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):974-975; doi:10.1093/jnci/djm006
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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: Division of Medical Oncology and Hematology (DRF), Endocrinology Service (AJM), and Genitourinary Oncology Service, Division of Solid Tumor Oncology (RJM), Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, The Methodist Hospital, Houston, TX (RJR)
Correspondence to: Robert J. Motzer, MD, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (e-mail: motzerr{at}mskcc.org.
Rini et al. (1) report on the incidence of hypothyroidism in patients treated with sunitinib for metastatic renal cell carcinoma. These authors found a high (85%) rate of abnormalities in the thyroid function tests of patients with renal cell carcinoma who were treated with sunitinib. In addition, they noted that 84% of patients with abnormal thyroid function tests experienced symptoms possibly related to hypothyroidism. These findings support a recent report by Desai et al. (2), in which 62% of patients had an abnormal level of thyroid-stimulating hormone and 36% had hypothyroidism during treatment with sunitinib for gastrointestinal stromal tumors (GISTs). Another group (3) reported a similar 30%–40% incidence of hypothyroidism in patients with renal cell carcinoma or GIST who were treated with sunitinib.
Hypothyroidism is described in the sunitinib package insert (4); however, the incidence was thought to be less than indicated in these recent reports (1–3). At the Memorial Sloan-Kettering Cancer Center, we have observed hypothyroidism in 14 (18%) of 80 patients enrolled in prospective clinical trials with sunitinib for metastatic renal cell carcinoma. Thyroid-stimulating hormone levels were obtained only from symptomatic patients and ranged from 6.0 to 146.4 mU/mL (normal range = 0.35–5.5 mU/mL). Hypothyroidism was detected after a median of 10 months of therapy (range = 1–26 months), with the predominant symptom leading to elevated levels of thyroid-stimulating hormone being fatigue. Although the majority of hypothyroid patients had no associated metabolic abnormalities, two patients with very high thyroid-stimulating hormone levels (i.e., >140 mU/mL) developed hypercholesterolemia and profound hypertriglyceridemia. These laboratory abnormalities are known consequences of hypothyroidism and underscore the need to address sunitinib-induced hypothyroidism to prevent other metabolic effects. The lower incidence of hypothyroidism in our series likely reflects the fact that we obtained thyroid function tests only from symptomatic patients.
We would like to highlight three important issues to consider when interpreting the results of these recent publications (1,2). First, there appears to be an elevated incidence of abnormal thyroid function tests in their study populations before treatment with sunitinib. In the report by Desai et al (2), seven (10%) of 69 patients were noted to have an elevated level of thyroid-stimulating hormone before treatment with sunitinib and an additional eight (12%) were being treated with L-thyroxine replacement therapy before enrollment. Thus, 22% of patients had evidence of abnormal thyroid function at baseline, a level exceeding that expected for the general population (4%–8.5%) (5). Likewise, Rini et al. report patients with thyroid-stimulating hormone values as high as 34.8 mU/mL before sunitinib treatment. It would be useful to know whether patients with preexisting thyroid function abnormalities required a higher L-thyroxine dose to maintain a euthyroid state while they were being treated with sunitinib.
Second, the increased use of thyroid function tests to monitor patients treated with sunitinib has increased the detection of abnormalities in the absence of symptoms, a finding that may not always have clinical consequences. Moreover, as noted by Wolter et al. (3), many hypothyroid symptoms such as fatigue and hair and skin changes are also side effects of sunitinib, and differentiation between these two processes can be difficult. In a large phase III study of sunitinib for advanced renal cell carcinoma (6), the incidence of fatigue was 51%. The association of fatigue with sunitinib (or underlying cancer) independent of thyroid dysfunction was indicated by the observation of fatigue in sunitinib-treated patients with normal thyroid function tests and the lack of symptomatic improvement in nearly 50% of patients treated with L-thyroxine replacement by Rini et al. These findings suggest that a proportion of patients with abnormal thyroid function tests on sunitinib therapy may not truly have hypothyroidism. In our series, we treated all 14 patients with hypothyroidism with L-thyroxine replacement and noted symptomatic improvement in 11 (79%). Because we did not evaluate thyroid function tests in all patients treated with sunitinib at our center, the true incidence of thyroid function abnormalities in our patients cannot be determined. However, our higher threshold for assessing thyroid function may explain why a greater proportion of our patients benefited from L-thyroxine replacement than those reported in the two other series (1,2).
Third, physicians must recognize that even when moderate or severe clinical hypothyroidism occurs in patients on sunitinib therapy, it is readily correctable with thyroid hormone replacement. We and others (1,2) have observed rapid correction of thyroid-stimulating hormone levels of greater than 100 mU/mL to within normal limits, and others (1) have reported complete resolution of extreme hypothyroid symptoms (myxedema) attributable to sunitinib. Therefore, oncologists should not be deterred from using sunitinib to treat patients with advanced re-nal cell carcinoma or imatinib-resistant GIST.
In summary, Rini et al. highlight hypothyroidism as an adverse event associated with sunitinib therapy and the need for routine thyroid function test assessment. Prospective studies incorporating thyroid function testing are underway to further define the incidence of sunitinib-induced hypothyroidism. We emphasize that this is easily treatable and should not affect the use of this agent when indicated for the treatment of malignancy.
NOTES
Editor's note: Dr R. J. Motzer has received research funding from Pfizer, Inc.
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) 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.
(3) Wolter P, Dumez H, Schöffski P. Laboratory abnormalities suggesting thyroid dysfunction in patients treated with sunitinib. Ann Intern Med [rapid response—November 27, 2006]. Available at: http://www.annals.org/cgi/eletters/145/9/660. [Last accessed: December 11, 2006.].
(4) Sutent (sunitinib malate) [package insert]. (2006) New York (NY): Pfizer Inc.
(5) Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease—scientific review and guidelines for diagnosis and management. JAMA (2004) 291:228–38.
(6) Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med (2007) 356:115–24.
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J Natl Cancer Inst 2007 99: 976-977.
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