Single-institutional outcome-analysis of low-dose stereotactic body radiation therapy (SBRT) of adrenal gland metastases

The adrenal gland is a frequent target of malignant tumor cells of different entities, as it is characterized by a rich blood supply [1]. To make the right therapy decision, it is essential to differentiate between various benign and malignant neoplasia of the tissue. For example, pheochromocytomas arise from the cells of the adrenal medulla, while benign adenomas and metastatic lesions mainly form in the cortical regions [2]. Therefore, radiologic imaging is an indispensable tool for distinguishing between the most diverse types of tumors, as these have different characteristics on computed tomography (CT) and magnet resonance imaging (MRI) [3]. The diagnostic proceeding of adrenal metastases has undergone significant changes lately. In the past, lesions of the adrenal gland were incidental findings, manifested by symptomatic development, or were detected at autopsies [4, 5]. Since the introduction of systematic and more accurate tumor staging and the high-frequency use of imaging, the incidence of adrenal tumors has increased, as they are frequently discovered by chance, without any suggestive symptomatology [4, 6].

Once the adrenal gland metastasis is diagnosed through imaging procedures or biopsy, there are several options for curative and palliative treatment. Particularly for patients with isolated lesions, laparoscopic or open surgery is performed. Further treatment options are systemic chemo−/immunotherapy or ablative strategies such as cryoablation and radiofrequency ablation [3]. In the past, hypofractionated radiotherapy (RT) was often used for palliative purposes to reduce physical complaints caused by symptomatic adrenal metastases, such as back/flank pain, nausea, or hypoadrenalism [7]. With the introduction of stereotactic body radiation therapy (SBRT), a promising option for treating adrenal gland metastases appeared in the field of radiation oncology. Previously SBRT has been very extensively used in treating inoperable lung, liver, prostate, and brain tumors [8].

SBRT is characterized by its excellent local tumor control and is a good, non-invasive alternative treatment option, especially in patients, who decline any invasive- or ablative treatment, or when surgery is contraindicated due to multiple comorbidities [3, 6, 9‐14]. The high-precision irradiation is applied in high single doses and few fractions. Due to the rapid dose-reduction outside the target volume, surrounding, healthy structures can be spared [6, 8, 15, 16]. This present retrospective study aims to contribute to the knowledge regarding hypofractionated low-dose SBRT of adrenal gland metastases. In particular, the primary endpoints local control (LC), progression-free survival (PFS) and overall survival (OS) will be evaluated as well as acute and late toxicity rates.

The median age was 66 years (range: 27–82 years). Of all, 25 (25/31, 81%) patients suffered from advanced tumor disease with multiple metastases in different organs. 28 (28/31, 90%) patients showed an oligoprogression with a maximum of ≤3 metastases/tumor areas. In almost all patients (25/31, 81%), the primary tumor was controlled before irradiation. Isolated adrenal metastases without further tumor manifestation occurred in six (6/31, 19%) patients. Only two (2/31, 6%) patients reported symptoms related to the adrenal lesions, including back pain, flank pain, and abdominal pain; the applied RT had a positive effect on the pain situation in both patients. In 44% (15/34) adrenal lesions occurred synchronously during the diagnosis of the primary tumor, while 56% (19/34) of the metastases were diagnosed metachronously (> 3 months after initial diagnosis). The median time between the diagnosis of the primary tumor and the occurrence of adrenal metastases was 12.3 months (range: 0–169.0 months). Of all, 19 (19/31, 61%) patients received systemic tumor therapy, such as chemo, immuno- or hormone therapy, within four weeks before or after RT. It was ensured that this therapy was administered only in exceptional cases at the same time. The median planning target volume (PTV) was 76.8 ml (range: 24.1–434.8). Further planning and irradiation parameters are shown in Table 2.

Hypofractionated low-dose stereotactic body radiation therapy of adrenal metastases has become increasingly important in recent years. We analyzed a cohort of 31 patients with 34 irradiated adrenal lesions. Occurred side-effects were extremely rare, mild, and well treatable. Local control was promising and comparable to other studies [6, 13, 14, 22‐25].

In the past, surgical resection of adrenal metastases (adrenalectomy) was the gold standard for patients with isolated adrenal gland metastases. Especially if the metastases were isolated, the open or laparoscopic adrenalectomy was and is the first choice, depending on the tumor size and patient condition. Certainly, the postoperative side-effects associated with this invasive treatment should not be underestimated. Since 1992, the laparoscopic approach has been increasingly used as the postoperative complications are significantly lower, and both the duration and intensity, as well as the hospital stay can be reduced [3, 26‐28].

Other treatment options include ablative procedures, such as cryoablation or radiofrequency ablation. However, these ablative measures bear a higher risk of blood pressure derailment and intensive post-intervention care [29]. In contrast to these invasive methods, SBRT is a non-invasive alternative with an outstanding risk-benefit profile. Due to the comparatively gentle tumor tissue inactivation and the biological effects, there is no associated secretion of catecholamines during therapy; thus, a therapy-associated hypertensive crisis is avoided, and adrenal hormonal function can be preserved in most cases, as our results showed [30].

According to Toesca et al., who compared the glomerular filtration rate (GFR) before and after stereotactic treatment, kidney function is also little or not affected by SBRT. According to several studies conducted in the past, LC after SBRT is equaled to or even better than ablative procedures [13].

The studies investigating RT of adrenal gland metastases conducted in the last six years report a 1-year LC rate between 73 - 97% [6, 13, 14, 22‐25]. Our 1-year probability of local failure was 25.9%. The effect of BED₁₀ on local tumor control has already been investigated in several studies, and it was noted that a higher applied dose tends to be associated with a better local outcome. Ippolito et al. reported an LC-rate of > 70% if BED₁₀ is > 60 Gy and > 90% with BED₁₀ > 90 Gy. In the cohort of Chance et al. appeared no local relapses by applying a BED₁₀ > 100 Gy and Rudra et al. noted that all occurred local failures in their cohort were treated with the lowest mean BED₁₀ of 43.2 Gy [8, 14, 31]. In our patients, we could not find any significant influence of BED₁₀ on local control. Only a non-significant trend towards better local control with higher BED could be identified (p = 0.115). All adrenal metastases that showed a local relapse after RT were treated with a BED₁₀ of 37.5 and 59.5 Gy. No local failure occurred with BED₁₀ > 59.5 Gy. In order to better assess the correlation between BED₁₀ and local tumor control in adrenal metastases, a larger group of patients would be necessary.

Therapy-associated toxicity is an important limiting factor of any new therapy. SBRT proved to be beneficial in our study as no side-effects >grade 2 occurred. Also, in other studies on SBRT of adrenal metastases, no grade 3–5 toxicity was reported [8, 14, 24, 25, 32, 33], except for grade 3 diarrhea in the patient cohort of Zhao et al. [6]. Due to the high precision and exact application of radiation, both acute and late toxicities are rare and usually very mild. However, due to the respiratory dependence of adrenal tumor volume, dosimetry may often prove very difficult for the multiple adjacent organs at risk, such as the liver and bowel. Excellent and precise respiratory tumor motion management is crucial during the radiation treatment, and the dose must be reduced or adjusted to the circumstances, especially to avoid late toxicity [24].

Furthermore, according to Holy et al., treatment on an empty stomach has a positive effect on the described side-effects, as it ensures a better reproducibility of the position of the internal organs, and the intestinal movements can be minimized [32]. Another factor influencing the onset of late-toxicities is the tumor volume. The smaller the irradiated lesion, the less likely it is the appearance of late therapy-associated side-effects, as Zhao et al. found in their study of 2018 [6]. Overall, our LC and treatment-associated toxicity results are very similar to previous studies, supporting the assumption that SBRT is a valid treatment option for metastases of the adrenal gland.

Limitations of the study were the relatively small patient cohort, the short follow-up, and the retrospective design. The heterogeneously designed irradiation regimens were also among the limiting factors, as no consistent treatment guidelines regarding fractionation and dose exist.

Low-dose SBRT is an excellent, effective, and safe method to treat metastases in the adrenal gland. Due to the exact application and the precise dosing of the radiation, all toxicities have been low and easy to treat. High-precision RT is a promising alternative for patients for whom surgical treatment is not possible due to poor general conditions or other treatment-limiting factors. Based on our results, which support existing studies, SBRT should be considered as a therapy option for adrenal metastases as an alternative to surgical or systemic treatment. Prospective studies are nevertheless necessary for the validation of these results.