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Case history

image A 52-year-old woman with metastatic renal cell carcinoma and lung metastases, on sunitinib therapy, was admitted to the acute oncology unit with a 1 week history of increasing shortness of breath and bilateral ankle swelling. On questioning she had a 3 week history of fatigue that was limiting her daily activities. She was also troubled with constipation. The differential diagnosis included progressive renal cell carcinoma, cardiac failure (possible secondary to her sunitinib therapy) or pulmonary embolus.

On examination the patient had dry skin, bilateral leg oedema to the mid-calf, and periorbital oedema. She was bradycardic and had a respiratory rate of 24 breaths/min. Her chest was dull to percussion to the level of the mid-zones, with decreased breath sounds bilaterally. An ECG confirmed bradycardia, rate 45 beats/min; a chest X-ray confirmed bilateral pleural effusions and the known pulmonary metastases, which appeared unchanged compared with previous films. Full blood count was normal; she had mild hyponatraemia (130 mmol/l) and normal liver function.

She was initially managed with oxygen therapy and drainage of pleural fluid. Subsequent thyroid function tests revealed overt hypothyroidism: thyroid-stimulating hormone (TSH) 42 mU/l (reference range 0.2–6.0 mU/l) and free thyroxine 5.6 pmol/l (reference range 10–25 pmol/l). She was commenced on thyroxine 25 μg/day.

What was the cause of her thyroid dysfunction?

How should this patient be managed?

What other conditions may present with similar features?

What are the new developments with tyrosine kinase inhibitor (TKI) treatment?

What other metabolic complications may be caused by systemic anticancer therapy (SACT)?

What was the cause of her thyroid dysfunction?

A number of cancer therapies may lead to thyroid dysfunction. These include targeted therapies such as TKIs, which include the first generation agents sunitinib, pazopanib and sorafenib, currently used in a range of cancers; for example, sunitinib is licensed for use in renal cell carcinoma, gastrointestinal stromal tumour (GIST) and pancreatic neuroendocrine tumours. TKIs cause thyroid dysfunction through different mechanisms. It has been proposed that sunitinib may prevent vascular endothelial growth factor from binding to normal thyroid cells (resulting in loss of capillary circulation), reduce synthesis of thyroid hormones (through decreased iodine uptake or decreased peroxidise activity) or cause destructive thyroiditis.1 TKIs such as sunitinib are likely to worsen pre-existing hypothyroidism as well as cause a newly developed condition. Sunitinib can induce hypothyroidism in 36–85% of patients, while sorafenib and pazopanib may present a slightly lower incidence.13 Most thyroid dysfunction associated with TKI use is asymptomatic biochemical subclinical hypothyroidism (raised TSH, with thyroid hormones within the reference range). Abnormalities of thyroid function tests may be transient. Thyroid autoantibodies are usually negative.

It has been reported that the duration of TKI treatment is an important risk factor for the development of hypothyroidism. For example, Desai et al.4 reported that 18% of patients on sunitinib treatment for GIST developed hypothyroidism by 36 weeks, 29% by 52 weeks and 90% ...

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