Introduction
Metastatic involvement of adrenal glands is very common.
Many different tumors can metastasize to the
adrenal gland. Lung, breast, kidney and colon cancers
are the most common tumors with a high potential of spread to the adrenal glands.[] Adrenal metastasis does
not have specific symptoms. Patients usually present
with pain when the metastatic mass in the adrenal gland
is large. Adrenal insufficiency with the presentation of
fatigue, nausea, hyperpigmentation, hypotension and
electrolyte disturbances are rarely observed and usually occur when both glands are involved.[] The classical
treatment of adrenal metastasis is systemic chemotherapy.
However, in solitary adrenal metastases with
the primary tumor under control, surgical resection
(adrenalectomy) is the primary treatment modality providing
the cure.[,] Local therapies other than surgery,
namely radiotherapy or radiofrequency ablation, are offered
mostly in the palliative setting. Recently, with the
technological improvements in radiation oncology, it
has become possible to deliver high radiation doses to
localized tumors. Stereotactic body radiotherapy (SBRT)
has gained popularity and emerged as a noninvasive
technique. The advantage of SBRT is the delivery of
ablative radiation doses in a shorter time, resulting in a
potent radiobiological effect. While classical fractionated
radiotherapy provides only palliative benefit, SBRT can
be an alternative to surgery in localized tumors.[,-]
Recently, the oligometastatic disease has been defined
by Hellman and Weichselbaum as an intermediate state
between locoregional and metastatic disease.[] SBRT is
now a prominent treatment modality in oligometastatic
cancer patients with isolated metastatic masses.
Long term survival has been reported after
adrenalectomy in patients with solitary adrenal metastases.[] For patients with medically inoperable or
technically unresectable masses, SBRT has emerged
as an encouraging method instead of surgery, and
recently, data have accumulated in the treatment of
adrenal metastasis with SBRT.[,,-]
In the present study, we aimed to analyze the results
of stereotactic body radiotherapy (SBRT) in patients
with adrenal metastasis associated with different
primary tumors.
Methods
Twenty-six patients with 29 adrenal gland metastases
who were treated between 2011-2018 were evaluated
retrospectively in this study. All of the patients had
biopsy-proven primary disease and either positron
emission tomography (PET/CT) or biopsy-confirmed
adrenal metastases. Patients having a life expectancy
of >3 months, with Karnofsky performance score ?70,
and who were not operable were considered for SBRT.
This study was approved by the local ethics committee
of the hospital, and informed consent was obtained
from all the patients.
Treatments
All patients presented with oligometastatic disease or
solitary adrenal metastasis. Among 29 tumors treated with SBRT, nine patients had bulky tumors. SBRT was
delivered by CyberKnife Robotic System (Accuray
Corporation, Sunnyvale, CA, USA). The CyberKnife
system consists of a six megavolt linear accelerator
(LINAC) mounted on to a precisely controlled industrial
robotic arm and image guidance system. Before
the treatment, one to three gold fiducials were placed
by a radiologist under computed tomography (CT)
guidance around the tumor within the adrenal gland
at least seven days before the treatment to account for
seed migration.
Immobilization was achieved with a vacuum bed,
and patients lied in the supine position. Simulation CT
(GE Healthcare, Waukesha, WI, USA) was obtained
by 1.25-mm slice thickness while administering intravenous
contrast material. Synchrony? Respiratory
Tracking System was utilized in all patients, which is
a realization of real-time tracking of tumors that move
with respiration. The gross tumor volume (GTV) was
defined as the visible tumor in the CT. While the clinical
target volume (CTV) was equal to the GTV, planning
target volume (PTV) was obtained by adding a
5-mm margin to the CTV. Treatment planning was
performed in MultiPlanTM software. Figure 1 demonstrates
the treatment plan for one of our patients.
Fig 1: The treatment plan for one of our patients.
An illustrative case of the fifty-years-old man with metastatic
non-small cell lung cancer. SBRT was performed for left adrenal
metastasis. Fiducials were placed around the lesion one week before
treatment as a tracking marker for respiratory movements.
45 Gy in 3 fractions prescribed to the 87% isodose line.
SBRT was performed in median 3 fractions (range,
3?5 fractions), and the median prescription dose to
PTV was 30 Gy (range, 18-45 Gy), which was biologically
equivalent (BED 10) to the dose of 60 Gy (range,
28.8-112,5 Gy). The median tumor volume was 66,6 ml
(range: 25.6?78.4 ml). The treatment parameters were
summarized in Table 1.
Table 1: SBRT treatment parameters
End-Points and Follow-Up
Patients were followed regularly with CT scans or PETCT
scans after SBRT at every three months. Toxicities
were graded according to the Common Terminology
Criteria for Adverse Events version 4.0.[] Tumor
responses were evaluated according to the Response
Evaluation Criteria in Solid Tumors (RECIST), version
1.1.[] and considered as either complete response
(CR), partial response (PR), stable disease (SD), or progressive
disease (PD). The local control (LC) rate was defined
as the ratio of the number of lesions with a response
after SBRT to a total number of lesions at the beginning
of this study. Overall survival after SBRT (OS) and time
to local failure (tLF) were calculated from the date of
completion of SBRT to death from any cause or the last
follow-up. Adrenal function was evaluated during follow
up for patients with bilateral adrenal gland metastases.
Statistical Analysis
The local control (LC) and OS rates were computed using
the Kaplan-Meier analysis. Prognostic factors associated
with LC and OS were evaluated using univariate
log-rank test and multivariate Cox regression analysis.
P values of less than 0.05 were regarded as statistically
significant. All statistical analyses were performed using
the SPSS 17.0 software (The Statistical Package for
Social Sciences 17).
Results
Patient Characteristics
A total of 26 patients with a median age of 57 (34-
78), including 22 male and four female patients, were treated with SBRT. While 12 lesions treated were rightsided,
11 lesions were left-sided, and three lesions were
located on both sides. The origin of adrenal gland
metastasis was lung in 22 patients, breast in one patient,
the parotid gland in one patient, and sarcoma in two
patients. The pathologic diagnosis of the patients with
lung cancer was adenocarcinoma in 14 patients (53%),
squamous cell carcinoma in six patients (23%), and
small cell cancer in two patients (8%). Fifteen patients
(58%) had other organ metastasis in addition to the
adrenal metastases. While six patients presented with
synchronous metastasis, the other 20 patients presented
with metachronous metastasis. While 20 out of 26 patients
(77%) had received chemotherapy before SBRT,
18 patients (69%) received chemotherapy after SBRT.
Adrenal metastases were asymptomatic in the majority
of the patients (21 out of 26 patients, 81%), while five
patients (19%) suffered from abdominal pain. Patient
and tumor characteristics are summarized in Table 2.
Table 2: Patient and tumor characteristics
Efficacy Outcomes
At the time of analysis, only seven of the 26 patients
(16.6 %) were alive. The median follow-up time from the initial diagnosis was 26 months (12?149 months). The
median follow-up time from SBRT was 11 months (1-34
months). Median overall survival from initial diagnosis
was 33 months, and 1, 3, 5-years overall survival rates
were 96%, 43%, and 33%, respectively. Median overall
survival after SBRT was 12 months, and 1,2-years survival
rates were 49.7%, 21%, respectively. Median time
to local failure was not reached, and the 6-month, 1-year and 2-year local failure-free survival rates were 78,6%,
66,5% and 66,5%, respectively (Fig. 2a-c).
Fig 2: Actuarial survival analysis of patients. (a) Overall
survival, (b) Survival after SBRT, (c) Local control.
According to RECIST criteria, CR, PR, SD, and
rates were 14% (n=4), 17% (n=5), and 45% (n=13), respectively,
while seven patients (24%) had progressed
(PD) after SBRT. The local control rate after SBRT
was found to be 76%. Disease progression outside the
adrenal gland was observed in 19 patients (73%) after
SBRT.
While presence of metastatic disease besides
adrenal gland (oligometastatic vs. solitary metastasis),
synchronous or metachronous disease presentation,
laterality versus bilateral disease presentation was
found to be significant for overall survival after SBRT
according to the univariate analysis, the presence of
metastatic disease outside the adrenal gland was found
to be a significant prognostic factor on survival after
SBRT in both univariate and multivariate analyses.
None of the risk factors were found to be significant
for local control in the univariate analysis. Univariate
analysis findings were summarized in Table 3.
Table 3: Univariate analysis for LC and OS rates
Overall survival was found to be nine months in
oligometastatic patients, whereas it was 34 months in
patients treated for solitary adrenal metastasis (HR 3;
95% CI 1.06-8.55 p=0.04).
SBRT provided pain relief in all patients presenting
with pain. The treatment was well-tolerated. Seven patients
developed acute grade I-II toxicity, including nausea
(n=6), and fatigue (n=5) and abdominal pain (n=1).
No patients presented with grade III-IV late toxicity.
Discussion
Metastatic disease presentation in the adrenal gland
is very common. Diagnosis and treatment of tumors
in the adrenal gland is very problematic, especially in
patients with a controlled primary tumor. The optimal
management of patients with adrenal metastases
is unclear, and there is heterogeneity in oncologist"s
approach to these patients. Surgical resection is the
primary treatment for patients with isolated adrenal
metastases. There are several studies reporting long
survival after adrenalectomy.[]
The role of surgical and ablative therapies in
adrenal metastases has been reviewed in a recent publication.[] Image-guided RFA is another effective local-
regional treatment. A retrospective study evaluated
35 patients who were treated with RFA for 41 adrenal
metastases with a mean size of 3.3 cm from various
primary tumors and demonstrated a 77% local control
rate. The 1-, 3-, and 5-year OS rates were 75%, 34%,
and 30%, respectively, with a median survival time of
26.0 months.[]
Classically fractionated external radiotherapy has
been used with palliative intent and provides good response
rates and pain relief. Recent advances in stereotactic
radiotherapy made it possible to safely apply
larger doses of radiation to the adrenal tumors with a
limited number of fractions. SBRT is a novel modality
and being used with increased frequency in radiation
oncology practice with accumulating experience nowadays.
The biologically equivalent doses (BED) delivered
by SBRT are much higher than doses delivered by normal
fractionated radiotherapy. SBRT is a non-invasive
treatment alternative to surgery in selected patients.[-] There are few studies reporting the treatment results
of SBRT in adrenal gland metastases. To our knowledge,
there are no standard prescription doses, and fractionation
regimens and the reported studies are heterogeneous
concerning patient selection (primary tumors,
previous treatments, performance status and disease
extension) and prescribed radiation dose and fractionation
schedules.[] The radiation doses in the published
studies ranged from 16 to 60 Gy and were delivered in 1
to 10 fractions.[,,,-] In our study, the median
prescription dose was 30 Gy (range,18-45 Gy) administered
in median 3 fractions (range, 3?5 fractions) determined
according to patient and tumor characteristics.
There are several reasons for the difference in survival
obtained with surgery and other local ablative therapies.
The patients selected for surgery are generally in good
performance status, have no major co-morbidities, and, most of the time, have controlled extra-adrenal disease
when compared with the patients had other local ablative
treatments, namely the SBRT.[] A recent analysis
demonstrated 2-year OS rates in favor of surgery when
compared to SBRT (44% vs. 19%).[]
A recent study in 30 patients who underwent SBRT
for adrenal metastases of different primary tumors reported
1-year OS, LC, and distant control rates as 44%,
55%, and 13%, respectively. No grade II or greater toxicity
was observed.[19] Another study by Franzese et al.
found similar outcomes with 28.5 months median OS
and 65.5% and 40.7% 1-year and 2-year LC rates, respectively.[] Scorsetti et al. reported the results of 34
patients with adrenal metastasis who were treated with
SBRT.[] They delivered a median dose of 32 Gy in 4
fractions. Local control rates were 66% at 1 year, and 32%
at 2 years after a median follow-up time of 41 months.
The median time to local progression was 19 months,
and the median survival time was 22 months. No grade
III toxicity was observed. In our patients, the median follow-
up time from SBRT was 11 months (1-34 months).
Median overall survival after SBRT was 12 months, and
1.2-years survival rates were 49.7%, 21%, respectively.
Local control rates in the literature vary among
studies. While Casamassima et al. reported a 90% local
control rate at 2 years [], Chawla et al. reported a
55% 1-year local control rate.[] We found 6-months,
1-year and 2-year local failure-free survival rates to be
78.6%, 66.5% and 66.5%, respectively, which was in accordance
with the literature.
Lower doses seem to be associated with poor tumor
control rates, as reported by Chawla et al. The
differences in local control rates may be explained by
differences in dose and fractionations used in SBRT.
There are significant differences in the prescribed
BED. While maximum delivered BED was 137 Gy (36
Gy in 3 fractions) in the study of Casamassima et al.,
it was only between 22 Gy (16 Gy in 4 fractions) and
75 Gy (50 Gy in 10 fractions) in the study of Chawla
et al.[,] Several studies demonstrated that a
BED10 value <60Gy was predictive of lower 1-year
LC rates [,,] while several other studies identified
that BED10 value >85Gy correlated with better
LC.[,,] Other series have suggested that a BED
value >100 Gy is necessary to achieve optimal local
control.[,] Rudra et al. treated 13 patients with
SBRT and noticed that the local failures were observed
in three patients with the lowest BED10 values, with a
mean BED value of 43.2 Gy.[] In our study, we did
not find any relation between BED10 value (100 Gy>
and 100 Gy ≤) and treatment results.
Holy et al. reported a median progression-free
survival (PFS) of 4.2 months in 18 NSCLC patients
who were treated with SBRT. However, in 13 patients
with isolated adrenal gland metastases, the PFS was
markedly longer and reported as 12 months. After a
median follow-up of 21 months, 10 of these 13 patients
achieved local control, and the median overall survival
was 23 months.[] These results were similar to the
results obtained by surgery. Porte et al. reported PFS
of 13 months with surgical resection of solitary adrenal
metastasis.[] In different SBRT series, one-year LC
rates reported ranged between 44% to 100% depending
on the radiation doses and the fractionation scheme.
[,,] Although isolated adrenal gland involvement
was not found as a prognostic factor for local
control in our study, we found it as a prognostic factor
for overall survival after SBRT in both univariate and
multivariate analyses. While overall survival was nine
months for oligometastatic patients, the overall survival
was 34 months for patients with isolated adrenal
gland metastasis (HR 3; 95% CI 1.06-8.55 p=0.04).
Bilateral adrenal gland metastasis was associated
with significantly worse PFS and OS. This is probably
related to the aggressiveness and high tumor burden
of the disease in these patients in comparison to the
patients with unilateral metastasis.[] In univariate
analysis, we found that patients treated for bilateral
adrenal gland metastasis had worse survival as compared
with the patients treated for unilateral adrenal
gland metastasis. However, this significance was not
observed in the multivariate analysis.
In general, SBRT to the adrenal gland is well tolerated
with acceptable acute toxicity. The most commonly
reported acute toxicities are nausea, vomiting
6% to 40%,[,,,-] and fatigue 38% to 88%.
[,,] We observed mostly nausea, vomiting, and
abdominal pain (grade I or II) and no grade III/IV
acute toxicity. All patients tolerated the treatment well.
Grade III/IV late gastrointestinal or renal toxicities
were not observed, as in the other studies reported in
the literature.[,,,]
Our study has several limitations. Our study was a
retrospective study with a limited number of patients.
The patient population was heterogeneous, consisting
of several different primary tumors. In addition,
the treatment parameters, i.e. the radiation doses and
fractionations, were heterogeneous. Different systemic
chemotherapy schemes administered to our patients
was another important confounding factor.
Our study confirmed the efficacy of SBRT in the
treatment of adrenal gland metastases with high local control rates and acceptable acute and late toxicity.
Our findings were comparable to the results reported
in the literature.
Conclusion
Recently with the technological improvements in radiation
oncology, it is possible to deliver stereotactic ablative
radiation doses to the adrenal gland metastases.
SBRT is a well-tolerated treatment in patients with
adrenal metastases and provides good local control
rates. Survival is particularly encouraging for patients
with a solitary metastasis in the adrenal gland. High local
control rates with low toxicity make this treatment
an alternative to surgery, especially in patients with
solitary metastases.
Ethics Committee Approval: This study was approved by
the local ethics committee of the hospital (2019/514/154/16).
Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors have no conflicts of interest
to declare.
Financial Support: There is no financial support from any
foundation.
Authorship contributions: Concept - G.Y., N.I.; Design -
G.Y., N.I.; Supervision - H.D., M.P.; Materials - C.G., M.P.;
Data collection &/or processing - C.G., H.D.; Analysis and/
or interpretation - G.Y., N.I.; Literature search - C.G., H.D.;
Writing - G.Y., M.P.; Critical review - G.Y., H.D.
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