Stereotactic Radiotherapy for Adrenal Metastases: A Multi-Institutional Review of Patient Characteristics and Outcomes – Turkish Society for Radiation Oncology SBRT Group Study (Trod SBRT 10-004)

Adrenal glands are one of the most common sites for metastasis of various malignancies [1]. The management strategy of adrenal metastasis involves several options including surgery, chemotherapy, palliative therapy, and local ablative therapies. Although adrenalectomy is usually the first-line approach, the evidence is limited and optimal treatment of adrenal metastasis is a big challenge [2].

Previously, radiotherapy (RT) to adrenal metastases was limited and used only for a palliative intent with successful pain relief rates [3]. With the development of stereotactic body RT (SBRT) which provides a high dose in a limited number of fractions with a high conformity, the opportunity to deliver ablative doses has become possible and the role of RT has expanded. SBRT is a promising alternative treatment modality for metastatic lesions, owing to its noninvasive, effective, and tolerable nature [4]. In selected patients, a durable disease control and even cure may be achieved with SBRT [5, 6]. Although no randomized controlled trials have compared the efficacy and toxicity of adrenalectomy and SBRT, there is promising evidence in the literature regarding the use of ablative local RT for the treatment of adrenal metastasis [3, 7‒16].

SBRT is increasingly being used as an alternative ablative option with high rates of local control (LC). Despite the available data, there is no consensus on the optimal local treatment approach for adrenal metastasis. This multi-institutional study aimed to report the treatment and toxicity outcomes of SBRT for adrenal metastasis.

Data of a retrospective multi-institutional patient cohort with adrenal metastasis from six centers were analyzed. The selection criterion for this cohort was at least one adrenal metastasis treated via SBRT of any histologically proven primary solid tumor. Patients that underwent partial or total adrenalectomy were excluded. The diagnosis of adrenal metastasis was made based on computed tomography (CT) and/or magnetic resonance imaging (MRI) with or without 18F fluorodeoxyglucose positron emission tomography/CT (PET/CT). Histological assessment was not mandatory. A written informed consent for the use of data for future studies was obtained from every patient or a next of kin before treatment. The Local Ethics Committee approved this study (Project No: KA19/226).

A planning CT was performed for each patient with a slice thickness of 1–2.5 mm in the supine position, and images from the planning CT and MRI and/or PET/CT were fused for contouring. Motion management was used in all patients, either with fiducials or with adding an internal margin for the internal target volume (ITV), depending on the preference of the treating center. In centers where fiducials are used, the gross tumor volume (GTV) was defined as the contrast-enhanced lesion, the clinical target volume was formed with a 3- to 5-mm margin, and the planning target volume (PTV) was defined as the clinical target volume plus a margin of 1–3 mm according to the tumor location. In our centers, an ITV was defined as the contrast-enhanced lesion formed by fusing images where the dimensions of the lesion differed at most, and the PTV was defined as the ITV plus a margin of 1 mm. Organs at risk (OAR) were also contoured at each slice. Treatment plans were optimized according to the requirement that at least 99% of the PTV received 95% of the prescribed dose. The OAR limits recommended by the AAPM Task Group 101 [17] and Timmerman [18] were used. For large lesions and lesions in direct contact with adjacent critical structures, a more prolonged schedule and lower fraction dose were preferred to meet the OAR dose limits.

The tumor response was assessed by CT and/or MRI and/or PET/CT 12 weeks after SBRT was completed. A local recurrence (LR) was defined as ≥25% increase in the longest dimension of the adrenal tumor based on the World Health Organization (WHO) criteria [19]. The incidence of acute and late toxicity was defined as the total number of patients reaching that grade at any time divided by the total number of assessable patients. Late toxicity was reported if it appeared more than 3 months after the end of the treatment. The toxicity scoring was made according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [20].

All statistical analyses were performed using the Statistical Package for the Social Sciences version 21.0 (SPSS Inc., Chicago, IL, USA). The primary end points were LC and LR-free survival (LRFS). Secondary end points included overall survival (OS), progression-free survival (PFS), and treatment toxicity. Survival analyses were carried out using the Kaplan-Meier method and compared using the log-rank test. Survival outcomes were calculated over the number of patients, whereas the LC rate was calculated over the number of metastatic lesions. Age (<60 vs. ≥60 years), gender (male vs. female), tumor laterality (right vs. left), primary tumor site, tumor size at diagnosis, fraction dose (<8 Gy vs. ≥8 Gy), biologically effective dose (BED)10 (calculated with the formula: BED [Gy] = dose/fraction × fraction number [1 + fraction dose/α/β] in which α/β is 10) (≤65 Gy vs. >65 Gy), GTV volume (<300 cc vs. ≥300 cc), and PTV volume (<1,250 cc vs. ≥1,250 cc) were included in univariate analysis. A p value <0.05 was considered significant. LC was defined as no tumor progression at the last follow-up (FU) or death. LRFS was defined as the time from the end of SBRT to the progression of the adrenal metastasis or death whichever comes first. OS was defined as the time from the end of SBRT to the last control or death, and PFS was defined as the time from the end of SBRT to any progression (local and/or distant) or death whichever comes first. The Cox proportional hazards model was used for multivariate analysis. The potentially significant covariates following univariate analyses with significant contribution to the survival estimation (p < 0.10) were preserved in the final multivariate model. Hazard ratios with 95% confidence interval (CI) were reported.

A total of 124 cases with 146 adrenal metastases treated with SBRT between 2008 and 2019 were retrospectively evaluated. The median age was 60 years (interquartile range 55–66 years). The majority of the patients were male (n = 89, 72%). The most frequent primary tumor site was the lung (76%), followed by the gastrointestinal system (8%) and breast (6%). Twenty-two (18%) patients had bilateral adrenal metastases, and eight of these were synchronous. The adrenal gland was the sole metastatic site in 49 (40%) patients. The most common fractionation schedules were 30 Gy in 5 fractions, 36 Gy in 3 fractions, and 35 Gy in 5 fractions. Four patients were re-irradiated due to LR. Other detailed tumor and treatment characteristics are listed in Tables 1 and 2.

The median FU duration was 8 months (range: 1–124 months). At the time of analysis, 53 patients were alive, 26 of whom were disease-free. The overall LC rate was 83%. There were 24 local failures, with 1- and 2-year LRFS rates of 45% and 29%, respectively. Median LRFS was 10.37 months (SE: 1.07, 95% CI: 8.27–12.46). In univariate analysis, LRFS was higher in patients with BED10 >65 Gy and >8 Gy dose per fraction (p = 0.01 and p = 0.02, respectively) (Fig. 1a, b). Multivariate analysis revealed no significant prognostic factors for LRFS.

Median OS was 14.6 months (SE: 1.89, 95% CI: 10.88–18.32), and the 1- and 2-year OS rates were 56% and 36%, respectively. In univariate analysis, OS was higher in patients with non-lung primary compared to patients with lung cancer (p < 0.001). Among various primary tumors, the highest OS was observed in patients with breast cancer with a median of 83 months (p = 0.001). OS was also significantly higher in female patients (p = 0.04) and in patients with a tumor diameter of <4 cm (p = 0.04). The LC rate was not correlated with the OS rate. On the other hand, a higher OS rate was observed in patients with an isolated adrenal metastasis, although not statistically significant. The 1- and 2-year OS rates were 85% and 75% in patients with isolated adrenal metastasis compared to 85% and 55% in patients with additional metastasis (p = 0.06). In multivariate analysis, no independent prognostic factor was found for OS.

During FU, de novo DM was observed in 92 (63%) patients. Median PFS was 5.9 months (SE: 0.73, 95% CI: 4.46–7.34). The 1- and 2-year PFS rates were 31% and 12%, respectively. In univariate analysis, a higher SBRT fraction dose and BED10 and an isolated adrenal metastasis significantly improved the PFS. The 1- and 2-year PFS rates were 42% and 17% for the ≥8 Gy fraction dose (vs. 17% and 5% for <8 Gy, p = 0.001), 42% and 16% for BED >65 Gy (vs. 21% and 8% for ≤65 Gy, p = 0.03), and 41% and 14% for isolated adrenal metastasis (vs. 25% and 11% for additional metastases, p = 0.04) (Fig. 2a–c). In multivariate analysis, isolated adrenal metastasis was the only positive prognostic factor for PFS (hazard ratio: 2.1, 95% CI: 1.11–4.09, and p = 0.023).

Fourteen (11%) patients experienced acute grade 1–2 toxicity. Fatigue was the most common acute toxicity (n = 11), followed by nausea and vomiting (n = 5). No grade 3 or higher acute toxicity was observed in any patient. Late toxicity was observed in 3 (2%) patients (Table 3). Two of these patients had bilateral adrenal metastases, underwent SBRT to both adrenal tumors, and experienced adrenal insufficiency. One of these patients succumbed to this toxicity. Another patient experienced duodenal ulcer. Renal or hepatic toxicity was not observed in any patients. The overall acute toxicity rate was significantly higher in patients treated with BED10 >65 Gy (p = 0.018). However, the BED10 value was <65 Gy in all 3 patients with severe late toxicity.

A growing number of small retrospective series have recently been reported on the outcomes of SBRT for adrenal metastases [3, 7, 12, 21‒26]. These reports are limited in sample size which hinders robust estimates of treatment efficacy and the identification of optimal dosimetric details. The results of the current study demonstrate that LC after SBRT is satisfying with an overall rate of 83% with a low rate of toxicity. A higher BED10 and higher dose per fraction were positively correlated with LRFS and PFS; however, no similar correlation was found with regard to OS. Furthermore, we found no correlation between LC and OS which can be attributed to the fact that the main reason for death in these patients is distant failure. The rate of OS in our study was higher for non-lung cancers and the highest for breast cancer; however, this was not true for LRFS. In addition, an isolated adrenal metastasis yielded an improved PFS and a trend for improved OS.

Reported outcomes in patients irradiated with SBRT for adrenal metastasis reveal promising survival results. In one meta-analysis including ten studies, nine of which were retrospective, the 1- and 2-year LC rates were >70% for patients with a median BED10 of ≥60 Gy [27]. Similarly, in a recent meta-analysis which included >1,000 patients from 39 studies, SBRT ensured a 1-year LC rate of 82% with an excellent safety profile, and a higher SBRT dose was strongly associated with improved LC [5]. In the most recent and largest retrospective series of adrenal SBRT in the literature, Buergy et al. [16] reported the results of 326 patients with adrenal metastasis in which the 1-year LRFS rate was 80% in 260 patients treated with SBRT. The dominant primary tumor site was the lung and median BED10 was >50 Gy in all these studies.

Previous studies have shown that LC is improved when BED10 is >100 in primary lung cancer and >70 Gy in primary pancreatic cancer [28, 29]. In the light of these data, the impact of a higher BED10 was studied by several authors for adrenal metastases, and it has been stated that higher doses were associated with a better LC [12, 13, 30]. Chance et al. [31] reported no local failures following adrenal SBRT with a BED10 >100 Gy in which 84% of cases had primary lung cancer. Furthermore, in the SABR-COMET study which resulted in an improved survival for oligometastatic disease, a dose of BED10 >100 Gy was used for adrenal metastases [32]. In the study by Scouarnec et al. [33] where more than 80% of patients were irradiated by BED10 >100 Gy, the LC rates were stated to be relatively higher than other similar series in the literature. A number of studies reported improved outcomes with a lower BED10 threshold ranging from 72 Gy to 90 Gy [15, 34‒36]. In our study, a threshold value of BED10 >65 Gy was detected for improved LC.

Most likely due to heterogeneous patient and treatment characteristics, the 1-year OS rates for adrenal metastasis treated via SBRT have been reported in a wide range of 39–90% in previous series [5, 12, 34]. We also found a 1-year OS rate within this range (83%). Although OS was strongly correlated with the SBRT dose in a pooled meta-analysis, we could not find a similar association [5]. This finding is probably due to distant metastasis being the main reason for death although LC was achieved. Tumor diameter is one of the prognostic parameters for OS in our study, similar to the study by Toesca et al. [25]. In studies which refer to the primary tumor site, no correlation was found regarding OS [9, 25]. However, we observed an improved OS in patients with non-lung primary cancer, the highest being for breast cancer. This may also be the reason for the significantly higher OS rate in female patients in our study. Additionally, in the meta-analysis by Chen et al. [5], a lower LC rate was reported for studies in which the proportion of lung cancer patients is high. On the contrary, we did not observe any difference between the LC rate and the primary tumor site which is the precious proof of SBRT being able to control all adrenal metastases independent from the primary histology.

Although surgery remains the standard in patients with adrenal metastases with regard to its survival advantage, SBRT is a noninvasive, effective, and tolerable treatment alternative for patients that are not candidates for surgery due to severe comorbidities or unresectable tumors [2, 34, 37‒41]. Albeit no randomized controlled trials compared the efficacy and toxicity of adrenalectomy and SBRT, multiple small and retrospective studies reported comparable results [7, 9, 11, 12, 24, 25, 31, 42, 43]. However, almost all these studies do not primarily address oligometastatic disease and include patients treated with a palliative intent. Local ablative treatment strategies are frequently utilized for patients with adrenal oligometastases [44, 45]. The SABR-COMET study demonstrated that the addition of a local ablative treatment to standard of care palliative therapy for oligometastatic disease improves PFS and OS [46‒48]. Buergy et al. [16] reported improved OS and PFS in patients with isolated adrenal metastases. Our patient cohort includes 49 cases with isolated adrenal metastases in whom a higher OS rate was observed; however, this finding has a borderline significance.

SBRT of adrenal metastasis was well tolerated in our study. Acute toxicities were rare, and the vast majority were mild. Severe late toxicity was observed in 3 (2%) patients; adrenal insufficiency in 2 patients treated with bilateral SBRT and duodenal ulcer in 1 patient. Late toxicity has rarely been reported in the literature, the most common being adrenal insufficiency and gastric and duodenal ulcers [9, 49]. In a recent single-institution retrospective trial, in which 31 patients with a total of 34 lesions were evaluated, 2 patients developed a mild adrenal insufficiency after SBRT. However, it was not disclosed whether both adrenal glands were treated in those patients. Merely, it was stated that both patients were irradiated with a cumulative dose of 35 Gy and 25 Gy with a single dose of 7 Gy and 5 Gy which equals to BED10 59.5 and 37.5, respectively [50]. Given the lack of data, it is not possible to establish a threshold dose for the development of adrenal insufficiency following SBRT. Besides the fact that bilateral SBRT can cause adrenal insufficiency, metastases have a potential for dysfunction per se, and SBRT may only be exacerbating this adrenal insufficiency. The BED10 was <65 Gy in all patients that developed adrenal insufficiency in our series. Therefore, the SBRT dose should not be lowered with regard to concerns on toxicity as higher BED10 values improve LC.

Although the present study includes a high number of patients, its results should be cautiously evaluated due to its limitations. Major limitations of our study are the retrospective nature and the inhomogeneity of the cohort in terms of primary tumor and treatment characteristics. Due to various treatment protocols in different centers, we could not give detailed dose constraints for OARs. Also, the lack of data on the last status of the primary disease, exact total tumor burden/number of metastases at the SBRT time, performance status of the patients, and concurrent systemic therapy use also make our results questionable. The cases we included in our study belong to 2019 and before, when the ICRU91 report not available yet. For this reason, only a minority of our case data have PTV D98%, D2%, and GTVD50%, and we did not include that in our results. Although there is a significant deficiency for such a study today, we believe our results will contribute to the literature in every way.

In conclusion, SBRT seems an effective and safe treatment option for adrenal metastasis. The SBRT dose (BED10 and dose per fraction) is an important prognostic factor for local tumor control, and dose escalation may improve the outcomes. SBRT to the adrenal glands can lead to adrenal insufficiency, particularly when delivered bilaterally. However, this cannot justify lowering the total dose. Prospective studies on the effectiveness and toxicity of SBRT will provide more reliable information and assist selecting the optimal approach based on individual patient and disease characteristics.

This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Baskent University Institutional Review Board (Project No: KA19/226). We gathered the data of patients in a retrospective manner. However, as a general approach, consent forms are obtained from all patients prior to treatment. These forms included detailed information about the treatment method and toxicity, and we also got approval for their data to be used in future studies. Patients were not recontacted prior to the study.

The authors have no competing interests to declare that are relevant to the content of this article.

No funding was received to assist with the preparation of this manuscript.

Aysenur Elmali: conceptualization, methodology, investigation, material preparation, data collection, and writing – original draft. Berna Akkus Yildirim: conceptualization and visualization. Mustafa Cengiz and Sezin Yuce Sari: methodology, formal analysis, and writing – review and editing. Huseyin C. Onal and Banu Atalar: conceptualization and supervision. Tanju Berber, Aysun Arslantaş Erken, Teuta Zoto Mustafayev, Ilhami Unal, and Nuri Kaydihan: material preparation and data collection. Fazilet Oner Dincbas: conceptualization, methodology, investigation, project administration, and writing – review and editing. The first draft of the manuscript was written by Aysenur Elmali, and all authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

The data that support the findings of this study are available from the corresponding author upon reasonable request.