Risk of developing hypothyroidism with the use of tyrosine kinase inhibitors and immune checkpoint inhibitors

1Background

The paradigms of cancer treatment have evolved from relatively nonspecific cytotoxic agents to selective mechanism-based therapeutics. The survival rate of patients with cancer has been increasing because of the sustained anticancer effect of new drugs, such as immune checkpoint inhibitors (ICI), and the development of chemotherapy [12] . Many patients receive ICI in combination with other immunotherapy, cytotoxic chemotherapies, or targeted therapies to increase the effect [3] . Several clinical trials have been conducted on the effectiveness of immunotherapeutic agents with various combination strategies with targeted agents in various carcinomas 4567 . As a result, more patients with cancer are now eligible to receive immunotherapy in combination with other agents.

The side effects of immunotherapy are important to manage. With the significant reduction of side effects, such as hair loss, nausea, vomiting, anorexia, stomatitis, and diarrhea, of cytotoxic and targeted chemotherapy, the side effects related to immune system disturbance have emerged. In a study [8] on 3803 patients who received immunotherapy, hypothyroidism (5.6 %), pneumonia (2.2 %), enteritis (0.7 %), hepatitis (0.2 %), and pituitary infection (0.3 %) occurred. Some side effects of existing cytotoxic chemotherapies, such as fatigue (32 %), diarrhea (19 %), and rash (10 %), were also reported. Immunotherapy has a very long memory for T cells, and adverse reactions may occur at the beginning and late phase of treatment [9] . Therefore, the observation period for side effects is about 10 weeks longer for immunotherapy than for other drugs [10] . Combining immunotherapy with cytotoxic or targeted chemotherapy is more likely to cause side effects. Drug-related hypothyroidism is not limited to immunotherapy but is also a significant side effect of angiogenesis inhibitors (AI). There had been concerns on the increased risk of hypothyroidism in patients receiving AI and immunosuppressants [11] .

However, studies that investigated the incidence of hypothyroidism after ICI in the clinical setting had been limited. In addition, comparative studies on hypothyroidism following administration of ICI alone and in combination with other drugs are scarce. Therefore, we investigated the incidence of hypothyroidism after ICI in patients with cancer using a national population-based database. We further assessed whether there was an additional risk of developing hypothyroidism in patients who have received AI, which is well-known to lead to thyroid dysfunction, compared with using ICI alone.