1 Department of Neuroscience, 2 Department of Diagnostic Imaging, 3 Service of Anatomo-Pathology, 4 Service of Clinical Pathology and 5 Statistical Unit, Regina Elena National Cancer Institute, Rome, Italy
Received 19 June 2003; revised 30 September 2003; accepted 2 October 2003
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Abstract |
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The optimal treatment for low-grade glioma (LGG) is still controversial. Recent data indicate a potential influence of chemotherapy on the natural evolution of these tumors, allowing for the deferral of more aggressive therapies.
Patients and methods:
Forty-three patients affected with LGG (29 astrocytoma, four oligodendroglioma and 10 mixed oligo-astrocytoma) were treated with temozolomide (TMZ) at the time of documented clinical and radiological progression. McDonalds response criteria were utilized to evaluate TMZ activity. Thirty patients (69.7%) had previously received radiotherapy; 16 (37.2%) had received prior chemotherapy. Clinical benefit was evaluated measuring seizure control, reduction in steroid dose and modification of Karnofsky performance status and Barthel index. Quality of life was assessed with the QLQ-C30 questionnaire.
Results:
We observed a complete response in four patients, 16 partial responses, 17 stable disease (with four minor response) and six progressive disease. Median duration of response was 10 months [95% confidence interval (CI) 812], with a 76% rate of progression free survival (PFS) at 6 months, and a 39% rate of PFS at 12 months. A relevant clinical benefit was observed particularly in patients presenting epilepsy.
Conclusions:
The high response rate of 47% (95% CI 31% to 61%) confirms that TMZ chemotherapy is a valid option in the treatment of progressive LGG. The present preliminary results seem interesting and warrant further evaluation of TMZ clinical activity in a larger series of progressive LGG.
Key words: chemotherapy, epilepsy, low-grade glioma
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Introduction |
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In this context, there is increasing attention on the potential influence of chemotherapy on the natural evolution of these tumors, allowing for the deferral of more aggressive therapies. In recent years, there have been many reports on the efficacy of chemotherapy in children with newly diagnosed or recurrent LGG treated with a variety of drugs [79]. The results of these studies have demonstrated that objective responses can be achieved in patients with LGG, and prolonged disease stabilization can be observed even in the absence of significant neuroimaging variations. In adults, chemotherapy activity has been demonstrated clearly, particularly in pure oligodendrogliomas and mixed oligo-astrocytomas [10, 11], even if more substantial therapeutic activity has been observed in anaplastic oligodendrogliomas [12]. The scarce data on chemotherapy in adult LGG reported in the literature [13, 14] reveal that LGG seems to be less chemosensitive than anaplastic forms, but that chemotherapy may induce long-term stabilization of the disease and important clinical benefits, including control of epilepsy.
Genetic alterations, such as loss of the heterozigosity of chromosomes 1p and 19q, have been shown to be powerful predictors of survival and chemosensitivity in oligodendroglial tumors [15, 16]. At present, the role of molecular changes in astrocytoma is less clear, but many authors suggest that genetic alterations may help to identify chemosensitivity in low-grade astrocytomas as well [17]. Furthermore, the evaluation of therapeutic response to chemotherapy in patients affected by indolent, infiltrating and often non-enhancing tumors, is not easy using common neuroimaging response criteria.
Temozolomide (TMZ) is a methylating agent that has shown clinical activity in the treatment of recurrent anaplastic astrocytoma and glioblastoma multiforme. Recent data have suggested a possible role of TMZ chemotherapy in LGG [18]. The primary aim of this study was to assess the activity of TMZ chemotherapy in patients with progressive LGG, evaluated with conventional clinical and neuroimaging response criteria. A further aim was to evaluate the patients clinical benefits, in terms of seizure control and improvement in quality of life (QoL).
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Patients and methods |
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Eligibility criteria
Patients with grade II (WHO) histologically confirmed glioma (astrocytoma, oligodendrogliomas and mixed oligo-astrocytoma) entered the study at the moment of clinically and radiologically documented progression. All patients were required to present measurable disease on pretreatment contrast-enhanced magnetic resonance imaging (MRI), Karnofsky performance status (KPS) >60 and Barthel index (BI) >80. The study was approved by our ethics committee and all patients were required to provide signed informed consent.
Treatment schedule
TMZ was administered orally, once a day, for five consecutive days every 4 weeks, at a starting dose of 200 mg/m2/day if not pretreated, or 150 mg/m2/day in procarbazinelomustinevincristine (PCV) pretreated patients, with dose escalation to 200 mg/m2/day in the absence of toxicity.
Tumor response criteria
TMZ activity was evaluated using established response criteria that also consider patient neurological function and steroid dosage [19]. T1 enhanced, T2 and FLAIR MRI images were obtained every three treatment cycles. The tumor area was measured using the maximum perpendicular cross-sectional diameters. A complete response (CR) was defined as the complete disappearance of enhancing or non-enhancing tumor; partial response (PR) was defined as a shrinkage >50% of the tumor area; stable disease (SD) was defined as a reduction of tumor area from 0 to 50% with stable or reduced steroid dosage; and minor response (MR) a reduction >25% but <50% of the tumor area. Clinical response was evaluated by measuring variations in QoL, reduction in frequency of seizures per month, reduction in steroid dose and modifications of KPS and BI. QoL was assessed at baseline and during treatment with EORTC QLQ-C30 (version 3.0) and Brain Cancer Module (BCM-20) questionnaires [20]. Clinical evaluation was performed every three treatment cycles. Partial seizure control (PSC) was defined as a reduction of >50% in the number of seizures, with the steroid dose stable or reduced, and no modification of anti-convulsant treatment; complete seizure control (CSC) was defined as absence of seizures in patients presenting uncontrolled epilepsy before treatment. Progression-free survival (PFS) at 6 and 12 months was measured from day 1 of treatment to the radiographical or clinical evidence of disease progression.
Statistical analysis
We used a single-stage design for the trial. A response rate of 10% was considered of no interest, while the study would be considered as positive if the responses rate was of at least 25%. At a significance level of 5% with a power of 80%, 40 patients were required to enter the study, and eight objective responses needed to be observed to consider the study as positive. 2-test was used to study the association between response and variables. Survival curves were estimated by the KaplanMeier method and differences were evaluated by the log-rank test.
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Results |
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We observed an objective response rate of 47% [four CR plus 16 PR; 95% confidence interval (CI) 31% to 61%], a disease control rate of 86% (four CR plus 16 PR plus 17 SD, with four minor responses; 95% CI 76% to 96%) and six progressive disease (PD) (Table 2). Median duration of response was 10 months, with a PFS rate of 76% at 6 months and 39% at 12 months. The response rate in patients presenting non-enhancing lesions on MRI (17 patients) was lower than that observed in patients presenting enhancing lesions on MRI (26 patients): 29% (95% CI 8% to 51%) versus 58% (95% CI 38% to 76%), respectively.
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The clinical benefit was significantly higher in patients with non-enhancing lesions than in those with enhancing lesions, with 81% (nine of 11; 95% CI 59% to 100%) of seizure control (CSC in two cases, PSC in seven) and 30% (six of 20; 95% CI 10% to 50%) of seizure control (two CSC and four PSC), respectively (P <0.05) (Table 3).
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The median PFS was 10 months for the whole population. Patients with a radiological response of SD showed a relevant clinical benefit during TMZ treatment, with 41% gaining seizure control (Table 3) and QoL improvement in five patients (29.4%). PFS at 6 and 12 months was not significantly different in patients with radiological response (CR plus PR) and in patients with SD (Table 4).
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Discussion |
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The patients included in our study presented an initial histological diagnosis of well-differentiated glioma, and in all cases showed clinical and neuroimaging documented progression. Histological restaging at recurrence was possible only in 16 patients, with demonstration of anaplastic progression in eight, but the radiological characteristics of enhancing lesion in 25 patients, and non-enhancing lesion in 17, probably reflects the variability of LGG, which may recur with or without histological progression.
Another critical issue in this field is the criteria for evaluating treatment efficacy. Chemotherapy response criteria are usually based on volumetric neuroimaging aspects that evaluate the objective tumor response by measuring its shrinkage. The response rate as evaluated by these classical criteria is considered a traditional end point in clinical trials, but it is also well known that there is not necessarily a correlation between objective response and other measures of clinical benefit, considered as beneficial effects on disease-related symptoms and QoL. It has been suggested that new imaging modalities, such as PET and MRI spectroscopy, may offer new possibilities for evaluating treatment results in brain tumors. Since LGG are characterized by reduced growth potential, and a very low proliferating cell population, assessment of response with radiological criteria could be less appropriate than in anaplastic tumors.
The radiological response rate in the whole population was 47%, but was higher, though not statistically significant, in the group of patients showing enhancing areas on MRI (58%) than in patients without enhancing lesions (29%).
In contrast, the clinical benefits of chemotherapy, such as a reduction in steroid dosage, improvement in KPS and BI, and particularly epilepsy control, were significantly higher in patients with non-enhancing lesions, who often showed an SD on radiological examination. In fact, in many cases seizures are the only symptom, which implies that performance status and neurological status may be well preserved even in the presence of voluminous tumors. Moreover, despite limitations due to the small size of this study, QoL measurements indicate an improvement of function scores in a larger proportion than patients who achieved an objective radiological response. The effect of chemotherapy differed between enhancing and non-enhancing tumors, with more prolonged PFS being achieved in the latter. PFS was similar in patients with CR/PR and with SD. Recent studies on recurrent anaplastic astrocytoma, anaplastic oligodendroglioma and mixed anaplastic oligo-astrocytoma [2426] included patients with history of low-grade disease reporting variable response rates to TMZ chemotherapy ranging from 35% to 61%. The remarkable heterogeneity of LGG in biological behavior and response to treatment should be considered in patients selection criteria of clinical trials. The results of the present study seem to indicate that chemotherapy may produce a different response in LGG: a radiological sprinter response or a jogger response with long stabilization of disease often associated with considerable clinical benefits, particularly in patients presenting with epilepsy. Other reports support our observation of relevant clinical benefit induced by chemotherapy, often not related to radiological response, in the subgroup of patients with non-enhancing LGG [12, 27]. The different biological behavior of progressive LGG should be better identified taking into account radiological, histological and genetic characteristics that will indicate the optimal treatment. In particular, it has already been suggested that indolent gliomas with low mitotic index may be treated with new schedules of administration of TMZ with chronic low-dose exposure [27, 28].
The results of our study indicate that TMZ is active in progressive LGG. The high response rate of 47% confirms that chemotherapy is a valid option in the treatment of this group of tumors. However, the role of TMZ chemotherapy in progressive LGG needs to be studied in larger series.
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Footnotes |
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References |
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