Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection
- Pierina Navarria1,
- Federico Pessina2,
- Luca Cozzi1Email author,
- Anna Maria Ascolese1,
- Fiorenza De Rose1,
- Antonella Fogliata1,
- Ciro Franzese1,
- Davide Franceschini1,
- Angelo Tozzi1,
- Giuseppe D’Agostino1,
- Tiziana Comito1,
- Cristina Iftode1,
- Giulia Maggi1,
- Giacomo Reggiori1,
- Lorenzo Bello2 and
- Marta Scorsetti1
© The Author(s). 2016
Received: 3 March 2016
Accepted: 26 May 2016
Published: 2 June 2016
Hypo-fractionated stereotactic radiotherapy (HSRT) is emerging as a valid treatment option for patients with single, large brain metastases (BMs). We analyzed a set of our patients treated with HSRT. The aim of this study was to evaluate local control (LC), brain distant progression (BDP), toxicity and overall survival (OS).
From July 2011 to May 2015, 102 patients underwent HSRT consisting of 27Gy/3fractions for lesions 2.1–3 cm and 32Gy/4 fractions for lesions 3.1–5 cm. Local progression was defined as increase of the enhancing abnormality on MRI, and distant progression as new brain metastases outside the irradiated volume. Toxicity in terms of radio-necrosis was assessed using contrast enhanced T1MRI, T2 weighted-MRI and perfusion- MRI.
The median maximum diameter of BM was 2.9 cm (range 2.1–5 cm), the median gross target volume (GTV) was 16.3 cm3 and the median planning target volume (PTV) was 33.7 cm3 The median,1,2-year local control rate was 30 months, 96, 96 %; the median, 1–2-year rate of BDP was 24 months, 12, 24 %; the median,1,2-year OS was 14 months, 69, 33 %. KPS and controlled extracranial disease were associated with significant survival benefit (p <0.01). Brain radio-necrosis occurred in six patients (5.8 %).
In patients with single, large BMs unsuitable for surgical resection, HSRT is a safe and feasible treatment, with good brain local control and limited toxicity.
Brain metastases (BMs) occur in 20–40 % of adult cancer patients and the incidence increased two to five times over the last 40 years [1, 2]. In cases of single, large BMs, the treatment approach includes surgical resection, whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). Although surgical resection is the main treatment option, many patients are unsuitable for surgery due to their general condition, Karnofsky Performance Scale (KPS), age and comorbidity, critical location of lesions or uncontrolled primary tumor and/or extracranial metastatic site. For several years, WBRT has been considered the standard of care for these cancer patients but considering the poor local control (LC) rate in the case of large brain lesions , other radiation therapy modalities were investigated. SRS, whether combined or not with WBRT, is increasingly used for patients with solitary or limited BMs (up to four) with a recorded local control of 70–90 % at 12 months [4–7]. However, SRS, using the dose guidelines recommended by the Radiation Therapy Oncology Group (RTOG) 90-05 study, achieves a LC of 49 % in metastases between 2.1 and 3 cm and of 45 % in metastases between 3.1 and 4.0 cm . On this topic, literature data showed a 3-fold increased risk of local failure for tumor treated with 15–18Gy compared to 24Gy, with a 1-year local control <50 % . On the other hand, single large doses may be associated with an increased risk of neurologic morbidity from radiation necrosis, and this is of concern especially for lesions larger than 2.5–3.0 cm or that are in close proximity to critical structures, such as optic apparatus or brainstem [8–13]. In such cases, hypo-fractionated stereotactic radiotherapy (HSRT) using up to five fractions was employed with the aim to maintain a high local control rate whilst decreasing the late radiation-induced toxicity. There is limited evidence for the treatment of larger brain metastases, specifically those greater than 3 cm in maximum diameter. Many of published studies, included patients treated both for small and for large lesions and results were not stratified according to the tumor size [14–25]. In our department, we choose to treat patients with single large (≥2.1 cm) BMs, unsuitable for surgical resection, using a multi-fraction stereotactic radiotherapy rather than SRS in a single session. This analysis concerns only patients with single large BMs treated in this way. Primary objective was to evaluate the safety and the feasibility of HSRT in terms of toxicity and its impact on brain LC. In addition, brain distant progression (BDP) and overall survival (OS) were evaluated.
Methods and materials
Patients and procedures
Clinical outcome was evaluated by neurological examination and a brain MRI was performed two months after RT and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the irradiated volume on serial MR imaging. Distant failure, instead, was defined as the presence of new brain metastases or leptomeningeal enhancement outside the irradiated volume. LC was assessed and reported for alive patients while the OS analysis was performed on all patients. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. Radio-necrosis was assessed using contrast enhanced T1MRI, T2 weighted-MRI and perfusion-MRI. Radio-necrosis was considered as the presence of central hypo-density and peripheral enhancement on T1-weighted post-contrast imaging, with edema on T2-weighted sequences and a clear lack of perfusion without any nodular highly vascularized area within the contrast enhanced lesion on perfusion MRI. Histologic confirmation of radio-necrosis was not required except for patients in which surgical resection has been needed. Patients with uncontrolled extracranial disease, at the first examination time, underwent systemic therapy, chemotherapy, hormonal therapy or biological target therapy, as appropriate for the tumour histology.
Standard descriptive statistics (mean, standard deviation and cross tabulation analysis) were used to describe the general data behavior. Survival and recurrence time observations were plotted according to the method of Kaplan and Meier, starting from the date of HSRT. The log-rank test was used to carry out the univariate analysis, in order to investigate the prognostic role of individual variables. For analysis, variables analyzed were age, KPS, histology of primary tumor, extracranial disease status (controlled/uncontrolled) at the time of HSRT, recursive partitioning analysis (RPA) class, diagnosis- specific Graded Prognostic Assessment (DS-GPA), and size of BMs. Groups were defined according to discrete volume of each variables. For age the analysis was dichotomized according to 65 years threshold. Multivariate Cox model was used as a method to estimate the independent association of a variable set with overall survival (OS), local control (LC), and brain distant progression (BDP). Statistical software used was STATA v. 13.1.
Patients and treatments
Patients, tumor and treatment characteristics
61 years (range 30–93 years)
Other (CCC, Colon)
Stage at diagnosis of primary tumor
KPS at BM diagnosis
Other extracranial metastatic site at diagnosis of BM
BM median maximum diameter cm (range cm)
BM diameter cm
GTV median volume cm3 (range cm3)
PTV median volume cm3 (range cm3)
HSRS Total dose/dose per fraction/n fractions
27 Gy/9 Gy/3
32 Gy/8 Gy/4
Gross target volume (GTV) and planning target volume (PTV) of the entire cohort of patients treated for single large brain metastases (BMs)
Median GTV and range for the entire cohort
16.3 cm3(3.9–64.5 cm3)
Median PTV and range for the entire cohort
33.7 cm3(9.2–122.3 cm3)
Steroid dependency occurred in 12 patients who received high-dose dexamethasone for more than 6 months in relation to the increased perilesional edema. No close correlation was recorded in respect to the RT scheme used, as half of these have received 27 Gy in three fractions and the other 32 Gy in four fractions. Among these, six patients had progressive symptoms uncontrolled by medical drugs and in such patients surgical resection was required for grade 3 radio-necrosis. No severe grade IV toxicities occurred. Minor disorders were represented by grade I-II headache in 12 patients, grade I-II hydrocephalus in six, and grade I-II ischemia cerebrovascular in six. No visual or new motor sensory deficits were recorded for patients treated for lesions in close proximity of optical nerves, chiasmas or brainstem. Six (5.8 %) cases of brain radio-necrosis occurred, and surgical resection was performed. Histological data confirmed the presence of extensive radio-necrosis that occurred at a mean time of 11 months (range 10–12 months) from HSRT. Considering the few cases observed, it was not possible to evaluate the relation between dose level and volume. In these patients the BMs were larger than 4.1 cm in maximum diameter, the PTV was between 72.4 and 122.3 cm3 and the total dose given was 32 Gy/4 fractions.
Salvage treatment for intracranial/local progression
Among 36 brain relapse patients, six had local progression in site of HSRT and 30 in other brain site. The six patients with local progression had also diffuse extracranial progression and died early. About 30 patients with BDP, 21 received single section stereotactic radiosurgery (SRS) to other brain site and nine did not undergo further treatment for widespread disease progression. No patients had WBRT. Among the re-treated patients, 12 were alive at 6 months and nine patients dead within 7 months.
The treatment of patients with single, large brain metastases, unsuitable for surgical resection, is a challenge. Several radiation strategies have been used and described in literature: whole brain radiation therapy (WBRT), single dose stereotactic radiosurgery (SRS) and more recently multi-fraction or hypo-fractionated stereotactic radiotherapy (HSRT). WBRT has been the mainstay of treatment, but local control of single, large brain metastases is suboptimal [3, 4]. Nieder analyzed the efficacy of WBRT in 108 patients treated for 336 BMs. The LC rate was 52 % for metastases <0.5 cm3 and 0 % for those >10 cm3. Authors concluded that considering the low LC using WBRT to a total dose of 30Gy even for small metastases, patients should be treated with locally more effective dose and fractionation schedules when local control is the aim . As well as achieve an inadequate LC, WBRT has several drawbacks: takes more time to deliver (2–3 weeks), thereby delaying systemic therapy that in metastatic disease is fundamental; results in loss of hair which can impact on patients’ quality of life; requires the use of steroid for a longer time, generating in some cases, many different comorbidities. In addition, the neurocognitive effects of WBRT are becoming increasingly important as improved systemic therapies increase life expectancy for patients with brain metastases. The RTOG 9508 randomized trial  evaluated patients with one to three newly diagnosed brain metastases receiving SRS with WBRT or SRS alone showed a decline in learning and memory function for patients who underwent WBRT compared to SRS alone (54 % vs 24 %). Although, these data revised using a different neurocognitive test showed a minor decline in neurocognitive function, this report increased the interest in omitting WBRT when possible . Another RT strategy is represented by SRS, whether combined or not with WBRT that it is becoming the major treatment used for patients with solitary or limited BM (up to four). The RTOG protocol 90-05, suggested three dose levesl based on maximal tumor diameter , 24 Gy for lesions with maximal diameter ≤20 mm, 18 Gy in case of lesions 21–30 mm, and 15 Gy for 31–40 mm in maximum diameter. As reported by Vogelbaum a dose of 24 Gy to the tumor margin had a significantly lower risk of local failure than 15 or 18 Gy (p =0.0005; hazard ratio 0.277, confidence interval [CI] 0.134–0.573). With a 1-year local control rate of 85 % (95 % CI 78–92 %) compared with 49 % (CI 30–68 %) for tumors treated with 18 Gy and 45 % (CI 23–67 %) for tumors treated with 15 Gy. . Chang  identified a 1-cm cutoff for radiosurgical control of BMs; instead using 20 Gy or more in single fraction radiosurgery, the 1- and 2-year actuarial local control rates for lesions of 1 cm (0.5 cm3) or less were 86 and 78 %, respectively, compared to 56 and 24 %, for lesions larger than 1 cm (0.5 cm3) (p <0.001). Other reports, defined a total tumor volume cutoff value of ≥2 cm3 (p = 0.008) as a stronger predictor of overall survival, distant brain failure and local control rate (p <0.001) [10–12]. Although, comparative studies of SRS and multi-fractions radiosurgery are not available, the published data confirmed that for large BMs, using a single dose radiosurgery, local control has proven to be inadequate.
Some of larger published papers about hypo-fractionated stereotactic radiotherapy (HSRT) alone for large brain metastases
1 yr b LC%
1 yr b OS%
In conclusion, in patients with single, large BM unsuitable for surgical resection, HSRT is a safe and feasible treatment, with good brain local control and limited toxicity.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was based on a retrospective analysis of treatment charts and received approval by the Humanitas Hospital Ethical Committee. All patients, during admission, signed a consent to the use of their data for scientific scopes.
Consent for publication
Availability of data and materials
Datasets can be retrieved from authors upon formal request from interested readers. Datasets cannot be directly shared on public repositories due to the national personal data protection act.
4D, four-dimensional; AAPM, American association of physicists in medicine; BDP, brain distant progression; BED, biological equivalent dose; BM, brain metastases; CI, confidence interval; CTV, clinical target volume; DS_GPA, diagnosis-specific graded prognostic assessment; GTV, gross tumor volume; HSRT, hypo-fractionated stereotactic radiotherapy; ICRU, international commission of radiological units; KPS, Karnofsky performance scale; LC, local control; MRI, magnetic resonance imaging; OAR, organs at risk; OS, overall survival; PTV, planning target volume; RPA, recursive partitioning analysis; RT, radiotherapy; RTOG, radiation therapy oncology group; SBRT, stereotactic body radiation therapy; SCLC, small cell lung cancer; SRS, stereotactic radiosurgery; TPS, treatment planning system; WBRT, whole brain radiation therapy
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- Patchell RA. The management of brain metastases. Cancer Treat Rev. 2003;29:533–40.View ArticlePubMedGoogle Scholar
- Lin X, DeAngelis LM. Treatment of brain metastases. J Clin Oncol. 2015;33:3475–84.View ArticlePubMedGoogle Scholar
- Nieder C, Berberich W, Schnabel K. Tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys. 1997;39:25–30.View ArticlePubMedGoogle Scholar
- Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665–72.View ArticlePubMedGoogle Scholar
- Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29:134–41.View ArticlePubMedPubMed CentralGoogle Scholar
- Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483–91.View ArticlePubMedGoogle Scholar
- Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47:291–8.View ArticlePubMedGoogle Scholar
- Vogelbaum M, Angelov L, Lee S, et al. Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. J Neurosurg. 2006;104:907–12.View ArticlePubMedGoogle Scholar
- Choi C, Chang S, Gibbs I, et al. What is the optimal treatment of large brain metastases? An argument for a multidisciplinary approach. Int J Radiat Oncol Biol Phys. 2012;84:688–93.View ArticlePubMedGoogle Scholar
- Lee C, Yen C, Xu Z, et al. Large intracranial metastatic tumors treated by Gamma Knife surgery: outcomes and prognostic factors. J Neurosurg. 2014;120:52–9.View ArticlePubMedGoogle Scholar
- Baschnagel A, Meyer K, Chen P, et al. Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg. 2013;119:1139–44.View ArticlePubMedGoogle Scholar
- Sheehan J, Sun M, Kondziolka D, et al. Radiosurgery for non-small cell lung carcinoma metastatic to the brain: long-term outcomes and prognostic factors influencing patient survival time and local tumor control. J Neurosurg. 2002;97:1276–81.View ArticlePubMedGoogle Scholar
- Hasegawa T, Kondziolka D, Flickinger J, et al. Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery. 2003;52:1318–26.View ArticlePubMedGoogle Scholar
- Aoyama H, Shirato H, Onimaru R. Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull. Int J Radiat Oncol Biol Phys. 2003;56:793–800.View ArticlePubMedGoogle Scholar
- Ernst-Stecken A, Ganslandt O, Lambrecht U, et al. Phase II trial of hypofractionated stereotactic radiotherapy for brain metastases: results and toxicity. Radiother Oncol. 2006;8:18–24.View ArticleGoogle Scholar
- Fahrig A, Ganslandt O, Lambrecht U, et al. Hypofractionated stereotactic radiotherapy for brain metastases—results from three different dose concepts. Strahlenther Onkol. 2007;183:625–30.View ArticlePubMedGoogle Scholar
- Narayana A, Chang J, Yenice K, et al. Hypofractionated stereotactic radiotherapy using intensity-modulated radiotherapy in patients with one or two brain metastases. Stereotact Funct Neurosurg. 2007;85:82–7.View ArticlePubMedGoogle Scholar
- Kwon A, Dibiase S, Wang B, et al. Hypofractionated stereotactic radiotherapy for the treatment of brain metastases. Cancer. 2009;115:890–8.View ArticlePubMedGoogle Scholar
- Kim Y, Cho K, Kim J, et al. Single-dose versus fractionated stereotactic radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys. 2011;81:483–9.View ArticlePubMedGoogle Scholar
- Ogura K, Mizowaki T, Ogura M, et al. Outcomes of hypofractionated stereotactic radiotherapy for metastatic brain tumors with high risk factors. J Neurooncol. 2012;109:425–32.View ArticlePubMedGoogle Scholar
- Jiang X, Xiao J, Zhang Y, et al. Hypofractionated stereotactic radiotherapy for brain metastases larger than three centimeters. Radiat Oncol. 2012;7:36.View ArticlePubMedPubMed CentralGoogle Scholar
- Fokas E, Henzel M, Surber G, et al. Stereotactic radiosurgery and fractionated stereotactic radiotherapy: comparison of efficacy and toxicity in 260 patients with brain metastases. J Neurooncol. 2012;109:91–8.View ArticlePubMedGoogle Scholar
- Minniti G, D’Angelillo R, Scaringi C, et al. Fractionated stereotactic radiosurgery for patients with brain metastases. J Neuro-Oncol. 2014;117:295–301.View ArticleGoogle Scholar
- Rajakesari S, Arvold N, Jimenez R, et al. Local control after fractionated stereotactic radiation therapy for brain metastases. J Neurooncol. 2014;120:339–46.View ArticlePubMedGoogle Scholar
- Croker J, Chua B, Bernard A, et al. Treatment of brain oligometastases with hypofractionated stereotactic radiotherapy utilising volumetric modulated arc therapy. Clin Exp Metastasis. 2015. doi:10.1007/s10585-015-9762-x.PubMedGoogle Scholar
- Esposito M, Maggi G, Marino C, et al. Multicentre treatment planning inter-comparison in a national context: the liver stereotactic ablative radiotherapy case. Phys Med. 2015;32(1):277–83.View ArticlePubMedGoogle Scholar
- Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–51.View ArticlePubMedGoogle Scholar
- Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77:655–61.View ArticlePubMedGoogle Scholar
- Chang E, Wefel J, Hess K, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037–44.View ArticlePubMedGoogle Scholar
- Chang E, Hassenbusch S, Shiu A, et al. The role of tumor size in the radiosurgical management of patients with ambiguous brain metastases. Neurosurgery. 2003;53:272–80.View ArticlePubMedGoogle Scholar