International Journal of Radiation Oncology*Biology*Physics
Clinical investigationBrainTreatment of recurrent glioblastoma multiforme with GliaSite brachytherapy
Introduction
Glioblastoma multiforme (GBM) is a primary malignancy of the central nervous system that is fatal despite treatment with surgery and adjuvant therapy. In the United States, GBM occurs at a frequency of approximately 5,000 cases annually, and constitutes up to 80% of all malignant gliomas (1). Long-term control of these tumors is rarely achieved, despite surgical resection and external beam radiation therapy, and GBM recurs within 6–10 months. Most relapses occur within 2 cm of the margin of resection (2, 3). Disease progression is followed shortly by death.
Standard therapy consists of surgical resection followed by radiotherapy (RT). However, because of the infiltrative nature of glioblastoma multiforme, tumor control after resection alone is poor. Postoperative external beam radiation therapy has been shown to result in a modest increase in median survival in newly diagnosed patients (4, 5). Average survival is 9–12 months, and the 2-year survival is 5–10% (5, 6). Systemic chemotherapy provides an additional marginal benefit in survival for selected patients (5, 6, 7, 8). Similarly, biodegradable carmustine wafers (Gliadel) have been shown to increase survival by about 2 months with fewer toxicities than with systemic chemotherapy (9). A Phase III trial has shown that the use of temozolomide, an oral alkylating agent with some activity against glioma during and after RT increases median survival to 15 months (10).
After initial resection, RT is delivered using external beam techniques with standard fractionation to a total dose of 60 Gy. Increasing the radiation dose beyond 60 Gy using teletherapy has not resulted in improved survival (11, 12). This lack of benefit is likely a result of injury to the normal brain. Interstitial brachytherapy has been used to attempt to escalate the dose delivered to tumor cells while limiting toxicity. This modality is appealing because of its higher spatial localization of dose, which can theoretically spare greater amounts of normal brain tissue from adverse radiation effects. A number of trials have reported the results of treatment of primary and recurrent glioblastoma with temporary 125I seed implants. Although improved survival was seen in a number of cases, these results are dampened by the high rates of radionecrosis observed (13, 14, 15, 16). Seed placement can produce inhomogeneous radiation dose distributions, which are associated with repeated operations for radionecrosis occurring in up to 64% of patients treated with interstitial implants (16, 17, 18, 19). In addition, because stereotactic placement of multiple sources around a resection cavity is technically challenging, areas of inadequate dosing may frequently occur. Thus, it is possible that suboptimal dosimetry may explain the relatively poor results seen in some trials (15, 20). Indeed, in a randomized trial comparing external beam radiotherapy alone to external beam radiotherapy plus interstitial brachytherapy boost, Laperriere et al. did not observe a difference in survival (15). Moreover, interstitial brachytherapy for brain tumors requires stereotactic frame placement, drilling of multiple openings in the skull to place seeds, and movement of catheters through functioning brain tissue, maneuvers that can increase the risk of intracranial bleeding.
The use of low-dose-rate interstitial brachytherapy with permanent 125I implants has reduced the rate of severe complications such as symptomatic radionecrosis. Permanent low-dose-rate brachytherapy does not require stereotactic frame placement or the drilling of multiple holes in the skull for seed placement. However, as with high-dose-rate temporary implants, optimal dosimetry may be difficult to achieve. Survival in patients with recurrent GBM treated with this technique is comparable to that observed in similar patients treated with brachytherapy using temporary high-activity implants (21, 22).
The GliaSite system was designed to allow the delivery of radiation dose to areas most at risk of recurrence while addressing some of the potential limiting factors of interstitial brachytherapy. The GliaSite Radiation Therapy System (RTS) makes use of a silicone balloon catheter and an aqueous iodinated radiation source (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]). Immediately after surgery, the distal balloon portion of the GliaSite device is placed in the resection cavity. The proximal end consists of a catheter and an injection port. After placement of the balloon, the injection port is brought to the surface of the skull to allow subcutaneous access to the balloon. Intracavitary brachytherapy is then performed by filling the balloon with Iotrex using the subcutaneous port. The balloon is inflated with Iotrex so that the balloon fills the resection cavity, and the filled GliaSite balloon becomes a spherically shaped volumetric radiation source that produces a precisely and easily defined dose distribution. After treatment, the Iotrex is taken out of the balloon, and the implanted device is surgically removed. The safety and feasibility of the GliaSite RTS has been previously described (23).
Here, we report the clinical outcome of 24 patients with recurrent glioblastoma multiforme that were treated with GliaSite brachytherapy at the Johns Hopkins Hospital.
Section snippets
Methods and materials
Between February 2000 and April 2004, 24 patients with recurrent glioblastoma multiforme (World Health Organization IV malignant glioma) were treated with surgical resection and GliaSite brachytherapy. The characteristics of the patients are shown in Table 1. The median age of the patients was 48 years (range, 29–79 years). Mean Karnofsky performance status (KPS) at initial diagnosis was 80 (range, 60–100). Recursive partitioning analysis (RPA) class distribution at initial diagnosis was as
Results
A total of 24 patients with recurrent GBM underwent re-resection and treatment with GliaSite brachytherapy. Table 2 shows the treatment parameters used. Four patients (17%) were treated with a 2-cm GliaSite balloon, 11 patients (46%) were treated with a 3-cm balloon, and 9 patients (37%) were treated with a 4-cm balloon. The standard dose prescribed was 45 to 60 Gy delivered to a distance of 0.5 to 1.0 cm from the surface of the balloon. The mean dose prescribed was 53.1 Gy with a standard
Discussion
Radiation therapy is a treatment modality that has been proven to increase survival in patients with malignant glioma (4, 5). However, dose escalation beyond 60 Gy using external beam techniques has not resulted in improved survival, likely because of injury to the normal brain. Interstitial brachytherapy has been used in an attempt to increase the radiation dose delivered to tumor cells while limiting dose to normal brain tissue. Although results from some studies with interstitial implants
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The authors have no financial interest in GliaSite. Under an agreement between Proxima and Johns Hopkins University, Johns Hopkins University is entitled to a share of the sales royalty for the GliaSite system. The terms of these arrangements are managed by the University in accordance with its conflict of interest policies.