Fractionated stereotactic radiotherapy boost after post-operative radiotherapy in patients with high-grade gliomas

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Abstract

Purpose: To determine the value and the toxicity of an additional fractionated stereotactic boost as used in the joint randomized EORTC-22972/MRC-BR10 study in patients with malignant gliomas.

Materials and methods: Seventeen patients (11 male, six female) with a high-grade glioma (two WHO III, 15 WHO IV) ≤4 cm in maximum diameter, with a good performance status (WHO ≥2), were treated with a fractionated stereotactic radiotherapy (SRT) boost to 20 Gy in four fractions following partial brain irradiation to a dose of 60 Gy in 30 fractions. This patient group was compared with historical data in a matched-pair analysis.

Results: All patients were treated by conventional radiotherapy and a SRT boost (15 patients received 20 Gy and two patients 10 Gy). Acute side effects included fatigue (two), impairment of short-term memory (one) and worsening of pre-existing symptoms (one). No patient developed steroid dependence after SRT. One patient was re-operated for radiation necrosis. At a median follow-up of 25 months (9–50 months) 14 patients recurred locally. Survival was 77% at 1 year and 42% at 2 years; progression-free survival was 70% at 1 year and 35% at 2 years for all patients, respectively. Median survival for the whole patient group is 20 months. Comparison with a matched historical group showed a significantly better survival for the group treated with a stereotactic boost (P<0.0001).

Conclusion: A fractionated stereotactic boost after standard external beam radiotherapy in selected patients with high-grade glioma is feasible and well tolerated with low toxicity. Compared to historical data survival is significantly better with an additional SRT boost. However, its effectiveness has to be proven in a randomized trial.

Introduction

High-grade gliomas are the most common of all CNS tumours. Primary treatment options include surgical resection and radiotherapy. The effectiveness of radiotherapy in terms of a survival benefit was demonstrated in prospective randomized studies [1], [38], [39], [40]. There is evidence of a dose response relationship with doses of ≤60 Gy [1]. However, the Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG) study with an additional boost of 10 Gy to a total dose of 70 Gy in a large volume did not result in further improvement of survival [4]. The main pattern of failure is local and local control of high-grade glioma may be achieved by increasing the dose to the tumour without increasing the dose to normal brain tissue. Therefore, stereotactic radiotherapy (SRT) was proposed for dose escalation with doses of >70 Gy.

Focal radiotherapy has been used in the treatment of recurrent gliomas or as a boost in the initial management with encouraging preliminary results. It was administered by interstitial brachytherapy (IRT) [11], [12], [20], [21], as SRT [19], [30], as radiosurgery [14], [32], [36] or as an integrated boost with intensity-modulated radiotherapy [35]. Single-dose irradiation or radiosurgery carries an increased risk of radiation necrosis [31]. Published data suggest that fractionated SRT is associated with a lower incidence of necrosis compared with IRT [19], [26], [30]. Fractionated SRT combines the radiobiological advantages (normal tissue sparing) and precise focal dose delivery [9], [10], [15].

This prospective study was conducted in order to assess the value of a fractionated stereotactic boost after conventional radiotherapy with respect to survival, local control and toxicity in the initial management of selected patients with malignant glioma.

Section snippets

Inclusion criteria

For this study the same design as for the randomized phase III EORTC 22972 trial was used. Eligible patients were those with malignant high-grade glioma (WHO grade III/IV), enhancing tumours of ≤4 cm in maximum diameter on pre-operative imaging (computed tomography (CT) or magnetic resonance imaging (MRI)), age between 18 and 65 years and WHO performance status of 0–2 (Table 1).

Patient characteristics

Between March 1997 and June 1999, 17 patients (11 male, six female) met the inclusion criteria (see Section 2.1 and

Overall survival

The median follow-up was 25 months (range 9–50 months). Twelve patients died and five patients were still alive at the time of the analysis. The median overall survival for all patients is 20 months, with a survival of 77%, 42%, 28%, and 22% at 1, 2, 3, and 4 years, respectively (Fig. 1). The overall and progression-free survival for the 15 patients with the diagnosis of a glioblastoma multiforme (WHO grade IV) were not significantly different: the median survival was 19 months. Survival

Discussion

Compared with historical reports, the combination of single fraction radiosurgery (SRS) and conventional external beam radiotherapy in the initial management of patients with malignant gliomas has not conclusively proved to result in an increase in survival. The increase in survival which has been shown in studies using an interstitial radiotherapy boost is supposed to be mainly the result of patient selection [7]. In phase II studies with an additional IRT boost [12], [21], [41] the reported

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