Pediatr Blood Cancer 2007;49:808–811

Temozolomide in Pediatric Low-Grade GliomaSeong L. Khaw, MBBS,1* Lee T. Coleman, MBChB, BSc, FRANZCR,2 Peter A. Downie, MBBS, FRACP,1,3

John A. Heath, MBBS, BVSc, MS, PhD, FRACP,1 and David M. Ashley, MBBS, PhD, FRACP1

INTRODUCTION

Low-grade gliomas represent almost half of all central nervous

system tumors in children. Astrocytomas are the most common

subgroup, regardless of site [1]. Surgery is the mainstay of therapy,

and extent of resection is the most important factor consistently

impacting on prognosis [1–3]. Management of incompletely

resected tumors may include observation, second surgery, radiation

and/or chemotherapy depending on factors such as age, site,

symptoms, and comorbidities such as neurofibromatosis.

Temozolomide is an alkylating agent with excellent oral

bioavailability, good penetration across the blood brain barrier,

and low toxicity profile. It has been demonstrated to be well

tolerated in adults and children with cancer [4,5]. Non-cumulative

myelosuppression is the dose-limiting toxicity. Divided dosing

schedules have been found to be more efficacious than single bolus

dosing, and a regimen of 200 mg/m2 daily for 5 consecutive days per

4-week cycle is currently standard. Continuous administration

schedules have been developed to increase dose intensity, but have

yet to be shown to improve outcome [6].

We describe a series of patients with low-grade glioma who

received temozolomide as second-line chemotherapy at the Royal

Children’s Hospital (RCH) and Monash Medical Centre (MMC),

Melbourne.

PATIENTS AND METHODS

Patients

Patients were treated at the RCH and MMC, Melbourne. They

were retrospectively identified through a search of and comparison

across the respective departmental patient databases and hospital

pharmacy records. Eligible patients had a diagnosis of low-grade

glioma with or without histological confirmation, and had received

temozolomide as second-line chemotherapy.

Treatment and Evaluation

Temozolomide was administered at a dose of 200 mg/m2 daily

for the first 5 days of every 4-week cycle. Therapy was ceased on

completion of the targeted 12 cycles or on evidence of tumor

progression. Hematological parameters were evaluated at the start

of each cycle, and at additional time points according to clinical

indication. As per standard guidelines, grade IV toxicity resulting in

delay in treatment of greater than 2 weeks was an indication for dose

reduction.

All patients underwent serial MRI scans at 3 monthly intervals,

with additional scans when clinically indicated. All imaging

relevant to the study period was retrospectively reviewed with a

pediatric neuroradiologist (LTC) at the RCH. Tumor size was

measured as the product of the two maximum perpendicular

diameters. Response was graded as follows: complete response

(CR), complete disappearance of tumor; partial response (PR), 50–

99% reduction in tumor size; minor response (MR), 25–49%

reduction in tumor size; stable disease (SD), less than 25% change in

tumor size; progressive disease (PD), at least 25% increase in tumor

size or appearance of new lesions. Data on adverse events were

collected through review of patient’s medical records and

investigations.

Data Analysis

Duration of progression-free survival was calculated from the

date of commencement of temozolomide treatment to the time of

first clinical or radiological progression, or last follow-up. Event-

free survival rate was calculated using the Kaplan–Meier product

limit method.

RESULTS

Patients

Thirteen patients with progressive low-grade glioma were

treated with temozolomide at the RCH and MMC between 1999

and 2005. Their characteristics are outlined in Supplemental Table I.

Background. We describe a retrospective series of children withlow-grade glioma who received temozolomide. Procedure. Eligiblepatients had had a diagnosis of low-grade glioma with or withouthistological confirmation. Temozolomide was administered at adose of 200 mg/m2 daily for 5 days, in a 4-week cycle. Therapy wasstopped on completion of the targeted 12 cycles of chemotherapy oron evidence of tumor progression. Results. Thirteen eligible patientswere identified, eight male and five female. Median age at diagnosiswas 5.5 years (range 2.6–15.0 years) and at commencement oftemozolomide treatment was 9.0 years (range 3.8–15.2 years). Ninepatients had a histological diagnosis of pilocytic astrocytoma.

Twelve patients had received carboplatin prior to temozolomide,including three in combination with vincristine. A total of 111 cyclesof therapy have been administered. Hematological toxicity andnausea were the most common adverse effects. Median time toprogression was 6.7 months (range 1.5–41.8 months). Event-freesurvival rate at 3 years was 57%. Twelve of 13 patients remain aliveat the time of report. Eleven have stable disease (SD). Conclusion.Temozolomide appears to be active in pediatric low-grade glioma,with the advantage of oral administration and excellent tolerability.Pediatr Blood Cancer 2007;49:808–811. � 2007 Wiley-Liss, Inc.

Key words: low-grade glioma; pediatrics; temozolomide

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21270

——————This article contains Supplementary Material available at http://www.

interscience.wiley.com/jpages/1545-5009/suppmat.

1Children’s Cancer Centre, Royal Children’s Hospital, Melbourne,

Australia; 2Medical Imaging Department, Royal Children’s Hospital,

Melbourne, Australia; 3Children’s Cancer Centre, Monash Medical

Centre, Melbourne, Australia

*Correspondence to: Seong L. Khaw, Children’s Cancer Centre, Royal

Children’s Hospital, Flemington Road, Parkville VIC 3052, Australia.

E-mail: khaw@wehi.edu.au

Received 10 May 2006; Accepted 17 April 2007

The median age at diagnosis was 5.5 years (range 2.6–15.0 years).

Median age at commencement of temozolomide treatment was

9.0 years (range 3.8–15.2 years). There were eight male and five

female patients.

Nine patients had been diagnosed with pilocytic astrocytoma

following biopsy. One patient had a diagnosis of a likely low-grade

glioma on examination of limited biopsy material. Surgery (and

hence histopathological examination) for these 10 patients was

undertaken at the RCH. Three patients were diagnosed with

probable low-grade gliomas on the basis of primary site, presenting

history and imaging characteristics. One patient with optic pathway

gliomas had been diagnosed with neurofibromatosis type 1 (NF-1).

Treatment Prior to Temozolomide

Twelve patients had received carboplatin prior to temozolomide,

including three who received it in combination with vincristine. Five

developed PD off therapy, while two had PD despite ongoing

carboplatin treatment. Four switched to temozolomide because

of difficulties with venous access (two patients), anaphylaxis

post-carboplatin treatment (one patient), and status epilepticus

post-carboplatin treatment (one patient). One patient who had PD

on carboplatin treatment (Supplemental Table I, patient 10) then

received 12 months of 6-thioguanine, procarbazine, lomustine and

vincristine (TPCV), radiation therapy, and finally temozolomide.

Including the latter patient, two received radiation therapy prior

to temozolomide treatment. One patient (Supplemental Table I,

patient 2) who had a large, progressive brainstem glioma underwent

concurrent radiation therapy while commencing temozolomide

treatment. One patient received temozolomide because of progres-

sion whilst receiving cyclophosphamide.

Treatment With Temozolomide

Eight patients have completed planned treatment with temozo-

lomide. For the four patients who commenced temozolomide

treatment because of inability to continue carboplatin treatment, this

was when they had received an aggregate total of 12 cycles of both

drugs. Four patients stopped therapy because of PD. One patient

remains on treatment at the time of this report. A total of 111 cycles

of therapy have been administered.

Response and Salvage Therapy FollowingTemozolomide Treatment

Seven patients had an objective response (at least a 25%

reduction in tumor size) to temozolomide, including two patients

who had a CR (Figs. 1 and 2), three patients a PR, and three patients

an MR. Of note, two patients continued to demonstrate ongoing

reduction in tumor size through the duration of therapy. Median time

to best response was 7.7 months (range 1.5–13.5 months). All three

patients in this series with low-grade gliomas of the spinal cord

demonstrated an objective response. In four patients, the best

observed response was SD.

Four of eight patients commenced on temozolomide treatment

because of PD on or following carboplatin treatment developed

further progression whilst receiving temozolomide. Of these, two

have subsequently been treated with TPCV, one of whom has

completed the planned course of therapy. Both patients have SD

currently. Another patient has SD following radiotherapy. The

fourth patient died of PD. The four patients who received

temozolomide because of other problems related to carboplatin or

its administration have had SD to date following completion of

therapy.

Two patients developed PD following completion of therapy

with temozolomide. One developed radiological, but not clinical,

progression shortly after completing the planned treatment course.

She is being followed expectantly, and has not received further

treatment. The other developed PD 2 years following completion of

an initial course of temozolomide treatment. He received a course of

radiation, and then a second course of six cycles of temozolomide

treatment. He currently has SD.

In summary, six patients developed PD whilst on or following

completion of therapy with temozolomide. Median time to

progression was 6.7 months (range 1.5–41.8 months). Event-free

survival rate at 3 years was 57% (Fig. 3).

Overall, 12 of 13 patients remain alive at the time of report.

Eleven have SD.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Post-gadolinum coronal MRI brain images of patient 9. A: Rind of enhancement in roof of surgical cavity in right cerebellar hemisphere

prior to commencing temozolomide treatment. B: Resolution of enhancement.

Temozolomide in Pediatric LGG 809

Toxicity

Six episodes of grade III/IV thrombocytopenia were observed in

four patients, with two requiring a platelet transfusion. One of these

patients also had two episodes of grade III/IV neutropenia. Only one

patient required dose reduction for prolonged thrombocytopenia.

Hematological toxicity occurred early in treatment for two patients,

and following multiple courses in the other two. Four patients reported

nausea as a significant adverse effect. There were no documented

episodes of clinically significant skin rash or constipation.

DISCUSSION

Chemotherapy has an increasingly well-defined role in the

treatment of progressive pediatric low-grade glioma not amenable

to complete resection. A variety of agents have demonstrated

efficacy in large clinical trials, either as monotherapy or in

combination regimens, in stabilizing disease or inducing an

objective response. These are summarized in Supplemental

Table II [7–14]. This has allowed radiation and its associated

adverse effects to be avoided or deferred.

Temozolomide is an attractive candidate chemotherapeutic

agent against central nervous system tumors for reasons stated

above. It has been demonstrated to be active against high-grade

gliomas in adults [15–18], including patients with recurrent disease

following prior chemotherapy [19–22]. However, published studies

to date have failed to show a clear role for temozolomide as a single

agent in pediatric high-grade gliomas [23–25], although this is the

subject of ongoing study.

In the treatment of low-grade gliomas, there is mounting

evidence that temozolomide has significant activity in adult

patients, both as first-line chemotherapy, and in patients with

recurrent disease following prior chemotherapy [26–31] (Supple-

mental Table III).

The promising results from our series suggest that temozolomide

is also active in pediatric low-grade glioma. That they were achieved

in this group, all except for one of whom had previously been

treated with chemotherapeutic regimens currently regarded as the

standard of care, is even more encouraging in terms of both efficacy

and tolerability. There has to date been one other published

retrospective case series, where Kuo et al. described their experience

with temozolomide in 13 children with progressive, unresectable

low-grade glioma [32]. Four patients received temozolomide

150 mg/m2 for 5 out of every 28 days, while nine patients received

75 mg/m2 daily for 42 days, repeated every 56 days. This was

different to the regimen used in our series. In contrast to our cohort,

only 5 patients had been treated with other chemotherapy or

radiation prior to receiving temozolomide. Nine patients achieved

and maintained disease stabilization or better whilst on temozolo-

mide. Episodes of significant thrombocytopenia or neutropenia

occurred in five patients, including all the patients on the 5-day

regimen. Other reported toxicities were nausea and vomiting

and fatigue, which were severe enough to result in cessation of

temozolomide treatment in two patients. Of the four patients who

had PD on temozolomide, only one had previously received other

chemotherapy. All were on the 42-day regimen, and all were

successfully salvaged with other therapy.

Eight episodes of significant hematological toxicity were

observed in our cohort, following 111 cycles administered

(incidence 7.2%). This is comparable to the rates reported in the

above studies involving adults with low-grade glioma (range 3.5–

8%). No data are available for children with low-grade glioma. In

one study of children with high-grade gliomas however, significant

hematological toxicity was reported in 12% [23]. In our cohort, the

incidence of other well-recognized side effects of temozolomide

treatment such as nausea, rash, and constipation was lower than

expected. This may however, reflect the retrospective nature of this

report.

Temozolomide appears to be active in pediatric low-grade

glioma, with the advantage of oral administration and excellent

tolerability. Comparison with contemporary chemotherapy regi-

mens in a prospective randomized trial is indicated. Questions such

as associated risk of second malignancies (particularly in patients

with neurofibromatosis), optimal duration of therapy (especially

given toxicity is non-cumulative, and some patients demonstrate a

slow but ongoing response), identification of biological predictors

of response, and use in combination regimens are also of interest.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 2. Post-gadolinum sagittal MRI spine images of patient 12.

A: Complex solid and cystic tumor mass measuring approximately

9.9 cm in length extending from T7 to T12 prior to commencing

temozolomide treatment. B: Resolution of enhancement and reduction

in size of tumor post-temozolomide treatment.

0 50 100 150

0.00

0.25

0.50

0.75

1.00

Time from commencement of temozolomide (weeks)

Event-

free S

urv

ival

Fig. 3. Event-free survival for 13 patients with low-grade glioma

treated with temozolomide as second-line therapy.

810 Khaw et al.

ACKNOWLEDGMENT

We would like to thank Gemma Rigutto for her help with

searching the patient database and with the statistical analysis. We

are also grateful to Roxanne Dyas, Susan Mitchell, and Karen Egan

for their help in collecting patient data.

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Temozolomide in Pediatric LGG 811