Brachytherapy in Brain Metastasis Treatment: A Scoping Review of Advances in Techniques and Clinical Outcomes

Simple Summary Brain metastases are cancerous growths that spread to the brain from other parts of the body, causing severe health problems. This review explores brachytherapy, a treatment where radioactive sources are placed directly into or near tumors or tumor beds to deliver targeted radiation, with the goal of minimizing damage to healthy brain tissue. Here, we aim to summarize the history and recent advancements of brachytherapy techniques and clinical outcomes in brain metastasis treatment, showcasing its benefits and limitations and providing a clearer understanding of how brachytherapy may potentially improve quality of life for patients with brain metastases. Abstract Brain metastases pose a significant therapeutic challenge in the field of oncology, necessitating treatments that effectively control disease progression while preserving neurological and cognitive functions. Among various interventions, brachytherapy, which involves the direct placement of radioactive sources into or near tumors or into the resected cavity, can play an important role in treatment. Current literature describes brachytherapy’s capacity to deliver targeted, high-dose radiation while minimizing damage to adjacent healthy tissues—a crucial consideration in the choice of treatment modality. Furthermore, advancements in implantation techniques as well as in the development of different isotopes have expanded its efficacy and safety profile. This review delineates the contemporary applications of brachytherapy in managing brain metastases, examining its advantages, constraints, and associated clinical outcomes, and provides a comprehensive understanding of advances in the use of brachytherapy for brain metastasis treatment, with implications for improved patient outcomes and enhanced quality of life.


Introduction
Brain metastases are secondary tumors that have spread to the brain from primary cancer sites elsewhere in the body.They are a significant cause of morbidity and mortality in cancer patients and represent one of the most common neurological complications associated with systemic disease [1].Whole-brain radiation therapy (WBRT) was once the standard radiotherapeutic approach to brain metastases (BMs) [2].While effective at disease control, WBRT is also prone to iatrogenic injury of at-risk healthy organs in the brain like the hippocampus, leading to post-irradiation cognitive impairment and worsened quality of life.With the intent to minimize the collateral effects of radiation on healthy brain tissue, new radiation protocols have given rise to more targeted techniques such as stereotactic radiosurgery (SRS) and hippocampal avoidance WBRT [3,4].Importantly, SRS is now the standard of care in most cases of BM [5].
Brachytherapy involves the placement of radioactive sources directly into, or adjacent to tumor sites or resection cavities.This method allows for highly localized radiation to be administered to tumor tissues or to eradicate microscopic disease post-tumor resection, while sparing surrounding healthy structures [6].Primarily utilized for conditions like prostate and cervical cancers, its applications have extended to include tumors of the central nervous system like BM [7].The expansion of its applications is supported by technological improvements, a better understanding of tumor radiobiology, and a need for therapies with reduced long-term side effects.
This literature review will explore current applications of brachytherapy in the treatment of brain metastases, showcasing its advantages, limitations, and clinical outcomes.We would like to emphasize that this review is not intended as a clinical guideline or a definitive clinical reference.Instead, it is meant to provide a comprehensive overview of the current state of brachytherapy used in the treatment of BM, summarizing recent advancements and clinical outcomes.This review aims to inform both researchers and clinicians about the evolving landscape of brachytherapy and its potential future applications to brain metastases.

Methods
Adhering to PRISMA Extension for Scoping Reviews guidelines (PRISMA-ScR), a comprehensive literature search was conducted using two online databases: PubMed/MEDLINE and Embase.ClinicalTrials.govwas similarly queried to determine the number of ongoing brachytherapy trials for BM treatment.This review was not prospectively registered.
The following search was performed: ("brachytherapy") AND ("brain metastasis" OR "brain metastases").Titles and abstracts of the resulting articles were screened by one reviewer (SL).English language in vivo prospective studies, retrospective studies, randomized controlled trials, and case series/case studies with mention of brachytherapy and BM in the title and/or abstract were further scrutinized for eligibility.Non-English language studies, ex vivo studies, in vitro studies, feasibility studies, planning/modeling studies, quality control studies, pediatric studies, editorials, commentaries, and abstractonly articles were excluded.The abstracts of screened studies were further analyzed and included in the final analysis if they reported brachytherapy techniques, isotopes, and patient outcomes.The final search was conducted on 19 July 2023.

Results
Our initial search yielded 1813 articles.Following the removal of duplicates, 1359 articles were screened.Of these, 65 articles were further assessed for eligibility (Figure 1).Ultimately, 34 studies met inclusion criteria reporting on brachytherapy techniques in BM treatment, the isotopes utilized, and patient outcomes (Tables 1 and 2).In addition, we identified three registered national clinical trials examining the use of Cs-131 brachytherapy for BM treatment (Table 3).
x FOR PEER REVIEW 3 of 22 The number of patients with BM treated with brachytherapy ranged from 1 to 95 across studies, with a total of 1135 patients.Twenty-five (73.5%) studies assessed brachytherapy use in newly diagnosed or untreated BM (Table 1), seven (20.6%) studies evaluated recurrent BM (Table 2), and two (5.9%) evaluated both newly diagnosed and recurrent.Twenty-one studies reported on single BM-both newly diagnosed and recurrentand eighteen studies assessed brachytherapy use in single newly diagnosed BM.Iodine-125 (I-125) seeds were utilized as the radioactive source in 14 studies, I-125 GliaSite in 1 study, Cesium-131 (Cs-131) seeds in 13 studies, Cs-131 GammaTile in 4 studies, and both I-125 and Cs-131 seeds in 2 studies.The number of patients with BM treated with brachytherapy ranged from 1 to 95 across studies, with a total of 1135 patients.Twenty-five (73.5%) studies assessed brachytherapy use in newly diagnosed or untreated BM (Table 1), seven (20.6%) studies evaluated recurrent BM (Table 2), and two (5.9%) evaluated both newly diagnosed and recurrent.Twenty-one studies reported on single BM-both newly diagnosed and recurrent-and eighteen studies assessed brachytherapy use in single newly diagnosed BM.Iodine-125 (I-125) seeds were utilized as the radioactive source in 14 studies, I-125 GliaSite in 1 study, Cesium-131 (Cs-131) seeds in 13 studies, Cs-131 GammaTile in 4 studies, and both I-125 and Cs-131 seeds in 2 studies.

A. Radioactive Isotopes: Iodine-125
Of the 17 total studies assessing I-125 brachytherapy, 14 were retrospective cohort studies, 2 were prospective cohort studies, and 1 was a case report.Fourteen studies utilized I-125 seeds as the radioactive source, one utilized GliaSite, and two studies used both I-125 and Cs-131 seeds, treating a total of 792 patients with BM.
I-125 has an extensive history [41][42][43].In 1981, Gutin et al. placed both permanent and temporary radioactive sources made of I-125, gold-198, and iridium-192 directly into the tumors of 37 patients with recurrent primary or metastatic brain tumors [44].While all the isotopes were effective to some degree, I-125 in particular became favored for its low energy emissions [44].In 1989, Prados et al. published a retrospective study on the use of interstitial brachytherapy in the treatment of patients with single metastatic lesions to the brain.I-125 radioactive sources were placed directly into the lesion.Ten out of fourteen patients survived for over one year, eight showed stabilization in neurological function, and six showed improvement on follow-up imaging [45].
The largest studies evaluating the efficacy and safety of I-125 brachytherapy in the treatment of BMs were conducted following surgical resection and permanent I-125 seed implantation to treat patients with newly diagnosed BM [19].These studies revealed high local control rates and median survival times with low incidences of radiation necrosis (RN).In one study, the average radiation dose delivered was 150 Gy with a seed activity ranging from 4.04 to 40.38 mCi.The authors reported a 93% local control rate and a median overall survival of 14 months.All patients experienced stable or improved Karnofsky performance status (KPS) scores post-treatment and the reported RN rate was 6% [19].
In a retrospective study of 219 patients with single, newly diagnosed BMs who were either treated with SRS (n = 142) or permanent interstitial I-125 brachytherapy, Ruge, Kocher et al. reported a local control rate of 94.6% and a median overall survival of 8 months in patients treated with brachytherapy [24].In another 2011 study, Ruge, Suchorska et al. retrospectively reviewed 90 patients with single BMs who were treated with stereotactic I-125 brachytherapy.The cumulative surface dose to the BMs was 50 Gy.They found that median overall survival was 8.5 months, and the 1-year local control rate was 94.6% [25].Ostertag et al. evaluated 93 patients who were treated for single BMs with interstitial I-125 brachytherapy with a reference tumor dose of 60 Gy.In patients with newly diagnosed BM treated with I-125 brachytherapy only, median overall survival was 15 months.In patients with previously treated BMs, median overall survival was 6 months.79% of patients had a stable or improved KPS score at three months.No patients developed RN requiring surgical intervention [18].
While many studies evaluated permanent forms of I-125 brachytherapy, temporary forms, such as that delivered by the GliaSite radiation therapy system (Figure 2), similarly represented a unique approach to treating BM following surgical resection.Though no longer in use, GliaSite was an FDA-approved balloon catheter device that was placed in the resection cavity immediately after tumor removal.After surgical placement, the balloon is filled with an aqueous form of a radioactive isotope, typically I-125, which delivers a high dose of radiation to the tumor bed while sparing the surrounding normal brain tissue [46].The aqueous form of the isotope provides a conformal dose distribution to the resection cavity, allowing for controlled radiation delivery.The treatment duration with GliaSite typically ranges from a few days to a week, after which the radioactive solution is withdrawn, and the balloon is removed [47].Reportedly, GliaSite therapy post-resection was able to achieve local control rates comparable to those achieved with WBRT or SRS, but also exhibited a high rate of RN, with a 1-year actuarial incidence rate of 23% [22].Although I-125 brachytherapy was found to be effective in BM treatment with local control rates and median overall survival paralleling SRS and WBRT, particularly when coupled with surgical resection, the rates of RN were concerning [14,19].

B. Radioactive Isotopes: Cesium-131
Of the 19 total studies assessing Cs-131 brachytherapy, 9 were retrospective cohort studies, 2 were prospective cohort studies, 5 were phase I/II clinical trials, and 3 were case reports.Thirteen studies utilized Cs-131 seeds as the radioactive source, four utilized GammaTile, and two studies used both I-125 and Cs-131 seeds, treating a total of 466 patients with BM.
In a phase I/II clinical trial of 24 patients with BMs, Wernicke et al. implanted permanent intracavitary Cs-131 stranded seeds with a median seed activity of 3.82 mCi and a prescribed dose of 80 Gy 5 mm from the surface of the resection cavity.Local freedom from progression (FFP) was 100% and 1-year regional FFP was 93.8% due to one patient experiencing leptomeningeal spread.Median overall survival was 9.9 months and 1-year overall survival was 50%.They reported no instances of RN [28].Another study described 13 patients with previously irradiated BMs who were treated with Cs-131 stranded seeds with the same dose prescription as in the phase I/II study.Median seed activity was 2.25 mCi and median number of implanted seeds was 19.The 1-year local FFP was 83.3%, median overall survival was 7 months, and 1-year overall survival was 24.7%, with only one reported case of RN [39].
As salvage therapy for recurrent BMs, Cs-131 brachytherapy has shown efficacy, providing good local control with minimal toxicity.A prospective study of 20 patients who had undergone failed treatment of BMs with SRS were treated with resection and Cs-131 seeds embedded into the resection cavity.Two tumors recurred after 1.6 years followup, amounting to a 1-year incidence of progression rate of 8.4% [49].A similar study in patients with BMs that had previously been treated with either SRS or WBRT were treated for recurrence with embedded Cs-131 seeds demonstrated 83.3% 1-year local FFP and a median survival of 7 months [39].In this study, only one patient experienced RN.
It is important to note that post-surgical resection cavity shrinkage affects the distribution and effectiveness of brachytherapy.After surgical resection, the tumor cavity shrinks by a median percent volume of 30%, with larger resection cavities exhibiting greater shrinkage.This volume decrease occurs quickly, within 0-3 days post-resection [50].In the placement of radioactive seeds (Figure 3), post-resection cavity shrinkage brings the seeds closer together, and closer to healthy brain tissue, affecting dose strength and radiation homogeneity, possibly contributing to an increased RN risk [51,52].In a retrospective study that included patients from their phase I/II trial, Wernicke et al. observed significantly less cavity shrinkage in patients treated with Cs-131 versus SRS during the first-month post-resection [30].This reduced shrinkage after 1 month coincided with the absorption of 88% of the Cs-131 dose, potentially diminishing the RN risk by minimizing the decrease in inter-seed distance [30].

B. Radioactive Isotopes: Cesium-131
Of the 19 total studies assessing Cs-131 brachytherapy, 9 were retrospective cohort studies, 2 were prospective cohort studies, 5 were phase I/II clinical trials, and 3 were case reports.Thirteen studies utilized Cs-131 seeds as the radioactive source, four utilized GammaTile, and two studies used both I-125 and Cs-131 seeds, treating a total of 466 patients with BM.
In a phase I/II clinical trial of 24 patients with BMs, Wernicke et al. implanted permanent intracavitary Cs-131 stranded seeds with a median seed activity of 3.82 mCi and a prescribed dose of 80 Gy 5 mm from the surface of the resection cavity.Local freedom from progression (FFP) was 100% and 1-year regional FFP was 93.8% due to one patient experiencing leptomeningeal spread.Median overall survival was 9.9 months and 1-year overall survival was 50%.They reported no instances of RN [28].Another study described 13 patients with previously irradiated BMs who were treated with Cs-131 stranded seeds with the same dose prescription as in the phase I/II study.Median seed activity was 2.25 mCi and median number of implanted seeds was 19.The 1-year local FFP was 83.3%, median overall survival was 7 months, and 1-year overall survival was 24.7%, with only one reported case of RN [39].
As salvage therapy for recurrent BMs, Cs-131 brachytherapy has shown efficacy, providing good local control with minimal toxicity.A prospective study of 20 patients who had undergone failed treatment of BMs with SRS were treated with resection and Cs-131 seeds embedded into the resection cavity.Two tumors recurred after 1.6 years follow-up, amounting to a 1-year incidence of progression rate of 8.4% [49].A similar study in patients with BMs that had previously been treated with either SRS or WBRT were treated for recurrence with embedded Cs-131 seeds demonstrated 83.3% 1-year local FFP and a median survival of 7 months [39].In this study, only one patient experienced RN.
It is important to note that post-surgical resection cavity shrinkage affects the distribution and effectiveness of brachytherapy.After surgical resection, the tumor cavity shrinks by a median percent volume of 30%, with larger resection cavities exhibiting greater shrinkage.This volume decrease occurs quickly, within 0-3 days post-resection [50].In the placement of radioactive seeds (Figure 3), post-resection cavity shrinkage brings the seeds closer together, and closer to healthy brain tissue, affecting dose strength and radiation homogeneity, possibly contributing to an increased RN risk [51,52].In a retrospective study that included patients from their phase I/II trial, Wernicke et al. observed significantly less cavity shrinkage in patients treated with Cs-131 versus SRS during the first-month post-resection [30].This reduced shrinkage after 1 month coincided with the absorption of 88% of the Cs-131 dose, potentially diminishing the RN risk by minimizing the decrease in inter-seed distance [30].Dosimetric analyses seem to favor Cs-131 over I-125, revealing that Cs-131 exposed smaller mean volumes of brain tissue to radiation and delivered lower doses to equivalent clinical target volumes compared to I-125.Furthermore, Cs-131 demonstrated higher homogeneity and conformity indices, suggesting more uniform and accurate dose delivery [33].Additionally, since Cs-131 has a short half-life of 9.7 days and about 90% of the intended dose is absorbed within 1 month following Cs-131 placement, as opposed to 32% with I-125 placement, patients can commence adjuvant systemic therapy as soon as 1 month following resection and seed implantation [53].However, despite its potential in minimizing RN rates, Cs-131's relative novelty in BM treatment needs further study to establish long-term outcomes [54].New techniques like the FDA-approved GammaTile (GT Medical Technologies, Tempe, AZ, USA) have been formulated with the intent of mitigating dosing and safety concerns.In this formulation, radioactive seeds are encapsulated in titanium and embedded in a collagen carrier that can be placed in the tumor resection cavity (Figure 4) [37,55,56].Studies evaluating this technique are ongoing.Dosimetric analyses seem to favor Cs-131 over I-125, revealing that Cs-131 exposed smaller mean volumes of brain tissue to radiation and delivered lower doses to equivalent clinical target volumes compared to I-125.Furthermore, Cs-131 demonstrated higher homogeneity and conformity indices, suggesting more uniform and accurate dose delivery [33].Additionally, since Cs-131 has a short half-life of 9.7 days and about 90% of the intended dose is absorbed within 1 month following Cs-131 placement, as opposed to 32% with I-125 placement, patients can commence adjuvant systemic therapy as soon as 1 month following resection and seed implantation [53].However, despite its potential in minimizing RN rates, Cs-131's relative novelty in BM treatment needs further study to establish long-term outcomes [54].New techniques like the FDA-approved GammaTile (GT Medical Technologies, Tempe, AZ, USA) have been formulated with the intent of mitigating dosing and safety concerns.In this formulation, radioactive seeds are encapsulated in titanium and embedded in a collagen carrier that can be placed in the tumor resection cavity (Figure 4) [37,55,56].Studies evaluating this technique are ongoing.

C. Clinical Outcomes and Safety
The ability of brachytherapy to concentrate high radiation doses directly to the tumor site while preserving surrounding normal tissue has been associated with increased local control rates, particularly for patients with one or a few lesions.In their study of 72 patients with BM, Petr et al. reported local control rates that were directly comparable to the control rates seen in WBRT while sparing patients of the often-deleterious neurological consequences post-WBRT [19].In a retrospective study by Ruge et al. evaluating the efficacy of stereotactic I-125 brachytherapy in non-resected BM, the authors found rates of local control and median overall survival similar to SRS [24].In a study comparing postresection I-125 brachytherapy to external beam radiotherapy (EBRT) in BM treatment, Yang et al. found no significant difference in overall survival and progression-free survival between patients treated with EBRT and those treated with I-125 brachytherapy, with the latter group showing superior six-month progression-free survival [32].As an adjunctive therapy, brachytherapy complements surgical resection by targeting potential microscopic remnants to minimize tumor recurrence [21,29].
Brachytherapy has also shown favorable outcomes in the treatment of large, irregular BMs [54].In a 2016 retrospective study of 95 patients with BM treated with resection and I-125 permanent seed placement, Raleigh et al. observed crude local control rates as high as 90% and an RN rate of approximately 15% [21].The risk of RN was higher with lesions that had undergone previous treatment with SRS.They compared this to similar studies of patients with BM who underwent surgical resection plus WBRT and SRS plus WBRT, which reported local control rates of 86% [57] and 82-89% [58,59], respectively.Raleigh et al. concluded that surgical resection plus brachytherapy is comparable to the effectiveness of SRS or WBRT, and that the technique may actually be a better option than SRS in treating large tumors due to their observed local control rate of 90% even with the inclusion of

C. Clinical Outcomes and Safety
The ability of brachytherapy to concentrate high radiation doses directly to the tumor site while preserving surrounding normal tissue has been associated with increased local control rates, particularly for patients with one or a few lesions.In their study of 72 patients with BM, Petr et al. reported local control rates that were directly comparable to the control rates seen in WBRT while sparing patients of the often-deleterious neurological consequences post-WBRT [19].In a retrospective study by Ruge et al. evaluating the efficacy of stereotactic I-125 brachytherapy in non-resected BM, the authors found rates of local control and median overall survival similar to SRS [24].In a study comparing post-resection I-125 brachytherapy to external beam radiotherapy (EBRT) in BM treatment, Yang et al. found no significant difference in overall survival and progression-free survival between patients treated with EBRT and those treated with I-125 brachytherapy, with the latter group showing superior six-month progression-free survival [32].As an adjunctive therapy, brachytherapy complements surgical resection by targeting potential microscopic remnants to minimize tumor recurrence [21,29].
Brachytherapy has also shown favorable outcomes in the treatment of large, irregular BMs [54].In a 2016 retrospective study of 95 patients with BM treated with resection and I-125 permanent seed placement, Raleigh et al. observed crude local control rates as high as 90% and an RN rate of approximately 15% [21].The risk of RN was higher with lesions that had undergone previous treatment with SRS.They compared this to similar studies of patients with BM who underwent surgical resection plus WBRT and SRS plus WBRT, which reported local control rates of 86% [57] and 82-89% [58,59], respectively.Raleigh et al. concluded that surgical resection plus brachytherapy is comparable to the effectiveness of SRS or WBRT, and that the technique may actually be a better option than SRS in treating large tumors due to their observed local control rate of 90% even with the inclusion of tumors that measured up to 76 cm 3 [21].Similarly, in a prospective trial of 42 patients with a total of 46 BMs, Wernicke et al. applied surgical resection and Cs-131 brachytherapy to patients with BMs measuring larger than 3 cm [29].The authors secured a local FFP rate of 100% and a 1-year regional FFP of 80%.They also reported no cases of RN.In comparison to other studies using SRS that reported local control rates of 94% [60] and 85.5% in tumors greater than 3 cm [61], brachytherapy appears comparable in maintaining local control [29].
Safety studies by Yondorf et al. indicate that standard protective measures are sufficient for handling Cs-131 seeds, ensuring safety for both medical personnel and patient contacts [62].The study concluded that the use of leaded aprons and gloves in the operating room is adequate to protect surgical staff.Individuals who interact with a treated patient should maintain a conservative distance of 35 cm for about 2 weeks postoperatively due to the relatively short half-life of Cs-131 [62].In a study that included radiation precautions following the implantation of I-125 sources, radiation levels were measured at a distance of 1 m from the patient.If the radiation levels were at or above 0.2 mR/h, patients were provided with lead shielding in the form of lead sheets inserted into special hats.The radioactive sources were left in place permanently, with their activity naturally decreasing over time.Radiation precautions were necessary for 2 to 4 months until the exposure levels at 1 m fell below 0.2 mR/h [14].

D. Knowledge Gaps and Future Directions
Clear criteria to identify which patients with BMs may benefit from brachytherapy, versus other treatment modalities, are lacking.Currently, the American Brachytherapy Society consensus statement on intraoperative radiation therapy recommends the use of brachytherapy for BM treatment for "appropriately selected patients" and suggests placing patients on institutional registries or enrolling them in prospective studies to allow for more data to compare brachytherapy to techniques like SRS [54].
Although brachytherapy is designed to spare healthy brain tissue, the long-term cognitive effects of this treatment modality in patients with BM are not understood.In a 2016 prospective trial involving 24 patients with BM treated with surgical resection and Cs-131 seed placement, Pham et al. found a statistically significant improvement in cognitive functioning (measured by Mini Mental Status Exam scores) and quality of life (measured by the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire) at both 4 and 6 months after brachytherapy treatment [20].While there are studies investigating cognitive function and quality of life measures in patients treated with Cs-131 brachytherapy, they are too few to draw strong correlations between brachytherapy treatment and improved mental status.
Standardization of newer technologies, seed placement strategies, and dose calculations are necessary.Wernicke et al. initially proposed placement strategies for Cs-131 seeds [30] and the advent of GammaTile has further increased standardization [63,64].However, more research and consensus guidelines could ensure consistent and optimized delivery of brachytherapy using various isotopes, particularly in the treatment of BMs.Additionally, more comparative studies evaluating the effectiveness, safety profile, and long-term outcomes associated with different isotopes are needed.
To date, there are two ongoing randomized controlled trials and one prospective cohort study analyzing the use of Cs-131 brachytherapy as an adjuvant therapy in the treatment of BMs (Table 3).Memorial Sloan Kettering Cancer Center is comparing the efficacy of surgical resection and Cs-131 versus surgical resection alone in maintaining freedom from local progression [65].Two trials sponsored by GT Medical Technologies, Inc. are exploring the use of GammaTile.The first is assessing surgical resection plus GammaTile placement in various brain neoplasms including BM, with a primary outcome of surgical bed recurrence-free survival (NCT04427384).The second is comparing the intraoperative placement of GammaTile versus SRS 3-4 weeks after BM resection, with a primary outcome of surgical bed recurrence-free survival up to two years post-RT [66].

Figure 1 .
Figure 1.PRISMA flowchart detailing the search strategy and exclusion criteria used in this review.

Figure 1 .
Figure 1.PRISMA flowchart detailing the search strategy and exclusion criteria used in this review.

Table 1 .
Overview of included published institutional series and case reports examining the use of brachytherapy in newly diagnosed BM treatment.

Table 2 .
Overview of included published institutional series and case reports examining the use of brachytherapy in recurrent BM treatment.

Table 3 .
Overview of ongoing clinical trials evaluating the use of brachytherapy in the treatment of BM.