This study retrospectively analyses therapeutic results in 75 patients treated with hfSRT to limited brain metastases in a primary, or recurrence, situation. Since 2006 we are offering this option to patients who suffer from limited brain metastases and where surgery or SRS is not a suitable treatment option. We applied different dose concepts dependent on primary or recurrence situation, localization and volume of brain lesion. Dose concepts with a total EQD2 >35 Gy achieved best local control rates with acceptable toxicity. 12-months LC rates of 52% are lower in comparison to other hfSRT studies or SRS probably because we used very different dose concepts [16, 22–27].
The aim of our study was to find the most suitable regime with respect to disease control and side effects. Fahrig et al. also compared different dose concepts like 5x6-7 Gy, 7x5 Gy and 10x4 Gy and achieved 12 months OS of 43%, 60% and 67%, respectively . They preferred the 10x4 Gy fractionation, depending on the size and localization of the metastases, and detected no adverse side effects. However, a trend towards higher rates of complete remission in patients with brain metastases was seen treated with 5x6–7 Gy or 7x5 Gy in comparison with 10x4 Gy . We preferred using restrictive dose concepts (EQD2 < 40 Gy) in patients with prior WBRT as well as in patients with high tumour volume or tumour proxicity to critical structures. The median EQD2 for GTV < 2 ccm was 40 Gy and for GTV ≥ 2 ccm 38 Gy. The GTV was significantly higher for metastases treated with a single dose of 3–4 Gy (median 4.76 ccm) than with 5–6 Gy (median 1.00 ccm, p < 0.001). Recent studies yielded LC rates of 58.6% after 12 months in mean volumes of 8 ccm (24 Gy in 3 fractions)  and 76% in median volumes of 4.23 ccm (5x6 Gy after prior WBRT, otherwise 5x7 Gy) . Aoyama et al. found a significant lower tumour control rate for tumours >3 ccm (35 Gy in 4 fractions) . Nevertheless, above mentioned hfSRT studies included volumes higher than 3 ccm and showed good results.
Conclusions can be drawn from our study results only to a limited extent because of the relatively small number of patients included, it being a mono-institutional series and the potential risk of selection biases due to the retrospective study design. However, we consider the results to be valuable with regard to the objective of our analysis. Conclusions of our analysis are also limited due to high diversity of dose concepts (Table 2). In our study only 48% could be classified into dose concepts defined by Fahrig et al. . Therefore, we could not see significant difference for a specific dose concept for LC or OS.
Furthermore, we detected a significant influence of the EQD2 (p = 0.004) on LC (14.9 months for doses >35 Gy and 3.4 months for doses ≤ 35 Gy) in this study.
An EQD2 >35 Gy is associated with better control rates along with higher but acceptable toxcitiy. Therefore, we consider it is most effective for tumour control.
In SRS higher absolute doses (24 Gy) are associated with higher LC (85%) after 12 months (compared to 45-49% with 15–18 Gy) . For brain metastases ≤2 ccm SRS studies found that a single time 20 Gy application seems to render superior results [31, 32].
Rades et al. achieved higher LC rates with upfront WBRT (77%) than with SRS alone (49%), and thereby showed a benefit of up-front WBRT .
Half of our patients (45%) were treated in a recurrence situation after prior WBRT. LC was not significantly different (49% after 12 months) in comparison to patients who received primary treatment (55% after 12 months). Lindvall et al. combined WBRT and hfSRT (30 Gy in 10 fractions and 17 Gy in 1–3 fractions) in 11 patients and compared them to 44 patients with hfSRT (40 Gy in 5 fractions) alone. They showed high LC rates of 100% and 84% in a short observation time (mean 3.7 months) .
Nevertheless, GTV significantly influenced OS in our study (< 2 ccm median 11.5 months ≥2 ccm median 5.4 months). Ernst-Stecken et al. defined GTV and PTV volume above 6 ccm and 13 ccm as negative prognostic factor for OS .
According to the results of Ernst-Stecken et al. brain volume receiving >4 Gy per fraction should not exceed 23 ccm . Takening this into account, overall adverse effects were only mild in our study. None of our patients suffered from seizures classified as a higher grade side effect. In contrast, 11% of patients suffered of seizures within 3 months after SRS .
A recurrence situation after WBRT or hfSRT has not shown a statistically significant influence on LC, IC or OS in our and other studies . Overall survival for hfSRT in primary and recurrence situations was median 8.8 months and 10 months, respectively. The actuarial OS of 35% one year after treatment with hfSRT is comparable to the reported SRS series (30-50%) [16, 23, 25–27] and hfSRT studies (25%) . Different studies compared SRS alone with WBRT plus a SRS boost. The omission of WBRT in the initial management of patients who underwent SRS alone did not compromise survival or intracranial control [24, 27, 34, 35]. De Potter et al.  achieved a DC at 1 year of 75%. They used 5x6 Gy as a boost in addition to WBRT. Patients with primary hfSRT treatment in our study achieved a DC of only 51% after one year and 60% of them had a WBRT as salvage therapy. Similar DC results of 36% without up-front WBRT were presented by Narayana et al. .
Therefore, up-front WBRT is worth discussing and not simply expendable to avoid neurotoxicity of the normal brain tissue. Regular MR imaging is necessary to detect cerebral progress as soon as possible. Patients with limited brain metastases should be clearly informed about all possible advantages and disadvantages of the different therapy options.