Lutetium-177 DOTATATE Therapy Is Associated With Biochemical Endocrine Abnormalities in the Immediate Post-Treatment Period

Abstract

Abstract Introduction: Lutetium-177(177Lu) DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) targeting somatostatin receptor-2 (SSTR2), that is utilized in the treatment of neuroendocrine tumors. As various endocrine glands express SSTR2, 177Lu-DOTATATE can potentially disrupt endocrine function. The immediate post-treatment effects of 177Lu-DOTATATE on endocrine function are not known. Methods: We performed a retrospective analysis of data obtained from patients (≥18 years) enrolled under the 177Lu-DOTATATE trial (NCT03206060) for treatment of SSTR2 positive inoperable/metastatic pheochromocytoma/paraganglioma. 177Lu-DOTATATE (200 mCi) was administered intravenously every 8 weeks, for a total of 4 cycles. Endocrine evaluation was performed on blood samples obtained through an indwelling intravenous catheter during each cycle of PRRT on day 1 (pre-PRRT), day 2 (post-PRRT day 1), day 3 (post-PRRT day 2), day 30 (post-PRRT day 29), and day 60 (day 1 of the next cycle). Hormonal evaluation included ACTH, cortisol, TSH, free T4, GH, FSH, LH, testosterone, estradiol, and prolactin. Baseline abnormal hormonal values, and gonadotrophs in premenopausal women were excluded. Results: Data from 27 subjects (age: 54 ± 12.7 years; 13 female, 14 male) were analyzed. Three out of 27 patients (11.1%) developed clinically significant persistent endocrinopathies - secondary adrenal insufficiency (AI): (n=1 male), primary hypothyroidism: (n=1 male) and hypergonadotropic hypogonadism: (n=1 female). Compared to day 1, there were significant reductions in 1) ACTH (pg/mL) levels on day 2 (36.8 ± 34.1 vs. 23.1 ± 21; p<0.0001), day 3 (36.8 ± 34.1 vs. 24.3 ± 19.4; p<0.0001), and day 30 (36.8 ± 34.1 vs. 27.7 ± 19.1; p=0.01), without significant changes in average cortisol level, apart from 1 patient with undetectable cortisol, who developed secondary AI after 2nd cycle 2) LH (IU/L) levels on day 3 (16.4 ± 13.5 vs. 15.4 ± 13.5; p=0.014), 3) prolactin (ng/mL) on day 2 (9.9 ± 7.0 vs. 7.1 ± 5.7; p<0.0001), day 3 (9.9 ± 7.0 vs. 7.1 ± 5.4; p<0.0001), and day 30 (9.9 ± 7.0 vs. 7.6 ± 5.7; p=0.005), without significant changes in average estrogen and testosterone levels, apart from 1 woman with low estrogens developing hypergonadotropic hypogonadism after 3rd cycle 4) TSH (microIU/L) on day 2 (2.2 ± 1.4 vs. 1.4 ± 0.9; p<0.0001), and day 3 (2.2 ± 1.4 vs. 1.7 ± 1.3; p=0.001), and 5) free T4 (ng/dL) on day 2 (1.1 ± 0.2 vs. 1 ± 0.2; p=0.002). Hormonal values on day 60 were not significantly different from those on day 1, suggesting that majority of these changes were transient. Conclusions:177Lu-DOTATATE can be associated with transient endocrine disruption in the immediate post-treatment period. However, some of these changes may lead to persistent endocrinopathies which are likely associated with radiation exposure to the tissues expressing SSTR2. It is therefore important to periodically assess endocrine function during PRRT.