Whole-brain radiotherapy with simultaneous integrated boost in treatment of patients with brain metastases: a systematic review and meta-analysis

Abstract

Purpose

Whole-brain radiotherapy (WBRT) remains the standard treatment for patients with multiple brain metastases (BM), who are not candidates for focal radiotherapy or surgery. A novel approach, WBRT with simultaneous integrated boost (WBRT-SIB), has shown promising results in improving intracranial control and survival compared with WBRT alone. However, no meta-analysis has comprehensively compared those strategies.

Methods/patients

A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Studies indexed up to September 1, 2025, were identified in PubMed, Embase, and Web of Science. Pooled hazard ratios (HRs) were calculated for overall survival (OS), intracranial progression-free survival (iPFS), and intracranial local PFS (iLPFS); odds ratios (ORs) were used for treatment-related adverse events (TRAEs).

Results

Thirty studies involving 2,033 patients were analyzed. WBRT-SIB significantly improved OS (HR = 0.7, 95%CI 0.5–0.96, p = 0.03), iPFS (HR = 0.67, 95%CI 0.47–0.96, p = 0.03), and iLPFS (HR = 0.55, 95%CI 0.4–0.79, p < 0.01) compared with WBRT alone. The benefit was mostly driven by patients with small-cell lung cancer (SCLC) (HR = 0.54, 95%CI 0.31–0.92, p = 0.025), while no significant effect was observed for other tumor types. Median OS after WBRT-SIB was 16.78 months, iPFS was 13.07 months, and the objective response rate was 69.5%. WBRT-SIB did not increase the risk of TRAEs, and the incidence of radiation necrosis was 5.05% (95%CI 1.19%-10.77%).

Conclusion

WBRT-SIB improves intracranial control and may improve overall survival compared with WBRT alone, mostly in patients with SCLC, achieving high response rates with acceptable safety. These results support further investigation of WBRT-SIB for patients with BM who are not candidates for stereotactic radiosurgery.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12094-026-04387-5.

Introduction

Brain metastases (BM) occur in approximately 10–40% of patients with advanced solid tumors, and their incidence is increasing as local and systemic therapies extend overall survival [1, 2]. Despite therapeutic progress, patients with BM—particularly those with multiple metastatic lesions—continue to face poor prognosis and limited quality of life, as they are often ineligible for surgical resection or stereotactic radiosurgery (SRS) [3]. For these individuals, standard whole-brain radiotherapy (WBRT) combined with systemic treatment frequently provides insufficient intracranial control, commonly due to local recurrence [2, 4, 5]. Moreover, WBRT is associated with well-documented neurocognitive decline, further constraining its benefit despite its widespread palliative use [6]. Improving intracranial tumor control remains a critical therapeutic goal, as it may directly influence overall survival and neurological function, particularly in patients with multiple brain metastases treated in the era of targeted and immune therapies. In clinical practice, WBRT remains the standard of care for patients with multiple brain metastases, whereas SRS is reserved for those with a limited number of lesions and good performance status [3–5]. These limitations highlight the need for more effective and better-tolerated BM-directed therapies.

Recent advances in radiation technology have led to the development of whole-brain radiotherapy with a simultaneous integrated boost (WBRT-SIB), which combines conventional WBRT with focal dose escalation to individual metastases using intensity-modulated radiotherapy (IMRT) [7–10]. This technique enables differential dosing within a single treatment plan, allowing higher doses to be delivered to visible lesions while sparing normal brain tissue. Compared with WBRT with a sequential boost, WBRT-SIB offers logistical and dosimetric advantages, including shorter overall treatment time and lower cumulative radiation dose to normal brain tissue [11].

Despite its technical and biological rationale, the clinical efficacy and safety of WBRT-SIB remain uncertain [7, 8]. Although several studies have evaluated WBRT-SIB, their findings remain inconsistent, and prospective data are scarce [8]. It is still unclear whether this approach provides superior intracranial control, prolongs overall survival, or maintains acceptable toxicity as compared to standard WBRT. These gaps in evidence underscore the need for a systematic synthesis of available data to clarify the therapeutic value of WBRT-SIB.

This meta-analysis aimed to determine whether WBRT-SIB improves intracranial control and overall survival compared to standard WBRT, while maintaining an acceptable safety profile in patients with brain metastases from extracranial malignancies. Subgroup analyses were performed to explore whether treatment outcomes differ by tumor histology, study region, or other study characteristics.

Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [12]. The study protocol was registered in the PROSPERO database (ID: CRD420251147084).

Data sources and literature searches

A systematic literature search was performed in the PubMed, MEDLINE, Embase, and Scopus databases from their inception until September 1, 2025. The search strategy combined controlled vocabulary and free-text terms for whole-brain radiotherapy and simultaneous integrated boost, using the following query: (“whole-brain radiotherapy” OR “WBRT” OR “Whole-brain external beam radiotherapy” OR “intensity-modulated radiotherapy”) AND (“simultaneous integrated boost” OR “SIB” OR “boost”) AND (“brain” OR “central nervous system”). The complete search strategy is provided in Supplementary Table 1. Only peer-reviewed articles in English were included. Two independent reviewers (D.W. and A.S.) performed manual searches to identify additional eligible studies.

Eligibility criteria and outcomes of interest

Eligible studies included patients with brain metastasis from extracranial solid tumors who received whole-brain radiotherapy with a simultaneous integrated boost, with at least 10 patients treated per study. Studies using a sequential boost or lacking specification of the boost technique were excluded. Only human studies were included.

Eligible reports had to provide at least one predefined endpoint: overall survival (OS), defined as the time from start of brain radiation therapy until death of any cause or last follow-up; progression-free survival (PFS) defined as the time between the start of brain radiation therapy and any progression in brain, death or last follow-up; or intracranial local progression-free survival (iLPFS) defined as the time between the start of brain radiation therapy and pre-existing intracranial lesions progression, death or last follow-up; all reported as hazard ratios (HRs) with 95% confidence intervals (CIs); grade ≥ 3 treatment-related adverse events (TRAEs); disease control rate (DCR), or objective response rate (ORR), according to RECIST 1.1 [13], reported as odds ratios (ORs); or the incidence of radiation necrosis among patients treated with WBRT-SIB. Outcomes were analyzed using pairwise or incidence meta-analysis as appropriate.

Study selection

Two investigators (A.S. and A.K.) independently screened all titles and abstracts according to the inclusion and exclusion criteria, followed by full-text assessment of eligible records. Discrepancies were resolved through discussion with a third reviewer (J.B.). The study selection process is illustrated in the PRISMA flow diagram (Fig. 1).

Fig. 1.

PRISMA flowchart

Data extraction and verification

Data were extracted independently by two investigators (A.S. and A.K.) using a predesigned spreadsheet to ensure standardized collection of study-level variables, including authorship, year of publication, study region, design, treatment regimen, radiotherapy dose, sample size, patient characteristics, treatment allocations, and reported effect estimates (hazard ratios and odds ratios) for each outcome. All extracted data were cross-checked by a third investigator (D.W.) for completeness and accuracy. Reference lists of all included studies were manually reviewed to identify additional relevant publications. Any discrepancies were resolved through discussion until a consensus was reached.

Quality assessment

The methodological quality of the included studies was independently assessed by two investigators (D.W. and A.S.), with discrepancies resolved by consensus with a third investigator (J.B.). The Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool was applied for nonrandomized studies (Supplementary Fig. 1) [14]. Quality assessment was limited to eight studies that reported key survival outcomes (OS, iPFS, or iLPFS), as a complete and meaningful appraisal could be performed only for these datasets.

Statistical analysis

Pooled hazard ratios and odds ratios with corresponding 95% confidence intervals were calculated for the respective outcomes. Between-study heterogeneity was assessed using the χ² test and quantified with the I² statistic, interpreted as low (25%−50%), moderate (50%−75%), or high (> 75%) [15]. Random-effects model (DerSimonian-Laird method) was applied to account for variability across populations and study designs [16]. For incidence data, the Freeman–Tukey double-arcsine transformation was used to stabilize the variance of proportions, particularly for outcomes with low incidence rates [17]. Pooled effects were tested using the Z statistic, with a two-sided p value < 0.05 considered statistically significant. For studies presenting Kaplan–Meier curves without directly reported HRs, effect estimates were derived using the method proposed by Tierney et al. [18]. Publication bias was evaluated visually through funnel plots and statistically with Egger’s regression test (p < 0.05 indicating potential asymmetry). Subgroup analyses were conducted by study region, primary tumor histology, and sample size (> 100 patients). All analyses were performed using STATA version 19.5 (StataCorp LP, College Station, Texas).

Results

Database searches yielded 2,857 records, of which 820 duplicates were removed. The remaining 2037 titles and abstracts were screened, resulting in the exclusion of 1,945 studies that did not meet the eligibility criteria. 92 articles underwent full text review, and 30 studies—including three identified by citation tracking—were finally included in the analysis (Fig. 1). The included studies comprised 22 retrospective and 8 prospective cohort studies, published between 2011 and 2025 [7, 8, 19–45]. In total, 2033 patients were analyzed, 1,282 of whom received WBRT-SIB. The key characteristics of the included studies are summarized in Table 1, and the results of the methodological quality assessment are presented in Supplementary Fig. 1.

Table 1.

Baseline characteristics of included studies

Study	Country	Study type	Median or mean age of patients with WBRT-SIB	Histology of extracranial cancer	Number of brain metastases	WBRT-SIB radiation dose (Gy)	Number of patients with WBRT-SIB	Number of patients with WBRT
Agolli 2024	Germany	Retrospective	63	Primary NSCLC	1–45	37.8–42	35
Bauman 2016	Canada	Prospective		Primary lung and breast cancer	1–42	60	87
Bii 2024	China	Retrospective	59.3	Primary NSCLC and SCLC		56–60	107
Christina 2025	India	Prospective		Primary lung and breast cancer	1–5	40	36
Dong 2018	China	Retrospective	60	Primary NSCLC	1–7	52.5	46
Dong 2023	China	Retrospective	60.1	NSCLC		45	42
Du 2021	China	Retrospective		NSCLC and SCLC	1–10	56.0–62.4	28	71
Kim 2016	South Korea	Retrospective	56	NSCLC	2–15	40–48	11
Kim 2019	South Korea	Retrospective	63	Primary NSCLC	1–12	35–55	42
Lebow 2020	USA	Retrospective		Primary NSCLC		37.5	32
Li 2024	China	Prospective	60.95	NSCLC and SCLC	1–10	44–52	40
Lin 2021	China	Retrospective		Primary NSCLC		45	37
Liu 2025	China	Retrospective		Primary NSCLC		40–50	69	69
Ma 2022	China	Retrospective	58	NSCLC		49.5–52.5	16
Popp 2020	Germany	Prospective/Retrospective	58.34	Primary NSCLC and breast cancer	4–16	30–51	62	62
Rades 2023	Germany	Retrospective		Primary NSCLC and breast cancer		42–45	103	275
Rodrigues 2011	Canada	Prospective		Primary NSCLC and renal cancer	1–3	35–60	48
Shan 2025	China	Retrospective		SCLC	1–34	18–60	56	71
Tao 2025	China	Retrospective	60	Primary NSCLC and breast cancer	1–7	54	32
Tiwari 2015	India	Retrospective	60.88	Primary NSCLC and breast cancer	1–3	36–40	17	12
Vargo 2011	USA	Retrospective	61	Primary NSCLC and breast cancer		40–48	40	32
Wang 2023	China	Retrospective	58	Primary NSCLC	4–15	48	56	56
Westover 2020	USA	Prospective	60	Primary NSCLC	1–8	40	49
Xu 2025	China	Retrospective	56.5	SCLC		35–50	23	19
Yang 2017	China	Prospective	60	Primary NSCLC	1–3	40	24
Yao 2024	China	Retrospective	63	SCLC		50–60	23	32
Zhang 2023	China	Retrospective	60	Primary NSCLC and SCLC		35–52.5	52	52
Zhang 2024	China	Retrospective	51	Breast cancer	1–9	36–50	27
Zhong 2020	USA	Prospective	55	Primary NSCLC and breast cancer	2–10	45–52.5	13
Zhou 2014	China	Retrospective	58	NSCLC	3	60	29

Overall survival

Eight studies involving 1067 patients were eligible for comparative analysis of overall survival between the WBRT-SIB and WBRT alone [7, 25, 31, 32, 34, 40, 42, 43]. High heterogeneity was observed between studies. WBRT-SIB was associated with significant improvement in OS compared with WBRT alone (HR = 0.7, 95% CI 0.5–0.96, p = 0.03; Fig. 2). The pooled median OS for patients treated with WBRT-SIB, including the data from single-arm studies, was 16.78 months (95% CI 13.74–20.49) [8, 10, 18, 21, 23, 25, 26, 28, 29, 31, 45]. Analysis of publication bias indicated a borderline, although nonsignificant risk of bias for overall survival analysis, as per Egger’s test p = 0.0519 (Supplementary Fig. 2).

Fig. 2.

Pooled analysis for overall survival

In subgroup analysis, the survival benefit remained significant in studies conducted in China (HR = 0.63, 95% CI 0.4–0.98, p = 0.04), in cohorts with small cell lung cancer (HR = 0.54, 95% CI 0.31–0.92, p = 0.025), and in smaller studies enrolling ≤ 100 patients (HR = 0.42, 95% CI 0.23–0.74, p = 0.003). No significant difference in OS was observed in German studies (HR = 0.84, 95% CI 0.53–1.37, p = 0.467), in patients with malignancies other than small-cell lung cancer (SCLC) (HR = 0.77, 95%CI 0.53–1.11, p = 0.159), and in larger studies enrolling > 100 patients (HR = 0.89, 95% CI 0.71–1.11, p = 0.289; Supplementary Fig. 3).

Intracranial progression-free survival

Four studies comprising a total of 744 patients were included in the comparative analysis of iPFS between WBRT-SIB and WBRT alone [7, 31, 32, 43]. WBRT-SIB significantly improved iPFS compared with WBRT alone (HR = 0.67, 95% CI 0.47–0.96, p = 0.03; Fig. 3a). The pooled median iPFS for patients treated with WBRT-SIB, including data from single-arm studies, was 13.07 months (95% CI 10.18–16.78) [8, 21, 23, 25, 28, 31, 45].

Fig. 3.

Pooled analysis for iPFS and iLPFS. iPFS intracranial progression-free survival, iLPFS intracranial local progression-free survival

Three studies, including 366 patients, were available for comparative analysis of iLPFS between WBRT-SIB and WBRT-alone [7, 31, 43]. Low heterogeneity was observed across studies. WBRT-SIB was associated with significant improvement in iLPFS compared with WBRT alone (HR = 0.55, 95% CI 0.4–0.79, p < 0.01; Fig. 3b).

Treatment-related adverse events

Five studies were included in the comparative analysis of TRAEs [7, 37, 38, 40, 43], and 10 studies were analyzed for the incidence of radiation necrosis among patients treated with WBRT-SIB [8, 19–21, 31, 37–40, 43].

No significant differences were observed between WBRT-SIB and WBRT-alone groups in the rates of grade ≥ 3 TRAEs (OR = 1.2, 95% CI 0.58–2.48, p = 0.62), grade ≥ 3 dizziness (OR = 1.73, 95% CI 0.76–3.98, p = 0.19), grade ≥ 3 headache (OR = 1.41, 95% CI 0.57–3.46, p = 0.46), or any-grade radiation necrosis (OR = 1.79, 95% CI 0.91–3.71, p = 0.12; Fig. 4). Heterogeneity for these comparisons was low or negligible.

Fig. 4.

Pooled analysis for treatment-related adverse events. TRAEs treatment-related adverse events

The pooled incidence of radiation necrosis among patients treated with WBRT-SIB was 5.05% (95% CI 1.19–10.77%), although high heterogeneity was observed across studies (Fig. 5).

Fig. 5.

Pooled incidence of radiation necrosis

Best radiological response

Sixteen studies including 538 patients assessed radiological response after WBRT-SIB [19, 22–24, 26, 27, 29, 30, 33–36, 41, 44–46]. The pooled objective response rate (ORR) was 69.5% (95% CI 61.64–76.86%), and the disease control rate (DCR) reached 89.99% (95% CI 81.97–96.09%). The analyses demonstrated moderate and high interstudy heterogeneity, respectively (Supplementary Fig. 4).

Discussion

To the best of our knowledge, this is the first meta-analysis to comprehensively evaluate the efficacy and safety of WBRT-SIB and to provide a detailed comparison with standard WBRT. The principal finding is that WBRT-SIB significantly improves overall survival compared with WBRT, particularly in small-cell lung cancer, accompanied by superior intracranial progression-free survival and improved local tumor control. In addition, WBRT-SIB was associated with high response rates and an acceptable safety profile.

WBRT remains a standard treatment option for patients with multiple brain metastases; however, the effectiveness of WBRT alone is often limited by suboptimal intracranial control and modest survival outcomes [19]. A 30% reduction in the risk of death with WBRT-SIB provides strong evidence for establishing it as a priority for investigation in upcoming randomized trials comparing WBRT-SIB with WBRT alone for patients who are not candidates for SRS [25]. The concomitant improvements in iPFS and local control suggest that effective radiotherapy-based intracranial control remains a key determinant of survival, even in the setting of modern targeted and immune therapies that can exert intracranial activity [21]. Furthermore, the objective response rate to WBRT-SIB was 69.5%, and those responses were durable as determined by iPFS. These effects, however, vary across subgroups and study settings.

The generalization of our results is limited by considerable heterogeneity and conflicting subgroup findings. The OS benefit was not observed in studies from Europe (particularly Germany) or in larger cohorts (> 100 participants), whereas it remained significant in studies of small-cell lung cancer, likely reflecting the marked radiosensitivity and poor prognosis of this malignancy [47]. No significant OS effect was seen in studies focusing on other primary tumors, mainly non-small-cell lung cancer. Importantly, several studies reporting favorable outcomes with WBRT-SIB were excluded from the OS analysis due to unavailable hazard ratios or unclear timing of boost (simultaneous vs. sequential) [38, 48, 49]. Despite these constraints, the consistent improvement in intracranial control across studies indicates a meaningful biological advantage of dose intensification.

Although the OS benefit remains somewhat controversial, the advantage of WBRT-SIB in intracranial control appears robust. As local and systemic therapies become more effective, with better overall survival and extracranial disease control, maintaining intracranial control and preserving neurological function are key therapeutic goals. Available evidence indicates that WBRT alone offers limited benefits for both quality of life and neurological outcomes [50, 51]. WBRT-SIB may therefore help preserve quality of life by mitigating neurological decline through improved intracranial control. Furthermore, incorporating hippocampal avoidance may further preserve cognitive function without substantially increasing the risk of hippocampal recurrence [52, 53]. Data on neurocognitive and quality-of-life outcomes after WBRT-SIB were insufficient for pooling analyses; these variables should be assessed in future prospective trials.

The safety analysis indicates that WBRT-SIB is not associated with an increased risk of serious treatment-related adverse events when compared with WBRT, with only a non-significant numerical trend toward higher rates of radiation necrosis. The pooled incidence of radiation necrosis in the WBRT-SIB arm was 5.05%. Because definitions and diagnostic criteria varied widely across studies—some studies described it simply as “necrosis”, while others used broader terms such as “brain injury”—we pooled radiation necrosis under a single outcome; most cases were radiologically diagnosed on follow-up and were low-grade. Furthermore, whether the number of metastases or the SIB dose increases radiation necrosis risk and toxicity overall remains unclear and requires further study, as we could not perform subgroup analysis with these variables as stratification factors. To improve consistency, future research should adopt standardized toxicity criteria, such as CTCAE or RANO, to ensure consistent reporting and enable reliable cross-study comparisons [54, 55]. Prospective trials should establish evidence-based selection criteria and dose thresholds for WBRT-SIB, particularly regarding the maximum number of safely treatable lesions.

Another combined strategy based on the similar principles is whole-brain radiotherapy with sequential stereotactic radiosurgery (WBRT-SRS). In the RTOG 9508 phase III trial, which enrolled patients with one to three brain metastases, WBRT-SRS improved 1-year intracranial progression-free survival compared with WBRT alone (82% vs. 71%, p = 0.013) [56]. A Cochrane review confirmed better local control and performance status with WBRT-SRS than with WBRT alone, without a survival advantage [57]. In contrast, WBRT-SIB offers practical advantages over WRBT-SRS–simpler planning, shorter treatment times, lower costs, and no restrictions on the number or volume of lesions—and its fractionation pattern may confer radiobiological benefits by limiting tumor cell repopulation and redistribution [7, 58]. Although WBRT-SIB improved OS compared with WBRT alone in this meta-analysis—a benefit not observed for WBRT-SRS—these findings should be interpreted with caution, given the relatively lower methodological quality and higher risk of bias of the included studies [57]. Head-to-head trials are needed to clarify the relative efficacy of WBRT-SIB and WBRT-SRS.

Limitations

We could not pool quality-of-life or neurocognitive outcomes due to insufficient data. Including multiple primary tumor types introduces biological heterogeneity that may bias pooled estimates, particularly for OS; subgroup analyses were limited by small study numbers for key endpoints. Most included studies originated from China, with only two from Europe, which may limit the generalizability to a non-Chinese population. Another limitation of our study is that the population of patients is somewhat limited to those with BM originating primarily from NSCLC, SCLC, and breast cancer. The lack of patients with BM of malignant melanoma is especially interesting. We suspect that it is primarily explained by the relative radioresistance of melanoma, as well as the remarkable efficacy of recent systemic treatments in controlling melanoma CNS metastases [59]. Finally, heterogeneity across most endpoints was considerable, and most included studies were retrospective, with no randomized trials identified in our literature search, which introduces several sources of bias. We were not able to adequately explain the inconsistencies in our findings and find it likely to be attributable the to a confounding bias—with heterogeneity of effect resulting from heterogeneity of population and therapy parameters which we were not able to address using publication-level data included in this analysis. A randomized trial to investigate the OS-benefit from SIB as compared to WBRT in SCLC seems particularly warranted, as well as an individual patient data meta-analysis to investigate the scale of benefit from WBRT-SIB in the treatment of BM from other primaries.

Conclusions

WBRT-SIB improves intracranial progression-free survival and local intracranial control and may also improve overall survival compared with WBRT alone, particularly in patients with brain metastases from SCLC. It is associated with high response rates and an acceptable safety profile. These findings support further investigation of WBRT-SIB, preferably in a randomized setting and in patients with BM originating from SCLC, for patients who are not candidates for stereotactic radiosurgery.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

BM

Brain metastases

WBRT

Whole-brain radiotherapy

WBRT-SIB

Whole-brain radiotherapy with simultaneous integrated boost

SRS

Stereotactic radiosurgery

IMRT

Intensity-modulated radiotherapy

CI

Confidence interval

OS

Overall survival

iPFS

Intracranial progression-free survival

iLPFS

Intracranial local PFS

HR

Hazard ratio

OR

Odds ratio

TRAEs

Treatment-related adverse events

ORR

Objective response rate

DCR

Disease control rate

SCLC

Small-cell lung cancer

NSCLC

Non-small-cell lung cancer

Author contributions

Dominik Wróbel: Conceptualization, Methodology, Formal analysis, Writing—Original Draft, Visualization; Aleksandra Sobieryn: Investigation, Formal analysis, Writing—Original Draft; Adam Kozik: Investigation, Formal analysis, Writing—Original Draft; Paweł Potocki: Conceptualization, Supervision, Writing—Review & Editing; Michał Seweryn: Supervision, Writing—Review & Editing; Jędrzej Borowczak: Conceptualization, Writing—Review & Editing, Supervision.

Funding

No funding was received for conducting this study.

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Declarations

Conflicts of interest

None declared.

Ethical approval

Not applicable.

Consent for publication

Not applicable.

Informed Consent

Not applicable.