THYROID Volume 24, Number 8, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2014.0006
LETTER TO THE EDITOR
Sunitinib Does Not Block Thyroid Peroxidase in Patients Llanyee Liwanpo, Cynthia Ro, Salman Haq, and Jerome M. Hershman
Dear Editor: Sunitinib (Sutent) was approved in January 2006 by the Food and Drug Administration for the treatment of renal cell cancer and gastrointestinal stromal tumors. Fatigue is often observed in cancer patients taking sunitinib and is most likely multifactorial in nature. Initial retrospective studies have shown that the incidence of hypothyroidism in patients treated with sunitinib varied from 18% to 35% (1). Nine prospective studies [summarized in reference (2)] showed that sunitinib caused hypothyroidism in 33.4% (170 of 509) of patients, with a median of 35%. The mechanism by which sunitinib induces hypothyroidism is unclear. Our previous work in vitro showed that sunitinib inhibited peroxidase activity, and we hypothesized that this is a possible cause of the hypothyroidism (1). To test this hypothesis, we performed tests of peroxidase activity in patients taking sunitinib for approved indications in this investigator-initiated study. Perchlorate discharge tests were performed to test thyroid peroxidase activity in patients taking sunitinib for metastatic renal cell carcinoma using an established protocol (3). Studies were carried out at the end of the two-week rest period off drug and at the end of the four-week period on sunitinib. Patients had thyroid function tests consisting of measurement of serum thyrotropin (TSH), free thyroxine (fT4), and total triiodothyronine (TT3). Patients received a 200 lCi dose of 123I with 0.5 mg iodide as potassium iodide; thyroid uptake was measured at 3 h. Then patients received 1000 mg perchlorate to displace the 123I that had been taken up but not organified, and thyroid uptake was measured at 4 h. A positive test was reduction of thyroid uptake by at least 15% at 4 h compared with the value at 3 h (3). The study was approved by the VA Greater Los Angeles Healthcare System Institutional Review Board, and each patient gave informed consent. Studies were completed for eight patients, and the data are summarized in Table 1. Each patient had been taking sunitinib for at least two cycles of four weeks each before the study tests. Three patients had serum TSH > 20 mU/L during the sunitinib therapy, but none of these three hypothyroid patients had a positive perchlorate discharge test. One of the eight patients had a positive perchlorate discharge test of - 18.9% when his TSH was 11 mU/L and fT4 was 0.92 ng/dL
on sunitinib, but his very low uptake of 1.5% at 3 h reduced the reliability of the test. It is notable that the 3 h thyroid radioiodine uptakes on sunitinib were all lower than those during the rest period off drug, and that the mean uptake on drug was significantly lower than that off drug (Table 1). Based on clinical studies of thyroid radioiodine uptake in patients taking sunitinib, Mannavola et al. proposed that hypothyroidism was due to inhibition of iodide transport (4), but in vitro studies with rat thyroid cells showed that cells incubated with sunitinib had no impairment of iodide transport or downregulation of the sodium–iodide symporter (5). Sunitinib inhibits vascular endothelial growth factor receptors (VEGF-R) as a principal mechanism of its action on tumors. Sunitinib caused marked regression of thyroid capillaries in rats (6). Makita et al. reported a patient who developed hypothyroidism during her first cycle of therapy (7). Measurements of thyroid volume and blood flow were both reduced on sunitinib compared to values obtained when sunitinib was stopped. These authors proposed the unifying hypothesis that sunitinib causes regression of the thyroid vascular bed, resulting in impairment of thyroid function. Vasoconstriction of thyroid vessels could reduce glandular uptake of radioiodine. In summary, studies of eight patients taking sunitinib showed no significant impairment of thyroid peroxidase based on perchlorate discharge tests.
Table 1. Thyroid Function Tests, Thyroid Uptake, and Perchlorate Discharge in Eight Patients Who Were Treated with Sunitinib
fT4 TSH 3 h uptake 4 h uptake % discharge
Off sunitinib
On sunitinib
p
1.10 – 0.13 2.98 – 1.47 5.77 – 2.56 5.34 – 2.49 - 1.72 – 4.70
1.01 – 0.23 12.27 – 10.7 2.90 – 1.67 2.95 – 1.62 2.14 – 11.88
n.s. 0.029 0.018 0.039 0.407
Values are presented as mean – standard deviation. fT4, free thyroxine; TSH, thyrotropin, n.s., not significant.
Department of Endocrinology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
1325
1326 Acknowledgment
The study was supported by a grant from Pfizer, Inc. Author Disclosure Statement
The authors declare that no competing financial interests exist. References
1. Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM 2007 Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17:351–355. 2. Torino F, Barnabei A, Paragliola R, Baldelli R, Appetecchia M, Corsello SM 2013 Thyroid dysfunction as an unintended side effect of anticancer drugs. Thyroid 23: 1345–1366. 3. Roti E, Minelli R, Gardini E, Bianconi L, Salvi M, Gavaruzzi G, Ugolotti G, Braverman LE 1994 The iodine perchlorate discharge test before and after one year of methimazole treatment of hyperthyroid Graves’ disease. J Clin Endocrinol Metab 78:795–799. 4. Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L 2007 A novel
LIWANPO ET AL.
tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531–3534. 5. Salem AK, Fenton MS, Marion KM, Hershman JM 2008 Effect of sunitinib on growth and function of FRTL-5 thyroid cells. Thyroid 18:631–635. 6. Kappers MH, van Esch JH, Smedts FM, de Krijger RR, Eechoute K, Mathijssen RH, Sleijfer S, Leijten F, Danser AH, van den Meiracker AH, Visser TJ 2011 Sunitinibinduced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 96:3087–3094. 7. Makita N Miyakawa M, Fujita T, Iiri T 2010 Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid 20:323–326.
Address correspondence to: Jerome M. Hershman, MD Department of Endocrinology VA Greater Los Angeles Healthcare System 11301 Wilshire Boulevard Los Angeles, CA 90073 E-mail: [email protected]
LETTER TO THE EDITOR
Sunitinib Does Not Block Thyroid Peroxidase in Patients Llanyee Liwanpo, Cynthia Ro, Salman Haq, and Jerome M. Hershman
Dear Editor: Sunitinib (Sutent) was approved in January 2006 by the Food and Drug Administration for the treatment of renal cell cancer and gastrointestinal stromal tumors. Fatigue is often observed in cancer patients taking sunitinib and is most likely multifactorial in nature. Initial retrospective studies have shown that the incidence of hypothyroidism in patients treated with sunitinib varied from 18% to 35% (1). Nine prospective studies [summarized in reference (2)] showed that sunitinib caused hypothyroidism in 33.4% (170 of 509) of patients, with a median of 35%. The mechanism by which sunitinib induces hypothyroidism is unclear. Our previous work in vitro showed that sunitinib inhibited peroxidase activity, and we hypothesized that this is a possible cause of the hypothyroidism (1). To test this hypothesis, we performed tests of peroxidase activity in patients taking sunitinib for approved indications in this investigator-initiated study. Perchlorate discharge tests were performed to test thyroid peroxidase activity in patients taking sunitinib for metastatic renal cell carcinoma using an established protocol (3). Studies were carried out at the end of the two-week rest period off drug and at the end of the four-week period on sunitinib. Patients had thyroid function tests consisting of measurement of serum thyrotropin (TSH), free thyroxine (fT4), and total triiodothyronine (TT3). Patients received a 200 lCi dose of 123I with 0.5 mg iodide as potassium iodide; thyroid uptake was measured at 3 h. Then patients received 1000 mg perchlorate to displace the 123I that had been taken up but not organified, and thyroid uptake was measured at 4 h. A positive test was reduction of thyroid uptake by at least 15% at 4 h compared with the value at 3 h (3). The study was approved by the VA Greater Los Angeles Healthcare System Institutional Review Board, and each patient gave informed consent. Studies were completed for eight patients, and the data are summarized in Table 1. Each patient had been taking sunitinib for at least two cycles of four weeks each before the study tests. Three patients had serum TSH > 20 mU/L during the sunitinib therapy, but none of these three hypothyroid patients had a positive perchlorate discharge test. One of the eight patients had a positive perchlorate discharge test of - 18.9% when his TSH was 11 mU/L and fT4 was 0.92 ng/dL
on sunitinib, but his very low uptake of 1.5% at 3 h reduced the reliability of the test. It is notable that the 3 h thyroid radioiodine uptakes on sunitinib were all lower than those during the rest period off drug, and that the mean uptake on drug was significantly lower than that off drug (Table 1). Based on clinical studies of thyroid radioiodine uptake in patients taking sunitinib, Mannavola et al. proposed that hypothyroidism was due to inhibition of iodide transport (4), but in vitro studies with rat thyroid cells showed that cells incubated with sunitinib had no impairment of iodide transport or downregulation of the sodium–iodide symporter (5). Sunitinib inhibits vascular endothelial growth factor receptors (VEGF-R) as a principal mechanism of its action on tumors. Sunitinib caused marked regression of thyroid capillaries in rats (6). Makita et al. reported a patient who developed hypothyroidism during her first cycle of therapy (7). Measurements of thyroid volume and blood flow were both reduced on sunitinib compared to values obtained when sunitinib was stopped. These authors proposed the unifying hypothesis that sunitinib causes regression of the thyroid vascular bed, resulting in impairment of thyroid function. Vasoconstriction of thyroid vessels could reduce glandular uptake of radioiodine. In summary, studies of eight patients taking sunitinib showed no significant impairment of thyroid peroxidase based on perchlorate discharge tests.
Table 1. Thyroid Function Tests, Thyroid Uptake, and Perchlorate Discharge in Eight Patients Who Were Treated with Sunitinib
fT4 TSH 3 h uptake 4 h uptake % discharge
Off sunitinib
On sunitinib
p
1.10 – 0.13 2.98 – 1.47 5.77 – 2.56 5.34 – 2.49 - 1.72 – 4.70
1.01 – 0.23 12.27 – 10.7 2.90 – 1.67 2.95 – 1.62 2.14 – 11.88
n.s. 0.029 0.018 0.039 0.407
Values are presented as mean – standard deviation. fT4, free thyroxine; TSH, thyrotropin, n.s., not significant.
Department of Endocrinology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
1325
1326 Acknowledgment
The study was supported by a grant from Pfizer, Inc. Author Disclosure Statement
The authors declare that no competing financial interests exist. References
1. Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM 2007 Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17:351–355. 2. Torino F, Barnabei A, Paragliola R, Baldelli R, Appetecchia M, Corsello SM 2013 Thyroid dysfunction as an unintended side effect of anticancer drugs. Thyroid 23: 1345–1366. 3. Roti E, Minelli R, Gardini E, Bianconi L, Salvi M, Gavaruzzi G, Ugolotti G, Braverman LE 1994 The iodine perchlorate discharge test before and after one year of methimazole treatment of hyperthyroid Graves’ disease. J Clin Endocrinol Metab 78:795–799. 4. Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L 2007 A novel
LIWANPO ET AL.
tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531–3534. 5. Salem AK, Fenton MS, Marion KM, Hershman JM 2008 Effect of sunitinib on growth and function of FRTL-5 thyroid cells. Thyroid 18:631–635. 6. Kappers MH, van Esch JH, Smedts FM, de Krijger RR, Eechoute K, Mathijssen RH, Sleijfer S, Leijten F, Danser AH, van den Meiracker AH, Visser TJ 2011 Sunitinibinduced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 96:3087–3094. 7. Makita N Miyakawa M, Fujita T, Iiri T 2010 Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid 20:323–326.
Address correspondence to: Jerome M. Hershman, MD Department of Endocrinology VA Greater Los Angeles Healthcare System 11301 Wilshire Boulevard Los Angeles, CA 90073 E-mail: [email protected]
