Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up

Abstract

Introduction: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment.

Objective: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity.

Methods: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time.

Results: A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes.

Conclusions: No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.

Keywords: 177Lu-DOTATATE; Neuroendocrine tumor; Peptide receptor radionuclide therapy; Pituitary; Radiotherapy.

Fig. 1

Images of the head-and-neck region of an NET patient from pre-therapeutic ⁶⁸Ga-DOTATATE PET/CT illustrating the distinct tracer uptake in the pituitary gland (arrows) indicating a high expression of somatostatin receptors in this endocrine organ.

Fig. 2

Three-planar, post-therapeutic, scintigraphic images of the head-and-neck region of the same patient as in Figure 1 after receiving PRRT with ¹⁷⁷Lu-DOTATATE. The images correspond to 24, 96, and 168 h after injection, respectively, with arrows indicating the uptake in the pituitary region.

Fig. 3

Box plots illustrating the development of hormone levels over time. The p values are from the mixed model analysis. The median value is indicated by a black horizontal line, and the 25th and 75th percentiles define the limits of the box. The whiskers indicate the minimum and maximum values found within 1.5 interquartile ranges from these percentiles, and values beyond that range are considered outliers. The scales on the y-axes have been adjusted for improved readability, in some cases leaving out outlier values. a IGF1-, gonadotropin, and albumin values. b Adrenal and thyroid axis values. BL, baseline; TSH, thyroid-stimulating hormone; fT4, free thyroxine; SHBG, steroid hormone binding globulin; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

Fig. 4

Box plot illustrating the relationship between percent change in IGF-1 from baseline and the number of treatment cycles received. p = 0.008 (mixed model analysis). IGF-1, insulin-like growth factor 1.