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Originally published as JCO Early Release 10.1200/JCO.2008.18.8680 on September 29 2008 © 2008 American Society of Clinical Oncology.
Documentation of Thyroid Function in Clinical Studies With Sunitinib: Why Does It Matter?
University of Colorado Comprehensive Cancer Center, Denver, CO
Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH
Ordway Research Institute, Albany, NY To The Editor: We read with interest the three recent articles in this Journal in which results of phase II studies with sunitinib in metastatic colorectal cancer,1 advanced non–small-cell lung cancer (NSCLC),2 and metastatic breast cancer3 were presented. We noted with some surprise that unlike almost all previous studies4-13 that involved this drug for different types of cancer, none of these studies made any mention of thyroid function before or during treatment. Hypothyroidism is a well-known adverse effect of sunitinib,8-12 and in these three publications, symptoms possibly attributable to hypothyroidism were reported in the majority of patients. For example, fatigue/asthenia, the most frequent symptom of hypothyroidism, was seen in 53% to 70% of patients, and grade 3 or 4 toxicity was noted in 14% to 29%. The authors also reported that 12% to 24% (all grades) of patients developed constipation, and that 11% (all grade 1 or 2) developed dry skin. This is a significant issue because such symptoms might be due to sunitinib-induced hypothyroidism and therefore might be reversible with thyroid hormone (TH) replacement. However, there is uncertainty as to how to interpret and deal with sunitinib-induced hypothyroidism. An article was published recently in this Journal that presented the results of a prospective study of sunitinib-induced thyroid dysfunction in patients with advanced renal cell carcinoma (RCC).13 Of 40 patients, 28 (70%) developed thyroid function test abnormalities, in line with most published studies.8-12 Of the 28, 13 (32.5%) were considered to have clinical or subclinical hypothyroidism, and TH therapy was started at low doses to diminish symptoms possibly attributable to hypothyroidism and to prevent serious complications such as myxedema coma, reported with sunitinib.12 Of note, the median progression-free survival (PFS) of patients with thyroid abnormalities was 10.3 months, whereas for those without thyroid abnormalities, it was 3.6 months (P = .047, log-rank test). In addition, the group with thyroid dysfunction had a median overall survival (OS) of 18.2 months, compared with 6.6 months in the euthyroid group (P = .13).13 These observations raise several questions. First, might TSH, which is broadly available and much less expensive than other candidate biomarkers, be a surrogate marker for efficacy of sunitinib in patients with advanced RCC? Second, might differences in pharmacokinetics (PK) at least partially explain the observed difference in PFS between patients who develop thyroid dysfunction with sunitinib and those who do not? Sunitinib has a high interpatient PK variability, and it is known that patients with higher plasma levels of sunitinib (SU11248) have a better outcome than those with lower exposure to the agent and its metabolite, SU12662.14 Is there a positive correlation between side effects, such as hypothyroidism, and dose of sunitinib? Does this have a pharmacodynamic (PD) impact? Are there pharmacogenomic differences in the metabolism of sunitinib? PK/PD analyses in clinical studies with sunitinib could answer these questions. "Tailored" therapy means bringing the right drug to the right patient, and at the right dose.
Third, might there be a completely different explanation for our observations?.15-17 Thyroid hormone has been shown in preclinical models to induce tumor growth and angiogenesis via a plasma membrane hormone receptor on integrin Based on these studies, we wish to suggest that in our study,13 prolonged PFS in the group that developed thyroid dysfunction might have been due, at least in part, to sunitinib-induced hypothyroidism. This observation raises the possibility that some of the beneficial effect of sunitinib in the three recent phase II studies,1-3 and perhaps in other settings, was due to thyroid hormone depletion. What are the clinical implications of these observations? We recommend measuring TSH levels in all patients treated with sunitinib at baseline and during treatment, both within and outside of clinical trials. We have proposed an algorithm to deal with this problem,10 and the problem will require prospective evaluation. In patients with sunitinib-induced hypothyroidism, a "safe" serum TSH level remains to be defined. In the meanwhile, as recommended by American Thyroid Association guidelines,30 cautious, nonaggressive lowering of serum TSH in patients with subclinical hypothyroidism (TSH of 5 to 10 mU/mL, or even higher), but without clinically significant symptoms, may be warranted until further clinical evidence becomes available. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Patrick Schöffski, Pfizer (C) Stock Ownership: None Honoraria: Patrick Schöffski, Pfizer Research Funding: Pascal Wolter, Pfizer, GlaxoSmithKline Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on September 29, 2008 REFERENCES
1. Saltz LB, Rosen LS, Marshal JL, et al: Phase II trials of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25:4793-4799, 2007 2. Socinski MA, Novello S, Brahmer JR, et al: Multicenter, phase II trial of sunitinib in previously treated, advanced non–small-cell lung cancer. J Clin Oncol 26:650-656, 2008 3. Burstein HJ, Elias AD, Rugo HS, et al: Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26:1810-1816, 2008 4. Demetri GD, van Oosterom AT, Garrett CR, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 368:1329-1338, 2006[Medline] 5. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006 6. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115-124, 2007 7. Rini BI, Tamaskar I, Shaheen P, et al: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81-83, 2007 8. Desai J, Yassa L, Marqusee E, et al: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660-664, 2006 9. Rini BI, Tamaskar I, Shaheen P, et al: Hypothyroidism in patients with metastatic renal cell carcinoma treated with Sunitinib. J Natl Cancer Inst 99:81-83, 2007 10. Wolter P, Stefan C, Decallonne B, et al: The clinical implications of sunitinib-induced hypothyroidism: A prospective evaluation. Br J Cancer (in press) 11. Wong E, Rosen LS, Mulay M, et al: Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17:351-355, 2007[CrossRef][Medline] 12. Mannavola D, Coco P, Vannucchi G, et al: A novel tyrosinekKinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531-3534, 2007 13. Wolter P, Stefan C, Decallonne B, et al: Evaluation of thyroid dysfunction as a candidate surrogate marker for efficacy of sunitinib in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol 26:280s, 2008 (suppl; abstr 5126) 14. Houk BE, Bello CL, Michaelson MD, et al: Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. J Clin Oncol 25:241s, 2007 (suppl; abstr 5027)[CrossRef] 15. Garfield DH, Hercbergs A, Davis P: Management issues in the hypothyroidism developing in cancer patients treated with sunitinib and other multitargeted tyrosine kinase inhibitors. Nat Clin Pract Oncol 4:674, 2007[CrossRef][Medline] 16. Garfield DH, Hercberg A, Davis P: The management of hypothyroidism after radiotherapy for nasopharyngeal carcinoma. Med Oncol 2008 Apr 30; [epub ahead of print on April 30, 2008] 17. Garfield DH, Hercbergs A: Fewer dollars, more sense. J Clin Oncol (in press) 18. Davis FB, Tang H-Y, Shih A, et al: Acting via cell surface receptor, thyroid hormone is a growth factor for glioma cells. Cancer Res 66:7270-7275, 2006 19. Davis PJ, Davis FB, Lin H-Y, et al: Cell surface receptor for thyroid hormone and tumor cell proliferation. Expert Rev Endocrin Metab 1:753-761, 2006[CrossRef] 20. Davis PJ, Leonard JL, Davis FB: Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol 29:211-218, 2008[Medline] 21. Theodossiou C, Skrepnik N, Robert EG, et al: Propylthiouracil-induced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 86:1596-1601, 1999[CrossRef][Medline] 22. Mishkin SY, Pollack R, Yalovsky MA, et al: Inhibition of local and metastatic hepatoma growth and prolongation of survival after induction of hypothyroidism. Cancer Res 41:3040-3045, 1981 23. Kumar MS, Chiang T, Deodhar SD: Enhancing effect of thyroxine on tumor growth and metastases in syngeneic mouse tumor systems. Cancer Res 39:3515-3518, 1979 24. Shoemaker JP, Bradley RL, Hoffman RV: Increased survival and inhibition of mammary tumors in hypothyroid mice. J Surg Res 21:151-154, 1976[CrossRef][Medline] 25. Nelson M, Hercbergs A, Rybicki L, et al: Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 132:1041-1046, 2006 26. Hercbergs A, Suh JH, Lee S, et al: Propylthiouracil-induced chemical hypothyroidism with high dose tamoxifen prolongs survival with increased response rate in recurrent high-grade gliomas. Anticancer Res 23:617-626, 2003[Medline] 27. Hercbergs A, Suh J, Reddy C, et al: Early onset propylthiouracil-induced hypothyroidism is associated with improved survival in recurrent high grade glioma. Am Assoc Cancer Res Proceed 49:2008 (abstr 1211) 28. Cristofanilli M, Yamamura Y, Kau SW, et al: Thyroid hormone and breast carcinoma: Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103:1122-1128, 2005[CrossRef][Medline] 29. Weijl NI, Van der Harst D, Brand A, et al: Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin Oncol 11:1376-1383, 1993 30. Surks ML, Ortiz E, Daniels GH, et al: Subclinical thyroid disease. JAMA 291:228-238, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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