A total of 55 patients with 72 AGM treatments were identified. Forty AGMs (56%) were right-sided; the remaining 32 metastases were located on the left (44%). A total of 14 patients (25%) were treated for more than one AGM during the course of their disease. The median age at treatment was 66.3 years and the median Karnofsky performance status (KPS) was 90%. Most AGMs originated from lung tumors, including NSCLC (19 patients, 35%) and SCLC (four patients, 7%). The second most frequent primary tumor was the renal cell carcinoma (21 patients, 38%). Thirty-eight cases (53%) had received a systemic treatment in the period of up to three months until the respective SBRT, most of them receiving chemotherapy (18 cases, 47%). At the time of SBRT, 60% of patients were suffering from metastatic spread to at least one more organ other than the adrenal gland. SBRT was the primary treatment modality for 59 AGMs (82%). The remaining 13 metastases (18%) were recurrences. Patient characteristics are summarized in Table 1.
The median gross tumor volume (GTV) and planning target volume (PTV) were 16.8 and 38.3 cubic centimeters (cc) respectively; the latter was created by adding a median (mean) safety margin of 5 (3.8) mm to the GTV. The median prescription dose and isodose line were 24 Gy and 70%, respectively. Single-fraction prescription doses ranged from 19 to 25 Gy. The median and mean prescribed BED10 were 80.4 and 75.1 Gy, respectively. Sixty-one treatments (85%) had a BED10 ranging between 70 and 90 Gy. Sixty-one AGMs (85%) had been treated with one fraction, ten metastases (14%) had received three fractions, and one patient had received five fractions (1%). Prescription doses for fractionated treatments ranged from 24 to 45 Gy. The median conformity and homogeneity indices were 1.1 and 1.4, respectively. A median coverage of 97.9% was achieved in this series. All but one AGM treatment had utilized fiducial tracking with the Synchrony® respiratory tracking system (Accuray Inc., Sunnyvale, CA, USA), one small metastasis had been planned with an internal target volume (ITV). Treatment characteristics are summarized in Table 1.
Treatment outcomes, survival, and toxicity
The mean and median follow-up durations, beginning on the first day of SBRT, were 16.4 and 24.1 months, respectively. Eight (11%) AGMs did not have a radiographic follow-up before the patients’ transition to best supportive care, death, or being lost to follow-up. The LC at the last available follow-up was 79.6%. LC rates after 6, 12, 18, and 24 months were 98.1%, 92.9%, 78.8%, and 67.8%, respectively (95% confidence interval (CI) LC 12 months: 82.7–98.0, 95% CI LC 24 months: 49.8–81.4) (Fig. 1). Thirteen LF were observed. The median and mean BED10 for LF were 70 and 66 Gy. The median time to LF was 13.7 months. The observed PFS after 6, 12, 18, and 24 months were 73.0%, 46.2%, 31.9%, and 24.3%, respectively (95% CI PFS 12 months: 32.9-59.9, 95% CI PFS 24 months: 13.2-38.1) (Fig. 2). The median time to progression was 8.2 months. Distant progress was the primary reason for progression in the majority of patients (88%). In regard to the OS, 35 patients (64%) were alive at the last available follow-up and 20 had died (36%). OS rates after 6, 12, 18, and 24 months were 90.0%, 79.1%, 71.4%, and 68.3%, respectively (Fig. 3) (95% CI OS 12 months: 65.0-88.3, 95% CI OS 24 months: 51.6-79.9). Various patient, tumor, and treatment characteristics were analyzed for their impact on LC, PFS, and OS. The BED10 showed a significant impact on LC in the multivariable analysis after adjustment for GTV, applied PTV margin, and coverage (hazard ratio 0.85, p < 0.01). AGMs receiving more than the median BED10 showed a significantly improved LC (p < 0.01) (Fig. 4). Other factors did not impact LC. A significant PFS difference between single AGM and patients with additional metastases besides the treated AGM was detected (p = 0.04) (Fig. 5). However, this difference did not translate into an improved OS for patients with just one AGM (p = 0.74). No significant variables for the OS were identified.
In regard to the treatment toxicity, a total of 13 patients (24%) had side effects potentially associated with AGM SBRT. The most commonly observed toxicities were low-grade (1 and 2) nausea (five patients, 9%) and low-grade (1 and 2) fatigue (four patients, 7%). No treatment-related toxicities ≥ grade 3 were observed. In case of three patients (5%), who had only one remaining adrenal gland after surgical resection for metastasis, SBRT of the AGM of the contralateral gland caused adrenal insufficiency grade 2. In these patients, close monitoring of the hormone status before and after treatment delivery was indicated. One patient (2%) developed another adrenal insufficiency after SBRT in the presence of metastatic destruction of the contralateral adrenal gland. Due to a significantly decreased hormone production, all four patients had to start with hormone replacement therapy. No adrenal crisis occurred throughout the available follow-up of the affected patients.