Abstract
Objectives
Stereotactic radiotherapy (SRT) for brain metastases (BM) allows very good local control (LC). However, approximately 20%-30% of these lesions will recur. The objective of this retrospective study was to evaluate the impact of dosimetric parameters on LC in cerebral SRT.
Methods
Patients treated with SRT for 1-3 BM between January 2015 and December 2018 were retrospectively included. A total of 349 patients with 538 lesions were included. The median gross tumour volume (GTV) was 2 cm3 (IQR, 0-7). The median biological effective dose with α/β = 10 (BED10) was 60 Gy (IQR, 32-82). The median prescription isodose was 71% (IQR, 70-80). Correlations with LC were examined using the Cox regression model.
Results
The median follow-up period was 55 months (min-max, 7-85). Median overall survival was 17.8 months (IQR, 15.2-21.9). There were 95 recurrences and LC at 1 and 2 years was 87.1% (95% CI, 84-90) and 78.1% (95% CI, 73.9-82.4), respectively. Univariate analysis showed that systemic treatment, dose to 2% and 50% of the planning target volume (PTV), BED10 > 50 Gy, and low PTV and GTV volume were significantly correlated with better LC. In the multivariate analysis, GTV volume, isodose, and BED10 were significantly associated with LC.
Conclusion
These results show the importance of a BED10 > 50 Gy associated with a prescription isodose <80% to optimize LC during SRT for BM.
Advances in knowledge
Isodose, BED, and GTV volume were significantly associated with LC. A low isodose improves LC without increasing the risk of radionecrosis.
Keywords: stereotactic radiotherapy, brain metastases, dosimetric parameters, local recurrence
Introduction
Brain metastases (BM) will occur in nearly 30%-40% of patients with cancer.1 The incidence is increasing notably due to the ageing of the population, as well as the increase in patients’ survival with the improvement of systemic treatments. Managing the progression of BM is crucial for both neurological morbidity and survival.2,3 BM requires specific management as many systemic treatments do not cross the blood-brain barrier.4 Different assessment scores based on independent prognostic factors have been developed to help select the most appropriate treatment for each patient as RPA (Recursive Partitioning Analysis) score or DS-GPA (Diagnosis-Specific Graded Prognostic Assessment) score.5 Historically, treatment of BM was based on whole-brain radiotherapy (WBRT) which resulted in neurological toxicity in the form of cognitive decline that appears in the year following treatment, such as alterations of executive function, fine motor control, and episodic memory disorders.6,7 In the last few years, stereotactic radiotherapy (SRT) has developed. This technique uses multiple beams, converging on a small-volume target. Precision of the order of a millimetre is required to deliver very high doses, and must therefore be supported by a high degree of reproducibility at the time of treatment. SRT has then emerged as a less toxic and more efficient option as it spares healthy tissues while delivering a high dose to the BM owing to its high precision and strong dose gradient.8 SRT achieves a high local control (LC) >75% at 1 year9 with a low rate of adverse events and reduces neurological symptoms. Moreover, it has become possible to irradiate new lesions in cases of disease progression. SRT can be performed by dedicated systems like GammaKnife or CyberKnife, or adapted conventional linear accelerators (LINAC). There is an important variability in the delivery of SRT treatments. Indeed, multiple treatment delivery parameters can be used as modulated or non-modulated beams, X-ray beam or cobalt gamma-ray beam, etc. There is also a large heterogeneity in delivered doses parameters regarding the total dose, number of fractions, isodose, and target volume. The aim of this retrospective study was to investigate the impact of dosimetric factors on LC.
Methods
Patients and tumour characteristics
All patients treated with SRT for BM at two French centres between January 2015 and December 2018 were retrospectively identified. Patients older than 18 years, with a maximum of three brain lesions to be irradiated, and patients who underwent brain imaging by MRI within 3 months after treatment were included. Patients who underwent several SRT at different time for different lesions were included. RPA score10 was used to characterize patients. This score demonstrated a prognostic impact and includes the Karnofsky index, age, primary disease control, and presence of extracerebral disease. The pretreatment workup consisted of a physical examination, a brain MRI, and an evaluation of extra-cerebral disease by CT of the chest, abdomen, and pelvis (CT-TAP) and/or 18-flurodeoxyglucose PET—CT (FDG PET/CT), depending on the histology of the primary site. Patients with a history of previous WBRT, preoperative SRT, or re-irradiation on the same lesion were excluded from this study. A total of 349 patients representing 538 lesions with 93 postoperative SRT were included in this retrospective study. The main characteristics of the patients and their tumours are presented in Table 1. All the patients provided permission for the use of their clinical data. The institutional review board approved this study.
Table 1.
Patient clinical and pathologic characteristics.
| Characteristics | Number (%) |
|---|---|
| Age, average (max-min) | 62 (25-88) |
| Sex | |
| Female | 161(46.1%) |
| Male | 188 (53.9%) |
| ECOG PS | |
| 0 | 167 (47.9%) |
| 1 | 176 (50.4%) |
| 2 | 6 (1.7%) |
| Primary | |
| Lung | 189 (54.2%) |
| EGFR | 7/189 (3.7%) |
| ALK | 17/189 (9%) |
| Breast | 56 (16%) |
| RH−, HER2− | 14/56 (25%) |
| RH−, HER2+++ | 18/56 (32.2%) |
| RH+, HER2− | 9/56 (16%) |
| RH+, HER2+++ | 15/56 (26.8%) |
| Melanoma | 34 (9.7%) |
| Renal | 22 (6.3%) |
| Other | 48 (13.8%)a |
| Number of treated metastases | |
| 1 | 222 (63.6%) |
| 2 | 103 (29.5%) |
| 3 | 24 (6.9%) |
| Extra cerebral disease | |
| Yes | 210 (60.1%) |
| No | 139 (39.9%) |
| Neurologic symptoms | |
| Yes | 126 (36.1%) |
| No | 223 (63.9%) |
| RPA class | |
| I | 85 (24.4%) |
| II | 257 (73.6%) |
| III | 7 (2.0%) |
| Systemic treatment | |
| Yes | 187 (53.6%) |
| No | 162 (46.4%) |
The results are detailed only for the 4 most frequent primary.
Abbreviations: IQR = interquartile range, ECOG PS = Eastern Cooperative Oncology Group performance status, HER-2 = Human Epidermal Growth Factor Receptor 2, HR = Hormone Receptor, EGFR = Epithelial Growth Factor Receptor, ALK = activin-like kinase.
Stereotactic radiotherapy
The SRT was performed using a linear accelerator (TrueBeam® STX linac) and Cyberknife® (Accuray) depending on treatment centre. A tight thermoplastic mask was used for immobilization. Planning CT images (1-1.5 mm slice thickness) were fused with thin-slice MRI images (performed within 2 weeks before SRT) using an image-fusion software. Gross tumour volume (GTV) was defined as a contrast-enhanced tumour on the T1 sequence of the fusion MRI. The clinical target volume (CTV) was equal to that of the GTV. The planning target volume (PTV) was defined from the CTV with an isotropic margin of 1 and 2 mm in the Cyberknife® and LINAC treatments, respectively. For postoperative irradiation, the CTV was defined as a margin of 1 mm from the GTV, and the PTV corresponded to the CTV with a margin of 1 mm. SRT was performed every day (68% of the lesions) or every other day, depending on the treatment centre. Several treatment regimens have been used, the number of fractions and total dose depended on the treatment centre, location, size of the PTV, and proximity to organs at risk. For example, tumours smaller than 1 cm were preferentially treated with 1 fraction. To compensate the heterogeneity of prescription, we used the biological effective dose (BED) to evaluate quantitatively the biological effect of a treatment, taking into account dose-per-fraction and total dose.11,12 The BED was calculated using an estimated α/β of 10 with the following formula: BED = D × (1 + [d/(α/β)]), where d = dose per fraction, in Gy, D = total dose (number of fractions × dose per fraction), in Gy, and α/β ratio = property of irradiated tissue.
Outcome evaluation
Outcomes were evaluated using brain MRI performed within 3 months following SRT and every 3 months thereafter. LC was defined as the absence of local recurrence (LR), which was defined as the radiographic appearance of a new or increasingly enhancing lesion in the treated area. In cases of doubtful results, MRI could be performed earlier or complemented by dual-phase FDG-PET imaging of the brain to help characterize radionecrosis (RN) or LR.13 Since normal grey matter shows an intense and early physiological [18F]-FDG uptake, standard [18F]-FDG can be inadequate. An additional delayed PET images 4-5 h after [18F]-FDG injection can be performed to reach a sensitivity of 93%-95% and a specificity of 94%-100%.14 If the [18F]-FDG uptake intensity was higher than the contralateral normal grey matter, lesions were considered as viable tumours. Cerebral recurrence was defined as the appearance or progression of cerebral lesions outside of the irradiated sites. RN was defined on MRI as the presence of central hypodensity and peripheral enhancement on T1, associated with oedema on T2 and a lack of perfusion. No histological confirmation of the RN was required.
Statistics
Analyses were conducted at the level of the individual metastases. Time to LR was defined from the start of SRT until recurrence. Intracranial failure was defined as the period from the start of SRT to the time of any new central nervous system progression. Follow-up was calculated using reverse Kaplan-Meier estimation.15 The OS was calculated as the period from the first day of radiotherapy to the date of death from any cause. Patients who were alive at the time of the analysis were censored at the last date of follow-up. OS, LC, and LR estimations were computed using the Kaplan-Meier method, and a two-sided log-rank test was used to compare the groups. The following parameters were tested: Age, performance status, RPA, systemic treatment, primary, GTV volume, PTV volume, BED10, isodose, dose to 2%, 50%, and 98% of the PTV (known as D2%, D50%, and D98%, respectively), and dose gradient (defined as the ratio between the volume receiving 50% of the prescribed dose and the volume receiving 100%). We performed analyses on the general population, on in-place lesions, postoperative site and lesions that received one session. Many prescription isodoses are routinely used even though the 80% isodose is commonly used. To identify a potential threshold effect, 3 isodose groups encompassing PTV were created by categorizing them as follows: ≤ 70%, 70%-80%, and > 80%. Two BED10 groups were created by using a threshold of 50 Gy according to the literature.16 Univariate Cox analysis was performed to assess all clinical and treatment parameters for LR. Following univariate analyses, factors with a significance of P-value <.1 were assessed using a multivariate Cox regression model with backward elimination. Variables were removed from the model if P > .1. Following the multivariate analysis, we performed a Sperman test to identify the relationship between the quantitative variables. We also calculated the variance inflation factor (VIF) to quantify the strength of the multicollinearity of each covariate in the model. Chi-square analysis was used to test for differences in RN.
Data were analysed using the R software package (R Core Team, https://www.R-project.org/) version 4.1.0 (released on May 18, 2021).
Results
Dosimetric results
The median number of fractions was three (range, 1-5). The median BED10 at the prescription isodose was 60 Gy (range, 32-82). The radiation schedule used is listed in Supplementary Table S1. The dosimetric parameters are presented in Table 2.
Table 2:
SRT characteristics.
| Parameters | Number (%) |
|---|---|
| Adjuvant radiotherapy | |
| Yes | 95 (17.7%) |
| R1 | 31/95 (32.6%) |
| R0 | 64/95 (67.4%) |
| No | 443 (82.3%) |
| GTV volume (cm3) | 2 (0-7)a |
| PTV volume (cm3) | 3 (1-9)a |
| Number of fractions | |
| 1 | 104 (19.3%) |
| 3 | 321 (59.7%) |
| 4 | 2 (0.4%) |
| 5 | 111 (20.6%) |
| BED10 (Gy) | 60 (41-60)a |
| Median dose (Gy) | 29,2 (24.4-35.9)a |
| D98% (Gy) | 24.5 (23.2-0.0)a |
| D2% (Gy) | 33 (28-42)a |
| D50% (Gy) | 29.2 (24.4-35.9)a |
| V10 (cm3) | 27 (8-52)a |
| V12 (cm3) | 21 (6-38)a |
| V14 (cm3) | 18 (10-32)a |
| Conformity index | 1.19 (1.13-1.48)a |
| Gradient index | 3.72 (3.01-4.57)a |
| Prescription isodose (%) | 71 (70-80)a |
| Treatment duration (days) | 4.35 (3-6)a |
Median (IQR).
Abbreviations: R0 = complete resection, R1 = incomplete resection, GTV = gross tumour volume, PTV = planning treatment volume, BED10 = biological effective dose with alpha/beta= 10, Dx% = dose to x % of the PTV, Vx = volume of (brain—PTV) receiving X Gy.
Clinical results
The median follow-up time was 55 months (min-max, 7-85) and recurrence occurred in 95 of 538 irradiated metastases. The 1-, 2- and 3-year LC rates were 87.1% (95% CI, 84%-90%), 78.1% (95% CI, 73.9%-82.4%), and 74,8% (95% CI, 70.3%-79.7%), respectively. The 6-month, 1- and 2-year brain recurrences were 30% (95% CI, 25.9-33.8), 49% (95% CI, 44.2-53.3), and 61.8% (95% CI, 56.8-66.2), respectively. At the last follow-up, 87 patients were still alive. The median survival time was 17.8 months (IQR, 15.2-21.9) and the 1-, 2- and 3-year OS rate was 62.9% (95% CI, 58-68.2), 41.1% (95% CI, 36.2%-46.7%) and 32.6% (95% CI, 28%-38%), respectively.
Predictors of recurrence
Figure 1 shows the clinical parameters tested in the univariate analysis for recurrence. The administration of a systemic treatment (HR, 0.52; 95% CI, 0.34-0.77; P = .016) was associated with a decrease of LR. Figure 2 shows the dosimectrics factors tested in the univariate analysis for LR. The significant parameters correlated with recurrence were PTV volume (HR, 1.02; 95% CI, 1-1.04; P = .03), BED10 (HR, 0.94; 95% CI, 0.92-0.96; P < .01), isodose (HR, 1.05; 95% CI, 1.02-1.07; P < .01), D2% (HR, 0.96; 95% CI, 0.94-0.99; P = .005), and D50% (HR, 0.96; 95% CI, 0.93-1; P = .025). In the multivariate analysis, a high isodose (HR, 1.023; 95% CI, 1-1.1048; P = .05) and a high GTV volume (HR, 1.023; 95%CI, 1.001-1.045; P = .042) were significantly correlated with a higher risk of recurrence, while a high BED10 (HR, 0.95; 95%CI, 0.93-0.97; P < .01) decreased significantly recurrence (Figure 3). There was no correlation between isodose and volume (Spearman r = 0.04; P = 0.3185). There was a weak inverse correlation between isodose and BED (Spearman r = −0.22; P = 2.926−7) and volume and BED (Spearman r = −0.21; P = 9.119−7). The VIF is equal to 1.3 for BED, 1.3 for isodose and 1.01 for the volume, indicating a low correlation between the parameters.
Figure 1.
Cox regression univariate analysis of clinical factors for local recurrence. Abbreviations: HR = hazard ratio, RPA = recursive partitioning analysis.
Figure 2.
Cox regression univariate analysis of dosimetrics factors for local recurrence. Abbreviations: HR = hazard ratio, GTV = gross tumour volume, PTV = planning target volume, Dmean = mean dose to the PTV, DX% = dose to X% of the PTV, Gy = grey.
Figure 3.
Cox regression multivariate analysis of dosimetrics factors for local recurrence. Abbreviations: HR = hazard ratio, GTV = gross tumour volume, Gy = grey.
Regarding isodose, a value of >80% was correlated with a poorer LC (Figure 4). No significant difference was found between values ≤70% and those ranging from 70% to 80% (HR, 1.29; 95% CI, 0.8-2.1; P = .296). Concerning BED10, a threshold higher than 50 Gy was significantly correlated with a better LC (HR, 0.33; 95% CI, 0.22-0.5, P < .01) (Figure 4).
Figure 4.
Kaplan-Meier curves for LC according to isodose (A) and BED10 (B). Abbreviations: BED = biological effective dose, Gy = grey, LC = local control.
In the analysis of postoperative lesions (90 lesions), no parameter was significant in univariate analysis.
Analysis of the in-place lesions showed the same results as for the general population (Supplementary Figure S1). Concerning lesions that received one session (104 lesions), there were no significant dosimetric parameters in univariate analysis. The results for patients treated in several sessions were similar to those of the general population.
Radionecrosis was observed in 74 of the lesions. There was no correlation between the occurrence of RN and BED10 (P = .11) nor isodose prescription (P = .29). The numbers of RN cases according to the BED10 and isodose prescription are shown in Supplementary Table S2.
Discussion
In our retrospective multicentre study included more than 500 BM treated with SRT, we showed that dosimetric parameters could impacted the LC. Indeed, BED10 and isodose were significantly correlated with LR.
We found a LC at 12 months of 87.1% (95% CI, 84-90). However, a significant difference was found between a BED10 >50 Gy (91.6%) and a BED10 <50 Gy (76.5%). Several studies have shown a correlation between the delivered dose and LC.17,18 Due to the heterogeneity in dose prescription, we substituted the total dose with BED10 to compensate for the different fractions. By definition, fractionation was strongly correlated with total dose and dose per fraction. Indeed, various prescription doses were used in our study (Supplementary Table S1). According to the literature, a BED10 between 40-50 Gy and 50-60 Gy would provide at least 70% and 80% of LC at 12 months,19 respectively. However, the concept of BED may have some limitations. The use of the linear quadratic model, and thus the calculation of the BED, is questioned in high and ablative doses used in SRT. The model was validated for doses per fraction between 1 Gy and 8-10 Gy. Some authors have validated the use of this model up to approximately 18 Gy per fraction (19), even though others consider that in these conditions, there is a risk of underestimation of the efficacy, given the failure to take into account the tumour environment and the impact on radio-resistant subpopulations.20–22 We chosen a value for α/β of 10 to calculated the BED, without adjusting it according to the primary, as usually performed in the literature.
Gross tumour volume was a significant factor in multivariate analysis. Several studies have shown that LR can be influenced by the tumour volume. However, the influence of GTV is difficult to quantify, as the delivered dose often decreases according to the tumour volume.18 In the RTOG 90-05 study, a prospective dose escalation trial in stereotactic re-irradiation including 168 patients, tumour volume was not significantly related to LC in multivariate analysis.23 Similarly, 1 retrospective study including 150 lesions with a prescription dose decreasing with tumour size found better LC with a low tumour volume in univariate analysis. However, in a multivariate analysis, only dose and Karnofsky Performance Status were significantly correlated with LC.24 In contrast, another retrospective study, which included 573 lesions treated with SRT with a BED10 close to 80 Gy, showed that tumour size was a negative predictive factor for LC in multivariate analysis (P = .001).19 Thus, results differ in the literature, although the respect of a high BED seems to be the major point. However, the results tended to show an impact of GTV volume.
In our series, the prescription isodose was correlated to recurrence in the multivariate analysis. Few retrospective studies have evaluated this impact. With regard to SRT performed using Volumetric Modulated Arc Therapy (VMAT), a study analysed 18 patients with 20 brain tumours.25 For each patient, five treatment plans were performed with prescription isodoses ranging from 50% to 90%, with a total dose of 50 Gy in 10 fractions of 5 Gy. Authors showed that for BM volume <10 cm3 the optimal prescription isodose was approximately 60%-70%, which allows a low dose gradient with a low dose to healthy tissue as well as a higher average dose within the tumour. A similar study reported results in 13 patients with 16 lesions treated with Cyberknife® with three treatment plans: low (50%), medium (70%), and high (90%) prescription isodoses.26 The authors showed that with a low prescription isodose, the dose to the healthy brain was lower, as well as the conformality, except for lesions <0.5 cc. The results were similar to those obtained with the medium isodose prescription. By lowering the isodose, the irradiation of healthy tissues was less important, with the possibility of increasing the dose and, therefore, probably LC. Clinical data on isodoses are controversial. In 2017, the impact of GammaKnife® treatment on LC was retrospectively evaluated in 134 patients, representing 374 BM. 27 In multivariate analysis, progression-free survival (defined by the absence of local tumour progression only) was positively correlated with the prescription isodose (P = .003). Similarly, in a study including patients with non-small cell lung cancer BM treated with a single fraction with GammaKnife®, the isodose prescription was an independent predictive factor of LC (HR, 0.953; P = .031).28 Moreover, the impact of 2 different isodose were evaluated in a retrospective study which included 134 patients. Inhomogeneous prescription (using isodose 70%) were significantly correlated with a better LC compare to the homogenous treatment (99% isodose line covering 99% of the PTV), with a 12 months LC of 93% compared to 78% (P = .005).29 The authors suggested that the increase in LC may be due to the increased dose to hypoxic tumour cells.
Our results are in favor of the use of a low prescription isodose (<80%). Some studies described above found results in favor of an isodose higher than 60% (compared to an isodose of 50%), which is in line with our results. In our cohort, we did not observe a difference between lesions treated with an isodose between 80% and 70% and those with an isodose ≤70%. However, this may be explained by a lack of power. In our study, isodose and dose had a significant impact on recurrence in multivariate analysis. In the case of heterogeneous treatment, the choice of isodose influences the average and maximum doses received by the PTV. The impact of the isodose on recurrence can be explained using these parameters.
Few patients in our cohort benefited from new SRT at cerebral progression. With the evolution of systemic treatments and the increased life expectancy of patients with BM, repeated courses of SRT are more frequent. Recently a retrospective study included 184 patients and 915 BM treated between 2010 and 2020, showed that 81 patients had no immediate neurological symptoms during any treatment session. Only worst RPA score was correlated with the presence of neurologic symptoms in the univariate analysis (P = 0.02). Sixty-seven patients developed acute toxicity without grade 3 or 4. The corticosteroid therapy was the only parameter significantly correlated with the cumulative acute toxicity in multivariate analysis.30 A small number of BM (7%) showed RN during repeated SRT for local or distant recurrent BM. Local reirradiation (P < .001) and the number of SRT (P < .001) were statistically associated with RN in multivariate analysis per BM.31 Repeated SRT for local or distant recurrent BM appears to be a feasible and well-tolerated treatment.
Our study had several limitations, with possible bias inherent to its retrospective and non-comparative design. Our population was heterogeneous in many ways. A large panel of treatment regimens was used, with different total doses and numbers of fractions (Supplementary Table S1), leading to difficulties in comparing such patients. However, these differences were compensated for using the BED. However, we were unable to identify any significant dosimetric parameters for patients treated in one session due to the homogeneity of this population and the small number of patients (BED > 50Gy and only 2 patients with isodose >80%). MR images as old as 2 weeks were used for some patients according to current recommendations.32 Later, according to the literature, MRIs of less than 1 week were used. Finally, some systemic treatments, particularly targeted therapies, could have an impact on LC.33 However, the impact of these treatments is difficult to be analysed because a large majority of patients are treated with different therapies at different times. Moreover, given the retrospective nature of the study, MRI controls were not included in a protocol. Undiagnosed recurrences cannot therefore be excluded.
Conclusion
In case of SRT for BM, the use of a BED10 >50 Gy and an isodose <80% is correlated with a high LC (>90%), without increasing the risk of RN. No significant clinical benefit of low isodose (≤70%) was observed. Small tumours appear to have better LC than large tumours.
Supplementary Material
Contributor Information
Camille Berthet, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France.
François Lucia, Radiation Oncology Department, University Hospital, Brest, 29200, France.
Vincent Bourbonne, Radiation Oncology Department, University Hospital, Brest, 29200, France.
Ulrike Schick, Radiation Oncology Department, University Hospital, Brest, 29200, France.
Isabelle Lecouillard, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France.
Coralie Le Deroff, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France.
Anais Barateau, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France; Univ Rennes, CLCC Eugène Marquis, Inserm, LTSI – UMR 1099, Rennes, 35000, France.
Renaud de Crevoisier, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France; Univ Rennes, CLCC Eugène Marquis, Inserm, LTSI – UMR 1099, Rennes, 35000, France.
Joel Castelli, Radiation Oncology Department, CLCC Eugene Marquis, Rennes, 35000, France; Univ Rennes, CLCC Eugène Marquis, Inserm, LTSI – UMR 1099, Rennes, 35000, France.
Author contributions
C. Berthet, F. Lucia, and V. Bourbonne contributed equally to this work.
Supplementary material
Supplementary material is available at BJR online.
Funding
None declared.
Conflicts of interest
None declared.
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