Immune checkpoints inhibitors have fundamentally changed the management of oncologic patients. These treatments consist of monoclonal antibodies directed against CTLA-4 (cytotoxic T-lymphocyte antigen 4), PD-1 (programmed cell death protein-1) and PD-L1 (one of its ligands). By blocking these receptors or ligands, the antibodies reverse the immune tolerance induced by the cancerous cell on the T-lymphocyte and favour lymphocytic reactivation and anti-tumor activity. Immune tolerance to auto-antigens is maintained with the help of these checkpoints. Targeting them can lead to auto-immune side effects. These latter mostly impact the cutaneous and digestive system, but the endocrine glands are not spared.
Aim of the work: The aim of this retrospective study was to establish the prevalence and characteristics of endocrine immune-related adverse events in order to provide monitoring and treatment algorithms.
Methods: We identified patients who developed biological hormonal anomalies during their immunotherapy treatment at Liège University Hospital. We collected data regarding the types of cancers treated with immunotherapy, the treatments administered, the time to onset of adverse events and their clinical presentation. We also recorded information on the treatment of these side effects and their evolution.
Results: 1277 patients were identified from the electronic medical records, with keywords corresponding to the names of the different immunotherapies. Of these patients, 434 were actually treated with the molecules of interest between the 1st of January 2009 and the 31st of December 2018. 113 patients with biological anomalies compatible with endocrine immune-related adverse events were found. Thyroid function anomalies and hypophysitis were the most frequent endocrine side effects. No cases of adrenalitis, autoimmune diabetes or parathyroiditis were identified. In our study population, 22.3% of patients (97/434) presented an alteration of the thyroid function. It was more frequent with combined treatments (47.3% of the patients on anti-CTLA-4 and anti-PD-1) and with anti-PD-(L)1 molecules (20.1%). Hypothyroidism can occur following transitory hyperthyroidism. Hypophysitis was shown in 5.3% of patients (23/434). It was mostly due to combined treatment (36.8% of the patients treated with the association) and to anti-CTLA-4 therapies (7.7%). Pituitary damage led to hormonal deficiency. Central adrenal insufficiency was observed in 73% of these patients followed in frequency by hypogonadotropic hypogonadism (56.5%) and central hypothyroidism (30.4%). Recovery of the thyroid and gonadal axes was encountered in 57 and 46% of cases respectively. The recovery is inconstant and does not depend on the administration of systemic glucocorticoids.
Conclusions: Endocrine immune-related adverse events are frequent and can be severe. An early diagnosis and, consequently, the appropriate management would help reduce the morbidity, sometimes even the mortality and would allow to pursue the immunotherapy.
21 Oct 2019
Belgian Endocrine Society