Clinical Investigations
Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma

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Abstract

Purpose: A randomized study was undertaken to assess the role of brachytherapy as a boost to external beam radiation therapy in the initial management of patients with malignant astrocytomas.

Methods and Materials: Inclusion criteria included the following: biopsy-proven supratentorial malignant astrocytoma of brain ≤6 cm in size, not crossing midline or involving corpus callosum, age 18–70, Karnofsky Performance Status (KPS) ≥70. Patients were randomized to external radiation therapy only delivering 50 Gray (Gy) in 25 fractions over 5 weeks or external radiation therapy plus a temporary stereotactic iodine-125 implants delivering a minimum peripheral tumor dose of 60 Gy. Patients were stratified to age ≤50 or >50, and KPS ≥90 or ≤80.

Results: There were 140 patients randomized between 1986 and 1996, 71 to the implant arm and 69 to external irradiation only. Pathologically 125 patients had necrosis noted in their tumor specimen. Factors associated with improved survival in univariate analysis were age ≤50, KPS ≥90, chemotherapy at recurrence, and reoperation at the original tumor site. The Cox proportional hazards model revealed the following significant factors: treatment at recurrence (chemotherapy or reoperation) with a relative risk (RR) of 0.6 (p = 0.004) and KPS ≥90 with a RR 0.6 (p = 0.007). Randomization to the implant arm was associated with a RR of 0.7 (p = 0.07). Median survival for patients randomized to brachytherapy or not were 13.8 vs. 13.2 months, respectively, p = 0.49.

Conclusions: We conclude that stereotactic radiation implants have not demonstrated a statistically significant improvement in survival in the initial management of patients with malignant astrocytoma.

Introduction

Despite the fact that two randomized studies have demonstrated a statistically significant improvement in survival with the use of postoperative radiation therapy in patients with malignant astrocytomas, patients continue to recur locally and die of their disease 1, 2. A retrospective review of radiation dose in three sequential Brain Tumor Study Group studies demonstrated a statistically significant improvement in survival in the 60 Gray (Gy) group over the 50 Gy group (3). Subsequently, a joint Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) randomized study found no advantage for patients who had received 70 Gy as opposed to 60 Gy (4).

It has been well documented that most patients with malignant astrocytoma recur at the site of their original tumor mass 5, 6. Brachytherapy has both radiobiologic and dose distribution advantages over conventional external beam radiation therapy that were compelling, and led to an increased interest in the use of brachytherapy as a means of boosting the dose at the site of the original tumor in these patients 7, 8.

Accordingly, investigators began developing brachytherapy techniques for brain tumors, and reports started appearing in the literature in the early 1980s. These were Phase II studies, where brachytherapy was being utilized for recurrence in previously irradiated patients 9, 10, 11, 12, 13, 14, 15. Subsequent reports described the use of brachytherapy as a boost following external beam radiation in the initial management of patients with malignant gliomas 13, 14, 16, 17, 18, 19. Although these authors were reporting encouraging results, by necessity, patients with smaller more peripherally located tumors were undergoing brachytherapy, and it was not possible to discern whether their improved survival was due to brachytherapy or partially due to a selection of patients with better prognoses. Additionally, brachytherapy is an invasive procedure that can be associated with significant toxicity. It was for these reasons that our group decided to embark on a randomized study of brachytherapy as a boost to conventional external radiation therapy in the initial management of patients with malignant astrocytomas.

Section snippets

Methods and materials

The trial was designed to compare conventional external radiation therapy alone vs. conventional radiation therapy plus a brachytherapy boost in patients with malignant astrocytoma. The primary end point was the overall survival from the date of initial surgery. Patients satisfying the eligibility criteria below were randomized by a telephone call to the biostatistics department at the Princess Margaret Hospital. All patients were treated with external radiation therapy at one of the two

Results

Between 1986 and 1996, 142 patients were randomized on the study. On pathologic review, two patients were excluded on the basis of wrong histology (both were metastases, one from each arm of the study). This left a study population of 140 patients, 71 randomized to the implant arm and 69 to the nonimplant arm. Two patients had gliosarcomas, and all others had malignant astrocytomas.

Table 1 outlines the pretreatment characteristics, surgical procedures, the completion rates for external

Discussion

The report by Walker et al. suggested an advantage of 60 over 50 Gy in patients with malignant astrocytoma, but this was a retrospective review in which dose was not a randomized variable (3). In 1991, the Medical Research Council published the results of their randomized study comparing 60 Gy in 30 fractions to 45 Gy in 20 fractions in 474 patients (24). After adjusting for a slight imbalance in age distribution between the two arms, the Cox proportional hazards model estimated an improvement

Conclusions

This randomized study of a brachytherapy boost in addition to conventional external beam radiation therapy has not shown a statistically significant improvement in survival. Because of the relatively small number of patients randomized in this study, it is possible that a larger study might demonstrate a small benefit. There was a decrease in local recurrence and a trend for improved survival in the implant arm, and it is possible that brachytherapy concurrent with other therapies may be useful

Acknowledgements

The authors are grateful to their radiation oncology (in particular, Dr. Charlene Young) and neurosurgical colleagues for having referred their patients for inclusion in this study, and to Dr. Juan Bilbao for acting as the reference neuropathologist.

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    This study in part was supported by a grant from the National Cancer Institute of Canada.

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