Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas

M. Brada1,3,+, L. Viviers1,3, C. Abson1,3,§, F. Hines1,3, J. Britton4, S. Ashley2, S. Sardell1,3, D. Traish1,3, A. Gonsalves1,3, P. Wilkins4 and C. Westbury1,3

1 Neuro-Oncology Unit, 2 Computing Department, The Royal Marsden NHS Trust, Sutton; 3 Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research, Sutton; 4 Atkinson Morley’s Hospital, London, UK

Received 17 January 2003; revised 21 March 2003; accepted 21 May 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The aim of this study was to assess the efficacy of temozolomide in patients with World Health Organisation (WHO) grade II gliomas treated with surgery alone using imaging and clinical criteria.

Patients and methods:

Thirty patients with histologically verified WHO grade II gliomas (17 astrocytoma, 11 oligodendroglioma, two mixed oligoastrocytoma) following surgery 2–104 months (median 23 months) after initial diagnosis received temozolomide 200 mg/m2/day for 5 days, on a 28-day cycle, for a maximum of 12 cycles or until tumour progression. Median age was 40 years (range 25–68 years). Median follow-up from entry into the study was 3 years [range 23–47 months (for patients alive)]. Objective response was assessed by 3-monthly magnetic resonance imaging and monthly health-related quality of life (HQoL) and clinical assessment. Tumour size was measured as the high signal intensity area on fluid attenuated inversion recovery sequences. Responses were assessed using change in the product of two perpendicular diameters as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD).

Results:

Twenty-nine of 30 patients entered into the study were evaluable for response. Three patients had a PR, 14 MR, 11 SD and one PD. Twenty-four patients received 12 cycles of chemotherapy. Of 29 evaluable patients, three discontinued after four, five and six cycles and two after 10 cycles. Nine patients progressed (three during chemotherapy—one PD and two initial SD—and six after completion of chemotherapy); five had evidence of transformation. The 3-year progression-free survival was 66%. Five patients died; the actuarial 3-year survival was 82%. Ninety-six per cent of patients with impaired HQoL had improvement in at least one HQoL domain. There was improvement in 115 of the 207 domains (56%). Fifteen of 28 patients (54%) with epilepsy had reduction in seizure frequency, of whom six became seizure free. Six patients had transient grade III/IV haematological toxicity (11 episodes; 3.5%).

Conclusions:

Temozolomide has single-agent activity in patients with WHO grade II cerebral glioma, with modest improvement in quality of life and improvement in epilepsy control. On present evidence, temozolomide cannot be considered as primary therapy without formal comparison with other treatment modalities.

Key words: chemotherapy, low-grade glioma, temozolomide


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Debate about the role of surgery, radiotherapy and surveillance in the primary management of low grade gliomas [World Health Organisation (WHO) grade II astrocytoma, oligodendroglioma and mixed oligoastrocytoma] continues unresolved. With recognition of the chemoresponsiveness of grade III anaplastic oligodendroglioma [1] and a suggestion of efficacy of chemotherapy in grade II oligodendroglioma [24], an increasing number of patients with grade II neuroepithelial tumours have been treated with chemotherapy, although this has largely been reserved for patients who fail first-line treatment with surgery and radiotherapy.

Initial reports of effectiveness of chemotherapy in grade II glial tumours employed nitrosoureas, typically the procarbazine, CCNU, vincristine (PCV) regimen [24]. Temozolomide has been introduced as a well-tolerated oral alkylating agent and has been licensed for the treatment of recurrent malignant glioma (glioblastoma multiforme and anaplastic astrocytoma) [57]. The 35% response rate in WHO grade III astrocytoma (anaplastic astrocytoma) [5] in comparison with a 6–8% response rate in grade IV tumours (glioblastoma multiforme) [6, 7] suggests a possible trend of increasing efficacy in lower grade tumours previously noted for nitrosourea-containing chemotherapy [8]. On the basis of excellent tolerance and potential efficacy in lower grade tumours, we evaluated temozolomide as primary treatment following surgery in patients with grade II glial tumours in a single arm phase II study.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Design
The aim of the study was to assess the response rate to temozolomide in patients with low grade gliomas using imaging as the primary end point. The study design was for inclusion of adults (>18 years of age) with histologically confirmed grade II astrocytoma, grade II oligodendroglioma or grade II mixed oligoastrocytoma with evaluable disease on imaging and no previous antitumour treatment other than surgery with either stable or progressive disease. Patients with imaging or histological evidence of transformation to high grade tumours were excluded. They had to have satisfactory haematological and biochemical parameters, as defined in the initial temozolomide studies [57], and female patients had to have a negative urine pregnancy test. Patients in need of urgent decompressive surgery or radiotherapy due to rapidly evolving neurological deficit or raised intracranial pressure with papillodema and corticosteroid dependence were also not included. The study protocol was approved by local Scientific and Ethics Committees, and patients were required to provide informed consent prior to entry into the study.

Treatment
Patients received temozolomide 200 mg/m2 orally daily for 5 days given every 28 days, and the dose and frequency were adjusted according to standard toxicity criteria [5, 7, 9]. They were planned to receive a maximum of 12 cycles of temozolomide. The treatment was discontinued in the presence of disease progression or due to unacceptable toxicity.

End points
The primary end point was response on magnetic resonance imaging (MRI). An initial MRI scan was performed within 2 weeks prior to commencing chemotherapy. Subsequent scans were performed every 3 months in the first year and every 6 months in the second and third year.

The size of lesion was assessed on fluid attenuated inversion recovery (FLAIR) sequences. The region of high signal intensity was measured as a product of two perpendicular diameters. Baseline assessment was on a transverse MR slice of the pre-treatment scan where the lesion was largest. Subsequent assessment was made on the same MRI transverse slice (FLAIR sequence) with correction for varying obliquity. Complete response (CR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD) were defined on the basis of measurement in relation to baseline MRI (Table 2). To minimise interobserver variation in the assessment of the high signal region, the measurements were made independently by two observers (L.V. and C.A.) with the help of a neuroradiologist (J.B.). In patients considered to have MR or PR, the imaging was verified by a third observer (M.B.). In 12 patients, there was agreement between three observers. In five patients, the assessment of response was downgraded (from PR to MR or from MR to SD) following a review. An assessment of SD or PD by two observers was not altered.


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Table 2. Classification of response on MRI FLAIR sequence
 
Clinical response criteria in patients with neurological deficit were classified as a change in neurological deficit on a subjective (observer) scale and as an improvement in frequency of seizures. Health-related quality of life (HQoL) was assessed at baseline, after each course of treatment and at 3-monthly and later 6-monthly intervals during follow-up using an European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C 33 questionnaire and the Brain Tumour Module [10]. In patients with impaired indices on quality of life scales, a change of >=20% in a selected domain which was maintained for at least two successive visits was considered a response in HQoL (improvement).

Statistical design
The response rate of low grade gliomas was not known at the initiation of the study, but based on the published experience was estimated to be between 40 and 70%. The drug was considered to be ineffective and not worthy of further study if the response rate was <=30%. A standard two stage phase II trial design was used. In the first stage, 12 patients were recruited. If less than three responses were seen, the trial was to be discontinued and the treatment considered ineffective. Following subsequent recruitment to a total of 23 patients (second stage of the trial), the treatment was considered to be ineffective/effective according to whether the total number of responses was equal or greater than nine (Fleming’s Two Stage Design) [11] ({alpha} = 0.04; power, 90%). The initial design did not distinguish between astrocytomas and oligodendrogliomas but an amendment was made to the protocol to continue recruitment in order to look separately at the response rate in oligodendrogliomas. The study was terminated prematurely due to availability of the investigational agent.

Patients
From March 1998 to March 2000, 30 patients were entered into the study (Table 1). All had previous surgery (biopsy alone, 18; surgical resection, 12); three patients had two or more attempts at excision. None received previous radiotherapy or chemotherapy. All had histologically verified WHO grade II glioma (17 astrocytoma, 11 oligodendroglioma and two mixed oligoastrocytoma; for the purpose of response assessment mixed tumours were grouped with astrocytomas). Histology was centrally reviewed by one neuropathologist (P.W.). Median age was 40 years (range 25–68 years); 13 patients were male and 17 female. At the time of entry into the study, two patients had a Karnofsky performance status (KPS) of 60, one KPS 80, 11 KPS 90 and 16 had normal functional status (KPS 100). Treatment commenced 2–104 months (median 23 months) after initial diagnosis. Median follow-up from entry into the study was 3 years [range 23–47 months (of patients alive)].


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Table 1. Patient and disease characteristics of 30 patients with low grade glioma treated with primary chemotherapy
 

    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thirty patients (17 astrocytoma, 11 oligodendroglioma and two mixed oligoastrocytoma) were entered into the study. One patient discontinued temozolomide after 3 days due to lactose intolerance and 29 patients were eligible for evaluation of response.

Imaging response
During the observation period, three patients had a PR, 14 MR, 11 SD and one PD (Table 2). Respective rates for astrocytoma (which included mixed oligoastrocytoma) and oligodendroglioma are shown in Table 3. Examples of the responses are shown in Figure 1. The maximum response scored by two observers was reached after a median of 12–15 months. MR was reached after a median of 8 months.


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Table 3. Initial imaging response to temozolomide on MRI FLAIR sequence in 29 evaluable patients
 


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Figure 1. Examples of imaging responses on magnetic resonance imaging fluid attenuated inversion recovery (FLAIR) sequences. (A) and (B) Oligodendroglioma; (C) and (D) astrocytoma; (A) and (C) partial response (PR), (B) and (D) minimal response (MR). (A) Baseline and post cycle 10 scan; oligodendroglioma (PR); (B) baseline and post cycle 12; oligodendroglioma (MR). (C) Baseline and 1 year after cycle 12; astrocytoma (PR). (D) Baseline and 7 months after cycle 12; astrocytoma (MR).

 
Clinical response
Twenty-seven patients had a history of seizures at the time of entry into the study. During chemotherapy 14 had improvement in seizure frequency. This occurred in 10 of 15 patients who had a PR or MR and four of 12 patients who did not demonstrate an imaging response.

Twenty-eight patients were evaluable for quality of life (one patient received only one course of treatment) (Table 4). One patient had unimpaired HQoL at the start of treatment. Twenty-seven of 28 patients (96%) had an improvement in at least one HQoL domain. Improvement in HQoL was seen more frequently in responders (74/112 domains; 66%) compared with non-responders (41/95 domains; 41%) (P <0.001).


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Table 4. Response in health-related quality of life in 28 evaluable patients
 
All 28 patients had impairment in at least one of the functional scales (physical, role, emotional, cognitive, social and global health); 24 (86%) of these had a response. Twenty-seven patients had an impairment in at least one of the symptomatic HQoL domains (fatigue, headaches, visual, weakness, communication and seizures) and 22 (81%) of these responded. Twelve of 24 patients (50%) reported an improvement in their global health.

Treatment toxicity
A total of 324 cycles of temozolomide were administered. Twenty-four of 29 patients completed 12 months of treatment. Treatment was discontinued due to disease progression in three patients, due to persistent skin eruption in one patient and early death in one patient. There were 11 episodes (3.5%) of grade III/IV haematological toxicity seen in six patients and this was in the form of thrombocytopenia (six), neutropenia (three) and combined thrombocytopenia and neutropenia (two). One patient died following the sixth cycle of chemotherapy due to presumed cardiovascular cause (previous history of pulmonary embolism). Two patients had grade III constipation and one patient had grade III nausea and vomiting. One patient was diagnosed with breast cancer after two cycles.

Tumour control and survival
Nine patients had progressive disease either during (three patients) or after completion (six patients) of chemotherapy. Progression-free survival (PFS) from starting temozolomide is shown in Figure 2. Two-year PFS was 76% and 3-year PFS 66%. Following progression, six patients commenced radiotherapy (five completed treatment). Two patients had PCV chemotherapy and one temozolomide followed by radiotherapy. Five patients died: four of progressive glioma and one due to a presumed cardiovascular event. Two-year and 3-year actuarial survival were 87% and 82%, respectively (Figure 3).



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Figure 2. Progression-free survival of the cohort of 30 patients with WHO grade II glioma treated with temozolomide from the start of chemotherapy.

 


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Figure 3. Survival of the cohort of 30 patients with WHO grade II glioma treated with temozolomide from the start of chemotherapy.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This phase II study aimed to assess the efficacy of well tolerated and easily administered single-agent chemotherapy in patients with grade II glial tumours. To avoid the confounding effect of other oncological treatments, particularly radiotherapy, patients were entered into the study after surgery alone without prior irradiation. The effectiveness in terms of imaging response on the strict radiological criteria was 10% for a >50% reduction in tumour size (PR), with 45% of patients achieving a reduction of 25–50% (MR). The radiological response was associated with an improvement in some parameters of quality of life and with an improvement in seizure frequency.

While there is no agreement on the appropriate management of patients with grade II glial tumours, a policy of surveillance is widely accepted. As part of surveillance, active treatment, in the form of surgery or radiotherapy, is generally offered at the time of tumour progression. However, there is no evidence from randomised studies that this approach is more or less effective compared with other treatment policies. The only supporting evidence comes from a randomised EORTC study, which demonstrated no survival disadvantage for delayed radiotherapy [12]. This provides some confidence as to the safety of a policy of surveillance following surgery. On this basis, it is therefore not unreasonable to offer chemotherapy after surgery, as it does not deny an effective treatment offering gain in life expectancy.

While the study aimed to provide an objective assessment of the effectiveness of chemotherapy, there is no uniformly agreed imaging end point in patients with WHO grade II tumours. Low grade gliomas are usually unenhancing tumours shown as low density on T1 and high signal intensity on T2 weighted MRI sequences. FLAIR sequences, which are heavily T2 weighted, show the best contrast between presumed tumour and normal brain, and these were chosen as an objective measure of tumour size. While it is reasonable to interpret changes in the size of high signal abnormality as a reduction in tumour size, and therefore tumour cell mass, there is no definite imaging–pathological correlation to ensure that the changes represent a reduction in the number of clonogenic tumour cells. FLAIR sequences detect alterations in free water in the soft tissues. In low grade glioma the areas of altered signal are postulated to reflect the combination of tumour cells and increased water (oedema) in the adjacent tissues. Alteration in the size of the high signal region on FLAIR sequences may indicate both a reduction in the number of viable tumour cells and a reduction in oedema. The area of signal change gives an approximation of the extent of tumour involvement, as tumour cells migrate along the widened oedematous white matter tracts. Biopsies of areas that show signal change usually demonstrate the presence of tumour cells.

Abnormalities seen on FLAIR sequences considered to represent the tumour can be measured on sequential imaging with relative ease, but remain subject to interobserver variation, particularly due to a gradation of signal change between the normal and abnormal areas. There are other pitfalls in the assessment of tumour size. They include lack of strict co-registration of images, variation due to changing slice angles and different windowing of images. To improve the reliability of the measurements and reduce bias in favour of treatment efficacy, the images were assessed by three observers. All patients who were considered to have a PR or MR were reviewed by the senior author and five were downgraded. SD was not classified as a ‘response’ and patients who had SD or PD were not reviewed. The PR rate of 10% is lower than previously reported, but is not outside the range of the 24% PR rate reported for oligodendrogliomas assessed on T2 weighted images [13].

The correlation between imaging response, improvement in HQoL and frequency of epilepsy does suggest a beneficial and clinically meaningful effect of the observed MRI response and is likely to represent a worthwhile reduction in tumour size. The initial study design aim, which was to assess the effectiveness of chemotherapy separately in astrocytoma and oligodendroglioma, was not achieved and the available information is on the whole group of patients with grade II glial tumours. The differences between the two histological groups are not statistically significant, although the study is not sufficiently powered to demonstrate differences in the two tumour types. While the present perception is of a higher response rate in grade II oligodendrogliomas compared with grade II astrocytomas, there is insufficient data in the literature to fully substantiate this assumption.

The change in tumour size on imaging was slow, with a continued reduction over a number of months, which suggests that studies in patients with previously untreated low grade gliomas need to be performed over a considerable time. The high inter-observer variation and difficulty in precise assessment of tumour size also argues for a study design with multiple observers.

Despite the suggestion of effectiveness of primary chemotherapy, the PFS and survival results appear disappointing. However, this should not be taken as evidence of a lack of long-term efficacy of chemotherapy, as it is more likely a reflection of patient selection, as demonstrated by the wide range of timing of chemotherapy after primary diagnosis and the distribution by prognostic factors [14] shown in Table 1. Patients received treatment up to 9 years after the initial diagnosis and were therefore at different stages of evolution of the tumours, ranging from indolent to more malignant variants. Relatively early progression following chemotherapy is therefore likely to represent the duration of response that would be seen in a more malignant glioma. The survival outcome is also likely to be a reflection of patient selection at different time points along the natural history of the disease and distribution by prognostic factors [14]. The median survival of this cohort from primary diagnosis has not been reached. The 5-year survival from initial diagnosis was 84% at a median follow-up from initial diagnosis of 5 years, which suggests a selection of good prognosis patients from first diagnosis.

The majority of patients with low grade gliomas tend to be well, with seizures as the main clinical problem, and these are controlled to a lesser or greater extent with anticonvulsants. While there is no clear evidence that antitumour treatment is effective in controlling epilepsy, this study suggests that chemotherapy is associated with an improvement in seizure control. The mechanism is not clear.

In terms of quality of life assessment, there was an improvement in one or more domains in HQoL in 96% of patients who had impairment prior to treatment, and this occurred more frequently in patients who had an imaging response, suggesting that the improvement was a reflection of the effect of chemotherapy rather than a placebo effect.

The use of chemotherapy in grade II astrocytoma is largely based on the experience of efficacy of nitrosourea-based chemotherapy in anaplastic oligodendroglioma [1] with a reported response rate in the region of 70–80%.

While there is a suggestion of efficacy of chemotherapy in grade II oligodendrogliomas, the high response rate reported (<=63%) is largely in patients with enhancing oligodendrogliomas [15], which may represent higher grade variants. The combined response rate from three reported studies of PCV chemotherapy in grade II oligodendroglioma in patients with recurrent disease following surgery and radiotherapy [2, 4, 16] was 38%. The combined reported response rate from four studies in patients prior to radiotherapy [2, 4, 16, 17] was 67%. The reported studies did not use as strictly defined response criteria in unenhancing tumours as reported here, and the results should be viewed with caution. Nevertheless, the apparent difference in response rates suggests that either radiation may be responsible for inducing chemoresistance, or that patients in the post-radiotherapy cohort may have more malignant tumours further in the natural history of the disease which are less chemoresponsive. The most recent report of efficacy of PCV chemotherapy in newly diagnosed oligodendroglioma and oligoastrocytoma noted only a 20% rate of ‘tumour regression’ and 46% of these also had enhancing tumours [18].

Temozolomide has been employed in patients with recurrent anaplastic oligodendroglioma with a reported response rate of 26% and this included patients who received prior PCV chemotherapy [19]. Chinot [20] reported a 43% response rate in patients with oligodendroglioma who relapsed after PCV chemotherapy, which is higher than reported here and most likely reflects different patient selection. Quinn et al. [21] reported an imaging response rate of 61% (24% CR and 37% PR) in a cohort of 46 patients with apparent low grade glioma. However, 70% of patients had enhancing lesions, suggesting that these patients do not represent the generality of unenhancing low grade tumours reported here.

There is limited information on chemotherapy in patients with grade II astrocytoma. Chemotherapy has been used in the adjuvant setting together with radiation in a randomised study [22] with no clear evidence of survival benefit, although the study was underpowered. The use of chemotherapy was shown not to be a prognostic factor for survival in two retrospective studies [23, 24]. A report by Quinn et al. [21] included 16 patients with astrocytoma with a remarkable response rate of 69%, out of keeping with previous reports and our own observations, suggesting patient selection and/or end point assessment bias.

We conclude that temozolomide has single-agent activity in patients with WHO grade II gliomas both on imaging and clinical end points. However, the responses observed were slow, complete tumour disappearance was not recorded and objective partial response rate was only 10%. While previous studies concentrated on the chemoresponsiveness of oligodendroglioma, this is a report of the largest cohort of patients with grade II astrocytoma showing some, albeit limited, chemoresponsiveness to temozolomide. Future studies should test alternative administration schedules of temozolomide alone and in combination with other chemotherapeutic and biological agents before proceeding to randomised studies against other management policies. On the basis of the available data, temozolomide alone should not be considered as effective first-line therapy in this group of tumours.


    Acknowledgements
 
The work was supported in part by the Neuro-Oncology Research Fund, The Royal Marsden NHS Trust and Cancer Research UK (formerly Cancer Research Campaign). The work was undertaken by the Royal Marsden NHS Trust who received a proportion of its funding from the NHS Executive; the views expressed are those of the authors and not necessarily those of the NHS Executive. Temozolomide for this study was provided by Schering Plough UK (Welwyn Garden City, Herts) at no cost.


    Footnotes
 
+ Correspondence to: Dr M. Brada, The Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-2086-613-272; Fax: +44-2086-613-127; E-mail: mbrada{at}icr.ac.uk Back

§ Present address: Mid Kent Oncology Centre, Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK Back


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 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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