(carmustine or lomustine), temozolomide, procarbazine, vincristine, and platinum-based agents. The most common regimen combines procarbazine, lomustine, vincristine, and single or multiagent therapy with temozolomide. A biodegradable polymer wafer impregnated with carmustine (Gliadel® Wafer; Guilford Pharmaceuticals) also can be implanted into the surgical cavity as an adjunct to surgery and radiation. It is indicated for newly diagnosed high-grade malignant glioma and for recurrent glioblastoma multiforme.   

 

 

 

 

 

 

 

 

 

 

There is an ongoing trial of GliaSite in patients with newly diagnosed brain metastases.  Phosphorus 32 is being studied in patients with glioblastoma multiforme.  

 

Selker and associates reported results of a randomized controlled trial in 2002 and concluded that there was no long-term survival advantage of increased radiation dose with (125)I seeds in newly diagnosed glioma patients.

 

Chan and associates reported 24 patients with recurrent glioblastoma multiforme.  Median survival was 9.3 months for patients with a Karnofsky performance status of 70 or greater but only 3.1 months in patients with a Karnofsky less than 70.  "Additional data are needed to fully assess the therapeutic benefit of GliaSite brachytherapy for recurrent GBM."

 

A literature search was conducted for studies reporting on intracavitary balloon catheter brain brachytherapy published through February 2010. For newly diagnosed glioblastoma multiforme (GBM) patients treated after surgery, one prospective (Johannesen, 1999) and one retrospective (Welsh, 2007) study were identified. Four studies focused on patients treated after surgery for recurrent glioma (Tatter, 2003) (Chan, 2005) (Payne, 2005) (Gabayan, 2006).  Additionally, there has been one study published on patients treated for newly diagnosed and resected single brain metastasis (Rogers, 2006).  An additional study on 8 patients with glioma or brain metastasis focused on computed tomography and magnetic resonance imaging after balloon placement but did not report patient outcomes (Matheus, 2004).  

 

In each of 3 reports on recurrent high-grade gliomas (Tatter, 2003) (Gabayan, 2006) (Wernicke, 2010), all patients were treated with the commercially available GliaSite® RTS device. The first (Tatter, 2003) reported on a multicenter safety and feasibility trial (n=21; 15 with GBM; 5 with anaplastic astrocytoma and one with anaplastic oligodendrogliomas [ODG]). All patients (n=11) received first-line therapy with resection and radiation, with or without systemic chemotherapy. Time from end of first-line therapy to repeated resection for recurrent disease was not reported. Although not a primary endpoint, median overall survival was 12.7 months (95% CI: 6.9–15.3), and a Kaplan-Meier curve showed estimated overall survival at 1 year was just over 50%. Investigators reported no serious device-related adverse events during brachytherapy and no symptomatic radiation necrosis during follow-up.

 

The largest group was reported in a retrospective multi-institutional analysis (n=95; 80 with GBM, 9 with anaplastic astrocytoma, 4 with anaplastic ODG, and one each with a mixed anaplastic tumor or gliosarcoma) (Gabayan, 2006).  All patients received external-beam radiation after initial resection, and 55 (58%) also received systemic chemotherapy. Time from end of front-line therapy to repeated resection for recurrent disease was not reported. Fifteen patients (16%) who had previously been treated with external-beam radiation following maximal debulking surgery were treated with GliaSite® (average dose of 60 Gy) upon tumor recurrence. Median overall survival from the time of GliaSite® placement was 9.1 months (95% CI: 7.8–10.4), and overall survival at 1 year was 31.1% (95% CI: 21.2–41.0%). Only 2 patients experienced Radiation Therapy Oncology Group (RTOG) grade 3 toxicity attributable to radiation and none experienced grades 4 or 5. However, 10 adverse events were attributed to surgery. The authors concluded that survival benefit was modest and that these data were similarly inconclusive to previous feasibility studies.

 

The retrospective analysis on GliaSite® (Gabayan, 2006) did not report important prognostic factors available from the Gliadel® randomized trial (e.g., median interval from first operation; cumulative radiation dose and proportion given WBRT vs. local radiation vs. both in first-line therapy and completeness of the second resections). The authors concluded that it is a challenge to assess survival value from these studies without better comparative evidence on demonstrably similar patient groups, preferably from a randomized comparative trial.

 

Johannesen et al. reported a phase I/II study on 44 newly diagnosed glioblastoma multiforme (GBM) patients implanted with intracavitary balloon catheters at resection (Johannesen, 1999). Two to 3 days after surgery, high dose-rate 192-Ir sources were inserted twice daily for 15 minutes over 5 to 6 days, using remote after-loading devices designed and fabricated by the investigators. Cumulative radiation doses were 60 (n=33) or 72 Gy (n=11). Median survival was 11.7 months (range: 2.7 to 50.9 months) for all patients, 12.8 months for those treated with 60 Gy, and 9.9 months for those treated with 72 Gy. Overall survival at 1 year was 46%. Relapses occurred in 89% of patients at a median follow-up time of 8.3 months after treatment (range: 1.2 to 34.7 months). These outcomes are similar to those of conventional WBRT after resection, although investigators emphasized the shorter treatment time (1 vs. 5 to 6 weeks) with balloon catheter brachytherapy. While the authors asserted that hospital stays were shorter (median, 21 days) and quality of life over the first 6 months was better than after conventional WBRT, they did not report data to support these claims.

 

In the multicenter, retrospective study performed by Welsh et al. data were compiled from 8 centers on 20 patients with GBM patients with median age and Karnofsky performance status of 59 and 89, respectively (welsh, 2007). Following maximal tumor debulking patients were treated with GliaSite® (median dose 60 Gy) prior to external-beam radiation (median dose 110 Gy). In this cohort, average survival was 11.4 months (range 4-29); 4 months longer than historical controls (95% CI: 0.23–4.9). RTOG grade 3 central nervous system toxicity was observed in 3 patients (14%). It is noteworthy that 50% of treatment failures had the balloons placed ≥2 cm from the margin of the tumor. While this study may suggest that administration of increased doses (up to 100 Gy) using GliaSite® is feasible and relatively well tolerated, the authors acknowledge that putative survival advantage must be interpreted with caution. Additional studies using GliaSite® in conjunction with external beam radiation following surgery for newly diagnosed GBM would be required to adequately assess safety and efficacy.

 

In an additional clinical trial on recurrent GBM performed at Johns Hopkins Medical Center, investigators reported results to be inconclusive (Chan, 2005). Front-line therapy included surgery followed by external-beam radiation. Time from primary resection (or from end of primary treatment) to recurrence was not reported. Median overall survival was 23.3 months from diagnosis of the primary tumor, and 9.1 months  from GliaSite® RTS treatment. Kaplan-Meier analyses showed overall survival at 1 year to be approximately 33%. GliaSite® was relatively well-tolerated in this cohort with few serious adverse events. Acute adverse effects were reportedly mild; 1 patient experienced mild nausea and vomiting and 10 experienced mild to moderate headaches. Late complications included 1 case of global aphasia and 2 incidents of symptomatic necrosis.

 

Finally, Payne published a case report of one GBM patient undergoing implantation with 2 brachytherapy balloons (Payne, 2005); however, there are no additional studies assessing the 2-balloon approach.

 

A prospective, multicenter, Phase II trial enrolled 71 patients with 1 to 3 brain metastases from a solid tumor of distant origin (Rogers, 2006). Patients enrolled received either GliaSite® (n=62); or, standard brachytherapy with lotrex solution (n=54). Outcomes were analyzed without an intention-to-treat model. Primary malignancies included non-small-cell lung  and gastrointestinal cancers, melanoma, renal carcinoma, and others. While most patients (57%) had only brain metastases, many (43%) also had extracranial metastases. Prior therapies varied widely, and included no treatment, surgery, surgery and radiation or surgery in addition to chemotherapy followed by radiation. The investigators estimated local control at 1 year was 79%, and the median duration of local control was greater than 16.5 months. Median overall survival was 10 months, overall survival at 1 year was 40%, and median duration of functional independence was 10 months. Symptomatic imaging changes led to repeated operation in 13 patients, 9 of whom had radiation necrosis, 2 had mixed tumor and necrosis, and 2 had tumor recurrence only. A total of 9 grade 3 and one grade 4 toxicities were reported in the treated population.

 

Investigators indirectly compared the rate of local control in the GliaSite® treated population: 79% with historical data showing 80–90% local control after resection plus WBRT and only 40% after resection only. However, an accompanying editorial cautions that the rate of new metastases elsewhere in the brain was 50% by 1 year after treatment, and attributes this to omission of WBRT (Barker, 2006). The editorial also stresses the need for direct comparative evidence to determine whether neurocognitive function and quality of life are adequately maintained for longer durations with initially focal treatment and WBRT at recurrence or with focal treatment immediately combined with WBRT.

 

Wernicke and colleagues conducted a single institution, dose escalation study to investigate safety and feasibility of GliaSite® following surgical resection of localized brain tumors (Wernicke, 2010) The balloon was implanted during surgery; then 2 to 3 weeks later aqueous solution of 125-I was introduced for times ranging from 68 to 120 hours. Median total dose was 52 Gy. Median survival for this cohort was 14 months. There were no reports of RTOG Grade 3 or 4 toxicities. Similarly to the other studies cited, results from this trial suggest that the GliaSite® radiation therapy system is relatively safe and well-tolerated in patients with localized brain tumors. However, further studies would be required to assess efficacy.

 

Another study (Chino, 2008) examined feasibility of outpatient GliaSite® brachytherapy in 37 patients. Rather than overnight hospitalization, patients were released after the treatment sessions. Although the study was small and ultimately inconclusive, the outpatient approach did not appear to increase adverse events and seemed to be generally well tolerated.

 

Overall, adverse events with GliaSite® are not greatly varied from those observed with other brain brachytherapy techniques; however, in 2008, Adkison and colleagues reported a case where linens of a patient with the GliaSite® implant were contaminated with radiation (Adkison, 2008). Recovery studies confirmed that systemic absorption is greater than anticipated. Adkison concluded that precaution with a Foley catheter should be taken in patients with urinary incontinence. Some cases of brain hemorrhage have been reported, so careful coagulation control is critical (Gerber, 2007).  

 

The NCCN guidelines for glioblastoma state, “The role of focal radiation techniques in this diffusely infiltrative disease remains undefined.”

 

A search on ClinicalTrials.gov did not reveal any ongoing studies. One study testing GliaSite® in conjunction with temozolomide for primary brain tumors was terminated due to loss of funding.

 

To date, no standard medical care is established for primary brain malignancies or brain metastases of solid tumors and, there are no clinical data available to provide convincing evidence that intracavitary balloon brachytherapy extends the duration of survival, time to relapse, quality of life, or progression.