Temo Zolo Mide

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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

56 Darkes et al.

Adis International Limited. All rights reserved. Am J Cancer 2002; 1 (1)


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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

Temozolomide: A Review 57



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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-

58 Darkes et al.



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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.



7/26

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.




8/26

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.

62 Darkes et al.



9/26

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-




10/26

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.

64 Darkes et al.



11/26

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


12/26

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


13/26

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




14/26

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


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.

68 Darkes et al.



15/26

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.

70 Darkes et al.



17/26

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:


18/26

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)


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.

72 Darkes et al.



19/26

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.




20/26

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.

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