:
UKT-03. J. Clin. Oncol. 2006, 24 (27): 4412-7.
25- Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten
M, Blaschke B, et al. Efficacy and Tolerability of
Temozolomide in an Alternating Weekly Regimen in
Patients With Recurrent Glioma. J. Clin. Oncol. 2007,
25 (22): 3357-61.
26- Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas
DC, Doherty L, et al. Phase II study of temozolomide,
thalidomide, and celecoxib for newly diagnosed
glioblastoma in adults. Neuro Oncol. 2008, 10:
300-8.
27- Wakabayashi T, Kayama T, Nishikawa R, Takahashi
H, Yoshimine T, Hashimoto N, et al. A Multicenter
Phase I Trial of Interferon-{beta} and Temozolomide
Combination Therapy for High-grade Gliomas
(INTEGRA Study). Jpn. J. Clin. Oncol. 2008, 38:
715-8.
28- Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle
KA, Uhm JH, et al. Phase I/II Trial of Erlotinib and
Temozolomide With Radiation Therapy in the
Treatment of Newly Diagnosed Glioblastoma
Multiforme: North Central Cancer Treatment Group
Study N0177 J. Clin. Oncol. 2008, 26: 5603-9.
29- Prados MD, Chang SM, Butowski N, DeBoer R,
Parvataneni R, Carliner H, et al. Phase II Study of
Erlotinib Plus Temozolomide During and After
Radiation Therapy in Patients With Newly Diagnosed
Glioblastoma Multiforme or Gliosarcoma. J. Clin.
Oncol. 2009, 27: 579-84.
30- van den Bent MJ, Brandes AA, Rampling R,
Kouwenhoven MCM, Kros JM, Carpentier AF, et al.
Randomized Phase II Trial of Erlotinib Versus
Temozolomide or Carmustine in Recurrent
Glioblastoma: EORTC Brain Tumor Group Study
26034. J. Clin. Oncol. 2009, 27: 1268-74.
31- Glas M, Happold C, Rieger J, Wiewrodt D, Bahr O,
Steinbach JP, et al. Long-Term Survival of Patients
With Glioblastoma Treated With Radiotherapy and
Lomustine Plus Temozolomide. J. Clin. Oncol. 2009,
27: 1257-61.
32- Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-
Schughart L A, Leukel P, et al. Temozolomide
Preferentially Depletes Cancer Stem Cells in
Glioblastoma. Cancer Res. 2008, 68: 5706-15.
33- Newlands ES, Blackledge GR, Slack JA, Rustin GJ,
Smith DB, Stuart NS, et al. Phase I trial of
temozolomide (CCRG 81045: M&B 39831: NSC
362856). Br J Cancer. 1992, 65: 287-91.
34- Marzolini C, Decosterd LA, Shen F, Gander M,
Leyvraz S, Bauer J, et al. Pharmacokinetics of
temozolomide in association with fotemustine in
malignant melanoma and malignant glioma patients:
Comparison of oral, intravenous, and hepatic intraarterial
administration. Cancer Chemother Pharmacol.
1998, 42: 433-40.
35- Stupp R, Ostermann S, Leyvraz S, Csajka C, Buclin
T. Cerebrospinal fluid levels of temozolomide as a
surrogate marker for brain penetration. Proc Am Soc
Clin Oncol. 2001, 20: 59a, (abstr 232).
36- Brock CS, Newlands ES, Wedge SR, Bower M, Evans
H, Colquhoun I, et al. Phase I trial of temozolomide
using an extended continuous oral schedule. Cancer
Res. 1998, 58: 4363-7.
37- Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond
LA, Patnaik A, et al. Marked inactivation of O6-
alkylguanine-DNA alkyltransferase activity with
protracted temozolomide schedules. Br J Cancer.
2003, 88: 1004-11.
38- Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller
M, et al. Correlation of O6-Methylguanine
Methyltransferase (MGMT) Promoter Methylation
With Clinical Outcomes in Glioblastoma and Clinical
Strategies to Modulate MGMT Activity. J. Clin.
Oncol.2008, 26 (25): 4189-99.
39- Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession
A, Tallini G, et al. MGMT Promoter Methylation
Status Can Predict the Incidence and Outcome of
Pseudoprogression After Concomitant
Radiochemotherapy in Newly Diagnosed Glioblastoma
Patients. J. Clin. Oncol. 2008, 26 (13): 2192-7.
40- Esteller M, Garcia-Foncillas J, Andion E, Goodman
SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of
the DNA-repair gene MGMT and the clinical response
of gliomas to alkylating agents. N Engl J Med. 2000,
343: 1350-4. [Erratum, N Engl J Med. 2000, 343:
1740].
41- Hegi ME, Diserens AC, Godard S, Dietrich P-Y, Regli
L, Ostermann S, et al. Clinical trial substantiates the
predictive value of O-6-methylguanine-DNA
methyltransferase promoter methylation in
glioblastoma patients treated with temozolomide. Clin
Cancer Res. 2004, 10: 1871-4.
42- Chakravarti A, Erkkinen MG, Nestler U, Stupp R,
Mehta M, Aldape K, et al. Temozolomide-Mediated
Radiation Enhancement in Glioblastoma: A Report
on Underlying Mechanisms. Clin. Cancer Res. 2006,
12 (15): 4738-46.
43- Stupp R, Dietrich P-Y, Ostermann Kraljevic S, Pica
A, Maillard I, Maeder P, et al. Promising survival for

118
The Outcomes of Concomitant Radiation Plus Temozolomide
patients with newly diagnosed glioblastoma
multiforme treated with concomitant radiation plus
temozolomide followed by adjuvant temozolomide.
J Clin Oncol. 2002, 20 (5): 1375- 82.
44- Mirimanoff RO, Gorlia T, Mason W, Van den Bent
MJ, Kortmann RD, Fisher B, et al. Radiotherapy and
Temozolomide for Newly Diagnosed Glioblastoma:
Recursive Partitioning Analysis of the EORTC
26981/22981-NCIC CE3 Phase III Randomized Trial.
J. Clin. Oncol. 2006, 24 (16): 2563-9.
45- Macdonald DR, Cascino TL, Schold SC Jr, Cairncross
JG. Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol. 1990, 8: 1277-80.
46- Kaplan EL, Meier P. Nonparametric estimation from
incomplete observations. J Am Stat Assoc. 1958, 53:
457-81.
47- Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme
I, Nesbakken R, et al. Combined modality therapy of
operated astrocytomas grade III and IV: Confirmation
of the value of postoperative irradiation and lack of
potentiation of bleomycin on survival time-A
prospective multicenter trial of the Scandinavian
Glioblastoma Study Group. Cancer. 1981, 47: 649-
52.
48- Shapiro WR. Chemotherapy of malignant gliomas:
studies of the BTCG. Rev Neurol. 1992, 148: 428-
34.
49- Grossman SA, O'Neill A, Grunnet M, Mehta M,
Pearlman JL, Wagner H, et al. Phase III study
comparing three cycles of infusional carmustine and
cisplatin followed by radiation therapy with radiation
therapy and concurrent carmustine in patients with
newly diagnosed supratentorial glioblastoma
multiforme: Eastern Cooperative Oncology Group
Trial 2394. J Clin Oncol. 2003, 21: 1485-91.
50- Deutsch M, Green SB, Strike TA, Burger PC,
Robertson JT, Selker RG, et al. Results of a randomized
trial comparing BCNU plus radiotherapy,
streptozotocin plus radiotherapy, BCNU plus
hyperfractionated radiotherapy, and BCNU following
misonidazole plus radiotherapy in the postoperative
treatment of malignant glioma. Int J Radiat Oncol
Biol Phys. 1989, 16: 1389-96.
51- Fisher BJ, Scott C, Macdonald DR, Coughlin C, Curran
WJ. Phase I study of topotecan plus cranial radiation
for glioblastoma multiforme: Results of Radiation
Therapy Oncology Group Trial 9507. J Clin Oncol.
2001, 19: 1111-7.
52- Del Rowe J, Scott C, Werner-Wasik M, Bahary JP,
Curran WJ, Urtasun RC, et al. Single-arm, open-label
phase II study of intravenously administered
tirapazamine and radiation therapy for glioblastoma
multiforme. J Clin Oncol. 2000, 18: 1254-9.
53- Kleinberg L, Grossman SA, Piantadosi S, Zeltzman
M, Wharam M. The effects of sequential versus
concurrent chemotherapy and radiotherapy on survival
and toxicity in patients with newly diagnosed highgrade
astrocytoma. Int J Radiat Oncol Biol Phys.
1999, 44: 535-43.
54- Brem H, Piantadosi S, Burger PC, Walker M, Selker
R, Vick NA, et al. Placebo-controlled trial of safety
and efficacy of intraoperative controlled delivery by
biodegradable polymers of chemotherapy for recurrent
gliomas: The Polymer-Brain Tumor Treatment Group.
Lancet. 1995, 345: 1008-12.
55- Westphal M, Hilt DC, Bortey E, Delavault P, Olivares
R, Warnke PC, et al. A phase 3 trial of local
chemotherapy with biodegradable carmustine (BCNU)
wafers (Gliadel wafers) in patients with primary
malignant glioma. Neuro-Oncology. 2003, 5 (2): 79-
88.
56- Friedman HS, Kerby T, Calvert H. Temozolomide and
treatment of malignant glioma. Clin Cancer Res. 2000,
6: 2585-97.
57- Reid JM, Stevens DC, Rubin J, Ames MM.
Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-
4-carboximide following administration of
temozolomide to patients with advanced cancer. Clin
Cancer Res. 1997, 3: 2393-8.
58- van den Bent MJ, Taphoorn MJB, Brandes AA, Menten
J, Stupp R, Frenay M, et al. Phase II Study of First-
Line Chemotherapy With Temozolomide in Recurrent
Oligodendroglial Tumors: The European Organization
for Research and Treatment of Cancer Brain Tumor
Group Study 26971. J. Clin. Oncol. 2003, 21 (13):
2525-8.
59- Newlands ES, Stevens MFG, Wedge SR, Wheelhouse
RT, Brock C. Temozolomide: a review of its discovery,
chemical properties, pre-clinical development and
clinical trials. Cancer Treat Rev. 1997, 23: 35-61.
60- Stupp R, Gander M, Leyvraz S, Newlands E. Current
and future developments in the use of temozolomide
for the treatment of brain tumours. Lancet Oncol,
2001;2: 552 - 60.
61- Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA,
Abrey LE. A phase II study of extended low-dose
temozolomide in recurrent malignant gliomas. Neurooncol.
2002, 4 (1): 39 - 43.
62- Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS,
Brada M, Friedman HS, et al. Multicenter phase II
trial of temozolomide in patients with anaplastic
astrocytoma or anaplastic oligoastrocytoma at first
relapse. J Clin Oncol. 1999, 17 (9): 2762- 71.
63- Yung WK, Albright RE, Olson J, Fredericks R, Fink
K, Prados MD, et al. A phase II study of temozolomide
vs. procarbazine in patients with glioblastoma
multiforme at first relapse. Br J Cancer. 2000, 83:
588- 93.
64- Brada M, Hoang-Xuan K, Rampling R, Dietrich P-Y,
Dirix LY, Macdonald D, et al. Multicenter phase II
trial of temozolomide in patients with glioblastoma
multiforme at first relapse. Ann Oncol. 2001, 12: 259-
66.
65- Kocher M, Kunze S, Eich HT, Semrau R, Muller RP.
Efficacy and toxicity of postoperative temozolomide
radiochemotherapy in malignant glioma. Strahlenther
Onkol. 2005, 181: 157-63.

Hanan Shawky, et al. 119
66- Stupp R, Mason WP, van den Bent MJ, Weller M,
Fisher B, Taphoorn MJ, et al. Radiotherapy plus
Concomitant and Adjuvant Temozolomide for
Glioblastoma. N Engl J Med. 2005, 352: 987-96.
67- Stupp R, Hegi ME, Gilbert MR, Chakravarti A.
Chemoradiotherapy in Malignant Glioma: Standard
of Care and Future Directions. J. Clin. Oncol. 2007,
25 (26): 4127-36.
68- Perry J, Laperriere N, Zuraw L, Chmbers A, Spithoff
K, Cairncross JG. Adjuvant chemotherapy for adults
with malignant glioma: a systemic review. Can J
Neurol Sci. 2007, 34: 402-10.
69- Sathornsumetee S, Rich JN and Reardon DA. Diagnosis
and treatment of high-grade astrocytoma. Neurol Clin.
2007, 25: 1111-39.
70- Cohen MH, Johnson JR and Pazdur R. Food and Drug
Administration Drug Approval Summary:
Temozolomide Plus Radiation Therapy for the
Treatment of Newly Diagnosed Glioblastoma
Multiforme. Clin. Cancer Res. 2005, 11 (19): 6767-
71.
71- Athanassiou H, Synodinou M, Maragoudakis E,
Paraskevaidis M, Verigos C, Misailidou D, et al.
Randomized Phase II Study of Temozolomide and
Radiotherapy Compared With Radiotherapy Alone in
Newly Diagnosed Glioblastoma Multiforme. J. Clin.
Oncol. 2005, 23 (10): 2372-7.
72- Glas M, Happold C, Rieger J, Wiewrodt D, Bahr O,
Steinbach JP, et al. Long-Term Survival of Patients
With Glioblastoma Treated With Radiotherapy and
Lomustine Plus Temozolomide. J. Clin. Oncol. 2009,
27: 1257-61.
73- Cairncross G, Berkey B, Shaw E, Jenkins R,
Scheithauer B, Brachman D, et al. Phase III trial of
chemotherapy plus radiotherapy compared with
radiotherapy alone for pure and mixed anaplastic
oligodendroglioma: Intergroup Radiation Therapy
Oncology Group Trial 9402. J Clin Oncol. 2006, 24:
2707-14.
74- Corsa P, Parisi S, Raguso A, Troiano M, Perrone A,
Cossa S, et al.. Temozolomide and Radiotherapy as
first-line treatment of high-grade gliomas. Tumori.
2006, 92: 299-305.
75- Oshiro OS, Tsugu H, Komatsu F, Ohmura T, Ohta M,
Sakamoto S, et al. Efficacy of Temozolomide
Treatment in Patients with High-grade Glioma.
Anticancer Res. 2009, 29: 911-7.
76- Wick W, Platten M and Weller M. New (alternative)
temozolomide regimens for the treatment of glioma.
Neuro-oncol, 2009, 11 (1): 69-79.
77- Vogelbaum MA, Berkey B, Peereboom D, Macdonald
D, Giannini C, Suh JH, et al. Phase II trial of
preirradiation and concurrent temozolomide in patients
with newly diagnosed anaplastic oligodendrogliomas
and mixed anaplastic oligoastrocytomas: RTOG
BR0131. Neuro Oncol. 2009, 11: 167-75.