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. 2019 Mar 1;104(3):779-784.
doi: 10.1210/jc.2018-01836.

Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy

Carla Colombo  1   2 , Simone De Leo  2 , Marta Di Stefano  3 , Guia Vannucchi  1 , Luca Persani  1   3 , Laura Fugazzola  1   2
Affiliations

Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy

Carla Colombo et al. J Clin Endocrinol Metab. .

Abstract

Context: Two tyrosine kinase inhibitors (TKIs), lenvatinib and vandetanib, are often used to treat advanced radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) and medullary thyroid cancer (MTC), respectively. Fatigue is a common adverse event during treatment with these and other TKIs and a common cause of drug discontinuation or dosage reduction.

Cases description: We evaluated the basal and stimulated adrenal function in 12 patients with advanced RAI-R DTC and MTC treated with lenvatinib or vandetanib, respectively. Ten patients complaining of fatigue showed a progressive ACTH increase with normal cortisol levels. Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI). The causal relationship between TKIs and PAI onset was also demonstrated by the repeated testing of adrenal function before and during treatment. Patients with PAI received cortisone acetate replacement therapy, with a substantial and prompt improvement in the degree of fatigue, as assessed by the Common Terminology Criteria for Adverse Events version 4.03, thus supporting the major impact of impaired adrenal function in the genesis of this adverse event.

Conclusions: We show that the occurrence of PAI may be a common cause of fatigue during lenvatinib and vandetanib treatment, and we therefore recommend testing adrenal function for a prompt start of replacement therapy to avoid treatment discontinuation, dosage reduction, and potentially severe PAI complications.

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Figures

Figure 1.
Figure 1.
(A) Cortisol (μg/dL) and ACTH (ng/L) levels in the patients treated with lenvatinib (n = 7) and vandetanib (n = 5) according to treatment duration. In particular, the first adrenal function evaluation and the last assessment before the start of cortisone acetate replacement are reported. Interestingly, for patient 7, the evaluation of adrenal function was available before the start of the lenvatinib treatment (asterisk), and the two following evaluations without cortisone acetate therapy are also reported. The lowest normal cortisol level (5 μg/dL) and the highest normal ACTH level (50 ng/mL) are reported in the figure. (B) Cortisol levels at baseline and at 30, 60, and 90 minutes after infusion of 250 mμg ACTH in the 12 patients. CA replacement treatment was started in patients 1, 2, 3, 7, 9, and 11. Peak cortisol levels <500 nmol/L (18 μg/dL, dotted line) at 30 or 60 minutes indicate adrenal insufficiency.
Figure 2.
Figure 2.
(A) Degree of fatigue according to the CTCAE (version 4.03) in patients before treatment with CA and at each control after the start of the replacement therapy. (B) ACTH and cortisol levels during TKI treatment in patients started on CA therapy. The basal evaluation of the adrenal function was always assessed during the morning (8:00 to 9:00 am) and in a fasting state.
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