Abstract
Background
We evaluated the outcome of radiosurgically treated patients with ≥10 brain metastases (BM), compared to patients <10 BM.
Methods
Patients, who underwent at least one Gamma Knife radiosurgical (GKRS) treatment for at least one BM without previous Central Nervous System (CNS) treatments, were retrospectively divided into 2 groups: (1) < 10 or (2) ≥ 10 BM.
Results
At GKRS1, 1293 patients had <10 BM and 126 patients had ≥10 BM. The estimated median survival after GKRS1 was significantly longer in patients with <10 BM (9.9 months), compared to patients with ≥10 BM at GKRS1 (5.3 months; P < .001). Age >65 years (P < .001), male sex (P = .001), Karnofsky Performance Status Scale <80 (P < .001), presence of extracranial metastases (P = .008), presence of neurological symptoms (P = .019), a cumulative BM volume of all BM treated at GKRS1 ≥ 10 cm3 (P = .017), no concomitant immunotherapy or targeted therapy at GKRS1 (P < .001), and the number of ≥10 BM at GKRS1 (P < .001) were identified as independent prognostic factors for an increased risk of death. In patients with ≥10 BM, poor clinical condition, a cumulative BM volume of all BM treated ≥25 cm3, and no concomitant immunotherapy or targeted therapy at GKRS1 were identified as significant independent prognostic factors. The occurrence of post-radiosurgical complications and local tumor control did not differ between the groups.
Conclusions
In addition to BM count, multiple factors may influence survival and should be considered during the pre-radiosurgery assessment. GKRS represents a safe and effective first-line treatment method even for patients with ≥10 BM, particularly in the era of modern systemic therapies.
Keywords: brain metastases, Gamma Knife radiosurgery, multiple brain metastases
Key Points.
GKRS represents an effective first-line treatment for patients with ≥10 BM.
The number of BM alone should not guide treatment decisions for patients with BM.
Importance of the Study
According to the recent brain metastases (BM) guidelines, stereotactic radiosurgery is not recommended for patients with ≥10 BM, and whole brain radiotherapy or SRS plus whole brain radiotherapy is still considered the standard treatment.
In our study with 1419 patients, age >65 years, male sex, Karnofsky Performance Status Scale (KPS) < 80, presence of extracranial metastases, presence of neurological symptoms, a cumulative BM volume of all BM treated at first Gamma Knife radiosurgical treatment (GKRS1) ≥ 10 cm3, no concomitant immunotherapy or targeted therapy at GKRS1, and the number of ≥10 BM at GKRS1 were identified as independent prognostic factors for an increased risk of death. Furthermore, the occurrence of post-radiosurgical complications as well as local tumor control after GKRS1 did not differ between patients with <10 and ≥10 BM. Therefore, Gamma Knife radiosurgical treatment represents a safe and effective first-line treatment for patients with ≥10 BM, particularly in the era of modern systemic therapies. In addition to BM count, multiple prognostic factors may influence survival outcomes and should be considered during the pre-radiosurgery assessment.
For patients with brain metastases (BM), the standard local treatment options are microsurgical resection, stereotactic radiosurgery (SRS), fractionated radiotherapy (fRT), and whole brain radiotherapy (WBRT).1
Compared to microsurgical resection, the noninvasive Gamma Knife radiosurgical treatment (GKRS) allows the treatment of patients with multiple, disseminated, eloquent or non-resectable BM but also multimorbid patients with contraindications for surgery in general anesthesia.2-4 Historically, SRS plus WBRT was used for patients with multiple BM.5 However, this combination of SRS and WBRT showed a significant higher risk of decreased neurocognitive function than treatment with SRS alone.5 Therefore, WBRT was recommended to be deferred as long as possible.6 For patients with 5-10 BM, radiosurgical treatment may be considered, since previous studies have reported no decrease in survival or increase in post-radiosurgical complications.3,6
However, the radiosurgical treatment of >10 BM is still not recommended in the current BM guidelines due to ongoing safety concerns.7 Despite the demonstrated survival benefits associated with the modern systemic therapies, their role in the radiosurgical treatment of patients with more than 10 BM remains limited.7,8
Therefore, this study aimed to evaluate the outcome differences in radiosurgically treated patients with <10 BM, compared to patients ≥10 BM, as well as to evaluate the safety and efficacy profile of GKRS for radiosurgically treated patients with ≥10 BM, especially in the era of modern systemic therapies.
Methods
Study Inclusion
This study complied with the Declaration of Helsinki and was approved by the institutional ethics review board. Patient consents were not obtained due to the retrospective study design.
At our institution, 1913 patients with BM underwent radiosurgical treatment between June 2012 (implementation of the new Gamma Knife Perfexion at our institution) and December 2022. For this retrospective study, all patients with age ≥18 years and at least one GKRS for at least one BM from NSCLC, melanoma, breast, gastrointestinal, or genitourinary cancer were included. To avoid any potential biases from previous Central Nervous System (CNS) treatment, all 328 patients with any history of previous CNS treatments, including microsurgical resection or any type of radiation therapy (eg WBRT, fRT), were excluded.
After excluding patients according to our criteria, 1419/1913 (74%) patients could be included in this study (Figure 1, Table 1).
Figure 1.
Flow chart on inclusion criteria and follow-up evaluation. At our institution, a total of 1913 patients with BM underwent radiosurgical treatments between June 2012 and December 2022. For this retrospective study, all patients with age ≥18 years and at least one Gamma Knife radiosurgical treatment for at least one BM from NSCLC, melanoma, breast, GI or GU cancer were included. After applying our inclusion criteria, 166/1913 (9%) patients with other primary tumor were excluded. To avoid any potential biases from previous CNS treatment, 323/1747 (18%) patients with any history of previous CNS treatments, including microsurgical resection or any type of radiation therapy (eg WBRT, fRT) were excluded. After excluding patients according to our criteria, 1419/1913 (74%) patients could be included in this study. In accordance with our clinical standard procedure, all patients were clinically and radiologically followed in a 3-month interval. However, as commonly known in clinical practice, not all patients adhered to their follow-up appointments. Consequently, 14/1419 (1%) patients without any clinical or radiological FU or known data from death register were excluded, resulting in a final cohort of 1405/1419 (99%) patients for outcome analyses. To review post-radiosurgical complications and tumor control rates after GKRS1, only data from patients (1072/1405, 76%), who underwent a follow-up MRI after the procedure, were included in the analyses. BM, brain metastases; CNS, central nervous system; FU, follow-up; GI, gastrointestinal; GU, genitourinary NSCLC, non-small-cell lung cancer.
Table 1.
Baseline characteristics of the study population
| Total study population (n = 1419) | Patients with < 10 BM (n = 1293; 91%) | Patients with ≥ 10 BM (n = 126; 9%) | P-values between the BM groups | |
|---|---|---|---|---|
| Age, years, median (range) | 65 (24-92) | 65 (24-92) | 63 (24-86) | ns |
| Age groups | ns | |||
| ≤65 years | 741 (52%) | 670 (52%) | 71 (56%) | |
| >65 years | 678 (48%) | 623 (48%) | 55 (44%) | |
| Female: male ratio | 733:686 | 663:630 | 70:56 | ns |
| KPS, %, median (range) | 80 (40-100) | 80 (40-100) | 80 (40-100) | ns |
| KPS groups | ns | |||
| ≥80% | 994 (70%) | 907 (70%) | 87 (69%) | |
| <80% | 425 (30%) | 386 (30%) | 39 (31%) | |
| Primary tumor | <.001 | |||
| Lung cancera | 730 (51%) | 681 (53%) | 49 (39%) | |
| Melanoma | 255 (18%) | 212 (16%) | 43 (34%) | |
| Breast cancer | 150 (11%) | 137 (11%) | 13 (10%) | |
| GI/GU cancer | 147 (10%) | 141 (11%) | 6 (5%) | |
| Multiple | 137 (10%) | 122 (9%) | 15 (12%) | |
| ECM at time of BM diagnosis | 0.005 | |||
| Yes | 1111 (78%) | 1000 (77%) | 111 (88%) | |
| No | 308 (22%) | 293 (23%) | 15 (12%) | |
| Neurological symptoms | ns | |||
| Yes | 924 (65%) | 848 (66%) | 76 (60%) | |
| No | 495 (35%) | 445 (34%) | 50 (40%) | |
| Number of BM at diagnosis | <.001 | |||
| Single | 519 (37%) | 519 (40%) | – | |
| Multiple | 900 (63%) | 774 (60%) | 126 (100%) | |
| Treated BM at GKRS1, median (range) | 2 (1-20) | 2 (1-9) | 10 (3-20) | .001 |
| Cumulative volume of all BM at GKRS1 | <.001 | |||
| <10 cm3 | 1255 (88%) | 1169 (90%) | 86 (68%) | |
| ≥10 cm3 | 164 (12%) | 123 (10%) | 40 (32%) | |
| Cumulative volume of all BM at GKRS1 | <.001 | |||
| <25 cm3 | 1406 (99%) | 1286 (99%) | 120 (68%) | |
| ≥25 cm3 | 13 (1%) | 7 (1%) | 6 (5%) | |
| Concomitant use of immunotherapy or targeted therapy at GKRS1 | <.001 | |||
| Yes | 611 (43%) | 525 (41%) | 86 (68%) | |
| No | 788 (56%) | 751 (58%) | 37 (30%) | |
| Not known | 20 (1%) | 17 (1%) | 3 (2%) | |
| Predicted survival after prognostic scores, months, median (range) | ||||
| GPA general | 3.8 (2.6-11.0) | 3.8 (2.6-11.0) | 2.6 (2.6-3.8) | <.001 |
| GPA disease-specific | 5.5 (3.0-25.3) | 5.5 (3.0-25.3) | 4.4 (3.0-25.3) | <.001 |
| RPA | 4.5 (2.3-7.7) | 4.5 (2.3-7.7) | 4.5 (2.3-7.7) | ns |
| SIR | 6.0 (2.1-8.8) | 6.0 (2.1-8.8) | 6.0 (2.1-8.8) | <.001 |
| Lung-molGPA for adenocarcinoma | 13.7 (6.9-46.8) | 13.7 (6.9-46.8) | 13.7 (6.9-46.8) | ns |
| Lung-molGPA for nonadenocarcinoma | 9.8 (5.3-12.8) | 9.8 (5.3-12.8) | 5.3 (5.3-5.3) | .043 |
This table provides detailed baseline characteristics of our 1419 study patients at the time of first GKRS.
Lung cancer patients only included non-small cell lung cancer patients. Small cell lung cancer patients were excluded from our study.
BM, brain metastases; ECM, extracranial metastases; GI, gastrointestinal; GKRS1, first Gamma Knife Radiosurgery treatment; GPA, Graded Prognostic Assessment; GU, genitourinary; KPS, Karnofsky Performance Status Scale; Lung-molGPA, updated Graded Prognostic Assessment for lung cancer using molecular markers; RPA, recursive partitioning analysis; SIR, Score Index for Radiosurgery.
Radiosurgical Technique
According to our standard clinical protocol, radiosurgical treatments were planned with GammaPlan (Elekta AB, Stockholm, Sweden) and performed with Leksell Gamma Knife Perfexion (Elekta AB, Stockholm, Sweden). The radiosurgical technique has previously been described in detail.9 In brief, planning sequences were performed on a 1.5 or 3 Tesla magnet MRI and always included gadolinium contrast-enhanced T1-weighted MRI sequences in the axial and coronal planes.
The target was defined as a contrast-enhanced tumor mass on T1 sequences. The entire tumor mass was covered without additional margins. The volume of the treated BM was automatically calculated by the treatment planning software “GammaPlan”.9
For high-risk or large BM, the dose-staged GKRS treatment method was applied in 2 reduced fractions, as previously described.10 A total of 7192 BM were treated in 2214 radiosurgical procedures, with a median of 3 BM per radiosurgical treatment. More than half of the patients (898/1419, 63%) underwent only 1 GKRS treatment, whereas 521/1419 (37%) received multiple treatments for newly diagnosed BM or 2-fraction dose-staged GKRS. Details on different treatment methods are displayed in Supplementary Table S1.
Outcome Evaluation
To evaluate the outcome data between patients with <10 or ≥10 BM, the pre-radiosurgical MRI data of each patient was reviewed, and patients were grouped accordingly.
According to our clinical standard follow-up (FU) procedure, patients were clinically and radiologically assessed in a 3-month interval after GKRS treatment.9
The primary study endpoint was patients’ death. To further evaluate the outcome data, a death register comparison was carried out for all patients. Patients without any clinical or radiological FU or unknown data the from death register were excluded (14/1419, 1%), resulting in a final cohort of 1405/1419 (99%) patients for outcome analyses.
Furthermore, overall survival was predicted for each patient based on the Graded Prognostic Assessment (GPA; general and disease-specific), updated GPA for lung cancer using molecular markers (lung-molGPA), Recursive Partitioning Analysis (RPA), and Score Index for Radiosurgery (SIR).11-15 The predicted scores according to the different prognostic scales were compared with the actual observed survival.
After GKRS1, post-radiosurgical complications, local, and distant tumor control were evaluated on follow-up MRI and reported even if patients were asymptomatic. Post-radiosurgical complications were defined as radiation reaction, radiation necrosis, and intralesional hemorrhage, as previously defined.9,14 Radiation reaction was defined as progressive surrounding edema, while radiation necrosis was defined as a progressive ring-enhancing lesion with central necrosis and surrounding edema.14,16 Radiological progression of treated BM was defined as an increase of at least 20% in the longest diameter, compared with baseline measurements, according to the Response Assessment in Neuro-Oncology (RANO) criteria.17,18
Statistical Analyses
Statistical analyses were performed using SPSS Statistics for Windows (version 28.0.1.0; IBM Corp., Armonk, NY, USA). Categorical data were shown as counts and percentages and continuous parameters as medians and ranges. For group comparisons, Chi-square, Mann-Whitney U, Kruskal-Wallis and Wilcoxon signed-rank tests were performed as appropriate.
The Kaplan-Meier method was used to estimate the median and mean survival after GKRS1. Mean survival was reported if median survival was not reached in a group. Differences between groups were compared using the generalized Wilcoxon-Breslow test or log-rank test, as appropriate. Bonferroni-Holm correction was used for multiple comparisons as appropriate. To further evaluate any potential survival predictors for radiosurgically treated patients with BM, univariable followed by multivariable Cox proportional hazard regression analyses were performed and included age groups (≤65 vs. >65 years), sex, Karnofsky Performance Status Scale (KPS) groups (<80 vs. ≥80), primary tumor types (NSCLC, melanoma, breast, gastrointestinal / genitourinary cancer, multiple), presence of extracranial metastases (ECM), presence of neurological symptoms, cumulative BM volume of all BM treated at GKRS1 (<10 vs. ≥10 cm3 or <25 vs. ≥25 cm3) number of BM (<10 vs. ≥10 BM) at GKRS1, use of dose-staged technique for high-risk and large BM, subsequent WBRT, and concomitant use of immunotherapy or targeted therapy. Multivariable Cox regression analysis included only significant variables from the univariable Cox regression analyses and was performed using the backward Wald method. For all statistical analyses, statistical significance was defined as a P-value of ≤.05.
Results
Patients’ Characteristics
Details on patients’ characteristics are displayed in Table 1. The median time between initial primary tumor and BM diagnosis was 11.0 months (range: 0-431.0) with significant differences between the different primary tumors (P < .001). Patients with breast cancer had the longest median time between PT and BM diagnosis, while NSCLC had the shortest (breast cancer: 41.6 months; melanoma: 30.2 months; gastrointestinal / genitourinary cancer: 23.0 months and multiple PT: 16.0 months; NSCLC: 1.5 months; P < .001).
The median time between initial BM diagnosis and first Gamma Knife radiosurgical treatment (GKRS1) was 0.5 months (range: 0.0-84.6).
At the time of GKRS1, 91% (1293/1419) patients had <10 BM, while 9% (126/1419) patients had ≥10 BM. The primary tumor distribution was significantly different between patients <10 and ≥10 BM (P < .001): in patients with ≥10 BM, NSCLC (39%) and melanoma (34%) were the most common primary tumors. In contrast, in patients with <10 BM, NSCLC alone represented the most common primary tumor (53%).
Patients with ≥10 BM had significantly more extracranial metastases (ECM, P = .005) and a larger cumulative BM volume of all BM (defined as ≥10 cm3 as well as ≥25 cm3) at GKRS1 (P < .001). In addition, the concomitant use of immunotherapy or targeted therapy at the time of GKRS1 (±30 days) was more common in patients with ≥10 BM (P < .001).
In contrast, other baseline characteristics, such as age, sex, KPS and presence of neurological symptoms, did not differ between patients with <10 or ≥10 BM.
Interestingly, the median time between initial primary tumor and BM diagnosis was significantly longer in patients with ≥10 BM (16.9 months, range: 0-312.7), compared to patients with <10 BM (10.4 months, range: 0-431.0; P = .028).
Overall Survival After GKRS1
In our study population, only 14/1419 (1%) patients were lost to FU and were excluded from the survival analysis. Thereby, a total of 1405/1419 (99%) patients with BM could be evaluated for survival. From these 1405 patients with radiosurgically treated BM, 123/1405 (9%) patients had ≥10 BM, while 1282/1405 patients had <10 BM (<5 BM: 1112/1405 patients; 5-9 BM: 170/1405 patients) at GKRS1. The estimated median overall survival was 31.9 months (95% CI, 28.8-35.1) after the initial PT diagnosis, 10.2 months (95% CI, 9.2-11.2) after the initial BM diagnosis, and 9.2 months (95% CI, 8.1-10.2) after GKRS1. The survival after initial BM diagnosis was significantly longer than the predicted survival by all prognostic BM scores (GPA, lung-molGPA, RPA, and SIR; P < .001).
After GKRS1, the estimated median survival was significantly longer in younger patients (≤65 years; P < .001), female patients (P < .001), patients with Karnofsky Performance Status Scale (KPS) ≥ 80 (P < .001; Figure 2A), patients without ECM (P = .014; Figure 2B), asymptomatic patients (P < .001; Figure 2C), patients with concomitant immunotherapy or targeted therapy at GKRS1 (P < .001; Figure 2D), patients with a cumulative BM volume of <10 cm3 or <25 cm3 for all BMs treated at GKRS1 (P < .001; Figure 2E and F), and patients with <10 BM (P < .001; Figure 2G). The estimated median survival did not differ between patients who underwent dose-staged treatment for larger or high-risk BM and those who did not (P = .934).
Figure 2.
Survival after radiosurgery. (A) The estimated median survival after GKRS1 was significantly longer in patients with KPS ≥80 (13.1 months, 95% CI, 11.5-14.7), compared to patients with KPS <80 (4.2 months, 95% CI, 3.4-5.0; P < .001). (B) The estimated median survival after GKRS1 was significantly longer in patients without ECM (11.8 months, 95% CI, 9.7-13.9), compared to patients with ECM (8.3 months, 95% CI, 7.2-9.3; P = .014). (C) The estimated median survival after GKRS1 was significantly longer in asymptomatic patients (14.9 months, 95% CI, 11.9-17.8), compared to symptomatic patients (7.0 months, 95% CI, 6.2-7.9; P < .001). (D) The estimated median survival after GKRS1 was significantly longer in patients with concomitant immunotherapy or targeted therapy at GKRS1 (11.8 months, 95% CI, 10.2-13.4), compared to patients without concomitant immunotherapy or targeted therapy at GKRS1 (7.3 months, 95% CI, 6.3-8.3; P < .001). (E) The estimated median survival after GKRS1 was significantly longer in patients with a cumulative BM volume of <10 cm3 for all BM at GKRS1 (10.0 months, 95% CI, 8.9-11.1), compared to patients with a cumulative BM volume of ≥10 cm3 (4.5 months, 95% CI, 3.4-5.6; P < .001). (F) The estimated median survival after GKRS1 was significantly longer in patients with a cumulative BM volume of <25 cm3 for all BM at GKRS1 (9.3 months, 95% CI, 8.3-10.4), compared to patients with a cumulative BM volume of ≥25 cm3 (2.7 months, 95% CI, 1.3-4.2; P < .001). (G) The estimated median survival after GKRS1 was significantly longer in patients with <10 BM (9.9 months, 95% CI, 8.8-10.9), compared to patients with ≥10 BM at GKRS1 (5.3 months, 95% CI, 4.1-6.4; P < .001). (H) The estimated median survival after GKRS1 was the longest in patients with <5 BM (9.9 months, 95% CI, 8.7-11.0), followed by patients with 5-9 BM (8.3 months, 95% CI, 5.4-11.2), and patients ≥10 BM at GKRS1 (5.3 months, 95% CI, 4.1-6.4; P < .001). The pairwise comparisons between patients with <5 or 5-9 BM showed significant longer estimated median survival durations, compared to patients with ≥10 BM (P = .003 for <5 vs. ≥10 BM; P = .006 for 5-9 vs. ≥10 BM). However, the pairwise comparison between patients with <5 and 5-9 BM did not show any significant differences (P = .895). BM, brain metastases; CI, confidence interval; ECM, extracranial metastases; KPS, Karnofsky Performance Status Scale; GKRS1, first Gamma Knife Radiosurgery treatment.
Of note, the estimated median survival after GKRS1 did not differ between patients with <5 or 5-9 BM (P = .895; Figure 2H). However, the estimated median survival was significantly longer in patients with <5 or 5-9 BM compared to patients with ≥10 BM (P = .003 for <5 vs. ≥10 BM; P = .006 for 5-9 vs. ≥10 BM).
Moreover, estimated median survival was the longest in patients with BM from breast cancer (15.0 months, 95% CI, 8.5-21.5), followed by melanoma (9.9 months, 95% CI, 6.4-13.3), lung cancer (NSCLC; 9.7 months, 95% CI, 8.4-11.1), gastrointestinal / genitourinary cancer (7.6 months, 95% CI, 5.5-9.6), while patients with BM from multiple cancers had the shortest survival (6.9 months, 95% CI, 5.3-8.5; P = .002).
After GKRS1, 174/1405 (12%) patients underwent WBRT. Patients with ≥10 BM were significantly more likely to receive WBRT (23/123, 19%) than those with <10 BM (151/1282, 12%; P = .026). However, the estimated median survival after GKRS1 did not differ between patients who underwent WBRT after GKRS and those who did not (P = .068).
To further evaluate any potential survival predictors for radiosurgically treated patients with BM, univariable followed by multivariable Cox proportional hazard regression analyses were performed. Consequently, age >65 years (P < .001), male sex (P = .001), KPS groups <80 (P < .001), presence of ECM (P = .008), presence of neurological symptoms (P = .019), a cumulative BM volume of all BM treated at GKRS1 ≥ 10 cm3 (P = .017), no concomitant immunotherapy or targeted therapy at GKRS1 (P < .001), but also the number of ≥10 BM at GKRS1 (P < .001) were identified as independent prognostic factors for an increased risk of death (Table 2).
Table 2.
Negative prognostic factors for survival after radiosurgical BM treatment (n = 1405)
| Univariable analysis |
Multivariable analysis |
|||
|---|---|---|---|---|
| Variable | Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value |
| Age >65 years | 1.396 (1.241-1.571) | <.001 | 1.230 (1.090-1.389) | <.001 |
| Male sex | 1.306 (1.161-1.469) | <.001 | 1.216 (1.080-1.370) | .001 |
| KPS groups <80 | 2.234 (2.049-2.636) | <.001 | 1.925 (1.668-2.221) | <.001 |
| Primary tumor types | 1.040 (0.997-1.085) | ns | – | – |
| Presence of ECM | 1.200 (1.041-1.383) | .012 | 1.221 (1.055-1.413) | .008 |
| Presence of neurological symptoms | 1.577 (1.389-1.789) | <.001 | 1.184 (1.028-1.364) | .019 |
| Cumulative volume of all BM treated at GKRS1 ≥ 10 cm3 | 1.547 (1.293-1.852) | <.001 | 1.256 (1.041-1.515) | .017 |
| Cumulative volume of all BM treated at GKRS1 ≥ 25 cm3 | 2.638 (1.486-4.649) | <.001 | 1.175 (0.647-2.135) | ns |
| Number of ≥10 BM at GKRS1 | 1.488 (1.214-1.823) | <.001 | 1.610 (1.299-1.997) | <.001 |
| Dose-staged technique for high-risk or large BM | 0.959 (0.817-1.126) | ns | – | – |
| No concomitant immunotherapy or targeted therapy at GKRS1 | 1.396 (1.238-1.575) | <.001 | 1.422 (1.252-1.614) | <.001 |
| WBRT after GKRS1 | 0.902 (0.764-1.064) | ns | – | – |
BM, brain metastases; ECM, extracranial metastases GKRS, Gamma Knife Radiosurgery; KPS, Karnofsky Performance Status Scale; WBRT, whole brain radiotherapy.
Survival Predictors for Patients With ≥10 BM
From 1405 radiosurgically treated patients with FU, 123/1405 (9%) patients had ≥10 BM at GKRS1. After GKRS1, the estimated median survival was significantly longer in patients with KPS ≥80 (P = .007; Figure 3A), asymptomatic patients (P = .004; Figure 3B), patients with concomitant immunotherapy or targeted therapy at GKRS1 (P = .007; Figure 3C), and a cumulative BM volume of <25 cm3 for all BMs treated at GKRS1 (P = .003; Figure 3D).
Figure 3.
Survival after GKRS1 for patients with ≥10 brain metastases. (A) The estimated median survival after GKRS1 was significantly longer in patients with KPS ≥80 (6.5 months, 95% CI, 3.8-9.2), compared to patients with KPS <80 (4.2 months, 95% CI, 2.3-6.1; P = .007). (B) The estimated median survival after GKRS1 was significantly longer in asymptomatic patients (9.2 months, 95% CI, 5.5-12.8), compared to symptomatic patients (4.2 months, 95% CI, 2.6-5.7; P = .004). (C) The estimated median survival after GKRS1 was significantly longer in patients with concomitant immunotherapy or targeted therapy at GKRS1 (6.9 months, 95% CI, 4.8-9.0), compared to patients without concomitant immunotherapy or targeted therapy at GKRS1 (3.2 months, 95% CI, 2.2-4.3; P < .001). (D) The estimated mean survival after GKRS1 was significantly longer in patients with a cumulative BM volume of <25 cm3 for all BM at GKRS1 (14.7 months, 95% CI, 10.6-18.8), compared to patients with a cumulative BM volume of ≥25 cm3 (2.0 months, 95% CI, 1.1-2.8; P < .001). BM, brain metastases; CI, confidence interval; KPS, Karnofsky Performance Status Scale; GKRS1, first Gamma Knife Radiosurgery treatment.
However, the estimated median survival after GKRS1 did not show any significant differences between age groups (P = .470), sex (P = .212), primary tumor types (P = .140), status of ECM (P = .286), cumulative BM volume between <10 or ≥10 cm3 of all BMs treated at GKRS1 (P = .288), use of dose-staged technique for high-risk or large BM (P = .655), and subsequent WBRT (P = .119).
To further evaluate any potential survival predictors, univariable followed by multivariable Cox proportional hazard regression analyses were performed. Consequently, KPS <80 (HR: 1.702, P = .017), a cumulative BM volume of all BM treated at GKRS1 ≥ 25 cm3 (HR: 2.648, P = .031), and no concomitant immunotherapy or targeted therapy at GKRS1 (HR: 1.939, P = .002) were identified as independent prognostic factors for an increased risk of death (Table 3).
Table 3.
Negative prognostic factors for survival for radiosurgically treated patients with ≥10 BM (n = 123)
| Univariable analysis |
Multivariable analysis |
|||
|---|---|---|---|---|
| Variable | Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value |
| Age >65 years | 1.169 (0.791-1.727) | ns | – | – |
| Male sex | 1.303 (0.884-1.923) | ns | – | – |
| KPS groups <80 | 1.790 (1.169-2.741) | .007 | 1.702 (1.098-2.639) | .017 |
| Primary tumor types | 0.933 (0.813-1.072) | ns | – | – |
| Presence of ECM | 1.044 (0.592-1.841) | ns | – | – |
| Presence of neurological symptoms | 1.809 (1.206-2.714) | .004 | 1.426 (0.910-2.235) | ns |
| Cumulative volume of all BM treated at GKRS1 ≥ 10 cm3 | 1.080 (0.707-1.649) | ns | – | – |
| Cumulative volume of all BM treated at GKRS1 ≥ 25 cm3 | 3.983 (1.678-9.456) | .002 | 2.648 (1.091-6.428) | .031 |
| Dose-staged technique for high-risk or large BM | 0.785 (0.453-1.359) | ns | – | – |
| No concomitant immunotherapy or targeted therapy at GKRS1 | 2.018 (1.327-3.069) | .001 | 1.939 (1.263-2.975) | .002 |
| WBRT after GKRS1 | 1.101 (0.680-1.782) | ns | – | – |
BM, brain metastases; ECM, extracranial metastases GKRS, Gamma Knife Radiosurgery; KPS, Karnofsky Performance Status Scale; WBRT, whole brain radiotherapy.
Post-Radiosurgical Complications, Local, and Distant Tumor Control After GKRS1
After excluding patients who were completely lost to FU or those without radiological FU or who died prior to any FU, a total of 1072/1405 (76%) patients could be evaluated for radiologically diagnosed post-radiosurgical complications and local and distant tumor control. All radiologically diagnosed post-radiosurgical complications, local and tumor control, were reviewed, regardless of whether patients were symptomatic or asymptomatic.
Overall, the occurrence of post-radiosurgical complications (eg radiation reaction, radiation necrosis, and intralesional hemorrhage) as well as local tumor control after GKRS1 did not differ between patients with <10 and ≥10 BM. The use of dose-staged techniques for high-risk or large BM did also not influence the local tumor control rates (P = .338).
However, the distant failure rates were higher in patients with ≥10 BM (56%), compared to patients with <10 BM (46%; P = .017).
Moreover, the estimated median time to new BM was 16.8 months (95% CI, 13.3-20.3) and was shown to be significantly longer in patients with <10 BM (17.8 months, 95% CI, 14.1-21.6), compared to patients with ≥10 BM (6.4 months, 95% CI, 13.3-20.3; P < .001).
Discussion
So far, WBRT or SRS plus WBRT has been considered as the standard treatment for patients with multiple BM.5,6 However, WBRT has been linked to long-term neurocognitive decline, and the combination of SRS and WBRT showed a significantly higher risk of decreased neurocognitive function than treatment with SRS alone.5,6 A recent randomized clinical trial even showed that the stereotactic radiation in patients with 5-20 BM had greater improvement in mean symptom severity and interference score compared to hippocampal-avoidance whole brain therapy.19
Since the first report by Yamamoto et al in 1997, which described the radiosurgical treatment of 42 BM, several studies have further explored and reported on the safety and efficacy of SRS in patients with a higher number of BM, typically defined as 5-10 BM.3,5,6,20 Chang et al analyzed 323 patients with BM and found no significant differences in overall survival or local tumor control rates after SRS among patients with ≤5, >5, >10, or >15 BM.6 However, patients with >15 BM developed new lesions more rapidly, likely reflecting the higher metastatic potential of the progressive primary tumors.6
A recent systemic review and meta-analysis by Rozati et al reported that overall survival in patients with >10 BM was only slightly worse than in those with 2-9 BM.7 However, the authors pointed out that many included patients had been even treated prior to 2010, before the widespread use of intracranially active systemic therapies.7 Moreover, the lower limit of the 95% CI was close to unity, suggesting potential confounding factors affecting survival outcomes.7 In the study of Yamamoto et al, including 1515 patients with 5-10 BM and 804 patients with >10 BM, the median survival was also shorter in patients with >10 BM.21
In a recent study, Beckham et al compared survival outcomes in 440 patients with 5-9 BM and 117 patients with ≥10 BM in relation to systemic therapy. An increase in systemic therapy CNS activity score from before SRS to after SRS was associated with improved overall survival, highlighting the evolving importance of systemic therapies on outcomes in patients with multiple BM. The authors also reported that the number of BM was not predictive of overall survival. However, other potentially important prognostic factors, such as presence of neurological symptoms, were not included in the analysis.8
According to the latest European Society for Medical Oncology—European Association of Neuro-Oncology BM guidelines, SRS may be considered for patients with 5-10 BM and a cumulative tumor volume <15 mL.22 However, the guidelines also emphasize that WBRT should still be considered for patients with multiple BM not amendable to SRS, depending on the presence of neurological symptoms, as well as the size, number, and location of BM, and availability of CNS-active systemic therapy.22 Similarly, the American Society for Radiation Oncology guidelines do not recommended SRS for patients with more than 10 BM.23 The authors also noted the limited number of patients with >10 BM included in previous studies and criticized the fact that recommendations of BM treatment are still largely based on BM number.23 Nevertheless, they highlighted the importance of additional factors, such as BM size, location, and cumulative volume, as well as tumor histology, age, extracranial disease status, molecular profile, systemic treatment options, performance status, prognosis, and baseline neurocognitive function, which should also be considered for treatment considerations.23
So far, previous studies and guidelines concluded that the selection of appropriate BM treatment modality should not be only based on the number of BM.6-8,23
Therefore, we conducted a study of 1419 radiosurgically treated patients with BM to compare outcomes between patients with <10 vs. ≥10 BM and to further evaluate for any additional factors potentially influencing survival, such as cumulative BM volume, concomitant oncological therapies, or primary tumor types.6,7,23
In our cohort, patients with <10 BM demonstrated a longer survival duration after GKRS1, compared with those with ≥10 BM. As previously reported, we could also show that the survival did not differ between patients with <5 or 5-9 BM.6
Furthermore, we could identify several independent prognostic factors in association with an increased risk of death: age >65 years, male sex, poorer clinical condition (KPS <80), presence of ECM, neurological symptoms, a cumulative BM volume of all BM treated at GKRS1 ≥ 10 cm3, absence of concomitant immunotherapy or targeted therapy at GKRS1 and having ≥10 BM at GKRS1.23
Notably, in the era of modern systemic therapies, the absence of concomitant immunotherapy or targeted therapy at GKRS1 was associated with a 1.4-fold higher risk of death, independent of other prognostic factors. Our findings suggest that BM count should not alone guide treatment decisions during the pre-radiosurgery assessment, given the influence of multiple prognostic factors on survival outcome.
Cumulative BM Volume as a Strong Indicator for Radiosurgery
In the study of Niranjan et al, the authors reported that the cumulative BM volume should be considered as the most important factor in treatment selection.24 For better illustration, they presented 2 example patients. The first patient had 2 BM with a cumulative tumor volume of about 10 cm3, treated with margin doses of 17-18 Gy and a total 12 Gy volume of 24.3 cm3. Based on the low number of BM, this patient would traditionally be considered as an ideal candidate for SRS. In contrast, the second patient had 28 small lesions, who would typically not be considered as a good candidate and therefore, undergo WBRT. However, the total BM volume in this patient was only 2.7 cm3, with a total 12 Gy volume of 16 cm3. On these parameters, the second patient would more likely benefit from SRS.24
Rivers et al reported that the integral brain dose exceeded 3.0 J only when the tumor volume surpassed 25 cm3, corresponding to a total brain dose of 2.4 Gy, and thereby was lower than a single fraction of WBRT.25 Based on these data, the authors therefore concluded that patients with a tumor volume ≤ 25 cm3 can be safely treated with a single SRS session, whereas those with a tumor volume ≥25 cm3 should be considered for either multiple SRS sessions or WBRT.24 Additionally, other studies have reported that a cumulative BM volume >10 cm3 may be a more accurate predictor of SRS feasibility than the number of BM alone.26,27
The 2-fraction dose-staged treatment concept allows the treatment of large or high-risk BM with good results.10 In our cohort, the use of dose-staged technique for high-risk or large BM did not impact the survival. Moreover, including all patients, regardless of BM number, a cumulative tumor volume of ≥10 cm3 was shown as an independent risk factor in survival in our study. In the subgroup of only patients with ≥10 BM, a cumulative tumor volume ≥25 cm3 was associated with a 2.6-fold higher risk of death, independent of other prognostic factors. However, this finding should be interpreted with caution, given the small number of patients with a cumulative volume ≥25 cm3 in this group. Overall, our findings suggest that BM volume should also be considered alongside BM count during pre-radiosurgery assessment.
Post-Radiosurgical Complications, Local, and Distal Tumor Control
In the study of Chang et al, the incidence of post-radiosurgical complications was not higher in patients with >15 BM compared to patients with fewer lesions.6 Similar findings were reported by Yamamoto et al who found no significant differences in post-radiosurgical complications between patients with 2-4 and 5-15 BM.28 Furthermore, local tumor control rates after SRS have been reported to be comparable across patient groups with ≤5, >5, >10 or >15 BM.6
In line with these findings, our analysis also showed no significant differences in post-radiosurgical complications and local tumor control rates between patients with <10 vs. ≥10 BM. These results support that radiosurgical treatment remains a safe and effective treatment option, even for patients with ≥10 BM.
Of note, radiosurgically treated patients with multiple BM (eg >15 BM) were previously found to have faster development of new BM than patients with fewer BM.6 In our study, similar results could be seen after GKRS1: patients with ≥10 BM had a faster and a more frequent development of new BM than patients with <10 BM. These findings replay the clinical course of the progressive disease. However, the median time until the occurrence of new BM was 16.8 months for the study population and even 6.4 months for patients with ≥10 BM, displaying the importance of the radiosurgical treatment for this patients’ group.
Survival Predictors for Patients With ≥10 BM in the Era of Modern Systemic Therapies
In the era of modern systemic therapies with previous studies demonstrating clear survival benefits in radiosurgically treated patients with BM and concomitant systemic therapies, data on their use in patients with more than 10 BM are still scarce.7,14
The largest study by Yamamoto et al included 804 patients with 11-20 BM. The authors identified male sex, KPS <80, presence of neurological symptoms, cumulative tumor volume of ≥7 cm3, uncontrolled primary cancer, and presence of ECM as significant predictors of shorter survival.21 However, this study did not account for concomitant therapies to their multivariable analysis.21
To our knowledge, our study is the first to evaluate survival predictors for radiosurgically treated patients with ≥10 BM and concomitant immunotherapy or targeted therapy at GKRS1.
In our analysis, including only patients with ≥10 BM, poor clinical condition (KPS <80), a cumulative BM volume of all BM treated at GKRS1 ≥ 25 cm3 and absence of concomitant immunotherapy or targeted therapy at GKRS1 could be identified as significant independent prognostic factors for an increased risk of death.
Notably, among patients with ≥10 BM, the absence of concomitant immunotherapy or targeted therapy at GKRS1 was even associated with a 1.9-fold higher risk of death. Therefore, the number of BM should not be the sole criterion in the management plan for patients with multiple BM.
Conclusions
Our findings suggest that, in addition to BM count, multiple prognostic factors may influence survival outcomes and should be considered during pre-radiosurgery assessment. Gamma Knife radiosurgery represents a safe and effective treatment method for patients with ≥10 BM, particularly in the era of modern systemic therapies, which can further improve survival in patients with multiple BM. These findings support a more liberal use of SRS in patients with multiple BM.
Limitations
The main study limitations were the retrospective, single-center, non-randomized design, the small sample sizes within individual histology subgroups, the absence of neurocognitive and quality-of-life data, the inability to separate immunotherapy from targeted therapy effects, and the lack of information on treatment sequencing relative to systemic therapies. As the study was not intended to compare SRS with upfront WBRT, but rather to evaluate the safety and efficacy of SRS in patients with ≥10 BM, the potential for selection bias should be acknowledged.
Supplementary Material
Contributor Information
Anna Cho, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Thore Jankowski, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Yiru Chen, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Lukas Kohlmaier, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Brigitte Gatterbauer, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Philip Lederer, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Lukas Haider, Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria.
Sonja Tögl, Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria.
Karl Rössler, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Christian Dorfer, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Philippe Dodier, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Christoph Höller, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Rupert Bartsch, Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
Maximilian J Hochmair, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria.
Josa M Frischer, Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Supplementary Material
Supplementary material is available online at Neuro-Oncology Advances (https://academic.oup.com/noa).
Author Contributions
Anna Cho, Thore Jankowski, Yiru Chen, and Josa M. Frischer contributed to data acquisition. Anna Cho, Thore Jankowski, Yiru Chen, Lukas Kohlmaier, and Josa M. Frischer drafted the initial version of the manuscript, tables and figures, and performed the statistical analyses. All authors were involved in data interpretation and editing of the manuscript. All authors critically reviewed the manuscript and approved the final draft.
Conflict of Interest Statement
LH received honoraria for presentations or consulting from Biogen, Eisai, Eli-Lilly and Teva. PD received honoraria for lectures from Olympus. MJH received honoraria from MSD, Roche, BMS, Lilly, Astra Zeneca, Takeda and Pfizer. JMF received honoraria for advisory boards or lectures from Elekta and Lilly/Takeda. The other authors have no conflict of interest to disclose.
Funding
None declared.
Ethics Approval Statement
This study was approved by the institutional ethics review board (EK 2032/2022 and 2033/2022).
Data Availability
Research data will not be shared.
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Supplementary Materials
Data Availability Statement
Research data will not be shared.