Introduction: The most common intracranial neoplasm diagnosed in adults are brain metastases (BrM). The benefit in terms of clinical control and toxicity for stereotactic radiotherapy (SRT) has been investigated for patients with low load of BrM. Aim: The aim of this single-institution experience was to investigate the best dose schedule for five-fraction SRT (FFSRT). Methods: A retrospective analysis of patients treated for BrM with different dose schedules of FFSRT was performed. Local control (LC) and clinical outcomes were evaluated with magnetic resonance imaging at 3, 6, and 9 months. Toxicity data were also collected. Results: A total of 41 patients treated from November 2016 to September 2020 were enrolled in the analysis. Non-small cell lung cancer (51.2%) and breast cancer (24.3%) represented the most frequent primitive tumors. Treatment was performed on 5 consecutive days with prescribed dose ranging from 30 to 40 Gy, prescribed to the 95% isodose line that covered at least 98% of the gross tumor volume. Statistically significant differences (p = 0.025) with higher LC rates for dose schedules >6 Gy for fractions. Toxicity rates were not found to be higher than G1. Conclusion: The results of this retrospective analysis suggest that FFSRT for BrM seems to be safe and feasible. Our results also underline that a total dose lower than 30 Gy in 5 fractions should not be used due to the expected minor LC.

Brain metastases (BrM) are the most common intracranial neoplasms in adults, with 10–20% of patients affected by cancer, being diagnosed with BrM over their disease course [1, 2]. Whole brain radiotherapy (WBRT) is the standard of care in patients with diffuse BrM. WBRT is well known to provide improvement in neurological symptoms with overall response rates of 70%–93% [3].

Historically, WBRT has often been cited as the major cause of neurocognitive decline in cancer patients [4]. In patients with few metastases, the addition of a boost has demonstrated an increase in local control (LC) [4]. Nevertheless, recent randomized trials supported the use of single fraction radiosurgery (SRS) alone in the definitive setting, after demonstrating less neurocognitive decline compared to WBRT with SRS boost, with no difference in overall survival [5‒8].

Target lesion size and proximity to critical structures represent the main limiting factors for SRS [9, 10]. An international meta-analysis of 24 trials and other more recent studies suggest that fractionated stereotactic radiotherapy (FSRT) achieves better LC rates comparable to SRS, but with lower toxicity profile [11‒19].

Despite these promising results, no randomized trials have been performed to define the most appropriate hypofractionated approach for BrM management. The optimal dose fractionation is still unknown and requires further investigation [20].

Therefore, the purpose of this retrospective study is to analyze our single-institution experience, in order to investigate the best dose schedule for five-FSRT (FFSRT).

Patient Selection

A retrospective analysis of patients treated with FFSRT for BrM in our department was performed. Patients with different primitive diseases were enrolled retrospectively. The Eastern Cooperative Oncology Group performance status scale was collected.

Different dose fractionations were administered and patients underwent magnetic resonance imaging (MRI) checks at 3, 6, and 9 months. We evaluated the acute and late toxicity and the LC during follow-up.

Treatment Planning

Patients were positioned supine and immobilized with a personalized thermoplastic Posicast CIVCO mask. Each patient underwent simulation computed tomography, and the images were co-registered with diagnostic 1.5 T 3D-MRI.

The visible lesion and surrounding enhanced tissue were segmented as gross tumor volume (GTV) using axial contrast-enhanced T1w co-registered diagnostic images. The GTV was considered equal to the clinical target volume, according to our institutional practice. A 3 mm margin was then geometrically added to the GTV to generate the planning target volume.

International consensus guidelines were considered for organs at risk OAR contouring and dose constraints definition [21‒23]. Radiation treatment was delivered with stereotactic radiation therapy (SRT) technique on Synergy® (Elekta, Stockholm, Sweden) and Trilogy® (Varian, Palo Alto, CA, USA) linear accelerators.

Image guidance throughout the treatment was ensured through the acquisition of daily cone-beam computed tomography, with reconstructed slice thickness between 1.2 and 2.5 mm.

Treatment plans were calculated using Pinnacle3 vers.16.02 (Philips Radiation Oncology Systems, Fitchburg, WI, USA). The automatic calculation module with collapsed algorithm with convolution was used to optimize the calculation.

Radiobiology

The linear-quadratic (LQ) model is widely accepted as a simple and accurate tool to predict the biological response after irradiation. In particular, in 1989, Fowler proposed that LQ model could be used to compare different fractionation schemes of radiotherapy, determining the biological effective dose (BED) as BED = Nd (1 + d/[α/β]), where N is the total number of fractions, d is the dose per fraction and α/β ratio is a term that allows a description of the sensitivity of tissues to radiotherapy fraction size. This model has proved to be reasonably predictive of dose-response relations in the dose per fraction range from 2 Gy up to about 18 Gy [24]. For a total number of fractions N = 5, we calculated BED for doses per fraction of 6 Gy, 7 Gy, 7.5 Gy, and 8 Gy, using α/β = 10 Gy or α/β = 12 Gy for BrM (Table 1).

Table 1.

BED for dose schedule

 BED for dose schedule
 BED for dose schedule

Analysis

LC at 3, 6, and 9 months and radionecrosis (RN) which correlated with the V25 Gy and V30 Gy of the residual brain (brain – GTV), were analyzed for each dose fractionation. Statistical analysis was performed with Statistical Package for the Social Sciences (SPSS, IBM Corporation, Armonk, NY, USA, and statistical significance was set at p ≤ 0.05.

Two groups of patients were considered, the first treated with 6 Gy dose per fraction and the latter with higher dose per fraction. Differences in the two groups in percent of LC survival (yes or not) at 3 , 6, and 9 months were analyzed independently, using a χ2 test with Yates’ continuity correction.

Patient Characteristics

Forty-one patients with 57 BrM treated in our center from November 2016 to September 2020, were enrolled in this retrospective study. Nineteen patients were male and 22 females with the median age of 68 years (range 49 – 83 years), at the time of treatment. Primitive tumors were small cell lung cancer (4.9%), non-small cell lung cancer (51.2%), breast cancer (24.3%), colorectal cancer (9.7%), melanoma (4.9%), endometrial cancer (2.4%), and sarcoma (2.4%).

The Eastern Cooperative Oncology Group performance status before the treatment was 0 in 9 patients, 1 in 18 patients, 2 in 9 patients, and 3 in 5 patients. The number of lesions per patient was one (73.2%), two (17%), three (7.3%), four (2.4%), and the sites of the lesions were: cerebellar 15, frontal 16, occipital 6, parietal 10, temporal 4, and other 6. The median value of the maximum diameter of the lesions was 1.5 cm (range 0.4–3.5 cm). The metastatic tumor stage resulted in a short median follow-up of 6 months (range 1–21), with 68% of the patients performing 9 months MRI. Patients’ characteristics are reported in Table 2.

Table 2.

Patients’ characteristics

 Patients’ characteristics
 Patients’ characteristics

Radiation Therapy

Different dose fractionations were reported; radiation therapy was delivered in 5 fractions of 6–8 Gy prescribed to 95% isodose line that covered at least 98% of the GTV according to International Commission on Radiation Units and Measurements [25, 26].

The criteria used for dose selection were based on primitive tumor histology, BrM size and proximity to OAR (e.g., brainstem, optic pathways), were considered as guiding criteria for dose prescription by the different prescribing radiation oncologists. The number of lesions treated with each fractionation is as follows for 6 Gy/fr, 7 Gy/fr, 7.5 Gy/fr, and 8 Gy fractions: 36 lesions, 5 lesions, 7 lesions, and 9 lesions, respectively.

All treatment fractions were delivered on 5 consecutive days. Technical RT data are reported in Table 2.

Outcomes

For the dose schedule of 6 Gy × 5 fractions, the observed rate of LC at 3, 6, and 9 months were 69.4%, 41.7%, and 16.7%, respectively, against 81%, 76.2%, and 57.1% for the dose schedule ≥7 Gy/fr. Statistically significant differences (p = 0.025) were found in the two groups for 6- and 9-month LC (p = 0.004). Outcomes are summarized in Table 3.

Table 3.

LC for subgroups

 LC for subgroups
 LC for subgroups

Toxicities

Patients were visited during radiation therapy, and support therapy was administered throughout the treatment with low doses of steroids, with the aim to prevent inflammation-related side effects. All the patients completed the treatment without interruptions and toxicities were recorded, using the Common Terminology Criteria for Adverse Events scale version 4.

The most significant recorded side effects within the first 3 months were, nausea grade 1 (4 patients), balance disorders grade 1 (11 patients), asthenia (10 patients of grade 1 and 3 of grade 2), speech disorders grade 1 (3 patients), headache grade 1 (3 patients), and hyposthenia of the lower limbs grade 1 (3 patients) (Table 4). No late toxicities were observed, although 1 patient presented a case of asymptomatic RN on MRI at 9 months. The median value of V25 Gy of residual brain was 0.02 + 0.04 cm3 standard deviation, while the median value of V30 Gy was 0.02 + 0.09 cm3 standard deviation.

Table 4.

Toxicity acute

 Toxicity acute
 Toxicity acute

This study analyzes a single-institutional experience in FFSRT of BrM with the main objective of suggesting the best dose schedule for LC. In recent years, in patients with BrM <5, SRS and SRT have been increasingly used at the detriment of WBRT, due to increased LC and reduced cognitive decline [5, 6].

Despite the recent increase in the use of the SRS, FSRT in 3 or 5 fractions is still very widespread, especially in medium-large-sized metastatic lesions >3 cm [15, 27‒32]. The results of this study seem to be comparable to other published experiences of FFSRT as higher LC rates are shown in FFSRT with cumulative dose >30 Gy [32‒34].

In our study, we did not evaluate the combined use of SRT with targeted agents and immunotherapy which is still debated. In a recent systematic review, concomitant immunotherapy with SRT is associated with improved survival and LC, with a modest rate of RN, but there is a need for prospective studies [35].

Clinical Comparison between SRS and FSRT

Several studies compared SRS and FSRT, demonstrating safety and feasibility of both treatments. Fahrig et al. [29] showed that FSRT for large metastases and metastases located in critical brain regions, has similar tumor control rates compared with radiosurgery, without damaging normal brain tissue. Minniti et al. [17] also demonstrated that FSRT (27 Gy in 3 consecutive fractions) seemed to be an effective treatment modality for BrM >2 cm in size and is associated with improved LC and reduced risk of RN, as compared with SRS.

Furthermore, Park et al. [36] indicated that FSRT appeared to reduce tumor volume more rapidly compared with SRS, being burdened by a lower rate of severe radiation-induced toxicity in the meantime. Similarly, Kim et al. [37] showed that FSRT with 36 Gy in 6 fractions is effective and safe, with lower risks of toxicity in comparison to SRS.

Clinical Comparison between SRS and FFSRT

Alternatively, several studies also compared SRS and FFSRT. In the study of Narayana et al. [38], FFSRT (6 Gy × 5 fractions) were comparable to both surgery and SRS data for solitary BrM in terms of LC and OS, with acceptable morbidity in this cohort of patients.

Fokas retrospectively evaluated and compared the efficacy and the toxicity profile of SRS (20 Gy median dose) and FSRT/FFSRT (5 Gy × 7 fr or 4 Gy × 10 fr), for the treatment of patients with BrM. FSRT/FFSRT presented low toxicity and appeared to be an effective and safe treatment for patients affected by BrM, who resulted in not being candidates for SRS [15]. Similar survival, LC and toxicity rates were also observed by de la Pinta et al. [11] who compared SRS to FSRT (30 Gy in 5–6 fractions).

Ernst-Stecken et al. [33] showed that FFSRT 6–7 Gy/fr was an effective and safe treatment for BrM, not treatable with SRS. On the other hand, Chon compared SRS (20 Gy) to FFSRT (7 Gy/fr) for medium-sized BrM of 2.5 to 3 cm, suggesting higher safety and efficacy profile for FFSRT [12]. In addition, Lischalk et al. [34] retrospectively observed that FFSRT to a total dose of 35 Gy, appeared to be a safe and effective management strategy for single high-risk inoperable NSCLC BrM.

Financial Comparison between SRS and FSRT/FFSRT

Besides the clinical aspects, other studies analyzed the economic benefits of FSRT over SRS. Manning et al. [16] demonstrated that FSRT (9 Gy × 3) was less expensive than SRS in the treatment of selected patients with BrM and was also more comfortable for patients. They showed that the median absolute cost of SRS was USD 4,119 higher than that of FSRT.

Lindvall suggested that FFSRT (40 Gy/fr) may be an advantageous alternative to SRS. Indeed, the treatment with FSRT/FFSRT requires only few days more than a SRS procedure, moreover, FSRT/FFSRT costs are reduced, as conventional linear accelerators are adequate for the delivery of such treatments [39].

Radionecrosis

Several studies demonstrated that the risk of RN is high. The aforementioned 2018 meta-analysis by Lehrer et al. [13] observed that FSRT allows a 48–68% relative reduction of the incidence of RN for large BrM when compared to SRS, while maintaining or improving relative rates of 1-year LC compared to SRS.

Donovan et al. [19] indicated that patients receiving SRS for multiple BrM, experience a higher rate of RN than literature values. Interestingly, the maximum dose did not appear to be associated with RN risk in their cohort, while a significant association was observed for volume. Fractionated treatment might therefore play a role in reducing the RN risk for large-volume lesions. These results deviate from the study of Lischalk et al. [34] in which a total dose of 40 Gy in 5 fractions of 8 Gy was correlated to a significant increase of RN risk in FSRT setting.

Several studies investigated the possibility to identify RN predictors. Zhuang et al. [40] identified a BED dose of 74.1 Gy as the threshold, while Minniti et al. [10, 17] in their studies, identified V12 Gy > 8.5 cm3 and V18 Gy > 30.2 cm3 as significant predictors of RN in FSRT setting (9 Gy × 3).

Interestingly, Inoue et al. [41] showed that the incidence of RN increased in the long-term survival in patients treated with FFSRT with a residual brain V14 Gy ≥ 7.0 cm3. Residual brain V25 Gy < 16 cm3 and V30 Gy < 10 cm3 were recently proposed as dosimetric RN predictors in FFSRT for BRM by Andruska et al. [42].

In our study, we reported the residual brain of V25 Gy and V30 Gy, and these did not exceeded correlated constraints, although the median follow-up was lower, when compared with Andruska’s study. We ensured that all the proposed constraints (V25 Gy, V30 Gy) were respected and only 1 patient showed RN at 9 months. The patient was always asymptomatic and was addressed to close instrumental-clinical monitoring. Moreover, with respect to the recalled constraints, this very favorable RN incidence could also be related to the short follow-up in our cohort of patients.

Radiobiology

Matsuyama et al. [43] showed that BED-based prescription FSRT for BrM represents a promising strategy that may yield excellent outcomes with acceptable toxicity. We calculated BED for doses per fraction of 6 Gy, 7 Gy, 7.5 Gy, and 8 Gy, using α/β = 10 Gy or α/β = 12 Gy for BrM. The maximum dose BED10 was 72 Gy and dose BED12 66.7 for 8 Gy per fraction. However, these BEDs respect the predictive value of RN of Zhuang’s et al. [40] study.

In a recent dose fractionation comparison study for the treatment of BrM, no difference in LC or RN was observed between FSRT and SRS. In this study, Remick et al. [18] suggested that a BED10 ≥ 50 Gy may improve LC for FSRT. Similarly, Jeong et al. [44], in a study of FSRT for large BrM, showed total prescription dose when ≥35 Gy was significantly correlated with LC. Dupic et al. [45] postulated that dose prescription should provide for a GTV BED12 98% ≥ 52.4 Gy, to significantly improve LC (92% vs. 70%, p = 0.030), getting closer to a 100% 1-year LC when ≥53.4 Gy were reached.

In a systematic review, Wiggenraad et al. [46] studied dose-effect relation in FSRT for BrM. They concluded that FSRT for BrM should preferably be applied with a BED12 of at least 40 Gy corresponding with a single fraction of 20 Gy, two fractions of 11.6 Gy, or three fractions of 8.5 Gy, associated to 1-year LC rates >70%. Although the LQ model is debated at high dose per fraction, these studies suggest that BED increase may explain the efficacy of FSRT in BrM.

Kirkpatrick et al. [47] showed that FSRT has theoretical radiobiological advantages as shown by BED isoeffect plots calculated with the LQ model. This is probably due to the better balance between lower BED2 (associated with normal tissue toxicity) and higher BED10 (associated with control of rapidly proliferating tumors), which should produce lower toxicity and better tumor control for FSRT than SRS schemes.

In addition, Shuriak et al. [48] analyzed tumor control probability data for BrM from 2,965 SRT patients, covering a wide range of doses and fraction numbers. They concluded that distinct tumoricidal mechanisms do not determine tumor control at high doses/fraction, showing that multi-fractions schemas seem to be more effective than single fraction. It could be hypothesized that tumor reoxygenation plays a role in these findings.

Although this study has major biases such as small number of patients and significant BrM size variability, FFSRT for BrM appeared to be safe and feasible and we conclude that a total dose higher than 30 Gy in 5 fractions should be used due to the LC rates. Therefore, this study suggests to deliver doses ranging from 7 to 8 Gy in FFSRT. The extension of the follow-up period for these patients will help us in reaching more robust results for LC and RN rates, providing more information to support clinical decision-making.

In conclusion, FSRT may be appropriate for the treatment of large lesions, as allowing higher doses administered did not increasing the risk for complications (i.e., RN). A prospective randomized trial comparing SRS and FSRT on BrM would give us further indication as to which technique is more effective and safer.

The study was conducted according to the guidelines of the declaration of Helsinki. This study protocol was reviewed by the institutional review board of Villa Santa Teresa Hospital, Bagheria, Palermo, Italy. Signed document is provided attached. Approval from institutional review board was provided on November 23rd, 2021. Patients enrolled signed an informed consent for data collection and publication, according to the study design requirements and also to department regulation.

The authors have no conflicts of interest to declare.

All authors received no specific funding for this work.

Antonio Piras contributed to the paper conceptualization and to methodology definition, data analysis, and original draft writing. Luca Boldrini contributed to the paper conceptualization and to methodology definition, data analysis, and original draft writing. Sebastiano Menna contributed to the paper methodology definition, data analysis and curation, and original draft writing. Antonella Sanfratello contributed to the paper methodology definition, data analysis and curation, and original draft writing. Andrea D’Aviero contributed to the paper methodology definition, data analysis and curation, and original draft writing. Davide Cusumano contributed to the paper conceptualization and to methodology definition and original draft writing. Luciana Di Cristina contributed to the paper final supervision. Marco Messina contributed to the paper final supervision. Massimiliano Spada contributed to the paper final supervision. Tommaso Angileri contributed to the paper conceptualization and to the paper final supervision. Antonino Daidone contributed to the paper conceptualization and to the paper final supervision.

The data presented in this study are available on request from the corresponding author.

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