UPDATES IN ENDOCRINE IMMUNE-RELATED ADVERSE EVENTS IN ONCOLOGY IMMUNOTHERAPY

Abstract

Immunotherapy in Oncology, a fundamental distinctive treatment in cancer patients, needs molecules with different mechanisms: immune checkpoint inhibitors (ICIs) who attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. Although their success in improving overall patient survival, unfortunately, superior clinical response of immunotherapy is often associated with treatment toxicity. European Society of Medical Oncology (ESMO) published in 2021 a comprehensive review of qualitatively resynthesized information on endocrinopathies after cancer immunotherapy with ICIs with practical recommendations for screening and management. Endocrinopathy such as thyroid dysfunctions, hypophysitis, primary adrenal insufficiency, type 1 diabetes mellitus, central diabetes insipidus, or hypoparathyroidism were reported and called immune-related adverse effects (irAEs). Practical guidelines for monitoring, diagnosis, and treatment of ICIs related endocrine toxicities are constantly updated. Given the increasing use of ICIs, cooperation between oncologists and endocrinologists is crucial in the management of oncologic patients.

INTRODUCTION

Since 2011, when the first Immune checkpoint inhibitor – Ipilimumab (1), was approved by the FDA for use in patients with melanoma – till October 2021, when the Committee for Medicinal Products for Human Use (2) (CHMP) adopted a positive opinion recommending Pembrolizumab (3) for a new indication in endometrial carcinoma, Immunotherapy in Oncology has become a fundamental distinctive treatment in cancer patients.

Usually, cancer cells hijack the immune checkpoints – inhibitory immune regulators assigned to ensure immune tolerance – in order to evade immune surveillance. Designated as a scientific breakthrough of the current decade, immune checkpoint inhibitors (ICIs) attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance.

The major team players in this field for adult patients are: Ipilimumab (1) (the only antibody anti-CTLA-4), Nivolumab (6) and Pembrolizumab (3) (anti-PD-1 antibodies, with the broadest area of indications and most widely used in clinical practice), Atezolizumab4, Avelumab (7) and Durvalumab (5) (anti-PD-L1 antibodies). As all of them finally “release the brakes of the immune system”, the differences in their mechanism of action explains the differences in the immune-related adverse events. Due to T-lymphocytes immune activation in an early education phase or priming phase in lymph nodes, Ipilimumab use is associated with a significant immune-related toxicities, greater than anti-PD-1/PD-L1 agents are used. On the other hand, programmed cell death-1 (PD-1) is a checkpoint inhibitor localized on activated T-lymphocytes, which is active in the effective immune phase on tumor cells and its metastasis. While anti-PD-1 agents block PD-1/PD-L1 and also PD-1/PD-L2 interactions, anti-PD-L1 antibodies block just PD-1/PD-L1 and not PD-1/PD-L2 interactions. Theoretically, autoimmune toxicity of anti-PD-L1 antibodies is less intense than anti-PD-1 agents, taking into consideration that PD-1/PD-L2 activity is still functional in immune homeostasis and in reducing the autoimmune reactions. Practically, updated systematic metanalysis do not reveal a frequency reduction of other immune-related adverse events, except immune-pneumonitis (8).

Although immunotherapy has been revolutionizing the management of advanced malignancies with their success in improving overall patient survival, unfortunately, superior clinical response is often associated with treatment toxicity called immune-related adverse effects (irAEs). Endocrinopathy has emerged as an important group of irAEs. Thyroid disorders typically associated with anti-PD-1 antibodies and hypophysitis commonly related to anti-CTLA-4 therapy, are the most frequent endocrine toxicities. ICI induced insulin-deficient diabetes mellitus and primary adrenal insufficiency, though rare, can be life-threatening if not promptly diagnosed and treated. The combination of anti-CTLA-4 and anti-PD-1 treatment has generally been associated with the highest incidence and severity of ICI-induced endocrinopathies. Considering the growing population of patients receiving immunotherapy with increasingly broad indications, a rising number of patients with endocrine irAEs should be expected in the near future. Additionally, new endocrine irAEs, such as primary hypoparathyroidism, acquired generalized lipodystrophy, and autoimmune polyglandular syndrome, have been described recently (9).

Importantly, whilst most irAE’s are reversible with prompt treatment cessation and glucocorticoids treatment, endocrinopathies usually persist and often require lifelong hormonal replacement. Untreated endocrinopathy can be life threatening (10). Some endocrinopathies, such as thyrotoxicosis, may be transient and resolve spontaneously after only monitoring or symptom control, whereas others, such as central adrenal insufficiency, primary hypothyroidism, or insulin-deficient diabetes, are persistent and require appropriate lifelong hormonal replacement. Endocrine toxicity is difficult to diagnose, because most symptoms, such as nausea, vomiting, appetite loss, weight loss, general weakness, fatigue, mild cognitive dysfunction hypotension, and headache, are nonspecific. Besides, the symptoms are similar to cancer progression or brain metastasis, resulting in delayed diagnosis. Delayed diagnosis can lead to fatal side effects, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis (11). Therefore, clinicians need to be vigilant to ensure rapid recognition and treatment, especially in those individuals with increased risk of autoimmune reactions.

European Society of Medical Oncology (ESMO) published this year a comprehensive review of qualitatively resynthesized information on endocrinopathies after cancer immunotherapy with ICIs. Besides clinical characteristics, frequency events, possible pathogenesis, the guide offers insightful practical recommendations for screening and management (12). All patients that will be initiated on ICIs, should benefit from a distinctive baseline endocrine assessment, including clinical evaluation for symptoms (extreme weakness, unusual headache patterns, vision changes, increased sweating, rapid heartbeat, weight loss or weight gain, mood changes, constipation or diarrhea, deepening of the voice, changes in urination, polydipsia, extreme or low hunger, nausea or vomiting, abdominal pain) and laboratory tests (morning TSH, FT4, cortisol, glucose, electrolytes). Routine oncological practice supervise patients on ICIs immunotherapy every 4-6 weeks (sometimes even before each administration) and also 4-6 weeks after the last cycle. In case of endocrinopathy suspected, additional tests are performed, as followed:

- Anti-TPO (thyroid peroxidase) and anti-TG (thyroglobulin) antibodies in case of hypothyroidism;

- T3 (triiodothyronine), TSH (thyroid stimulating hormone), FT4 (free thyroxine) every 2-3 weeks to diagnose persistent hyperthyroidism or hypothyroidism (due to destructive thyroiditis) if hyperthyroidism suspected; additional TRAb (TSH receptor antibodies), TSI (thyroid stimulating immunoglobulin) might help;

- ACTH (adrenocorticotropic hormone), ACTH stimulation (250μg i.v.), adrenal CT if primary adrenal insufficiency is suspected in low cortisol levels;

- ACTH, LH (luteinizing hormone), FSH (follicle stimulating hormone), testosterone (men) or E2 (estradiol) if hypophysitis is suspected; PRL (prolactin), IGF-1 (insulin-like growth factor 1) can also be measured; In multiple endocrine abnormalities, headaches or visual defects is useful to perform a pituitary IRM, if available. Diabetes insipidus is rare, but monitoring is important in some cases;

- In case of hyperglycemia is useful to test pH, urine ketones, autoantibodies (GADA- glutamic acid decarboxylase autoantibodies, IA2- islet autoantibodies, IAA- insulin autoantibodies, anti-ZnT8), C peptide.

Endocrine complications, after ICIs specifically, are categorized in five grades, in order of increasing toxicity: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening) and grade 5 (death). In general, grade 4 toxicities warrant permanent discontinuation of ICIs. However, endocrinopathies that are well controlled by appropriate hormone replacement are an exception to this rule, indicating the importance of early identification and treatment of these complications. Of course, holding ICI treatment until the patient is stabilized on hormone replacement, especially in the case of adrenal insufficiency, is often necessary. To summarize the practical measures for medical care it is important to emphasize that patients, family members or physicians that take care of these patients should receive early and detailed education about the clinical profile of possible endocrine complications of ICIs prior to initiation and throughout treatment, ideally by a joint team of oncologists and endocrinologists.

Interestingly, the presence of certain irAEs, such as thyroid dysfunctions and hypophysitis, is associated with significant improvement in clinical outcomes in cancer patients, that is, longer median progression free survival and overall survival (13,14). On the other hand, there could be a potential negative effect of high-dose GCSs on ICI treatment efficacy (15).

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with ICI are currently studied. In order to identify individuals who are susceptible to irAE, thyroid dysfunction specifically, for earlier diagnosis and appropriate follow-up, there is a published study that aimed to investigate biomarkers of thyroid irAE. There was no association of thyroid peroxidase (TPO) antibody titer with the occurrence or time to occurrence of thyroid IRAEs. On subgroup analysis, the TPO antibody titer was higher in patients with new-onset overt hypothyroidism and in those treated with thyroid hormone replacement than in those with subclinical hypothyroidism and in those managed with observation, respectively. These findings suggest that elevated TPO antibodies may not be very helpful for identifying those at risk of thyroid irAEs; however, elevated TPO antibodies at the time of thyroid irAEs might influence the severity of thyroid dysfunction, thus helping identifying patients who will progress to overt hypothyroidism and require thyroid hormone replacement (16).

As discussed above, the presence of irAEs is associated with a better response to immunotherapy. The association with a favorable response is even stronger in patients with radiologic manifestations of the immune-mediated adverse reactions. There has been reported a significant association between the onset of radiological manifestations of irAEs and disease control compared to irAEs without radiological expression. Similarly, the rate of favorable response was significantly higher in patients with irAEs, irrespective of whether or not they had radiological expression. Therefore, the onset of irAEs may indicate that the immune response has initiated and may be an indirect marker of response to immunotherapy (17).

Considering the ability of 18F-FDG PET/CT to detect autoimmune thyroiditis, diffuse 18F-FDG uptake in the thyroid could be used to predict treatment response and prognosis in oncological diseases after immunotherapy. Thyroiditis may be an adverse event in patients treated with immunotherapy and may be detected by 18F-FDG PET/CT; in fact, several patients treated with immunotherapy may show diffuse increased 18F-FDG uptake in the thyroid both during and after immunotherapy due to autoimmune thyroiditis. The normal thyroid gland usually shows low fluorine-18 fluorodeoxyglucose (18F-FDG) uptake and is usually not clearly visualized on whole-body maximum-intensity projection images. Despite this, the diffusion of 18F-FDG PET/ CT as a diagnostic tool for staging, restaging, and prognostic purposes, both in oncological and non-oncological settings, has increased the number of incidental findings detected by this imaging method. The mechanisms underlying18F-FDG uptake in thyroiditis are not yet known. One explanation could be the uptake of 18F-FDG in an activated lymphocyte infiltrate within the thyroid gland. In fact, inflammatory cells show increased expression of glucose transporters (GLUTs) when activated. The result of inflammatory reactions might affect thyroid uptake of 18F-FDG in thyroiditis (18).

Last, but not least, there is data proving that patients who developed thyroid IRAEs had a lower mortality risk than those who did not. This suggests that thyroid IRAEs may be a biomarker for antitumor immune response. The hypothesis is that enhanced T cell function and signaling caused by PD-L1 inhibitors likely influence both the development of IRAEs and antitumor responses (19).

In conclusion, there is a relatively high risk of endocrine irAEs during therapy with checkpoint inhibitors, particularly when combination therapy is implemented. Patients treated with anti-CTLA-4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti-PD-1/PD-L1 antibodies have a higher risk of primary thyroid dysfunction. Rarely, patients develop type 1 diabetes mellitus, central diabetes insipidus, or hypoparathyroidism. A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement (20).

Practical guidelines for monitoring, diagnosis, and treatment of ICI related endocrine toxicities are constantly updated. As immunotherapy becomes widespread and approved for new malignancies, increased incidences of endocrine irAEs are expected in the future. Endocrinologists will often be requested to co-manage patients with endocrine irAEs and should be familiar with details specific to ICI induced endocrinopathies. Given the increasing use of ICIs, cooperation between oncologists and endocrinologists is crucial in the management of patients receiving the same. Establishing an appropriate diagnosis and adequate management may improve the prognosis of oncological patients suffering from immunotherapy-induced endocrinopathy.

Conflict of interest

The authors declare that they have no conflict of interest.