1. health and fitness
2. therapy

Promising Survival for Patients With Newly Diagnosed
Glioblastoma Multiforme Treated With Concomitant
Radiation Plus Temozolomide Followed by
Adjuvant Temozolomide
By Roger Stupp, Pierre-Yves Dietrich, Sandrine Ostermann Kraljevic, Alessia Pica, Ivan Maillard, Phillipe Maeder, Reto Meuli,
Robert Janzer, Gianpaolo Pizzolato, Raymond Miralbell, Franc¸ois Porchet, Luca Regli, Nicolas de Tribolet,
Rene´ O. Mirimanoff, and Serge Leyvraz
Purpose: Temozolomide is a novel oral alkylating
agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma
and glioblastoma multiforme (GBM). This phase II study
was performed to determine the safety, tolerability,
and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.
Patients and Methods: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide
(75 mg/m2/d ⴛ 7 d/wk for 6 weeks) was administered
orally concomitant with fractionated radiotherapy (60
Gy total dose: 2 Gy ⴛ 5 d/wk for 6 weeks) followed by
temozolomide monotherapy (200 mg/m2/d ⴛ 5 days,
every 28 days for six cycles). The primary end points
were safety and tolerability, and the secondary end
point was overall survival.
Results: Concomitant radiation plus temozolomide
therapy was safe and well tolerated. Nonhematologic
toxicities were rare and mild to moderate in severity.
During the concomitant treatment phase, grade 3 or 4
neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with
grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients
who underwent debulking surgery had the best survival outcome.
Conclusion: Continuous daily temozolomide and
concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a
randomized trial is ongoing.
J Clin Oncol 20:1375-1382. © 2002 by American
Society of Clinical Oncology.
RIMARY BRAIN TUMORS comprise only approximately 2% of all malignant diseases. 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.1 In adults, the most
common histologies are grade 3 anaplastic astrocytoma
(AA) and grade 4 glioblastoma multiforme (GBM).2,3 The
standard management of malignant gliomas involves cytoreduction through surgical resection, when feasible, followed by radiotherapy (RT) with or without adjuvant
chemotherapy.4,5 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
only6,7 8% to 12%.
Nitrosoureas are the main chemotherapeutic agents used
in the treatment of malignant brain tumors; however, they
have shown only modest antitumor activity.7,8 Although
frequently prescribed in the United States, the benefit of
adjuvant chemotherapy with single-agent carmustine
(BCNU) or lomustine or the combination regimen procarbazine, lomustine, and vincristine has never been conclusively demonstrated. A meta-analysis on published data
suggested a possible benefit of adjuvant chemotherapy,
mainly for AA.9 However, in a large randomized trial
conducted by the British Medical Research Council, adjuvant combination regimen procarbazine, lomustine, and
vincristine chemotherapy was of no benefit to AA or GBM
patients, with a median survival of only 10 months.10 The
absence of chemotherapeutic efficacy in this and other
clinical trials may be due in part to the inability of these
agents to sufficiently penetrate the blood-brain barrier.
P
From the Departments of Medical Oncology, Radiation Therapy,
Neurosurgery, Pathology, and Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, and Hoˆpital Universitaire Genevois, Geneva, Switzerland.
P.Y.D. and S.O.K. contributed equally to this study.
Submitted July 26, 2001; accepted October 12, 2001.
Supported in part by an unrestricted educational grant by ScheringPlough Research Institute, Kenilworth, NJ.
Address reprint requests to Roger Stupp, MD, Centre Hospitalier
Universitaire Vaudois, Multidisciplinary Center for Oncology, Rue du
Bugnon 46, CH-1011 Lausanne, Switzerland; email: roger.stupp@chuv
.hospvd.ch.
© 2002 by American Society of Clinical Oncology.
0732-183X/02/2005-1375/$20.00
Journal of Clinical Oncology, Vol 20, No 5 (March 1), 2002: pp 1375-1382
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1375
1376
STUPP ET AL
Temozolomide (Temodal, Temodar; Schering-Plough,
Kenilworth, NJ) is a novel alkylating agent that has demonstrated activity in recurrent gliomas.11-16 After oral administration, temozolomide is rapidly absorbed with almost
100% bioavailability.17 It readily crosses the blood-brain
barrier and achieves effective concentrations in the CNS
with a reported plasma-CSF ratio of approximately 30% to
40%.18,19 In a phase II trial in patients with recurrent GBM,
the objective response rate was only 8%; however, an
additional 45% of patients had disease stabilization, suggesting that 53% of patients experienced a clinical benefit
with temozolomide treatment.20 The 6-month progressionfree survival rate for temozolomide-treated patients was
18%, and the 6-month overall survival rate was 46%. In a
large randomized phase II trial in patients with recurrent
GBM, the efficacy of temozolomide was compared with that
of procarbazine.16 In this study, the 6-month progressionfree survival rate was 21% for patients treated with temozolomide, compared with only 8% for patients treated with
procarbazine (P ⬍ .008). In all these trials, temozolomide
was administered at a dose of 150 to 200 mg/m2/d ⫻ 5 days,
every 28 days. This treatment is usually well tolerated, with
grade 3 and 4 thrombocytopenia and neutropenia occurring
in fewer than 10% of patients.
Resistance of temozolomide is mediated in part through
O6-alkylguanine DNA alkyltransferase (AGT). This repair
enzyme, also known as methylguanine-DNA methyltransferase, was found to be a major determinant of temozolomide cytotoxicity in vitro; continuous exposure to temozolomide leads to depletion of this enzyme.21 Therefore, a
continuous administration schedule for temozolomide has
been investigated, and a dose of 75 mg/m2 daily for 6 to 7
weeks seems safe.22
The rationale for combining temozolomide with RT is
based on preclinical data suggesting additive or perhaps
synergistic activity. Temozolomide with concurrent irradiation demonstrated additive cytotoxicity against the
U373MG glioblastoma cell line with low AGT expression,
whereas this effect was absent in a colorectal cell line that
expresses high levels of AGT.23 Van Rijn et al24 investigated prolonged temozolomide exposure followed by single-dose and fractionated irradiation in two glioma cell
lines. No enhancement of cytotoxicity could be demonstrated in the U251 cell line, but prolonged exposure to
temozolomide and fractionated irradiation enhanced cytotoxicity in the D384 cell line. It has been shown that
temozolomide induces a G2-M arrest in glioma cells, thus
synchronizing the cell cycle in a radiosensitive phase.25
On the basis of this preclinical evidence and the clinical
experience with temozolomide in recurrent gliomas, we
initiated this study to investigate the safety, tolerability, and
survival of concomitant RT plus temozolomide therapy
followed by adjuvant temozolomide therapy in patients with
newly diagnosed GBM.
PATIENTS AND METHODS
Patients
This two-center, open-label, phase II pilot study was conducted in
patients (ⱖ 18 years) with newly diagnosed and histologically proven
GBM. All histology was reviewed by a second neuropathologist (R.J.
and G.P.) and graded according to the World Health Organization
classification. Patients were required to have an Eastern Cooperative
Oncology Group performance status ⱕ 2 and adequate hematologic,
renal, and hepatic functions, defined as absolute neutrophil count ⱖ 1.5
⫻ 109 cells per liter; platelet count ⱖ 100 ⫻ 109 cells per liter;
hemoglobin more than 90 g/L; serum creatinine and total serum
bilirubin ⱕ 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 28 days from diagnostic
biopsy or resection. Eligible patients were also required to have no
other severe underlying disease (including human immunodeficiency
virus and chronic hepatitis B or C infection). All patients gave written
informed consent. Exclusion criteria included any medical condition
that could interfere with the oral administration of temozolomide or any
previous or concurrent malignancies at other sites, with the exception
of surgically cured carcinoma-in-situ of the cervix and nonmelanoma
skin cancer. The protocol was reviewed and approved by the local
ethics committees.
Treatment
Patients received temozolomide (75 mg/m2/d ⫻ 7 d/wk) for 6 to 7
weeks in a fasting state, 1 hour before RT, and in the morning on days
without RT. The first 16 patients treated received temozolomide only
on days of RT. Concomitant focal RT was delivered once daily at 2 Gy
per fraction, 5 d/wk, for a total of 60 Gy, and was prescribed according
to the guidelines of the International Commission on Radiological
Units. Adequate immobilization masks were required to ensure reproducibility. Treatment volumes were determined on the basis of preoperative contrast-enhanced computed tomography (CT) or gadoliniumenhanced magnetic resonance imaging (MRI) of the brain. Treatment
volume generally included the contrast-enhancing lesion plus a 2- to
3-cm margin, depending on the location. Planning for RT always
included dedicated CT, three-dimensional reconstruction with treatment planning computation, and beam eye’s view for the choice of
treatment field number, size, and shape. RT was delivered with ⱖ
6-MV photons from linear accelerators. Four weeks after RT, patients
received adjuvant temozolomide chemotherapy (200 mg/m2 daily ⫻ 5,
every 28 days for six cycles). Prophylactic antiemetics were used only
as required during concomitant RT plus temozolomide therapy. Prophylactic antiemetics, including 5-hydroxytryptamine-3 antagonists
(pediatric dose: ondansetron 4 mg or granisetron 1 mg), were routinely
prescribed once a day before adjuvant temozolomide. After concomitant RT plus temozolomide therapy was administered to 15 patients,
prophylaxis against Pneumocystis carinii pneumonia was introduced and
consisted of pentamidine inhalations during the first and fifth week of RT.
Anticonvulsants and corticosteroids were administered as needed.
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1377
CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA
Table 1.
Patient Evaluation
Baseline evaluations were performed within 14 days (28 days for
imaging) from study entry and included a complete medical history,
physical examination, determination of performance status, hematology and clinical chemistry assessments, and gadolinium-enhanced MRI
or contrast-enhanced CT of the brain. During RT, complete blood
counts were checked weekly, and blood chemistry was checked
monthly. During adjuvant temozolomide treatment, patients underwent
at least one monthly physical examination. Complete blood counts and
blood chemistry were drawn before each cycle; the complete blood
count was also checked on day 21 (⫾ 48 hours). Gadolinium-enhanced
MRI was performed before the first adjuvant treatment cycle and then
every 2 months during the first year and every 2 to 3 months during the
second year after study entry.
Statistical Methods
Toxicity was graded according to the common toxicity criteria
(version 2.0). Safety and toxicity are reported for all treated patients.
Overall survival was calculated from the time of study entry until death
or last follow-up according to the Kaplan-Meier method with SPSS
statistical software (release 7.5, 1996; SPSS Inc, Chicago, IL). The
95% confidence intervals were calculated as follows: survival ⫾ 1.96
⫻ SE. Survival analysis is reported for all patients enrolled onto the
study (intent-to-treat [ITT] population) and separately for eligible
patients with confirmed glioblastoma.
Patient Demographics and Baseline Disease Characteristics
Intent-to-Treat
Parameter
No.
Total no. of patients, n
Age, years
Median
Range
Sex
Male
Female
ECOG performance status
0 or 1
2
Karnofsky performance status
90%-100%
ⱕ 80%
Prior surgery
Complete resection
Incomplete resection
Biopsy
Time from diagnosis to treatment, days
Median
Range
64
%
52
24-70
39
25
61
39
55
9
86
14
41
23
64
36
27
22
15
42
34
23
25
14-45
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
RESULTS
Patient Characteristics
Sixty-four patients were enrolled (ITT population). Six
patients were ineligible, not treated, or incorrectly treated:
reasons included treatment refusal (n ⫽ 1), chronic hepatitis
B (n ⫽ 1), ineligible histology (n ⫽ 3; one AA and two
anaplastic oligoastrocytoma), and toxic death caused by
chemotherapy overdose (n ⫽ 1). Of the 64 patients, 62 were
treated with temozolomide and were analyzed for safety in
the concomitant RT plus temozolomide phase, and 49
patients who received at least one cycle of adjuvant temozolomide were assessable for safety in the adjuvant temozolomide phase.
Patient demographics and baseline disease characteristics
are listed in Table 1. The median age was 52 years, and the
majority of patients had an Eastern Cooperative Oncology
Group performance status ⱕ 1. Thirty-six percent of patients had a Karnofsky score of ⱕ 80. Two thirds (66%) of
the patients were ⱖ 50 years old, and 20% of the patients
were between 40 and 50 years old. The majority (77%) of
patients had undergone prior debulking surgery, with 42%
being considered macroscopically complete resections;
however, immediate postoperative imaging was not performed in all patients. Fifteen patients (23%) had a stereotactic biopsy only. The median time from diagnosis to the
start of therapy with RT plus temozolomide was 25 days
(range, 14 to 45 days).
Sixty-two patients were treated with concomitant RT plus
temozolomide (Fig 1). Two of the 64 patients enrolled onto
the study received RT alone; one patient refused treatment
with temozolomide, and one patient was ineligible because
of chronic hepatitis. Temozolomide was discontinued early
during RT in four patients because of toxicity (two patients
with an infection and two patients with grade 3 thrombocytopenia after 4 to 5 weeks). All but four patients received
the planned 60 Gy of RT; disease progressed in three patients
and infection progressed in one patient. The majority of
patients completed their RT within the prescribed 6 weeks (42
⫾ 3 days). In 19 patients, the duration of RT was more than 6.5
weeks (maximum, 52 days), and in two of these patients RT
was delayed because of grade 3 or 4 hematologic toxicities
Fig 1.
Treatment scheme. TMZ, temozolomide; RT, radiotherapy.
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1378
STUPP ET AL
Table 2.
Hematologic Toxicities and Infection
RT With Continuous TMZ (62 patients)
Grade 3
Adverse Event
No. of
Patients
Anemia
Neutropenia
Thrombocytopenia
Lymphocytopenia
Infection*
2
2
3
14
1
Adjuvant TMZ Cycle 1 (49 patients)
Grade 4
%
No. of
Patients
3
3
5
23
2
0
2
1
35
2
Grade 3
%
No. of
Patients
0
3
2
57
3
1
1
5
14
0
Adjuvant TMZ All Cycles (216 cycles)
Grade 4
%
No. of
Patients
2
2
10
29
0
0
2
2
20
0
Grade 3
%
No. of
Cycles
0
4
4
41
0
1
3
12
78
0
Grade 4
%
No. of
Cycles
%
⬍1
1
6
36
0
0
2
2
60
0
0
1
1
28
0
Abbreviation: TMZ, temozolomide.
*Pneumocystis carinii pneumonia (n ⫽ 2); craniotomy scar infection/osteomyelitis (n ⫽ 1).
(leukocytopenia and thrombocytopenia). All other RT delays
were due to holidays or accelerator downtime.
Adjuvant temozolomide was administered to 49 patients
for a total of 216 cycles. The median time from the
completion of RT and the beginning of adjuvant temozolomide treatment was 29 days (range, 20 to 63 days).
Adjuvant therapy was delayed in three patients because of
grade 3 or 4 leukopenia or thrombocytopenia. The median
number of adjuvant cycles per patient was 5.5. Adjuvant
chemotherapy was discontinued early because of progressive disease in 24 patients (39%). Twenty-four patients
(39%) received all concomitant and adjuvant temozolomide
as planned in the protocol.
Safety and Tolerability
Hematologic toxicity and infection. In both intermittent
and continuous administration of temozolomide monotherapy, the dose-limiting toxicity is myelosuppression.
However, the hematologic toxicities of concomitant RT
plus temozolomide therapy have not been previously reported. Herein, we report the hematologic toxicities associated with concomitant RT and temozolomide therapy (continuous temozolomide schedule) separately from
hematologic toxicities associated with adjuvant temozolomide treatment (the approved intermittent daily ⫻ 5 temozolomide schedule).
Concomitant phase of treatment. During the concomitant RT plus temozolomide phase, grade 3 or 4 neutropenia
occurred in four patients (6%) (Table 2), and grade 3 or 4
thrombocytopenia occurred in four patients (6%), with two
patients experiencing platelet counts of less than 25,000
cells per cubic millimeter. Only one patient experienced
platelet counts less than 10,000 cells per cubic millimeter.
Grade 3 or 4 lymphocytopenia occurred in 49 patients
(79%).
Three patients had infections that required hospitalization
and treatment interruption. Analysis indicated that two of
the three patients developed P carinii pneumonia. Both of
these patients were receiving corticosteroids and experienced grade 3 or 4 neutropenia and lymphocytopenia at the
time of infection. After these two episodes of opportunistic
infections occurred, we introduced prophylactic pentamidine inhalations during the concomitant treatment phase. No
additional opportunistic infections were observed with prophylaxis in place. One patient required surgical revision of
a scar infection and osteomyelitis 3 weeks after 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 2% and 6% of cycles, respectively. Twelve
patients required a dose reduction or delay because of grade
3 or 4 thrombocytopenia. One patient received daily temozolomide 200 mg/m2 for 30 days instead of for 5 days and
died subsequent to profound thrombocytopenia, neutropenia, and septicemia.
Nonhematologic Toxicities
Nonhematologic toxicities were mild to moderate (Table
3). During the concomitant RT plus temozolomide phase,
prophylactic antiemetics were required in 39% of patients;
however, only seven patients (11%) received antiemetics for
longer then the first week of the concomitant treatment.
During the adjuvant temozolomide phase, 30% of patients
required antiemetic therapy. One patient experienced a
treatment-induced rash that resulted in early discontinuation
of temozolomide after 7 days of concomitant chemoradiotherapy. Moderate to severe fatigue was reported in eight
patients during the concomitant RT plus temozolomide
phase (grade 3; two patients) and in eight patients during the
adjuvant temozolomide phase (grade 3; one patient).
The short duration of follow-up precludes definitive
assessment of late radiation toxicity; only 14 patients were
alive with a follow-up longer than 18 months. However,
signs of leukoencephalopathy, without evident clinical impairment, were apparent on MRI in all of these patients. One
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1379
CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA
Table 3.
Nonhematologic Toxicities
RT With Continuous TMZ (62 patients)
Grade 2
Adjuvant TMZ (49 patients)
Grade 3
Grade 4
Grade 2
Grade 3
Grade 4
Adverse Event
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
Nausea/vomiting
Rash
Fatigue
5
0
6
8
0
10
2
1
2
3
2
3
0
0
0
0
0
0
5
0
7
10
0
14
3
0
1
6
0
2
0
0
0
0
0
0
Abbreviations: RT, radiation therapy; TMZ, temozolomide.
patient developed intracranial hypertension, refractory seizures, and loss of vision 33 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.
Survival
ITT and eligible patient populations. At the time of this
analysis, 38 patients had died. The median duration of
follow-up was 23 months, with a minimum follow-up for
surviving patients of 10 months. On the basis of KaplanMeier estimates, the median survival for the ITT population
was 16 months (95% confidence interval, 11 to 21 months)
(Fig 2). Fifty-eight percent and 31% of ITT patients were
alive at 1 and 2 years, respectively (Table 4). The median
survival in the eligible patient population was also 16
months. There was no difference in 1- and 2-year survival
between the ITT and the eligible patient populations.
Prognostic factors. We separately analyzed the median
survival and survival rates of both the ITT and eligible
patient populations in relation to prognostic indicators.
Because there is no significant difference in outcome, we
report only the results for the ITT population (Table 4). In
patients younger than 50 years old, the median survival was
not reached at 18 months in the ITT population, with 56%
of these patients still alive at 18 months. In patients ⱖ 50
years old, the median survival was only 11 months. Patients
who underwent debulking surgery had a median survival of
17 months. However, for patients who did not undergo
debulking surgery, survival time was 5 months.
We also analyzed our patients according to the recursive
partitioning analysis (RPA) prognostic classes,26 which are
based on a large Radiation Therapy Oncology Group
(RTOG) database of patients with malignant gliomas27
(Table 5). In particular, younger patients and patients whose
tumor could be resected seem to have an improved outcome.
Patients classified as RPA III (⬍ 50 years old) had longer
1-year and 18-month survival rates than patients classified
as RPA V or VI (ⱖ 50 years old).
DISCUSSION
GBM is the most common primary brain tumor in adults.
Despite surgery and RT with or without adjuvant chemotherapy, malignant glioma remains an almost uniformly
fatal disease characterized by a rapid and devastating
clinical course. The value of RT was established in randomized trials in the late 1970s and is now considered the
standard of care4,5,28; however, concomitant or adjuvant
chemotherapy has never been conclusively demonstrated to
have a clear clinical benefit.
The concept of RT concomitantly with chemotherapy has
been explored by using several agents with radiosensitizing
properties, recently with topotecan and tirapazamine. A
RTOG phase I trial, in which 47 GBM patients were treated
Fig 2. Kaplan-Meier estimates of median survival of all patients
(intent-to-treat).
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1380
STUPP ET AL
Table 4.
Variable
Median Survival and Survival Rates
Patients
(n)
Survival, Median
(months)
1-Year
Survival
(%)
18-Month
Survival
(%)
2-Year
Survival
(%)
64
16.0
10.9-21.2
58
46-70
36
24-50
31
19-44
22
42
18.8
11.1
73
50
56
25
50
20
27
22
15
18.8
16.0
5.3
73
61
18
52
35
9
47
35
0
n
95% Confidence interval
Age
⬍ 50 years
ⱖ 50 years
Prior surgery
Complete resection
Partial resection
Biopsy only
with concomitant RT plus topotecan, reported a median
survival of 9.7 months.29 Similarly, 124 GBM patients
treated with concomitant RT plus tirapazamine, a hypoxiaselective cytotoxin, had a median survival of approximately
10 months.30 Furthermore, Kleinberg et al31 reported a
median survival of 12.8 months for patients treated with
concomitant RT plus cisplatin and BCNU. Because most
recurrences in malignant gliomas occur within 2 cm of the
previous resection, local chemotherapy with biodegradable
polymers has been investigated in patients with recurrent
gliomas.32 In a randomized phase III trial with newly
diagnosed glioma patients, BCNU polymers were implanted
during the initial resection, and then patients were subsequently treated with standard RT. Preliminary analysis
indicated that patients implanted with BCNU polymers had
a prolonged median survival (13.9 months; P ⫽ .08)
compared with patients implanted with placebo polymers
(11.6 months).33
In this study, we examined the safety and efficacy of
concomitant RT plus temozolomide therapy followed by
adjuvant temozolomide in patients with newly diagnosed
GBM. Our study confirms the overall excellent tolerability
of temozolomide both with a continuous and intermittent
Table 5.
administration regimen. Myelosuppression, in particular
thrombocytopenia, was the predominant toxicity. Hematologic toxicity during the adjuvant temozolomide treatment
phase was in agreement with previous reports.15,16,20 The
prior concomitant radiochemotherapy did not appreciably
increase the incidence of myelosuppression compared with
previous reports administering temozolomide to chemotherapy-naive patients.16
Lymphocytopenia is often observed with temozolomide
treatment but may, in part, be due to the frequent administration of corticosteroids. In this study, lymphocytopenia
was more common with continuous exposure to temozolomide, as was previously described in the phase I trial of this
regimen.22 Although lymphocytopenia occurs frequently, it
is not typically associated with clinical sequelae. However,
two of the first 15 patients we treated with concomitant RT
plus temozolomide therapy developed P carinii pneumonia.
The frequency of opportunistic infections in a similar
patient population treated with RT alone is unknown.
Nonetheless, after the subsequent introduction of prophylactic administration of aerosolized pentamidine, no further
episodes of P carinii pneumonia or other opportunistic
infections were observed.
Comparison of Survival According to Recursive Partitioning Analysis Criteria
Present Study
RPA Class
III
95% CI
IV
95% CI
V
95% CI
Patients
(n)†
Survival, Median
(months)
18
⬎ 24
28
13.8
9.9-17.7
9.2
6.2-12.3
14
RTOG 90-06*
2-Year
Survival
(%)
51
26-76
32
12-51
0
Patients
(n)
Survival
(median)
2-Year
Survival
(%)
105
17.5
15.6-20.2
11.5
10.8-12.7
7.4
6.2-9.1
30
21-39
17
12-22
8
3-12
240
150
Abbreviation: CI, confidence interval.
*Data from Scott et al.27
†One patient RPA class II and three patients RPA class VI were not reported.
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA
1381
Late toxicity resulting from long-term exposure to alkylating agents or combined modality treatment remains a
concern. Concomitant RT plus temozolomide therapy did
not increase late toxicities associated with RT during the 18
months of follow-up; however, follow-up remains too short
to make any conclusions with regard to late toxicities
resulting from treatment with temozolomide.
Survival results in this pilot study are encouraging.
Indeed, the median survival of 15.8 months compares
favorably with most other reported regimens. Furthermore,
most reports in the literature include patients with more
favorable histologic grades of glioma, whereas our study
was limited to patients with histologically confirmed GBM.
Performance status is considered an important prognostic
factor and might be somewhat higher in this study compared
with that in other reported series. Nevertheless, this treatment protocol was offered to all patients treated with
radiation therapy at our two institutions, and most patients
accepted participation in the trial. The performance status in
our trial may also be somewhat overestimated, because the
scoring was based on the initial assessment of residents
rotating through the oncology department. Age and extent
of resection are the most important prognostic factors for
GBM. As expected, younger patients and patients with
debulked disease had substantially better survival rates than
patients who had a biopsy only. However, we could not
demonstrate a statistically significant difference between
patients who had a gross complete or subtotal resection.
Nonrandomized comparisons between trials have to be
approached with caution. Differences in study protocols and
changes in response evaluations, pathologic classifications,
imaging techniques, and standard and supportive care make
comparing trials difficult. The prognostic classes model
from RPA of the RTOG database of malignant glioma
patients may overcome some of the shortcomings associated
with comparing trials.26,27 RPA suggests that patients in this
study compared favorably with patients in the RTOG
database who were treated on a randomized trial in the early
1990s (Table 5).
In summary, the results of this trial demonstrate that
concomitant RT plus continuous daily temozolomide therapy followed by additional cycles of the standard regimen
of adjuvant temozolomide therapy is well tolerated and may
prolong survival in patients with malignant glioma. However, it remains unclear whether the improved survival
resulted from the continuous administration schedule of
temozolomide (which depletes AGT), an additive cytotoxic
effect of combined RT and temozolomide, or simply because of adjuvant therapy with an active agent. The survival
benefits may also be attributed to the ability of temozolomide to penetrate the CNS to a greater extent than many
other chemotherapy agents. Temozolomide and concurrent
RT, followed by adjuvant temozolomide chemotherapy, is a
promising regimen for patients with malignant glioma. This
regimen is currently being compared with standard RT
alone in an international randomized trial coordinated by the
European Organization for Research and Treatment of
Cancer and the National Cancer Institute of Canada.
ACKNOWLEDGMENT
We thank Sally Willcox, RN, for dedicated care; Drs P. Coucke, A.
Telenti, and P.A. Despland for advice; Drs C. Collao, N. Doser, R.
Greiner, A. Hottinger, B. Rilliet, J.G. Villemure, D. Wellmann, and A.
Zouhair for treating patients; M.C. Verbist and A. Magraouhi for
administrative support; and Essex/Schering-Plough (H. Egger, PhD; S.
Zaknoen, MD) for providing temozolomide.
REFERENCES
1. Ries LAG, Eisner MP, Kosary CL, et al (eds): SEER Cancer
Statistics, 1973-1998. Bethesda, MD, National Cancer Institute, 2001
2. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3:255-268, 1993
3. Burger PC, Vogel FS, Green SB, et al: Glioblastoma multiforme
and anaplastic astrocytoma: Pathologic criteria and prognostic implications. Cancer 56:1106-1111, 1985
4. Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of
BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A
cooperative clinical trial. J Neurosurg 49:333-343, 1978
5. Kristiansen K, Hagen S, Kollevold T, 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 47:649-652, 1981
6. 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, LippincottRaven, 1997, pp 2022-2082
7. Galanis E, Buckner J: Chemotherapy for high-grade gliomas. Br J
Cancer 82:1371-1380, 2000
8. DeAngelis LM: Brain tumors. N Engl J Med 344:114-123, 2001
9. Fine HA, Dear KB, Loeffler JS, et al: Meta-analysis of radiation
therapy with and without adjuvant chemotherapy for malignant gliomas
in adults. Cancer 71:2585-2597, 1993
10. Randomized trial of procarbazine, lomustine, and vincristine in
the adjuvant treatment of high-grade astrocytoma: A Medical Research
Council trial. J Clin Oncol 19:509-518, 2001
11. Newlands ES, Stevens MF, Wedge SR, et al: Temozolomide: A
review of its discovery, chemical properties, pre-clinical development
and clinical trials. Cancer Treat Rev 23:35-61, 1997
12. Stupp R, Gander M, Leyvraz S, et al: Current and future
developments in the use of temozolomide for the treatment of brain
tumors. Lancet Oncol 2:552-560, 2001
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
1382
STUPP ET AL
13. Reid JM, Stevens DC, Rubin J, et al: Pharmacokinetics of
3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. Clin Cancer
Res 3:2393-2398, 1997
14. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment
of malignant glioma. Clin Cancer Res 6:2585-2597, 2000
15. Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial
of temozolomide in patients with anaplastic astrocytoma or anaplastic
oligoastrocytoma at first relapse. J Clin Oncol 17:2762-2771, 1999
16. Yung WK, Albright RE, Olson J, et al: A phase II study of
temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-593, 2000
17. Newlands ES, Blackledge GR, Slack JA, et al: Phase I trial of
temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer
65:287-291, 1992
18. Marzolini C, Decosterd LA, Shen F, et al: Pharmacokinetics of
temozolomide in association with fotemustine in malignant melanoma
and malignant glioma patients: Comparison of oral, intravenous, and
hepatic intra-arterial administration. Cancer Chemother Pharmacol
42:433-440, 1998
19. Stupp R, Ostermann S, Leyvraz S, et al: Cerebrospinal fluid
levels of temozolomide as a surrogate marker for brain penetration.
Proc Am Soc Clin Oncol 20:59a, 2001 (abstr 232)
20. Brada M, Hoang-Xuan K, Rampling R, et al: Multicenter phase
II trial of temozolomide in patients with glioblastoma multiforme at
first relapse. Ann Oncol 12:259-266, 2001
21. Friedman HS, McLendon RE, Kerby T, et al: DNA mismatch
repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol
16:3851-3857, 1998
22. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of
temozolomide using an extended continuous oral schedule. Cancer Res
58:4363-4367, 1998
23. Wedge SR, Porteous JK, Glaser MG, et al: In vitro evaluation of
temozolomide combined with x-irradiation. Anticancer Drugs 8:92-97,
1997
24. van Rijn J, Heimans JJ, van den Berg J, et al: Survival of human
glioma cells treated with various combination of temozolomide and
x-rays. Int J Radiat Oncol Biol Phys 47:779-784, 2000
25. Hirose Y, Berger MS, Pieper RO: p53 Effects both the duration
of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 61:1957-1963, 2001
26. Curran WJ Jr, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy
Oncology Group malignant glioma trials. J Natl Cancer Inst
85:704-710, 1993
27. Scott CB, Scarantino C, Urtasun R, et al: Validation and
predictive power of Radiation Therapy Oncology Group (RTOG)
recursive partitioning analysis classes for malignant glioma patients: A
report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40:51-55,
1998
28. Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant
glioma after surgery. N Engl J Med 303:1323-1329, 1980
29. Fisher BJ, Scott C, Macdonald DR, et al: Phase I study of
topotecan plus cranial radiation for glioblastoma multiforme: Results of
Radiation Therapy Oncology Group Trial 9507. J Clin Oncol 19:11111117, 2001
30. Del Rowe J, Scott C, Werner-Wasik M, et al: Single-arm,
open-label phase II study of intravenously administered tirapazamine
and radiation therapy for glioblastoma multiforme. J Clin Oncol
18:1254-1259, 2000
31. Kleinberg L, Grossman SA, Piantadosi S, et al: 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 44:535-543,
1999
32. Brem H, Piantadosi S, Burger PC, 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 345:1008-1012,
1995
33. Westphal M, Delavault P, Hilt D, et al: Placebo-controlled
multicenter double-blind randomized prospective phase III trial of local
chemotherapy with biodegradable carmustine implants (Gliadel) in 240
patients with malignant gliomas: Final results. Neurooncology 2:301,
2000 (abstr)
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2002 American Society of Clinical Oncology. All rights reserved.