Grade 3 and/or 4 toxicities are an indication for treatment discontinuation; however, lower-grade side effects may also lead to treatment withdrawal, especially when they appear in clusters and persist for a long time. Apart from implementation of supportive measures,30 as cited in our methodology, we applied drug discontinuation and dose reduction to alleviate symptoms in patients with toxicities.23Recently, a schedule change from 4 weeks on/2 weeks off during treatment with sunitinib to 2 weeks on/1 week off has resulted in significantly fewer events of hand-foot syndrome and fatigue.31 This alternative dosing led to fewer grade 3/4 adverse events without compromising drug efficacy, and so far appears superior to dose reduction.32 Adverse events with one TKI agent do not preclude the use of another drug in this category;33 improvement of hematological toxicity was observed in two patients when treatment was switched from sunitinib to sorafenib.

Previous reports advocate the use of tumor markers (thyroglobulin and calcitonin) as surrogate markers34 for follow-up in treated patients, along with CT and MRI. Although our patient population was small, we also observed a non-significant trend for reduction of tumor markers with treatment. An elevation in TSH was observed, and thyroxine was increased in three patients. In athyreotic patients, increases in TSH with TKI treatment have been previously documented in 17%–33% of patients, depending on the drug used.30 TKIs induce hypothyroidism, probably associated with poor absorption of thyroxine along the gastrointestinal tract as a consequence of diarrhea, thyroid hormone metabolism, or reduction of TSH clearance.35

Continue Reading

This was a retrospective study and included a relatively small number of patients. However, the fact that these data reflect the experience of a single center using standard therapeutic criteria and treating patients from a specific region could counterbalance some of the limitations. Further, since data related to specific populations are not widely available, the present series adds valuable information related to treatment with TKIs. Small groups of patients are common in this research area, as seen in other recently published studies that refer to similar numbers of patients36–38 and contain mixed DTC and MTC populations.16,39,40


TKIs represent a valuable therapeutic option in patients with thyroid cancer. However, these agents should be used with caution and under expert supervision because of their adverse events. Younger patients tolerate treatment better. In patients who continue therapy, adverse events may improve over time and become more tolerable. Apart from thorough education of selected patients, topical therapies, dose reduction of the administered TKI, temporary treatment interruption, and/or permanent discontinuation in severe cases may be considered in those not able to continue long-term treatment. As toxicities impact negatively on patients’ quality of life and often restrict their everyday activities, candidate patients must be meticulous selected and close follow-up should be applied.


The authors report no conflicts of interest in this work. The authors alone are responsible for the content and writing of the paper.


1. Ito Y, Nikiforov YE, Schlumberger M, Vigneri R. Increasing incidence of thyroid cancer: controversies explored.Nat Rev Endocrinol. 2013;9:178–184.

2. Kilfoy BA, Zheng T, Holford TR, et al. International patterns and trends in thyroid cancer incidence, 1973–2002.Cancer Causes Control. 2009;20:525–531.

3. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–2899.

4. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565–612.

5. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–1684.

6. Klein Hesselink EN, Steenvoorden D, Kapiteijn E, et al. Therapy of endocrine disease. Response and toxicity of small molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic analysis. Eur J Endocrinol. 2015;172:R215–R225.

7. Cabanillas ME, Brose MS, Holland J, Ferguson KC, Sherman SI. A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid. 2014;24:1508–1514.

8. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28:2323–2330.

9. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–3646.

10. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141.

11. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–655.

12. Keefe DM, Schubert MM, Elting LS, et al; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109:820–831.

13. Manchen E, Robert C, Porta C. Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse. J Support Oncol. 2011;9:13–23.

14. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). In: Protocol development. US National Institutes of Health, 2010. Available from: Accessed July 24, 2015.

15. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216.

16. Capdevila J, Iglesias L, Halperin I, et al. Sorafenib in metastatic thyroid cancer. Endocr Relat Cancer. 2012;19:209–216.

17. Abraham DT, Low TH, Messina M, et al. Medullary thyroid carcinoma: long-term outcomes of surgical treatment. Ann Surg Oncol. 2011;18:219–225.

18. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295:2164–2167.

19. Ball DW. Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol. 2007;19:18–23.

20. Kober F, Hermann M, Handler A, Krotla G. Effect of sorafenib in symptomatic metastatic medullary thyroid cancer. J Clin Oncol. 2007;25 Suppl 18:S14065.

21. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetics, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25–35.

22. Ravaud A, de la Fouchardiere C, Courbon F, et al. Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. J Clin Oncol. 2008;26 Suppl 15:S6058.

23. Brose MS, Nutting CM, Jarzab B, et al; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double blind, phase 3 trial. Lancet. 2014;384:319–328.

24. Khakoo AY, Kassiotis CM, Tannir N, et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008;112:2500–2508.

25. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–2019.

26. Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. Onco Targets Ther. 2009;2:51–61.

27. Autier J, Escudier B, Wechsler J, Spatz A, Robert C. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol. 2008;144:886–892.

28. Flaherty KT, Brose MS. Sorafenib-related hand-foot skin reaction improves, not worsens, with continued treatment. Clin Cancer Res. 2009;15:7749.

29. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Cancer related fatigue. Available from: Accessed July 24, 2015.

30. Carhill AA, Cabanillas ME, Jimenez C, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab. 2013;98:31–42.

31. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer. 2014;50:1084–1089.

32. Atkinson BJ, Kalra S, Wang X, et al. Outcomes associated with sunitinib alternative schedule compared to traditional schedule: a single-center experience. J Clin Oncol. 2013;31 Suppl 15:e15611.

33. Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology. 2009;76:350–354.

34. Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab. 2010;95:2588–2595.

35. Illouz F, Braun D, Briet C, Schweizer U, Rodien P. Endocrine side-effects of anti-cancer drugs: thyroid effects of tyrosine kinase inhibitors. Eur J Endocrinol. 2014;171:R91–R99.

36. Chen L, Shen Y, Luo Q, Yu Y, Lu H, Zhu R. Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma. Thyroid. 2011;21:119–124.

37. Frank-Raue K, Ganten M, Kreissl MC, Raue F. Rapid response to sorafenib in metastatic medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2011;119:151–155.

38. Marotta V, Ramundo V, Camera L, et al. Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET. Clin Endocrinol (Oxf). 2013;78:760–767.

39. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260–5268.

40. Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165:315–322.

Source: OncoTragets and Therapy
Originally published on September 3, 2015.