Immunotherapy-Associated Hypothyroidism: Comparison of the Pre-Existing With De-Novo Hypothyroidism

Abstract

BackgroundImmunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism.MethodsA retrospective analysis was conducted using patients who received immunotherapy between 2010‐2019 within a multicenter hospital system. Participants were separated in three groups—those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated.Results822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6‐8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009).ConclusionIt is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg.

Case Report: First-Line Immunotherapy for Esophageal Squamous Carcinoma Combined With Hypopharyngeal Squamous Carcinoma Yields Sustained Survival Benefit

“…Although the mechanism of immunotherapy-related adverse events is not clear, studies believe that this is an autoimmune reaction after blocking the normal immune regulation pathway, common adverse reactions are endocrine system-related adverse reactions, including immune-related thyroid toxicity, hypophysitis, adrenal insufficiency and diabetes, etc, the most common occurrence is immune-related thyroid toxicity, including thyrotoxicosis, hypothyroidism and thyroiditis. Hypothyroidism generally occurs around 10-20 weeks after receiving immunotherapy and is defined as high thyroid stimulating hormone(TSH) with low Free T4 (FT4) or total T3 (TT3) ( 32 ). In this patient, an immune-related adverse reaction event-hypothyroidism inevitably occurred after treatment, but it appeared later.…”

Immunotherapy-Related Hypothyroidism: Mechanisms and Management

“…Immunotherapy-related thyroiditis is painless, and the thyrotoxicosis phase, if occurs, is much shorter (approximately 3 months) compared to other thyroiditis [8]. Thyroid toxicity especially hypothyroidism is much more common in patients on PD-1 inhibitors than CTLA-4 and PD-L1 monotherapies [23][24][25][26]. Osorio et al included 35 clinical trials in a meta-analysis, with a total of 7318 patients, and the incidence of thyroid dysfunction was significantly higher in melanoma patients treated with anti-PD-1 (7.5%) than in those treated with anti-CTLA-4 antibody (3.6%), while no thyroid dysfunction was observed with anti-PD-L1 agents [22].…”

“…Primary hypothyroidism usually appears after 10 or 20 weeks of ICI treatment [11,12]. In the study where 822 patients treated by ICIs were investigated, de novo hypothyroidism occurred as early as 2 weeks [24][25][26]32]. The need for change in the levothyroxine replacements dose in patients with pre-existing hypothyroidism occurred later in the course, approximately in the 6th week.…”

“…Maekura et al demonstrated that hypothyroidism developed in 44.0% of the patients with antibody positivity at baseline but in only 2.0% of the patients with negative antibody levels [36]. Studies suggest that pre-existing antibodies are risk factors for thyroid dysfunction [24][25][26]32]. Not all studies correlate antibodies with ICI-related hypothyroidism and not all patients with antibodies develop hypothyroidism.…”