Fractionated Stereotactic Gamma Knife Radiosurgery for Large Brain Metastases: A Retrospective, Single Center Study
Fractionated Stereotactic Gamma Knife Radiosurgery for Large Brain Metastases: A Retrospective, Single Center Study
Joo Whan Kim 0 1 2
Hye Ran Park 0 1 2
Jae Meen Lee 0 1 2
Jin Wook Kim 0 1 2
Hyun-Tai Chung 0 1 2
Dong Gyu Kim 0 1 2
Hee-Won Jung 0 1 2
Sun Ha Paek 0 1 2
0 Funding: This study was supported by the Korea Institute of Planning & Evaluation for Technology in Food , Agriculture, Forestry, and Fisheries , Republic of Korea (311011-05-3-SB020); by the Korea Healthcare Technology R&D Project (HI11C21100200) funded by Ministry of Health & Welfare, Republic of Korea; by the Technology Innovation Program (10050154 , Business Model
1 Department of Neurosurgery, Seoul National University College of Medicine , Seoul , Korea , 2 Department of Neurosurgery, Seoul National University Hospital , Seoul , Korea
2 Editor: Deric M. Park, National Cancer Institute , UNITED STATES
Stereotactic radiosurgery (SRS) is widely used for brain metastases but has been relatively contraindicated for large lesions (>3 cm). In the present study, we analyzed the efficacy and toxicity of hypofractionated Gamma Knife radiosurgery to treat metastatic brain tumors for which surgical resection were not considered as the primary treatment option. Thirty-six patients, forty cases were treated with Gamma Knife-based fractionated SRS for three to four consecutive days with the same Leksell frame on their heads. The mean gross tumor volume was 18.3 cm, and the median dose was 8 Gy at 50% isodose line with 3 fractions for three consecutive days (range, 5 to 11 Gy and 2 to 4 fractions for 2 to 4 consecutive days). Survival rates and prognostic factors were analyzed.
Data Availability Statement: Data are available
upon request due to ethical restrictions regarding
patient privacy. Requests for the data may be sent
to the corresponding author.
The overall survival rate at one and two years was 66.7 and 33.1%, respectively. The
median survival time was 16.2 months, and the local control rate was 90%. RTOG toxicity
grade 1 was observed in 3 (8.3%) patients, grade 2 in 1 (2.7%) patient and grade 3 in 1
(2.7%) patient respectively. Radiation necrosis was developed in 1 (2.7%) patient. KPS
scores and control of primary disease resulted in significant differences in survival.
Our findings suggest that consecutive hypofractionated Gamma Knife SRS could be
applied to large metastatic brain tumors with effective tumor control and low toxicity rates.
Development for Personalized Medicine Based on
Integrated Genome and Clinical Information)
funded by the Ministry of Trade, Industry & Energy
(MI, Korea); and by the Bio & Medical Technology
Development Program of the NRF funded by the
Korean government, MSIP (2015M3C7A1028926).
Metastatic brain tumors are the most common intracranial tumors, outnumbering primary
brain tumors and occurring in up to 25–30% of cancer patients. The natural course of these
patients are approximately 1 month survival without any intervention. Aside from
chemotherapy, the treatment options for brain metastases include steroid medication, surgical
resection, whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS).
Corticosteroid treatment alone results in a median survival of 2 months; the median survival
with WBRT is 4 to 6 months, while for surgical resection of a single lesion, the median survival
is 9 to 14 months.[
] Brain metastases are often inoperable because of their location,
multiplicity, comorbidity, and performance status. SRS has resulted in local control rates of 71 to
96% and a median survival of 7 to 13.5 months in previous studies.[8–11] Traditionally, the
indication for SRS has been a lesion diameter of 3 cm or less, and large size is a relative
contraindication due to treatment-related toxicity. The concept of fractionation was first
introduced in radiotherapy to reduce the toxicity of treatment for large tumors. Similar efficacy and
lower toxicity risk of fractionated radiotherapy compared with single dose SRS has been
demonstrated in several studies.[13–15] Previous reports have only studied LINAC-based SRS;
however, Gamma Knife-based SRS has been rarely reported.[16, 17]
In this study we analyzed the efficacy and toxicity of hypofractionated Gamma Knife
radiosurgery in the treatment of large metastatic brain tumors. Our hypothesis was that
hypofractionated radiosurgery has equal effectiveness and tolerable toxicity rates.
Patients and Methods
Between January 2010 and July 2015, 70 patients with a total of 79 lesions of brain metastases
were treated with Gamma Knife-based fractionated radiosurgery. The patient selection criteria
for fractionation treatment instead of single fraction were lesions greater than 14 cm3 or lesions
greater than 10 cm3 located in posterior fossa. Because it is known that lesions greater than 3
cm in diameter is relative contraindication for single fraction radiosurgery due to risk for
edema after treatment. Therefore, 25 patients with lesions greater than 14 cm3 and 11
patients with posterior fossa lesions with volume greater than 10 cm3 were included in the
study. There were no patient exclusion criteria for number of metastases or previous radiation
treatment. The patient and treatment characteristics are summarized in Table 1. Patients were
treated with hypofractionated radiosurgery instead of surgery due to the location of the lesion,
poor general condition (age, comorbidities) and the wishes of the patients. The median age of
the patients was 56 years at the time of treatment; there were 16 men and 20 women. The
histology of the primary tumors included lung cancer, breast cancer, colorectal cancer and others.
A solitary metastasis was present in 17 patients, while multiple metastases occurred in 19.
Patients with multiple metastases were treated with single fraction radiosurgery for other
smaller lesions. Primary disease was controlled in 25 patients. The median Karnofsky
performance status (KPS) was 90, ranging from 60 to 100. Recursive partitioning analysis (RPA) and
graded prognostic assessment (GPA) were analyzed. The mean gross tumor volume was 18.3
cm3. All data were obtained from hospital chart and imaging study databases; the study was
approved by the Institutional Review Board. (IRB no. 1508-084-695) Patients and relatives
were informed about the role, limitation and toxicities of radiosurgery. The requirement for
obtaining informed consent from the patients was waived because the study was only based on
the information obtained as a part of routine clinical care and their medical records. All
patients received IV dexamethasone 10 mg on admission, followed by a maintenance dose of 4
mg every 6 hours for 3 consecutive days until the end of radiosurgery; oral prednisolone was
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then tapered over one week but was prolonged if symptoms caused by peritumoral edema
persisted. Prophylactic antiepileptic medication was not used.
Leksell Gamma Knife-based radiosurgery was performed (Elekta Instrument AB,
Stockholm, Sweden, Model Perfexion). The treatment plan utilized the Leksell Gamma Plan (version
8.3.1, 10.1.0, 10.1.1, Elekta Instrument) system with thin-section magnetic resonance imaging
(MRI). T1–weighted images with gadolinium enhancement were used to determine the target
volume. The radiosurgery isodose and marginal dose prescribed were initially determined
based on the tumor volume calculated during dose planning, using the best-fit isodose method;
the prescription volume covered 95 to 99% of the gross tumor volume (GTV). The treatments
were designed to cover 50% of the maximal dose to the margins of the target in a single
fraction. The mean prescribed tumor volume was 21.2 cm3. The main prescription dose was 8 Gy
of 3 fractions for three consecutive days (range, 5 to 8 Gy and 2 to 4 fractions for 2 to 4
consecutive days), using the same Leksell frame on the heads of the patients. The radiation dose was
calculated to biological equivalent dose (BED) using a/b ratio of 10 and single fraction
equivalent dose (SFED) using Dq of 1.8 for analysis of dose related response. The fractionation
radiation dose calculated to BED and SFED are summarized in Table 2.[
Follow up was typically conducted at one and three months after radiosurgery, followed by
MRI examinations at 3-month intervals. Additional neuroimaging was obtained if neurologic
signs or symptoms developed. The tumor volume was measured on the follow-up MRI scans
as previously described. Local control failure was defined as an increase in tumor volume to
>125% of that measured at the time of radiosurgery.[
] Distant control failure was defined as
progression in the brain but not within the radiosurgical target volume. Radiation-related
brain necrosis was thoroughly assessed using the T1/T2 mismatch on the MRI scan.[
Although there is no clear criteria for defining radiation necrosis, we performed positron
emission tomography (PET) imaging for those with high possibility.[
] Surgical resection was
encouraged when clinical signs of cerebral herniation or imminent herniation developed in the
context of a radiographic diagnosis of local tumor progression or radiation necrosis during the
follow-up period. Treatment toxicity was also assumed when the Karnofsky performance status
score decreased or when the neurologic signs or symptoms worsened, combined with a stable
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or decreasing contrast-enhancing lesion within the radiosurgical target volume with increasing
peritumoral edema. Overall survival was defined as the interval between radiosurgery and the
death of the patient. Kaplan-Meier survival plots were used to estimate the overall survival
distributions. The log-rank test (level of significance, p<0.05) was used to assess differences in the
overall survival distributions between the groups. The Cox proportional hazards model (level
of significance, p 0.05) was used to adjust for covariates, which were categorically tested. All
statistical analyses were performed using IBM SPSS Statistics, version 188.8.131.52.
The follow up period ranged from 1 to 51.9 months, with a median follow up period of 13.4
months. The one-year and two-year overall survival rates were 66.7 and 33.1%, respectively,
with a median survival time of 16.2 months. The local tumor control rate was 90%. Twenty
three had died, and thirteen patients survived to the last follow up. Sixteen patients died of
systemic progression, and seven patients died of neurological deterioration. New metastatic brain
lesions were found in eleven patients: four patients with a single lesion and seven patients with
multiple lesions. These new lesions were treated with repeat GK SRS in four patients, WBRT in
three patients, surgical removal in one and conservative management in three patients. Of
these, four survived and seven died. The clinical course of the neurologic deficits is shown in
Table 3. Symptoms such as headache, cranial nerve palsy and weakness were observed in 15
patients before treatment. Among these patients, 10 patients showed improvement, 4 patients
remained stable and only 1 patient was aggravated. All follow-up was done within 1 or 3
months after treatment. There were no cases of newly developed neurological deficit after SRS.
Toxicity was classified using RTOG CNS toxicity criteria. [
] Grade 1 toxicity was observed
in 3 (8.3%) patients, grade 2 in 1 (2.7%) patient and grade 3 in 1 (2.7%) patient respectively.
Radiation necrosis, which is classified as grade 4 toxicity in this criteria developed in 1 (2.7%)
patient. That patient underwent surgical treatment and radiation necrosis was pathologically
confirmed. There were 4 patients suspicious of radiation necrosis by MR imaging and all of
them underwent PET imaging. Other 3 patients showed true progression based on PET and
these cases were not pathologically confirmed.
Two representative cases are shown in Figs 1 and 2.
There was no significant difference in survival between single and multiple metastases
(p = 0.73) and between those who had no previous treatment and those who had WBRT
(p = 0.62). GPA scoring showed statistical significance related with survival (p = 0.002).
Median survival according to the GPA score was 3.7 months for scores of 0–1, 17.9 months for
No. of patients
Fig 1. Illustrative cases of fractionated radiosurgery for large brain metastases. A 50-year-old woman
was diagnosed with brain metastases 4 years after treatment for breast cancer. She underwent surgical
removal at the time of diagnosis. (A) After 6 months she presented with progressive dysarthria, and follow-up
MRI showed recurrence. Radiosurgery was performed because of the post-operative recurrence and tumor
abutting the transverse sinus. The 16.5 cm3 cerebellar mass with was treated with a marginal dose of 8 Gy
targeted to the 50% isodose line in 3 consecutive daily fractions. (B) One month after radiosurgery, the
patient started systemic chemotherapy with Capecitabine, and the lesion dramatically decreased, and
neurological symptoms also improved. (C) A final follow-up image obtained 27 months after radiosurgery
shows that the lesion almost disappeared; the patient was still alive and on Gemcitabine and Cisplatin
chemotherapy due to primary disease progression at the time of analysis, which was 30 months after SRS.
scores of 1.5–2.5, and 23 months for scores of 3–4. Univariate analysis revealed that primary
disease control (p = 0.001) and KPS score (p = 0.013) showed differences in survival outcomes.
Lesions greater than 14 cm3 (3 cm in diameter), compared with smaller tumors, showed no
significant differences in local control and overall survival. Multivariate analysis showed that
control of primary disease (p = 0.001; HR 0.16, 95% CI 0.04–0.33) and KPS 70 (p = 0.011; HR
0.96, 95% CI 0.06–0.5) were significantly related to overall survival. The results of the statistical
analyses are shown in Table 4.
This study was designed to assess the efficacy, side effects and overall survival of patients with
large metastatic brain lesions treated by gamma knife multi-fraction SRS for three to four
Fig 2. Another illustrative case of fractionated radiosurgery for large brain metastases. (A) A
53-yearold man was diagnosed with brain metastases on a staging work-up for non-small cell lung cancer. The
lesion was 24.1 cm3; radiosurgery was performed with a marginal dose of 8 Gy targeted to the 50% isodose
line in 3 consecutive daily fractions. The patient was also started on Gefitnib chemotherapy. (B) After 1
month, the lesion dramatically decreased to 4.9 cm3. (C) After 3 months, the lesion decreased to 3.4 cm3.
The patient was later diagnosed with leptomeningeal carcinomatosis and was on Erlotinib chemotherapy at
the time of analysis, which was 8 months after SRS.
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consecutive days using the same Leksell head frame. As described above, the treatment options
for brain metastases include surgical resection, WBRT and SRS. Metastatic lesion size, location,
multiplicity, comorbidity, and performance status are considered important factors when
deciding which treatment options should be used.[
6, 24, 25
] Large metastases with mass effect
and accessible location are good candidates for surgical resection. Lesions located in eloquent
areas and patients in poor general condition are good candidates for radiosurgery; however,
large size is a relative contraindication because of concerns regarding treatment-related toxicity
increased radiation exposure. Because the selection criterion for SRS was traditionally
limited to lesions smaller than 3 cm, the treatment of choice for large metastases has typically been
surgical resection. Occasionally, palliative WBRT or SRS was considered in inoperable cases.
Radiosurgery was originally defined as a conformal, single fraction of high dose radiation
using a stereotactic method aimed to destroy target tissue while preserving adjacent normal
] Local control is highly dependent on the radiation dose and is known to be less
effective in single fraction doses lower than 15 Gy.[
] The concept of radiosurgery has been
expanded up to 5 fractions. The linear quadratic (LQ) model is used to calculate the biologic
effective doses (BEDs) and to compare different tissues with different doses and fractionation.
] The α/β ratio for metastatic brain tumors is estimated from 10 to 20, and a high α/β ratio
indicates increased sensitivity to multiple-session treatments.[
Studies of single fraction SRS as a primary or salvage treatment for large brain metastases
have been reported in the literature. Clinical outcomes such as overall survival and local control
were favorable, but the treatment-related toxicity was considerable. Lee et al. treated 109
patients with a median dose of 18.0 Gy for a median tumor volume of 16.8 cm3, with
progressive peritumoral edema in 19 (16.0%) patients.[
] Han et al. administered a single dose of 10–
16 Gy to lesions with a mean volume of 22.4 cm3, and their results found unacceptable CNS
toxicity of 18.8%. These authors suggested that a marginal dose of 11–12 Gy might be tolerable
due to the high rate of radiation toxicities.[
] CNS toxicity has diverse manifestations ranging
from mild, acceptable neurological symptoms to radiation necrosis and neurological deaths.
The most significant risk factor for radiation necrosis is a high radiation dose in a large volume
because the high dose eventually gives a high dose to the normal tissue in the periphery. The
RTOG protocol 90–05 reported that lesions with a maximal diameter of 3 cm or more should
use a maximal tolerated dose of 15 Gy due to toxicity.[
] Minniti et al. showed that a dose of
12 Gy in lesions larger than 8.5 cm3 carries a risk of radiation necrosis of 10% or higher, and
the actuarial risk at 1 year was 24% for lesions 6.0–10.9 cm3 and 51% for those >10.9 cm3.[
In this study as in Table 2, BED ranges from 24.2–60 and SFED ranges from 14.6–26.4 Gy.
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Compared with previous single fraction studies, it can be suggested that hypofractionation
radiosurgery has similar efficacy and paucity of treatment related toxicity.
The significance of this study is the use of a daily fractionation method that was not
previously reported in the literature. In fact, Gamma Knife-based SRS fractionated with intervals
has been reported for large metastatic lesions.[16, 17] Higuchi et al. used a regimen of 30 Gy
given in 3 fractions with a 2-week interval and showed promising results.[
] Yomo et al.
performed two studies of fractionated Gamma Knife-based radiosurgery with 20 to 30 Gy at the
50% isodose line in two fractions, 3 to 4 weeks apart. One study of 27 patients with metastatic
brain lesions reported a one-year local control rate of 61% and an overall survival rate of 45%
with one patient (3.5%) experiencing radiation injury. Another study of 58 patients with
metastatic brain tumors reported a one-year local control rate of 64% and an overall survival of
47% with three patients (5.1%) having radiation injury. The strategy of those fractionated
GKS with an inter-fraction time of 2 to 4 weeks has the purpose of reducing tumor size so that
the second treatment can be performed on a smaller volume more safely. In the current study,
the overall survival rates at one and two years were 66.7 and 33.1%, respectively, and the medial
survival time was 16.2 months. The local control rate was 90%, and radiation necrosis
developed in one (2.7%). Compared to previous studies, our study produced good clinical outcomes
with no significant difference in radiation-related toxicity; however, the interval and overall
treatment periods were shorter in this study.[
15–17, 36, 37
] A daily consecutive treatment
schedule is appropriate in terms of its good efficacy and tolerable toxicity rate. The placement
of a stereotactic frame for several days on the patient had been our concern for this treatment;
however, headache, pain or discomfort was tolerable. Another concern was moving of target
between each fraction, and treatment location was confirmed by performing fusion of scout
Surgical resection is often used as a primary or adjuvant treatment option. Rapid
decompression of mass effect is the strong merit of surgery in large tumors. However, surgery is
difficult in some cases due to tumor size, the eloquent location of the lesion and perioperative
complications. In eloquent area lesions, postoperative neurological deficit is a major concern.
Obermueller et al. analyzed 56 patients with motor cortex metastatic lesions; 12 patients
(21.4%) showed aggravated paresis, which remained permanently in 7 patients (12.5%).
Paek et al. reported surgical outcomes in a series of 208 patients with single or multiple
metastases; the operative mortality rate was 1.9%, and neurological deterioration occurred in 13
patients (6%). There were also postoperative wound-related or systemic complications such as
sepsis, pneumonia, or deep vein thrombosis in 21 patients (10%). In the present study,
there were no new neurologic deficits after the procedure, and pre-existing symptoms were
mostly improved or at least stable, as shown in Table 3. Thus, it is difficult to conclude that
radiosurgery is superior to surgery in terms of efficacy, but it is definitely a safer method in
terms of immediate perioperative complications.
SRS to the resection cavity as an adjuvant to surgery is another treatment option. The
purpose of this method is to improve the local control rate and decrease the need for WBRT.
Several reports showed satisfactory outcomes, including in terms of local control. [40–43]
Compared with the surgery-only group, the adjuvant SRS group had a significantly lower local
failure rate; it can therefore be assumed that SRS is beneficial for local control. One study
used 9 Gy in 3 fractions to resection cavities larger than 3 cm in diameter and also showed
good local control and low toxicity rates. In our study, fractionated SRS was used as the
primary treatment option, and the local control rate was similar to that of surgery plus adjuvant
SRS. In patients with an inoperable condition or lesion, fractionated SRS as a primary
treatment option should be considered.
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LINAC-based, Cyberknife-fractionated radiosurgery has also been reported in many
studies. The results show a local control of 70 to 96%, a median survival of 7 to 13.5 months and a
radiation-related side effect rate of 5–10%.[8–11] Inoue et al. performed fractionation with
Cyberknife, and the marginal dose ranged from 25–40 Gy with 50–75% isodose line.[
advantage of the Gamma Knife method allows a steeper dose fall-off so that a lower marginal
dose can be prescribed with easier treatment planning compared to LINAC-based methods,
which can help spare normal structures.
This study was conducted in a retrospective manner with small number of cases with
heterogeneous patients. Correlation of toxicity between single and hypofractionation may be not
clear because this study does not have control group and have small number of cases. RTOG
toxicity criteria was used for evaluation of treatment related toxicity but use of other QOL
instruments and neurocognitive assessment should have been used for more accurate
interpretation of toxicity which is also another limitation. We did not perform statistical comparison of
various regimens. The optimal dose regimen is still unknown. Future prospective studies with
large patient populations are needed to conclude that it is a safe and effective method of
treatment. This study should serve as basis for prospective study.
In this study, we demonstrated the efficacy and safety of hypofractionated Gamma Knife
radiosurgery to treat large metastatic brain tumors or lesions located in the eloquent areas for three
consecutive days with the same Leksell head frame. This result suggests that consecutive
hypofractionated Gamma Knife SRS could be applied to large metastatic brain tumors with effective
tumor control and low toxicity rates.
S1 File. Patient clinical data.
Conceptualization: JWK HRP JML HTC SHP.
Data curation: JWK HRP JML.
Formal analysis: JWK SHP.
Funding acquisition: SHP.
Methodology: JWK DGK HWJ SHP.
Project administration: SHP.
Resources: JWK SHP.
Software: HTC SHP.
Supervision: JWK HTC DGK HWJ SHP.
Visualization: JWK SHP.
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Writing – original draft: JWK.
Writing – review & editing: JWK HRP JML SHP.
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