J Neurooncol (2012) 109:91–98 DOI 10.1007/s11060-012-0868-6
CLINICAL STUDY
Stereotactic radiosurgery and fractionated stereotactic radiotherapy: comparison of efficacy and toxicity in 260 patients with brain metastases Emmanouil Fokas • Martin Henzel • Gunnar Surber • Gabriele Kleinert • Klaus Hamm • Rita Engenhart-Cabillic
Received: 5 January 2012 / Accepted: 30 March 2012 / Published online: 15 April 2012 Ó Springer Science+Business Media, LLC. 2012
Abstract We retrospectively evaluated and compared the efficacy and the toxicity profile of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of patients with brain metastases (BM). Between 2000 and 2009, 260 patients with 1–3 BM were treated using either SRS (median dose 20 Gy; n = 138) or two different FSRT dose concepts: 7 9 5 Gy (n = 61) or 10 9 4 Gy (n = 61). The median survival for SRS, 7 9 5 Gy and 10 9 4 Gy was 8, 7 and 10 months (p = 0.575), respectively, and the overall survival (OS) was 9 months. Follow-up imaging data were available in 214 of the 260 patients. The 1-year local progression-free survival (LPFS) was 73, 75 and 71 %, respectively (p = 0.191). After a mean follow-up of 28 months (range: 2.1–77 months), the rate of complete remission, partial remission, stable disease and progressive disease were 29, 40, 21 and 10 %, respectively. On multivariate analysis, RPA class I was associated with better OS and regional progression-free Klaus Hamm and Rita Engenhart-Cabillic are co-senior authors. E. Fokas (&) M. Henzel R. Engenhart-Cabillic Department of Radiotherapy and Radiation Oncology, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany e-mail:
[email protected] Present Address: E. Fokas Department of Oncology, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK G. Surber G. Kleinert K. Hamm Department for Stereotactic Neurosurgery and Radiosurgery, HELIOS Klinikum Erfurt, Erfurt, Germany R. Engenhart-Cabillic Department of Radiotherapy and Radiation Oncology, Justus Liebig University Germany, Giessen, Germany
survival (both p \ 0.001). SRS was associated with a higher toxicity rate (grade I–III) compared to the 7 9 5 Gy and 10 9 4 Gy groups (14 vs. 6 vs. 2 %, respectively; p = 0.01). Although FSRT was used for large lesions and/ or lesions near critical structures, the LPFS was comparable to SRS. Importantly, FSRT presented low toxicity and appears to be an effective and safe treatment for BM not amenable to SRS. The 10 9 4 Gy fractionation scheme warrants further investigation due to its efficacy and safe toxicity profile. Keywords Brain metastases Stereotactic radiosurgery Hypofractionated Local control Toxicity
Introduction Brain metastases (BM) occur in 20–35 % of cancer patients and are associated with a poor prognosis [1]. The therapeutic modalities that are mainly used in the treatment of patients with BM include surgery, whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) [1]. Several studies have demonstrated the efficacy of SRS when used alone or in combination with WBRT [2–4]. Two randomised trials have revealed similar OS outcomes between SRS alone and SRS plus WBRT in patients with 1–3 BM, even though adjuvant WBRT reduced intracranial relapses [5, 6]. Although SRS is commonly used in the management of patients with BM, large or anatomically challenging lesions are difficult to treat efficiently using SRS. Indeed, for those lesions only lower SRS doses (\18 Gy) can be applied safely because normal brain tissue toxicity increases significantly with increasing radiation doses applied to volumes above 10 cm3 [3, 7].
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Fractionated stereotactic radiotherapy (FSRT) can offer an alternative possibility for the application of high cumulative doses to difficult-to-treat lesions while sparing normal brain tissue [8–15]. In the present retrospective study, we analysed the role of FSRT using two different dose concepts and compared the outcome and toxicity with those from patients treated with SRS. In addition, we investigated the prognostic significance of different clinical parameters.
Patients and methods Patient characteristics We examined the records of our patients with BM and included patients with only 1–3 BM that were primarily treated with either FSRT or SRS. Patients that had large lesions (total volume of metastases [3 cm) and/or close to brainstem, mesencephalon, basal ganglia or capsula interna were treated with FSRT instead of SRS. We identified 260 patients with BM from 2000 until 2009. SRS was administered in 138 patients and FSRT was applied using two different dose concepts: 7 9 5 Gy (n = 61) and 10 9 4 Gy (n = 61) depending on the size and location of the metastasis that influenced the treating physicians’ decision. For the 7 9 5 Gy group, 48 cases were due to large volume and 13 due to eloquent location. For the 10 9 4 Gy group, 34 cases were due to large volume and 27 due to eloquent location. FSRT was performed three times per week. Lesions were confirmed using computed tomography (CT) and/or magnetic resonance imaging (MRI). The characteristics of the patients are shown in Table 1. Of note, the difference in RPA class I between the different groups was significant (p \ 0.01), as calculated by the Fisher exact test. Similarly, the difference in RPA class III was also significant (p \ 0.05). All patients were informed of the treatment and signed a written informed consent in accordance with local institutional review board and federal guidelines. Radiotherapy planning and treatment Patients were immobilised with an individual mask fixation system attached to a stereotactic frame [16, 17]. After stereotactic co-registration and CT-MRI image fusion, planning target volume (PTV) and critical structures were drawn in each slice. 3-D dose distribution was calculated by Voxelplan or Brainlab software [16, 17]. Treatment was delivered by a linear accelerator with 6-MV photons. The PTV is consisted of gross tumour volume (GTV), based on contrast extension in MRI, plus a safety margin of 2 mm in SRS and 3 mm in FSRT. For SRS, a microleaf collimator
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with 1 mm leaf thickness and a single isocenter was used to apply 11–14 isocentric, irregularly shaped, non-coplanar static beams. FSRT was delivered by either conformal arc technique or conformal beams. The organs at risk (eyes, optic nerves, optic chiasma and brainstem) were also contoured and the doses were taken into consideration [7, 18, 19]. The dose for SRS was according to the RTOG criteria [7]. Eligibility criteria for SRS included: (1) maximum tumour diameter of 3 cm; (2) verification of the lesions histopathology by stereotactic biopsy in patients with uncertain primary diagnosis; (3) life expectancy longer than 3 months; (4) absence of ependymal or meningeal tumour spread; and (5) KPS [ 50. For salvage therapy, WBRT, surgery or repeated SRS was administered as described before. Follow up Clinical and MRI and/or CT scan data were used for the follow-up. Patients were followed-up every 3 months postRT and also according to their clinical symptoms. The response of BM to the treatment was assessed as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). OS was measured from the beginning of radiotherapy. Disease recurrence (local progression-free survival; LPFS) or progression to the brain (regional progression-free survival; RPFS) were also investigated. The prognostic value of various factors such as age, sex, RPA class, extracerebral metastases, number of BM, chemotherapy and surgery was also assessed. Toxicity was evaluated using the Common Toxicity Criteria 2.0 (National Cancer Institute, Bethesda, MD, USA). Statistical analysis The Kaplan–Meier method, using the Cox–Mantel longrank test (univariate analysis), was employed to assess OS and time to BM progression/recurrence. The median value was estimated from each subgroup and samples were divided into high and low subgroup to obtain an equal size each and better precision of the test. Multivariate analysis was conducted using the prognostic factors that were significant (p \ 0.05) in the univariate one. SPSS 15.0.0 software was used to compute the different tests.
Results Tumour response and local control The median planning tumour volume (PTV) was 1.87 cm3 (range: 0.03–11.17 cm3) in SRS, 2.04 cm3 (range: 1.17– 18.71 cm3) in 7 9 5 Gy and 5.93 cm3 (2.7–23.16 cm3) in
J Neurooncol (2012) 109:91–98 Table 1 Patient characteristics
93
Characteristic
SRS (n = 138) No. of patients (%)
FSRT 7 9 5 Gy (n = 61) No. of patients (%)
FSRT 10 9 4 Gy (n = 61) No. of patients (%)
Age \63 years
68 (49)
27 (44)
28 (46)
C63 years
77(51)
34 (56)
33 (54)
Gender Male
60 (43)
30 (49)
25 (41)
Female
78 (57)
31 (51)
36 (59)
Number of brain metastases 1
124 (90)
41 (67)
49 (80)
2–3
14 (10)
20 (33)
12 (20)
82 (59) 56 (41)
29 (47) 32 (53)
30 (49) 32 (51)
Class I
10 (7)
23 (38)
22 (36)
Class II
66 (49)
22 (36)
26 (43)
Class II
61 (44)
16 (26)
13 (21)
Median
0.87
2.04
5.93
Range
(0.03–13.4)
0.02–27.5
0.02–26.8
Yes
63 (45)
29 (47)
22 (36)
No
75 (55)
32 (53)
39 (64)
Extracerebral metastases Yes No RPA class
Tumour volume
Concurrent chemotherapy
Surgery at brain diagnosis
RPA recursive partitioning analysis, WBRT whole brain radiotherapy, SRS stereotactic radiosurgery, FSRT fractionated stereotactic radiotherapy
Yes
9 (6)
2 (3)
3 (5)
No
129 (94)
59 (97)
58 (95)
Primary tumour NSCLC
55 (40)
27 (44)
21 (34)
Breast cancer
14 (10)
4 (7)
6 (8)
Malignant melanoma
15 (11)
3 (5)
7 (11)
Gastrointestinal
18 (13)
9 (15)
10 (16)
Urogenital
19 (14)
7 (11)
11 (18)
Others
17 (12)
2 (3)
11 (18)
10 9 4 Gy groups. Follow-up imaging data were available in 214 of the 260 patients (n = 107 in SRS; n = 54 in FSRT 7 9 5 Gy; n = 53 in FSRT 10 9 4 Gy). After a mean follow-up of 28 months (range: 2.1–77 months), the rate of CR, PR, SD and PD for all BM were 29, 40, 21 and 10 %, respectively. Therefore, 90 % of the patients with BM were found to have local tumour control (CR, PR or SD). Table 2 shows the tumour response in the different treatment groups. There was no statistically significant difference in the PD between the different treatment modalities (p = 0.73).
respectively. The median OS time was 8 months for SRS group, 7 months for the 7 9 5 Gy group and 10 months for the 10 9 4 Gy group (p = 0.575; Fig. 1a). The median PTV did not alter survival rates in SRS group (p = 0.87), Table 2 Local control after stereotactic radiotherapy Treatment
SRS (n = 107)
7 9 5 Gy (n = 54)
10 9 4 Gy (n = 53)
CR
27 (25%)
19 (36%)
14 (26%)
PR
48 (45%)
17 (32%)
23 (44%)
SD
20 (19%)
13 (24%)
11 (20%)
Patient survival and prognostic factors
LP
12 (11%)
4 (8%)
5 (10%)
The median OS after treatment for BM was 9 months. The 6- and 12-months-survival rates were 75 and 49 %,
SRS stereotactic radiosurgery, CR complete response, PR partial response, PD progressive disease, SD stable disease, LP local progression
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7 9 5 Gy group (p = 0.424) or 10 9 4 Gy group (p = 0.462). All patients were followed until death. One hundred forty-one patients (54 %) presented with systemic disease, affecting mainly the liver and the lungs, while in 119 patient (46 %) the brain was the first site of disease. Forty-six patients (18 %) had more than one cerebral lesion. Regarding systemic treatment, chemotherapy was administered in 114 patients (44 %) during and shortly after BM diagnosis. Chemotherapy was associated with increased OS (p = 0.014). The majority of the
J Neurooncol (2012) 109:91–98
patients received at least one cycle of systemic chemotherapy. Surgical resection was performed at the primary diagnosis of BM in 13 patients (5 %) for cerebral lesions different than those treated with radiotherapy. There was no additional treatment applied for the resection cavity as the lesions were completely resected. Surgical resection did not affect OS (p = 0.391). We also investigated the impact of potential prognostic factors on survival (Table 3). RPA class I (p \ 0.001; Fig. 1b), single BM (p = 0.047) and the presence of extracerebral metastases (p = 0.042) were the strongest prognostic factor on univariate analysis. On multivariate analyses, which included all factors found to be significant in the univariate analysis, only RPA class I (HR: 2.22; 95% CI: 1.84–2.69; p \ 0.001) remained significant for predicting OS. Systemic chemotherapy (p = 0.122), extracranial metastases (p = 0.33) and single BM (p = 0.17) lost significance upon multivariate analysis.
Table 3 Results of the univariate analysis of survival Characteristic
6 months (%)
12 months (%)
SRS (n = 138)
90 (65)
FSRT 7 9 5 Gy (n = 61)
36 (59)
19 (31)
FSRT 10 9 4 Gy (n = 61)
38 (62)
21 (34)
p-value
39 (28) 0.476
Age \63 years (n = 123)
82 (67)
37 (30)
C63 years (n = 137)
82 (60)
42 (30)
72 (63)
40 (34)
102 (71)
45 (32)
0.970
Gender Female (n = 115) Male (n = 145)
0.302
Number of brain metastases 1 (n = 214)
136 (63)
69 (51)
2–3 (n = 46)
28 (67)
10 (22)
0.047
Extracerebral metastases Yes (n = 141) No (n = 119) RPA class
84 (60)
30 (21)
80 (67)
49 (41)
Class I (n = 55)
50 (90)
38 (42)
Class II (n = 115)
70 (61)
33 (29)
Class III (n = 90)
44 (49)
8 (9)
0.042
\0.001
Concurrent chemotherapy Yes (n = 114)
71 (62)
25 (22)
No (n = 146)
93 (64)
54 (37)
Yes (n = 13)
11 (85)
6 (46)
No (n = 247)
153 (62)
73 (29)
0.014
Surgery at brain diagnosis
Fig. 1 a Comparison of stereotactic radiosurgery (SRS) with 7 9 5 Gy and 10 9 4 Gy schemes with respect to overall survival in patients with brain metastases. b Survival in patients with brain metastases depending on the RPA class
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0.391
RPA recursive partitioning analysis, WBRT whole brain radiotherapy, SRS stereotactic radiosurgery, FSRT fractionated stereotactic radiotherapy
J Neurooncol (2012) 109:91–98
LPFS and RPFS The LPFS at 6 and 12 months were as follows: 84 and 73 % for the SRS group, 87 and 75 % for the 7 9 5 Gy group, and 81 and 71 % for the 10 9 4 Gy group (p = 0.191). LPFS was not affected by any of the prognostic factors. The RPFS at 6 and 12 months were as follows: 73 and 52 % for the SRS group, 71 and 58 % for the 7 9 5 Gy group and 70 and 54 % for the 10 9 4 Gy group (p = 0.136). In total, 60 patients (23 %) received WBRT, 18 patients (7 %) received surgery, 10 patients (4 %) received SRS and 14 patients (5 %) were treated with FSRT for either new or progressive cerebral lesions. The presence of extracranial metastases resulted in worse RPFS compared to the patients without systemic disease (p = 0.020). Similarly, concurrent chemotherapy (p = 0.031) and RPA I status (p \ 0.001) led to better RPFS. In multivariate analysis, only RPA I status (HR: 2.07; 95% CI: 1.45–2.13; p \ 0.001) remained significant while chemotherapy (p = 0.31) and extracranial metastases (p = 0.581) lost significance. Toxicity Patients received steroids (dexamethasone or prednisolone) in the case of BM-associated neurological deficits and/or MRI-based cerebral edema. In SRS, 7 9 5 Gy and 10 9 4 Gy groups, grade 3 acute toxicities (nausea, vomiting, headache) occurred in 3, 0 and 0 % of patients, respectively. With regards to chronic adverse effects, grade 3 chronic toxicities (alopecia, headache, neurocognitive and motor deficits, visual/hearing impairment) occurred in 6 % of the patients in SRS, 2 % in the 7 9 5 Gy group and 1 % in 10 9 4 Gy group. Overall, SRS was associated with a higher rate of toxicity (grades I–III) as compared to the 7 9 5 Gy and 10 9 4 Gy groups (14 vs. 6 vs. 2 %, respectively; p = 0.01). Importantly, the 10 9 4 Gy group presented an excellent toxicity profile with minimal side effects, both acute and chronic. Of all patients, five patients developed radionecrosis (n = 4 in the SRS group; n = 1 in the 7 9 5 Gy group) and received neurosurgical therapy. None of the patients died from the toxicity.
Discussion SRS can lead to equivalent local control and survival rates as compared to surgery in patients with BM [3]. However, lesions that are large and/or are located near critical structures are not amenable to SRS. In this retrospective analysis, we demonstrate that FSRT is an effective and safe approach for these lesions and it is associated with less
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toxicity, compared to SRS, especially in the 10 9 4 Gy group. The median OS time for the entire cohort was 9 months, being 8 months in the SRS group, 7 months in the 7 9 5 Gy group and 10 months in the 10 9 4 Gy group (p = 0.575). The 1-year LPFS was 73 % for the SRS group, 75 % for the 7 9 5 Gy group, and 71 % for the 10 9 4 Gy scheme (p = 0.191). Notably, we observed higher toxicity (grades I–III) after SRS, as compared to the 7 9 5 Gy and more prominently to 10 9 4 Gy group (14 vs. 6 vs. 2 %; p = 0.01). These are in line to the findings of other groups that investigated the outcome and toxicity of FSRT for the treatment of BM (Table 4). Low RPA class often has a prognostic role of RPA class in patients with BM after treatment with SRS and FSRT [3, 9, 20–22]. In line with these reports, RPA class I demonstrated statistical significance for better survival upon multivariate analysis in our series. Although some investigators have demonstrated that PTV could have prognostic value [8, 21], the PTV did not significantly affect survival or control in our cohort. Surprisingly, chemotherapy provided a survival benefit in the univariate analysis. We believe that this is probably due to the retrospective nature of our study as the current paradigm indicates lack of benefit after chemotherapy treatment in patients with brain metastases [23]. Importantly, chemotherapy lost significance in the multivariate analysis (p = 0.122), which is in accordance with previous reports [23]. Despite the controversy with regards to the validity of the linear-quadratic (LQ) model in predicting the biologically effective dose (BED) for high dose fractions, there is currently no evidence against its application in the clinical practice [24]. Thus, we calculated the BED for the different treatments in our study using an a/b ratio of 10 and 3 Gy for early and late effects, respectively. The BED for SRS (20 Gy; 1 fraction) was 60 Gy10 and 153 Gy3, respectively. The BED for 7 9 5 Gy scheme was 52.5 Gy10 and 93.3 Gy3, respectively. Finally, the BED values for 10 9 4 Gy scheme was 56 Gy10 and 92 Gy3, respectively. The above data indicate that FSRT is expected to result in local control that is comparable to the SRS and with the benefit of less toxicity. In previous studies investigating FSRT for the treatment of BM, the BED for acute effects varied from 37.5 to 59.5 Gy10 [8, 21]. In the cases where WBRT was used, BED was between 52.5 and 90.3 Gy10 [8, 20]. Accordingly, response rates (including SD) ranged from 90 to 100 %. In our series, response rates were 89, 92 and 90 % for SRS, 7 9 5 Gy and 10 9 4 Gy, respectively. Therefore, the BED for the two schemes of FSRT used in our studies were reasonably low and resulted in excellent responses, in agreement with observations of other groups. In regards to chronic effects, BED values of 90 up to 168 Gy3 have been reported for FSRT [20, 25]. Thus, the BED values of the FSRT schemes applied to our patients
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26
De Salles et al. [14] Tokuuye et al. [15]
32
87
61
51
150
20
27
Manning et al. [20]
Aoyama et al. [11]
Lindvall et al. [13]
ErnstStecken et al. [10]
Fahrig et al. [9]
Narayana et al. [25]
Kwon et al. [8]
64
No. of patients
Author
No WBRT
5 9 7 Gy
5 9 5 Gy
37.5/15 (in 45 metastases)
No WBRT
No WBRT
10 9 4 Gy
6 9 5 Gy
40/20
40/20
6 9 6 Gy
6-7 9 5 Gy
No WBRT
No WBRT 30/10
Only salvage
30/10
NA
NA
Previous WBRT Gy/fractions
7 9 5 Gy
5 9 8 Gy 17 Gy/ 1–3 fractions (90% isodose)
4 9 8.75 Gy (median isodose 4 9 7 Gy Dmin)
3 9 9 Gy (80–90% isodose)
2–3 9 6 Gy (isodose unclear) 7 9 6 Gy (isodose unclear)
Fractionation schedule
0.52
3.5
CR: 42 %, PR: 30 %,
6.1
head mask
SD: 42 %, PD: 10 %
contrast enhanced
PTV = GTV ? 1–2 mm
Gill-Thomas-Cosman ring and bite block
contrast enhanced
PTV = GTV ? 3 mm
SD: 45 %, PD: 0 %
TM
contrast enhanced
BrainLAB head mask & bite block PTV = GTV ? 3 mm
TM
contrast enhanced
BrainLAB
CR: 25 %, PR: 23 %,
TM
BrainLAB head mask & bite block PTV = GTV ? 3 mm
TM
contrast enhanced
Fixter plastic mask PTV = GTV ? 3 mm
TM
contrast enhanced
PTV = GTV ? 2 mm
and Alcare
CR: 15 %, PR: 30 %,
SD: 21 %, PD: 7 %
CR: 67 %, PR: 18 %, SD:13 %, PD: 3 %
LC 84 % (no WBRT) LC 100% (WBRT)
NA
TM
contrast enhanced
16 % PD Moldcare mask
PTV = GTV ? 2 mm
31 [ 25% 22 % no image-FU
GTC -frame
TM
contrast-enhanced
PTV = GTV ? 2-3 mm
Relocatable plastic
NA
Treatment technique
31 B 25 %
NA
LC 83 % (unclear time)
Lesion response
4.2
NA
3.3
2.2.
NA
5.22
Target volume (cm3)
Table 4 Review of previous studies in patients with brain metastases treated with FSRT
10.8
8.5
16
11
5
8.7
68 %
70 %
NA
76 %
NA
81 %
NA
91 %
8.3
12
NA
LPFS (1-year)
92 %
OS (months)
14.8 % (headache), 7.4 % (lethargy) Grade 3: 3.7 % (headache)
Grade 2: 7.4 % (neuropathy),
Increased steroid use: 15 %
Late: 22, 0 and 7 %, respectively
Acute: none
Increased steroid use: 52 %
Acute: none
Acute: 3.3 % Radionecrosis in 2 patients
Late: 2.7 %
Acute: 4.6 %
Late: 6 % (necrosis), 9 % (seizure),
Acute: 3 % (seizures)
Late toxicity: 2 patients
Acute: none
NA
Toxicity
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FSRT (7 9 5 Gy): 61
FSRT (10 9 4 Gy): 61
1 9 20 Gy SRS: 138
PD: 11 %, 8 % & 10 %
& bite block
TM
FSRT: BrainLAB mas
1 9 20 Gy SRS: 58
FSRT fractionated stereotactic radiotherapy, CR complete response, PR partial response, SD stable disease, PD progressive disease, LPFS local progression-free survival, OS overall survival, NA not available
SD: 19 %, 24 % & 20 %, 5.93 10 9 4 Gy
PTV = GTV ? 3 mm
SRS: Head mask, PTV = GTV ? 2-5 mm
PR: 45 %, 32 % & 44 %, 2.04 7 9 5 Gy
head
Contrast enhanced PD: 0 % & 7 %
CR: 25 %, 36 % & 26 %, 1.87 No WBRT
6 9 6 Gy FSRT: 40
Kim et al. [12]
Our data
contrast enhanced
10
71 %
Grade 3: 6, 2 and 1 % 75 %
73 % PTV = GTV ? 1 mm SD: 17 % & 26 %,
8
71 % 6 SRS: Head frame
7
Grade 3: 7 & 0 % 69 % 8 FSRT: Thermoplastic mask
PR: 68 % & 51 %,
CR: 15 % & 16 %,
2.2
5.0
30/10 (40%)
Fractionation schedule No. of patients
30/10 (20%)
LPFS (1-year) OS (months)
97
Author
Table 4 continued
Previous WBRT Gy/fractions
Target volume (cm3)
Lesion response
Treatment technique
Toxicity
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were reasonably low. The majority of those studies reported low toxicity. Notably, in two reports, the use of high BED (127 and 168 Gy3) led to dose- and normal brain volume-dependent toxicity characterised by brain edema, seizures and necrosis. The latter underline the importance of using schemes with lower doses and more fractions for large lesions. Unfortunately, to our knowledge, there are no definite guidelines to date with regards to the optimal dose to be used in FSRT for brain metastases, possibly due to the lack of data from randomised trials. Indeed, the choice of dose in the majority of centres has mostly been individual, according to the experience of the clinician and the centre. In general, the bigger the lesion and/or the more eloquent the location, the higher was the number of fractions applied, in order to decrease the risk of side effects. We chose 10 9 4 Gy for very large lesions (median volume: 5.93 cm3) and especially those very close to or even invading critical structures to minimise the risk of adverse effects, instead of 7 9 5 Gy, which was selected for relatively smaller lesions (median volume: 2.04 cm3) but still ineligible to SRS treatment. The regimen of 10 9 4 Gy was selected as the BED was comparable to SRS and was expected to better spare critical organs from radiationinduced toxicity. In addition, the number of patients with brain metastases in eloquent locations that were treated with FSRT was larger in the 10 9 4 Gy group compared to the 7 9 5 Gy group (27 vs. 13 patients, respectively). Similar dose regimens have been used by other centres. Ernst-Stecken et al. [21] also used 7 9 5 Gy for the treatment of brain metastases, as in our work. Tokuuye et al. have previously used 7 9 6 Gy and Kim et al. reported data after treatment with 6 9 6 Gy, which are comparable to the 7 9 5 Gy regimen used in our study [12, 15]. We acknowledge that different factors could potentially influence the present analysis of this retrospective study and bias cannot be excluded. Nevertheless, we believe that our study provides useful information as it directly compares the efficacy and toxicity profiles of SRS and FSRT in a relatively large number of patients with oligometastatic cerebral disease. Even though randomised clinical studies could be initiated to confirm these data, it could be difficult and ethically questionable to use SRS in larger lesions to compare the efficacy with FSRT due to the high toxicity encountered in this patient subgroup [7].
Conclusion Altogether, these data indicate that the local control conferred by FSRT is comparable to SRS. In addition, FSRT allows the application of high doses to large tumours or to
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those located near critical structures that are either ineligible for SRS or would require lowering of SRS doses, which could compromise local control. The 10 9 4 Gy fractionation scheme presented the safest toxicity profile. Conflict of interest of interest.
The authors declare that they have no conflict
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