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TemozolomideA Review of its Use in the Treatment of Malignant Gliomas,Malignant Melanoma and Other Advanced Cancers
Malcolm J.M. Darkes, Greg L. Plosker and Blair Jarvis
Adis International Inc., Langhorne, Pennsylvania, USA
Various sections of the manuscript reviewed by:
S. DAtri, Instituto Dermopatico DellImmacolata, Rome, Italy; H.S. Friedman, Duke University, Departments of Surgery, Medicine andPediatrics, Durham, North Carolina, USA; L.A. Hammond, Cancer Therapy and Research Center, The Institute for Drug Development, SanAntonio, Texas, USA;M.R. Middleton, Churchill Hospital, ICRF Medical Oncology Unit, Oxford, United Kingdom;J.M. Reid, Mayo Clinic,Department of Oncology, Rochester, Minnesota, USA;K. Warren, National Institutes of Health, Bethesda, Maryland, USA.
ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602.2 Antineoplastic and Cytotoxic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
2.2.1 In VitroStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612.2.2 In VivoStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2.3 Mechanisms of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643.2 Degradation and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653.3 In Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653.4 In Patients with Renal and Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663.5 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4. Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.1 Malignant Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664.1.1 Combined Malignant Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674.1.2 Glioblastoma Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.2 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714.3 Other Advanced Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725.1 Hematologic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5.1.1 In Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745.2 Other Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757. Place of Temozolomide in the Management of Advanced Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
7.1 Malignant Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757.2 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
ADIS DRUG EVALUATION Am J Cancer 2002; 1 (1): 55-801175-6357/01/0001-0055/$25.00/0 Adis International Limited. All rights reserved.
Data Selection
Sources: Medical literature published in any language since 1980 on temozolomide, identified using Medline and EMBASE, supplemented by AdisBase
(a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographic information,
including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were temozolomide. EMBASE search terms were temozolomide. AdisBase search terms were temozolomide
or CCRG 81045. Searches were last updated on 4 February 2002.
Selection: Studies in patients with cancer who received temozolomide. Inclusion of studies was based mainly on the methods section of the trials. When
available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are
also included.
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7.3 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
SummaryAbstract Temozolomide is a cytotoxic prodrug that, when hydrolyzed, inhibits DNA replication by methylating nucleotide
bases. In preclinical testing, temozolomide has shown a broad spectrum of antineoplastic activity.
In patients with malignant glioma, the objective response (complete or partial response) rate ranged from 11
to 47% in noncomparative studies. The highest objective response rate was observed in newly diagnosed
patients. Progression-free survival (PFS) at 6 months was consistently >20%.
In patients with relapsing anaplastic astrocytoma who were treated with temozolomide, the objective re-
sponse and 6-month PFS rates ranged from 11 to 35% and 22 to 49%, respectively, in noncomparative studies.
All patients with progression-free disease at 6 months had either similar or better scores in the seven
health-related quality-of-life (HR-QOL) domains when compared with baseline. In contrast, patients with
disease progression reported statistically significant deterioration in five of seven domain scores at 6 months.Of the patients with an objective response, 92 and 82% of those achieved an HR-QOL response in one or more
and three or more domains, respectively.
In patients with glioblastoma multiforme, temozolomide produced a greater 6-month PFS rate than that of
patients who were treated with procarbazine (21vs 8%) in a randomized, multicenter study. Survival at 6 months
was also greater in the temozolomide-treated group (60vs 44%). Moreover, the temozolomide-treated popula-
tion scored consistently higher in all HR-QOL domains measured.
In a randomized phase III trial involving patients with advanced malignant melanoma, temozolomide pro-
duced an objective response rate of 13.5% compared with 12.1% in the dacarbazine group. Temozolomide
produced a modest increase in PFS time compared with dacarbazine (1.9vs 1.5 months). There was a statistically
significant difference in favor of the temozolomide-treated group in the physical functioning and cognitive
functioning domains.
Temozolomide produced low objective response rates in patients with advanced soft tissue sarcoma, non-
Hodgkins lymphoma, hormone-refractory prostate cancer, pancreatic cancer, advanced nasopharyngeal carci-
noma and brain metastases in small noncomparative trials.Temozolomide is generally well tolerated. Mild to moderate myelosuppression is the primary dose-limiting
adverse effect of temozolomide, which is reversible and noncumulative. Nausea and vomiting, although com-
mon, are usually mild.
Conclusion: Temozolomide has demonstrated similar clinical responses to procarbazine and dacarbazine in
malignant glioma and melanoma, respectively. Although initial studies have not demonstrated an overall sur-
vival advantage associated with temozolomide in either disease, the drug has demonstrated clinically significant
HR-QOL benefits when compared with either procarbazine or dacarbazine. The favorable HR-QOL scores
confirm its acceptable tolerability profile. Temozolomides oral formulation allows patients to be treated in the
home setting.
Pharmacodynamic
Properties
Temozolomide, a prodrug, is a monofunctional alkylating agent that readily crosses the blood-brain barrier. It
is chemically related to dacarbazine and is the 3-methyl derivative of the experimental anticancer drug,
mitozolomide.
Unlike dacarbazine, temozolomide does not require hepatic metabolism to the intermediate species
methyltriazen-1-yl imidazole-4-carboxamide (MTIC) but spontaneously hydrolyzes to MTIC above pH7. MTIC
degrades to a highly reactive cation that methylates guanines in DNA at the O6 position, causing base pair
mismatch. Unsuccessful cycles of mismatch repair eventually lead to breaks and permanent nicks in the daughter
strand preventing mitotic division and the cell undergoes apoptosis.
Temozolomide has shown antiproliferative and cytotoxic activity in cell lines and tumor isolates from patients
in vitro. Moreover, temozolomide exerted cytotoxic effects on human tumors that were refractory to several
clinically relevant antitumor agents.
Temozolomide has demonstrated activity against a variety of experimentally induced tumors in mice and
rats. Its activity was equal to or greater than that of dacarbazine in a number of murine tumor models. Tem-
ozolomide has demonstrated tumor growth delays in athymic nude mice that displayed a panel of subcutaneous
central nervous system tumor xenografts. A 5-day intraperitoneal regimen of temozolomide (411 mg/m2/day)
produced 1.8- to 7.5-fold and 4.7- to 19-fold greater tumor growth delays than intraperitoneal procarbazine and
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carmustine, respectively. In mice with intracranial xenografts, temozolomide increased median survival times1.7- to 13.9-fold.
Three main DNA repair mechanisms are responsible for temozolomide resistance: increased intracellular
levels ofO6-alkylguanine-DNA alkyltransferase (AGT); a deficient mismatch repair process (MMR); and ac-
tivation of the poly(ADP)-ribose polymerase pathway. Primary resistance to temozolomide is directly correlated
to high AGT levels but in AGT-deficient cells, low or deficient MMR protein levels become important in
conferring resistance.
Pharmacokinetic
Properties
In adults and children with advanced cancer, oral temozolomide (50 to 250 mg/m2) exhibited predictable
pharmacokinetics that were adequately described by a one-compartment open model. Gastrointestinal absorp-
tion of temozolomide was complete (bioavailability100%) and rapid [time taken to reach peak plasma con-
centration (tmax) 1 hour]. However, the administration of temozolomide (200 mg/m2/day for 5 days) with food
delayed tmax values by 110% and suppressed both the maximum plasma concentration (Cmax) and the area under
the plasma concentration-time curve (AUC), by 32 and 9%, respectively. Cmax and AUC increased linearly with
dose. Temozolomide has a calculated volume of distribution (Vd) range of 28.3 to 47.2L. Neither temozolomide
nor its degradation products accumulated in plasma after multiple doses or during a 7-week daily dosageregimen. Plasma protein binding of temozolomide-derived14C averaged 12 to 16% when measured 1 and 4
hours after a single oral dose of14C-labeled temozolomide 200mg.
Plasma temozolomide concentrations declined with a mean elimination half-life of1.8 hours (range 1.7 to 1.9
hours). Following absorption, temozolomide is immediately subject to elimination processes that involve excre-
tion via the kidneys of both the unchanged drug and its degradation products. The main temozolomide elimi-
nation process is via pH-dependent hydrolysis to MTIC then degradation to 5-amino-imidazole-4-carbox-amide,
and a highly reactive methyldiazonium ion. Hepatic biotransformation of temozolomide to temozolomide acid
has a minor eliminatory role. Unchanged drug is eliminated in a dose-independent manner and clearance (CL)
ranged from 5.8 to 6.9 L/h/m2 in cancer patients who received temozolomide 200mg as a single dose or as a
daily dose for 5 days. A reduction in CL was reported in patients who had received prior nitrosourea therapy.
Although temozolomide pharmacokinetic data in children and adolescents are limited, measured parameters
are similar to those in adults. In a small study (n = 19), children and adolescents (aged 4 to 18 years) with
advanced cancer were given between 100 and 240 mg/m2 for 5 days, repeated every 4 weeks. Temozolomide
was rapidly absorbed (tmax range 1.27 to 1.9 hours) and Cmax and AUC increased linearly with dose. The Vd
and CL ranged from 10.4 to 13.9L and 4.32 to 5.58 L/h/m2. CL was independent of temozolomide dose.
Population pharmacokinetic studies indicated that CL increases with body surface area in both sexes and is
unaffected by smoking status, comedications and hepatic and renal function.
Currently, there is no evidence of pharmacokinetic interactions between temozolomide and either cisplatin,
carmustine, corticosteroids or a range of antiemetics (ondansetron, domperidone, haloperidol). Valproic acid
caused an 5% decrease in CL and may result in slightly elevated plasma temozolomide concentrations.
Therapeutic Use The majority of clinical trials have focused on the efficacy of temozolomide in malignant glioma and metastatic
malignant melanoma. The assessment of chemotherapy in patients with these malignancies is difficult because
of the poor prognosis, low sample numbers and subjective response criteria. Therefore, parallel health-related
quality-of-life (HR-QOL) studies are sometimes carried out to provide a further insight into the clinical efficacy
of anticancer drugs. The oral temozolomide dosage regimen used in these trials was 150 or 200 mg/m2/day for
5 consecutive days, repeated every 4 weeks.
Combined Malignant Glioma: Temozolomide showed promising activity in high-grade gliomas as judged
by the objective response rate, which ranged considerably from 11 to 47% in noncomparative trials. The highest
objective response rate was observed in newly diagnosed patients. The proportion of patients with disease
stabilisation also showed a wide range, varying from 16 to 47%. The median time to disease progression ranged
from 4.2 to 7 months and the median duration of survival ranged from 5.8 to 13.6 months. Progression-free
survival (PFS) at 6 months was consistently >20% and one trial reported a 34.7% PFS rate after 12 months.
The collation of intermediate endpoint data has demonstrated a relationship between the biochemical mech-
anism of resistance and clinical response to temozolomide. Three DNA repair enzymes were shown to be at
least partly responsible for cellular resistance to temozolomide and knowledge of their pretreatment cellular
levels may correlate with clinical response.
In patients with anaplastic astrocytoma (AA) who were treated with temozolomide the objective response
rate was 35%. The 6-month PFS rate was 49% and the median duration of PFS was 5.5 months. These positive
outcomes were reflected in enhanced HR-QOL benefits. Change from baseline analysis demonstrated that the
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63 patients who were progression-free at 6 months reported either similar or better scores in the seven HR-QOLdomains. In contrast, patients with disease progression reported statistically significant deterioration in five of
seven domain scores at 6 months when compared with baseline. Of the patients with an objective response, 92
and 82% of those achieved an HR-QOL response in one or more and three or more domains, respectively, but
patients with disease progression reported statistically significant worsening of domain scores compared with
baseline. The median duration of an HR-QOL improvement was longest in patients with an objective response.
Statistical analysis has isolated two prognostic factors that influence clinical endpoints. Baseline Karnofsky
performance status (>80 or80) is a prognostic factor with respect to 6-month PFS and median overall survival,
and an objective response to previous treatment increases time to disease progression.
Only preliminary evidence is available regarding the efficacy of temozolomide in pediatric patients diag-
nosed with malignant glioma.
Glioblastoma Multiforme: In a randomized, nonblind, multicenter phase III trial (n = 225), patients who
were treated with oral temozolomide had a greater 6-month PFS rate than that of patients who were treated with
oral procarbazine (125 or 150 mg/m2/day for 28 days every 8 weeks) [21vs 8% of patients]. Survival at 6 months
was greater in the temozolomide-treated group (60vs 44% of patients).The temozolomide-treated population scored consistently higher in all HR-QOL domains measured com-
pared with the procarbazine group. Procarbazine-treated patients who were progression-free at 6 months re-
ported deterioration in all seven preselected domains.
The PFS rate was 19% in a multicenter, noncomparative, phase II trial (n = 138), which evaluated the
antitumor activity of temozolomide. The objective response rate was 8% and 45% had stable disease. The parallel
QOL study found that patients with an objective response reported enhanced HR-QOL scores in all domains
except visual disorder. Interestingly, improvement from baseline was also observed in patients with stable
disease and with disease progression.
Malignant Melanoma: In a randomized, nonblind, phase III trial (n = 305), oral temozolomide produced a
modest but statistically significant increase in PFS time compared with an intravenous infusion of dacarbazine
(250 mg/m2/day for 5 days every 21 days) [1.9vs 1.5 months]. The median survival time in the temozolomide-
treated group was 7.7 months compared with 6.4 months in the dacarbazine-treated group. Objective response
rates were 13.5 and 12.1% in the temozolomide- and dacarbazine-treated groups, respectively.
The associated HR-QOL study had an understandably high attrition rate. Although no difference was ob-served between the two study arms after cycle one when more patients were involved, at 12 weeks, there was
a statistically significant difference in favor of the temozolomide-treated group in the physical functioning and
cognitive functioning domains. A statistically significant difference in favor of the temozolomide-treated group
was also observed for symptoms of insomnia and fatigue. Among the patients with an objective response in
both study arms, the temozolomide-treated group reported significantly greater improvements in the physical
and cognitive functioning domains.
Other Advanced Cancers: Temozolomide has been investigated in clinically diverse cancers including
advanced soft tissue sarcoma, non-Hodgkins lymphoma, hormone-refractory prostate cancer, pancreatic cancer,
advanced nasopharyngeal carcinoma and brain metastases in small noncomparative trials. Although the objec-
tive response rates were low, more data are required before temozolomide can be judged in these diseases.
Tolerability Mild to moderate myelosuppression (neutropenia and thrombocytopenia) is the primary dose-limiting adverse
effect of temozolomide. Nadir platelet and neutrophil counts typically occur 21 to 28 days after the first tem-
ozolomide dose and can be managed by reducing the next scheduled dose. Critical toxicity criteria (CTC) grade
1 myelosuppression is normally observed 21 to 28 days after beginning a cycle.A population pharmacokinetic study stated that the incidence of temozolomide-associated neutropenia and
thrombocytopenia was 7.4% (20 of 270 patients) and 5.3% (15 of 284 patients), respectively. Older female
patients who received higher temozolomide doses had a greater chance of developing myelosuppression.
It is debatable whether an increased incidence and severity of adverse effects to temozolomide exposure
occurs in patients who have received prior chemotherapy and/or radiotherapy compared with patients who have
not received prior treatment. Phase I and II trials have used different definitions to describe prior treatment and
blood count ranges. The maximum tolerated dose in patients who had prior exposure to nitrosourea therapy was
150 mg/m2/day for 5 days compared with 250 mg/m2/day for 5 days in patients without prior exposure. However,
another study reported a maximum tolerated dose of 150 mg/m2/day for 5 days, irrespective of prior treatment.
A dose-finding phase I trial (n = 24) found the maximum tolerated dosage in patients who received tem-
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ozolomide daily for 6 or 7 weeks was 75 mg/m2/day. CTC grade 0 to 2 leukopenia and thrombocytopenia wereobserved in the dosage range of 50 to 75 mg/m2/day.
CTC grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities in a dose-finding trial
involving 27 children and adolescents with advanced cancer who received between 150 and 240 mg/m2/day for
5 days. Temozolomide was well tolerated in a phase I study of 49 children and adolescents with recurrent solid
tumors. This study was stratified by prior therapy with craniospinal irradiation (CSI). A maximum tolerated
dosage in 27 patients with no prior irradiation was 215 mg/m2/day for 5 days and 180 mg/m2/day for 5 days in
22 patients with CSI.
The most common nonhematologic events associated with temozolomide are mild to moderate nausea and
vomiting, which can be assuaged with prophylactic and/or therapeutic antiemetics. In the 5-day schedule, these
symptoms were manifest only on day 1.
The most frequent nonhematologic adverse events (all grades) in patients with recurrent glioma (and malig-
nant melanoma) were: nausea 42% (52%); vomiting 34% (35%); headache 13% (22%); fatigue 20% (30%) and
constipation 17% (29%). Nonhematologic adverse reactions were found to be similar in frequency and severity
in patients with recurrent glioma and advanced malignant melanoma. However, there was a greater frequency
of fatigue in patients with recurrent glioma than in patients with melanoma. When alopecia could be assessed
it was mild (CTC grade 0 to 1). A skin rash has been observed in 2 of 51 and 6 of 110 patients.
Dosage and
Administration
Temozolomide capsules are indicated for AA in the US in adult patients who have relapsed disease after initial
therapy with a nitrosourea and procarbazine. In the European Union, temozolomide capsules are indicated for
the treatment of patients with malignant glioma, such as glioblastoma multiforme or AA, showing recurrence
or progression after standard therapy. In addition, temozolomide capsules are approved for use in patients with
metastatic melanoma in Australia, New Zealand and several Latin American countries.
The recommended starting dosage is 150 or 200 mg/m2/day for 5 consecutive days of a 4-week cycle for
adults who are heavily pretreated or not heavily pretreated, respectively. Temozolomide is administered orally
once daily and should be swallowed intact with water. Administration on an empty stomach is inadvisable.
The dosage should be adjusted according to tolerability; platelet and neutrophil blood counts form the basis
of measurement of hematologic toxicity.
Temozolomide should be used with caution in patients with severe hepatic or renal impairment. Mild tomoderate hepatic impairment does not alter the pharmacokinetic profile of temozolomide and CL is not affected
in patients with creatinine clearances of 2.16 to 7.80 L/h/m2. Geriatric patients and women have a greater risk
of developing myelosuppression.
1. Introduction
Current chemotherapies for advanced cancers are still inad-
equate. The large majority of licensed anticancer drugs exploit
only the proliferative pathways of cells within neoplastic tissue,
regardless of mitotic division rate. As a natural extension of these
antiproliferative actions, there remains a fine balance between
clinical efficacy and unacceptable toxicity in cancer patients.
Temozolomide, a prodrug, is a monofunctional alkylatingagent that readily crosses the blood-brain barrier. It is derived
from a series of modified imidazotetrazinones, is chemically re-
lated to dacarbazine and is the 3-methyl derivative of the experi-
mental anticancer drug mitozolomide (figure 1).[1]
Both in vitro and in vivo preclinical studies have shown that
temozolomide is active against a wide variety of tumor types. Of
particular interest is its clinical efficacy in patients with malignant
glioma or malignant melanoma and its ability to enhance health-
related quality of life (HR-QOL).
A previous review briefly highlighted the initial clinical out-
comes of temozolomide therapy in high-grade malignant
glioma.[2] The aim of this article is to provide a more comprehen-
sive review of the clinical pharmacology of temozolomide,
mainly in advanced malignant gliomas and metastatic malignant
melanoma but also in other advanced neoplasms. An account of
the individual management of these diseases is detailed in re-
views elsewhere.[3-7] The malignancies discussed in this article
have a poor prognosis. Therefore, parallel studies that also collectdata concerning HR-QOL issues are desirable and necessary.
2. Pharmacodynamic Properties
Temozolomides molecular mechanism of action, its antineo-
plastic activity and the biochemical mechanisms of tumor resis-
tance to it have been investigated extensively. Originally synthe-
sized in 1984, temozolomide (8-carbamoyl-3- methylimidazo
[5,1-d]-1,2,3,5-tetrazin-4(3H)-one) is a bicyclic heterocycle and
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is chemically classed as an imidazotetrazinone (figure 1).[1] The
defining characteristic of this class of compound is an imidazole
ring that is fused with a tetrazinone ring system that contains three
adjacently bonded nitrogen atoms.
2.1 Mechanism of Action
A putative molecular mechanism of action is detailed in fig-
ure 2, which also describes its route of elimination (section 3).
Unlike dacarbazine, temozolomide does not require hepatic me-
tabolism to the intermediate species methyltriazen-1-yl imida-
zole-4-carboxamide (MTIC). Chemical stability studies have
shown that temozolomide spontaneously hydrolyzes to MTIC
above pH7.[8] Therefore, following intestinal absorption, the elec-
tropositive carbonyl C4 position of the tetrazinone ring in tem-
ozolomide is susceptible to base-catalyzed nucleophilic attack by
water.[8] Ring cleavage and loss of carbon dioxide results in
MTIC formation which then rapidly degrades to an inactive
carboxylic acid derivative, 5-aminoimidazole-4-carboxamide
(AIC), and a highly reactive methyldiazonium ion. The nascent
cation is the active methylating agent and is vulnerable to instan-
taneous nucleophilic attack by electron donors within DNA nu-
cleotides, causing the transfer of a methyl group from the ion to
form a methylated-DNA adduct. The most common nucleophilic
centers within nucleotides that are accessible to methylation are
the 6 oxygen (O6) [5% of adducts] and 7 nitrogen of guanine (N7)
[70% of adducts], N1 and N3 of adenine and N3 of cytosine (25%
of adducts).[8,9]
The crystal structure of temozolomide has been solved,[10]
permitting meaningful structure-function molecular modelling of
its reaction with DNA.[8] The starting point of the simulation was
the intact temozolomide molecule residing in the major groove
of B-DNA, in proximity to a run of three guanine residues. The
calculated energy minimizations correlate well with the predicted
reactions that transform temozolomide from its prodrug status to
an active methyldiazonium cation. The model predicts that the
rate of temozolomide ring opening (and hence cytotoxic activity)
may be DNA sequence specific, as a run of three guanines pro-
vides an optimal steric and electronic (basic) microenvironment
for N7 methylation. However, more recent findings by the same
investigators propose that pH is the only factor that determines
the rate of tetrazinone ring opening and thus the chemical con-
version of temozolomide to an active species.[11] They argue that
susceptible DNA nucleotides only encounter the methydiazon-
ium ion and there are only weak (if any) non-covalent interactions
with temozolomide itself.
Ultimately, cytotoxicity depends on methylation of guanines
in genomic DNA at the O6 position,[12,13] despite the fact that theyconstitute only 5% of the total DNA-adducts formed. [9] Indeed,
cell lines and xenografts that express high levels of the DNA
repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) are
resistant to temozolomide exposure (section 2.3).[12-18] Muta-
genic lesions not repaired by AGT are recognized by mismatch
repair (MMR) enzymes, which mend the mismatch between O6-
methylguanine:thymine base pairs by excising the thymine base
in the daughter strand. However, if the O6-methylguanine lesion
is left intact, thymine is always re-mismatched. The attempts of
N
N
CH2N O
NN
N
O
CH3
N
N
CH2N O
NN
N
O
CH2CH2Cl
Temozolomide Dacarbazine
Procarbazine
C
O
NHCH
CH 3
CH 3
CH 2NH
NH
H3C
Mitozolomide
N
NH NN N
CH 3
CH 3
C
O
NH 2
Fig. 1. Chemical structures of temozolomide and other related alkylating agents.
60 Darkes et al.
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MMR proteins are unsuccessful and continual enzymatic cycleseventually lead to breaks and permanent nicks in the daughter
strand. As a consequence the cell arrests at the G2/M phase tran-
sition before undergoing apoptosis.[19,20] Therefore, like other al-
kylating agents, temozolomide may have a greater antitumor ef-
fect if a large population of cells is actively replicating.
2.2 Antineoplastic and Cytotoxic Activity
2.2.1 In Vitro Studies
Temozolomide has shown antiproliferative and cytotoxic ac-
tivity in cell lines[21,22] and tumor isolates[23] from patients in
vitro. The most comprehensive study measured the antiprolifera-
N
N
CH2N O
NN
N
O
CH3
N
NH
CH2N O
NH CH3NN
+H2O
+H
CO2
MTIC
(pH>7)
88a
5 4
3
2
1
6
7
N
NH
CH2N O
NH2
CH3
N
N N
N
N
HN
O
H2N
DNA
N
N
N
N
OCH3
H2N
DNA
++ +
Precursor in purine
and uric acid
biosynthesis
Excretion via
the kidneys
N2 H
Base-pair mismatch and
re-mismatch with thymine
Methyldiazonium
cation
AIC Guanine
5
4
3
9
8
76
1
2
Temozolomide
Fig. 2. The putative molecular mechanism of action of temozolomide. The first two steps also account for its pH-dependent elimination. Although O6-guanine methylation
accounts for only 5% of the total DNA-adducts formed, this lesion is regarded as the most cytotoxic.[8,9]AIC = 5-aminoimidazole-4-carboxamide;MTIC = methyltriazen-1-yl
imidazole-4-carboxamide.
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tive effects of temozolomide at clinically achievable concentra-
tions (0.1 to 10 mol/L) on 101 human tumor colony-forming
units.[23] A wide range of human tumors were investigated includ-
ing malignant melanoma, breast, ovarian, prostate and non-small
cell lung cancer. A decrease in human tumor colony formation
was considered significant if survival of colonies treated with
temozolomide was 50% of that in controls. Temozolomide con-
centrations of 0.1, 1.0 and 10mol/L caused significant responses
in 9, 16 and 35% of tumors, respectively. Interestingly, tem-
ozolomide also exerted cytotoxic effects on human tumors that
did not show significant inhibition after exposure to several clin-
ically relevant antitumor agents. In particular, temozolomide (10
mol/L) had activity in 4 of 12 tumor specimens resistant to
dacarbazine, 4 of 13 resistant to carmustine, 6 of 24 resistant to
cisplatin, 4 of 14 resistant to doxorubicin, 5 of 11 resistant tofluorouracil, 4 of 11 resistant to vinblastine and 2 of 8 resistant
to etoposide.
A drug sensitivity study examined the effect of temozolom-
ide and the nitrosourea lomustine in WHO grade III and IV as-
trocytomas.[21] Although the short-term cultures showed mixed
responses (30- and 10-fold response range for temozolomide and
lomustine, respectively), sensitivity to lomustine was consis-
tently greater. The cell cultures had different sensitivities towards
both drugs but cross-resistance was common. Cytotoxicity was
assessed by measuring the median drug concentration required toinhibit mitochondrial production of formazan by 50% (ID50). The
median ID50 concentration for temozolomide was 257.7 mol/L
compared with 16.1 mol/L for lomustine. The ID50 for the most
temozolomide-sensitive tumor (IN949) was 22.7 mol/L com-
pared with 2.8 mol/L for the most lomustine-sensitive tumor
(IN35). IN336 was the most chemoresistant tumor for both drugs:
temozolomide had an ID50 of 541.1 mol/L compared with 30.8
mol/L for lomustine. Importantly, if 60mol/L represents a clin-
ically achievable plasma temozolomide concentration then only
3 of 15 cultures had ID50 values below this concentration. In
contrast, 11 of 15 cultures had ID50 values below a clinically
relevant plasma lomustine concentration of 22 mol/L.
In human-derived D384 astrocytoma cell lines, temozolom-
ide significantly reduced the surviving fraction of cells when ad-
ministered once every 24 hours for 4 days compared with a single
24-hour exposure.[22] In addition, a 24-hour exposure to tem-
ozolomide 10 mol/L enhanced the cytotoxicity of fractionally
irradiated D384 astrocytoma cells but not U251 glioblastoma
cells. Interestingly, a 96-hour exposure to temozolomide 10
mol/L achieved optimal cytotoxicity of fractionally irradiated
D384 cells compared with radiation treatment alone. No such
enhancement of cytotoxicity was found for U251 cells.[22]
2.2.2In Vivo Studies
Temozolomide demonstrated activity against a variety of ex-perimentally-induced tumors in mice and rats.[24-28] As a single
subcutaneous injection, temozolomide (160 mg/kg) increased
survival time 1.51-fold in mice with an implanted subcutaneous
TLX5 lymphoma compared with untreated controls.[24] Interest-
ingly, a smaller daily dose over a 5-day period (40 mg/kg/day)
increased the survival time in mice 1.81-fold compared with un-
treated controls.
Temozolomide activity was equal to or greater than that of
dacarbazine in a number of murine tumor models (figure 3). [24]
Intraperitoneal temozolomide (100 mg/kg/day for 5 days) in-
duced a 1.76- and >2.35-fold increase in survival time in mice
with P388 and L1210 leukemia, respectively, compared with un-
treated controls. The same temozolomide dosage regimen givenorally in mice with L1210 leukemia resulted in a 1.74-fold in-
crease in survival times.
Intraperitoneal temozolomide has demonstrated growth de-
lays against a panel of central nervous system (CNS) tumor xe-
nografts in athymic nude mice.[25] The xenografts, which were
implanted either subcutaneously or intracranially, were derived
from ependymomas, medullablastomas and childhood and adult
high-grade gliomas. A growth delay was defined as the difference
between the median time for tumors in treated and untreated (con-
0
50
100
150
200
250
TLX5lym
phom
a
P388
leukem
ia
L1210
leuk
emia
,1
L1210
leukem
ia,2
Experimentally induced murine tumor models
Increaseinsurvivaltime(%)
TemozolomideDacarbazine
Fig. 3. Activity of temozolomide and dacarbazine against murine tumor models in
vivo.[24] Increase in survival time was quantified as the ratio, expressed as a
percentage, between survival durations in treated and untreated mice. Mice re-
ceived temozolomide and dacarbazine 80 (TLX5 lymphoma) or 100 (all others)
mg/kg/day by oral (L1210 leukemia, 2) or intraperitoneal (all others) administration
for up to 1 week.
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trol) animals to reach five times the volume recorded at treatmentinitiation.
A 5-day, intraperitoneal regimen of temozolomide (411
mg/m2/day) caused growth delays ranging between 40.8 days in
adult anaplastic astrocytoma (AA) [D-54MG] to >120 days in
childhood glioblastoma multiforme (GBM) [D-456 MG] subcu-
taneous xenografts.[25] Only one [medullablastoma (D341 Med)]
of seven xenografts was refractory to temozolomide treatment
presumably because of high AGT levels within the tumor (section
2.3). Here, the growth delay was 3.5 days but a single dose of
1200 mg/m2 extended this delay to 10.9 days. The 5-day in-
traperitoneal regimen of temozolomide (411 mg/m2/day) pro-
duced 1.8- to 7.5-fold and 4.7- to 19-fold greater tumor growth
delays than intraperitoneal procarbazine (700 mg/m2/day for 5
days) and carmustine (100 mg/m2 for 1 day), respectively. In mice
with intracranial xenografts, temozolomide (411 mg/m2/day for
5 days) increased median survival times 1.7- to 13.9-fold.
2.3 Mechanisms of Resistance
Three main DNA repair pathways are responsible for tem-
ozolomide resistance. AGT enzyme activity represents the most
important mechanism of cell defence. An internal cysteine resi-
due of AGT forms an irreversible covalent bond with the methyl
lesion (formed by the methyldiazonium cation) ofO6-guanine, a
reaction that transfers the offending one-carbon unit from theDNA base at the expense of enzyme inactivation.[29] Cytotoxicity
of temozolomide depends on the equilibrium between rate ofO6-
methylguanine formation and rate of repair. Intracellular tem-
ozolomide concentrations and AGT levels dictate the equilibrium
position. Thus, most cells that have low levels of AGT are sensi-
tive to temozolomide, whereas cells with high AGT levels are
often refractory to treatment.[12-18]
Support for this mechanism comes from findings that
the potent AGT inhibitors, O6-benzylguanine[14,30,31] and O6-
(4-bromothenyl)guanine, [32] have potentiated the in vitro and in
vivo cytotoxicity of temozolomide.[33-37] These inhibitors are
pseudosubstrates that exhibit a greater affinity for the active bind-
ing site of AGT than O6-methylguanine. [38] The transfer of the
benzyl group to AGT, and its resultant inactivation, effectively
decreases the AGT concentration within the cell. Only de novo
synthesis of the protein can replenish cellular levels. Therefore,
pretreatment with such inhibitors may offer an opportunity to
reduce temozolomide resistance and/or raise temozolomides
therapeutic index in the clinical setting.[39] Baer et al.[12] demon-
strated that human tumor cell lines pretreated with a nontoxic
dose ofO6-benzylguanine (33 mol/L) had a 3.5- and 6-fold in-
creased sensitivity to single dose temozolomide and lomustine,
respectively. Although five 24-hour doses of temozolomide werenot any more cytotoxic than a single 24-hour dose, MAWI and
MCF-7 cultured cells were 300-fold more sensitive to the multi-
ple dosage regimen when O6-benzylguanine was present. More-
over, in vivo studies by Wedge & Newlands[37] have shown that
nontoxic O6-benzylguanine pretreatment caused a potentiating
cytotoxic effect in tumors that had low AGT levels. In athymic
mice, intraperitoneal O6-benzylguanine (40 mg/kg) reduced AGT
levels in subcutaneous human glioblastoma (U87MG) xenografts
from 4.3 to 0.9 fmol/mg 24 hours after administration. O6-
benzylguanine was not solely cytotoxic but, when used as pre-
treatment 1 hour prior to a single intraperitoneal temozolomide
(5 to 10 mg/kg) injection, it caused a 1.66- to 11.78-fold increase
in tumor growth delays compared with temozolomide alone.
The second mechanism of resistance involves MMR pro-
teins.[14,15,19,40-42] The administration of temozolomide by oral
gavage (three cycles of 66 mg/kg/day for 5 days repeated every
21 days) produced a >50% decrease in volume in 47% (8 of 17)
of pediatric solid tumor xenografts in murine models. [15] The dos-
ages used in the murine models and resultant plasma temozolom-
ide concentrations were thought to mimic those recorded in hu-
mans (section 3). A relationship between sensitivity of xenografts
to temozolomide and DNA repair proteins was established. The
xenografts (4 of 5 tumors) that were most sensitive to temozolom-
ide had the lowest AGT levels, whereas 5 of the 9 most resistant
tumors had the highest AGT levels. An inverse correlation wasobserved when two MMR proteins were assayed. Resistant tu-
mors (6 of 9) had either a complete deficiency or only marginal
levels of at least one MMR protein. Both Rh28c (rhab-
domyosarcoma) and Rh30c lack AGT but MLH-1-competent
Rh30c tumors were highly sensitive to temozolomide 28 mg/kg,
whereas MLH-1-deficient Rh28c tumors were highly refractory
to temozolomide 66 mg/kg. These findings are supported by
Taverna et al.[41] who found that, in 60 tumor cell lines, an absence
of MLH-1 was always associated with temozolomide resistance,
regardless of cellular AGT levels. Finally, it has been shown that
a defective MMR confers resistance to temozolomide-induced
apoptosis.[19] The role of p53 and the molecular mechanism of
temozolomide-induced apoptosis has yet to be fully deter-mined.[16,18-20,43]
The third mechanism of resistance involves the nucleo-
tide excision repair pathway.[44] Temozolomide-induced N7-
methylguanine and N3-methyladenine adducts cause DNA chain
termination in the absence of the excision repair protein, poly
(ADP)-ribose polymerase (PADPRP).[45] Temozolomide has
been shown to activate the PADPRP[46] pathway and PADPRP
inhibitors potentiate temozolomide cytotoxicity.[45,47] However,
the cytotoxicity of N7-methylguanine and O3-methyladenine le-
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sions are unknown and the excision repair pathway is regarded as
being less important than the AGT and MMR pathways. [9]
In summary, primary resistance to temozolomide is directly
correlated to high AGT levels but in AGT-deficient cells, low or
deficient MMR protein levels become important in conferring
resistance. Within clinical trial design, there is increasing interest
in incorporating relevant intermediate clinical endpoints. These
data provide an opportunity to bridge our knowledge gaps be-
tween tumor cell biochemistry and clinical response (sections
4.1.1 and 4.2). Intermediate endpoints allow correlations to be
measured between tumor sensitivity to cytotoxic drugs and cel-
lular levels of key biomolecules thought to be involved in con-
ferring malignancy or drug resistance. In fact, some phase II trials
of temozolomide have attempted to identify preliminary
biomolecular markers that could predict which patients would
respond favorably to treatment (section 4).[48-51]
3. Pharmacokinetic Properties
3.1 Absorption and DistributionPharmacokinetic data for temozolomide have been collected
from a number of phase I studies in patients with advanced cancer
who had normal hepatic and renal function.[52-58] A summary of
the pharmacokinetic parameters of temozolomide at the recom-
mended therapeutic oral dose of 200 mg/m2/day[52] (section 6) is
provided in table I.
When measured against a 1-hour intravenous infusion, the
oral formulation of temozolomide had a bioavailability of
100%, which was primarily due to its acid-stability and lipo-
philic character.[52] Following oral administration, temozolomide
(200 mg/m2) was rapidly absorbed from the gastrointestinal tract
and the time taken to reach peak plasma concentration (t max) was
1 hour (range 0.33 to 2 hours).[52,53,56-58] A small crossover study
(n = 12) demonstrated that the bioavailability of temozolomide
(150 mg/m2/day for 5 days) was not influenced by a raised gastric
pH, as induced by ranitidine (150mg orally every 12 hours).[59]
When patients received ranitidine on day 1 and 2 or day 3 and 4of the temozolomide 5-day cycle, there was little change in tmax,
Cmax and area under the plasma concentration-time curve (AUC).
However, another small crossover study (n = 12) showed that the
administration of temozolomide (200 mg/m2/day for 5 days) 1
hour after a modified high-fat breakfast (587 calories, 36.3g of
fat) delayed tmax values by 110% and suppressed Cmax by 32% (p
< 0.001).[56] Although food decreased AUC by 9% (p = 0.048),
the confidence intervals for this value were within the 80 to 125%
guidelines for bioequivalence.
In phase I dose-ranging trials, oral temozolomide (50 to 250
mg/m2) exhibited predictable pharmacokinetics that were ade-
quately described by a one-compartment open model.[52,53,55-58]
Cmax[53] (regression co-efficient unavailable) and AUC[52] (r2 =0.74) increased linearly with dose. A continuous dosage regimen
could achieve greater systemic exposure to temozolomide with-
out the development of dose-limiting myelosuppression observed
with intermittent treatment (section 5).[60] Over a 4-week period,
AUC values were 2.1-fold greater when temozolomide 75 mg/m2
was given daily compared with an intermittent 5-day temozolom-
ide schedule of 200 mg/m2/day. Temozolomide did not accumu-
late in plasma after multiple doses[56,57] or during the 7-week
continuous dosage regimen.[60] Plasma protein binding of tem-
Table I. Mean pharmacokinetic parameters of oral temozolomide (TMZ) in patients with advanced cancers
Reference No. of
patients
Dosage
(mg/m2/day)
Cmax (mg/L) AUC (mg h/L) t12 CL (L/h/m2)a
day 1 day 5 day 1 day 5 day 1 day 5 day 1 day 5
In adults
Baker et al.[58]b
6 200 sd 5.2 NR 16 NR 1.9 NR 6.2 NR
Brada et al.[56]
12 200 for 5 days 13.9 13.0 33.2 34.5 1.8 1.8 11.8 L/h 11.3 L/h
Dhodapkar et al.[53]
6 200 for 5 days 9.8 12.1 31.2 32.3 1.8 1.7 6.4 6.3
Hammond et al.[57]
6 200 for 5 days 11 16 30 35 1.8 1.7 6.9 5.8
Newlands et al.[52]
34 200 sdc
NR NR 32.8 NR 1.8 NR 11.8 L/h NR
In children and adolescents
Estlin et al.[55]d
5 200 for 5 days 14.6 NR 48 NR 1.7 NR 4.3 NR
a Unless otherwise stated.
b Patients received TMZ-derived14
C.
c 9 patients received TMZ intravenously.
d Children were aged from 4 to 18 years.
AUC = area under the plasma concentration-time curve; CL = plasma clearance; Cmax = peak plasma concentration; NR = not reported; sd = single dose;
t12 = elimination half-life.
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ozolomide-derived 14C averaged 12 to 16% when measured 1and 4 hours after a single oral dose of14C-labeled temozolomide
200mg.[58]
In patients who received a single intravenous dose of tem-
ozolomide (50 to 200 mg/m2) or single or divided oral tem-
ozolomide (50 to 1250 mg/m2), a calculated volume of distribu-
tion (Vd) ranged from 28.3 to 47.2L.[52,56] When measured by
positron emission tomography scanning in eight patients, intra-
venous 11C-labeled temozolomide (50g) readily crossed the
blood-brain barrier by passive diffusion and entered brain tissue
(data published in an abstract).[61] Initial radiologic findings sug-
gest a relationship between brain tumor uptake of temozolomide
and response duration (r2 = 0.362, p < 0.01, n = 18) but no corre-
lation was observed between tumor uptake and overall survival
(regression coefficient and raw data not provided) [data published
in an abstract].[62]
3.2 Degradation and Elimination
Plasma temozolomide concentrations declined with a mean
elimination half-life (t1/2) of 1.8 hours (range 1.7 to 1.9
hours).[52,53,57,58] Following absorption, temozolomide is imme-
diately subject to three elimination processes that involve excre-
tion via the kidneys of the unchanged drug or its degradation
products. The main temozolomide elimination process is via a
pH-dependent hydrolysis to MTIC then degradation to AIC (seefigure 2), a process that is also responsible for its mechanism of
action (section 2.1). Hepatic biotransformation of temozolomide
to temozolomide acid (TMA) has a minor eliminatory role.[53,58]
Temozolomide elimination was independent of dose; the clear-
ance (CL) range after temozolomide dosages of 50 to 250mg daily
for 5 days in 21 cancer patients was 6.3 to 7.8 L/h/m2, there being
little interpatient variability (coefficient of variation
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3.3 In Children and Adolescents
Although temozolomide pharmacokinetic data in children
and adolescents are limited, measured parameters are similar to
those in adults (table I). In a small study (n = 19), children and
adolescents (aged 4 to 18 years) with advanced cancer were given
between 100 and 240 mg/m2 for 5 days, repeated every 4
weeks.[55] Temozolomide was rapidly absorbed (tmax range 1.27
to 1.9 hours) and Cmax (r2 = 0.36) and AUC (r2 = 0.69) increased
linearly with dose. Temozolomide was not quantifiable in plasma
24 hours after administration. The Vd and CL ranged from 10.4
to 13.9L and 4.32 to 5.58 L/h/m2. CL was independent of tem-
ozolomide dose. Over a 24-hour collection period, urinary recov-
ery of temozolomide ranged from 5 to 15% of the administered
dose (n = 13).
3.4 In Patients with Renal and Hepatic Impairment
Population pharmacokinetic analysis indicates that creati-
nine clearance over the range 2.16 to 7.80 L/h/m2 (36 to 217
ml/min/m2) has no effect on the clearance of temozolomide after
oral administration.[67] Temozolomide has not been studied in
patients with severely impaired renal function (creatinine clear-
ance
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4.1 Malignant Gliomas
Historically, malignant glioma has been used as a collective
term for a number of primary brain tumors. Malignant gliomas
have been classified histologically by the World Health Organi-
zation (WHO) and graded into a four-tier system according to
their prognosis.[3] This section focuses on AA (WHO classifica-
tion grade III) and the most common primary brain tumor, GBM
(grade IV). The combined annual incidence of these gliomas is 5
to 8 per 100 000.[4] AA is more common in the middle-aged,
whereas GBM is more commonly seen in the elderly. Patients
who receive only palliative care have a median survival of14
weeks.[4] Median survival after surgical resection is 20 weeks,
which can be extended to 36 weeks if additional radiotherapy is
received.[4,72] The use of adjuvant chemotherapy after surgery or
radiotherapy is still controversial but has been shown to increase
median survival to 40 to 50 weeks.[4,73] AA is regarded as a more
chemosensitive tumor than GBM and patients have a longer me-
dian survival time (157 weeks).[3] However, for relapsing patients
with AA, median survival rarely exceeds 1 year. [74] Prognosis is
better in young patients who have a high Karnofsky performance
status (KPS).[3,75]
Although recent studies with temozolomide evaluated data
from patients specifically with AA or GBM, a number of earlier
clinical trials included patients with both.[76-78] Many of the clin-
ical trials measured temozolomide efficacy as a function of ob-
jective response criteria. Response criteria were evaluated from
radiologic brain imaging (including computerized tomography
and gadolinium-enhanced magnetic resonance imaging) together
with clinical responses according to the US Medical Research
Council (MRC) neurologic scale[79] and corticosteroid require-
ments. The responses were then graded into four categories:[80]
complete response: disappearance of all enhancing tumor on
consecutive brain imaging scans at least 1 month apart, not
receiving corticosteroids, and neurologically stable or im-
proved
partial response: 50% reduction in size of enhancing tumor
on consecutive brain scans at least 1 month apart, corticoste-
roid dosage stable or reduced, and neurologically stable or
improved
progressive disease: 25% increase in the size of enhancing
tumor or any new tumor on brain scans, or neurologically
worse, and corticosteroid dosage stable or increased
stable disease: all other situations.
The objective response rate is defined to include patients
with a complete response or a partial response. Other primary
endpoints that were frequently evaluated include the progression-
free survival (PFS) rate at 6 and 12 months, median overall sur-
vival and median time to disease progression.
4.1.1 Combined Malignant GliomasThe earlier clinical trials evaluated temozolomide in AA,
GBM and other high-grade gliomas. Many patients included in
the studies had progressive disease after initial treatment with
surgery, radiotherapy and/or chemotherapy. Most of the trial data
generated are from noncomparative phase II trials.
The clinical trials discussed throughout sections 4.1.1 and
4.1.2 all had a slightly different set of patient eligibility criteria.
The most common criteria were:
histologically proven high-grade glioma [some trials have pre-
sented results of the intent-to-treat (ITT) population and then
stratified the results according to histological class of tumor]
radiologic evidence of enhancing or progressive disease
adequate bone marrow reserve, and hepatic and renal function age 18 years and over
a life expectancy of at least 8 weeks
a KPS 70
a stable dosage of corticosteroids over the last 7 days.
The efficacy of temozolomide in phase II trials is summa-
rized in table II. Temozolomide had measurable efficacy on high-
grade gliomas as judged by the objective response rate, which
ranged considerably from 11 to 47% (table II).[48,74,76-78] Of these
responses, the majority of patients had a partial rather than a
complete response. Interestingly, the highest objective response
rate was observed in newly diagnosed patients. [48] The proportion
of patients with disease stabilisation was also variable, ranging
from 16 to 47% (table II). The reasons for the large variation inresponse rates are due to both patient variation and measurement
error. Firstly, the proportions of patients with either AA or GBM
(and their individual pathologies) were different and factors such
as age and KPS varied in each trial. Secondly, the technologically
limited imaging techniques currently available make tumor mass
assessment difficult. In addition, the five-point MRC neurologic
scale is subjective and its interpretation may vary between clini-
cians.[76] The timing and frequency of the above assessments also
varied during the trials. The median time to disease progression
ranged from 4.2 to 7 months and the median duration of survival
ranged from 5.8 to 13.6 months (table II). The PFS rate at 6
months was consistently >20% and one trial reported a 34.7%
PFS rate after 12 months.[78]
One preliminary study, which included only newly diag-
nosed patients, incorporated a biochemical dimension to the clin-
ical trial design in order to collect intermediate endpoint data
(section 2.3).[48] In addition to measuring standard endpoints, the
investigators were interested in a relationship between the bio-
chemical mechanism of resistance and clinical response to tem-
ozolomide. The human mismatch repair proteins, MSH2 and
MLH1, and AGT were quantified in tumor cells using immuno-
histochemical staining techniques. Because high levels of MSH2
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or MLH1 and low levels of AGT facilitate temozolomide-induced
cell death (section 2.3), protein levels (percentage cellular reac-
tivity) were evaluated in patients with and without an objectiveresponse for comparison.
Of the 38 patients included, 33 had GBM and five had AA.
The results of the AGT status showed statistical significance
when related to objective response rate. AGT was detected in 20%
or more of the cells in 11 patients. The objective response in this
group was 9.1% compared with a response rate of 60% in patients
who had AGT detected in 60% of the cells and this high level is reflected
in an enhanced objective response rate of 50%. A lower objective
response rate of 33% was observed in patients who had MSH2
detected in 60% of cells. This difference was not statistically
significant (p = 0.66). The objective response rate in patients with>60% of cells detectable for MLH1 was 47% compared with a
response rate of 50% in patients who had MLH1 detected in 60%
of cells (p > 0.9). Further studies are required in this area to
confirm which molecular markers correlate with a temozolom-
ide-induced objective response.
In two independent trials, statistical analysis has isolated
prognostic factors that influence particular clinical endpoints.
Yung et al.,[74] using a Cox regression analysis, showed that the
baseline KPS score (>80 or 80) is a prognostic factor with re-
Table II. Efficacy of temozolomide (TMZ) at the recommended therapeutic dosage in patients with advanced malignant gliomas
Reference (study
design)
No.of pts (ITT
population)
Dosage regimen
(mg/m2/day)
Objective response
rate (% of pts) [CR
+ PR]
Disease
stabilisation
(% of pts)
Median time to
disease
progression (mo)
Progression-free
survival (% of pts
at 6, 12 mo)
Median
duration of
survival (mo)
Combined malignant gliomas
Bower et al.[76]
(mc)a,
b
103 TMZ 150 initially
then 200 for 5
days [q4wk]c
11 47 4.2 22, NR 5.8
[NR]
Brandes et
al.[78]a,
d
40 TMZ 150 for 5
days [q4wk]
22.5 42.5 5.6 48.5, 34.7 9.3
[7.5 + 15]
Friedman et
al.[48]e,
f
38 TMZ 200 for 5
days [q4wk]
47.4 15.8 7, 2g
NR 12, 6g
[7.9 + 39.5]
Newlands et
al.[77]h
75 TMZ 150 initially
then 200 for 5
days [q4wk]
27 41 NR NR NR
[NR]
Yung et
al.[74]
(mc)a,
i
162 TMZ 150 or 200
for 5 days [q4wk]j
35 27 NR 46, NR 13.6
[8 + 27]
Glioblastoma multiforme
Brada et
al.[81]
(mc)a,
k
138 TMZ 150 or 200
for 5 days [q4wk]
8 43 NR 19, NR 5.4
[1 + 7]
Yung et al.[82]
(r, nb)a,l
112 TMZ 150 or 200
for 5 days [q4wk]
5.4 40.2 NR 21*, NR NR
[0 + 5.4]
113 PCB 125 or 150
for 28 days [q8wk]
5.3 27.4 NR 8, NR NR
[0 + 5.3]
a Patients had relapsed or progressive disease.
b Radiologic evaluation performed prior to first and third cycles then after alternate treatment cycles thereafter.
c Dosage reduced to TMZ 100 mg/m2/day for 5 days if imaging showed midline shift or if tumor/edema occupied more than one-half of cerebral hemi-
sphere.
d Clinical and neurologic assessment made after every two treatment cycles or if clinical deterioration observed.
e Patients had newly diagnosed malignant glioma.
f Patients underwent physical, neurologic and brain imaging assessments prior to every 4-week cycle.
g Study separated into those who responded to treatment, and those who did not.
h 48 patients had relapsed malignant glioma disease and 27 had newly diagnosed disease.
i Neurologic assessments made at each study visit.
j Chemotherapy-naive patients received the larger dosage and chemotherapy-experienced patients received the smaller dosage.
k MRI performed at trial entry and after every second course of treatment. Neurologic examination at each study visit.
l Tumor assessed using imaging every 2 months. Monthly neurologic and clinical evaluations.
CR = complete response (defined in section 4); ITT = intent-to-treat; mc = multicenter; MRI = magnetic resonance imaging; nb = nonblind; NR = not reported;
PCB = procarbazine; PR = partial response (defined in section 4); pts = patients; q = every; r = randomized; * p = 0.008 vsPCB.
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spect to 6-month PFS rate and median overall survival (p 0.03).Comparing patients who had a KPS >80 with those with a KPS
80, 51% [95% confidence interval (CI) 40 to 62] versus 42%
(95% CI 31 to 53) were progression-free at 6 months and the
overall median survival was 16.8 versus 10.8 months. On multi-
variate analysis, Brandes et al.[78] showed that an objective re-
sponse to previous treatment (p = 0.03) increased time to disease
progression and a KPS >80 (p = 0.002) increased median overall
survival.
There are only limited clinical trial data that specifically de-
tail the efficacy of temozolomide in the treatment of AA, for
which temozolomide is licensed (section 6). One study stratified
results in order to analyze the effects of temozolomide on this
specific disease from the ITT population.[74] Of the 162 patients
enrolled in the ITT population, 111 had AA. The investigators
found that the objective response rate in patients with AA was
35%, similar to those of the ITT group (table II). The 6-month
PFS rate was 49% and the median duration of PFS was 5.5
months.
Health-Related Quality of Life
In an extension to the trial by Yung et al.,[74] a comprehensive
HR-QOL study was conducted.[83] A total of 138 (85%) patients
scored their own HR-QOL status using the European Organiza-
tion for Research and Treatment of Cancer (EORTC) Quality of
Life Questionnaire (QLQ-C30) and the Brain Cancer Module
(BCM).[84,85] Each questionnaire contained a list of items thatwere categorized into seven preselected health domains which
included global quality of life, social functioning, role function-
ing, visual disorder, drowsiness, communication deficit and mo-
tor dysfunction.
Each patient measured his or her HR-QOL score immediately
prior to the first cycle (pretreatment) and before each subsequent
cycle of temozolomide (post-treatment). A clinically significant
improvement was defined as a change of10 (on a scale of 0 to
100) lasting for at least two HR-QOL assessments 4 weeks apart
compared with the baseline value.[83]
The study revealed that the positive outcomes of the initial
clinical trial were reflected in enhanced HR-QOL benefits.
Change from baseline analysis demonstrated that all of the 63
patients with progression-free disease at 6 months reported either
similar or better scores in the seven HR-QOL domains. Impor-
tantly, statistical significance was observed in the social function-
ing and global quality-of-life domains. In contrast, patients with
disease progression reported statistically significant deterioration
on five of seven domain scores at 6 months when compared with
baseline.
Similar observations were also reflected in patients with an
objective response or with stable disease.[74] In fact, of the pa-
tients with an objective response, 92 and 82% of those achievedan HR-QOL response in one or more and three or more domains,
respectively, compared with baseline.[74] In contrast, patients
with disease progression reported statistically significant wors-
ening of domain scores compared with baseline (0.01 < p 8 months conferred a longer median PFS (2.6 vs 1.9 months, p
= 0.03) and overall duration of survival (7 vs 4.4 months, p = 0.04)
than a period 8 months.
HR-QOL domain scores were compared with baseline in pa-
tients who had an objective response and those who had either
stable disease or disease progression.[81] A total of 109 patientscompleted the baseline score plus at least 1 domain score while
on treatment. Only 29 patients remained on the study at 6 months.
The high dropout rate was attributable to progressive disease or
death. Patients with an objective response reported enhanced HR-
QOL scores in all domains except visual disorder. In particular,
global quality of life and motor dysfunction scores were the most
common areas of improvement. Of the patients with an objective
response, 90% of those reported an improvement in at least one
domain compared with 58% of those with stable disease and 52%
Objective responseStable diseaseProgressive disease
0 10 20 30 40 50 60 70
n = 85Role functioning
n = 92Social functioning
n = 114Global QOL
n = 43Visual disorder
n = 91Motor dysfunction
n = 84Communication deficit
n = 88Drowsiness
Patients who reported clinical improvement in selected health domains (%)
Fig. 5. Effects of temozolomide on health-related quality of life (HR-QOL) assessed by self-administration of the validated European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the Brain Cancer Module.[84,85] Relative incidence of clinically significant improvements in the seven
preselected health domains in patients with anaplastic astrocytoma who received oral temozolomide 150 or 200 mg/m2/day for 5 days every 4 weeks in a noncomparative
trial.[74] A clinically significant improvement was defined as a change of 10 (on a scale of 0 to 100) lasting for at least two HR-QOL assessments 4 weeks apart compared
with the baseline value. Each health domain is subdivided according to the relative clinical response of patients to temozolomide.
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of those with disease progression. Concomitant corticosteroid us-age was monitored throughout the study and 30% of HR-QOL
responders increased their usage, 60% maintained or reduced
their usage and five patients discontinued corticosteroid therapy.
A more complete HR-QOL study[90] (n = 288) combined the
results of the two previously mentioned clinical trials involving
temozolomide use in GBM.[81,82] The study highlights the corre-
lation between changes in disease status and HR-QOL scores.
Commonly, patients with an objective response or disease
stabilisation at 6 months had enhanced HR-QOL scores in the
seven preselected domains. In contrast, patients with disease pro-
gression invariably reported a deterioration in HR-QOL scores
across all domains. Regarding the comparative trial,[82] contrast-
ing results were recorded for the two patient groups. All seven
procarbazine-treated patients, who were progression-free at 6
months, reported deterioration in all seven preselected domains.
These scores matched scores in patients with progressive disease.
The mean duration of an HR-QOL response was greater in
the temozolomide group than the procarbazine group, except for
visual disorder. Responses were longest in patients with an ob-
jective response (25 to 33 13 to 15 weeks), shorter in patients
with stable disease (14 to 23 6 to 13 weeks) and shortest in
patients with progressive disease (8 to 10 0 to 4 weeks).
4.2 Malignant Melanoma
Malignant melanoma is the eighth most common cancer in
the US with a current incidence of 13 per 100 000. [7] Although
early detection and treatment of melanoma results in a high cure
rate, metastatic melanomas have a poor prognosis. With a median
survival time of about 6 months[6] (depending on number and site
of metastases) and a 5-year survival rate of 6%,[64] the aim of
chemotherapy is palliative.
Temozolomide efficacy has been measured according to
common primary endpoints. These focus on overall survival, PFS
and objective response rates. The objective response is measured
according to WHO criteria:[91]
complete response: complete disappearance of all detectablelesions as determined by two observations not less than 4
weeks apart
partial response: 50% reduction in the sum of the products
of the two largest perpendicular diameters of all measurable
lesions, determined by two observations not less than 4 weeks
apart
progressive disease: 25% increase in any measurable lesion
or the appearance of a new lesion
no change:
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ence between the two groups for HR-QOL scores at baseline or
at cycle one. However, at 12 weeks, change from baseline analy-
sis showed that there was a statistically significant difference in
favor of the temozolomide-treated group in the physical function-
ing and cognitive functioning domains (figure 6). A statistically
significant difference in favor of the temozolomide-treated group
was also observed for symptoms of insomnia and fatigue. Among
the patients with an objective response in both study arms, the
temozolomide-treated group reported significantly greater im-
provements in the physical and cognitive functioning domains (p
< 0.05 vs baseline).
In a noncomparative phase II study involving 56 patients (no
prior chemotherapy) with histologically confirmed malignant
melanoma and widely distributed metastases, standard tem-
ozolomide dosages (table III) produced a complete and partial
response in three and nine patients, respectively, to give an ob-
jective response rate of 21%.[94] The median duration of response
was 6 months (range 2.5 to >22 months) and the median overall
survival was 5.5 months (range, 0.5 to >29.5 months).
Similar results were reported in another noncomparativestudy in 50 patients with progressive advanced malignant mela-
noma (table III).[50] In contrast to findings in patients with GBM
(section 4.1.1), this study failed to define a relationship between
pretreatment AGT levels in cutaneous tumors (and involved
lymph nodes) and a subsequent clinical response to temozolom-
ide.
Temozolomide-based combinations have been investigated
in patients with advanced melanoma.[95-99] Although temozolom-
ide did not seem to enhance clinical responses in patients after
whole brain irradiation,[98] other trials have reported encouraging
objective response rates.[95,100] The combinations that have dem-
onstrated promising results in trials warrant further investigation.
4.3 Other Advanced Cancers
Temozolomide has been investigated in clinically diverse
cancers including advanced soft tissue sarcoma,[101] non-
Hodgkins lymphoma, [102] hormone-refractory prostate can-
cer[103], pancreatic cancer,[104] advanced nasopharyngeal carci-
noma[105] and brain metastases.[106] The largest trial consisted of
only 31 patients.[101] Generally, the prognosis for patients who
received temozolomide in these studies was grave and explains
the low objective response rate. More data are required before
temozolomide can be judged in these diseases. Extended dosage
regimens such as low-dose temozolomide concurrent with radia-
tion, and more intensive dosage regimes (150 to 200 mg/kg/day
for 7 days on then 7 days off) have also been been clinically
tested.[107,108]
5. Tolerability
In most clinical trials, adverse events associated with tem-
ozolomide toxicity were graded according to WHO[91] or Na-
tional Cancer Institute Common Toxicity Criteria (CTC).[109] The
most common adverse events associated with temozolomide are
drug class effects that stem from its cytotoxic mechanism of ac-
tion (section 2.1). The trial data described in this section were
collected from patients with advanced cancers. Figure 7 illus-
trates the incidence of hematologic and nonhematologic adverse
Table III. Efficacy of temozolomide (TMZ) in patients with metastatic melanoma
Reference (study
design)
No. of pts
(ITT
population)
Dosage regimen
(mg/m2/day)
Objective
response rate (%
of pts) [CR + PR]
Disease
stabilistaion
(% of pts)
Disease
progression
(% of pts)
Median time to
disease
progression (mo)
Median
duration of
survival (mo)
Bleehen et al.[94]
(mc)a
56 TMZ 150 for 5 days
[q4wk]
21 14 NR NR 5.5
[5 + 16]
Middleton et al.[64]
(mc, nb, r)bc
156 TMZ 200 for 5 days
[q4wk]
14 18 61 NR 7.7
[3 + 11]
149 DAC 250 0.5h inf for
5 days [q3wk]
12 16 63 NR 6.4
[3 + 9]
Middleton et al.[50]
(mc)
50 TMZ 150 initially
then 200 for 5 days
[q4wk]d
14 12 74 2.1 5.7
[6 + 8]
a Patients had no previous exposure to chemotherapy.
b Clinical assessment after each treatment cycle.
c 25 patients who were enrolled in the trial were not included in the efficacy analysis.
d Dose increased if there was no significant myelosuppression within the first treatment cycle.
CR = complete response (defined in section 4.2); DAC = dacarbazine; inf = infusion; ITT = intent-to-treat; mc = multicenter; NR = not reported; PR = partial
response (defined in section 4.2); pts = patients; q = every; r = randomized.
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events reported in 2% of patients in the temozolomide group (n= 101; 475 treatment courses).[76]
Adverse events data from the trial by Yung et al. [82] (section
4.1) suggest that temozolomide and procarbazine had similar tol-
erability profiles. The incidence of adverse events (all grades) in
the temozolomide and procarbazine groups was 77 and 76%, re-
spectively. The incidence of grade 3 or 4 treatment-related ad-
verse events was less in the temozolomide group (18% vs 25%).
Similarly, Middleton et al.[64] (section 4.2) found that tem-
ozolomide and dacarbazine were equally tolerable. The incidence
of adverse events (all grades) in the temozolomide group was
92% compared with 87% in the dacarbazine group. The incidence
of grade 3 or 4 adverse events in the temozolomide and dacarbaz-
ine groups was 77 and 76%, respectively. Furthermore, a similar
percentage of patients withdrew from the study because of ad-
verse events (3% in the temozolomide group compared with 5%
in the dacarbazine group).
In the temozolomide group, there were three deaths due to
adverse events; two patients died as a result of a cerebral hemor-
rhage, of whom one patient was thrombocytopenic, and one pa-
tient died from a coma. There were also three deaths in the
dacarbazine group, none of which were attributable to chemother-
apy. OReilly et al.[110] also reported the death of a patient who
received 200 mg/m2/day for 5 days as an initial temozolomide
dose. The patient, who had also previously received chemother-
apy and radiotherapy, died of intracerebral hemorrhage while se-
verely thrombocytopenic.
5.1 Hematologic Events
Mild to moderate myelosuppression (neutropenia and
thrombocytopenia) is the primary dose-limiting adverse event of
temozolomide. [52,63] Nadir platelet and neutrophil counts typi-
cally occur 21 to 28 days after the first temozolomide dose and
can be managed by reducing the next scheduled dose. CTC grade
1 myelosuppression is normally observed 21 to 28 days after
beginning a cycle.[57,82]
In a nonblind phase III trial,[64] 151 patients received a total
of 581 cycles of temozolomide (200 mg/m2/day), of which 24
were at a reduced dosage (150 mg/m2/day). Thrombocytopenia,
leukopenia and anemia occurred in 9, 2 and 8% of patients, re-
spectively. This compares with 9, 1 and 11% in the dacarbazinegroup, which included 501 treatment cycles in 142 patients. A
population study calculated the overall incidence of hematologic
toxicity (WHO grades 3 or 4) in the first treatment cycle as a
function of patient demographics and temozolomide exposure.
Neutropenia and thrombocytopenia had an incidence of 7.4% (20
of 270 patients) and 5.3% (15 of 284 patients), respectively.[63]
Older female patients who received higher temozolomide doses
had a greater chance of developing myelosuppression.
It is debatable whether an increased incidence and severity
of adverse effects to temozolomide exposure occurs in patients
who have received prior chemotherapy and/or radiotherapy com-
pared with treatment-nave patients.[53,57]
Phase I and II trialshave used different definitions to describe prior treatment and
acceptable hematologic parameters. Dhodapkar et al.[53] demon-
strated that the maximum tolerated dosage in patients who had
Temozolomide (n = 50)
Dacarbazine (n = 31)
0
20
40
60
80
100
Role
functioning
Emotional
functioning
Social
functioning
Global quality
of life
HR-QOL domains
Patientswithmaintenanceofor
improvementinQOL(%)
Physical
functioning
*
Cognitive
functioning
*
Fig. 6. Comparative efficacy of temozolomide on health-related quality of life (HR-QOL) assessed by the self-administration of the validated European Organization for
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). [84] Relative incidence of advanced malignant melanoma patients with a
maintenance of or improvement in QLQ-C30 function scores at week 12 in a randomized, nonblind trial.[64] A clinically significant improvement was defined as a change
of 10 (on a scale of 0 to 100) lasting for at least two HR-QOL assessments 4 weeks apart compared with the baseline value. [84,85] Patients received either oral
temozolomide 200 mg/m2/day for 5 days every 4 weeks or an intravenous infusion of dacarbazine 250 mg/m2/day for 5 days every 3 weeks. * p < 0.05 vsbaseline.
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prior exposure to nitrosourea therapy was 150 mg/m2/day for 5
days compared with 250 mg/m2/day for 5 days in patients without
prior exposure. However, Hammond et al.[57] reported a maxi-
mum tolerated dosage of 150 mg/m2/day for 5 days, irrespective
of prior treatment.
The hematologic adverse effects of temozolomide were
heightened when the drug was prescribed at a more intense dos-
age schedule.[51] Temozolomide 750 (prior chemotherapy) or
1000 mg/m2 (no prior chemotherapy) prescribed over a 24-hour
period resulted in marked myelosuppression.
A dose-finding phase I trial (n = 24) assessed the hematologic
toxicity of temozolomide when a total of 37 courses were pre-
scribed daily over a 6- or 7-week period.[60] CTC grade 0 to 2
leukopenia and thrombocytopenia were observed in the dosage
range of 50 to 75 mg/m2/day. Grade 4 leukopenia and thrombo-
cytopenia occurred in one of four and one of seven patients at the
100 and 85 mg/m2/day dosage level, respectively. Hematologic
toxicities did not exceed grade 2 in 10 patients who received
temozolomide at the reduced dosage level of 75 mg/m2/day.
5.1.1 In Children and Adolescents
CTC grade 4 neutropenia and thrombocytopenia were the
dose-limiting toxicities in a dose-finding trial in 27 children andadolescents with advanced cancer who received between 150 and
240 mg/m2/day for 5 days. [55] After the first course of treatment,
grade 4 thrombocytopenia occurred in one of six patients at the
200 mg/m2/day dose level and two of four patients at the 240
mg/m2/day level. Nadir platelet counts in these three patients oc-
curred on days 22 and 23 (twice) and had recovered by days 29,
32 and 65, respectively, after a temozolomide dosage reduction
for cycle two. These patients also experienced grade 3 anemia and
one patient at each dose level also developed grade 4 neutropenia.
Nadir neutrophil counts occurred on days 24 and 29 and had
recovered by days 27 and 43, respectively.
Temozolomide was well tolerated in a phase I study of 49
children and adolescents with recurrent solid tumors.[111] The
study was stratified by prior therapy with craniospinal irradiation
(CSI). Across both strata, the lower temozolomide dosage range
of 100 to 180 mg/m2/day caused hematologic dose-limiting tox-
icity in only one heavily pretreated patient. In the non-CSI stra-
tum (n = 27), one of six patients at the 215 mg/m2 dosage level
developed grade 3 hematologic toxicity and three of eight patients
at either the 245 or 260 mg/m2 level developed dose-limiting
toxicity. In the CSI stratum, two of four patients at the 215 mg/m2
level developed grade 4 neutropenia and thrombocytopenia. The
study concluded that the maximum tolerated dosage in 27 patients
with no prior irradiation was 215 mg/m2/day for 5 days and 180
mg/m2/day for 5 days in 22 patients with previous CSI.
5.2 Other Events
In clinical trials discussed in section 4, the most common
nonhematologic events associated with standard temozolomide
dosages were mild to moderate nausea and vomiting, which could
be assuaged with prophylactic and/or therapeutic antiemetic ther-
apy.[67] In the 5-day schedule, these symptoms were manifest only
on day 1.[52] Nonhematologic adverse events were found to be
similar in frequency and severity in patients with recurrent glioma
or advanced metastatic malignant melanoma.[64,82] The tolerabil-
ity of temozolomide was similar to that of procarbazine and
dacarbazine. [64,82] The most frequent nonhematologic adverse
events (all grades) in patients with recurrent glioma (and malig-
nant melanoma) were: nausea 42% (52%); vomiting 34% (35%);
headache 13% (22%); fatigue 20% (30%) and constipation 17%
Grade 1Grade 2
Grade 3Grade 4
0
1
2
3
4
5
6
7
8
Thrombocytopenia Neutropenia Vomiting Nausea Lethargy Constipation
Incidenceofevent(%)
Fig. 7. Tolerability of temozolomide reported in 2% of the 101 patients with high-grade glioma who received a total of 475 treatment courses. Patients received oraltemozolomide 150 to 200 mg/m2/day for 5 days every 4 weeks. The most frequent adverse events on Common Toxicity Criteria grades 1 to 4 are shown.