Clinical Neurology and Neurosurgery 206 (2021) 106645

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Clinical Neurology and Neurosurgery

journal homepage: [Link]/locate/clineuro

Hypofractionated versus single-fraction stereotactic radiosurgery for the

treatment of brain metastases: A systematic review and meta-analysis
Julius July a, *, Raymond Pranata b, 1
a
Department of Neurosurgery, Medical Faculty of Pelita Harapan University, Lippo Village Tangerang, Neuroscience Centre Siloam Hospital, Lippo Village, Tangerang,
Indonesia
b
Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Indonesia

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: This systematic review and meta-analysis aimed to synthesize the latest evidence on the hypo­
Stereotactic fractionated stereotactic radiosurgery (HF-SRS) compared to single-fraction stereotactic radiosurgery (SF-SRS)
Radiation for the treatment of brain metastases.
Radiotherapy
Methods: We systematically searched PubMed, Scopus, EuropePMC, ProQuest, and Cochrane Central Databases.
Metastasis
Tumor
Original research articles investigating patients with brain metastasis receiving HF-SRS or SF-SRS reporting the
local control/failure and/or radionecrosis during follow-up were included.
Results: There were 1100 patients from 7 studies. 616 lesions were allocated to HF-SRS group and 777 lesions
were allocated to SF-SRS group. Pooled rate of local control was 88% (95% CI 84%, 91%) in HF-SRS group and
81% (95% CI 74%, 88%) in the SF-SRS groups. Local control was higher in patients receiving HF-SRS compared
to SF-SRS (OR 1.53 [95% CI 1.08, 2.18], p = 0.018; I2: 0%). Pooled rate of radionecrosis was 7% (95% CI 3%,
12%) in HF-SRS group and 15% (95% CI 8%, 23%) in the SF-SRS groups. Similar rate of radionecrosis was
observed in both HF-SRS and SF-SRS (OR 0.82 [95% CI 0.31, 2.21], p = 0.698; I2: 61.3%). Grading of Rec­
ommendations, Assessment, Development and Evaluations (GRADE) qualification showed a low level of certainty
for the higher local control in patients receiving HF-SRS compared to SF-SRS and a very low level of certainty for
similar risk of radionecrosis between the two groups.
Conclusion: This meta-analysis showed that HF-SRS was associated with higher local control and similar rate of
radionecrosis compared to SF-SRS in patients with brain metastases.
PROSPERO ID: CRD42020210469

doses, enables a higher biologically effective dose (BED) delivery that is

potentially advantageous to SF-SRS in terms of local recurrence and
1. Introduction radionecrosis [9]. This systematic review and meta-analysis aimed to
synthesize the latest evidence on the HF-SRS compared to SF-SRS for the
Brain metastases is frequently encountered in patients with cancer treatment of brain metastases.
[1,2]. Surgery, whole brain radiation therapy (WBRT), and stereotactic
radiosurgery (SRS) are used to treat brain metastases [2]. Use of SRS 2. Material and methods
alone without the addition of WBRT has been shown to be favorable and
a study showed that SRS is preferred in 1–3 brain metastasis [3–5]. A This is a Preferred Reporting Items for Systematic Reviews and Meta-
recently published executive summary from American Radium Society Analyses (PRISMA) compliant systematic review and meta-analysis. The
state that SRS alone is appropriate for 2–10 brain metastases [6]. study protocol is registered in PROSPERO (CRD42020210469).
Single-fraction SRS (SF-SRS) is often problematic in large lesion,
higher doses may worsen local control and increase incidence of radi­
onecrosis [7,8]. Fractionating the doses theoretically can minimize the
toxicity. Hypofractionated SRS (HF-SRS), by dividing the radiation

* Corresponding author.
E-mail addresses: juliusjuly@[Link] (J. July), raymond_pranata@[Link] (R. Pranata).
1
ORCID: [Link] SCOPUS-ID:57201973901.

[Link]
Received 9 November 2020; Received in revised form 5 April 2021; Accepted 8 April 2021
Available online 20 April 2021
0303-8467/© 2021 Elsevier B.V. All rights reserved.
J. July and R. Pranata Clinical Neurology and Neurosurgery 206 (2021) 106645

3. Search strategy and study selection

Nomenclature
We systematically searched PubMed, Scopus, EuropePMC, ProQuest,
BED Biologically effective dose and Cochrane Central Databases using the terms “single-fraction” AND
GRADE Grading of Recommendations, Assessment, (“hypofractionated” OR “fractionated” OR “multifractionated”) AND
Development and Evaluations (“Stereotactic Radiosurgery” OR “radiotherapy” OR “radiation”) AND
OR Odds Ratio (“brain metastasis” OR “brain metastases” OR “intracranial metastasis“).
NOS Newcastle-Ottawa Scale Additional records were retrieved by manual searching of the published
SRS Stereotactic radiosurgery papers. Duplicates were removed and the articles were screened inde­
HF-SRS Hypofractionated SRS pendently by two authors. Afterwards, the full-texts of the residual ar­
SF-SRS Single-fraction SRS ticles were assessed for its relevance based on the inclusion and
WBRT Whole brain radiation therapy exclusion criteria. The literature search was finalized in 21 September
2020.

4. Eligibility criteria

Original research articles investigating patients with brain metastasis

Fig. 1. PRISMA Flowchart.

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J. July and R. Pranata Clinical Neurology and Neurosurgery 206 (2021) 106645

Fig. 2. Local control. Forest-plot showing comparison of local control in hypofractionated stereotactic radiosurgery group versus single-fraction stereotactic radi­
osurgery group. OR: odds ratio, 95% CI: 95% confidence interval.

receiving HF-SRS and SF-SRS reporting the local control/failure and/or Scale (NOS) was used to assess the risk of bias/quality of the included
radionecrosis during follow-up were included. Single-arm studies studies.
including HF-SRS or SF-SRS alone were excluded. We exclude review
articles, abstract-only publications, conferences abstract, case-reports, 6. Statistical analysis
commentaries, and articles in non-English language.
STATA 16.0 (StataCorp LLC, Texas, US) was used to performed meta-
5. Data extraction analysis. Meta-analysis of proportion was performed to pool the rate of
local control and radionecrosis in each groups. The pooled effect esti­
Two authors performed independent data extraction using stan­ mate was reported as odds ratios (ORs) along with its 95% confidence
dardized forms that contain first author, year of the publication, study interval (95% CI). Random-effects models were used regardless of het­
design, number of patients, number of metastatic lesions, fraction of erogeneity. P-values were two-tailed, and a p-value of ≤0.05 indicates
radiation therapy, median radiation dose, tumor size, mean/median statistical significance. Cochran’s Q test and I2 statistic were used to
follow-up, local control/failure, and radionecrosis. assess heterogeneity, I2 value >50% and p-value <0.10 indicated a
The primary outcome was local control of metastatic lesion and the statistically significant heterogeneity. Sensitivity analysis by leave-one-
secondary outcome was incidence of radionecrosis. Newcastle-Ottawa out was performed to single out heterogeneity and testing statistical

Fig. 3. Radionecrosis. Forest-plot showing comparison of radionecrosis between hypofractionated stereotactic radiosurgery group versus single-fraction stereotactic
radiosurgery group. OR: odds ratio, 95% CI: 95% confidence interval.

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J. July and R. Pranata Clinical Neurology and Neurosurgery 206 (2021) 106645

BED: Biologically Effective Dose, DBF: Distant Brain Failure, SRS: Stereotactic radiosurgery, HF-SRS: Hypofractionated SRS, SF-SRS: Single-fraction SRS, PFS: Progression Free Survival, RPFS: Regional Progression Free
NOS

7
follow-up
(months)
Median

10.6

7.2
12

10

14

29

28
50.1 vs 45.3 (PFS)

40.9 vs 27.3 (PFS)

progression free

56 vs 52 (RPFS)
(% of patients)

59 vs 61 (DBF-
51 (DBF free)
1-year

Free)
55.8 vs 65.4

69.4 vs 53.1

32.5 vs 28
1-year OS

patients)

56 vs 53

58 vs 27
(% of

54

3.4 vs 1.6

0.9 vs 3.7
RN (% of
lesions)

7 vs 10

8 vs 20
45.6 vs

0 vs 0
9.3 vs
43.6

25.6

91.6 vs 89
LC (% of

81 vs 90

90 vs 77

75 vs 71
lesions)

78.4 vs

88.2 vs

91.7 vs
88.1

57.2

84.6
2–3 cm: 47 vs

2.04 and 5.93

1.6 vs 0.7 cm

55% > 3: 53
2.5 – 3.0 cm
Tumor size

vs 1.87 cm3
0.21 cm3

0.13 mL

3.78 cm
vs 45%
2.36 vs

4.47 vs
8.1 vs
(BED10)

(BED10)

(BED12)
33.6 Gy
42.6 vs

40.9 vs
24 Gy

24 Gy

22 Gy
21 vs

40 vs
Dose

–
Fig. 4. Funnel plot analysis. Local Control (A) and Radionecrosis (B).
3 or 5 vs 1

3 or 5 vs 1

7 or 10 vs
Fraction

3 vs 1

3 vs 1

3 vs 1

3 vs 1
robustness. To assess publication bias, funnel-plot analysis was used.
(s)

1
Regression-based Egger’s test was performed to assess the small-study
effect quantitatively. The certainty of the evidence was assessed by
Adenocarcinoma (67

Adenocarcinoma (75
adenocarcinoma (35
primary tumor (%)

Lung (53.7 vs 52.6)

NSCLC (41 vs 42)

NSCLC (40 vs 39)

using Guideline Development Tool by GRADEpro GDT.
Most common

NSCLC (45.5)

Survival, NOS: Newcastle-Ottawa Scale, NSCLC: Non-small Cell Lung Carcinoma.

7. Results
NSCLC
vs 53)

vs 72)

vs 50)

The initial search yielded 2749 records, 325 duplicates were then
removed, leaving 2424 records which were then screened for relevance.
-(122 vs 138
(HF-SRS vs

164 vs 179

There were 13 potential records, and their eligibility was assessed by

patients)
113/222

141/105
SF-SRS)
Lesions

reading the full-text articles. We excluded 6 full-text articles because (1)

38/67

24/39

14/27

hypo-fractionated group without single-fraction arm (n = 5), (2) odds

ratio cannot be obtained/calculated due to lack of information (n = 1).
Patients

There were 7 studies eligible for qualitative and quantitative synthesis

(Fig. 1).
156

179

105

289

260
90

26
Baseline Characteristics of the included studies.

There were 1100 patients from 7 studies [8–14]. 616 lesions were
allocated to HF-SRS group and 777 lesions were allocated to SF-SRS
Germany

group. All of the studies were retrospective. Tumor size was reported
Republic
Country

of Korea
Canada
United

France

France
States

as diameter in 4 studies and as volume in 3 studies. In all studies, pa­

Italy

tients receiving HF-SRS have larger tumor size. One-year survival rate,
1-year progression free survival, and 1-year distant brain failure were
Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

approximately 50–60% of the patients in both groups. Assessment using

Newcastle Ottawa Scale showed a moderate-high quality of studies
Design

Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

Table 1.

8. Local control
Loo 2020

Donovan
Authors

Feuvret
Remick

Minniti
2020

2020

2019

2016

2014

2012
Table 1

Fokas
Chon

Pooled rate of local control was 88% (95% CI 84%, 91%) in HF-SRS
group and 81% (95% CI 74%, 88%) in the SF-SRS groups. Local control

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J. July and R. Pranata Clinical Neurology and Neurosurgery 206 (2021) 106645

Table 2
GRADE assessment of the outcomes.
Certainty assessment No of Effect Certainty
Lesions

No of Study design Risk of Inconsistency Indirectness Imprecision Other HF- SF- Relative Absolute
studies bias considerations SRS SRS (95% CI) (95% CI)

Local control
7 Observational Seriousa Not serious Not serious Not serious All plausible residual 616 777 OR 1.53 N/A ⨁⨁x̂x̂
studies confounding would (1.08–2.18) LOW
reduce the
demonstrated effectb
Radionecrosis
6 Observational Seriousa Not serious Not serious Not serious Noneb 616 777 OR 0.82 N/A ⨁x̂x̂x̂
studies (0.31–2.21) VERY
LOW

CI: confidence interval; OR: odds ratio; HF-SRS: Hypofractionated Stereotactic Radiosurgery; SF-SRS: Single-fraction Stereotactic Radiosurgery Explanations.
a
Mostly retrospective studies, inadequately adjusted for confounders.
b
Tumor size is often larger in patients receiving hypofractionatedstereotactic radiosurgery.

was higher in patients receiving HF-SRS compared to SF-SRS (OR 1.53 in those with smaller tumor size. This is strengthened by the fact that the
[95% CI 1.08, 2.18], p = 0.018; I2: 0%, p = 0.120) (Fig. 2). Sensitivity benefit persisted even after the removal of Minniti et al. and Chon et al.
analysis showed that removal of any study, and of both Minniti et al. and study, which enroll patients with >2 cm tumor size and 2.5–3.0 cm,
Chon et al. study, did not alter the direction of the effect estimate. from the pooled analysis. A single-arm study demonstrated that local
control was associated with smaller tumor size and higher radiation dose
9. Radionecrosis in patients receiving HF-SRS [15].
The incidence of radionecrosis is subjected to potential confounders,
Pooled rate of radionecrosis was 7% (95% CI 3%, 12%) in HF-SRS tumor size has been shown to be an independent predictor of radio­
group and 15% (8%, 23%) in the SF-SRS groups. Similar rate of radio­ necrosis [9,10]. Hence, the apparently similar incidence of radionecrosis
necrosis was observed in both HF-SRS and SF-SRS (OR 0.82 [95% CI in this meta-analysis might be due to the discrepancy in tumor size be­
0.31, 2.21], p = 0.698; I2: 61.3%, p = 0.083) (Fig. 3). Sensitivity anal­ tween the HF-SRS and SF-SRS groups. HF-SRS was associated with
ysis showed that removal of a single study did not alter outcome. markedly lower incidence of radionecrosis in a propensity-matched
analysis compared to SF-SRS in patients with >2 cm tumors and
adjusted analysis in 2.5–3.0 cm tumors [8]. In patients receiving
10. Publication bias
HF-SRS, lesion volume was not associated with radionecrosis, hence, it is
possible that the rate of radionecrosis is similar in smaller tumor size
Funnel-plot analysis showed a qualitatively symmetrical shape for
[16]. It is possible that the benefit in terms of radionecrosis is more
local control (Fig. 4A) and asymmetrical for radionecrosis (Fig. 4B).
apparent in larger tumor size due to higher risk of radionecrosis with
Regression-based Egger’s test showed no indication of small-study ef­
size in SF-SRS but not HF-SRS. On the other hand, a study showed that
fects for local control (p = 0.858) and radionecrosis (p = 0.847).
fractioning is not associated with reduced radionecrosis in both unad­
justed and adjusted model [11].
11. GRADE assessment of the outcomes The limitation of this systematic review is that the dosing and
method of fractionation varies across the studies. Thus, an optimal dose
Grading of Recommendations, Assessment, Development and Eval­ and fractions are yet to be determined. The tumor size also differs across
uations (GRADE) qualification showed a low level of certainty for the the groups and the question remains whether tumors with smaller size
higher local control in patients receiving HF-SRS compared to SF-SRS will have similar benefit from HF-SRS. The primary cancer pathologies
and a very low level of certainty for similar risk of radionecrosis be­ are also heterogeneous. Randomized controlled trials are needed to
tween the two groups (Table 2). provide a more rigorous comparison between the two modalities.

12. Discussion 13. Conclusion

This systematic review and meta-analysis demonstrated that HF-SRS This meta-analysis showed that HF-SRS was associated with higher
has higher local control and a similar incidence of radionecrosis local control and similar rate of radionecrosis compared to SF-SRS in
compared to SF-SRS. Sensitivity analysis showed that removal of one patients with brain metastases. The low certainty of evidence demands
study at a time did not alter the direction of effect estimate, indicating resolution by randomized controlled trials.
statistical robustness of the analysis.
Tumor size is a known predictor of local failure in patients receiving
Ethics approval and consent to participate
SRS [10]. In this pooled analysis, the patients receiving HF-SRS have
larger tumor size compared to those receiving SF-SRS. In a
Not applicable.
propensity-matched analysis of patients with >2 cm tumor size, HF-SRS
has a higher local control compared to SF-SRS [8]. Similar benefit can be
observed in a study enrolling 2.5–3.0 cm tumor size [14]. However, the Ethical approval
benefit is less clear in patients with smaller tumor size. Majority of pa­
tients in Remick et al. study have a tumor size of ≤2 cm, their study Not applicable.
demonstrated a similar local control in both groups [10]. Regardless, we
observe that most of the studies were not statistically significant on its Funding
own, this may indicate that larger sample size is required in order for the
advantage to become more apparent in the individual studies, especially None.

5
J. July and R. Pranata Clinical Neurology and Neurosurgery 206 (2021) 106645

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