Immunotherapy-Induced Thyroid Dysfunction - An Overview

Introduction:

Drugs like Pembrolizumab and Nivolumab have been in use for several years in treating various cancer types and have been successful in treating patients suffering from lung cancer and melanoma (a serious skin cancer). However, with time, increased side effects have cropped up with the usage of these drugs. In a study involving 1,146 participants who received checkpoint immunotherapy drugs for cancer, it was found that about 19 percent of patients had thyroid dysfunction. Of these, 13.4 percent had hypothyroidism (low levels of thyroid hormones), while 9.5 percent had hyperthyroidism (elevated levels of thyroid hormones). A few patients initially developed hyperthyroidism before experiencing hypothyroidism.

How Did the Side Effects of Immunotherapy Emerge?

Immune checkpoint inhibitors or immunotherapy work by assisting the immune system in identifying and attacking the cancer cells. An advantage of immunotherapy is that they have less harsh side effects when compared to radiation and chemotherapy (a drug treatment involving the use of powerful chemicals to kill rapidly-growing cancer cells), which can have a miserable effect on patients receiving cancer treatment.

With the advent of more immunotherapy drugs in the market and their use in the real world, more information about their side effects is being reported. Side effects may be higher in clinical use than in clinical trials since a few types of patients are prohibited from participating. However, in clinical use, the restrictions on who can receive these drugs are less. It is given to individuals with other health issues as well. The use of these drugs in a broader population has been associated with increased and new side effects.

Why Is the Thyroid Gland Sensitive to Immunotherapy?

The thyroid gland is sensitive to immunotherapy due to the following probable reasons:

• Although the exact reason why thyroid issues emerge so commonly in patients under immunotherapy is not known, one possible explanation could be that a few individuals may have mild undiagnosed thyroid dysfunction before they were diagnosed with cancer. The immune checkpoint inhibitors could trigger an underlying predisposition to thyroid problems.

• Other medications taken by cancer patients could also hinder normal thyroid function. For instance, patients with renal (kidney) cell carcinoma usually take a kinase inhibitor that could result in thyroid dysfunction.

• Immunotherapy or immune checkpoint inhibitors (ICIs) are usually harmless, but little evidence shows that they may trigger an autoimmune reaction in the thyroid gland that may disrupt the delicate balance of immune cells or disturb the manufacturing of cross-reactive cancer cell antigens.

• They may also alter thyroid-related gene expression, resulting in hypothyroidism. Studies are underway to determine whether certain risk factors like high blood pressure (hypertension), history of smoking, or opioid use could result in immunotherapy-induced thyroid dysfunction.

• Another study found that immunotherapy-induced thyroid dysfunction can be due to hereditary factors.

• Thyroid issues may be more prevalent in individuals suffering from certain types of cancer. For instance, thyroid dysfunction was noticed in 10 percent of patients with glioblastoma (a type of brain tumor) when compared to 40 percent of patients with renal cell carcinoma. More research is necessary to analyze why individuals with certain types of cancers are more likely to develop thyroid issues when receiving immunotherapy.

What Are the Clinical Manifestations of Immunotherapy-Induced Thyroid Dysfunction?

The following are some of the clinical manifestations:

• Weight gain.

• Changes in heart rate.

• Fatigue.

• Thyroid-hormone abnormalities.

Hence, patients receiving immunotherapy should be monitored carefully. The time of onset of thyroid dysfunction can vary in different patients. In a majority of reported cases, the time of onset is within the first 15 weeks of therapy, but the issue can emerge as early as seven days or even after three years in a few cases. The time of onset is short with combined immunotherapy when compared with monotherapy. Most cases of hypothyroidism are permanent and may need long-term replacement therapy with Levothyroxine.

What Are the Possible Risk Factors of Thyroid Dysfunction Induced by Immunotherapy?

The possible risk factors are as follows:

• Women: Women may be more susceptible to developing thyroid dysfunction than men. This could probably be attributed to sex-specific autoimmunity or sex-hormone-mediated immune regulation.

• Advanced Age: Advanced age may also pose a risk factor for severe thyroid dysfunction, which could result in increased risk of hospitalization, morbidity, and death.

• Elevated Body Mass Index: Elevated body mass index may be linked with early manifestation of symptoms, increased risk, and overt hyperthyroidism.

• Use of Tyrosine Kinase Inhibitor: Use of tyrosine kinase inhibitor may increase the risk of immunotherapy-induced thyroid dysfunction, but it can also independently cause thyroid dysfunction.

• Type of Agent Used: The manifestation of thyroid dysfunction is strongly associated with the type of agent and whether it is given as combined therapy or monotherapy.

How Can Immunotherapy-Induced Thyroid Dysfunction Be Treated?

Immunotherapy-induced thyroid dysfunction can be treated in the following ways:

• The treatment protocol requires a multidisciplinary approach. According to the ESMO (European Society for Medical Oncology) guidelines, in patients with thyroid dysfunction, immunotherapy should be delayed until the symptoms improve.

• Beta-blockers, radioactive iodine, and antithyroid drugs can be used to treat hyperthyroidism. Hypothyroidism is usually treated with Levothyroxine. Even Propranolol and Atenolol can be used to treat hyperthyroidism. These medications offer long-term advantages in managing the symptoms and improving tolerance to immunotherapy.

• It is necessary for all treating healthcare professionals of cancer patients to have a high level of clinical suspicion and focus on multidisciplinary team discussion in managing cancer patients receiving immunotherapy and displaying endocrine issues.

How Can the Thyroid Gland Be Protected From Immunotherapy?

Cancer patients can experience insomnia (difficulty falling and staying asleep), weight loss, and atrial fibrillation (irregular and rapid heart rate) as a result of hyperthyroidism, constipation, and fatigue due to hypothyroidism.

It is recommended that oncologists (professionals who treat cancer) carry out thyroid function tests before initiating immunotherapy. One study has found that if the thyroid function is slightly abnormal prior to immunotherapy, then there is an increased probability of developing thyroid dysfunction later. Usually, oncologists treat thyroid issues that emerge during cancer treatment, but it is better to be cautious before initiating immunotherapy. Extra support from endocrinologists (professionals who treat problems in the glands and hormones produced by them) would be beneficial.

Conclusion:

Though immunotherapy has few benefits when compared to radiation therapy and chemotherapy, thyroid dysfunction can occur as a side effect of immunotherapy. This should be managed carefully through a multidisciplinary approach involving primary care physicians, oncologists, and endocrinologists. Some of the recommended treatment options to deal with thyroid dysfunction include antithyroid drugs, beta-blockers, hormone replacement therapy, or radioactive iodine. Thyroid dysfunction can be diagnosed and monitored by thyroid ultrasonography, inflammatory markers, radioactive uptake scan, biomarkers, and PET-CT (positron emission tomography-computed tomography) scan.