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 cm
3 and 0 % for those >10 cm
3. 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 [
3]. 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 [
4] 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 [
29]. 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 [
7], 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. [
8]. Chang [
30] 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 cm
3) or less were 86 and 78 %, respectively, compared to 56 and 24 %, for lesions larger than 1 cm (0.5 cm
3) (
p <0.001). Other reports, defined a total tumor volume cutoff value of ≥2 cm
3 (
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.
These unsatisfying outcomes make HSRT a valid alternative for large brain metastases. Generally, the advantages of HSRT seem to be the following: i) the possibility to treat large brain lesions (≥2.1 cm) with lower risk of important radiation-induced neurotoxicity compared to single dose SRS; ii) the feasibility to treat lesions near to critical structures using few fractions of radiotherapy; iii) a theoretical advantage due to the re-oxygenation of hypoxic tumor cells between fractions; iv) an inferior risk of brain radio-necrosis compared to SRS; v) keeping a short treatment time compared to WBRT. In the recent years, several published papers about this issue, reported encouraging results with a 1-year LC ranging from 56 to 93 %, a median OS between 8 and 16 months and a 1-year rate of 34–66 %, and severe toxicity between 2 and 10 % as shown in table
3 [
14‐
25]. Unfortunately, these series are extremely heterogeneous for total dose and schedules used, number of fractions, different methodology utilized, different results recorded, more than 1 BMs treated at the same time, inclusion of small and large lesions without results divided in relation to volume of BMs, and to date a suggestion on the optimal treatment is not provided. Our series includes only patients with single, large (≥2.1 cm) BM unsuitable for surgical resection, underwent HSRT. Two different schedules were used in relation to the tumor size, 27Gy in three consecutive daily fractions or 32Gy in four consecutive daily fractions. The optimal fractionation schedule for HSRT, has not yet been established. Different total doses and schedules have been used with the aim to keep a biological equivalent dose (BED) of about 60Gy
10 (BED in Gy with α/β = 10) for tumor effects and BED of about 150Gy
3 (BED in Gy with α/β = 3) for late effects. We chose to treat patients with a total dose corresponding to a BED
10 greater than 50Gy considering the large volume treated. Using this approach, a local control rate of 96 % at 2 years was obtained. No differences were recorded in relation to the size of BM, 2.1–3 cm or 3.1–5 cm. Survival rates were also encouraging, with a median, 1 and 2-year OS of 14 months, 69 % and 33 %, respectively. Similar results were showed in the study of Minniti [
23]. Two different schedules of HSRS for 171 BMs treated were used in relation to the tumor size. Patients with tumor <2 cm received 36Gy in three fractions while patients with tumor ≥2 cm were treated with 27Gy in three fractions. The 1-year LC was 88 % and it was similar in both groups, and the median and 1 year OS was 14.8 months and 57 % respectively. The limitation of this study was that small brain lesions, potentially suitable for SRS, were included in this analysis. The study of Fahrig is one of the largest studies about this issue [
16] evaluating the outcome of 150 patients treated for 228 BM; different doses and schedules were used in relation to the size and location of the lesions. The 1-year LC was 93 % and the median and 1 year OS was 16 months and 66 % respectively but for BMs larger than 15 cm
3 (maximum diameter >3 cm) a longer schedule of HSRT (10 fractions) was also used. The other published studies are limited for number of patients enrolled, and/or for median local control and survival not reported, and/or for inclusion of patients underwent surgical resection too [
14,
15,
17,
19,
20,
24,
25]. Concerning toxicity, in different series, no severe grade III-IV neurological deficit were showed and symptomatic radio-necrosis occurred in less than 10 % of patients. Limits are that different methods were utilized for defining radio-necrosis and few studies showed data about this matter. Minniti showed that radio-necrosis occurred in nine patients (9 %), leading to severe neurologic complications in 5 (5 %) of them. The V
24Gy was the most significant predictor of radio-necrosis, with a cumulative risk of 14 % for volumes >16.8 cm
3 and 4 % for volumes ≤16.8 cm
3 [
23]. Ernst-Stecken showed that side effects, i.e., increase in T2w-signal area, duration of steroid intake and size of new or progressive necrotic centre of metastasis, were dependent on the volume of normal brain irradiated with more than 4Gy per fraction (V4Gy) [
15]. Kim, evaluating efficacy and toxicity of SRS compared to HSRT in 98 patients with BMs, showed similar LC and OS rates with a lower risk of toxicity for HSRT patients in comparison to those treated with SRS, despite the fact that HSRT was used for large lesions and lesions in adverse locations (17 % vs. 5 %,
p = 0.05) [
19]. In our series, no severe grade III–IV disorders were recorded and no visual or new motor-sensory deficit were observed for patients treated for lesions in close proximity of optical nerves, chiasmas or brainstem. Symptomatic radio-necrosis occurred in a limited number of patients (5.8 %) considering the large volume treated (91 % of lesions greater than 10 cm
3), and they were patients with lesions larger than 4.1 cm in maximum diameter and volume greater than 70 cm
3 suggesting that in these lesions a dose reduction should be considered. We are aware that our analyses has the limit of a retrospective study including patients with different histological subtypes, above all in RPA class II and in which GPA score was not represented in the entire cohort of patients. However, HSRT for patients with large brain metastases unsuitable for surgical resection has proven to be a safe and effective treatment with a high rate of local control and negligible toxicity. The use of new advanced RT techniques as volumetric modulated arc therapy permitted a high conformity for the tumor with maximum sparing of normal structures. This can be considered the main reason of the good treatment tolerance, and the lower incidence of radio-necrosis. The low toxicity recorded allowed, in case of brain distant progression, to perform a new outpatient radio-surgical treatment. More than 50 % of patients retreated are alive at about 6 months. One may argue that in our series, no WBRT was performed. Our choice, however, has proved to be winning, in fact only 12 and 24 % of patients had a BDP at 1 and 2 years, respectively. Finally, the observed OS was principally correlated with patients KPS, and controlled extracranial disease. The control of large brain metastases, however, in addition to improving quality of life, might affect survival in a selected group of patients with good KPS, controlled extracranial disease, and limited BMs.
Table 3
Some of larger published papers about hypo-fractionated stereotactic radiotherapy (HSRT) alone for large brain metastases
| 87 | 35 Gy/4 | NR | 81 | 8.7 | 39 | 5 |
| 51 | 35 Gy/5 | 7 | 76 % | 11 | NR | 2 |
| 150 | 30–35 Gy/5 | NR | NR | 16 | 66 | 10 |
40 Gy/10 | 0 |
35 Gy/7 |
| 20 | 30 Gy/5 | NR | 70 | 8.5 | 64.5 | 2 |
| 40 | 36 Gy/6 | NR | 69 | 8 | 34 | 5 |
| 39 | 35 Gy/5 | NR | 86.7 | | 64.5 | 2 |
| 135 | 36 Gy/3 | NR | 88 | 14.8 | 57 | 7 |
27 Gy/3 |
| 70 | 25 Gy/5 | 17 | 56 | 10.7 | NR | 4.3 |
| 61 | 24 Gy/3 | 9 | 69 | 21 | 60 | 7 |