Introduction
Cerebral metastases are diagnosed in about 30% of patients with advanced tumors [
1,
2]. Lung cancer, breast cancer and malignant melanoma are the most common causes for brain metastases. Symptoms depend on localization and size including signs of increased intracranial pressure, headaches, vertigo, nausea and vomiting, paraesthesia and seizures.
Patients having more than three brain metastases are generally treated with whole-brain radiotherapy (WBRT). Oligometastatic patients with 1–3 lesions have a better prognosis and are therefore treated more aggressively. Beside neurosurgical resection stereotactic radiosurgery (SRS) is an effective treatment option for patients with 1–3 brain metastases [
3,
4]. For radiation treatment some studies have shown that SRS alone might be superior to WBRT alone for survival advantage of RPA class I patients [
5,
6]. It cannot be excluded that this effect is partially caused by the available salvage options after radiosurgery.
In three randomized trials additional WBRT showed even better intracranial tumor control and reduced neurologic causes of death but failed to improve patients overall survival and functional independence [
7‐
9]. The 1-year local control rates at the initial tumor site after neurosurgical resection or SRS +/− WBRT were about 80% [
3,
4,
7,
8]. Intracranial relapse occurred more frequently in patients having received SRS or resection only. In this context WBRT was used more often as a salvage treatment. The deferred WBRT probably improved the length of the survival and functional independence in the observation arm. The latest Cochrane Analysis of WBRT reported an improved local and distant brain control but no difference in overall survival for SRS + WBRT compared to SRS alone [
10].
SRS as well as WBRT has a risk for adverse events. Radiation necrosis appears 1–2 years after radiotherapy (RT) and cognitive decline develops over many years. For fractionated RT (<2.5 Gy/d) high cumulative doses are tolerated. Radiation induced necrosis is predicted to occur in 5% at a biologically effective dose of 120 Gy [
11]. For SRS a correlation between the target volume, dose and the risk of adverse events has been demonstrated [
12,
13]. However the tolerated doses for SRS show a great range in literature. In dose escalation study RTOG 90–05 maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors ≤ 20 mm, 21–30 mm, and 31–40 mm [
14].
The present study was performed to assess factors that have prognostic relevance on survival in cerebral metastasized patients treated with stereotactic radiosurgery and to assess side effects with a special focus on radiation induced necrosis.
Patients and methods
Patient data and dose fractionation
Between March 2000 and December 2010 340 patients with 1–3 cerebral metastases were treated with stereotactic radiosurgery.
Patients with stable systemic disease at the time of SRS or general cerebral progression during follow-up received additional WBRT. The prescribed dose for WBRT usually was 35 Gy/37.5 Gy in 14/15 fractions of 2.5 Gy or 30 Gy in 10 fractions of 3 Gy at midline, 5 fractions per week. Patients showing further single brain metastases during follow-up, but stable systemic disease, again were treated with SRS.
Head frames
For stereotactic radiosurgery a Brown-Robert-Wells (BRW) or Gill-Thomas-Cosman (GTC) stereotactic head frame was used. While the BRW frame is fixated to the head with four screws to ensure a definite connection between cranium and head frame the GTC frame is less invasive by using dental fixation. Afterwards a planning computed tomography (CT) with localizer was performed. To ensure the correct position of the head frame a depth helmet was used to measure the distance between cranium and surface of the helmet. This control was done before planning CT and immediately before stereotactic radiosurgery.
Radiation planning
For radiation planning and image fusion Radionics Xknife™ was used. The gross tumor volume (GTV) was identified and delineated in fused image of the CT and the magnetic resonance imaging (MRI). Due to spherical growth of brain metastases the clinical target volume (CTV) was set equivalent to the GTV. Regarding risk structures and anatomical borders expansion of the GTV plus 1–2 mm resulted in the planning target volume (PTV).
Dose
Radiation dose was 24 Gy for metastases with a diameter <20 mm, 18 Gy for metastases between 20–30 mm and 15 Gy for a diameter >30 mm prescribed to the 80% isodose. Due to the geometry of the metastases some patients received 20 Gy. A modified Linear Accelerator (Mevatron M/Fa. Siemens) with 6 MV photons was used for treatment. The PTV was irradiated with three to eight arcs depending on size and localization.
MRI protocol
A T1 weighted contrast enhanced sequence was used to determine the gross tumor volume. No image tilt (0°) was allowed. Slice thickness ≤ 3 mm, Inter-Slice-Spacing 0 mm.
FET-PET
For PET scan the amino acid [18 F]-fluoro-ethyl-L-tyrosine (FET) was used. FET uptake in the tissue was measured as standardized uptake value (SUV). Maximum lesion-to-brain ratios (LBRs) were calculated and time–activity curves were analyzed.
Statistics
The patient data was collected between March 2000 and December 2010. All analyses were performed using the Statistical Package for Social Sciences (SPSS, Ver. 19.0, SPSS Inc, Chicago, IL). Survival analyses were based on Kaplan-Meier estimates, univariate testing was performed by means of the log-rank test and Cox regression analysis was used to determine hazard ratios as well as to perform a multivariate analysis. A two-tailed p-value ≤ 0.05 was considered significant.
Follow-up and assessment of radiation necrosis
Follow-up was regularly performed every three months. If patients did not keep the appointments, a telephone follow-up was used. Cerebral staging was done by contrast enhanced MRI. If radiation necrosis was suspected, diagnostics was completed either by FET-PET and/or brain biopsy, or patients were treated with dexamethasone only ex juvantibus. Alternatively a control MRI was done about 4 weeks later.
Discussion
The current study was performed to define prognostic factors for survival and the incidence of radiation necrosis in cerebral metastasized patients after treatment with stereotactic radiosurgery. The median overall survival was 282 days. Different prognostic factors could be identified including Karnofsky Performance Status, RPA class, irradiation volume, prescribed dose, gender and additional WBRT. Despite WBRT and gender these factors are well known to correlate with survival prognosis. RPA classes which were created as a prognostic tool are defined by age, KPS, presence of extracranial metastases and control of primary tumor. The overall survival of patients in the study cohort was 59.2 months for RPA class I, 9.2 months for RPA class II and 4.3 months for RPA class III. Compared to other historical groups the survival time, especially for RPA class I, is rather high. Sneed et al. reported a median survival time after SRS alone or SRS + WBRT of 14 and 15.2 months for RPA class I, 8.2 and 7 months for RPA class II and 5.3 and 5.5 for RPA class III [
16]. In our study cohort only a few patients (7.6%) met criteria for RPA class I and had more favorable features.
Male patients had a significantly shortened overall survival compared to females. This could be explained by the fact that fewer women smoke than men and breast cancer, which has better prognosis per se, occurred in women exclusively. Breast cancer as histologic entity had no significantly improved overall survival. This could be explained by the limited number of cases.
In categorical analysis high dose (>18 Gy) and small irradiation volume (≤2.5 ml) correlated with prolonged survival. Both parameters might result in an increased local control rate with a decreased chance for neurological cause of death.
The univariate analysis of survival data suggested a significant survival benefit for patients that had received a whole-brain radiotherapy (SRS + WBRT: 341 days/SRS alone: 231 days; p = 0.049). Another retrospective analysis was associated with a trend towards improved survival for additional WBRT (median survival time 15.4 versus 8.3 months, p = 0.08) [
17].
None of the prospective randomized studies could confirm these findings: Adding postoperative WBRT after surgical resection of single metastases prevented brain recurrence of tumor (18% vs 70%, p < 0.001) and reduced neurologic cause of death (14% vs 44%, p = 0.003) compared to patients in the observation group. There was no significant difference between the 2 groups in overall length of survival or the length of time that patients remained functionally independent [
9].
In another randomized trial from Japan 132 patients with 1 to 4 brain metastases where either treated with SRS + WBRT (65 patients) or with SRS alone (67 patients). The median survival time and 1-year survival rate were 8.0 months and 28% for the SRS group and 7.5 months and 39% for the SRS + WBRT group (p = 0.42). The 1-year local control rate (73% vs. 89%, p = 0.003) and 1-year distant control rate (36% vs. 58%, p = 0.003) were better for the combined treatment [
7].
The latest prospective trial with 359 patients was published in 2011 by Kocher et al. 199 patients received SRS, 160 patients were treated with surgical resection. After SRS, 100 patients were allocated to the observation group, 99 were allocated to WBRT. After surgery, 81 patients received WBRT while 79 patients had no further treatment. The median overall survival time, including surgical patients, was 10.7 months for the observation group and 10.9 for WBRT group (p = 0.89). The 2-year local control rate (69% vs. 81%, p = 0.04) and 2-year distant control rate (52% vs. 67%, p = 0.023) were improved by WBRT. Death caused by intracranial progression was 44% in the observation group and 28% in the WBRT group. Salvage therapies, e.g. WBRT, had to be used more frequently in the observation group [
8]. Regarding the health-related quality-of-life no sustained decline in physical, role, and cognitive functioning were found. The latest randomized trial described transient changes in quality-of-life only [
18].
In the retrospective analysis of the data base no difference was made between WBRT as an initial or salvage treatment. Given the fact that patients with favorable histology and stable extracranial disease were not distributed equally a selection bias cannot be excluded. Under these circumstances the survival benefit for WBRT has to be judged cautiously. Local control rates were not documented.
The most common late toxicity for SRS is radiation necrosis. In 21 patients (6.2%) radiation necrosis after SRS was assumed in MRI. Radiation necrosis can be difficult to distinguish from tumor recurrence on MRI and may require the use of surgery, positron emission tomography (PET) or magnetic resonance spectroscopy (MRS). In patients having neurologic symptoms maximum SUV and dynamic evaluation of FET-PET confirmed radiation necrosis in five individuals. Additional WBRT had no influence on the occurrence of radiation necrosis. Due to low incidence in the study no predictive factors for radiation necrosis were found. While the risk of radiation necrosis after conventional radiotherapy is highest in the first 2 years after treatment, appearance of radiation necrosis after SRS can be as short as 3 months [
19]. In literature the incidence of brain necrosis varies from about 5 – 32% [
7,
8,
13,
20‐
22]. Higher rate of necrosis occur with longer follow-up [
14]. By using the pattern of time–activity curve in FET-PET local brain metastasis recurrence can be differentiated from radiation necrosis with high accuracy [
23]. Radiation dose, tumor volume and radiation treatment planning factors are predictive for radiation induced necrosis [
12,
24,
25]. In RTOG 90–05 study tumor volume > 8.2 ml and a ratio of maximum dose to prescription dose > 2 were significantly associated with unacceptable toxicity [
26]. The only predictive parameter influencing the risk of radiation necrosis described by Valery et al. was the conformity index [
27].
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LHS collected patient data and wrote the manuscript. MN performed associated statistics, designed the protocol and critically revised the manuscript. AS built the departmental database and collected patient data. NJ analyzed FET-PET. SBN, AS and FM critically revised the manuscript, too. CB provided the idea and conception and took part in the preparation of the manuscript. All authors read and approved the final manuscript.