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Journal of Clinical Oncology, Vol 24, No 10 (April 1), 2006: pp. 1516-1521 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.0195 White Race As a Risk Factor for Hypothyroidism After Treatment for Pediatric Hodgkin's Lymphoma
From the Departments of Hematology-Oncology, Biostatistics, and Radiological Sciences and the Division of Endocrinology, St Jude Children's Research Hospital; and College of Medicine and Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN Address reprint requests to Monika L. Metzger, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794; e-mail: monika.metzger{at}stjude.org
PURPOSE: Hypothyroidism frequently occurs after treatment for pediatric Hodgkin's lymphoma, but race has not been investigated as a risk factor for this delayed toxicity. The aim of this study was to determine whether race is an independent risk factor for hypothyroidism in survivors of pediatric Hodgkin's lymphoma. PATIENTS AND METHODS: To identify differences between black and white patients in the development of hypothyroidism after treatment for Hodgkin's lymphoma, we conducted a retrospective study of consecutively treated pediatric patients with newly diagnosed Hodgkin's lymphoma treated at St Jude Children's Research Hospital (Memphis, TN) from January 1980 through December 2002. Clinical or biochemical hypothyroidism was defined by an above normal thyroxine-stimulating hormone concentration or by the need for thyroid hormone replacement therapy. RESULTS: The 461 patients (388 white patients, 73 black patients) where followed for a median of 11.3 years (range, 1.8 to 24.9 years). Hypothyroidism developed in 196 (43%) of 461 patients after a median of 2.9 years (range, 0.7 to 11.3 years) after diagnosis of Hodgkin's lymphoma. Hypothyroidism developed in 47% of white patients but in only 21% of black patients (hazard ratio = 2.7; 95% CI, 1.6 to 4.6). After adjusting for other risk factors for hypothyroidism (thyroid radiation dose, sex, and nodular sclerosis histology), the risk of hypothyroidism in white patients was 2.5 times (95% CI, 1.5 to 4.3 times) the risk in black patients (P < .001). CONCLUSION: White patients have a higher risk of hypothyroidism after neck irradiation for pediatric Hodgkin's lymphoma than black patients.
Compared with the general population, survivors of Hodgkin's lymphoma have a higher incidence of thyroid abnormalities, including hypothyroidism, hyperthyroidism, and thyroid neoplasms.1-3 Hypothyroidism is the most prevalent of these disorders.3-5 Several groups have investigated risk factors for thyroid abnormalities in children and adults treated for Hodgkin's lymphoma or other head and neck cancers.3,6-12 One report of 155 adults who had undergone head and neck irradiation has suggested that white race is a risk factor for hypothyroidism,9 but no study has assessed race as a primary risk factor in pediatric patients with Hodgkin's lymphoma who are treated with relatively low doses of irradiation. The aim of this study was to determine whether white race is an independent risk factor for hypothyroidism in survivors of pediatric Hodgkin's lymphoma.
From January 1980 through December 2002, 463 patients received treatment at St Jude Children's Research Hospital for newly diagnosed Hodgkin's lymphoma. Excluded from the analysis were one patient who abandoned treatment and one girl of Eastern Indian origin who was not classified as either black or white.
Treatment for Hodgkin's Lymphoma
Definition of Hypothyroidism After receiving institutional review board approval, we reviewed the medical records of all patients to obtain demographic information, details of chemotherapy or radiation therapy administered, the dose of radiation to the patient's thyroid, documentation of whether the patient received thyroid hormone replacement therapy, and T4 and TSH values.
Definition of Race
Statistical Analysis
The median age of the 461 patients was 15.3 years (range, 3.0 to 21.8 years) at the time of diagnosis of Hodgkin's lymphoma. Fifty-eight percent of patients were male; 84% were white; and 16% were black. At the time of last follow-up, 54 patients had died, nine of whom (17%) were black. The causes of death were progressive Hodgkin's lymphoma in 27 patients, second malignant neoplasms in 13 patients, accidents in six patients, cardiac causes in four patients, and infection in four patients. Thirteen of the patients who died had been diagnosed with hypothyroidism while alive and were hypothyroid when they died. Eighty-six percent of black patients and 87% of all surviving patients were contacted or seen within the past 2 years. Patients who remain alive were observed for a median time of 11.3 years (range, 1.8 to 24.9 years). The characteristics of the black and white patients are listed in Table 1. The groups did not differ significantly by sex, age, histologic characteristics of the tumor, B symptoms (ie, symptoms associated with a poor prognosis in patients with lymphoma, such as drenching night sweats, > 10% weight loss, and fever), or disease stage. Black and white patients received the same treatments and chemotherapeutic regimens. Relapse occurred in 76 patients, 17 of whom (22%) were black. All treatment received (whether for initial or relapsed disease) was included in the analysis. More than half of each group (59% of black patients and 65% of white patients) received more than 21 Gy of radiation to the thyroid.
Hypothyroidism Of the 461 patients with Hodgkin's lymphoma, 196 (43%) became hypothyroid (Table 2). According to univariate analysis, white race, female sex, a tumor with nodular sclerosis (shown by histology), and higher radiation dose to the thyroid were significantly associated with hypothyroidism (Table 2). Hypothyroidism developed in a significantly smaller percentage of black patients (21%) than white patients (47%). After adjustment for sex, race, and thyroid irradiation, nodular sclerosis was not a significant risk factor, but irradiation of the thyroid remained significantly associated with hypothyroidism; the risk of hypothyroidism in patients who received more than 21 Gy of radiation to the thyroid was 16.7 times the risk for patients who received no radiation (P = .005; Table 2). The median age at development of hypothyroidism was 18.3 years (range, 5.4 to 30.7 years) for the whole cohort, 16.1 years (range, 5.4 to 22 years) for black patients, and 18.5 years (range, 6.2 to 31 years) for white patients. There was no correlation between radiation dose and age at diagnosis of hypothyroidism or between radiation dose and time to hypothyroidism. Four patients with transient hypothyroidism were identified when they decided to stop taking their thyroid hormone replacement medication and their TSH returned to normal levels. These patients accounted for 2% of patients diagnosed with hypothyroidism. Exclusion of these patients did not significantly change the results.
Of the 196 patients with hypothyroidism, 173 started T4 replacement therapy at a median time of 0.1 year (range, 0 to 14.4 years) after the first elevated TSH level was noted. Of the 23 patients who did not receive thyroid hormone replacement therapy, six were found to have elevated TSH with normal T4 in the past 18 months and are still under observation, five (including one patient who left the country) were not retested at our institution, six had intermittently normal TSH levels but an elevated TSH level on their last test, three had persistently elevated TSH levels but did not receive T4, and three died before initiation of T4.
Cumulative Incidence of Hypothyroidism
Irradiation of the thyroid is the most important known risk factor for the development of hypothyroidism.1,3,6,19,20 Patients in our cohort who received more than 21 Gy of radiation were at significantly greater risk of hypothyroidism (hazard ratio = 16.7) than patients who received no radiation. White patients were at significantly greater risk of becoming hypothyroid than black patients who were administered the same dose of radiation. The risk of hypothyroidism in white survivors of pediatric Hodgkin's lymphoma was 2.5 times the risk in black survivors. These results cannot be explained by underestimation of hypothyroidism in our black patients because all patients were observed by the same clinicians at regular intervals in our After Completion of Therapy Clinic or through our tumor registry. Eighty-six percent of black patients and 87% of all surviving patients were contacted or seen within the past 2 years. Long-term follow-up (beyond 5 years) of cancer-related problems continues in the After Completion of Therapy Clinic for patients who are in remission 5 years after diagnosis, and patients at least 2 years after completion of therapy are eligible for transfer to this clinic. Survivors are evaluated annually by the clinic staff until they are 18 years of age or 10 years after diagnosis. After alumni survivors are discharged to the care of community physicians, the St Jude Cancer Registry continues to perform annual follow-up for the lifetime of the patient. The median duration of follow-up and time since last follow-up were not significantly different for black and white patients. Few publications have evaluated racial differences in the incidence and prevalence of hypothyroidism. Racial differences in the incidence of congenital hypothyroidism have been reported,21-23 and in one study, the risk of congenital hypothyroidism in white newborns was 6 times the risk in black newborns.21 A retrospective study of adult primary care patients showed that the odds of an abnormally high TSH level in white patients are 7.7 times the odds in black patients.24 In one study in which high-dose radiation therapy was used to treat head and neck carcinoma,9 none of 13% of the patients who were black became hypothyroid, but 48% of white patients did. The effect of race on the incidence of other endocrinopathies is under study. Genetic polymorphisms of an insulin gene promoter insertion explain the high incidence of diabetes mellitus in African Americans,25 and the high prevalence of osteoporosis among white women26 has led to studies of ethnic differences in polymorphisms of genes involved in bone metabolism.27 In our study, hypothyroidism was 1.4 times as frequent in women as in men after adjusting for race, histologic characteristics of the Hodgkin's lymphoma, and radiation dose to the thyroid. Although sex had no role in some studies7,9,10 involving much higher doses to the thyroid (40 to 60 Gy) than the doses received by our study cohort, our finding is in accordance with the results of other studies in which patients received similar doses (median, 35 Gy) of radiation to the thyroid.12,28 In the general population, hypothyroidism is more common in females than in males by a factor of 6 to 7.29 These observations suggest that different pathologic mechanisms lead to primary hypothyroidism and treatment-induced hypothyroidism. Primary hypothyroidism is largely attributed to a loss of functional thyroid tissue as a result of chronic or reversible autoimmune thyroiditis (silent and postpartum thyroiditis and cytokine-induced thyroiditis), to which women are much more susceptible.29 An autopsy study looking for thyroiditis in adults found that white Americans had a higher prevalence of thyroiditis than black or Japanese Americans, showing a clear racial difference in susceptibility to chronic thyroiditis.30 Treatment-related hypothyroidism is believed to result from direct cell injury or vascular injury caused by radiation and, possibly to some degree, immune-mediated damage.3,31,32 Illés et al28 postulated that hypothyroidism in patients with Hodgkin's lymphoma cannot simply be attributed to radiation-induced damage but may be attributable to thyroiditis, which seems to occur independently of the therapy used but to which patients with Hodgkin's lymphoma may be more susceptible. Indeed, patients with Hodgkin's lymphoma have dysregulated immunity, an altered cytokine network, and an increased susceptibility to infections, all of which may contribute to the development of hypothyroidism.28,33,34 Although age has been considered a potential risk factor for the development of hypothyroidism, neither pediatric nor adult studies have confirmed it.1,6,7,10,19,20,35,36 In this study, we found no significant association between age at the time of irradiation and development of hypothyroidism. One limitation of our study is that we did not differentiate between clinical and subclinical hypothyroidism. The need for T4 replacement therapy would seem to be a more clinically relevant outcome to evaluate than TSH elevation. However, the decision to initiate T4 replacement therapy depends on clinicians' judgment, and different clinicians use different thresholds for starting hormone replacement therapy, as evidenced by the range of 0 to 14.4 years between first elevation of TSH and initiation of T4 therapy in our study. By including all patients with elevated TSH levels in our analysis, we present an unbiased characterization of the affected population. Furthermore, overt hypothyroidism eventually developed in most of our patients (88%) who had subclinical hypothyroidism (increased TSH but normal T4 levels and no symptoms); the TSH level returned to normal in only 2% of patients, and the results of our analysis were unchanged when these patients were excluded. We also performed a separate analysis using T4 replacement as the outcome of interest. This analysis showed that the incidence of hypothyroidism in white patients is 2.7 times that in black patients (P < .001) and that neck irradiation at a dose of more than 21 Gy is also a strong risk factor (P < .001). Also, if we analyzed the data eliminating the six white females who were started on thyroid replacement therapy outside the institution, for whom no thyroid function studies were available, the incidence of hypothyroidism in white patients remained 2.4 times that in black patients (P = .001). Our study has shown that white patients have a high risk of hypothyroidism after neck irradiation for Hodgkin's lymphoma. However, patients of all races who receive more than 21 Gy of radiation have a high incidence of hypothyroidism and should be screened periodically.
The authors indicated no potential conflicts of interest.
We thank Janet R. Davies, PhD, for editing the manuscript.
Supported by Grants No. R01-CA600419 and P30-CA21765 from the National Institutes of Health, by the American Cancer Society F.M. Kirby Clinical Research Professorship, and by the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Constine LS, Donaldson SS, McDougall IR, et al: Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 53:878-883, 1984[CrossRef][Medline] 2. Devney RB, Sklar CA, Nesbit ME Jr, et al: Serial thyroid function measurements in children with Hodgkin disease. J Pediatr 105:223-227, 1984[CrossRef][Medline] 3. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599-605, 1991[Abstract] 4. Schimpff SC, Diggs CH, Wiswell JG, et al: Radiation-related thyroid dysfunction: Implications for the treatment of Hodgkin's disease. Ann Intern Med 92:91-98, 1980[Medline] 5. Tamura K, Shimaoka K, Friedman M: Thyroid abnormalities associated with treatment of malignant lymphoma. Cancer 47:2704-2711, 1981[CrossRef][Medline] 6. Bethge W, Guggenberger D, Bamberg M, et al: Thyroid toxicity of treatment for Hodgkin's disease. Ann Hematol 79:114-118, 2000[Medline] 7. Bhatia S, Ramsay NK, Bantle JP, et al: Thyroid abnormalities after therapy for Hodgkin's disease in childhood. Oncologist 1:62-67, 1996 8. Kuten A, Lubochitski R, Fishman G, et al: Postradiotherapy hypothyroidism: Radiation dose response and chemotherapeutic radiosensitization at less than 40 Gy. J Surg Oncol 61:281-283, 1996[Medline] 9. Mercado G, Adelstein DJ, Saxton JP, et al: Hypothyroidism: A frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 92:2892-2897, 2001[CrossRef][Medline] 10. Peerboom PF, Hassink EA, Melkert R, et al: Thyroid function 10-18 years after mantle field irradiation for Hodgkin's disease. Eur J Cancer 28A:1716-1718, 1992[CrossRef] 11. Reinhardt W, Sauter V, Jockenhovel F, et al: Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide). Exp Clin Endocrinol Diabetes 107:177-182, 1999[Medline] 12. Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin's disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-3232, 2000 13. Hudson M, Greenwald C, Thompson E, et al: Efficacy and toxicity of multiagent (COP/ABVD) chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease. J Clin Oncol 11:100-108, 1993[Abstract] 14. Donaldson SS, Hudson MM, Lamborn KR, et al: VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial. J Clin Oncol 20:3081-3087, 2002 15. Hudson MM, Krasin M, Link MP, et al: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 22:4541-4550, 2004 16. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 17. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data (ed 2). New York, NY, Wiley, 2002 18. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988 19. Atahan IL, Yildiz F, Ozyar E, et al: Thyroid dysfunction in children receiving neck irradiation for Hodgkin's disease. Radiat Med 16:359-361, 1998[Medline] 20. van Santen HM, Vulsma T, Dijkgraaf MG, et al: No damaging effect of chemotherapy in addition to radiotherapy on the thyroid axis in young adult survivors of childhood cancer. J Clin Endocrinol Metab 88:3657-3663, 2003 21. Brown AL, Fernhoff PM, Milner J, et al: Racial differences in the incidence of congenital hypothyroidism. J Pediatr 99:934-936, 1981[Medline] 22. Fernhoff PM, Brown AL, Elsas LJ: Congenital hypothyroidism: Increased risk of neonatal morbidity results in delayed treatment. Lancet 1:490-491, 1987[Medline] 23. Lorey FW, Cunningham GC: Birth prevalence of primary congenital hypothyroidism by sex and ethnicity. Hum Biol 64:531-538, 1992[Medline] 24. Schectman JM, Kallenberg GA, Shumacher RJ, et al: Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med 149:861-864, 1989[Abstract] 25. Karim MA, Wang X, Zhang Z, et al: Association of an insulin gene promoter insertion polymorphism with type 2 diabetes and diabetic nephropathy in African Americans. Mol Genet Metab 83:344-346, 2004[Medline] 26. Acheson LS: Bone density and the risk of fractures: Should treatment thresholds vary by race? JAMA 293:2151-2154, 2005 27. Dvornyk V, Liu XH, Shen H, et al: Differentiation of Caucasians and Chinese at bone mass candidate genes: Implication for ethnic difference of bone mass. Ann Hum Genet 67:216-227, 2003[CrossRef][Medline] 28. Illés A, Biro E, Miltenyi Z, et al: Hypothyroidism and thyroiditis after therapy for Hodgkin's disease. Acta Haematol 109:11-17, 2003[Medline] 29. Wiersinga WM: The thyroid and its diseases: Adult hypothyroidism. http://www.thyroidmanager.org/Chapter9/9-frame.htm 30. Okayasu I, Hara Y, Nakamura K, et al: Racial and age-related differences in incidence and severity of focal autoimmune thyroiditis. Am J Clin Pathol 101:698-702, 1994[Medline] 31. DeGroot LJ: Radiation and thyroid disease. Baillieres Clin Endocrinol Metab 2:777-791, 1988[CrossRef][Medline] 32. Hancock SL, McDougall IR, Constine LS: Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 31:1165-1170, 1995[CrossRef][Medline] 33. Poppema S: Immunology of Hodgkin's disease. Baillieres Clin Haematol 9:447-457, 1996[CrossRef][Medline] 34. Weetman AP, McGregor AM: Autoimmune thyroid disease: Further developments in our understanding. Endocr Rev 15:788-830, 1994[Abstract] 35. Khoo VS, Liew KH, Crennan EC, et al: Thyroid dysfunction after mantle irradiation of Hodgkin's disease patients. Australas Radiol 42:52-57, 1998[Medline] 36. Smith RE Jr, Adler AR, Clark P, et al: Thyroid function after mantle irradiation in Hodgkin's disease. JAMA 245:46-49, 1981[Abstract] Submitted November 18, 2005; accepted January 19, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to compare the presenting features of white and black patients. The outcome variable of interest was biochemical hypothyroidism, use of thyroid hormone replacement therapy, or both. To determine the independent prognostic significance of patient and treatment characteristics for hypothyroidism, we conducted a multivariate analysis using the Cox proportional hazards regression method.
