Abstract
Purpose:
Recurrence in glioblastoma (GBM) is common, and the success of salvage strategies, including re-resection and reirradiation, is limited. Brachytherapy with Cs-131 collagen tiles enables intraoperative focal dose intensification with rapid dose fall-off and limited normal brain radiation exposure. We report the outcomes of Cs-131 collagen tile implantation at the time of resection for recurrent GBM.
Methods and Materials:
We reviewed 15 adults with previously irradiated, recurrent isocitrate dehydrogenase (IDH) wild-type GBM who underwent maximal safe resection followed by intraoperative Cs-131 collagen tile implantation at a single institution. Candidates had surgically accessible, primarily enhancing recurrences ≥6 months after prior external beam radiation therapy, and were anticipated to have a gross total resection. The prescription dose was 60 Gy at a depth of 5 mm. We assessed overall survival, progression-free survival, toxicity, and patterns of failure (local ≤0.5 cm from the cavity, marginal 0.5–1 cm, and distant >1 cm) after implantation.
Results:
Patients (median age, 63 years; range, 39–76) had good performance status (median Karnofsky Performance Status score, 90; range, 70–100) and prior chemoradiation (most to 60 Gy/30 fractions). Tiles (median, 6.5/patient; range, 3–13) were implanted at first recurrence in 12 of 15 patients (80%) and at second recurrence in 3 (20%), at a median of 15 months after external beam radiation therapy (range, 8.9–47). At 13 months median follow-up (range, 1.4–21), the median overall survival after Cs-131 implantation was not reached (NR) (95% CI, 6.7-NR months); the median time to progression after Cs-131 implantation was 9 months (95% CI, 6.0-NR); and the cumulative incidence of first progression (local or distant) after Cs-131 implantation was 53.3% over the follow-up period. The first failures were local (n = 2), marginal (n = 2), distant (n = 3), and combined local and distant (n = 1). One patient developed symptomatic grade 3 radionecrosis, which improved with bevacizumab. No patients required reoperation for Cs-131 toxicity.
Conclusions:
Intraoperative Cs-131 tile brachytherapy for recurrent GBM is feasible and well tolerated. Distant failures remain common. Integrating effective systemic therapy and careful patient selection may optimize outcomes.
Introduction
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, with nearly universal recurrence, usually at or near the original tumor site.1 Standard initial treatment includes maximal safe resection and radiation with concurrent and adjuvant temozolomide (TMZ), with consideration of tumor treating fields.1–3 Despite aggressive multimodal therapy, long-term disease control is rare, with recurrence typically occurring within the high-dose radiation field.3–6
Management of recurrent GBM poses substantial challenges. Patients with surgically accessible recurrence can undergo repeat resection; however, surgery alone rarely offers durable local control, with most patients experiencing progression at the resection margin.7 Reirradiation may also be considered, either alone or after reoperation, to improve local control. Despite retrospective data supporting reirradiation with external beam radiation therapy (EBRT), Radiation Therapy Oncology Group (RTOG) 1205 demonstrated only a modest progression-free survival (PFS) benefit, without an improvement in overall survival (OS), for bevacizumab plus EBRT compared with bevacizumab alone.8,9 Escalating doses beyond those used in RTOG 1205 raise concerns about radionecrosis, cognitive decline, and quality of life. Moreover, the logistics of adjuvant EBRT over several weeks may be burdensome for patients with a limited prognosis who are often disabled by their disease.
Brachytherapy is an alternative for focal recurrences, delivering escalated doses directly to the resection cavity with steep dose fall-off and minimizing exposure to the adjacent normal brain. The historical use of individual I-125 seeds achieved high focal doses but was associated with substantial toxicity and reoperation rates of up to 50%,10–14 most likely due to seed clustering and a high surface dose at the cavity-brain interface.
Cs-131 collagen tile brachytherapy involves implanting bioresorbable collagen matrix tiles embedded with 4 Cs-131 seeds, positioned 3 mm from the cavity surface, to reduce the peak dose at the brain interface.15,16 This configuration leverages rapid dose fall-off to safely intensify the dose to the surgical cavity while minimizing exposure to surrounding brain tissue. Moreover, delivery of adjuvant radiation intraoperatively reduces treatment burden by obviating the need for return visits for fractionated EBRT. In this study, we report the clinical outcomes of intraoperative Cs-131 collagen tile brachytherapy in patients with recurrent GBM after prior radiation therapy (RT).
Methods and Materials
We reviewed 15 patients with recurrent isocitrate dehydrogenase (IDH) wild-type GBM after prior irradiation who underwent resection and intraoperative Cs-131 implantation at a single institution under an institutional review board-approved protocol. Preoperative magnetic resonance imaging (MRI) was used to estimate the resection cavity surface area. Cases were selected with input from neurosurgery, radiation oncology, neuro-oncology, and neuroradiology, and included magnetic resonance spectroscopy and perfusion sequences to assess suitability for resection and identify viable recurrent tumor. Appropriate candidates were those eligible for surgery (specifically gross total resection [GTR]) with recurrence ≥6 months after prior RT, which was primarily enhancing without a significant progressive infiltrative T2/fluid-attenuated inversion recovery signal.
Each patient’s most recent MRI scan, demonstrating gross tumor on the T1 postcontrast sequence, was uploaded into MIM Symphony (MIM Software Inc). The anticipated resection cavity was contoured, and the estimated surface area was used to guide the number of Cs-131 collagen tiles required. Each tile (GammaTile, GT Medical Technologies) measures 20 × 20 × 4 mm and contains 4 Cs-131 seeds (activity of 3.5 U per seed) embedded in a collagen matrix. The prescribed dose was 60 Gy to a depth of 5 mm. All patients underwent maximal safe resection; after intraoperative pathology confirmation of a viable tumor, cavities were lined with Cs-131 collagen tiles by the neurosurgeon in collaboration with the treating radiation oncologist. Both physicians confirmed adequate coverage of at-risk tissue during surgery. Following surgery, patients underwent thin-slice MRI and computed tomography (CT) imaging, and a postimplant treatment plan was generated in MIM Symphony. The MRI and CT scans were first fused, and the MRI was then used for postoperative gross tumor volume delineation, whereas the CT was used to identify the Cs-131 seeds.
Data collected included demographics, tumor characteristics, prior therapy, extent of resection, number of seeds and tiles, postimplant dosimetry (dose to 90% of the target [D90] and volume of the target receiving 100% of the prescribed dose [V100]), toxicity, efficacy, and patterns of failure.
Each treated lesion was systematically tracked on serial MRI scans at routine follow-up intervals to ensure accurate classification. Local failure (LF) was defined radiographically, clinically, or pathologically when surgery was performed for suspected progression. Radiographic LF required a sustained increase in enhancing lesion size on at least 2 consecutive MRI scans despite corticosteroid or bevacizumab therapy, prompting a change in clinical management (eg, initiation of systemic therapy or reresection). When available, advanced brain tumor imaging (ABTI), including magnetic resonance spectroscopy, dynamic susceptibility contrast, dynamic contrast enhancement, or arterial spin labeling perfusion MRI, was reviewed to assess relative cerebral blood volume; increased perfusion provided supportive evidence of a viable tumor. Pseudoprogression and treatment-related enhancement were excluded when radiographic changes subsequently stabilized or regressed without therapeutic intervention. The failure pattern was defined relative to the estimated epicenter of a grossly recurrent tumor: local if within 0.5 cm of the resection cavity, marginal if 0.5 to 1 cm, and distant if >1 cm.
For statistical analyses, marginal failures were grouped with distant failures in all time-to-event analyses (PFS and cumulative incidence).
Events, including OS, were calculated from the date of brachytherapy to the event. Death was treated as cumulative mortality from any cause. Progression (for PFS) was defined as the first occurrence of local or distant progression. Cumulative incidence was plotted from the time of implantation.
Results
We reviewed 15 patients with recurrent GBM treated with Cs-131 brachytherapy (Table 1); most (n = 10, 67%) were women, had a median Karnofsky Performance Status score of 90 (range, 70–100), and a median age of 63 years (range, 39–76). All patients had previously received standard EBRT to 60 Gy in 30 fractions (n = 14) or 40.05 Gy in 15 fractions (n = 1), combined with concurrent and adjuvant TMZ. Four patients received additional systemic agents during the adjuvant phase, including immunotherapy (eg, pembrolizumab, atezolizumab, or ipilimumab/nivolumab) and Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors.
Table 1.
Patient and treatment characteristics
| Characteristic | Value |
|---|---|
|
| |
| Patients, N | 15 |
| Age (y), median (range) | 63 (39-76) |
| Sex (women), % | 67 |
| Karnofsky Performance Status score, median (range) | 90 (70-100) |
| Prior EBRT dose 60 Gy/30 fractions, n | 14 |
| Prior EBRT dose 40.05 Gy/15 fractions, n | 1 |
| Concurrent & adjuvant TMZ, % | 100 |
| No. of recurrences prior to Cs-131 implantation, n (%) | |
| 1 | 12 (80) |
| 2 | 3 (20) |
| Pre–Cs-131 recurrence type, n (%) | |
| Local | 14 (93) |
| Distant | 1 (7) |
| Tumor laterality, % | |
| Left | 55 |
| Right | 45 |
| Tumor location, n (%) | |
| Temporal | 5 (33) |
| Parietal | 5 (33) |
| Frontal | 4 (26.66) |
| Frontotemporal | 1 (6.66) |
| MGMT promoter status, n (%) | |
| Methylated | 5 (33.3) |
| Unmethylated | 7 (46.7) |
| Unknown | 3 (20) |
| Time from prior RT to Cs-131 (mo), median (range) | 15 (8.9-47) |
| GTR at GT insertion, n (%) | 13 (86.6) |
| Preoperative GTV (cm3), median (range) | 32.4 (9.8-71.6) |
| Postoperative cavity volume (cm3), median (IQR) | 30.8 (23.6-43.9) |
| No. of Cs-131 tiles implanted, median (range) | 6.5 (3-13) |
| Follow-up time (mo), median (range) | 7.8 (1.4-21) |
Abbreviations: EBRT = external beam radiation therapy; GT = GammaTile; GTR = gross total resection; GTV = gross target volume; MGMT = O6-Methylguanine-DNA-methyltrasferase; RT = radiation therapy; TMZ = temozolomide.
Before implantation, 14 of 15 patients (93%) had local recurrence, and 1 (7%) had a prior distant recurrence followed by a local recurrence.
Cs-131 brachytherapy was delivered at first recurrence in 12 of 15 patients (80%) and at second recurrence in 3 patients (20%). For these patients, details regarding the initial recurrence and treatment were reviewed. Each initially experienced a local recurrence, managed with repeat surgery followed by systemic therapy (TMZ rechallenge, lomustine, or immune checkpoint inhibitors), with a median interval of 12 months (range, 8–30) between the first and second recurrences.
At the time of Cs-131 implantation, GTR was achieved in 13 of 15 cases (87%), while subtotal resection (STR) was performed in 2 cases (13%). The extent of resection was confirmed by immediate postoperative MRI (within 24–48 hours), which also served as the basis for postimplant dosimetry in the MIM Symphony software.
The median interval from prior EBRT to Cs-131 implantation was 15 months (range, 8.9–47). The median preoperative gross target volume was 32.4 cm3 (range, 9.8–71.6), and the median postoperative resection cavity volume was 30.8 cm3 (IQR, 23.6–43.9). A median of 6.5 Cs-131 tiles (range, 3–13) was implanted per patient. The median clinical follow-up interval was 7.8 months (range, 1.4–21).
After Cs-131 treatment, the median OS was not reached (NR) (95% CI, 6.7-NR months) (Fig. 1), and the median PFS was 9 months (95% CI, 6.7–11.2), with a 6-month PFS of 71.8% (95% CI, 41.1%–88.4%) and a 12-month PFS of 55.4% (95% CI, 25.8%–77.3%) (Fig. 2). The cumulative incidence of first progression (local or distant) after Cs-131 implantation was 53.3% over the follow-up period (Fig. 3). Patterns of first failure were local-only in 2 of 15 patients (13%), marginal-only in 2 (13%), distant-only in 3 (20%), and both local and distant in 1 (7%).
Figure 1.
Kaplan-Meier curve for overall survival (OS) after Cs-131 implantation.
Figure 2.
Kaplan-Meier curve for progression-free survival after Cs-131 implantation.
Figure 3.
Cumulative incidence of first progression after Cs-131 implantation, with death considered a competing risk. Blue indicates distant progression and yellow local progression.
All implants met the planning objectives. Across 15 evaluable plans, D90 was ≥60 Gy in 100% of cases, and V100 was ≥90% in 100% of cases. The median D90 was ~91.8 Gy (IQR, ~76.8–100.2; range, 61.8–124.2), and the median V100 was ~99.3% (IQR, ~97.6%–100.0%; range, 91.2%–100.0%). Dose volume histogram (DVH) curves demonstrated a steep fall-off to the brain/scalp with near-complete target coverage. These data support the technical feasibility of achieving robust cavity coverage with Cs-131 while maintaining rapid dose fall-off to surrounding tissues.
A representative case is shown to illustrate a typical patient considered suitable for Cs-131 brachytherapy. The patient developed an in-field local recurrence 14 months after initial management with surgery and postoperative RT with TMZ. Due to the highly local nature of the recurrence, the patient was dispositioned for re-resection with Cs-131 brachytherapy. Imaging demonstrated delayed subependymal enhancement 8 months following brachytherapy, consistent with treatment-related changes rather than tumor recurrence (patient trajectory, treatment plan, and DVH are shown in Fig. 4).
Figure 4.
Case of radiation necrosis following Cs-131 brachytherapy. (A, B) Initial disease (December 2021) and postoperative magnetic resonance images after gross total resection (January 2022). (C, D) Recurrent disease (March 2023) and postoperative magnetic resonance image after repeat gross total resection (April 2023). (E) Cs-131 brachytherapy treatment plan demonstrating isodose distribution (30–150 Gy) surrounding the resection cavity. (F) Asymptomatic enhancement along the lateral ventricle (July 2023). (G) Further marginal enhancement concerning recurrence, but imaging favored radiation necrosis (December 2023). (H) Improvement in enhancement after 3 cycles of bevacizumab (April 2024).
Two patients demonstrated new enhancement within the resection cavity 1 month after Cs-131 implantation. In one case, subsequent ABTI at 2 months showed elevated perfusion consistent with a viable tumor (BT-RADS 3B), confirming glioma recurrence. In the second case, early ABTI favored the treatment effect, but progression was confirmed 7 months postprocedure when serial MRI demonstrated enlarging, enhancing tissue. A third patient exhibited stable imaging for 9 months, followed by progressive enhancement and enlargement of the treated cavity, with new distant fluid-attenuated inversion recovery and enhancing foci at 10 months, confirming local and distant progression.
Acute toxicities were limited to grade 1 fatigue (n = 6, 40%), headache (n = 6, 40%), and nausea (n = 4, 26.7%). One of 15 patients (7%) developed symptomatic grade 3 radionecrosis at 3 months after Cs-131 implantation, which improved symptomatically with bevacizumab and is presumed to be likely related to Cs-131 implantation.
Discussion
Despite maximal multimodal therapy, GBM recurrence is nearly universal, with LF remaining the predominant pattern. This creates a challenging scenario: the team must treat a previously irradiated and resected site, both of which limit local options. In our cohort, initial recurrence was local in 93%, underscoring the predominantly local nature of GBM at progression. This aligns with prior reports; for example, Gebhardt et al15 found that 81% of recurrences occurred within the high-dose field. Reirradiation with EBRT shows similar patterns. Minniti et al16 reported that 50% to 60% of failures were local within the first year after reirradiation, and in a large series of IDH wild-type GBM (median OS, 9.6 months; median PFS, 5.3 months), 75% of relapses were in-field, highlighting the limits of EBRT for durable local control.17
Among patients with surgically accessible recurrence, re-resection is frequently pursued; however, durable local control is limited.18 In a retrospective series of 64 patients who underwent re-resection, the median local control time was 6.0 months, and the 1-year local control rate was 29.4%.19 The median PFS after surgery was 6.8 months, and the 1-year PFS rate was 27.2%, despite GTR in 75% of cases. Similarly, another cohort of 78 patients reported a 6-month PFS of 53% following reoperation, although many required multiple resections, and progression remained common.20 These data highlight the need for adjunctive local therapies. In our cohort, which received intraoperative Cs-131 collagen tile brachytherapy following resection, the 6- and 12-month PFS rates were 71.8% and 55.4%, respectively, suggesting that focal dose intensification with Cs-131 may help prolong disease control in appropriately selected patients, particularly those achieving GTR with adequate cavity coverage.
The extent of re-resection prior to Cs-131 implantation is likely critical for local control. In our series, GTR was achieved in 13 of 15 patients (87%) and STR in 2 patients (13%), as confirmed by immediate postoperative MRI (24–48 hours), which also informed postimplant dosimetry. Given the small number of STR cases, we did not perform subgroup analyses. Because Cs-131 is prescribed to 60 Gy at a depth of 5 mm, residual macroscopic disease beyond this margin is unlikely to be adequately covered, limiting the therapeutic benefit of brachytherapy. These observations underscore the importance of achieving GTR when safely feasible.
Only 3 patients experienced LF (crude local-failure incidence 20%). In the prospective study by Gessler et al,21 Cs-131 achieved local control rates of 86% at 6 months and 81% at 12 months, supporting reproducibility across institutions. Our 1-year cumulative incidence of LF after implantation was 33.3% (accounting for the competing risk of death). Several series evaluating EBRT reirradiation after surgery provide relevant benchmarks. In the randomized NRG Oncology/RTOG 1205 trial, concurrent bevacizumab plus 35 Gy in 10 fractions improved the median PFS to 7.1 months versus 3.8 months with bevacizumab alone, without an OS benefit (~10 months in both arms).9 Large retrospective EBRT series using intensity modulated RT or stereotactic radiosurgery report a median PFS of 5 to 8 months, 1-year local control of ~40% to 60%, and radionecrosis rates of 10% to 25%.16,17,22 Relative to these outcomes, our 6- and 12-month PFS rates (71.8% and 55.4%, respectively) with low radionecrosis incidence (7%) suggest that intraoperative Cs-131 can achieve at least comparable disease control.
Toxicity was acceptable. One of 15 patients (7%) developed grade 3 radionecrosis managed nonsurgically with bevacizumab; no reoperations were required for Cs-131-related toxicity. This compares favorably with earlier loose-seed I-125 approaches, which reported symptomatic radionecrosis rates of up to ~23% and frequent surgical reintervention.23,24 Our findings also align with those of Gessler et al,21 who observed no confirmed radiation necrosis or toxicity-related reoperation among 22 Cs-131-treated patients; enhancement within the treatment field was typically attributed to tumor progression rather than to treatment effect.
Distant failure remains a major challenge, reflecting the diffuse biology of GBM. In our cohort, 6 of 15 patients (40%) relapsed distantly, which may partly reflect limited postoperative systemic therapy use (4/15, 26.6%). By contrast, Gessler et al21 administered lomustine to 91% of patients and reserved bevacizumab for symptom progression, achieving longer PFS (8.1 months) and OS (24.4 months). Other series similarly suggest that effective systemic therapy can reduce out-of-field failure.8,22,23 These observations support integrating Cs-131 into active systemic regimens to optimize both local and distant control.
Finally, 3 of 15 patients (20%) received Cs-131 at second recurrence—a particularly challenging scenario—yet local control was still achieved, suggesting feasibility, even in multiply recurrent disease when maximal safe resection is possible.
Limitations
This is a highly selected cohort: radiographic progression was predominantly enhancing disease ≥6 months after prior RT, and all patients were surgical candidates with intent for GTR—features associated with a better prognosis and favorable anatomy. These selection factors likely contributed to outcomes that exceed those of unselected reirradiation cohorts and should be considered when interpreting the apparent benefit of Cs-131 brachytherapy.
Conclusions
Intraoperative Cs-131 tile brachytherapy is a feasible and well-tolerated salvage strategy for recurrent GBM, offering favorable local control with low toxicity. Distant failures remain a challenge, supporting the integration of effective systemic therapy regimens when available. These findings support further evaluation of Cs-131 in combination with systemic agents and highlight the importance of patient selection based on tumor biology and the timing of recurrence.
Acknowledgments
Chirag B. Patel is a McNair Scholar supported by the McNair Medical Institute at The Robert and Janice McNair Foundation. Ory Haisraely was responsible for statistical analysis.
Sources of support:
Supported in part by Cancer Center Support (Core) Grant P30 CA016672 from the National Cancer Institute, National Institutes of Health, to The University of Texas MD Anderson Cancer Center (PI: PW Pisters).
Footnotes
Disclosures
Thomas H. Beckham has received consulting fees from GT Medical Technologies. Rajat Kudchadker, Jeffrey S. Weinberg, and Thomas H. Beckham have received travel support from GT Medical Technologies.
All data supporting the findings of this study are available within the paper and its supplementary information.
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