Overview of Immune-related Endocrine Toxicities in NSCLC

Overview of Immune-related Endocrine Toxicities in NSCLC

Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, representing a significant public health challenge due to its high mortality rate (Zhang et al., 2023). Recent advancements in immunotherapy, particularly the use of immune checkpoint inhibitors like pembrolizumab, have transformed treatment paradigms, leading to improved survival outcomes for many patients (Zhang et al., 2023). However, the introduction of immunotherapy has also brought about new sets of complications, notably immune-related adverse events (irAEs). Among these, immune-related endocrine toxicities (E-irAEs) have garnered considerable attention due to their prevalence and potential impact on patient quality of life and treatment adherence.

E-irAEs can manifest across various endocrine glands, including the thyroid, adrenal glands, and pancreas. Thyroid dysfunction is particularly common, with studies demonstrating that up to 30% of patients receiving pembrolizumab experience thyroid-related side effects (Zhang et al., 2023). Irrespective of the specific gland affected, these toxicities can lead to significant clinical complications, including metabolic derangements, fatigue, and diminished overall well-being, necessitating a comprehensive understanding of their management.

Risk Factors Associated with Immune-related Endocrine Toxicities

Identifying risk factors for E-irAEs is crucial for early detection and management. Several studies have highlighted specific demographic and clinical characteristics that may predispose patients to develop these toxicities. According to a multicenter retrospective study, the monocyte-to-lymphocyte ratio (MLR) and the presence of autoantibodies, particularly thyroid peroxidase (TPOAb) and thyroglobulin (TGAb), have been identified as significant predictors of immune-related thyroid dysfunction (Zhang et al., 2023).

In the context of NSCLC patients treated with pembrolizumab, it was found that low MLR (OR = 0.060, 95% CI 0.000-0.375; p = 0.015) and positive TGAb (OR = 31.898, 95% CI 1.516-671.367; p = 0.026) at baseline are associated with an increased likelihood of developing thyroid dysfunction (Zhang et al., 2023). Furthermore, demographic factors such as sex have also been implicated, with male patients potentially benefiting more from the development of irTD, correlating with improved progression-free survival (PFS) outcomes (Zhang et al., 2023).

Table 1: Clinical Characteristics and Risk Factors for E-irAEs

Impact of Pembrolizumab on Patient Outcomes and Endocrine Function

Pembrolizumab has been associated with favorable outcomes in advanced NSCLC. The KEYNOTE-024 trial demonstrated that pembrolizumab significantly improves overall survival compared to chemotherapy in patients with high PD-L1 expression (Reck et al., 2016). However, this benefit does not come without risks, particularly the development of E-irAEs, which can complicate treatment regimens and affect patient compliance.

The relationship between E-irAEs and treatment efficacy has been a focal point of recent research. In a study involving 380 NSCLC patients treated with pembrolizumab, those who developed immune-related thyroid dysfunction exhibited a notably longer PFS compared to those who did not (44.72 weeks vs. 27.79 weeks, HR = 0.645, 95% CI 0.440–0.946; p = 0.025) (Zhang et al., 2023). This correlation suggests that while E-irAEs represent significant treatment-related challenges, they may also serve as indicators of positive therapeutic responses in certain patient populations.

Clinical Implications of Thyroid Dysfunction in Cancer Therapy

Thyroid dysfunctions following immunotherapy can take various forms, including hypothyroidism, hyperthyroidism, and thyroiditis. The clinical implications of these endocrine toxicities are multifaceted. Patients often experience symptoms such as fatigue, weight changes, and mood disturbances, which can significantly impair their quality of life and complicate cancer treatment protocols.

Monitoring thyroid function is essential for patients undergoing treatment with pembrolizumab. Regular screening for thyroid-stimulating hormone (TSH), free thyroxine (FT4), and thyroid autoantibodies can facilitate early detection and management of thyroid dysfunction, ultimately improving patient outcomes (Zhang et al., 2023). It is critical that healthcare providers are aware of these potential toxicities, as timely interventions—such as initiating hormone replacement therapy for hypothyroidism—can mitigate the adverse effects associated with E-irAEs.

Table 2: Summary of Thyroid Dysfunction Types and Management Strategies

Strategies for Monitoring and Managing Endocrine Adverse Events

Effective management of E-irAEs in NSCLC patients involves a multifaceted approach that includes proactive monitoring, patient education, and collaborative care among oncology and endocrinology specialists. Key strategies include:

1. Regular Screening: Patients on pembrolizumab should undergo regular thyroid function tests (TFTs) every 6-12 weeks during treatment, or sooner if symptoms arise (Zhang et al., 2023).

2. Patient Education: Educating patients about the signs and symptoms of endocrine dysfunction can empower them to seek assistance early, which is crucial for effective management.

3. Interdisciplinary Collaboration: Close collaboration between oncologists and endocrinologists can facilitate the timely management of E-irAEs, ensuring that patients receive comprehensive care tailored to their unique needs.

4. Personalized Treatment Plans: Developing personalized treatment plans that take into account the risk factors for E-irAEs can help mitigate their impact on patient outcomes.

5. Utilizing Emerging Therapies: Awareness of emerging treatments and clinical trials for patients experiencing severe E-irAEs can provide additional options for management and care.

Table 3: Recommended Monitoring Schedule for Thyroid Function in NSCLC Patients on Pembrolizumab

Frequently Asked Questions (FAQ)

What are immune-related endocrine toxicities?

Immune-related endocrine toxicities (E-irAEs) are adverse effects that occur when the immune system inadvertently attacks endocrine glands, leading to hormonal imbalances. Common manifestations include thyroid dysfunction, adrenal insufficiency, and diabetes mellitus, often associated with immunotherapy treatments like pembrolizumab.

How common are these toxicities in NSCLC patients?

The incidence of E-irAEs in NSCLC patients receiving pembrolizumab can be as high as 30%, with thyroid dysfunction being the most prevalent form (Zhang et al., 2023).

What should I do if I experience symptoms of thyroid dysfunction while on pembrolizumab?

If you experience symptoms such as fatigue, weight changes, or mood disturbances, it is crucial to report these to your healthcare provider promptly. Regular monitoring of thyroid function can help in the early detection and management of these toxicities.

Are there specific risk factors for developing E-irAEs?

Yes, certain risk factors, including baseline monocyte-to-lymphocyte ratio (MLR) and positive thyroid autoantibodies, have been identified as significant predictors of developing immune-related thyroid dysfunction (Zhang et al., 2023).

How are E-irAEs managed in practice?

Management involves regular monitoring of hormone levels, patient education on recognizing symptoms, and timely interventions such as hormone replacement therapy for hypothyroidism or other supportive measures for managing symptoms.

References

1. Zhang, H., Zheng, J., Ren, C., Ye, C., Wu, X., Lv, X., Li, Y., & Zhou, J. (2023). Risk factors of immune-related endocrine toxicities in non-small cell lung cancer patients treated with pembrolizumab and its impact on patient outcomes: a multicenter retrospective study. BMC Pulmonary Medicine, 23(1), 47. https://doi.org/10.1186/s12890-025-03570-8

2. Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Gottfried, M., Peled, N., Tafreshi, A., & Cuffe, S. (2016). Pembrolizumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New England Journal of Medicine, 375(18), 1823-1833

3. Dall’Olio, F. G., Rizzo, A., Mollica, V., Massucci, M., Maggio, I., & Massari, F. (2021). Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis. Immunotherapy, 13(3), 257-270

4. Pollack, R., Ashash, A., Cahn, A., Rottenberg, Y., Stern, H., & Dresner-Pollak, R. (2020). Immune checkpoint inhibitor-induced thyroid dysfunction is associated with higher body mass index. Journal of Clinical Endocrinology & Metabolism, 105(10), 3704-3713

5. Muir, C. A., Menzies, A. M., Clifton-Bligh, R. J., Tsang, V. H. M. (2021). Thyroid immune-related adverse events following immune checkpoint inhibitor treatment. Journal of Clinical Endocrinology & Metabolism, 106(9), e3704-e3713