JNCI Journal of the National Cancer Institute Advance Access published June 12, 2007
Re: Hypothyroidism in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib 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 func974 Correspondence
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tion 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 pro spective 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 Vol. 99, Issue 12
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were noted to have an elevated level of thyroid-stimulating hormone before treatment with sunitinib and an additional eight (12%) were being treated with lthyroxine 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 sunitinibtreated 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). jnci.oxfordjournals.org
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 renal 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. DARREN R. FELDMAN ANDREW J. MARTORELLA RICHARD J. ROBBINS ROBERT J. MOTZER
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]. New York (NY): Pfizer Inc; 2006. (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.
Notes Editor’s note: Dr R. J. Motzer has received research funding from Pfizer, Inc. 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 SloanKettering 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@ mskcc.org. DOI: 10.1093/jnci/djm006 © The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
[email protected].
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 thyroidstimulating 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 JNCI
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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 ␣V3 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 insulinlike 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 thyroidstimulating hormone concentration of between 5 and 10 µU /mL) is a general 976 Correspondence
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treatment guideline recently provided by the American Thyroid Association. DAVID H. GARFIELD ALECK HERCBERGS PAUL J. DAVIS
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. (3) Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, et al. Propylthiouracilinduced chemical hypothyroidism with highdose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 2003;23:617–26. (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. (7) Available at: http://www.eurekalert.org/pub_ releases/2007-02/gg-nst021107.php. [Last accessed: March 2007.]
Notes Editor’s note: Dr D. H. Garfield is a member of the AstraZeneca Speakers’ Bureau. 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:
[email protected]). DOI: 10.1093/jnci/djm008 © The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
[email protected].
Response We appreciate the interest of Feldman et al. and of Garfield et al. in our recent publication regarding thyroid function test (TFT) abnormalities in metastatic renal cell carcinoma (RCC) patients receiving sunitinib (1). The important conclusion is that hypothyroidism is commonly observed with sunitinib therapy and necessitates routine monitoring. Thyroid hormone replacement is easily administered in such patients when clinically indicated, and this phenomenon does not adversely impact the utility of sunitinib in metastatic RCC. As noted, some patients in our cohort had elevated levels of thyroid-stimulating hormone (TSH) at baseline. Seven (19%) of the 37 patients in our series with available baseline TFTs had an elevated TSH, although the majority were mild, not associated with other TFT abnormalities or clinical symptoms, and did not require hormone replacement. Feldman et al. cite a baseline hypothyroidism prevalence of 4%–8% in an adult population from a recent review (2). This review also states that the prevalence of subclinical hypothyroidism increases with age up to as high as 20%, consistent with our experience and that of others (3). Indeed, other series have noted that the incidence of thyroid dysfunction may be higher in RCC patients than in the general population (4). There were two patients on thyroid hormone therapy at the start of sunitinib therapy in our report. The TSH of such patients rose on sunitinib, requiring a modest increase in their synthroid dose to maintain a clinically euthyroid state. The retrospective reports of sunitinibinduced hypothyroidism which are currently available are likely to overestimate (if any biochemical TFT abnormality is considered) or underestimate (if only symptomatic patients are tested) the true incidence of thyroid dysfunction. As such, ongoing prospective trials will more fully define the treatment-induced incidence of this toxicity and, hopefully, elucidate the most appropriate management strategy and mechanism(s) underlying this phenomenon. Such studies can also accurately define the true incidence of thyroid abnormalities at baseline in this population of patients and determine whether baseline or posttreatment abnormalities are Vol. 99, Issue 12
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associated with any consequences relative to clinical outcome. Although TFT abnormalities are not always of clinical importance, Feldman et al. correctly state that the metabolic and other adverse effects can be severe if untreated. We also do not advocate reflexive thyroid hormone replacement for biochemical abnormalities alone. As with any population, clinical judgment as to the necessity and timing of replacement therapy must be exercised. Garfield et al. cite several references with indirect evidence that hypothyroidism can affect clinical outcome to cancer therapy. Although interesting, not all reports support these observations, and such an association may or may not hold for metastatic RCC patients and sunitinib therapy. As noted above, prospective testing of this hypothesis is needed. The demonstration of survival benefit to sorafenib in hepatocellular carcinoma is in no way a demonstration of an association between treatment-induced hypothyroidism and improved clinical outcome. There is, therefore, a need for monitoring, recogni-
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tion, and treatment of thyroid dysfunction in metastatic RCC patients receiving sunitinib.
Clinic Taussig Cancer Center, 9500 Euclid Ave, Desk R35, Cleveland, OH 44195 (e-mail: rinib2@ ccf.org).
BRIAN I. RINI
© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
[email protected].
References
DOI: 10.1093/jnci/djm009
(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) 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. (3) 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. (4) Rosenberg AG, Dexeus F, Swanson DA, von Eschenbach AC. Relationship of thyroid disease to renal cell carcinoma. An epidemiologic study. Urology 1990;35:492–8.
Notes Correspondence to: Brian I. Rini, MD, Department of Solid Tumor Oncology and Urology, Cleveland
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