Journal of the National Cancer Institute Advance Access originally published online on June 12, 2007
JNCI Journal of the National Cancer Institute 2007 99(12):975-976; doi:10.1093/jnci/djm008
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Hypothyroidism in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib
Affiliations of authors: University of Colorado Health Sciences Center, Aurora, CO (DHG); Department of Radiation Oncology, The Cleveland Clinic, Cleveland, OH (AH); Ordway Research Institute, Inc, Albany, NY (PJD); Research Service, Stratton Veterans Affairs Medical Center, Albany, NY (PJD); Division of Molecular Medicine, Wadsworth Center, New York State Department of Health, Albany, NY (PJD)
Correspondence to: David H. Garfield, MD, 57 Hyde Park Circle, Denver, CO, 80209 (e-mail: david.garfield{at}earthlink.net).
We wish to interject words of caution concerning Rini et al.'s conclusion (1) that "... replacement therapy should be undertaken as clinically indicated" in patients found to be hypothyroid while receiving sunitinib for renal cell carcinoma. We agree that moderately to severely symptomatic hypothyroid cancer patients require thyroid hormone replacement. However, we recommend caution in the reflex prescription of thyroid hormone for cancer patients with mildly elevated serum thyroid-stimulating hormone levels who are asymptomatic or for those with minimal symptoms. The reason for caution is evidence that a hypothyroid state may be associated with improved outcomes for patients with certain cancers.
In one study, hypothyroidism was associated with a reduced incidence of breast cancer, less aggressive cancers, and a diagnosis at an older age (2). Also, intentional induction of mild hypothyroidism was associated with statistically significant prolongation of survival in recurrent primary brain tumor patients (3). An association between development of hypothyroidism and improved survival in patients with head and neck cancer has been reported, as well (4).
Among 42 patients with gastrointestinal stromal tumor who were treated with sunitinib, in addition to antitumor activity being reported, thyroid blood test results for 26 (62%) noted "underactivity" (5). A drug similar to sunitinib, sorafenib, has been associated with hypothyroidism. As noted by Rini et al., thyroid dysfunction was also observed with interleukin 2 or interferon 
treatment for renal cell carcinoma. It should be determined whether induction of thyroid dysfunction by these agents contributes to the cancer treatment outcomes in those studies.
There is increasing anecdotal, preclinical, epidemiologic, and clinical evidence that L-thyroxine (T4) and triiodothyronine (T3) may be permissive for tumor growth in patients with active or previously treated cancer in remission. This possibility has long been noted but remains controversial. For example, accelerated growth of solid tumors has been observed clinically after thyroid hormone replacement. Studies have identified cell membrane receptors for thyroid hormone on V
3 integrin, mediating effects of thyroid hormone in vitro on cancer cell proliferation and on induction of new angiogenesis. Other possible permissive mechanisms of action of thyroid hormone on cancer include amplification of epidermal growth factor activity at its corresponding receptor; stimulation of tumor cell migration, a direct trophic effect on tumor cells; cell-specific antiapoptotic activity; and phosphorylation of insulin-like growth factor-1 receptor, leading to growth promotion (6).
A phase III study of sorafenib for hepatocellular carcinoma was recently terminated early because the treatment arm showed a "... superior overall survival ..." compared with the placebo control arm (7). Although there is as yet no thyroid function data, given the similarity of sorafenib to sunitinib, their association with hypothyroidism, and the worldwide availability of both drugs, we believe that a possible beneficial role of hypothyroidism and the subsequent risk of thyroid replacement therapy for patients with hepatocellular carcinoma should be explored before any recommendation that thyroid hormone be given to patients receiving either sunitinib or sorafenib for any solid tumor to achieve a euthyroid state. Withholding thyroid hormone replacement in asymptomatic, chemically hypothyroid patients (with a thyroid-stimulating hormone concentration of between 5 and 10 µU /mL) is a general treatment guideline recently provided by the American Thyroid Association.
NOTES
Editor's note: Dr D. H. Garfield is a member of the AstraZeneca Speakers’ Bureau.
REFERENCES
(1) Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst (2007) 99:81–3.
(2) Cristofanilli M, Yamamura Y, Kau S-W, Bevers T, Strom S, Patangan M, et al. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer (2005) 103:1122–8.[CrossRef][ISI][Medline]
(3) Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, et al. Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res (2003) 23:617–26.[ISI][Medline]
(4) Nelson M, Hercbergs A, Rybicki L, Strome M. Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg (2006) 132:1041–6.
(5) Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med (2006) 145:660–4.
(6) Davis PJ, Davis FB, Lin H-Y, Bergh JJ, Mousa S, Hercbergs A, et al. Cell surface receptor for thyroid hormone and tumor cell proliferation. Expert Rev Endocrinol Metab (2007) 1:753–61.[CrossRef]
(7) Available at: http://www.eurekalert.org/pub_releases/2007-02/gg-nst021107.php. [Last accessed: March 2007.].
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J Natl Cancer Inst 2007 99: 81-83.
J Natl Cancer Inst 2007 99: 976-977.
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