Local control and survival outcomes with stereotactic radiotherapy in cystic brain metastases: a systematic review

Introduction

Brain metastases affect up to 40% of patients with cancer and pose significant challenges in quality of life and survival (1). Although newer central nervous system (CNS)-penetrant systemic therapies are being established with long-term data, intracranial disease control still relies heavily on local treatment modalities (2,3).

Radiation therapy (RT) remains an integral part of brain metastases management, offering both palliation of symptoms and local control (LC) of the intracranial disease; stereotactic radiosurgery or radiotherapy (SRS/SRT) is the standard RT modality for patients with good performance status (4,5). Traditional whole-brain radiation therapy (WBRT) is being replaced by SRS in most patients. The elimination of WBRT, as shown in the N0574 Alliance trial, resulted in relatively lower intracranial disease control but similar overall survival (OS) (P=0.92), with significantly better neurocognitive function (P<0.001) and quality of life (P=0.001) (6). Salvage options, including further SRS to newly arising lesions, are effective in addressing intracranial progression and may have contributed to equivalent survival. In the postoperative setting, SRS also offers LC benefits, with 12-month freedom from recurrence reported in the MD Anderson trial to be 72% in the SRS group compared to 43% in the observation group [hazard ratio (HR) 0.46, P=0.015] (7). An ongoing trend in the preoperative setting documented encouraging early results comparable to or even better than historical controls, with a 6-month LC reported by Agrawal et al. to be as high as 100%, with the potential advantage of lesser incidence of leptomeningeal disease (8,9).

Despite the evidence of SRS in managing solid brain metastases, its effectiveness in treating cystic brain metastases (CBM) remains unclear. One retrospective study involving 290 breast cancer patients with brain metastases observed that cystic lesions have poorer response and inferior prognosis, although this was confounded by the use of WBRT and did not isolate the impact of SRS/SRT (10). Conversely, a retrospective study involving 356 patients with brain metastases directly compared cystic versus solid lesions, showing comparable outcomes (11). However, pooled outcome data specific to SRS/SRT in CBM remain limited. A focused synthesis of available literature is warranted to clarify clinical outcomes and inform treatment strategies for this subgroup of patients. This systematic review aims to consolidate the existing evidence on the oncologic outcomes of SRS in CBM. We present this article in accordance with the PRISMA reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-34/rc) (12).

Methods

The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) prior to the conduct of systematic search and data collection (PROSPERO Registry Number: CRD42024563456).

Search strategy and eligibility

A systematic literature search was completed on July 11, 2024, using PubMed, Scopus, ScienceDirect, ASCOpubs, EBSCOhost, and the Cochrane Library. A peer-reviewed PubMed search strategy was developed and adapted to the syntax and subject headings of the other databases (Table S1). The main search terms used were “radiotherapy”, “radiosurgery”, “brain metastases”, and “cystic”.

Studies were selected according to the following eligibility criteria:

• Clinical trials, prospective/retrospective cohorts, and case-control studies were included. Studies that are available only as an abstract or a conference proceeding were excluded; case series, case reports, pre-clinical studies, and studies that were available only as an abstract or a conference proceeding were excluded.
• Studies that included patients with both solitary and multiple CBM treated with SRS/SRT were eligible.
• Studies with co-interventions such as surgery, cyst aspiration, or systemic therapy were included to reflect real-world management patterns, while acknowledging the possibility of introducing confounders in assessing the efficacy of SRS/SRT.
• Studies with data on any of the following outcomes that could be derived for the above population and interventions were eligible: LC and OS.
• Studies reported in English language were included.
• The systematic search was complemented by bibliographic scanning of relevant reviews and hand-searching of citing or cited articles through Google Scholar.

Study abstraction and assessment

Literature search results were imported into a citation manager software. Duplicates were identified and removed. The titles and abstracts were screened. The full text for all relevant titles were retrieved and reviewed to confirm eligibility.

A Risk of Bias Assessment Template was used based on the Critical Appraisal Skills Program (CASP) Randomized Controlled Trial and Cohort Study Standard Checklists to assess quality and risk of bias for each study.

The quality of evidence for all outcomes will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) working group methodology, encompassing the following domains: risk of bias, consistency, directness, precision, and publication bias.

Assessment for eligibility, risk of bias, data extraction, and quality of evidence assessment were performed independently by two reviewers (C.J.E.J. and W.R.B.). Any disagreement between the reviewers in the study selection and data abstraction processes were resolved first by discussion and, if necessary, by adjudication by a third reviewer, or by an arbiter (T.T.S.O.).

Data collection and statistical analysis

The following data were extracted: study title, study design, study country, study size (i.e., number of patients and/or number of CBM), patient and disease characteristics (i.e., age, performance status, tumor volume, and primary cancer histology), treatment characteristics (i.e., RT modality, RT dose, systemic therapy, cyst aspiration, and pre-RT surgery), duration of follow-up, and outcomes (i.e., LC and OS).

The following operational definitions were used: cystic brain metastasis is defined as having a hypointense center on post-contrast T1-weighted magnetic resonance imaging with associated ring enhancement; LC is defined as tumor decreasing or remaining stable in size or volume after treatment.

When necessary, frequency, means, proportions, measures of dispersion, and/or ratios were derived from reported data or estimated from figures (such as Kaplan-Meier curves).

Baseline patient and disease characteristics and treatment outcomes in the included studies were summarized with descriptive statistics. The LC and OS rates were pooled through proportions meta-analysis using random-effects models, using RStudio version 2025.5.1.513 (Posit Software, PBC, Boston, MA, USA). Heterogeneity of effect measures between the studies were assessed using the I² statistic. Sensitivity analysis for intact CBM excluding postoperative SRS/SRT cohorts was done to explore the source of heterogeneity. Meta-regression analysis ideally should be carried out to examine the effects of other variables but was not done due to the paucity of studies (n<10 eligible studies per analysis of interest). A P value of <0.05 will be considered statistically significant in all analyses.

Results

Search results and study characteristics

The systematic search initially identified 199 studies. After removing 47 duplicates, 152 studies were left for abstract screening. Of these, 140 were excluded for the following reasons: 77 did not involve brain metastases, 19 were case reports, 14 did not involve RT, 10 were reported in non-English languages, 6 reported different outcomes of interest, 4 were abstracts or conference papers, 4 were review articles, 2 were inaccessible via DOI, 2 were case series, 1 reported only dosimetry analysis, and 1 was an editorial. Following full-text assessment of the remaining 12 studies, 1 study was excluded as it did not involve RT, and 2 studies were through hand searching.

A total of 13 studies were included for the synthesis, all of which were retrospective cohort studies. Five studies reported 1-year LC rates (13-17), and six studies reported 1-year OS rates (11,16,18-21); these studies were included in the meta-analysis (Figure 1).

Figure 1 PRISMA flow diagram. LC, local control; OS, overall survival.

Critical appraisal

All included studies had clearly defined objectives and employed valid SRS/SRT methodologies. Risk of bias assessment revealed uncertain-risk and high-risk with regard to confounding factors and precision of estimate, primarily due to the retrospective nature of the included studies, small sample size, and lack of comparator and control groups. Several studies had uncertain-risk for selection bias and measurement bias for both exposure and outcomes bias (Table S2). Nonetheless, the studies generally addressed the research question, applied similar interventions, and provided outcome data empirically congruent and relevant to the population of interest.

Study characteristics

The characteristics of the included studies on SRS/SRT in CBM are summarized in Table 1. All thirteen studies (n=1,792) were retrospective cohort studies published between 2008 and 2024. Tumor volumes varied widely, with median volumes ranging from 1.5 to 35.3 cm³ pre-aspiration. The most common primary histology was lung cancer across the studies. Most studies utilized Gamma Knife^® (GK) SRS, while three studies used linear accelerator (LINAC) SRS, and one study used Cyberknife^® (CK) SRS. The SRS doses used were similar across studies, generally ranging between 16 and 22 Gy. Two studies used SRT: one employed 21.1 Gy in 3 fractions (16), while another study used 25–30 Gy in 5 fractions (14). Systemic therapy use was mentioned in four studies, though specifics were not provided (13,16,22,23). Eight studies (n=365) performed cyst aspiration prior to the initiation of SRS/SRT (17-24). Three studies (n=210) included excision of CBM prior to SRS/SRT (13,16,22).

LC of CBM with SRS/SRT

The analysis of 1-year LC outcomes included five studies, with data from 359 cases of brain metastases (13-17). The pooled estimate of 1-year LC was 71% [95% confidence interval (CI): 60–81%], with moderate to high heterogeneity (I²=51.0%, P=0.09) (Figure 2). A sensitivity analysis, excluding postoperative SRS/SRT cohorts (13,16), focused on intact CBM (n=253), and yielded a similar 1-year LC pooled estimate of 72% (95% CI: 45–89%), indicating consistency of the result, but with persistently high heterogeneity (I²=66.7%, P=0.05) (Figure S1). Meta-regression analysis was not performed due to the limited number of studies.

Figure 2 Pooled 1-year local control with SRS/SRT in CBM. CBM, cystic brain metastases; CI, confidence interval; LC, local control; SRS/SRT, stereotactic radiosurgery or radiotherapy.

OS of CBM with SRS/SRT

Six studies, comprising 505 cases of brain metastases and reporting 1-year OS outcomes, were included in the analysis (11,16,18-21). The pooled estimate for 1-year OS was 55% (95% CI: 37–72%), with high heterogeneity (I²=72.9%, P<0.01) (Figure 3). Sensitivity analysis for intact CBM (n=483), excluding postoperative SRS/SRT cohorts (16), yielded a comparable 1-year OS pooled estimate of 53% (95% CI: 31–74%), but retained high heterogeneity (I²=78.3%, P<0.01) (Figure S2). Due to the limited number of studies, meta-regression analysis was not performed.

Figure 3 Pooled 1-year overall survival with SRS/SRT in CBM. CBM, cystic brain metastases; CI, confidence interval; OS, overall survival; SRS/SRT, stereotactic radiosurgery or radiotherapy.

Postoperative SRS/SRT cohorts

Three series reported outcomes for patients who underwent surgical excision of CBM followed by post-operative SRS/SRT (13,16,22). Amidon et al. included a mixed cohort of 54 patients (22.2% had surgery prior to SRS/SRT) treated with GK SRS to a median dose of 20 Gy (13). Evin et al. analyzed a postoperative cohort of 22 patients treated with LINAC-based SRS to 7.7 Gy × 3 fractions (16). Press et al. evaluated 134 patients who underwent surgical resection followed by either GK or LINAC-based SRS, with a median dose of 20.5 Gy for cystic lesions; this study specifically highlighted the association of leptomeningeal dissemination (LMD) with CBM (HR 2.34, P=0.13) (22). Across these postoperative series, the reported LC ranged from 61% to 76%, with a local recurrence rate of 13.6%.

Cyst aspiration prior to SRS/SRT

Eight studies reported outcomes with pre-SRS/SRT cyst aspiration (17-24). Cyst aspiration consistently reduced CBM volume by approximately 49–81% across series. For example, Park et al. reported substantial downsizing in 24 patients who underwent cyst aspiration, from pre-aspiration volume of 23.2 to 4.3 cm³ post-aspiration (24). Sadik et al. likewise documented downsizing from 35.3 to 14.2 cm³ in 83.6% of the cohort who underwent cyst aspiration (23). Across all cyst aspiration cohorts, prescription doses ranged from 13–25 Gy, with reported LC rates between 58.6% and 91.7%.

Discussion

In this review, the proportional meta-analysis of CBM treated with SRS/SRT-based treatment approach demonstrated a 1-year LC rate of 71%. Sensitivity analysis for intact brain metastases, excluding postoperative cohorts, yielded similar results, with a 1-year LC rate of 72%, showing directionally consistent outcomes despite moderate to high heterogeneity, though results should be interpreted cautiously. These LC outcomes are comparable to those reported in landmark studies of SRS for brain metastases. For example, the N0574 Alliance trial involving 213 patients with intact brain metastases found that the SRS alone arm had a 1-year LC rate of 72.8%—nearly identical to the findings in this meta-analysis (6). This trial also demonstrated less cognitive decline in the SRS alone group compared to patients treated with SRS and WBRT [difference, −28.2% (90% CI: −41.9% to −14.4%); P<0.001], without compromising survival outcomes [HR, 1.02 (95% CI: 0.75–1.38); P=0.92], establishing the role of SRS alone in brain metastases. Additionally, an individual patient data meta-analysis of three randomized controlled trials comparing SRS alone to SRS with WBRT reported a 27% local failure rate with SRS alone, again consistent with our findings (25). The trial also showed that the survival outcomes favored the SRS alone group in patients ≤50 years of age (P=0.04). These results suggest that SRS/SRT-based treatment approach may achieve favorable LC rates even in the context of CBM.

An important consideration in the treatment of CBM is the role of surgical excision prior to SRS/SRT. Surgical resection followed by SRS is a well-established strategy in larger brain metastases causing significant mass effect and neurological symptoms. The MD Anderson group conducted a phase III randomized controlled trial of 132 patients with resected brain metastases, establishing the role of SRS to the postoperative cavity in significantly improving LC outcomes, with a 12-month freedom from local recurrence rate of 72% versus 43% in the observation arm (HR 0.46, P=0.015) (7). Likewise, the N107C/CEC.3 trial involving 194 patients with resected brain metastases demonstrated that postoperative SRS achieved a 12-month LC rate of 64.7%, with the primary advantage of a significantly lower cognitive decline compared to WBRT [difference, –33.6% (95% CI: –45.3 to –21.8); P<0.00031] (26). In this review, three studies involved surgical excision of CBM prior to SRS/SRT, with LC rates ranging from 61% to 76% (13,16,22). These results are consistent with contemporary data, suggesting that SRS/SRT-based treatment approach may be effective as a postoperative treatment for CBM. Importantly, the increased risk of LMD observed in cystic lesions undergoing resection followed by SRS/SRT, as reported by Press et al. (22), highlights a potential concern and suggests the need for judicious patient selection to identify those most likely to benefit. Early reports on pre-operative SRS/SRT suggest a lower incidence of LMD (8,9), and further evidence is anticipated as ongoing studies mature.

Regarding OS, this review found a pooled 1-year OS estimate of 55%. Notably, this finding was consistent even after excluding postoperative cohorts (1-year OS 53%), suggesting similar survival outcomes regardless of whether patients undergo prior surgical resection. Relating this to randomized controlled trials, a Japanese trial by Aoyama et al. in 2006 comparing SRS plus WBRT versus SRS alone found no significant difference in OS outcomes between arms (P=0.42), with a 1-year actuarial survival rate of 28.4% in patients receiving SRS alone (27). The higher survival rates observed in this meta-analysis likely reflect the inclusion of patients treated in more recent years, where advances in systemic therapy could positively influence survival outcomes.

One key point of discussion in CBM management is the role of cyst aspiration prior to SRS/SRT. It is often performed to reduce the tumor volume and mitigate the effects of radiation dose inhomogeneity, thereby potentially enhancing SRS efficacy. This was a common intervention across several studies included in this review, with eight studies performing cyst aspiration before the initiation of SRS/SRT (17-24). This approach reduced tumor volume by as much as 81%, which could theoretically permit safer delivery of higher doses and may translate to improved LC and clinical outcomes. For instance, the study by Wang et al. that included CBM lesions with mean and median volumes of 6.87 and 3.073 cm³, respectively, demonstrated that combining stereotactic aspiration with GK SRS resulted in excellent outcomes, yielding comparable LC rates of 96.2% in cystic compared to 97% in solid brain metastases (11). In contrast, Brigell et al. did not perform pre-SRS aspiration in their study of CBM, where the mean lesion size was 14 mm for cystic versus 7 mm for solid lesions. Their results showed a numerically lower 1-year LC rate of 75% for cystic metastases, compared to 88% for solid metastases (14). This raises important questions regarding the necessity of cyst aspiration in all cases, suggesting that it may be more beneficial in cases where the cystic component significantly impacts treatment efficacy. The role of cyst aspiration in this context remains hypothesis-generating, warranting further investigation in prospective trials to identify the subset of patients who would benefit most from this procedure.

While the results of this systematic review provide valuable insights, the findings must be interpreted within the context of several limitations. Primarily, the retrospective nature of the included studies inherently introduces potential biases, such as selection bias, confounding bias, measurement bias, and analysis or attrition bias. Many patients received additional co-interventions, including prior WBRT, cyst aspiration, and systemic therapies, which may have contributed to LC and survival outcomes. Therefore, the observed efficacy should be attributed to the entire treatment approach rather than to SRS/SRT alone. Furthermore, this study synthesized data using single-arm proportional meta-analysis, as the included literature lacked consistent comparator groups. This precluded direct comparative analyses, and as such, causality or relative treatment efficacy cannot be inferred from the results. The findings are therefore best interpreted as descriptive and hypothesis-generating. Many studies had small sample sizes and employed varied methodologies, which may have contributed to the heterogeneity in the pooled analysis. However, in proportional meta-analyses, high statistical heterogeneity (I²) is frequently observed due to the bounded distribution of proportions and inherent variability across single-arm studies, where such heterogeneity does not necessarily indicate inconsistency or unreliability of results (28). High I² in this context should be interpreted with caution, as pooled proportions can still offer meaningful insights, especially when interpreted alongside clinical and biological plausibility. Additionally, the absence of meta-regression analysis due to the limited number of studies precludes detailed examination of potential confounding factors that might influence LC and survival outcomes and is worth exploring in future prospective and comparative studies. Moreover, the lack of comprehensive data on systemic therapy use in the included studies limits our understanding of its role and interaction with SRS/SRT outcomes, as newer systemic therapeutic agents could have a profound impact on survival and disease control in patients with CBM.

Despite these limitations, this review offers evidence suggesting efficacy of SRS/SRT in the treatment of CBM. The results suggest that SRS/SRT-based treatment approach appears to achieve favorable LC and survival outcomes, even in the context of cystic lesions that may add complexity to RT delivery. While the quality of included studies is limited, clinical recommendations are framed as suggestive based on the observed trends in LC and extrapolation from broader evidence supporting SRS/SRT in brain metastases (Table S3). The nuanced discussion on the role of cyst aspiration or surgical excision emphasizes the need for individualized treatment approaches, with decisions tailored to specific patient and tumor characteristics who may benefit the most. Given the limitations in this study, there is a need for future prospective trials with higher-quality comparative evidence to further elucidate the optimal management strategies for CBM. Nonetheless, the findings of this review suggest that SRS/SRT-based treatment approach remains a viable treatment option for patients with CBM.

Conclusions

The findings of this study suggest that SRS/SRT-based treatment approach appears to achieve favorable LC and survival outcomes in the management of CBM, despite inherent limitations from retrospective data. The role of cyst aspiration and/or surgical excision remains patient-specific and requires further investigation.

As the neuro-oncology treatment landscape advances, future prospective trials are warranted to further validate the efficacy of SRS/SRT in this population and to standardize treatment protocols for CBM.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-34/rc

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-34/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. As this study did not not involve human subjects nor identifiable human data, it was deemed exempt from review by the University of Santo Tomas Hospital - Research Ethics Committee (USTH-REC Protocol Reference No.: REC-2025-01-009-TR-EX).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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