Cortisol Deficiency in Lenvatinib Treatment of Thyroid Cancer: An Underestimated Common Adverse Event

Abstract

Background: Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment. Methods: We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 μg) stimulation test. Results: During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84.6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85.7%) in the PAI group, without the need to change the lenvatinib dosage. Conclusions: PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.

Keywords: fatigue; lenvatinib; primary adrenal insufficiency; thyroid cancer.

FIG. 1.

ACTH (250 μg) stimulation test of all 13 patients treated with lenvatinib at baseline (0, before starting therapy) and during follow-up (3, 6, 9, 12, 15, 18, 21, 24, and 27 months). Seven patients (#4, #6, #8, #9, #10, #11, and #12) had an insufficient response (cortisol peak <500 nmol/L) indicating adrenal insufficiency. After 12 months of treatment, PAI patient #6 interrupted lenvatinib for 34 days and ACTH stimulation was normal; after lenvatinib restarted, a recurrence of PAI (cortisol peak <500) was demonstrated (see Results). ACTH, adrenocorticotropic hormone; PAI, primary adrenal insufficiency. Color images are available online.

FIG. 2.

ACTH levels of seven patients that developed PAI, at baseline (0, before starting therapy) and during follow-up, until PAI diagnosis. The red line is the upper limit of the reference range 48.8 pg/mL. In six of seven PAI patients (#4, #6, #9, #10, #11, and #12), ACTH levels increased before diagnosis of PAI. Only #12 had very high ACTH levels (greater than twofold the upper limit of reference range) at the time of PAI diagnosis. In the only patient without an increase in ACTH levels (Fig. 3, patient #8), we excluded pituitary origin by evaluating other pituitary hormones and pituitary magnetic resonance. However, during follow-up, this patient manifested high levels of ACTH (maximum value 61.5 pg/mL). Color images are available online.

FIG. 3.

Fatigue in patients with PAI and without PAI (no-PAI). Fatigue was evaluated by the National Cancer Institute CTCAE version 4.03 (9). Fatigue is defined as a disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities. According to CTCAE, three grades of severity of fatigue were identified: Grade 1, fatigue relieved by rest; Grade 2, fatigue not relieved by rest, limiting activities of daily living, such as preparing meals, shopping for groceries or clothes, using the telephone, and managing money; Grade 3, fatigue not relieved by rest, limiting simple activities of daily living, such as bathing, dressing and undressing, feeding self, using the toilet, taking medications, and bedridden for much of the day. None of our patients at the onset of fatigue had tumor progression, increased TSH levels or alteration in hemoglobin levels, sodium levels, potassium levels, glycemia, albumin concentration, and abnormal hepatic and renal functions. Furthermore, there were no other known causes of fatigue in our patients. (a) Fatigue in PAI patients. All seven patients with PAI had fatigue (see Results). At the time of PAI diagnosis, three patients had grade 3 fatigue (#6, #9, and #10) and four patients had grade 2 fatigue (#4, #8, #11, and #12). After starting replacement CA therapy, six patients (#4, #6, #8, #9, #10, and #11), which constitutes 85.7%, had a significant improvement in fatigue that persisted during follow-up in five patients (#4, #6, #9, #10, and #11), without the need to change lenvatinib dosage. Two patients (#9 and #10) resolved fatigue with AC therapy. (b) Fatigue in patients with no-PAI. Four patients (#1, #5, #7, and #13) in the no-PAI group had fatigue. In two (#1 and #5) of the four patients, an improvement in fatigue was observed after reducing lenvatinib dosage: patient #1 reduced lenvatinib for other adverse events and patient #2 reduced lenvatinib due to the severity of fatigue (grade 3). CA, cortisone acetate; CTCAE, Common Terminology Criteria for Adverse Events; TSH, thyrotropin. Color images are available online.