Endocrine dysfunction induced by anti-PD-1 antibody and tyrosine kinase inhibitor in a pediatric patient with renal cell carcinoma

Abstract.

In recent years, the use of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has increased and has demonstrated excellent antitumor effects. However, immunotherapy in pediatric patients remains limited, and knowledge of endocrine-related adverse effects is scarce. Here, we report a pediatric case of hypothyroidism and adrenal insufficiency following treatment with a combination of ICI and TKI for renal cell carcinoma. Seven weeks after treatment initiation, laboratory tests revealed free thyroxine at the lower limit of the reference range (fT4 0.96 ng/dL) and elevated thyroid-stimulating hormone (TSH 20 µIU/mL), without clinical symptoms, consistent with hypothyroidism. Three months after treatment initiation, abnormally high early morning fasting ACTH levels were observed, and the patient subsequently developed nausea and fatigue. A rapid ACTH stimulation test revealed a peak cortisol level of 12.1 µg/dL, and urinary free cortisol was low (19.2 µg/d; 13.6 µg/m²/d), leading to a diagnosis of primary adrenal insufficiency. Hormone replacement therapy enabled the patient to continue the treatment. Given the limited number of reports on endocrine dysfunction in pediatric patients receiving combination therapy with ICIs and TKIs, this case highlights the importance of endocrine monitoring and management.

Highlights

● ICI/TKI therapy is associated with endocrinopathies in pediatric patients.

● Regular monitoring is essential to detect ICI/TKI-induced endocrinopathy.

Introduction

In recent years, indications for molecular targeted therapy using immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have expanded. Although these drugs have excellent antitumor effects, specific adverse events, including endocrine dysfunction, are well-known complications in adults (1, 2).

Currently, ICIs such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors or their ligands, and programmed cell death ligand 1 (PD-L1) inhibitors are approved for the treatment of various advanced tumors. Immune checkpoint molecules, such as CTLA-4 and PD-1, are negative regulators of the immune system expressed on T cells. Tumors exploit these mechanisms to escape host immune surveillance (3). Although ICIs block this inhibitory pathway and activate tumor immunity, resulting in an antitumor effect, they also interfere with the important roles of these molecules in maintaining immunological tolerance to self-antigens. This can result in autoimmune reactions known as immune-related adverse events (irAEs) in off-target organ systems (4). In adults, endocrine disorders reported as irAEs include hypophysitis, primary adrenal insufficiency, diabetes, and thyroid dysfunction (hypothyroidism and hyperthyroidism) (4, 5). Thyroid dysfunction is associated with the presence of antithyroid peroxidase and antithyroglobulin antibodies and is attributed to destructive thyroiditis (5, 6).

Over the past two decades, TKIs targeting a wide range of kinases, such as vascular endothelial growth factor receptor (VEGFR), have been developed (7, 8). TKIs include single- and multi-target agents; multi-target agents can inhibit multiple signaling pathways, including VEGFRs, fibroblast growth factor receptors (FGFRs), and platelet-derived growth factor receptors (PDGFRs). By blocking the receptor tyrosine kinases and intracellular kinases involved in cell proliferation and tumor neoangiogenesis, these drugs have contributed to advances in cancer therapy, improving efficacy and safety (7, 8). However, reports of TKI-induced adverse events, including endocrine dysfunction, are increasing (2, 8). Particularly, TKIs targeting VEGFRs are associated with a high risk of thyroid dysfunction (2, 9).

Recently, combination therapy with ICIs and TKIs has been used to treat malignant tumors and achieve synergistic effects. Although this approach is associated with a higher incidence of adverse events compared with that observed for monotherapy in adult patients (10), data on pediatric patients receiving combination therapy are limited.

Here, we report the case of a 13-yr-old boy with stage IV renal cell carcinoma who developed hypothyroidism and adrenal insufficiency after combination therapy with ICI (anti-PD-1 antibody) and TKIs, along with a review of the literature.

Case Presentation

A 13-yr-old Japanese boy presented to an orthopedic surgeon with sudden-onset back pain. Computed tomography (CT) revealed bilateral renal tumors, pulmonary metastases, and multiple spinal metastases (Fig. 1). He also experienced bilateral lower limb pain due to spinal cord compression. After initiating oral dexamethasone (DEX) treatment (45 mg/d), the patient was referred to our hospital for further management. Blood tests performed at the time of transfer are summarized in Table 1. Cortisol and adrenocorticotropic hormone (ACTH) levels were suppressed by DEX administration, and thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and insulin-like growth factor 1 (IGF-1) levels were low. At that time, the testicular volume was 10 mL, with Tanner stage III for genital development and stage I for pubic hair development. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone concentrations were also suppressed and considered low relative to the pubertal stage. Histopathological evaluation confirmed the diagnosis of stage IV renal cell carcinoma, and treatment with lenvatinib, a multi-target TKI, was initiated. After completing a 1-mo course of DEX (45 mg/d for the first 12 days, followed by tapering until discontinuation), combination therapy with the anti-PD-1 antibody pembrolizumab was initiated. One month after treatment initiation, blood tests revealed that cortisol, ACTH, TSH, and fT3 levels had improved to within normal ranges (Table 1). Four months after treatment initiation, IGF-1 had improved to 337 ng/dL (+0.32 SD), LH to 5.4 mIU/mL, FSH to 9.0 mIU/mL, and testosterone to 735 ng/dL.

Fig. 1.

CT images of the tumor at diagnosis. Abdominal CT images (left panel: coronal section; right panel: axial section) showing cystic lesions and solid tumors with indistinct borders in both kidneys. The maximum diameter was 7.5 cm on the right and 20.0 cm on the left.

Table 1. Laboratory test results.

Shortly after lenvatinib was initiated, the patient developed worsening liver function, necessitating a switch to axitinib, a VEGFR-TKI (Fig. 2). Seven weeks after treatment initiation, decreased free thyroxine (fT4) (0.96 ng/dL) and elevated TSH levels (20 µIU/mL) were observed. No preceding thyrotoxic phases were observed. The patient did not develop any clinical symptoms of hypothyroidism. Ultrasonography revealed a normal-sized thyroid gland with heterogeneous hypoechoic areas. Serum thyroglobulin levels were elevated, whereas antithyroglobulin and anti-thyroid peroxidase antibodies were undetectable. Based on these findings, the patient was diagnosed with hypothyroidism caused by ICI and TKI therapy, and levothyroxine (25 µg/d) was started. After levothyroxine therapy was initiated, TSH levels initially improved; however, fT4 levels began to decline, and TSH levels increased, necessitating an increase in levothyroxine dose (Fig. 2).

Fig. 2.

Clinical course and thyroid function progression. Lenvatinib treatment was initiated, followed by combination therapy with an anti-PD-1 antibody after the completion of DEX. The lenvatinib dose was reduced owing to hepatic dysfunction, and the treatment was eventually switched to axitinib. The patient received 45 mg DEX per day for 12 days, followed by a tapering regimen over a total duration of four weeks. Approximately seven weeks after treatment initiation, TSH levels increased, necessitating the initiation of levothyroxine therapy (25 μg/d). Although the TSH levels initially improved, the fT4 levels later declined, accompanied by an increase in TSH levels. This required an increase in levothyroxine dosage seven months after starting treatment. Orange line represents fT4, and green line represents TSH levels. *PD-1, programmed cell death 1; DEX, dexamethasone; TKI, tyrosine kinase inhibitor; HDC, hydrocortisone.

Adrenal function was evaluated every four weeks, and after three months of treatment, abnormally high levels of early morning fasting ACTH were observed (Table 2). The patient presented with nausea and fatigue, which are nonspecific and may have resulted from various causes during cancer therapy, making it difficult to determine whether they were due to adrenal insufficiency. No electrolyte abnormalities were noted, and renin and aldosterone levels remained within the normal ranges, ruling out mineralocorticoid dysfunction. Periodic CT scans were performed for tumor evaluation. Because the adrenal glands were not enlarged, tumor metastasis was not suspected. A rapid ACTH stimulation test revealed inadequate cortisol response, and urinary free cortisol levels were also low (Table 2). The patient was diagnosed with primary adrenal insufficiency and was started on hydrocortisone at a physiological dose (10 mg/d, 7.1 mg/m²/d).

Table 2. Data during diagnosis of adrenal insufficiency.

The patient continued combination therapy with an ICI and a TKI without interruption during hypothyroidism and adrenal insufficiency, as hormone replacement was promptly initiated. The levothyroxine dose was increased, and hydrocortisone replacement was continued.

Discussion

Here, we report a pediatric case of hypothyroidism and adrenal insufficiency occurring at seven weeks and three months, respectively, after the initiation of ICI-TKI combination therapy. This case highlights that regular endocrine monitoring can enable early hormone replacement and help maintain anticancer treatment, even in pediatric patients receiving ICIs and TKIs.

Recent studies have reported ICI-related endocrine adverse events in pediatric patients, including thyroid dysfunction, diabetes mellitus, hypopituitarism, and adrenal insufficiency (Table 3) (11,12,13,14). Among these, ICI-induced adrenal insufficiency is considered to result from the inflammatory involvement of the adrenal glands (15), although histological evidence is scarce in clinical practice. Aldosterone deficiency was not observed in our patient, suggesting either relatively mild adrenal involvement or selective impairment of cortisol secretion. Moreover, because isolated TKI-induced adrenal dysfunction is rare (2), an ICI-related mechanism is more likely to have been involved in our patient. Although the optimal endocrine monitoring interval for pediatric patients receiving ICIs remains undefined, periodic assessments (e.g., every 2–3 wk during the first 6 mo and/or before each cycle) have been suggested based on adult guidelines and pediatric proposals (14).

Table 3. Reported frequencies of ICI-related endocrine adverse events in pediatric/adolescent and young adult (AYA) and adult patients.

TKIs may induce thyroid dysfunction through thyroid follicular damage, followed by thyrotoxicosis and hypothyroidism, and increase the expression of type 3 deiodinase, an enzyme involved in thyroid hormone inactivation (9,16). Among pediatric and young adult cohorts, overt TKI-induced hypothyroidism has been reported in 17.4% of patients (17,18,19). Data on ICI-TKI combination therapy outcomes in pediatric patients are limited; however, a mixed adult-pediatric study has reported a high incidence of hypothyroidism due to this approach (20). In our patient, hypothyroidism developed seven weeks after the initiation of TKI treatment, which was earlier than the previously reported median time of onset (9). This early onset is consistent with recent observations regarding ICI-TKI combination therapy in adults, in whom hypothyroidism may occur early and without a preceding thyrotoxic phase (21,22,23,24). However, as destructive thyroiditis presents with nonspecific ultrasonographic features (25), distinguishing between drug-induced and autoimmune-mediated hypothyroidism remains challenging. Accordingly, for TKI-associated thyroid dysfunction, monthly monitoring is recommended during the first 4–6 mo of TKI therapy, which is the peak incidence window (26, 27).

In summary, repeated endocrine assessments in our patient receiving ICI-TKI combination therapy enabled the early detection of hypothyroidism and primary adrenal insufficiency. This case highlights the importance of timely hormone replacement, which may allow for the continuation of anticancer therapy.

Conflict of interests

The authors have no conflicts of interest to declare.