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Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases

Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain... Background and purpose: To evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT ) combined with whole brain radiotherapy ( WBRT ) in patients with brain metastases (BMs). Materials and methods: From May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18 Gy/3F) + WBRT (40 Gy/20F). The RECIST 1.1 and RANO‑BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS‑BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment. Results: Intracranial objective response rates (iORR) using the RECIST 1.1 and RANO‑BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6‑ and 12‑month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression‑free survival (iPFS) was not reached (range 0–23 months). The 6‑, 12‑, and 24‑month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST ) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS‑BM, and GGS classes. No acute toxicities of grade 3 or higher were noted. Conclusion: HFSRT combined with WBRT is a safe and effective local treatment modality for BM patients. Keywords: Brain metastases, Whole brain radiotherapy, Hypofractionated stereotactic radiotherapy, Efficacy, Safety Introduction penetration through the blood–brain barrier (BBB). The The development of brain metastases (BMs) is a com - current standard local treatment for BMs, consisting of mon complication in patients with advanced malignant a multimodal approach including surgery, stereotactic tumor, 10–40% of patients with solid tumors will develop radiosurgery (SRS), hypofractionated stereotactic radio- BMs over their clinical course [1]. The treatment of BMs therapy (HFSRT) and whole brain radiotherapy (WBRT) mainly includes systemic and local treatment, but con- [2, 3]. With the development of radiotherapy, the role of ventional systemic therapy often achieves unreliable surgery in local treatment is gradually reduced, and the radiotherapy is more recommended as the initial local treatment for BMs patients [4]. *Correspondence: phhksc@126.com; xy3caopg@csu.edu.cn Recently, HFSRT has been increasingly used to treat Department of Oncology, The Third Xiangya Hospital of Central South BMs [5, 6]. Some reports describing the treatment results University, Changsha, People’s Republic of China © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xie et al. Radiation Oncology (2022) 17:132 Page 2 of 10 of HFSRT versus those of SRS, indicated that HFSRT from 18 to 80  years. The exclusion criteria were: (1) had similar efficacy and lower toxicity compared to SRS, patients with a history of WBRT, SRT, or any other form especially for large lesions [7, 8]. In addition, the ideal of intracranial irradiation, (2) patients who received fol- dose-fractionation scheme of HFSRT is controversial low-up for < 1 month. [9, 10]. In many previous studies, patients with a poor The study was approved by the institutional review Karnofsky performance status (KPS) were considered board of our hospital; no patient consent was required ineligible for HFSRT [7, 11], but it remains unclear that owing to the retrospective study design. whether patients with a poor KPS (defined as KPS < 70) HFSRT was delivered by Linear Accelerator (Varian, due to BMs are ineligible for HFSRT [12]. As for WBRT, USA) at our institution. Patients were immobilized in a despite the potential risk of WBRT damage to neuro- supine position with a thermoplastic head mask fixa - cognitive function, studies have shown that it can sig- tion system (Klarity, Guangzhou, China), simulating a nificantly reduce intracranial tumor recurrence, and its high-resolution thin slice (1.2  mm) computed tomog- effect on neurocognitive function is much less than that raphy (CT). The target volumes and organs at risk were of patients with neurological impairment or loss caused contoured using the Eclipse version 11.0 (Varian, USA) by tumor progression [13, 14]. And it was observed in our treatment planning system. Gross tumor volume (GTV) clinical experience that the intracranial recurrence rate of of HFSRT was defined based on the enhanced volume patients with BMs without WBRT treatment was higher; that was detected during MRI T1-weighted contrast- thus, WBRT might be reserved in selected patients. enhanced sequencing. A 3.0  mm three-dimensional Conversely, the response and progression criteria used expansion was applied to the GTV to create the planning in clinical trials on BMs are disparate [15]. The Response gross tumor volume. Patients were treated with   True- Evaluation Criteria in Solid Tumors (RECIST) criteria Beam  Linear Accelerator (Varian, USA). Typical target generalizes the complexity of tumor geometry to a lin- volumes for BMs are shown in Fig.  1. The prescription ear dimension, disregarding the indication that lesion dose of HFSRT was 18  Gy in 3 fractions, and the pre- enlargement after treatment includes both radiation scription dose of WBRT was 40  Gy (2  Gy per fraction) necrosis and disease progression [16]. The Response for whole brain planning target volume. The median time Assessment in Neuro-Oncology Brain Metastases between diagnosis of BMs and HFSRT was 16.5  days. (RANO-BM) standard is currently a comparatively com- Patients received HFSRT daily, followed by WBRT, from prehensive evaluation standard, but it requires confirma - Monday to Friday; no treatment was administered over tion by more clinical studies [15]. the weekends. It seems noteworthy that the prognostic indexes (PIs) Follow-up of patients included the collection of clini- that are widely used in clinical practice include the recur- cal and head imaging data. Enhanced MRI or CT evalua- sive partitioning analysis (RPA) class [17] and the graded tions were scheduled for before treatment, 1 month after prognostic assessment (GPA) score [18]. With the grad- HFSRT, and every 3  months subsequently, until treat- ual increase in the application of local treatments, some ment failure or death. The assignment of central nervous scholars have begun to study prognostic scoring systems system response was independent of systemic disease that are based on stereotactic radiotherapy (SRT), such response. The treatment response of BMs was classified as the score index for radiosurgery (SIR) [19], the basic as complete response (CR), partial response (PR), stable score for BM (BS-BM) [20], and the golden grading sys- disease (SD), and progressive disease (PD), according to tem (GGS) [21]. It has not been established which PI is the RECIST (version 1.1) [22] and RANO-BM criteria most appropriate for patients with BMs who are receiv- [15]. Acute toxicity was classified according to the Com - ing HFSRT + WBRT. mon Terminology Criteria for Adverse Events (CTCAE) This study aimed to evaluate the efficacy and toxicity of version 4.0. Radionecrosis was diagnosed based on MRI HFSRT + WBRT in patients with BMs. We also sought to changes (including diffusion-weighted imaging, perfu - determine which of the five PIs was most suitable in our sion-weighted imaging, arterial spin labeling, and MR study, and we compared the accuracies of RECIST 1.1 spectroscopy) consistent with necrosis (central hypoden- and RANO-BM standards for efficacy evaluation. sity and peripheral enhancement on T1-weighted post-contrast imaging, with edema on T2-weighted Materials and methods sequences) in the setting of new neurologic symptoms or From May 2018 to July 2020, we enrolled patients with a new steroid requirement [23]. BMs who underwent HFSRT + WBRT in our hospital. The primary endpoint was intracranial local control The inclusion criteria were: (1) patients with histologi - (iLC). The iLC was defined as any intracranial lesion that cally confirmed malignancies who had 1–10 intraparen - did not meet the criteria for PD, in the absence of new chymal brain metastases and (2) patients aged ranged intracranial lesions. The intracranial objective response Xie  et al. Radiation Oncology (2022) 17:132 Page 3 of 10 Fig. 1 Target volumes of radiotherapy for brain metastases rate (iORR) was defined as proportion of patients who 50 patients with a total of 111 lesions. The median time obtained intracranial CR and PR. The intracranial pro - interval between primary tumor diagnosis and the mani- gression-free survival (iPFS) was defined as time between festation of BMs was 7.8 months (range 0–83.1 months). the start of HFSRT and intracranial PD. The secondary Metachronous BMs were considered present when the endpoint were OS and the safety of treatment. The OS time between primary tumor diagnosis and the occur- was defined as the time from HFSRT to death or loss to rence of intracranial metastasis exceeded 3  months follow-up. [24]. The median age of all patients was 56  years (range Numerical variables are expressed as median, inter- 31–77). The median number of target BMs was 2 (range quartile range (IQR), and range. Qualitative data are 1–6). The median diameter of lesions was 2.30 cm (range expressed as frequency and percentage. The Kaplan– 0.60–5.50 cm), and the median size of GTV was 8.56 cm Meier method was used to construct survival curves and (range 0.87–88.28 cm ). determine the median survival time (MST). The Cox proportional hazards model was used in univariate and multivariate analyses. The confidence interval (CI) was Intracranial efficacy designated 95%. Patients who did not undergo CT/MRI in our institu- tion before and after HFSRT were excluded. Eventually, 29 patients were included in intracranial efficacy analy - Result sis. The number of BMs in the patients varied between Patient and lesion characteristics 1 and 6, and the median GTV size was 7.24  cm (range Between May 2018 and July 2020, we enrolled 54 patients 0.87–88.28  cm ). Only 42 target lesions could be evalu- who had undergone HFSRT + WBRT. Of these patients, ated by the RECIST 1.1 criteria because the RECIST 1.1 2 patients were followed up for < 1  month, 1 patient had criteria stipulates that each organ can have a maximum a primary tumor with no pathological diagnosis, and of two target lesions; 48 target lesions could be evaluated 1 patient was 83  years old. These four patients were by the RANO-BM criteria. excluded from the analysis. The final analysis included Xie et al. Radiation Oncology (2022) 17:132 Page 4 of 10 Fig. 2 Tumor responses to hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy. Plane A shows the best response of patients evaluated by the RECIST 1.1 criteria. Plane B shows the best response of patients evaluated by the RANO‑BM criteria. The bars indicate the best percent change in target tumor burden from baseline. Letter A denotes a patient with a > 20% increase in the sum of the longest diameters of target lesions, but the absolute value of the diameter increase was only 3 mm; therefore, the efficacy assessment remains as SD. Letter C denotes a patient who was suspected to have a new intracranial lesion, but the lesion was < 10 mm in diameter on consecutive reexaminations and were assessed as SD. The letters B, D, and F indicate three patients with different numbers of target lesions in the two evaluation criteria, who had the same evaluation results. The letter E indicates a patient with different numbers of target lesions in the two evaluation criteria, which resulted in different evaluation results. The letter G denotes a patient with reduced target lesions but multiple new intracranial lesions. Plane C shows the intracranial progression‑free survival of the 27 patients. patients with efficacy evaluations of PD, one with target lesion progression and the other with distant intracranial progression. The median iPFS was not reached (range 0–23  months). At the time of data cutoff, 20 of the 27 intracranial controls (74.1%) had ongoing intracranial control (Fig.  2c). Of the 7 patients who progressed dur- ing follow-up, 2 had target lesion progression and 5 had distant intracranial progression. Analysis of survival At the time of analysis (January 2021), 27 patients (54.0%) had died. Three patients from radiologically confirmed intracranial progression, 14 from extracranial progres- sion, 7 from unspecified progression or unknown causes, and 3 from clinical complications related to systemic dis- ease (pulmonary infection, multiorgan failure and hem- orrhage of digestive tract). The median follow-up time was 9.3 months (IQR, 3.7–16.2) for 50 patients. The MST was 13.6  months (95% CI 9.0–18.2  months) and the 6-, 12-, and 24-month actuarial OS rates were 74.2%, 58.2%, and 22.9%, respectively (Fig. 3a). Eight potential prognostic variables were included in univariate analyses. As shown in Table 1, only KPS score (HR 5.455; 95% CI 2.384–12.482; p < 0.001) was statisti- cally significant. The median OS was 2.8  months (range 2.0–17.9) for patients with KPS < 70. For patients with We recorded the greatest change from baseline in KPS ≥ 70, the MST was 16.5  months (95% CI 12.2– the longest diameter of target lesions and evaluated 20.7 months), and the 6-, 12-, and 24-month actuarial OS treatment efficacy based on CR, PR, SD, and PD in the rates were 83.8%, 70.5%, and 29.7%, respectively (Fig. 4a). RECIST 1.1 (Fig.  2a) and RANO-BM criteria (Fig.  2b). Sex (HR 4.546; 95% CI 1.601–12.907; p = 0.004), KPS The iORR of the 29 patients using the RECIST 1.1 and score (HR 10.754; 95% CI 3.911–29.571; p < 0.001), and RANO-BM criteria was 62.1% and 58.6%, respectively. GTV size (HR 0.288; 95% CI 0.118–0.698; p = 0.006) were The iLC rate was 93.1% for both criteria, with the 6- and significant factors in the multivariate analysis (Table 1). 12-month iLC rate of 90.8% and 57.4%, respectively. Two Xie  et al. Radiation Oncology (2022) 17:132 Page 5 of 10 Fig. 3 Kaplan–Meier curve of overall survival in patients with brain metastases. A Kaplan–Meier curve of overall survival in patients with different KPS scores. B Overall survival for different RPA scores (n = 50); C Overall survival for different GPA scores (n = 50); D Overall survival for different SIR scores (n = 50); E Overall survival for different BS‑BM scores (n = 50); F Overall survival for different GGS scores (n = 50) Xie et al. Radiation Oncology (2022) 17:132 Page 6 of 10 Table 1 Median survival time according to potential factors and 17.9 months (95% CI 8.1–27.6 months) and 12.9 months the results of univariate and multivariate analyses (95% CI 6.2–19.6  months), respectively (HR 0.460; 95% CI 0.166–1.278; p = 0.136). Variables N (%) MST (months) P value Univariate Multivariate The five PIs Patients were classified into 3 or 4 classes, according to Sex 0.146 0.004 the corresponding grading requirements of PRA, GPA, Male 32 (64.0) 12.4 SIR, BS-BM, and GGS. Patient characteristics and sur- Female 18 (36.0) 23.2 vival analysis for each PI are listed in Table  2. Survival Age 0.532 0.630 curves are shown in Fig.  3. OS was significantly associ - < 60 27 (54.0) 12.9 ated with the RPA, SIR, BS-BM, and GGS classes. There ≥ 60 23 (46.0) 15.4 was no statistical significance between the GPA classes. KPS < 0.001 < 0.001 ≥ 70 41 (82.0) 16.5 BM‑related symptoms < 70 9 (18.0) 2.8 Of the 50 enrolled patients, 39 had symptoms associ- Primary tumor 0.619 – location ated with BM prior to treatment and 11 were asymp- Lung cancer 39 (78.0) 13.6 tomatic at the time of BM diagnosis. These 39 patients Others 11 (22.0) 12.4 were divided into two groups according to their KPS Extracranial 0.205 0.124 score. All 9 patients with KPS < 70 had BM-related metastases symptoms before treatment, which mainly included Existent 31 (62.0) 12.4 muscle weakness, dizziness, headache, unsteady gait, None 19 (38.0) 15.4 numbness, blurred vision or partial blindness, and Contemporane- 0.615 – symptomatic epilepsy. These symptoms seriously ous BM Yes 19 (38.0) 12.9 No 31 (62.0) 13.6 Table 2 Patient characteristics and survival analysis for the five Number of BMs 0.872 – prognostic indices Single 19 (38.0) 12.9 PI Grade No. of patients (%) MST (months) p Multiple 31 (62.0) 15.4 GT V (cm ) 0.092 0.006 RPA < 0.001 < 10.0 29 (58.0) 16.7 Class I 7 (14.0) 23.8 ≥ 10.0 21 (42.0) 12.9 Class II 34 (68.0) 16.5 MST, median survival time; BMs, brain metastases; GTV, gross tumor volume Class III 9 (18.0) 2.8 GPA 0.177 0–1.0 13 (26.0) 16.7 1.5–2.5 30 (60.0) 12.4 3.0–4.0 7 (14.0) 24.3 SIR < 0.001 1–3 11 (22.0) 3.0 4–7 36 (72.0) 16.5 8–10 3 (6.0) 27.8 BS‑BM 0.010 0 9 (18.0) 3.5 1 20 (40.0) 12.4 2 10 (20.0) 15.4 3 11 (22.0) 24.3 Fig. 4 Changes in the Karnofsky performance status (KPS) score GGS < 0.001 4 weeks after hypofractionated stereotactic radiotherapy (HFSRT ) in 0 12 (24.0) 23.2 nine patients with KPS score < 70 before treatment 1 25 (50.0) 16.5 2 10 (20.0) 12.4 3 3 (6.0) 2.8 Survival analysis was performed for lung adenocar- cinoma patients who were treated with (15 patients) or MST, median survival time; RPA, Recursive Partitioning Analysis; GPA, Graded Prognostic Assessment; SIR, Score Index for Radiosurgery; BS-BM, Basic Score for without (10 patients) targeted therapy, and the MST was Brain Metastases; GGS, golden grading system Xie  et al. Radiation Oncology (2022) 17:132 Page 7 of 10 Safety of treatment affected the quality of life of the patients. Most of the Radiation toxicities are reported using the CTCAE (ver- patients showed significant improvement in dizzi - sion 5.0). Regarding acute toxicity, all patients tolerated ness, headache, and limb weakness, but no significant the treatment well with no ≥ grade 3 toxicities. Only improvement in vision loss was associated with BMs. grade 1 or 2 adverse events were reported. The most One patient with symptomatic epilepsy before treat- common side effect was fatigue. Concerning late toxicity, ment was poorly managed with sodium valproate, intra-tumoral hemorrhage complications occurred in one with no recurrence of seizures after treatment. For patient (2%) 9  months after treatment completion, but patients with KPS score < 70, symptoms related to this did not progress into a neurologic degradation. BMs before and after treatment and changes in KPS score are shown in Table  3 and Fig.  4, respectively. The Discussion main symptoms in patients with KPS ≥ 70 included HFSRT + WBRT showed good results in terms of effi - headache, dizziness, muscle weakness, and numbness. cacy, toxicity and survival time. Symptoms improved in some patients after treatment, Based on previous clinical experience and the results while some symptoms such as blurred vision did not of this study, we considered that WBRT could not be improve significantly (Table 4 ). Table 3 Symptoms related to brain metastases in nine patients with KPS score < 70 pre‑treatment and 4 weeks after treatment Patient Pre‑treatment Four weeks after treatment Main symptoms KPS score Symptoms KPS score 1 Muscle weakness right‑sided and dizziness 30 Relief of muscle weakness and dizziness 60 2 Left eye hemianopsia and Headaches 40 No change in visual acuity; relief of headaches 40 3 Symptomatic epilepsy 40 Relief of seizure 60 4 Facial spasm, glossolalia, and dizziness 50 Relief of glossolalia and dizziness 60 5 Dizziness and blurred vision 50 Relief of dizziness 60 6 Muscle weakness in the lower limb 60 Roughly as before 60 7 Numbness of the lower limb 60 Relief of numbness 70 8 Numbness of the right limb and nausea 60 Roughly as before 60 9 Dizziness and unsteady gait 60 Relief of dizziness and unsteady gait 70 Table 4 Symptoms related to brain metastases in patients with KPS score ≥ 70 pre‑treatment and 4 weeks after treatment Symptoms Number of patients Pre‑treatment Four weeks after treatment Upturn No change Deterioration New symptoms Headache 12 11 1 0 0 Dizziness 10 5 5 0 0 Nausea 3 2 1 0 0 Vomiting 4 3 1 0 0 Tremor 1 1 0 0 0 Muscle weakness in the upper limb 3 2 1 0 0 Muscle weakness in the lower limb 5 3 2 0 0 Motor weakness 4 3 1 0 0 Numbness 6 4 2 0 0 Unsteady gait 2 1 1 0 0 Glossolalia 2 1 1 0 0 Blurred vision 2 0 2 0 0 Hiccup 1 0 1 0 0 Xie et al. Radiation Oncology (2022) 17:132 Page 8 of 10 ignored. Some studies suggest that SRT can be consid- were not uniformly recommended in different studies, ered a standard treatment that is a less toxic alterna- and there was a large discrepancy between the expected tive to SRT + WBRT [25]. However, WBRT reduction of and actual survival [18, 38–40]. brain tumor recurrence rate may translate to improved In this study, we used two instruments for efficacy survival in patients with intracranial tumor progres- evaluation. There was no significant difference in effi - sion; thus, it seems reasonable to suggest that the addi- cacy outcomes between the two criteria; this was pos- tion of WBRT may affect survival outcomes in selected sibly due to: (1) the small number of patients included patients [26, 27]. Wegner RE et  al. reviewed 36 patients in the efficacy analysis, (2) of all patients treated with who were treated with HFSRT alone (24 Gy in2-5F), with HFSRT, only one patient showed asynchronous changes 6- and 12-month LC rates of 73% and 63%, respectively in the intracranial lesions, which may have attenuated [28]. Kim et  al. reviewed 46 patients who were treated the difference in the number of target lesions between with HFSRT alone. Patients were randomized to receive the two criteria, and (3) although corticosteroid use is 24, 27, or 30 Gy in 3 fractions, with 12-month LC rates of not included in the RECIST 1.1 criteria, no patient who 65%, 80% and 75%, respectively [11]. The intracranial LC met the imaging criteria was ineligible for corticoster- rate in this study was superior to the two studies men- oid use, thus eliminating the potential discrepancy from tioned above, further studies are needed to investigate this definition. The RANO-BM criteria, may provide a the most suitable population for HFSRT + WBRT. more comprehensive assessment of patient outcomes In our study, the HFSRT group received a smaller total than the RECIST 1.1 criteria. However, in our practical dose and number of fractions than those reported in the application of the RANO-BM criteria we found that the literature. We reviewed recent studies on patients with criteria complicate the assessment of patients with BMs BMs who were treated with HFSRT or HFSRT + WBRT; in clinical trials. the most common HFSRT dose was 27  Gy/3F (range We believe the results of the present study are impor- 24–41  Gy/2–6F), the OS rates ranged from 13.0 to tant for several reasons. First, we used the same HFSRT 69.0% at 12  months, and the MST ranged from 12.2 to and WBRT scheme for the entire study, reduced treat- 16.2  months [6, 7, 11, 28–31]. Our results are also com- ment-derived differences in the analysis of treatment parable to those of several studies on HFSRT for BMs in efficacy. Second, to our knowledge, our study involved the surgical cavity. Two studies assessed the efficacy and the lowest total radiation dose and number of fractions, safety of postoperative HFSRT in patients with BMs. The but we observed desirable survival outcomes. Third, 12-month OS was 62% and 58%, respectively. The radia - we analyzed survival outcomes and symptom and KPS tion necrosis rate was 5.1% and 8.9%, respectively [32, score improvement in patients with a poor KPS post- 33]. treatment. Our findings demonstrate that patients with PI are beneficial to clinical and therapeutic decision- KPS < 70 may not be unfavorable candidates for SRT. making. However, GPA classes were not statistically Lastly, to our knowledge, this is the only study that has significant in our analysis. Conversely, many previous employed both RECIST 1.1 and RANO-BM criteria to studies concluded that GPA is a reliable, simplistic, and evaluate the HFSRT + WBRT efficacy for BM. powerful tool for predicting survival [18, 34]. The pos - This study was limited by its retrospective design. sible reasons for this difference include the following. During the radiotherapy and follow-up periods, First, GPA includes the number of metastases and does patients also received systemic treatments, which not involve metastasis volume. We noted that the num- might influence their survival and local control. In ber of BMs in the patients and the GTV size were not addition, we did not avoid the hippocampal regions proportional. The median GTV was greater in patients during irradiation in WBRT. We also did not evaluate with 1 BM than in patients with 2–3 BMs (9.45 and the neurocognitive function of patients, post-treatment 7.25 cm , respectively). Some studies concluded that using scores. brain tumor volume had a significant association with OS [35, 36]. Second, the primary tumors in our study included lung cancers, breast cancers, gastrointestinal Conclusions cancers, and gynecologic tumors. There was marked Despite limitation mentioned above, these data demon- heterogeneity in outcomes among patients with BMs strated that, for patients with BMs, HFSRT combined and the differences in outcome were not only related to with WBRT is a safe and effective local treatment modal - the diagnosis but also to diagnosis-specific prognostic ity. Patients with a poor KPS due to BMs can also benefit factors [34, 37]. Further, the dissimilar proportions of from the treatment. The response and progression crite - patients within the prognostic classes could be another ria for patients with BMs remain to be explored in fur- reason. In addition, we found that the PIs in our study ther studies. Xie  et al. Radiation Oncology (2022) 17:132 Page 9 of 10 Acknowledgements 11. Kim KH, Kong DS, Cho KR, et al. Outcome evaluation of patients treated We wish to thank Hui‑ Qun Fu, Xue‑ Yuan Tang, Yan‑Ming Cao, Juan Ding, with fractionated gamma knife radiosurgery for large (> 3 cm) brain Cheng‑Hui Huang, Ke Cao, Xi Pan, Jun Zhang and Ze ‑ Wen Song for their help metastases: a dose‑ escalation study. J Neurosurg. 2019;133:675–84. with data collection. 12. Kubicek GJ, Turtz A, Xue J, et al. Stereotactic radiosurgery for poor perfor‑ mance status patients. Int J Radiat Oncol Biol Phys. 2016;95(3):956–9. Author contributions 13. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole ‑brain radio ‑ X‑ YX and H‑HP analyzed and interpreted the patient data. And X ‑ YX was a therapy versus observation after radiosurgery or surgical resection of one major contributor in writing the manuscript. XZ, Y‑LP, and ZZ collected patient to three cerebral metastases: results of the EORTC 22952–26001 study. J data. P‑ GC made the radiotherapy plan. All authors read and approved the Clin Oncol. 2011;29(2):134–41. final manuscript. 14. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole‑brain Funding radiotherapy versus observation in patients with one to three brain This work was supported by the New Xiangya Talent Project of the Third metastases from solid tumors after surgical resection or radiosurgery: Xiangya Hospital of Central South University (Grant number: 20180301). quality‑ of‑life results. J Clin Oncol. 2013;31(1):65–72. 15. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for Availability of supporting data brain metastases: proposal from the RANO group. Lancet Oncol. All data generated or analysed during this study are included in this published 2015;16(6):e270–8. article. 16. Follwell M, Khu K, Cheng L, et al. 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Analysis of survival of patients with brain metastases according to prognostic indexes and treatment strate‑ gies. Turk Neurosurg. 2020;30(6):822–31. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases

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Abstract

Background and purpose: To evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT ) combined with whole brain radiotherapy ( WBRT ) in patients with brain metastases (BMs). Materials and methods: From May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18 Gy/3F) + WBRT (40 Gy/20F). The RECIST 1.1 and RANO‑BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS‑BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment. Results: Intracranial objective response rates (iORR) using the RECIST 1.1 and RANO‑BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6‑ and 12‑month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression‑free survival (iPFS) was not reached (range 0–23 months). The 6‑, 12‑, and 24‑month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST ) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS‑BM, and GGS classes. No acute toxicities of grade 3 or higher were noted. Conclusion: HFSRT combined with WBRT is a safe and effective local treatment modality for BM patients. Keywords: Brain metastases, Whole brain radiotherapy, Hypofractionated stereotactic radiotherapy, Efficacy, Safety Introduction penetration through the blood–brain barrier (BBB). The The development of brain metastases (BMs) is a com - current standard local treatment for BMs, consisting of mon complication in patients with advanced malignant a multimodal approach including surgery, stereotactic tumor, 10–40% of patients with solid tumors will develop radiosurgery (SRS), hypofractionated stereotactic radio- BMs over their clinical course [1]. The treatment of BMs therapy (HFSRT) and whole brain radiotherapy (WBRT) mainly includes systemic and local treatment, but con- [2, 3]. With the development of radiotherapy, the role of ventional systemic therapy often achieves unreliable surgery in local treatment is gradually reduced, and the radiotherapy is more recommended as the initial local treatment for BMs patients [4]. *Correspondence: phhksc@126.com; xy3caopg@csu.edu.cn Recently, HFSRT has been increasingly used to treat Department of Oncology, The Third Xiangya Hospital of Central South BMs [5, 6]. Some reports describing the treatment results University, Changsha, People’s Republic of China © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xie et al. Radiation Oncology (2022) 17:132 Page 2 of 10 of HFSRT versus those of SRS, indicated that HFSRT from 18 to 80  years. The exclusion criteria were: (1) had similar efficacy and lower toxicity compared to SRS, patients with a history of WBRT, SRT, or any other form especially for large lesions [7, 8]. In addition, the ideal of intracranial irradiation, (2) patients who received fol- dose-fractionation scheme of HFSRT is controversial low-up for < 1 month. [9, 10]. In many previous studies, patients with a poor The study was approved by the institutional review Karnofsky performance status (KPS) were considered board of our hospital; no patient consent was required ineligible for HFSRT [7, 11], but it remains unclear that owing to the retrospective study design. whether patients with a poor KPS (defined as KPS < 70) HFSRT was delivered by Linear Accelerator (Varian, due to BMs are ineligible for HFSRT [12]. As for WBRT, USA) at our institution. Patients were immobilized in a despite the potential risk of WBRT damage to neuro- supine position with a thermoplastic head mask fixa - cognitive function, studies have shown that it can sig- tion system (Klarity, Guangzhou, China), simulating a nificantly reduce intracranial tumor recurrence, and its high-resolution thin slice (1.2  mm) computed tomog- effect on neurocognitive function is much less than that raphy (CT). The target volumes and organs at risk were of patients with neurological impairment or loss caused contoured using the Eclipse version 11.0 (Varian, USA) by tumor progression [13, 14]. And it was observed in our treatment planning system. Gross tumor volume (GTV) clinical experience that the intracranial recurrence rate of of HFSRT was defined based on the enhanced volume patients with BMs without WBRT treatment was higher; that was detected during MRI T1-weighted contrast- thus, WBRT might be reserved in selected patients. enhanced sequencing. A 3.0  mm three-dimensional Conversely, the response and progression criteria used expansion was applied to the GTV to create the planning in clinical trials on BMs are disparate [15]. The Response gross tumor volume. Patients were treated with   True- Evaluation Criteria in Solid Tumors (RECIST) criteria Beam  Linear Accelerator (Varian, USA). Typical target generalizes the complexity of tumor geometry to a lin- volumes for BMs are shown in Fig.  1. The prescription ear dimension, disregarding the indication that lesion dose of HFSRT was 18  Gy in 3 fractions, and the pre- enlargement after treatment includes both radiation scription dose of WBRT was 40  Gy (2  Gy per fraction) necrosis and disease progression [16]. The Response for whole brain planning target volume. The median time Assessment in Neuro-Oncology Brain Metastases between diagnosis of BMs and HFSRT was 16.5  days. (RANO-BM) standard is currently a comparatively com- Patients received HFSRT daily, followed by WBRT, from prehensive evaluation standard, but it requires confirma - Monday to Friday; no treatment was administered over tion by more clinical studies [15]. the weekends. It seems noteworthy that the prognostic indexes (PIs) Follow-up of patients included the collection of clini- that are widely used in clinical practice include the recur- cal and head imaging data. Enhanced MRI or CT evalua- sive partitioning analysis (RPA) class [17] and the graded tions were scheduled for before treatment, 1 month after prognostic assessment (GPA) score [18]. With the grad- HFSRT, and every 3  months subsequently, until treat- ual increase in the application of local treatments, some ment failure or death. The assignment of central nervous scholars have begun to study prognostic scoring systems system response was independent of systemic disease that are based on stereotactic radiotherapy (SRT), such response. The treatment response of BMs was classified as the score index for radiosurgery (SIR) [19], the basic as complete response (CR), partial response (PR), stable score for BM (BS-BM) [20], and the golden grading sys- disease (SD), and progressive disease (PD), according to tem (GGS) [21]. It has not been established which PI is the RECIST (version 1.1) [22] and RANO-BM criteria most appropriate for patients with BMs who are receiv- [15]. Acute toxicity was classified according to the Com - ing HFSRT + WBRT. mon Terminology Criteria for Adverse Events (CTCAE) This study aimed to evaluate the efficacy and toxicity of version 4.0. Radionecrosis was diagnosed based on MRI HFSRT + WBRT in patients with BMs. We also sought to changes (including diffusion-weighted imaging, perfu - determine which of the five PIs was most suitable in our sion-weighted imaging, arterial spin labeling, and MR study, and we compared the accuracies of RECIST 1.1 spectroscopy) consistent with necrosis (central hypoden- and RANO-BM standards for efficacy evaluation. sity and peripheral enhancement on T1-weighted post-contrast imaging, with edema on T2-weighted Materials and methods sequences) in the setting of new neurologic symptoms or From May 2018 to July 2020, we enrolled patients with a new steroid requirement [23]. BMs who underwent HFSRT + WBRT in our hospital. The primary endpoint was intracranial local control The inclusion criteria were: (1) patients with histologi - (iLC). The iLC was defined as any intracranial lesion that cally confirmed malignancies who had 1–10 intraparen - did not meet the criteria for PD, in the absence of new chymal brain metastases and (2) patients aged ranged intracranial lesions. The intracranial objective response Xie  et al. Radiation Oncology (2022) 17:132 Page 3 of 10 Fig. 1 Target volumes of radiotherapy for brain metastases rate (iORR) was defined as proportion of patients who 50 patients with a total of 111 lesions. The median time obtained intracranial CR and PR. The intracranial pro - interval between primary tumor diagnosis and the mani- gression-free survival (iPFS) was defined as time between festation of BMs was 7.8 months (range 0–83.1 months). the start of HFSRT and intracranial PD. The secondary Metachronous BMs were considered present when the endpoint were OS and the safety of treatment. The OS time between primary tumor diagnosis and the occur- was defined as the time from HFSRT to death or loss to rence of intracranial metastasis exceeded 3  months follow-up. [24]. The median age of all patients was 56  years (range Numerical variables are expressed as median, inter- 31–77). The median number of target BMs was 2 (range quartile range (IQR), and range. Qualitative data are 1–6). The median diameter of lesions was 2.30 cm (range expressed as frequency and percentage. The Kaplan– 0.60–5.50 cm), and the median size of GTV was 8.56 cm Meier method was used to construct survival curves and (range 0.87–88.28 cm ). determine the median survival time (MST). The Cox proportional hazards model was used in univariate and multivariate analyses. The confidence interval (CI) was Intracranial efficacy designated 95%. Patients who did not undergo CT/MRI in our institu- tion before and after HFSRT were excluded. Eventually, 29 patients were included in intracranial efficacy analy - Result sis. The number of BMs in the patients varied between Patient and lesion characteristics 1 and 6, and the median GTV size was 7.24  cm (range Between May 2018 and July 2020, we enrolled 54 patients 0.87–88.28  cm ). Only 42 target lesions could be evalu- who had undergone HFSRT + WBRT. Of these patients, ated by the RECIST 1.1 criteria because the RECIST 1.1 2 patients were followed up for < 1  month, 1 patient had criteria stipulates that each organ can have a maximum a primary tumor with no pathological diagnosis, and of two target lesions; 48 target lesions could be evaluated 1 patient was 83  years old. These four patients were by the RANO-BM criteria. excluded from the analysis. The final analysis included Xie et al. Radiation Oncology (2022) 17:132 Page 4 of 10 Fig. 2 Tumor responses to hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy. Plane A shows the best response of patients evaluated by the RECIST 1.1 criteria. Plane B shows the best response of patients evaluated by the RANO‑BM criteria. The bars indicate the best percent change in target tumor burden from baseline. Letter A denotes a patient with a > 20% increase in the sum of the longest diameters of target lesions, but the absolute value of the diameter increase was only 3 mm; therefore, the efficacy assessment remains as SD. Letter C denotes a patient who was suspected to have a new intracranial lesion, but the lesion was < 10 mm in diameter on consecutive reexaminations and were assessed as SD. The letters B, D, and F indicate three patients with different numbers of target lesions in the two evaluation criteria, who had the same evaluation results. The letter E indicates a patient with different numbers of target lesions in the two evaluation criteria, which resulted in different evaluation results. The letter G denotes a patient with reduced target lesions but multiple new intracranial lesions. Plane C shows the intracranial progression‑free survival of the 27 patients. patients with efficacy evaluations of PD, one with target lesion progression and the other with distant intracranial progression. The median iPFS was not reached (range 0–23  months). At the time of data cutoff, 20 of the 27 intracranial controls (74.1%) had ongoing intracranial control (Fig.  2c). Of the 7 patients who progressed dur- ing follow-up, 2 had target lesion progression and 5 had distant intracranial progression. Analysis of survival At the time of analysis (January 2021), 27 patients (54.0%) had died. Three patients from radiologically confirmed intracranial progression, 14 from extracranial progres- sion, 7 from unspecified progression or unknown causes, and 3 from clinical complications related to systemic dis- ease (pulmonary infection, multiorgan failure and hem- orrhage of digestive tract). The median follow-up time was 9.3 months (IQR, 3.7–16.2) for 50 patients. The MST was 13.6  months (95% CI 9.0–18.2  months) and the 6-, 12-, and 24-month actuarial OS rates were 74.2%, 58.2%, and 22.9%, respectively (Fig. 3a). Eight potential prognostic variables were included in univariate analyses. As shown in Table 1, only KPS score (HR 5.455; 95% CI 2.384–12.482; p < 0.001) was statisti- cally significant. The median OS was 2.8  months (range 2.0–17.9) for patients with KPS < 70. For patients with We recorded the greatest change from baseline in KPS ≥ 70, the MST was 16.5  months (95% CI 12.2– the longest diameter of target lesions and evaluated 20.7 months), and the 6-, 12-, and 24-month actuarial OS treatment efficacy based on CR, PR, SD, and PD in the rates were 83.8%, 70.5%, and 29.7%, respectively (Fig. 4a). RECIST 1.1 (Fig.  2a) and RANO-BM criteria (Fig.  2b). Sex (HR 4.546; 95% CI 1.601–12.907; p = 0.004), KPS The iORR of the 29 patients using the RECIST 1.1 and score (HR 10.754; 95% CI 3.911–29.571; p < 0.001), and RANO-BM criteria was 62.1% and 58.6%, respectively. GTV size (HR 0.288; 95% CI 0.118–0.698; p = 0.006) were The iLC rate was 93.1% for both criteria, with the 6- and significant factors in the multivariate analysis (Table 1). 12-month iLC rate of 90.8% and 57.4%, respectively. Two Xie  et al. Radiation Oncology (2022) 17:132 Page 5 of 10 Fig. 3 Kaplan–Meier curve of overall survival in patients with brain metastases. A Kaplan–Meier curve of overall survival in patients with different KPS scores. B Overall survival for different RPA scores (n = 50); C Overall survival for different GPA scores (n = 50); D Overall survival for different SIR scores (n = 50); E Overall survival for different BS‑BM scores (n = 50); F Overall survival for different GGS scores (n = 50) Xie et al. Radiation Oncology (2022) 17:132 Page 6 of 10 Table 1 Median survival time according to potential factors and 17.9 months (95% CI 8.1–27.6 months) and 12.9 months the results of univariate and multivariate analyses (95% CI 6.2–19.6  months), respectively (HR 0.460; 95% CI 0.166–1.278; p = 0.136). Variables N (%) MST (months) P value Univariate Multivariate The five PIs Patients were classified into 3 or 4 classes, according to Sex 0.146 0.004 the corresponding grading requirements of PRA, GPA, Male 32 (64.0) 12.4 SIR, BS-BM, and GGS. Patient characteristics and sur- Female 18 (36.0) 23.2 vival analysis for each PI are listed in Table  2. Survival Age 0.532 0.630 curves are shown in Fig.  3. OS was significantly associ - < 60 27 (54.0) 12.9 ated with the RPA, SIR, BS-BM, and GGS classes. There ≥ 60 23 (46.0) 15.4 was no statistical significance between the GPA classes. KPS < 0.001 < 0.001 ≥ 70 41 (82.0) 16.5 BM‑related symptoms < 70 9 (18.0) 2.8 Of the 50 enrolled patients, 39 had symptoms associ- Primary tumor 0.619 – location ated with BM prior to treatment and 11 were asymp- Lung cancer 39 (78.0) 13.6 tomatic at the time of BM diagnosis. These 39 patients Others 11 (22.0) 12.4 were divided into two groups according to their KPS Extracranial 0.205 0.124 score. All 9 patients with KPS < 70 had BM-related metastases symptoms before treatment, which mainly included Existent 31 (62.0) 12.4 muscle weakness, dizziness, headache, unsteady gait, None 19 (38.0) 15.4 numbness, blurred vision or partial blindness, and Contemporane- 0.615 – symptomatic epilepsy. These symptoms seriously ous BM Yes 19 (38.0) 12.9 No 31 (62.0) 13.6 Table 2 Patient characteristics and survival analysis for the five Number of BMs 0.872 – prognostic indices Single 19 (38.0) 12.9 PI Grade No. of patients (%) MST (months) p Multiple 31 (62.0) 15.4 GT V (cm ) 0.092 0.006 RPA < 0.001 < 10.0 29 (58.0) 16.7 Class I 7 (14.0) 23.8 ≥ 10.0 21 (42.0) 12.9 Class II 34 (68.0) 16.5 MST, median survival time; BMs, brain metastases; GTV, gross tumor volume Class III 9 (18.0) 2.8 GPA 0.177 0–1.0 13 (26.0) 16.7 1.5–2.5 30 (60.0) 12.4 3.0–4.0 7 (14.0) 24.3 SIR < 0.001 1–3 11 (22.0) 3.0 4–7 36 (72.0) 16.5 8–10 3 (6.0) 27.8 BS‑BM 0.010 0 9 (18.0) 3.5 1 20 (40.0) 12.4 2 10 (20.0) 15.4 3 11 (22.0) 24.3 Fig. 4 Changes in the Karnofsky performance status (KPS) score GGS < 0.001 4 weeks after hypofractionated stereotactic radiotherapy (HFSRT ) in 0 12 (24.0) 23.2 nine patients with KPS score < 70 before treatment 1 25 (50.0) 16.5 2 10 (20.0) 12.4 3 3 (6.0) 2.8 Survival analysis was performed for lung adenocar- cinoma patients who were treated with (15 patients) or MST, median survival time; RPA, Recursive Partitioning Analysis; GPA, Graded Prognostic Assessment; SIR, Score Index for Radiosurgery; BS-BM, Basic Score for without (10 patients) targeted therapy, and the MST was Brain Metastases; GGS, golden grading system Xie  et al. Radiation Oncology (2022) 17:132 Page 7 of 10 Safety of treatment affected the quality of life of the patients. Most of the Radiation toxicities are reported using the CTCAE (ver- patients showed significant improvement in dizzi - sion 5.0). Regarding acute toxicity, all patients tolerated ness, headache, and limb weakness, but no significant the treatment well with no ≥ grade 3 toxicities. Only improvement in vision loss was associated with BMs. grade 1 or 2 adverse events were reported. The most One patient with symptomatic epilepsy before treat- common side effect was fatigue. Concerning late toxicity, ment was poorly managed with sodium valproate, intra-tumoral hemorrhage complications occurred in one with no recurrence of seizures after treatment. For patient (2%) 9  months after treatment completion, but patients with KPS score < 70, symptoms related to this did not progress into a neurologic degradation. BMs before and after treatment and changes in KPS score are shown in Table  3 and Fig.  4, respectively. The Discussion main symptoms in patients with KPS ≥ 70 included HFSRT + WBRT showed good results in terms of effi - headache, dizziness, muscle weakness, and numbness. cacy, toxicity and survival time. Symptoms improved in some patients after treatment, Based on previous clinical experience and the results while some symptoms such as blurred vision did not of this study, we considered that WBRT could not be improve significantly (Table 4 ). Table 3 Symptoms related to brain metastases in nine patients with KPS score < 70 pre‑treatment and 4 weeks after treatment Patient Pre‑treatment Four weeks after treatment Main symptoms KPS score Symptoms KPS score 1 Muscle weakness right‑sided and dizziness 30 Relief of muscle weakness and dizziness 60 2 Left eye hemianopsia and Headaches 40 No change in visual acuity; relief of headaches 40 3 Symptomatic epilepsy 40 Relief of seizure 60 4 Facial spasm, glossolalia, and dizziness 50 Relief of glossolalia and dizziness 60 5 Dizziness and blurred vision 50 Relief of dizziness 60 6 Muscle weakness in the lower limb 60 Roughly as before 60 7 Numbness of the lower limb 60 Relief of numbness 70 8 Numbness of the right limb and nausea 60 Roughly as before 60 9 Dizziness and unsteady gait 60 Relief of dizziness and unsteady gait 70 Table 4 Symptoms related to brain metastases in patients with KPS score ≥ 70 pre‑treatment and 4 weeks after treatment Symptoms Number of patients Pre‑treatment Four weeks after treatment Upturn No change Deterioration New symptoms Headache 12 11 1 0 0 Dizziness 10 5 5 0 0 Nausea 3 2 1 0 0 Vomiting 4 3 1 0 0 Tremor 1 1 0 0 0 Muscle weakness in the upper limb 3 2 1 0 0 Muscle weakness in the lower limb 5 3 2 0 0 Motor weakness 4 3 1 0 0 Numbness 6 4 2 0 0 Unsteady gait 2 1 1 0 0 Glossolalia 2 1 1 0 0 Blurred vision 2 0 2 0 0 Hiccup 1 0 1 0 0 Xie et al. Radiation Oncology (2022) 17:132 Page 8 of 10 ignored. Some studies suggest that SRT can be consid- were not uniformly recommended in different studies, ered a standard treatment that is a less toxic alterna- and there was a large discrepancy between the expected tive to SRT + WBRT [25]. However, WBRT reduction of and actual survival [18, 38–40]. brain tumor recurrence rate may translate to improved In this study, we used two instruments for efficacy survival in patients with intracranial tumor progres- evaluation. There was no significant difference in effi - sion; thus, it seems reasonable to suggest that the addi- cacy outcomes between the two criteria; this was pos- tion of WBRT may affect survival outcomes in selected sibly due to: (1) the small number of patients included patients [26, 27]. Wegner RE et  al. reviewed 36 patients in the efficacy analysis, (2) of all patients treated with who were treated with HFSRT alone (24 Gy in2-5F), with HFSRT, only one patient showed asynchronous changes 6- and 12-month LC rates of 73% and 63%, respectively in the intracranial lesions, which may have attenuated [28]. Kim et  al. reviewed 46 patients who were treated the difference in the number of target lesions between with HFSRT alone. Patients were randomized to receive the two criteria, and (3) although corticosteroid use is 24, 27, or 30 Gy in 3 fractions, with 12-month LC rates of not included in the RECIST 1.1 criteria, no patient who 65%, 80% and 75%, respectively [11]. The intracranial LC met the imaging criteria was ineligible for corticoster- rate in this study was superior to the two studies men- oid use, thus eliminating the potential discrepancy from tioned above, further studies are needed to investigate this definition. The RANO-BM criteria, may provide a the most suitable population for HFSRT + WBRT. more comprehensive assessment of patient outcomes In our study, the HFSRT group received a smaller total than the RECIST 1.1 criteria. However, in our practical dose and number of fractions than those reported in the application of the RANO-BM criteria we found that the literature. We reviewed recent studies on patients with criteria complicate the assessment of patients with BMs BMs who were treated with HFSRT or HFSRT + WBRT; in clinical trials. the most common HFSRT dose was 27  Gy/3F (range We believe the results of the present study are impor- 24–41  Gy/2–6F), the OS rates ranged from 13.0 to tant for several reasons. First, we used the same HFSRT 69.0% at 12  months, and the MST ranged from 12.2 to and WBRT scheme for the entire study, reduced treat- 16.2  months [6, 7, 11, 28–31]. Our results are also com- ment-derived differences in the analysis of treatment parable to those of several studies on HFSRT for BMs in efficacy. Second, to our knowledge, our study involved the surgical cavity. Two studies assessed the efficacy and the lowest total radiation dose and number of fractions, safety of postoperative HFSRT in patients with BMs. The but we observed desirable survival outcomes. Third, 12-month OS was 62% and 58%, respectively. The radia - we analyzed survival outcomes and symptom and KPS tion necrosis rate was 5.1% and 8.9%, respectively [32, score improvement in patients with a poor KPS post- 33]. treatment. Our findings demonstrate that patients with PI are beneficial to clinical and therapeutic decision- KPS < 70 may not be unfavorable candidates for SRT. making. However, GPA classes were not statistically Lastly, to our knowledge, this is the only study that has significant in our analysis. Conversely, many previous employed both RECIST 1.1 and RANO-BM criteria to studies concluded that GPA is a reliable, simplistic, and evaluate the HFSRT + WBRT efficacy for BM. powerful tool for predicting survival [18, 34]. The pos - This study was limited by its retrospective design. sible reasons for this difference include the following. During the radiotherapy and follow-up periods, First, GPA includes the number of metastases and does patients also received systemic treatments, which not involve metastasis volume. We noted that the num- might influence their survival and local control. In ber of BMs in the patients and the GTV size were not addition, we did not avoid the hippocampal regions proportional. The median GTV was greater in patients during irradiation in WBRT. We also did not evaluate with 1 BM than in patients with 2–3 BMs (9.45 and the neurocognitive function of patients, post-treatment 7.25 cm , respectively). Some studies concluded that using scores. brain tumor volume had a significant association with OS [35, 36]. Second, the primary tumors in our study included lung cancers, breast cancers, gastrointestinal Conclusions cancers, and gynecologic tumors. There was marked Despite limitation mentioned above, these data demon- heterogeneity in outcomes among patients with BMs strated that, for patients with BMs, HFSRT combined and the differences in outcome were not only related to with WBRT is a safe and effective local treatment modal - the diagnosis but also to diagnosis-specific prognostic ity. Patients with a poor KPS due to BMs can also benefit factors [34, 37]. Further, the dissimilar proportions of from the treatment. The response and progression crite - patients within the prognostic classes could be another ria for patients with BMs remain to be explored in fur- reason. In addition, we found that the PIs in our study ther studies. Xie  et al. 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Analysis of survival of patients with brain metastases according to prognostic indexes and treatment strate‑ gies. Turk Neurosurg. 2020;30(6):822–31. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Radiation OncologySpringer Journals

Published: Jul 26, 2022

Keywords: Brain metastases; Whole brain radiotherapy; Hypofractionated stereotactic radiotherapy; Efficacy; Safety

References