The purpose of this study was to study the clinical outcome for patients with metastases of the adrenal gland treated with stereotactic body radiation therapy.
Forty-six patients were studied retrospectively. The dose prescription was 40 Gy in four fractions. Dosimetric analysis was performed using the dose volume histograms while clinical outcome was assessed using actuarial analysis with determination of the overall survival (OS) and local control (LC) rates.
The planning objectives were met for all patients. With a median follow-up period of 7.6 months, at the last follow-up 42 patients (91.3%) were alive and four had died because of distant progression. The actuarial mean OS was 28.5±1.6 months, the median was not reached. One-year and 2-year OS were 87.6±6.1%. None of the risk factors was significant in univariate analysis. Actuarial mean LC was 14.6±1.8 months (95% confidence interval [CI], 11.0 to 18.2) and median LC was 14.5±2.0 months (95% CI, 10.5 to 18.5). One-year and 2-year LC were 65.5±11.9% and 40.7±15.8%, respectively. A mild profile of toxicity was observed in the cohort of patients. Forty patients (86.9%) showed no complication (grade 0); two patients reported asthenia, six patients (13.1%) reported either pain, nausea, or vomiting. Of these six patients, five patients (10.9%) were scored as grade 1 toxicity while one patient (2.2%) was scored as grade 2.
Stereotactic body radiation therapy treatment provided an adequate clinical response in the management of adrenal gland metastases.
Adrenal glands are a common site for metastatic spread, with autopsy studies documenting their presence in 27%-38% of all fatal malignancies [
The oligometastatic state [
Adrenalectomy is currently the most frequent treatment approach [
Several alternative approaches have been explored in recent years, including radiofrequency ablation (RFA) [
The role of radiotherapy (RT) has historically been limited to a palliative intent [
The aim of the current study is to report on the treatment outcome of patients treated with SBRT with volumetric modulated arc therapy (VMAT) for adrenal gland metastases, with special focus on local control, toxicity, and survival.
Between 2011 and 2015, 46 patients with adrenal gland metastases were treated with SBRT in our institute. Data collection and the analysis for an observational retrospective study were approved by the institutional review board based on an analysis of charts. All patients were treated in accordance with the Helsinki declaration. The inclusion criteria for the SBRT treatment were as follows: age greater than 18 years, World Health Organization performance status ≤ 2, histologically-proven primary cancer disease, M1 stage with primary cancer radically treated with complete or stable response, a maximum of five metastases, a lesion diameter < 5 cm, no previous radiation treatment or surgical intervention in the region. All patients signed an informed consent at registration.
Free breathing 4D computed tomography (4DCT) scans with 3-mm slice thickness were acquired for treatment planning in supine position, with the patient’s arms above the head. Thermoplastic chest masks with abdominal compression (made with the insertion of styrofoam blocks under the mask in correspondence with the diaphragm) were constructed to improve the patient immobilization and reduce the motion of internal organs. The clinical target volume (CTV) included the metastases’ mass as identified on the computed tomography (CT) images. Set-up margins were added with an isotropic expansion of 5 mm from the envelope of the CTV volumes reconstructed in all phases of the 4DCT. The new volume was labelled as the planning target volume (PTV). The organs at risk (OAR) defined included the stomach and the duodenum, the small bowel, the liver, the spinal cord, and the kidneys.
The dose prescription was 40.0 Gy in four daily fractions of 10 Gy (mean dose to CTV) for all patients. This prescription is a dose escalation from the earlier regimen of 45 Gy in six fractions of 7.5 Gy reported in the feasibility study [
SBRT treatments were performed using the RapidArc ver. of VMAT on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA) selecting the flattening filter free photon beams of 6 or 10 MV with a dose rate of 1,400 or 2,400 MU/min respectively to minimize the treatment time. The treatment plans were optimized using the Eclipse system ver.11 (Varian Medical Systems). The daily patient set-up was controlled using 3D cone beam CT images compared against the reconstructed image from the 4DCT planning scans. A free-breathing delivery was selected for all patients. Further details regarding the planning procedure and the dosimetric features of the treatment can be found in the feasibility investigation report published earlier [
All treatment plans were appraised by analysis of the dose volume histograms. The clinical outcome was evaluated during the periodic follow-up visits; CT scans were acquired at 1 month after treatment and then every 3 months. For a group of 14 patients (30%), a positron emission tomography scan was performed using 18F-fluorodeoxyglucose 6 months after the end of treatment. The radiological response was defined according to the Response Evaluation Criteria in Solid Tumors criteria and reported at the time of the maximal response. Toxicity was recorded using the Common Terminology Criteria for Adverse Events ver. 4.0. Descriptive statistics was used for characterization of the cohort data. The local control (LC) and OS rates were computed using the Kaplan-Meier analysis and univariate analysis performed using log-rank tests. The variables tested were age, sex, performance status, laterality, primary tumour histology, solitary metastasis versus oligometastatic status. SPSS software ver. 22 (IBM Corp., Armonk, NY) was used for the tests.
The patient’s characteristics are summarized in
At the last follow-up, 42 patients (91.3%) were alive, four patients (8.7%) died because of the disease. The crude local response resulted in 15 patients (32.6%) with complete response, 21 patients (45.6%) with partial response or stable disease, and 10 patients (21.7%) with local progression of the disease. Considering only the subgroup of patients with primary lung tumor, an overall benefit rate of 86.6% was observed. The four patients (13.3%) experiencing progression of the disease during the follow-up period were affected by lung adenocarcinoma (n=2) and small cell lung cancer (n=2). While the first two were still alive at the time of the analysis, the latter died because of the disease. Progression of metastasis after treatment was also observed in one patient affected by neuroendocrine carcinoma of the prostate and urothelial carcinoma of the bladder.
Accounting for the group of 20 patients with solitary single metastasis in the adrenal gland without other sites of disease, local progression of the disease was observed in five patients with a mean period of 6.7 months. On the contrary, new sites of distant metastasis appeared in 11 cases (55%) with a mean period of 5.2 months. Seven out of 20 patients (35%) were free from disease at the time of the analysis, two (10%) with only disease in the adrenal gland. Twenty-six patients (56.5%) had more than one metastasis at the time of treatment; all patients benefitted from SBRT but two showed local progression after 9.1 and 11.3 months.
Distant progression was observed in 27 patients (58.7%) with new metastases identified in other organs after SBRT treatment for the adrenal localization. The sites of distant progression included the lungs in 13 patients (48%), the liver in five patients (19%), the bones in four patients (15%) plus other localizations (e.g., brain, pelvic nodes, and bladder) with lower incidence. All four patients who died presented distant progression but only one also presented with local progression.
The actuarial mean OS was 28.5±1.6 months (95% confidence interval [CI], 25.4 to 31.6), median was not reached. The 1-year and 2-year OS were 87.6±6.1%. None of the risk factors showed a significant result in the univariate analysis. The actuarial mean LC was 14.6±1.8 months (95% CI, 11.0 to 18.2) and the median LC was 14.5±2.0 months (95% CI, 10.5 to 18.5). The 1-year and 2-year LC were 65.5±11.9% and 40.7±15.8%, respectively. In this case, no risk factors were distinguished among the subgroups of patients. The graphs for the actuarial OS and LC are shown in
A mild profile of toxicity was observed in the cohort of patients. Forty patients (86.9%) showed no complication (grade 0). Two patients reported asthenia, six patients (13.1%) reported either pain, nausea, or vomiting. Of these six patients, five (10.9%) were scored as grade 1 toxicity while one (2.2%) was scored as grade 2. All toxicity symptoms recovered with simple medication.
Although metastases to the adrenal glands are common, optimal management is still uncertain as clinical evidence is limited. A systematic review was recently published on the role of surgical and ablative therapies for oligometastatic patients with adrenal metastases [
Another weak point against radiotherapy is the heterogeneity of the prescription doses and fractionation regimens. Indeed, even if high doses can be administered in a few fractions sparing the most relevant OARs with SBRT, it is still unclear which one is the best schedule. To the best of our knowledge, the current report is the only one with consistent dose and fractionation. For all patients a total dose of 40 Gy in four fractions of 10 Gy each was delivered, representing a biological effective dose (BED10) of 80 Gy. A higher BED was administered only by Casamassima et al. [
Chawla et al. [
Considering the results of these two studies with an acceptable number of cases, and comparing them with the current data, it is clear that BED10 influences the LC. In fact [
In terms of toxicity, patients tolerated the treatment well without interruption. The total dose was administered in four consecutive days without interruptions. The compliance with treatment was optimal and the most common side effects were mild asthenia, nausea, and vomiting (grade 1 or 2); no grade 3 or 4 toxicities were observed. Several studies on surgical approaches were also published. In a recent study by Romero Arenas et al. [
Modern techniques of radiotherapy, such as VMAT, enable highly precise and rapid treatments respecting the dose constraints for all organs close to the affected gland. Although retrospective, our analysis on a homogeneous group of patients confirmed the promising local control rates achievable by means of SBRT with VMAT for adrenal metastases. The dose escalation applied in this study, compared with the feasibility phase, enabled management of the entire treatment within one single week with good compliance from the patients and minimum distress induced by the small number of fractions. No endocrinology assessment was performed so far, this evaluation will be included in a prospective trial, which could also help to confirm the optimal dose in a larger number of patients.
Treatment of adrenal gland metastases with VMAT based SBRT is consolidating and the results in terms of control of disease, survival, and toxicity confirm the efficacy of the approach. This treatment is now offered as standard to all eligible patients.
L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is a Clinical Research Scientist at Humanitas Cancer Center. All other co-authors have no conflicts of interest.
Typical dose distribution (in colowash from 5 to 45 Gy) for axial, sagittal, and coronal views.
Average dose volume histograms (blue line) and interpatient variability at 1 standard deviation (red lines) for target volumes and organs at risk.
Actuarial graphs for overall survival (A) and local control (B).
Summary of the patients’ characteristics
Parameter | No. (%) |
---|---|
Male | 34 (73.9) |
Female | 12 (26.1) |
46 (27-85) | |
1.7 (0.5-11.6) | |
0 | 28 (60.9) |
1 | 11 (23.9) |
2 | 7 (15.2) |
Solitary | 20 (43.5) |
Oligometastatic | 26 (56.5) |
Lung | 30 (65.2) |
Colorectal | 7 (15.2) |
Other | 9 (19.6) |
Adenocarcinoma | 29 (63.0) |
NSCLC | 5 (10.9) |
Other | 12 (26.1) |
Right | 30 (65.2) |
Left | 16 (35.8) |
SBRT, stereotactic body radiation therapy; WHO, World Health Organization; NSCLC, non-small-cell lung carcinoma.
Summary of the quantitative analysis of the dosimetric findings from the treatment plans
Variable | Planning objectives | CTV (26±20 cm3) | PTV (63±34 cm3) | Spinal cord | Liver ipsilateral | Kidneys ipsilateral | Duodenum | Stomach | Bowel |
---|---|---|---|---|---|---|---|---|---|
Mean (Gy) | 40.0 | 40.1±0.1 | 40.0±0.0 | - | - | - | - | - | - |
D1% (Gy) | < 31 Gy | 40.8±0.3 | 41.2±0.3 | 8.3±2.9 | - | - | 16.5±6.5 | 3.8±2.8 | 12.3±6.2 |
V98% (Gy) | > 98% (for CTV) | 99.9±1.3 | 90.4±3.4 | - | - | - | - | - | - |
V95% (%) | > 95% (for PTV) | 100.0±0.0 | 97.8±1.6 | - | - | - | - | - | - |
V15 Gy (%) | < 35% | - | - | - | - | 12.9±9.0 | - | - | - |
Vtot–V15 Gy (cm3) | > 700 cm3 | - | - | - | 1,374±133 | - | - | - | - |
V36 Gy (cm3) | < 1 cm3 | - | - | - | - | - | 0.0±0.0 | 0.0±0.0 | 0.0±0.0 |
Data are reported as mean±1 standard deviation to determine interpatient variability. CTV, clinical target volume; PTV, planning target volume.
Comparative summary of the studies reporting on SBRT treatment of adrenal gland metastases
Author | No. of patients | Histology | Dose (Gy)/Fractionation | Median/Mean follow-up (mo) | Local control (%) | Overall survival (%) |
---|---|---|---|---|---|---|
Katoh et al. (2008) [ |
8 | Miscellaneous | 30-48/8 | 16 | 1 Yr: 100 | 1 Yr: 78 |
2 Yr: 100 | - | |||||
Chawla et al. (2009) [ |
30 | Miscellaneous | 16-50/4-10 | 9.8 | 1 Yr: 55 | 1 Yr: 44 |
2 Yr: 27 | 2 Yr: 25 | |||||
Torok et al. (2011) [ |
7 | Miscellaneous | 10-36/3 | 14 | 1 Yr: 63 | - |
Oshiro et al. (2011) [ |
11 | Lung | 30-60/1-27 | 10.1 | 6 Mo: 97.4 | 1 Yr: 55.6 |
- | 2 Yr: 33.4 | |||||
Holy et al. (2011) [ |
18 | Lung | 20-40/5 | 12 | 1 Yr: 94.4 | - |
2 Yr: 78.7 | - | |||||
Casamassima et al. (2012) [ |
48 | Miscellaneous | 21-54/3 | 16.2 | 1 Yr: 90 | 1 Yr: 39.7 |
2 Yr: 90 | 2 Yr: 14.5 | |||||
Ahmed et al. (2013) [ |
9 | Lung | 20-37.5/5 | 7.3 | 1 Yr: 44 | 1 Yr: 62.9 |
2 Yr: 44 | - | |||||
Romero Arenas et al. (2014) [ |
13 | Miscellaneous | 33.7-60/5 | 12.3 | Crude: 100 | 1 Yr: 62.9 |
This study | 47 | Miscellaneous | 40/4 | 11.3 | 1 Yr: 65.5 | 1 Yr: 87.6 |
2 Yr: 40.1 | 2 Yr: 87.6 |
SBRT, stereotactic body radiation therapy.