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SBRT to adrenal metastases provides high local control with minimal toxicity

Open AccessPublished:August 04, 2017DOI:https://doi.org/10.1016/j.adro.2017.07.011

      Abstract

      Purpose

      The adrenal glands are a common site of metastases because of their rich blood supply. Previously, adrenal metastases were treated with systemic chemotherapy or, more rarely, with surgical resection or palliative radiation therapy. Stereotactic body radiation therapy (SBRT) has recently emerged as an attractive noninvasive approach to definitively treat these lesions. We present our experience in treating adrenal metastases using SBRT and review the current literature.

      Methods and materials

      This is a single-institution retrospective review of patients who received SBRT to adrenal metastases originating from various primary malignancies. Patients who were eligible for SBRT included those with limited metastatic disease (≤5 sites) with otherwise controlled metastatic disease and uncontrolled adrenal metastases.

      Results

      Ten patients met the study's inclusion criteria and received SBRT doses of 30 to 48 Gy in 3 to 5 fractions. Acute sequelae of SBRT treatment included 4 patients with grades 1 or 2 nausea, 3 patients with grade 1 fatigue, and 1 with grade 1 diarrhea. The median follow-up was 6 months with a median overall survival of 9.9 months. One patient demonstrated progressive adrenal gland disease 18.8 months after SBRT treatment. Seven patients developed new distant metastases after treatment, with a median progression-free survival of 3.4 months. Three months after SBRT to the adrenal gland, 1 patient developed a gastrointestinal bleed.

      Conclusions

      These results complement the limited existing body of literature by demonstrating that SBRT provides good control of treated adrenal gland metastasis; however, high-grade late toxicities may occur. More stringent dose constraint limits may prevent associated serious adverse events.
      Summary
      Stereotactic body radiation therapy (SBRT) has recently emerged as an attractive noninvasive approach to definitively treat adrenal gland metastases. We reviewed the records of 10 patients with oligometastatic disease who received SBRT (30-48 Gy in 3-5 fractions) to adrenal gland metastases. Our conclusions support the safety and efficacy data of SBRT treatment to adrenal gland metastases.

      Introduction

      The adrenal glands are a common site for metastases, mainly because of their rich sinusoidal blood supply.
      • Kung A.W.
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      • Lam K.
      • Wang C.
      • Leung C.Y.
      Addisonian crisis as presenting feature in malignancies.
      Metastatic disease in the adrenal gland is most often from a lung primary malignancy but can also be due to multiple other primary malignancies, including breast, kidney, colon, and liver cancer.
      • Lam K.Y.
      • Lo C.Y.
      Metastatic tumours of the adrenal glands: A 30-year experience in a teaching hospital.
      Historically, adrenal metastases were discovered symptomatically and treated with chemotherapy or, less often, with palliative external beam radiation therapy. However, with the increased use of imaging for cancer diagnosis and surveillance, occult adrenal metastases are more frequently identified. Many of these patients have a limited number of metastases (ie, oligometastatic disease). Aggressive use of definitive local therapies in oligometastatic disease may increase progression-free survival (PFS) and overall survival (OS).
      • Alongi F.
      • Arcangeli S.
      • Filippi A.R.
      • Ricardi U.
      • Scorsetti M.
      Review and uses of stereotactic body radiation therapy for oligometastases.
      • Weichselbaum R.R.
      • Hellman S.
      Oligometastases revisited.
      Recently, stereotactic body radiation therapy (SBRT) has emerged as a noninvasive technique to treat metastatic adrenal lesions definitively.
      • Ippolito E.
      • D'Angelillo R.M.
      • Fiore M.
      • Molfese E.
      • Trodellla L.
      • Ramella S.
      SBRT: A viable option for treating adrenal gland metastases.
      In contrast with conventional radiation therapy, SBRT allows for the delivery of large doses of radiation in a highly conformal manner. SBRT is frequently used as a definitive treatment modality for inoperable primary lung and liver malignancies,
      • Rubio C.
      • Morera R.
      • Hernando O.
      • Leroy T.
      • Lartigau S.E.
      Extracranial stereotactic body radiotherapy. Review of main SBRT features and indications in primary tumors.
      and a growing body of literature has explored SBRT for the definitive treatment of oligometastatic disease.
      • Alongi F.
      • Arcangeli S.
      • Filippi A.R.
      • Ricardi U.
      • Scorsetti M.
      Review and uses of stereotactic body radiation therapy for oligometastases.
      The safety and tolerability of SBRT in treating adrenal gland metastases have only been reported in small case series; metastases typically originated from a single primary cancer site without a consensus on overall radiation dose or fractionation scheme.
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      • Casamassima F.
      • Livi L.
      • Masciullo S.
      • et al.
      Stereotactic radiotherapy for adrenal gland metastases: University of Florence experience.
      • Chawla S.
      • Chen Y.
      • Katz A.W.
      • et al.
      Stereotactic body radiotherapy for treatment of adrenal metastases.
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      • Franzese C.
      • Franceschini D.
      • Cozzi L.
      • et al.
      Minimally invasive stereotactical radio-ablation of adrenal metastases as an alternative to surgery.
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      • Guiou M.
      • Mayr N.A.
      • Kim E.Y.
      • et al.
      Stereotactic body radiotherapy for adrenal metastases from lung cancer.
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      • Katoh N.
      • Onimaru R.
      • Sakuhara Y.
      • et al.
      Real-time tumor-tracking radiotherapy for adrenal tumors.
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      • Oshiro Y.
      • Takeda Y.
      • Hirano S.
      • Ito H.
      • Aruga T.
      Role of radiotherapy for local control of asymptomatic adrenal metastasis from lung cancer.
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      • Scorsetti M.
      • Alongi F.
      • Filippi A.R.
      • et al.
      Long-term local control achieved after hypofractionated stereotactic body radiotherapy for adrenal gland metastases: A retrospective analysis of 34 patients.
      • Torok J.
      • Wegner R.E.
      • Burton S.A.
      • Heron D.E.
      Stereotactic body radiation therapy for adrenal metastases: A retrospective review of a noninvasive therapeutic strategy.
      Herein, we present our institutional experience with SBRT to adrenal gland metastases originating from various primary cancer sites and demonstrate that administering SBRT to adrenal gland metastases has favorable treatment outcomes, although associated serious side effects may occur.

      Methods and materials

      Patient population

      After approval by our institutional review board, we reviewed a prospectively maintained database of patients who received SBRT to adrenal gland metastases. At our institution, the criteria for receiving SBRT to the adrenal gland include a limited metastatic disease burden and controlled systemic disease except for the adrenal metastasis.

      Stereotactic body radiation therapy

      Computed tomography (CT)-based treatment planning was used for all patients. Immobilization was obtained with either an arm board or a custom-made partial Vac-Lok (CIVCO Radiotherapy, Orange City, IA). Patients received a full expiration breath-hold contrast-enhanced CT scan with 2 mm slices and a 4-dimensional CT scan to quantify motion. The 4-dimensional CT data sets included 10 respiratory phases: 20%, 40%, 60%, 80%, and 100% inspiration phases, and 80%, 60%, 40%, 20%, and 0% expiration phases. If a motion greater than 1 cm was noted on the 4-dimensional CT scan, respiratory gating was used for treatment planning and delivery. In cases with ≤1 cm motion, an internal target volume (ITV) was created using the 100% inspiration, 0% expiration, and full-expiration breath-hold contrast-enhanced CT scan. In gated cases, beam-gating phases were designed to keep the tumor motion at ≤1 cm while the beam was on. The ITV included the full-expiration breath-hold contrast-enhanced CT scan and 4-dimensional CT data sets that corresponded to the gated phases. The planning target volume included an additional 5 mm margin around the ITV.
      Patients were treated with either intensity modulated radiation therapy–based plans, volumetric-modulated arc therapy, or 3-dimensional conformal treatment. Dose and fractionation were determined on the basis of tumor size and location; patients received total doses of 30 to 48 Gy in 3 to 5 fractions (Table 1). The dose constraints that were used in our series were as follows: 1) spinal cord was allowed to receive a maximum dose of ≤13 Gy delivered over 3 fractions; dose of ≤16 Gy delivered over 4 fractions; or dose ≤25 Gy delivered over 5 fractions; 2) ipsilateral kidney dose was kept as low as possible with at least 150 cc receiving a cumulative dose of ≤12 Gy; 3) the large and small bowel maximum doses were kept as low as possible.
      Table 1Patient characteristics
      PatientAgeSexPrimary HistologyAdrenal Met Size (cm3)Additional Sites of DiseaseBack or Flank Pain Prior to RTPrescribed DoseBED10 DeliveredAdrenal Disease Status Post SBRT (mo)
      172MEsophagus adenocarcinoma18.3Bone, lung, inguinal lymph nodeNo35 Gy/5fx59.5 GyStable (5.9)
      268FNSCLC7.5boneYes30 Gy/5fx48 GyStable (4.3)
      360MHCC40.5No45 Gy/3fx112.5 GyStable (7.4)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      465MSCLC25.4Liver, boneYes30 Gy/3fx60 GyStable (11.1)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      567MLeiomyosarcoma50.8Bone, liver, pancreasNo48 Gy/4fx105.6 GyStable (34.4)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      659MUnknown104.0boneYes30 Gy/3fx60 GyProgression (18.2)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      779FNSCLC17.2No30 Gy/5fx48 GyStable (9.9)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      836FNSCLC3.9BRAINNo36 Gy/3fx79.2 GyStable (4.5)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      959FNSCLC19.9BRAINYes36 Gy/3fx79.2 GyStable (4)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      1067MSCLC4.4BRAINNo35 Gy/5fx59.5 GyStable (6.6)
      The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      BED, biologically effective dose; fx, fraction; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SCLC, small cell lung cancer.
      a The patient is deceased. Stable and progression of disease were determined per Response Evaluation Criteria In Solid Tumors, Version 1.1.
      Fractions were delivered every other day, with at least 40 hours between fractions. Prior to treatment delivery, either a megavoltage or kilovoltage cone beam CT scan was acquired for localization. No patient received concurrent chemotherapy during the SBRT. A biological effective dose (BED)
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      for the tumor was calculated using the following equation:
      BED=nd[1+d/(α/β)]


      where d is the radiation dose per fraction, n is the number of fractions, and α/β is equal to 10 Gy.

      Follow-up and response evaluation

      All patients were assessed at least once during treatment for acute side effects as well as 1 month after completion of treatment and then every 3 months to assess late toxicities. Our institutional practice is to evaluate patients with a CT scan 1 to 3 months after treatment for a response assessment. Additional CT scans were typically obtained every 3 months. A complete blood count with differential and electrolyte panels, including blood urea nitrogen and creatinine, were drawn at each follow-up visit to assess the ability to receive systemic therapy and risk for kidney injury.

      Statistical analysis

      The Kaplan-Meier method was used to estimate OS and PFS from the completion of radiation therapy. Treated adrenal gland metastasis control was determined by the patient's most recent CT scan and was defined as the absence of progression at the treatment site per Response Evaluation Criteria In Solid Tumors, Version 1.1. Statistical analysis was performed with SPSS, Version 24 (IBM Corporation, Armonk, NY).

      Results

      The baseline demographic and clinical data of 11 patients who underwent SBRT to treat adrenal gland metastases are summarized in Table 1. One patient died during the course of radiation therapy because of aspiration pneumonia and was removed from the analysis, leaving 10 eligible patients. The median patient age was 66 years, and the mean tumor volume was 31.4 cm3 (range, 3.88-104 cm3). The mean duration from the time of initial cancer diagnosis to adrenal metastases development was 18.8 months (range, 0-74 months). Two patients had adrenal metastases at diagnosis. Eight patients received chemotherapy before SBRT treatment, and 3 patients received chemotherapy after SBRT treatment. Five patients received immunotherapy either before or after SBRT treatment.
      Four patients reported symptomatic back or flank pain as a result of the adrenal gland metastases before SBRT initiation. All of these patients reported improvement in their symptoms after SBRT treatment. One patient received SBRT after an unsuccessful palliative course of radiation treatment (30 Gy in 10 fractions) to adrenal metastases for pain control. This patient experienced an improvement in pain after completion of SBRT.
      Regarding acute toxicities, 4 patients developed grade 1 or 2 nausea, 2 patients developed grade 1 fatigue, and 1patient reported grade 1 diarrhea (Table 2) in the acute period after treatment. The median follow-up duration after SBRT was 6 months (range, 1-34 months) with follow-up CT scans available for 10 patients. At the last follow-up, 8 of 10 patients had died. Median OS was 9.9 months (Fig 1a). Seven patients developed new distant metastases after SBRT treatment; median PFS was 3.4 months (Fig 1b). Nine patients (90%) achieved control of treated adrenal gland metastasis after completion of SBRT, with 1 patient experiencing progression of the adrenal gland metastasis 18.2 months after completion of treatment (Table 1). The other 9 patients had stable disease in treated adrenal glands at the time of the final follow-up visit or at death.
      Table 2Acute and late toxicities during and after SBRT to adrenal gland metastases
      ToxicityN (%)
      Acute
      Nausea (Grade 1 and 2)4 (36.4)
      Fatigue (Grade 1)3 (27.3)
      Diarrhea (Grade 1)1 (9.1)
      Late
      Gastrointestinal bleed1 (9.1)
      SBRT, stereotactic body radiation therapy.
      Figure 1
      Figure 1Overall survival and progression-free survival of patients with oligometastatic disease treated with stereotactic body radiation therapy to adrenal gland metastasis. Kaplan-Meier curve for overall survival (A) and progression-free survival (B). Median overall survival was 9.9 months, and median progression-free survival was 3.4 months. Patients alive at the time of analysis were censored to the date of last follow-up.
      For chronic toxicities, 1 patient developed a gastrointestinal bleed 3 months after completion of SBRT treatment. An upper gastrointestinal endoscopy noted a subepithelial hemorrhage in the proximal jejunum, but no definitive source of bleeding was identified. This individual's maximum bowel radiation dose was calculated as 52.8 Gy delivered over 3 fractions.

      Discussion

      This study used a prospectively maintained database of patients who received SBRT to the adrenal gland for metastatic disease. We found that SBRT provides good control of treated adrenal gland metastasis with acceptable acute toxicity; OS and treated adrenal gland metastasis control rates were similar to other reports in the literature given the relatively short follow-up period (Table 3). However, 1 patient developed a gastrointestinal bleed 3 months after completion of SBRT to the adrenal gland.
      Table 3Published adrenal SBRT case series
      StudyPatientsLesionsPrimary HistologyMedian Follow-up (mo)Total Dose (Gy)Pain ReliefLocal ControlOverall Survival (median, mo)Toxicity
      Katoh et al, 2008
      • Katoh N.
      • Onimaru R.
      • Sakuhara Y.
      • et al.
      Real-time tumor-tracking radiotherapy for adrenal tumors.
      9105 NSCLC

      1 SCLC

      2 HCC

      1 prostate
      1630-48yes, 1/1 patients100%15NR
      Chawla et al, 2009
      • Chawla S.
      • Chen Y.
      • Katz A.W.
      • et al.
      Stereotactic body radiotherapy for treatment of adrenal metastases.
      303520 Lung

      4 GI

      3 breast

      1 head and neck

      1 melanoma

      1 unknown
      9.816-50NR27%11Grade 1 nausea and fatigue “common”
      Casamasssima et al, 2011
      • Casamassima F.
      • Livi L.
      • Masciullo S.
      • et al.
      Stereotactic radiotherapy for adrenal gland metastases: University of Florence experience.
      485824 Lung

      12 colon

      4 melanoma

      3 breast

      1 uterus

      1 unknown
      16.221.69-54.09yes, 4/4 patients94%NR1 case grade 2 adrenal insufficiency
      Torok et al, 2011
      • Torok J.
      • Wegner R.E.
      • Burton S.A.
      • Heron D.E.
      Stereotactic body radiation therapy for adrenal metastases: A retrospective review of a noninvasive therapeutic strategy.
      794 NSCLC

      1 SCLC

      2 HCC
      1416 or 27yes, 1/2 patients89%8NR
      Holy et al, 2011
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      131313 NSCLC2120-40yes, 6/8 patients77%2346% grade 1 nausea, 15% gastric/duodenal ulcer
      Oshiro et al, 2011
      • Oshiro Y.
      • Takeda Y.
      • Hirano S.
      • Ito H.
      • Aruga T.
      Role of radiotherapy for local control of asymptomatic adrenal metastasis from lung cancer.
      191914 NSCLC

      5 SCLC
      10.130-60NR72%NR1 grade 2 duodenal ulcer
      Guiou et al, 2012
      • Guiou M.
      • Mayr N.A.
      • Kim E.Y.
      • et al.
      Stereotactic body radiotherapy for adrenal metastases from lung cancer.
      9104 NSCLC

      5 SCLC
      7.3 (mean)40NRNR10.222% nausea, vomiting
      Scorsetti et al, 2012
      • Scorsetti M.
      • Alongi F.
      • Filippi A.R.
      • et al.
      Long-term local control achieved after hypofractionated stereotactic body radiotherapy for adrenal gland metastases: A retrospective analysis of 34 patients.
      343622 NSCLC

      3 SCLC

      3 Melanoma

      1 Sarcoma

      1 Colorectal adenocarcinoma

      1 RCC

      1 Unknown
      4120-37.5NR93%226% grade 2 nausea
      Ahmed et al, 2013
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      13134 NSCLC

      2 RCC

      1 melanoma

      1 skin SCC

      1 bladder

      1 colon 1 cholangiocarcinoma
      12.333.75-60NR92%7.238% grade 1 fatigue

      8% grade 1 abdominal pain

      8% grade 1 diarrhea 15% grade 2 nausea

      8% late grade 2 fatigue, abdominal pain, and nausea
      Rudra et al, 2013
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      10136 NSCLC

      2 SCLC

      2 RCC
      14.924-50NR73%1780% grade 1-2 fatigue

      40% grade 1-2 GI toxicity

      1 case grade 2 adrenal insufficiency
      Li et al, 2013
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      26262 Pheochromocytoma

      10 lung

      6 bladder

      4 unknown

      4 RCC
      NR30-50yes, 15/16 patients77%1788% grade 1-2 fatigue

      69% grade 1-2 anorexia

      38% grade 1-2 N/V

      23% grade 1-2 skin rxn 4% grade 3 nausea/vomiting
      Desai et al, 2015
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      14146 NSCLC

      2RCC

      1 melanoma

      1 primary adrenal

      1 mixed Mullerian

      1 GE junction

      1 bladder

      1 lymphoma
      NR20-30NR45.5%NRNR
      Gamsiz et al, 2015
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      151715 NSCLC1630yes, 2/2 patients86.7%NR46% grade 1 nausea

      80% grade 1 fatigue

      1 case dyspeptic disorder
      Franzese et al 2016
      • Franzese C.
      • Franceschini D.
      • Cozzi L.
      • et al.
      Minimally invasive stereotactical radio-ablation of adrenal metastases as an alternative to surgery.
      464630 lung

      7 colorectal adenocarcinoma

      9 other
      7.640NR78.3%28.5 (mean)13.1% pain, nausea, or vomiting

      2 cases asthenia
      Present study 201710104 NSCLC

      2 SCLC

      1 esophageal carcinoma

      1 HCC

      1 leiomyosarcoma

      1 unknown
      630-48yes, 4/4 patients70%9.936.4% nausea (grade 1 and 2)

      27.3% fatigue (grade 1)

      1 case diarrhea (grade 1)

      1 case GI bleed
      GE, gastroesophageal; GI, gastrointestinal; HCC, hepatocellular carcinoma, NR, not reported; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
      There is considerable heterogeneity with respect to the SBRT technique, radiation dose, and radiation fractionation schemes in the adrenal gland SBRT literature. Published series have used a variety of radiation approaches, including 3-dimensional conformal intensity modulated radiation therapy, volumetric-modulated arc therapy, and robotic radiosurgery techniques. In addition, SBRT dose and fractionation have varied both among and within case series, with the radiation doses ranging from 16 to 60 Gy delivered in 1 to 10 fractions.
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      • Casamassima F.
      • Livi L.
      • Masciullo S.
      • et al.
      Stereotactic radiotherapy for adrenal gland metastases: University of Florence experience.
      • Chawla S.
      • Chen Y.
      • Katz A.W.
      • et al.
      Stereotactic body radiotherapy for treatment of adrenal metastases.
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      • Franzese C.
      • Franceschini D.
      • Cozzi L.
      • et al.
      Minimally invasive stereotactical radio-ablation of adrenal metastases as an alternative to surgery.
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      • Guiou M.
      • Mayr N.A.
      • Kim E.Y.
      • et al.
      Stereotactic body radiotherapy for adrenal metastases from lung cancer.
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      • Katoh N.
      • Onimaru R.
      • Sakuhara Y.
      • et al.
      Real-time tumor-tracking radiotherapy for adrenal tumors.
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      • Oshiro Y.
      • Takeda Y.
      • Hirano S.
      • Ito H.
      • Aruga T.
      Role of radiotherapy for local control of asymptomatic adrenal metastasis from lung cancer.
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      • Scorsetti M.
      • Alongi F.
      • Filippi A.R.
      • et al.
      Long-term local control achieved after hypofractionated stereotactic body radiotherapy for adrenal gland metastases: A retrospective analysis of 34 patients.
      • Torok J.
      • Wegner R.E.
      • Burton S.A.
      • Heron D.E.
      Stereotactic body radiation therapy for adrenal metastases: A retrospective review of a noninvasive therapeutic strategy.
      In our series, 30 to 48 Gy was administered in 3 to 5 fractions, with all evaluable patients achieving treated adrenal gland metastasis control on initial follow-up imaging. Only 1 patient demonstrated adrenal gland progression 18.2 months after completion of SBRT per Response Evaluation Criteria In Solid Tumors, Version 1.1. Reported treated adrenal gland metastasis control rates have typically been high in published case series, with rates between 70% and 100%, with the exception of the studies by Chawla et al and Desai et al, who reported rates of 27% and 45.5%, respectively.
      • Chawla S.
      • Chen Y.
      • Katz A.W.
      • et al.
      Stereotactic body radiotherapy for treatment of adrenal metastases.
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      Several studies have explored the effect of BED on local tumor control and noted higher local tumor control as associated with higher BED values. Li et al noted greater treated adrenal gland metastasis control rates of 100% for tumors with a BED10 >100 Gy and 82% for tumors with a BED10 <100 Gy.
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      Desai et al reported a mean BED10 of 96.7 Gy for nonlocally failing tumors and 76 Gy for locally failing tumors.
      • Desai A.
      • Rai H.
      • Haas J.
      • Witten M.
      • Blacksburg S.
      • Schneider J.G.
      A retrospective review of CyberKnife stereotactic body radiotherapy for adrenal tumors (primary and metastatic): Winthrop University Hospital experience.
      In examining their 13-lesion cohort, Rudra et al noted that the 3 local failures had the lowest BED10, with a mean of 43.2 Gy.
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      In our cohort, we did not find an association between BED10 and treated adrenal gland metastasis control. The patient who demonstrated adrenal gland progression post-SBRT had a BED10 of 105.6 Gy. Greater numbers of patients may allow for a better correlation between BED and treated adrenal gland metastasis control.
      Dosimetry to the adrenal gland is complicated because these tumors can have considerable respiratory motion in addition to multiple nearby organs at risk, which could lead to selectively underdoing tumor coverage. For the credentialing of NRG BR001, a current ongoing multicenter phase 1 study investigating SBRT treatment for oligometastatic disease, conformity and underdosing of the target were affected because of the closeness of the stomach or other organs at risk.
      • Al-Hallaq H.A.
      • Chmura S.J.
      • Salama J.K.
      • et al.
      Benchmark credentialing results for NRG-BR001: The first National Cancer Institute-sponsored trial of stereotactic body Radiation Therapy for Multiple Metastases.
      Of note, NRG BR001 has selected an initial dose of 45 Gy in 3 fractions to adrenal gland metastases with a decreased dose of 42 Gy in 3 fractions allowed if there are adjacent dose-limiting structures.
      • NRG Oncology
      Stereotactic body radiation therapy in treating patients with metastatic breast cancer, non-small cell lung cancer, or prostate cancer.
      This study has closed accrual to abdominal SBRT sites, including the adrenal glands, and the outcome report from the study is pending.
      Although the reported treated adrenal gland metastasis control rates for adrenal SBRT are high, OS and distant control rates for patients receiving SBRT to the adrenal gland have varied more than control rates of treated adrenal gland metastasis. We reported a median OS of 9.9 months, which is within the literature-reported range of median OS (range, 7.2-23 months). Distant control has been evaluated by several case series, with 1 year distant control reported as 9% to 55%.
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      • Casamassima F.
      • Livi L.
      • Masciullo S.
      • et al.
      Stereotactic radiotherapy for adrenal gland metastases: University of Florence experience.
      • Chawla S.
      • Chen Y.
      • Katz A.W.
      • et al.
      Stereotactic body radiotherapy for treatment of adrenal metastases.
      Our median PFS rate was 3.4 months. Although both our median OS and PFS were at the lower end of reported values, this is likely because of differences in patient population histologies, prior treatment, and extent of disease (patient selection) at the time of SBRT treatment. Four of ten evaluable patients had non-small cell lung cancer primary disease. A recent report showed that local consolidative therapy of oligometastatic non-small cell lung cancer disease had improved PFS.
      • Gomez D.R.
      • Blumenschein Jr, G.R.
      • Lee J.J.
      • et al.
      Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: A multicentre, randomised, controlled, phase 2 study.
      Although SBRT is used for definitive treatment, symptom palliation can also be achieved through radiation therapy. Six studies evaluating SBRT's effects on pain control all reported an improvement in pain after SBRT, with response rates ranging from 50% to 100%.
      • Casamassima F.
      • Livi L.
      • Masciullo S.
      • et al.
      Stereotactic radiotherapy for adrenal gland metastases: University of Florence experience.
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      • Katoh N.
      • Onimaru R.
      • Sakuhara Y.
      • et al.
      Real-time tumor-tracking radiotherapy for adrenal tumors.
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      • Torok J.
      • Wegner R.E.
      • Burton S.A.
      • Heron D.E.
      Stereotactic body radiation therapy for adrenal metastases: A retrospective review of a noninvasive therapeutic strategy.
      This is consistent with our outcome of improvement in pain in all 4 patients who reported back or flank pain before SBRT, including 1 patient who did not achieve pain control after receiving palliative radiation to the adrenal gland (30 Gy in 10 fractions).
      SBRT to adrenal gland metastasis provides high local control with acceptable acute toxicity, with most treatment-related toxicities being self-limited and occurring in the acute phase. The most commonly reported side effects are nausea, vomiting, and fatigue, with rates of nausea ranging from 6% to 40%
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      • Guiou M.
      • Mayr N.A.
      • Kim E.Y.
      • et al.
      Stereotactic body radiotherapy for adrenal metastases from lung cancer.
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      • Scorsetti M.
      • Alongi F.
      • Filippi A.R.
      • et al.
      Long-term local control achieved after hypofractionated stereotactic body radiotherapy for adrenal gland metastases: A retrospective analysis of 34 patients.
      and fatigue ranging from 38% to 88%
      • Ahmed K.A.
      • Barney B.M.
      • Macdonald O.K.
      • et al.
      Stereotactic body radiotherapy in the treatment of adrenal metastases.
      • Gamsiz H.
      • Beyzadeoglu M.
      • Sager O.
      • et al.
      Evaluation of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer.
      • Rudra S.
      • Malik R.
      • Ranck M.C.
      • et al.
      Stereotactic body radiation therapy for curative treatment of adrenal metastases.
      when reported, which is consistent with our outcomes of 36% (nausea) and 27% (fatigue). Late toxicities reported in the literature include adrenal insufficiency and gastric/duodenal ulcers.
      • Holy R.
      • Piroth M.
      • Pinkawa M.
      • Eble M.J.
      Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer.
      • Li J.
      • Shi Z.
      • Wang Z.
      • et al.
      Treating adrenal tumors in 26 patients with CyberKnife: A mono-institutional experience.
      • Oshiro Y.
      • Takeda Y.
      • Hirano S.
      • Ito H.
      • Aruga T.
      Role of radiotherapy for local control of asymptomatic adrenal metastasis from lung cancer.
      A case report also detailed late gastric perforation and hemorrhage leading to the death of a patient who received 60 Gy in 5 fractions to an adrenal lesion with concurrent vinorelbine.
      • Onishi H.
      • Ozaki M.
      • Kuriyama K.
      • et al.
      Serious gastric ulcer event after stereotactic body radiotherapy (SBRT) delivered with concomitant vinorelbine in a patient with left adrenal metastasis of lung cancer.
      A review of the gastric radiation dose found that the stomach received >52.5 Gy to 2.9 mL of dose. Although these radiation doses met their predefined organ-at-risk dose limits, concurrent chemotherapy may have potentiated the radiation dose effect in that setting. Our series had 1 patient who developed an upper gastrointestinal bleed after SBRT to the left adrenal gland, with a maximum bowel dose of 52.8 Gy in 3 fractions. This serious adverse event occurred without the addition of chemotherapy. Bowel dose constraints should be strongly considered to prevent late toxicity. Given the lack of literature on abdominal SBRT and with most reports consisting of small case series, SBRT bowel dose volume constraints need further refinement.

      Conclusions

      Our results complement the existing literature by providing further safety and efficacy data on SBRT to adrenal gland metastases. Adrenal SBRT may provide better pain control than conventional palliative radiation therapy. However, associated serious adverse events may occur, and more stringent dose constraint limits and avoidance of concurrent chemotherapy should be considered. Further large-scale studies will be necessary to determine the acceptable dose parameters for both efficacy and avoidance of toxicity.

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