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GIST Support International - Thyroid Damage from Tyrosine Kinase Inhibitors
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Thyroid Damage from Tyrosine Kinase Inhibitors

GIST Support International asked questions about thyroid damage from tyrosine kinase inhibitor drugs such as sunitinib to experts  Professor Patrick Schöffski, MD, MPH and Pascal Wolter, MD.

Professor Patrick Schöffski, M.D., M.P.H., is head of both the Department of General Medical Oncology and the Laboratory of Experimental Oncology at the University Hospitals Leuven, Catholic University Leuven. He is a board-certified internist, haematologist and oncologist who serves as secretary-general of the Executive Committee and Board within the European Organisation for Research and Treatment of Cancer (EORTC). Professor Schöffski’s main scientific interest is the treatment of solid tumours and lymphomas. His current clinical research activities are mainly in the fields of new drug development.  Professor Schöffski has a strong background in the field of sarcoma and gastrointestinalstromal tumors (GIST). He is involved in numerous trials in this field, mainly for patients with soft tissue sarcoma and GIST, and coordinates various translational research projects in this domain. He has been involved in the registrational trials of antitumor agents in gastrointestinal stromal tumours and soft tissue sarcoma and leads several sarcoma research projects for the Connective Tissue Cancers Network (CONTICANET).

Pascal Wolter, MD earned his medical degree at the University of Cologne in Germany  and subsequently completed assistantships in the fields of anatomic pathology, neurology, internal medicine, cardiology, endocrinology, nephrology, and hematology and oncology.  Since 2007 he has been a staff member of the Department of General Medical Oncology at the University Hospital of the Catholic University in Leuven, Belgium.  Together with Dr. Schöffski and other colleagues, he has co-authored numerous papers on thyroid function in patients taking tyrosine kinase inhibitors.

References to papers on thyroid damage from TK inhibitors are shown at the end of this page, including papers by Dr. Schöffski and Dr. Wolter.  A short summary about this topic is included on our webpage on sunitinib (Sutent) side effects at this link

 

For some background information about the thyroid and its function, please refer to:

  • a 1-page fact sheet about hypothyroidism from The Endocrine Society.  Symptoms may include Tiredness/sluggishness, Mental depression, Feeling cold, Weight gain (only 5–10 pounds or 2–4 kg, Dry skin and hair, Constipation, and Menstrual irregularities. 
  • a summary about Thyroid Function Tests from the American Thyroid Association

Below are these experts' answers to our questions.

1.  Is the mechanism of thyroid damage from tyrosine kinase inhibitors (TKI) understood?

The mechanism of thyroid damage is poorly understood. The thyroid hormone metabolism is very complex, and thyroid dysfunction can be induced by TKIs at various levels. Probably, there is not only one explanation. In the literature there are several hypotheses on this question, but none of them has been proven yet. Our group is currently exploring a number of these theories in cell line and animal models in the context of a PhD thesis project. We expose cells and animals to the drugs in question to better understand why the thyroid function problems do occur.

2.  Which TKIs have this effect on what percent of patients?

Thyroid function problems are observed with many TKIs, but published data are more or less restricted to sorafenib and sunitinib. The interpretation of these reports is difficult due to methodological differences in most of these studies (some are retrospective, some prospective, small numbers of patients, various definitions of “thyroid dysfunction”, inclusion of patients with different tumor types, ….). Additional factors that may be relevant and which have not been adequately reported in most of the published series are the past medical history of the patient (previous treatment with other drugs affecting the thyroid gland such as cytokines) or previous exposure to radiotherapy to the neck region. According to our own data in patients with GIST or renal cell carcinoma , roughly one third of patients receiving sunitinib will develop thyroid dysfunction requiring hormone substitution. One third of patients under sunitinib will develop only occasionally elevated TSH, without requiring substitution therapy. The rest will not develop any thyroid dysfunction at all. In our hands thyroid dysfunction may be less severe in GIST-patients than in patients with renal cell carcinoma, but this has to be confirmed in larger cohorts of patients. In patients receiving Sorafenib the incidence of thyroid dysfunction seems to be lower, with 13% of the patients requiring treatment and 37% having occasionally elevated TSH. Reliable data on other TKIs are sparse.

3.  After how short or long a time in treatment may this show up, and should monitoring go on as long as patients remain on TKI therapy?

Thyroid function abnormalities can occur very early during the treatment of patients with TKIs, the median time to elevated TSH is in the range of 4 weeks. The timing of the monitoring and the frequency of the tests depends on the drug that is given (the incidence varies from drug to drug) and the schedule how the drug is given (continuous vs. discontinuous dosing). For sunitinib-treated patients we have proposed an algorithm on how to screen and when to substitute patients with hormones. [See figure below.]  We suggest to screen during the first four treatment cycles on days 1 and 28. If there are no signs of thyroid dysfunction during these cycles, the interval between screenings can be prolonged. The decision whether to go on with screening should be based on thyroid function tests (TFT) on day 28, the treatment decisions should be taken based on thyroid function on d1 (if Sunitinib is given according to the classical 4 week on, 2 week off schedule).

4.  Is this effect reversible if the patient stops the offending drug?

At least during the early treatment cycles sunitinib-induced thyroid dysfunction seems to be reversible, and the laboratory abnormalities or clinical symptoms related to the thyroid function problems can even normalize during short scheduled or unscheduled treatment breaks (the latter not recommended in the context of GIST). On the other hand we have also seen a number of patients who developed severe thyroid dysfunction associated with a significant reduction in thyroid volume. It is possible that in these cases thyroid function will not fully recover, but we have no proof for this. In patients receiving the 4 week on, 2 week off schedule of Sunitinib we believe that abnormal TFT on day 1 during consecutive cycles are very suggestive that the repair capacity of the thyroid might be exhausted, but this theory will also require further systematic study. In the latter group of patients long-lasting hormone replacement therapy may be necessary, which is usually well tolerated.

5.  Can patients take thyroxine replacement drugs forever if the thyroid is permanently damaged?

Yes, without any problem, as do thousands of patients all over the world for other thyroid gland diseases.


6.  Papers by Schmid et al from the Wiesli lab (2004, 2006) discuss the effect of thyroxine administration on VEGF and IGF1 levels.   Their data indicated that IGF1 and VEGF increase in response to thyroxine replacement in patients with primary hypothyroidism.  Also, your group (Garfield et al, 2008) raised the possibility that some of the beneficial effect of sutent was due to thyroid hormone depletion.  In your opinion, is it reasonable to question whether correction of the hypothyroid state could counterproductively influence the therapeutic effects of VEGF or IGF inhibitors?

It is reasonable to question this, but this is based on some weak evidence from the literature and personal experience. The evidence level of such theory is very low. At present we would recommend to follow recommendations for thyroid hormone substitution as published by us (Wolter et al)  in the Br J Cancer (see above).  Nowadays we tend to be less aggressive with starting hormone replacement therapy and lowering TSH levels by hormone substitution. We initiate hormone replacement therapy in patients with high TSH/low T3 and T4 and also in patients with high TSH and normal T3/T4 associated with typical symptoms compatible with hypothyroidism.  Our aim is to lowering the TSH to values around 10 mIU/L. These recommendations are based on clinical experience and require further systematic evaluation, as no intervention has been explored properly in prospective clinical trials.

7.  In your group’s study (British Journal of Cancer 2008; 99(3):448-454), were you able to record whether treatment of sunitinib-related hypothyroidism resulted in improvement of other side effects (for example—did patients report or demonstrate less fatigue, decreased hypertension, improved LVEF, improved kidney function, etc?)

There are preliminary data in the literature suggesting that hormone replacement therapy in general can lower the blood pressure, can ameliorate the lipid profile and improve renal and cardiac function. Therefore, in theory, an effect of  thyroid hormone replacement on the arterial blood pressure, the left ventricular cardiac function or the kidney function might be possible. We have also the impression that fatigue can benefit from hormone replacement, but this is not the case in all patients and there is no formal study data available to address this question.

Related References and Additional Reading

CLICK HERE to link to a listing in PubMed of all the papers below.  In PubMed you can read the abstracts of all papers and the full text of some that are free-access.

Alexandrescu DT, Popoveniuc G, Farzanmehr H, Dasanu CA, Dawson N, Wartofsky L.
 Sunitinib-associated lymphocytic thyroiditis without circulating antithyroid antibodies.
Thyroid. 2008 Jul;18(7):809-12. No abstract available.
PMID: 18631016

de Groot JW, Links TP, van der Graaf WT.
 Tyrosine kinase inhibitors causing hypothyroidism in a patient on levothyroxine.
Ann Oncol. 2006 Nov;17(11):1719-20. Epub 2006 May 26. No abstract available.
PMID: 16731538

Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK.
 Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors.
Ann Intern Med. 2006 Nov 7;145(9):660-4. Summary for patients in: Ann Intern Med.
2006 Nov 7;145(9):I44.
PMID: 17088579

Dora JM, Leie MA, Netto B, Fogliatto LM, Silla L, Torres F, Maia AL.
 Lack of imatinib-induced thyroid dysfunction in a cohort of non-thyroidectomized patients.
Eur J Endocrinol. 2008 May;158(5):771-2. No abstract available.
PMID: 18426838

Faris JE, Moore AF, Daniels GH.
 Sunitinib (sutent)-induced thyrotoxicosis due to destructive thyroiditis: a case report.
Thyroid. 2007 Nov;17(11):1147-9.
PMID: 17714037

Feldman DR, Martorella AJ, Robbins RJ, Motzer RJ.
 Re: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib.
J Natl Cancer Inst. 2007 Jun 20;99(12):974-5; author reply 976-7. Epub 2007 Jun
12. No abstract available.
PMID: 17565156

Garfield D, Hercbergs A, Davis P.
 Unanswered questions regarding the management of sunitinib-induced hypothyroidism.
Nat Clin Pract Oncol. 2007 Dec;4(12):674. Epub 2007 Oct 23. No abstract
available.
PMID: 17955044

Garfield DH, Wolter P, Schöffski P, Hercbergs A, Davis P.
 Documentation of thyroid function in clinical studies with sunitinib: why does it matter?
J Clin Oncol. 2008 Nov 1;26(31):5131-2; author reply 5132-3. Epub 2008 Sep 29. No
abstract available.
PMID: 18824699

Garfield DH, Hercbergs A, Davis PJ.
 Re: Hypothyroidism in patients with metastatic renal cell carcinoma treated with  sunitinib.
J Natl Cancer Inst. 2007 Jun 20;99(12):975-6; author reply 976-7. Epub 2007 Jun
12. No abstract available.
PMID: 17565154

Grossmann M, Premaratne E, Desai J, Davis ID.
 Thyrotoxicosis during sunitinib treatment for renal cell carcinoma.
Clin Endocrinol (Oxf). 2008 Oct;69(4):669-72. Epub 2008 Apr 3.
PMID: 18394019

Illouz F, Laboureau-Soares S, Dubois S, Rohmer V, Rodien P.
Tyrosine kinase inhibitors and modifications of thyroid function tests: a review.
Eur J Endocrinol. 2009 Mar;160(3):331-6. Epub 2008 Dec 22.
PMID: 19103722

Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha
SY, Kweon GR, Lee SJ, Jo KW, Shong M.
 An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.
J Clin Endocrinol Metab. 2006 Oct;91(10):4070-6. Epub 2006 Jul 18.
PMID: 16849418

Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG,
Beck-Peccoz P, Fugazzola L.
 A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake.
J Clin Endocrinol Metab. 2007 Sep;92(9):3531-4. Epub 2007 Jun 26.
PMID: 17595247

Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy S, Dreicer R, Bukowski RM.
 Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib.
J Natl Cancer Inst. 2007 Jan 3;99(1):81-3.
PMID: 17202116

Salem AK, Fenton MS, Marion KM, Hershman JM.
 Effect of sunitinib on growth and function of FRTL-5 thyroid cells.
Thyroid. 2008 Jun;18(6):631-5.
PMID: 18578612

Schmid C, Brändle M, Zwimpfer C, Zapf J, Wiesli P.
 Effect of thyroxine replacement on creatinine, insulin-like growth factor 1, acid-labile subunit, and vascular endothelial growth factor.
Clin Chem. 2004 Jan;50(1):228-31. No abstract available.
PMID: 14709659

Schmid C, Zwimpfer C, Brändle M, Krayenbühl PA, Zapf J, Wiesli P.
 Effect of thyroxine replacement on serum IGF-I, IGFBP-3 and the acid-labile subunit in patients with hypothyroidism and hypopituitarism.
Clin Endocrinol (Oxf). 2006 Dec;65(6):706-11.
PMID: 17121519

Vetter ML, Kaul S, Iqbal N.
 Tyrosine kinase inhibitors and the thyroid as both an unintended and an intended target.
Endocr Pract. 2008 Jul-Aug;14(5):618-24. Review.
PMID: 18753108

Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, Schöffski P.
 The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation.
Br J Cancer. 2008 Aug 5;99(3):448-54.
PMID: 18665181

Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM.
 Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity.
Thyroid. 2007 Apr;17(4):351-5.
PMID: 17465866

[No authors listed]
 Summaries for patients. Underactive thyroid function after treatment with sunitinib for gastrointestinal cancer.
Ann Intern Med. 2006 Nov 7;145(9):I44. No abstract available.
PMID: 17088575
 

 

 



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