Clinical investigation
Brain
Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy

https://doi.org/10.1016/j.ijrobp.2004.12.032Get rights and content

Purpose: In this study, we assess the efficacy of GliaSite brachytherapy in the treatment of patients with recurrent glioblastoma multiforme (GBM).

Methods and Materials: Between 1999 and 2004, 24 patients with recurrent glioblastoma multiforme were treated with the GliaSite Radiation Therapy System (RTS). The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of surgical resection. Low-dose-rate radiation is then delivered locally by temporarily inflating the balloon with an aqueous solution of organically bound 125I (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]). Patients at the Johns Hopkins Hospital with recurrent GBM, who were previously treated with surgery and external beam radiotherapy, underwent surgical resection followed by GliaSite balloon implantation. Subsequently, the patients received radiation therapy using the GliaSite to a mean dose of 53.1 Gy. Ten patients were male, and 14 patients were female. The mean age was 48.1 years. All patients had pathologically confirmed recurrent GBM. The median Karnofsky performance status (KPS) was 80. Median follow-up time was 21.8 months.

Results: At the time of analysis, 18 patients (75%) had died; 6 patients (25%) were alive. Median survival from diagnosis for all patients was 23.3 months. Median survival after GliaSite brachytherapy was 9.1 months. Patients with a KPS ≥70 had a median survival of 9.3 months, whereas patients with a KPS <70 had a median survival of 3.1 months (p < 0.003). Survival was not significantly different between patients receiving 45 Gy and patients receiving a dose greater than 45 Gy. Acute side effects were minor, consisting of mild nausea and/or headache. One patient developed a wound infection. No incidents of meningitis were observed. Late sequelae were rare, but 2 incidents of symptomatic radiation necrosis were observed. One patient developed transient expressive aphasia.

Conclusions: GliaSite radiotherapy confers a prolongation of survival in patients with recurrent glioblastoma multiforme compared to historical controls with recurrent GBM. GliaSite therapy leads to a favorable survival outcome of 9.3 months in patients with KPS ≥70, but only 3.1 months in patients with KPS <70. Favorable survival is observed for patients within each recursive partitioning analysis class. Treatment with GliaSite is safe and generally well tolerated. Additional data are needed to fully assess the therapeutic benefit of GliaSite brachytherapy for recurrent GBM.

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.

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