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TKI-induced hypothyroidism common, but exact causes remain unclear
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Tyrosine kinase inhibitors frequently cause adverse effects that are different from those caused by classical antineoplastic agents.
These effects include hypertension, skin/hair/nail changes, and metabolic and endocrine abnormalities — specifically hypothyroidism.
Overt hypothyroidism can be defined as an elevated thyroid-stimulating hormone (TSH) level (normal range, 0.4-5 mU/L) with a concurrent low thyroxine (T4) level (normal range, 0.7-1.85 mg/dL). Most patients with these levels demonstrate symptoms of hypothyroidism, but not all do.
The symptoms of hypothyroidism — which vary depending on duration, severity and rapidity of development — are fairly vague and nonspecific (see Table 1). Many patients with cancer exhibit these symptoms, but it is difficult to determine the exact etiology. They may be caused by chemotherapy or radiation treatments, adverse effects from supportive care medications or from the cancer itself.
Lisa Lohr
Subclinical hypothyroidism is seen in patients who have high TSH levels but have T4 levels in the normal range. These patients may or may not have symptoms of hypothyroidism. Subclinical hypothyroidism may represent early, mild thyroid dysfunction. In the noncancer population, these patients progress to overt hypothyroidism at a rate of 5% to 18%.
Hypothyroidism with TKIs was first described with the use of sunitinib (Sutent, Pfizer) but has been reported with the use of several others (see Table 2). The reported incidence of hypothyroidism varies widely. With sunitinib, the reported incidences range from 36% to 85%, depending on the type of study, time course and definition of hypothyroidism. Axitinib (Inlyta, Pfizer) has a reported incidence of 89%, but the other agents generally have a reported frequency of 30% or less.
The clinical course of the hypothyroidism is variable. It can appear after 1 month of therapy or after a year of therapy.
Many patients with sunitinib-associated hypothyroidism were shown to have a low triiodothyronine (T3) level (not a low T4 level), along with a high TSH value. Some patients with cancer treated with TKI — especially older patients — may have undiagnosed underlying hypothyroidism before they even start the TKI.
The risk for TKI-induced hypothyroidism increases with each cycle of therapy. In some patients on sunitinib, the TSH level may increase during each 4-week treatment period and decrease during the 2-week rest period. In many patients, the TSH level may revert to normal when the TKI therapy finally stops, but some are left with permanent hypothyroidism.
Causes remain unclear
The exact causes of TKI-induced hypothyroidism are still unclear.
The leading hypotheses describe two different mechanisms. With imatinib (Gleevec, Novartis) and sorafenib (Nexavar, Bayer HealthCare), it appears the metabolism of T4 is increased, leading to increased levothyroxine requirements in patients with pre-existing hypothyroidism. This has been seen in patients who have had a thyroidectomy. The effects can be seen within 2 weeks. Monthly monitoring of the TSH level is recommended, with appropriate levothyroxine dosage modification.
Another hypothesis is related to the mechanism of action of several TKIs.
The thyroid gland is very vascular, with expression of VEGF and VEGF receptors. Animal studies have shown capillary regression and reduction in blood flow in the thyroid gland with administration of VEGF receptor inhibitors. These capillaries have some ability to regenerate after the inhibition of VEGF receptors stops. Most of the TKI associated with hypothyroidism are inhibitors of VEGF receptors.
Other possible mechanisms include destructive thyroiditis, inhibition of thyroid peroxidase activity and inhibition of iodine uptake. Immune modulation or autoimmune processes probably are not involved.
The best screening test for hypothyroidism is the TSH level, with the free T4 level to be done if the TSH level is high. In patients treated with a TKI associated with hypothyroidism, it is recommended to test the TSH at baseline, then on day 1 of each cycle or monthly.
If the screening has been normal for four cycles or 4 months, the frequency of screening can be pushed out to every two to three cycles. In patients with pre-existing hypothyroidism, monthly monitoring is recommended because levothyroxine requirements may change. In addition, after the end of the TKI therapy, monitoring is needed because the hypothyroidism may resolve over time.
Treatment options
Treatment of TKI-induced hypothyroidism can improve the symptoms of hypothyroidism and potentially improve the patient’s quality of life. It also may allow TKI therapy to continue.
The level of elevation of TSH that warrants treatment is, in some situations, controversial.
In general, treatment with levothyroxine is appropriate if the TSH is very elevated (>10 mU/L) and/or the T4 level is low (<0.7 ng/dL).
If the TSH is only moderately elevated (5 mU/L to 10 mU/L), treatment decisions should take into consideration the patient’s symptoms and treatment preferences. However, it can be very difficult to discern whether nonspecific symptoms such as fatigue, skin/hair changes, anorexia and constipation are due to hypothyroidism or due to the cancer, other treatments or concomitant supportive care medications.
Table 3 summarizes TKI-induced hypothyroidism treatment decisions. Treatment with levothyroxine has been shown to improve the symptoms of 50% to 79% of these patients.
Levothyroxine (LT4) is the preferred treatment. It is converted to T3 in the tissues and has a long half-life appropriate for once-daily administration. Most patients with overt hypothyroidism can be started at the target dose of 1.6 mcg/kg/day to 1.8 mcg/kg/day, which is based on lean body mass.
The usual dose for women is 100 mcg/day to 150 mcg/day and 125 mcg/day to 200 mcg/day for men. Those patients aged older than about 60 years with coronary artery disease should be started at only 25 mcg/day to 50 mcg/day, and the dose should be slowly titrated — about every 6 to 8 weeks — to the target dose. Patients with subclinical hypothyroidism can be controlled with doses as low as 50 mcg/day.
LT4 should be administered on an empty stomach because of improved bioavailability (about 80%). Bedtime administration is acceptable if it is at least 2 hours after supper. If the patient cannot take the medication on an empty stomach, the dosage could be adjusted because the bioavailability only decreases from 80% to 60%.
After initiation of LT4 therapy, the repeat TSH and T4 levels should be done after at least 6 to 8 weeks. Some patients have symptom relief only after the TSH is brought down to the lower end of the normal range, but the TSH should not be driven down to less than 0.1 mU/L because this increases the risk for atrial fibrillation and osteoporosis. After the patient becomes euthyroid, labs should be re-checked every 3 to 6 months, then yearly.
In some studies, there is evidence that the development of hypothyroidism may be an indicator of improved antineoplastic efficacy of the TKI. In these studies, the PFS was longer in those patients who had developed hypothyroidism compared with those who did not.
Recent evidence has alleviated concerns that treatment of TKI-induced hypothyroidism could hinder the cancer treatment. Researchers have concluded that hormone replacement did not affect survival, and the survival did not differ between those patients who developed hypothyroidism and were treated with LT4 and those patients who did not develop hypothyroidism.
Conclusion
TKI-induced hypothyroidism is commonly seen with some TKI due to either increased T4 metabolism or changes on the vascular supply to the thyroid gland caused by VEGF receptor inhibition.
Careful monitoring of thyroid function is necessary. Symptoms of hypothyroidism are vague and nonspecific, and they are difficult to differentiate from symptoms of the cancer itself or other treatments.
Patients with overt hypothyroidism and those patients who are symptomatic from subclinical hypothyroidism should be treated. Treatment with LT4 can improve the patient’s quality of life and may allow the TKI treatment to continue.
References:
- Brown RL. Target Oncol. 2011;6:217-226.
- Hamnvik OP. J Natl Cancer Inst. 2011;103:1572-1587.
- Illouz F. Eur J Endocrinol. 2009;160:331-336.
- Khandelwal D. Drugs. 2012;72:17-33.
For more information:
- Lisa K. Lohr, PharmD, BCOP, BCPS, is a clinical pharmacy specialist and oncology medication therapy management provider at Masonic Cancer Center at the University of Minnesota/Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. Disclosure: Dr. Lohr reports no relevant financial disclosures.