In a real-world study of the use of immune checkpoint inhibitors (ICIs), approximately half of patients with advanced cancers developed thyroid dysfunction related to the cancer treatment within about a year; however, most cases were mild and were even associated with an increase in overall survival.
Nevertheless, with thyroid dysfunction rates notably higher than those reported in clinical trials, "the findings suggest that the incidence of immune thyroid dysfunction caused by ICIs in the clinical sphere may be underestimated," report the authors in research published recently in The Journal of Clinical Endocrinology and Metabolism.
The results underscore that "thyroid function in patients treated with immunotherapy should be monitored to detect immune thyroid dysfunction and permit early intervention," they add.
Commenting on the study, Jennifer S. Mammen, MD, PhD, said the findings are consistent with her experience that the thyroid side effects from ICIs typically are indeed manageable.
"Luckily, hypothyroidism is easy to treat and to get patients back on track with [cancer] therapy," said Mammen, of the Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University Medical Center, Baltimore, Maryland. "And it may even suggest a better prognosis, so I try to just help my patients past this bump in the road as quickly as possible by getting them treated and euthyroid and back on ICIs."
The association between ICIs and immune thyroid dysfunction has been consistently reported. However, most data detailing the effects come from pharmaceutical clinical studies that involved carefully screened participants.
Evaluation of Thyroid Dysfunction in Real-World Study
To evaluate the effects in a real-world population, Xiaoyang Lai and colleagues with the Department of Metabolism and Endocrinology at the Second Affiliated Hospital of Nanchang University, Nanchang, China, conducted a retrospective, case-control study in which they identified 560 patients who were treated with ICIs at their center between January 2019 and December 2021.
Most cancers were either of stage III (n = 145) or IV (n = 390), and most patients had received treatments such as radiotherapy, chemotherapy, or targeted drugs prior to treatment with ICIs. The patients were tested for thyroid function every 3 weeks.
The ICIs used in the study included programmed cell death protein–1 (PD-1) inhibitors sintilimab (n = 166), tislelizumab (n = 93), and camrelizumab (n = 175), which have all been approved in China but not yet in the US.
In the study, the incidence of thyrotoxicosis caused by ICIs was significantly lower than that of hypothyroidism, mainly because thyrotoxicosis occurs before hypothyroidism in immune thyroid dysfunction caused by ICIs and can eventually evolve into hypothyroidism, "and therefore cases of thyrotoxicosis may be missed in some clinical studies," the authors observe.
With a median follow-up of 11 months, the overall incidence of immune thyroid dysfunction was 50.7%. The rate of thyrotoxicosis-related dysfunction was approximately 18.8%, and the rate of hypothyroidism-related immune thyroid dysfunction was about 32.0%.
Of note, the prevalence reported in large phase 3 clinical trials of drugs targeting PD-1 and programmed cell death–ligand-1 inhibitors varied between 10% to 20% or lower, the authors report.
The median time to the development of thyroid dysfunction following initiation of ICI treatment was 73 days.
Overall, thyroid dysfunction cases were mild. The vast majority (95.8%) were of grade 1 or 2. The incidence of grade 3 thyroid dysfunction was 4.2%, and there were no thyroid-related adverse effects of grade 4 or higher.
The strongest factor associated with the development of immune thyroid dysfunction was having baseline thyroglobulin antibody abnormalities (odds ratio [OR], 67.393; P = .001).
The next strongest risk factors were baseline thyroid stimulating hormone levels (OR, 1.935/μIU/L; P < .001) and the receipt of combination targeted therapy (OR, 2.101; P < .001).
The highest incidence of thyroid effects was associated with the use of the PD-1 inhibitor camrelizumab (58.3%).
Consistent with previous reports, the effects on the thyroid were associated with a paradoxical improvement in overall survival (hazard ratio [HR], 0.523; P < .001). The association between thyroid dysfunction and improved overall survival was consistent across types of thyroid dysfunction, including hypothyroidism (HR, 0.526; P < .001), thyrotoxic dysfunction (HR, 0.695; P = .005), and immune-related thyroiditis (HR, 0.330; P < .001).
It has been speculated that the improvement in survival is indicative of ICI activity, the authors note.
"[The improvement in survival] may be explained by the fact that when immune-related adverse reactions occur after treatment with ICIs, it indicates that the body's immune system has been effectively activated, thus allowing for better anti-tumor efficacy and possibly better patient prognosis," they explain.
In support of the theory is a 2022 study in which investigators reported that thyroid dysfunction that occurred with ICI treatment was an indicator of antitumor effects and that it can be used as a predictor of clinical response to therapy.
Guidelines Recommend Regular Monitoring of Thyroid Function With ICI Use
Nevertheless, guidelines from the American Society of Clinical Oncology/National Comprehensive Cancer Network (ASCO/NCCN) and the European Society of Medical Oncology (ESMO) recommend that thyroid function be followed up every 4–6 weeks for patients receiving immunotherapy to detect thyroid dysfunction at an early stage, likely before patients even have symptoms.
ASCO guidelines further recommend that patients who are taking ICIs and who develop thyrotoxicosis be closely monitored for thyroid function and that suspension of ICI therapy be considered until symptoms resolve. Patients should then be evaluated for reactivation of immunotherapy, the authors note.
Overall, "it can be presumed that thyroid-related adverse events occurring in patients treated with ICIs in clinical practice are not severe and are manageable with regular monitoring of thyroid function," they conclude.
However, they add: "For serious life-altering thyroid adverse events, NCCN guidelines recommend suspending ICIs therapy until symptoms resolve."
Mammen said the higher rates of thyroid dysfunction observed in this new real-world study could be caused by differences in how dysfunction is defined and how often patients are assessed.
In addition, the use of certain drugs and differences in population effects, such as iodine sufficiency in Asian populations, may limit generalizability to the US, she noted.
Either way, Mammen underscored, "my bottom line for patients [is that] out of all the targets of autoimmune disease, the thyroid is just about the easiest to deal with because we don't try to save it, just replace it and move on."
The authors have disclosed no relevant financial relationships.
J Clin Endocrinol. Published May 18, 2023. Abstract
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