Radiation of Bilateral Adrenal Metastases Is Associated With a High Risk of Primary Adrenal Insufficiency

Justine Herndon; Christopher Hallemeier; Krishan Jethwa; Afreen Shariff; Irina Bancos

Clin Endocrinol. 2023;99(1):35-42.

Abstract and Introduction

Abstract

Background: Adrenal metastasis is the most common adrenal malignancy and can be bilateral in up to 43% of patients. Radiotherapy (RT) is one option available to treat adrenal metastases. The risk of primary adrenal insufficiency (PAI) after adrenal RT is unclear.

Objective: Determine the incidence and the timeline of PAI in patients undergoing adrenal RT.

Design, Setting and Participants: Single-centre longitudinal retrospective cohort study of adult patients with adrenal metastases treated with RT between 2010 and 2021.

Results: Of 56 patients with adrenal metastases treated with adrenal RT, eight (14.3%) patients developed PAI at a median of 6.1 months (interquartile range [IQR]: 3.9–13.8) after RT All patients developing PAI had either unilateral RT in the setting of contralateral adrenalectomy or bilateral adrenal RT. Patients who developed PAI received a median RT dose of 50 Gy (IQR: 44–50 Gy), administered in a median of five fractions (IQR: 5–6). Treated metastases decreased in size and/or metabolic activity on positron emission tomography in seven patients (87.5%). Patients were initiated on hydrocortisone (median daily dose of 20 mg, IQR: 18–40) and fludrocortisone (median daily dose of 0.05 mg, IQR: 0.05–0.05 mg). At the end of the study period, five patients died, all due to extra-adrenal malignancy, at a median time of 19.7 months (IQR: 16–21.1 months) since RT and median time of 7.7 months (IQR: 2.9–12.5 months) since the diagnosis of PAI.

Conclusion: Patients receiving unilateral adrenal RT with two intact adrenal glands have a low risk of PAI. Patients receiving bilateral adrenal RT have a high risk of PAI and require close monitoring.

Introduction

Adrenal metastasis is the most common adrenal malignancy encountered in clinical practice, accounting for approximately 7.5% of all adrenal masses, and 85%–90% of malignant adrenal masses.^[1,2] While many are diagnosed during cancer staging imaging, approximately one-third are found incidentally.^[1,3] Bilateral disease is common, including approximately 24% of patients at initial diagnosis and up to up to 43% will ultimately develop bilateral adrenal metastases.^[3] Primary adrenal insufficiency (PAI) is diagnosed in 12.7% of all patients with bilateral adrenal metastases, and in 20% if adrenal metastases are >4 cm.^[3] Adrenal radiotherapy (RT) is a standard therapeutic modality employed in the treatment of adrenal metastases and is generally effective and well-tolerated.^[4–15] In addition to the already high risk of PAI in patients with bilateral adrenal metastases, superimposed adrenal RT may contribute to the residual adrenal cortex destruction through direct cellular and DNA damage.^[16]

Few studies have described the incidence of PAI in patients with adrenal RT^{[5,6,10,11,13,15,17,18]} though relationship to RT was not always conclusive due to concomitant exogenous glucocorticoid use or other systemic treatments that may induce PAI.^[5] Available data are further limited by incomplete characterisation of the time to PAI onset after RT, clinical presentation and details on PAI diagnosis and management.

The aim of our study was to determine the incidence, and the timeline for development of PAI in patients undergoing adrenal RT.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusion
References

Table 1. Characteristics of patients undergoing adrenal radiation.
Age, years (Median, [IQR])	69.5 (64–79.3)
Sex (n, %)
Female	22 (39.3%)
Male	34 (60.7%)
Primary tumour (n, %)
Breast	1 (1.8%)
Colorectal	1 (1.8%)
GE junction	1 (1.8%)
Lung	41 (73.2%)
Lymphoma	1 (1.8%)
Melanoma	4 (7.1%)
Neuroendocrine	1 (1.8%)
Ovarian	1 (1.8%)
Pancreas	1 (1.8%)
Prostate	1 (1.8%)
Renal Cell	3 (5.3%)
Radiation laterality (n, %)
Bilateral^a	9 (16.1%)
Unilateral, solitary adrenal^a	1 (1.8%)
Unilateral^b	46 (82.1%)
Radiation dose, Gy (Median, [IQR])	50 (40–50)
Radiation fractions, # (Median, [IQR])	5 (5–5)

Abbreviations: #, number; GE, gastroesophageal; Gy, gray; IQR, interquartile range.
^aGroup 1 for the study.
^bGroup 2 for the study.

Table 2. Clinical, biochemical and therapy data of patients diagnosed with primary adrenal insufficiency.
	Sex	Age	Primary malignancy	Adrenal metastasis size at time of radiation (mm)	Radiation dose (Gy)	Number of radiation fractions	Adrenal metastasis at the time of last follow-up (mm)	Time since radiation to diagnosis of PAI (months)	Symptoms at the time of diagnosis	Initial daily dose of glucocorticoid and mineralocorticoid replacement (mg)	Last documented daily dose of glucocorticoid and mineralocorticoid replacement (mg)	Time since radiation to last follow-up (months)
Biochemical diagnosis
Patient 1	F	72	Lung	L: 28 R: 34	50	5	L: 18 R: 14	20.4	Yes	HC: 15 FC: 0.05	HC: 15 FC: 0.075	60.8
Patient 2	M	72	Lung	L: 22 R: 26	20	5	L: 14 R: 49	7.2	Yes	HC: 20 FC: 0.05	HC: 20 FC: 0.05	19.7
Patient 3	F	63	Lung	L: 15 R: 0^a	50	5	L: 8 R: 0^b	14.8	Yes	HC^c: x FC^c: x	HC^c: x FC^c: x	16^d
Patient 4	M	69	Lung	L: 10 R: 19	50	5	L: 9 R: 10	4.1	Yes	HC^e: 40 FC: 0.05	HC^e: 40 FC: 0.1	4.4
Patient 5^f	M	68	Melanoma	L: 40 R: 21	40	5	L: 44 R: 20	4.9	No	HC: 15 FC: x	HC: 20 FC: x	7.9
Clinical diagnosis
Patient 6	F	59	Lung	L: 25 R: 17	45	18	L: x^g R: 11	0.5	No	HC: 20 FC: 0.1	HC: 35 FC: 0.1	55.8^d
Patient 7	M	58	Lung	L: 0^a R: 0^a	65	Unknown	L: 0^b R: 0^b	3.2	Yes	HC: 80 FC: 0.05	HC: 160 FC: 0.05	6.1^d
Patient 8	F	78	Lung	L: 25 R: 25	50	5	L: 17 R: 7	13.4	Yes	HC: 40 FC: x	HC: 80 FC: x	21.1^d

Abbreviations: F, Female; FC, fludrocortisone; Gy, gray; HC, hydrocortisone; L, left; M, male; R, right.
^aIncreased uptake in the adrenal gland, no nodule noted and metastasis presumed.
^bDecreased uptake in adrenal gland.
^cPatient had was diagnosed with partial adrenal insufficiency; utilised sick day rules for HC only, no daily dose.
^dPatient expired at the time of study conclusion.
^ePatient was on prednisone 10 mg for a separate side effect related to immune checkpoint inhibitor therapy.
^fPrevious radiation to left adrenal, completed right adrenal radiation at the time of study enrolment.
^gAdrenalectomy.

Table 3. Biochemical assessment.
Test description (Units)	Baseline lab tests before radiation	Lab tests at the time of PAI Diagnosis	Reference range
Sodium (mEq/L)			135–145
Median (IQR)	141 (139–143)	134 (133–137)
Patient 1	139	132
Patient 2	144	139
Patient 3	144	134
Patient 4	139	132
Patient 5	140	139
Patient 6	143	-
Patient 7	141	135
Patient 8	141	134
Potassium (mEq/L)			3.8–5.2
Median (IQR)	4.7 (4.4–4.8)	5.0 (4.5–5.5)
Patient 1	4.9	5.6
Patient 2	4.5	4.8
Patient 3	4.8	3.9
Patient 4	4.3	5.8
Patient 5	4.4	4.2
Patient 6	1.8	-
Patient 7	4.8	5.0
Patient 8	4.8	5.4
Adrenocorticotropic Hormone (pg/mL)			7.2–63
Median (IQR)	21 (20–26)	124 (70–311)
Patient 1	-	498
Patient 2	41	124
Patient 3	21	-
Patient 4	-	-
Patient 5	-	-
Patient 6	17	-
Patient 7	-	-
Patient 8	-	15a
Morning cortisol (mcg/dL)			7–25
Median (IQR)	12.3 (10.6–14.7)	6.4 (6.1–7.8)
Patient 1	-	6.1
Patient 2	15	9.9
Patient 3	10	7.8
Patient 4	-	-
Patient 5	10.6	6.4
Patient 6	19	-
Patient 7	-	-
Patient 8	-	1.0
Renin (ng/mL/h)			0.6–4.0 (sodium replete, upright)
Median (IQR)	2.2 (1.7–2.6)	8.0 (2.5–13.5)
Patient 1	-	13
Patient 2	-	1.3
Patient 3	1.1	-
Patient 4	2.2	2.9
Patient 5	3.0	-
Patient 6	-	-
Patient 7	-	15
Patient 8	-	-
Aldosterone (ng/dL)			<21
Median (IQR)		4 (4–7.5)
Patient 1		4
Patient 2		-
Patient 3		-
Patient 4		4
Patient 5		-
Patient 6		-
Patient 7		11
Patient 8		-

Abbreviations: IQR, interquartile range; PAI, primary adrenal insufficiency.
^aPatient was on prednisone, potentially impacting result.

Table 4. Recommended follow-up for adrenal radiation patients.
Baseline
• Patient education regarding risk and symptoms of PAI • Baseline electrolytes (sodium, potassium), ACTH, 8 AM cortisol and renin plasma activity
Every 3–6 months
• Clinical assessment for signs and symptoms of PAI • Laboratory testing including electrolytes, ACTH, 8 AM cortisol, renin plasma activity and aldosterone
After diagnosis
• Initiation of physiologic glucocorticoid replacement • Initiation of mineralocorticoid replacement when applicable • Patient education regarding stress-dosing/sick day rules for glucocorticoid replacement • Establish follow-up plan with clinical assessment of symptom control and laboratory testing to include electrolytes ± renin plasma activity