Highlights:
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MRgSBRT revealed a 2- year LPFS rate of 88%.
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Tumors treated with PTV CI of ≥ 0.90 had an improved LPFS.
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No local recurrences were observed after a total dose of BED10>100 Gy, with single fraction or fractional dose of >10 Gy.
Keywords: Adrenal gland metastases, MR-guided, Stereotactic body radiotherapy, Stereotactic ablative radiotherapy
Abstract
Purpose
Stereotactic body radiotherapy (SBRT) is an effective treatment for adrenal gland metastases, but it is technically challenging and there are concerns about toxicity. We performed a multi-institutional pooled retrospective analysis to study clinical outcomes and toxicities after MR-guided SBRT (MRgSBRT) using for adrenal gland metastases.
Methods and Materials
Clinical and dosimetric data of patients treated with MRgSBRT on a 0.35 T MR-Linac at 11 institutions between 2016 and 2022 were analyzed. Local control (LC), local progression-free survival (LPFS), distant progression-free survival (DPFS) and overall survival (OS) were estimated using Kaplan-Meier method and log-rank test.
Results
A total of 255 patients (269 adrenal metastases) were included. Metastatic pattern was solitary in 25.9 % and oligometastatic in 58.0 % of patients. Median total dose was 45 Gy (range, 16–60 Gy) in a median of 5 fractions, and the median BED10 was 100 Gy (range, 37.5–132.0 Gy). Adaptation was done in 87.4 % of delivered fractions based on the individual clinicians' judgement. The 1- and 2- year LPFS rates were 94.0 % (95 % CI: 90.7–97.3 %) and 88.3 % (95 % CI: 82.4–94.2 %), respectively and only 2 patients (0.8 %) experienced grade 3 + toxicity. No local recurrences were observed after treatment to a total dose of BED10 > 100 Gy, with single fraction or fractional dose of > 10 Gy.
Conclusions
This is a large retrospective multi-institutional study to evaluate the treatment outcomes and toxicities with MRgSBRT in over 250 patients, demonstrating the need for frequent adaptation in 87.4 % of delivered fractions to achieve a 1- year LPFS rate of 94 % and less than 1 % rate of grade 3 + toxicity. Outcomes analysis in 269 adrenal lesions revealed improved outcomes with delivery of a BED10 > 100 Gy, use of single fraction SBRT and with fraction doses > 10 Gy, providing benchmarks for future clinical trials.
Introduction
The adrenal glands represent a common site of metastatic dissemination, with a prevalence of around 0.5–3.8 % and originate most commonly from lung, genitourinary, and gastrointestinal malignancies [1], [2]. Adrenal metastases are increasing being identified because of comprehensive disease-specific staging and follow-up guidelines. The proximity of the adrenal glands to stomach, liver, kidneys, bowel and large vessels poses a challenge for local radiation therapy (RT) [3]. Although adrenalectomy has long been the gold standard in the management of adrenal gland metastases [4]; local control (LC) and overall survival (OS) at 2-year were a modest 84 % and 46 %, respectively. In addition, 6 % of patients can develop intraoperative complications, 13.4 % postoperative complications, and 2.6 % with severe postoperative complications [5], [6].
In patients who are medically unfit for metastasectomy, stereotactic body radiation therapy (SBRT, also known as stereotactic ablative radiation therapy [SABR]), and percutaneous catheter ablation techniques have been explored [5]. For SBRT, continuous and unpredictable motion of abdominal structures results in inherent positional uncertainties, causing both intra- and inter-fraction changes, particularly challenging when employing hypofractionated schedules [7], [8]. However, the integration of an magnetic resonance imaging (MRI) system and a megavoltage RT system into a single treatment delivery unit has provided the possibility to acquire an MRI in the treatment position and continuously during RT delivery [9]. MR-guided SBRT (MRgSBRT), with its ability to better visualize soft tissue and track tumors during treatment, has been shown to be a novel but reproducible and accurate treatment modality that may reduce treatment volumes and may consequently minimize toxicity [10]. Early single-institution clinical outomes of adrenal SBRT with MRgRT have also been published [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. The main aim of this multi-institutional pooled analysis was to report the clinical outcomes and toxicities after adrenal MRgSBRT on a 0.35 T MR-linac. A secondary objective was to study the prognostic factors that may be related to the long-term control rates.
Materials and methods
We analyzed clinical and dosimetric data of patients treated with MRgSBRT for adrenal metastases at 11 institutions across Europe (7) and USA (4) between 2016 and 2022 retrospectively. Ethics approval had been obtained in the coordinating study center (Acibadem MAA University, 2022-13/20) and in participating institutions in accordance with local standards through individual data transfer agreements. Institutional databases for medical records were reviewed for demographic, pathologic, radiologic, treatment and outcome related information. Part of this data has been reported recently by Amsterdam University Medical Centers (AUMC) [19]. Baseline patient characteristics including age, gender, performance status, histopathology, the timing of metastasis (synchronous, metachronous, oligoprogressive, or oligopersistent based on the ESTRO-ASTRO consensus definition [20]), metastatic pattern, laterality, and whether chemotherapy or immunotherapy was administered concurrently (within 3 months before and/or after MRgSBRT) were recorded. For dosimetric analysis, prescription dose (cGy), number of fractions, fractional dose, respiratory motion management techniques, tracking boundary (mm), number of adapted fractions, gross tumor volume (GTV) (cc), planning target volume (PTV) (cc), margin expansion (mm), GTV Dmean (Gy), GTV D95%, PTV D95%, PTV conformity index (CI), and PTV homogeneity index (HI) were recorded. Patients treated up to 8 fractions with a minimum dose of 5 Gy per fraction were included. All patients were treated with MRgSBRT on 0.35 T MR Linac units. Simulation protocols, and total dose and fractionation schedules were at the discretion of the treating institution. The dose was prescribed to PTV to ensure the required coverage of the PTV with the 95 % isodose line. The response evaluation included clinical and radiological (CT scan, MRI, or PET/CT) evaluations as well as toxicity scoring at each visit according to each institutional practice. Details of adaptive MRgSBRT procedures have been reported previously [9], [17]. Organ-at-risk (OAR) dose constraints were set according to the institutional protocols or international guidelines. The BED was calculated due to heterogeneous dose prescription patterns and fractionation schedules; an α/β ratio of 10 Gy was assumed for the adrenal metastases.
Tumor responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria [21]. Acute toxicity was defined as toxicity occurring up to 90 days post-MRgSBRT and late toxicity as occurring after more than 90 days after treatment. Radiation-related toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Descriptive statistics were used to describe demographic, clinical, and treatment-related characteristics. The start date for the time-to-event analysis was defined as the first day of MRgSBRT treatment. Treatment response to adrenal MRgSBRT was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). LC was defined as no progressive disease (CR, PR, or SD) of the treated adrenal metastasis. OS was calculated from the first date of MRgSBRT to the day of last follow-up or death. Time from the MRgSBRT to the in-field progression was defined as local progression-free survival (LPFS) and out of field progression was defined as distant progression-free survival (DPFS). LPFS, DPFS, and OS were estimated using Kaplan-Meier method and log-rank test. OS and DPFS were calculated on a per-patient basis, while LC and LPFS were calculated on a per-lesion basis. Univariate analysis was performed with the log-rank test, and Cox proportional hazards regression was used to estimate hazard ratios (HR). Multivariate Cox regression analysis was performed to evaluate the association between clinical factors and survival for the variables. Variables which were determined to have a potential effect on results with a p value < 0.15 were entered into multivariable models. A p-value below 0.05 was accepted as statistically significant. Data analysis was performed using SPSS version 23.0 (IBM, Armonk, USA).
Results
A total of 255 patients treated to 269 adrenal tumors between 2016 and 2022 with MRgSBRT were included in this retrospective multi-institutional study. Forty patients were excluded due to lack of follow-up or response evaluation data. Baseline patient characteristics are summarized in Table 1. The median patient age at the start of treatment was 65 years (range, 28–91 years) and 66.3 % were male. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 83.9 % of patients. The most common primary tumor was lung cancer (68.6 %), followed by genitourinary system tumors (9.9 %). Adrenal metastases were synchronous, metachronous, oligoprogressive or oligopersistent in 19.2 %, 41.6 %, 35.3 %, and 3.9 % of patients, respectively. Metastatic pattern was solitary in 25.9 % and oligometastatic in 58.0 % of patients. Metastases were right sided in 41.6 %, left sided in 52.9 %, and bilateral in 5.5 % of patients. Patients with bilateral adrenal metastases were treated synchronously except one patient who had a treatment interval of 8 months. The primary tumor was definitively treated in 84.3 % of patients, and chemotherapy and immunotherapy were administered in 66.7 % and 61.1 % of patients, respectively. Of nine patients (3.5 %) tumor-induced symptoms were reported before MRgSBRT initiation, of which palliation of symptoms were described in eight patients (89 %).
Table 1.
Baseline patient characteristics.
| Characteristics (255 patients) | Number (%) |
|---|---|
| Median age (at the start of MRgSBRT) | 65 (range, 28–91 years) |
| Gender | |
| Male | 169 (66.3 %) |
| Female | 86 (33.7 %) |
| Performance score (ECOG) | |
| 0 | 93 (36.5 %) |
| 1 | 121 (47.5 %) |
| 2 | 37 (14.5 %) |
| 3 | 4 (1.5 %) |
| Primary tumor | |
| Lung | 175 (68.6 %) |
| Genitourinary | 25 (9.8 %) |
| Gastrointestinal | 14 (5.5 %) |
| Hepatobiliary | 13 (5.1 %) |
| Melanoma | 11 (4.3 %) |
| Gynecological | 5 (2.0 %) |
| Other | 12 (4.7 %) |
| Tumor laterality | |
| Right | 107 (42.0 %) |
| Left | 136 (53.3 %) |
| Bilateral | 12 (4.7 %) |
| Timing of metastases | |
| Synchronous | 49 (19.2 %) |
| Metachronous | 106 (41.6 %) |
| Oligoprogressive | 90 (35.3 %) |
| Oligopersistent | 10 (3.9 %) |
| Metastatic pattern | |
| Solitary | 66 (25.9 %) |
| Oligometastatic | 148 (58.0 %) |
| Multiple | 41 (16.1 %) |
| Primary tumor definitively treated | |
| Yes | 215 (84.3 %) |
| No | 37 (14.5 %) |
| Unknown | 3 (1.2 %) |
| Systemic chemotherapy | |
| 3 months before MRgSBRT | 102 (40.0 %) |
| 3 months after MRgSBRT | 19 (7.5 %) |
| Concurrent | 24 (9.4 %) |
| None | 85 (33.3 %) |
| Others | 25 (9.8 %) |
| Immunotherapy | |
| 3 months before MRgSBRT | 59 (23.1 %) |
| 3 months after MRgSBRT | 36 (14.1 %) |
| Concurrent | 39 (15.3 %) |
| None | 92 (36.1 %) |
| Others | 29 (11.4 %) |
Median GTV was 22.0 cc (range, 1.1–383.2 cc) and median PTV was 37.1 cc (range, 2.9–516.9 cc). Median PTV margin was 3 mm (range, 3–6 mm), 29 lesions (10.8 %) were treated with a margin greater than 3 mm. Median total dose was 45 Gy (range, 16–60 Gy), median fraction number was 5 (range, 1–8) and median fractional dose used was 10 Gy (range, 5–24 Gy). Twelve patients (4.7 %) were treated with single fraction MRgSBRT (fraction dose range, 16–24 Gy). Median BED10 was 100 Gy (range, 37.5–132.0 Gy). Twenty-five patients (9.3 %) were treated with a BED10 > 100 Gy. The median PTV CI and HI were 1.02 (IQR, 0.95–1.11) and 1.23 (IQR, 1.17–1.30), respectively. A total of 1203 fractions of MRgSBRT were delivered, with 87.4 % of fractions (n = 1052) using on-table adapted plans based on the individual clinicians' judgement. Breath hold was used for respiratory motion management in majority of patients (98.9 %). Median tracking boundary was 3 mm (range, 2–5 mm) and 98.1 % of lesions were treated with a 3 mm boundary. Patients were treated on consecutive days (26.7 %), every other day (68.6 %) or with single fraction (4.7 %). MRgSBRT tumor and treatment planning details are summarized in Table 2.
Table 2.
MRgSBRT tumor and treatment planning characteristics.
| Characteristics (269 lesions) | Number (%) |
|---|---|
| Median gross tumor (GTV) volume | 22.0 cc (range, 1.1–383.2 cc) |
| Median planning target (PTV) volume | 37.1 cc (range, 2.9–516.9 cc) |
| Median PTV margin | 3 mm (range, 3–6 mm) |
| 3 mm | 240 (89.2 %) |
| 4 mm | 2 (0.7 %) |
| 5 mm | 25 (9.3 %) |
| 6 mm | 2 (0.7 %) |
| Median total dose | 45 Gy (range, 16–60 Gy) |
| <45 Gy | 118 (43.8 %) |
| ≥45 Gy | 151 (56.2 %) |
| Median fraction number | 5 fractions (range, 1–8) |
| Single fraction | 12 (4.5 %) |
| <5 | 51 (18.9 %) |
| ≥5 | 206 (76.6 %) |
| Median fraction dose | 10 Gy (range, 5–24 Gy) |
| <10 Gy | 87 (32.3 %) |
| ≥10 Gy | 182 (67.7 %) |
| Median BED10 (Biologically Effective Dose 10) | 100 Gy (range, 37.5–132 Gy) |
| <100 Gy | 124 (46.1 %) |
| ≥100 Gy | 145 (53.9 %) |
| Median PTV conformity index (CI) | 1.02 (IQR, 0.95–1.11) |
| Median PTV homogeneity index (HI) | 1.23 (IQR, 1.17–1.30) |
| Adapted fractions | 1052/1203 fractions (87.4 %) |
| Respiratory motion management | |
| Breath hold | 266 (98.9 %) |
| Free breathing | 3 (1.1 %) |
| Median tracking boundary | 3 mm (range, 2–5 mm) |
| 2 | 1 (0.4 %) |
| 3 | 264 (98.1 %) |
| 4 | 1 (0.4 %) |
| 5 | 3 (1.1 %) |
At a median follow-up of 17.7 months (range, 0.4–72.6 months), local responses were scored as CR, PR, SD, or PD in 35.5 %, 30.2 %, 25.0 %, and 9.3 %, respectively.
Median OS was 30.4 months (95 % CI 22.7–38.0 months), with 1- and 2- year OS rates of 74.1 % (95 % CI 67.8–80.4 %) and 56.3 % (95 % CI 48.3–64.3 %), respectively (Fig. 1a). On univariate analysis, ECOG of 0–1 (p < 0.0001, HR 0.39, 95 % CI 0.25–0.61) and achieving a CR (p < 0.0001, HR 0.42, 95 % CI 0.26–0.67) were significant prognostic factors for increased OS. This correlation remained statistically significant for ECOG score (p < 0.0001, HR 0.43, 95 % CI 0.27–0.68) and patients achieving a CR (p < 0.0001, HR 0.42, 95 % CI 0.26–0.68) on multivariate analysis. On multivariate analysis gender was a significant prognostic factor and female gender had a worse OS (p = 0.04, HR 1.57, 95 % CI 1.02–2.41).
Fig. 1.
Kaplan-Meier curves for a) overall survival, b) local progression free survival, c) distant progression free survival.
Median LPFS was not reached and the 1- and 2- year LPFS rates were 94.0 % (95 % CI 90.7–97.3 %) and 88.3 % (95 % CI 82.4–94.2 %), respectively (Fig. 1b). Patients whose primary tumor were definitively treated had better LPFS in multivariate analysis (p = 0.004, HR 1.96, 95 % CI 1.33–3.09). For LPFS, comparison between immunotherapy groups (none, concurrent, 3 months before MRgSBRT, 3 months after MRgSBRT or others) the difference was statistically significant (p = 0.004, HR 1.73, 95 % CI 1.19–2.51). Patients in whom lesions were treated with a PTV CI of ≥ 0.90 (p = 0.016, HR 2.70, 95 % CI 1.21–6.08) was associated with improved LPFS on univariate analysis. On multivariate analysis, significant findings were (i) patients whose primary tumors were definitively treated (p = 0.017, HR 3.44, 95 % CI 1.25–9.43) and (ii) a PTV CI of < 0.90 (p = 0.024, HR 2.58, 95 % CI 1.13–5.87). Although not statistically significant, no local recurrences were observed after treatment to a total dose of BED10 > 100 (24 lesions), with single fraction (range, 16–24 Gy, 12 lesions) or fractional dose of > 10 Gy (50 lesions).
Median DPFS was 7.9 months (95 % CI 5.7–10.0 months) with a 1- and 2-year DPFS rates of 41.0 % (95 % CI 34.3–47.7 %) and 28.4 % (95 % CI 21.5–35.3 %), respectively (Fig. 1c). For DPFS, the comparison between chemotherapy groups (none, concurrent, 3 months before MRgSBRT, 3 months after MRgSBRT or others) was statistically significant (p = 0.003, HR 1.19, 95 % CI 1.06–1.33) on univariate analysis. Patients receiving chemotherapy concurrently had the worst DPFS rates. Achieving a CR improved DPFS significantly on univariate analysis (p < 0.0001, HR 0.46, 95 % CI 0.32–0.65). Chemotherapy groups and achieving a CR remained significant on multivariate analysis with p values of 0.003 (HR 1.49, 95 % CI 1.14–1.93) and < 0.0001 (HR 0.45, 95 % CI 0.32–0.65), respectively. Univariate and multivariate analysis detailed results are shown in Table 4.
Table 4.
Univariate and multivariate analysis.
| Overall survival (OS) |
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|---|---|---|---|---|---|---|
| Univariate analysis |
Multivariate analysis |
|||||
| HR | 95 % CI | P value | HR | 95 % CI | P value | |
| Age (≤65 years vs > 65 years) | 1.17 | 0.78–1.75 | 0.452 | – | – | – |
| Gender | 1.40 | 0.92–2.14 | 0.117 | 1.57 | 1.02–2.41 | 0.04 |
| ECOG PS (0–1 vs 2–3) | 0.39 | 0.25–0.61 | p < 0.0001 | 0.43 | 0.27–0.68 | p < 0.0001 |
| Primary (lung vs others) | 0.81 | 0.51–1.29 | 0.376 | – | – | – |
| Laterality | 0.88 | 0.62–1.24 | 0.460 | – | – | – |
| Timing of metastases | 0.99 | 0.77–1.27 | 0.941 | – | – | – |
| Metastatic pattern | 1.19 | 0.84–1.68 | 0.322 | – | – | – |
| Primary treated | 1.22 | 0.17–8.78 | 0.845 | – | – | – |
| Systemic chemotherapy | 1.25 | 0.87–1.81 | 0.225 | – | – | – |
| Systemic immunotherapy | 0.83 | 0.62–1.11 | 0.204 | – | – | – |
|
Local Progession Free survival (LPFS) |
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|
Univariate analysis |
Multivariate analysis |
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| HR | 95 % CI | P value | HR | 95 % CI | P value | |
| Age (≤65 years vs > 65 years) | 0.93 | 0.42–2.06 | 0.864 | – | – | – |
| Gender | 0.66 | 0.25–1.78 | 0.413 | – | – | – |
| ECOG PS (0–1 vs 2–3) | 0.99 | 0.55–1.79 | 0.969 | – | – | – |
| Primary (lung vs others) | 0.97 | 0.40–2.31 | 0.936 | – | – | – |
| Laterality | 0.89 | 0.46–1.75 | 0.752 | – | – | – |
| Timing of metastases | 0.81 | 0.50–1.33 | 0.409 | – | – | – |
| Metastatic pattern | 1.65 | 0.83–3.28 | 0.157 | 1.17 | 0.57–2.40 | 0.676 |
| Primary treated | 1.96 | 1.33–3.09 | 0.004 | 3.44 | 1.25–9.43 | 0.017 |
| Systemic chemotherapy | 1.09 | 0.83–1.44 | 0.542 | – | – | – |
| Systemic immunotherapy | 1.73 | 1.19–2.51 | 0.004 | 1.20 | 0.91–4.57 | 0.196 |
| PTV volume (<37.1 cc vs ≥ 37.1 cc) | 1.58 | 0.71–3.51 | 0.262 | – | – | – |
| GTV volume (<22 cc vs ≥ 22 cc) | 1.38 | 0.62–3.07 | 0.425 | – | – | – |
| Median dose (<45 Gy vs ≥ 45 Gy) | 0.95 | 0.40–2.24 | 0.910 | – | – | – |
| Fraction dose (<10 Gy vs ≥ 10 Gy) | 0.04 | 0.00–13.40 | 0276 | – | – | – |
| BED10 (<100 Gy vs ≥ 100 Gy) | 1.01 | 0.43–2.39 | 0.974 | – | – | – |
| PTV CI (<0.90 vs ≥ 0.90) | 2.70 | 1.21–6.08 | 0.016 | 2.58 | 1.13–5.87 | 0.024 |
|
Distant Progession Free survival (DPFS) |
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|
Univariate analysis |
Multivariate analysis |
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| HR | 95 % CI | P value | HR | 95 % CI | P value | |
| Age (≤65 years vs > 65 years) | 0.76 | 0.55–1.04 | 0.086 | – | – | – |
| Gender | 1.18 | 0.85–1.64 | 0.324 | – | – | – |
| ECOG PS (0–1 vs 2–3) | 0.89 | 0.58–1.36 | 0.591 | – | – | – |
| Primary (lung vs others) | 0.75 | 0.53–1.06 | 0.103 | 0.85 | 0.59–1.21 | 0.360 |
| Laterality | 0.84 | 0.64–1.10 | 0.208 | – | – | – |
| Timing of metastases | 1.02 | 0.84–1.24 | 0.819 | – | – | – |
| Metastatic pattern | 1.23 | 0.96–1.58 | 0.104 | 1.21 | 0.97–1.58 | 0.910 |
| Primary treated | 0.92 | 0.58–1.44 | 0.703 | – | – | – |
| Local control (CR vs others) | 0.46 | 0.32–0.65 | p < 0.0001 | 0.45 | 0.32–0.65 | p < 0.0001 |
| Systemic chemotherapy | 1.19 | 1.06–1.33 | 0.003 | 1.49 | 1.19–1.07 | 0.002 |
| Systemic immunotherapy | 1.04 | 0.93–1.16 | 0.521 | – | – | – |
ECOG Eastern Cooperative Oncology Group, BED biological effective dose.
Only 2 patients (0.8 %) had ≥ grade 3 late toxicity, one was adrenal insufficiency in a patient with prior contralateral SBRT who was treated with a dose of 40 Gy in 5 fractions and the other was a vertebral insufficiency fracture 5 months after MRgSBRT of 50 Gy in 5 fractions. The detailed toxicities are summarized in Table 3.
Table 3.
Acute and chronic toxicity scores (CTCAE v5.0).
| Acute toxicity | Patient number (%) |
|---|---|
| Fatigue | 5 (1.9) Grade I; 6 (2.2) Grade II |
| Gastrointestinal | 7 (2.6) Grade I; 4 (1.5) Grade II |
| Abdominal pain | 1 (0.4) Grade I |
| Anorexia | 2 (0.7) Grade I; 1 (0.4) Grade 1 |
| Chronic toxicity | |
| Fatigue | 3 (1.1) Grade I |
| Adrenal insufficiency | 3 (1.1) Grade II; 1 (0.4) Grade III |
| Other (vertebral fracture) | 1 (0.4) Grade III |
Discussion
This multi-institutional pooled retrospective analysis of adrenal MRgSBRT with daily online adaptation in the majority of patients revealed 1-year and 2-year LPFS rates of 94 % and 88.3 %, respectively. A median dose delivered was a BED10 of 100 Gy, and progressive disesase was noted in just 9.3 % of lesions. To our knowledge, this study is the largest series evaluating outcomes of MRgSBRT for adrenal metastases.
A strength of the present analysis was inclusion of patients from 11 institutions, using a range of delivered doses. A previous systematic review and pooled meta-analysis of SBRT for adrenal metastases in 1036 patients had demonstrated a significant and positive correlation between the dose of SBRT and the LC rates at 1- and 2-years (p < 0.0001, p = 0.0002), as well as a correlation with the 2-year OS (p = 0.03)22. Prescribed doses exceeding 60, 80, and 100 Gy (BED10) resulted in an improved local control in the higher-dose groups and the overall rate of grade 3 or higher toxicity was 1.8 % [22]. In the present study, 65.4 % of patients received a BED10 ≥ 80 Gy and 53.9 % received BED10 ≥ 100 Gy. Although we did not find a correlation between higher BED10 doses and improved LC, local recurrences were not observed after treatment to a total dose of BED10 > 100, as was SBRT delivered in a single fraction or using a fraction dose of > 10 Gy.
Frequent changes in OAR position can occur during MRgSBRT, and dosimetric advantages have been shown for online plan of adaptation to take such changes into account [17]. In the present study, 87 % of all SBRT fractions were treated using on-table adapted plans. This approach could lead to decreases in PTV coverage. Our analysis revealed that a PTV CI of ≥ 0.90 was associated with an improved LPFS on both univariate and multivariate analysis. Previous studies found that compromises in delivered PTV doses are common in adrenal SABR due to the proximity of critical normal organs. For example, it was reported that the coverage compromise index (CCI, defined as D99/prescription dose) was lower for adrenal metastases as compared to bone, liver, and lung metastases, in patients treated in both the SABR-COMET and SABR 5 trials [23], [24]. A single institutional experience with adrenal MRgRT revealed that the CCI exceeding 0.90 in just 48 % of all cases, no differences in dose-related LC rates were seen using a BED10 80 or 100 Gy19.
Results of selected studies of SBRT for adrenal gland metastases have been summarized in Table 5. Previous studies have suggested that MRgSBRT is effective for adrenal metastases, delivering a higher median BED10 doses, and with better 1-year LC rates and comparable late toxicity rates. The low incidence of grade 3 or worse late toxicity of 0.8 % after MRgRT contrasts with the reported outcomes after adrenalectomy for adrenal metastasis [5], [6], [25]. Similarly, microwave and radiofrequency ablation have been used for the treatment of adrenal metastases, the pooled rates of treatment-related failure or toxicity ranging from 44 to 48 % and 6.6–8 %, respectively. A single center evaluation of treatment patterns for adrenal metastases during a 10-year period using either surgery (43 patients) or SBRT (54 patients) concluded that both treatments resulted in low rates of acute toxicity and similar survivals, but 1-year LC rates were higher for MRgSBRT (96 %) compared to 74 % for surgery (p = 0.003) [14].
Table 5.
Summary of selected cited studies of SBRT in adrenal gland metastases.
| Study | Lesion number | IGRT method | BED10 | Median Follow-up | Local control | Overall survival | Grade 3 + toxicity |
|---|---|---|---|---|---|---|---|
| Buergy D, 2021 [26] | 260 | CBCT | 60.3 (38.3–102.7) | 11.7 months | 1-year 80.8 % | 1-year 67.1 % | 0.4 % |
| Franzese C, 2021 [27] | 149 | CBCT | 78.75 (20–120.0) | 14.4 months | 1-year 85.4 % | 1-year 72.3 % | 0.7 % |
| Zhao X, 2020 [28] | 84 | Cyberknife | 79.6 (44.8–112.5) | 12.7 months | 1-year 83.8 % | 1-year 62.5 % | 2.6 % |
| Michalet M, 2022 [13] | 13 | MR-guided | 75.6 (59.5–100.0) | 15.5 months | 1-year 100 % | 1-year 91.7 % | 0 % |
| Schneiders FL, 2023 [19] | 114 | MR-guided | ≥100 Gy 67.5 % | 13.8 months | 1-year 98.5 % | 1-year 67.8 % | 1.8 % |
| Current study | 269 | MR-guided | 100 (37.5–132.0) | 17.7 months | 1-year 94 % | 1-year 74.1 % | 0.8 % |
Some limitations of our study include its retrospective nature and the heterogeneity of the cohort in terms of primary tumors and SBRT doses.. Additionally, longer follow-up is necessary to further analyze the prognosis of MRgSBRT.
Conclusion
This pooled retrospective analysis of MRgSBRT in 269 lesions revealed a 2- year LPFS rate of 88 %, and that tumors treated with PTV CI of ≥ 0.90 had an improved LPFS. Although not statistically significant, outcomes analysis in 269 adrenal lesions revealed improved outcomes with delivery of a BED10 > 100, use of single fraction SBRT (range between 16 and 24 Gy) and with fraction doses > 10 Gy, providing benchmarks for future clinical trials with more patients and longer follow-up, suggesting that techniques such as adaptive MRgSBRT may be beneficial as they facilitate delivery of such doses.
The authors received no specific funding for this work.
CRediT authorship contribution statement
Gamze Ugurluer: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. Famke L. Schneiders: Data curation, Investigation, Methodology, Project administration. Stefanie Corradini: Data curation, Investigation, Methodology, Project administration. Luca Boldrini: Data curation, Investigation, Methodology, Project administration. Rupesh Kotecha: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. Patrick Kelly: Data curation, Investigation, Methodology, Project administration. Lorraine Portelance: Data curation, Investigation, Methodology, Project administration. Philip Camilleri: Data curation, Investigation, Methodology, Project administration. Merav A. Ben-David: Data curation, Investigation, Methodology, Project administration. Spencer Poiset: Data curation, Investigation, Methodology, Project administration. Sebastian N. Marschner: Data curation, Investigation, Methodology, Project administration. Giulia Panza: Data curation, Investigation, Methodology, Project administration. Tugce Kutuk: Data curation, Investigation, Methodology, Project administration. Miguel A. Palacios: Data curation, Investigation, Methodology, Project administration. Alessandra Castelluccia: Data curation, Investigation, Methodology, Project administration. Teuta Zoto Mustafayev: Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft. Banu Atalar: Data curation, Investigation, Methodology, Project administration. Suresh Senan: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. Enis Ozyar: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing.
Data availability:
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.