BACKGROUND
Immune checkpoint inhibitor (ICI) drugs are now standard-of-care treatments for several types of cancer, including melanoma and kidney cancer. ICI drugs have been shown to significantly prolong patient survival. These cancer drugs help the body recognize cancer and use the immune system to attack and destroy cancer cells. In addition to attacking the cancer cells, some normal cells can be attacked, causing complications known as immune-related adverse events (IrAEs).

The thyroid is a common target for IrAEs, occurring in more than 10% of patients. While a classical inflammation known as a thyroiditis seems to most common, virtually all types of thyroid autoimmune disease patterns have been reported. Thyroiditis is an inflammation of the thyroid, most commonly caused by antibodies that attack the thyroid. It usually begins with a period of increased thyroid function tests (thyrotoxicosis) followed by a period of hypothyroidism followed by the return to normal thyroid function. Interestingly, several prior studies have suggested that the development of thyroid IrAEs might be associated with improvements in survival related to ICI therapy. In the current study, the investigators sought to characterize thyroid IrAEs related to ICI treatment in a large group of patients with melanoma and to investigate associations with survival.

THE FULL ARTICLE TITLE
Muir CA et al 2021 Thyroid immune-related adverse events following immune checkpoint inhibitor treatment. J Clin Endocrinol Metab 106:e3704–e3713. PMID: 33878162.

SUMMARY OF THE STUDY
This study was conducted of adult patients undergoing ICI treatment for melanoma between 2009 and 2019 in an Australian population. Serum TSH measurements were performed in all subjects prior to ICI initiation and repeated at 3- to 4-week intervals for a minimum of 6 months. After 6 months, testing occurred every 6 to 8 weeks for 6 months and then every 12 weeks after 1 year.

There were 1246 patients in the study with an average age of 65 years; 34% were female. Average follow-up was 11.3 months for the group. Thyroid IrAEs occurred in 518 patients (42%) and IrAEs affecting other tissues occurred in 69% of patients. The most common category of thyroid problems was increased thyroid function tests (thyrotoxicosis), affecting 388 patients (31% of the group and 75% of thyroid IrAEs). There were 234 subclinical and 154 overt thyrotoxicosis cases. Both overall thyroid IrAEs and overt thyrotoxicosis were 2.2-times more common in women. Of the patients with subclinical thyrotoxicosis, 97% returned to normal thyroid function during follow-up, whereas only 57% of those with overt thyrotoxicosis returned to normal thyroid function. Hypothyroidism occurred in 100 patients (8% of the group). None of the patients developed thyrotoxicosis that persisted beyond the end of follow-up. More overall thyroid IrAEs, in particular overt thyrotoxicosis, were observed when 2 ICI drugs were used together (47% for combination ICI therapies vs. 19-37% ICI drugs used alone).

While cancer death did not differ between patients with or without thyroid IrAEs as a group, patients with overt thyrotoxicosis had longer overall survival and longer survival without the cancer progressing. No survival benefit was seen with overt hypothyroidism.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study shows that thyroid problems are common in cancer patients treated with ICI drugs. Overt thyrotoxicosis due to thyroiditis is the most common thyroid problem. Further, this may be a good sign that may indicate a much better immune response to ICI drugs, leading to improved cancer survival outcomes.

— Alan P. Farwell, MD

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