- Email: [email protected]
Expanding use of recombinant hTSH
Annales d’Endocrinologie 68 (2007) 220–223
Expanding use of recombinant hTSH L. Fugazzola Endocrine Unit and Department of Medical Sciences, Fondazione Policlinico IRCCS and University of Milan, Italy Available online 08 August 2007
Abstract The clinical benefits of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen®, Genzyme Corp., Cambridge, MA, USA) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the follow-up of thyroid cancer patients. rhTSH has the advantage to avoid both hypothyroidism, with a major impact on the quality of life, and the side effects on tumor growth related to the longlasting TSH increase. More recently, alternative uses have been proposed, including treatment of nodular goiter, TSH stimulation to enhance PET scanning and chemotherapy treatment, and differential diagnosis of congenital hypothyroidism. In benign thyroid diseases, rhTSH administration increases thyroid uptake resulting in a more homogeneous distribution of the tracer, and allows to reduce the dose of 131I maintaining the same effects on thyroid shrinkage. Moreover, rTSH stimulation improves the detectability of occult thyroid metastases with FDG-PET, and promising results have been obtained in the response rate of poorly differentiated thyroid cancer submitted to chemotherapy after rhTSH stimulation. Finally, rhTSH testing has been proved to be safe and to lead, in association with ultrasound, to the differential diagnosis of congenital hypothyroidism during L-thyroxine, allowing the appropriate clinical/genetic management of the disease and thus representing a valuable alternative to L-thyroxine withdrawal. © 2007 Elsevier Masson SAS. All rights reserved. Keywords: Recombinant human TSH; Congenital hypothyroidism; Nodular goiter; Radioiodine uptake
1. Introduction The clinical benefits of recombinant human thyroidstimulating hormone (rhTSH; Thyrogen®, Genzyme Corp., Cambridge, MA, USA) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the follow-up of thyroid cancer patients. Indeed, it has been demonstrated that rhTSH administration (0.9 mg/die in following 2 days) is effective in the stimulation of 131I uptake and thyroglobulin (Tg) production by normal residual tissue, local relapse or metastases and comparable to thyroxine withdrawal [4,7,9,14]. Main advantages of rhTSH are the higher reliability of the diagnostic investigations and the possibility to avoid periods of hypothyroidism. Consequently, patients do not suffer from a decreased quality of life and keep their ability to work. More recently, successful thyroid ablation has been reported after rhTSH preparation using 131I activity determined by individual dosimetry [15], or after a fixed dose of 3700
E-mail address: [email protected] (L. Fugazzola). 0003-4266/$ - see front matter © 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ando.2007.06.010
MBq [12]. The latter procedure has been approved in 2005 in Europe for the preparation to the administration of 131I to lowrisk patients. When using rhTSH for thyroid ablation, the patient should receive one i.m. injection of 0.9 mg rhTSH on consecutive 2 days and receive radioiodine 24 h after the second injection. Finally, though not yet approved for this purpose, rhTSH has been successfully used in a compassionate use program for the preparation to 131I therapy of patients with distant metastases [8]. Although the majority of the literature regarding the diagnostic uses of rhTSH relates to thyroid cancer detection and treatment, alternative uses have been proposed, including treatment of nodular goiter, TSH stimulation to enhance PET scanning and chemotherapy treatment, and differential diagnosis of congenital hypothyroidism. 2. RhTSH in the radiometabolic treatment of non-toxic nodular goiter Patients with large non-toxic nodular goiters (MNG) frequently suffer with symptoms of neck compression. These symptoms can include dysphagia, odynophagia and sensations of throat compression. Additionally, these patients can have
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
extrathoracic airway obstruction resulting in impaired airflow. Although treatment of these large, compressive nontoxic nodular goiters is usually accomplished by surgical resection, radioiodine has been used to reduce goiter volume, particularly in patients who are poor surgical candidates due to other comorbid conditions. In the last 15 years, a growing interest in 131 I treatment of MNG has been recorded. Several studies demonstrated that 131I treatment is followed by a significant and permanent thyroid volume reduction (typically 50–60% reduction at 2–5 years) and improvement of obstructive symptoms [5,6,11,19,20]. Nontoxic nodular goiters usually have relatively low radioiodine uptake values and high treatment doses of 131I are often required to induce substantial goiter size reduction. Pretreatment of patients with rhTSH may enhance radioiodine uptake and improve efficacy of 131I to reduce goiter volume. Different doses of rhTSH have been used to this purpose, ranging from very low doses (0.01 and 0.03 mg, [10]) up to higher doses (0.45 mg, [17]). In all cases, two or more folds increased thyroid uptake and a more homogeneous uptake was observed. Moreover, it has been demonstrated that the administration of rhTSH before radiodiodine treatment allows reducing the dose of 131I to be administered, without compromise of efficacy [10]. Alterations in thyroid function constitute the main side effects of 131I treatment. In particular, transient thyrotoxicosis has a prevalence varying between 3 and 27%, while hypothyroidism has been reported after a follow-up of 1–2 years in 21– 48% of treated patients, depending on the dose of 131I employed and on the thyroidal uptake [5,6,11,19,20]. In this context, a major disadvantage of the pretreatment with rhTSH is the high prevalence of 131I-induced hypothyroidism. Indeed, while radioiodine induced hypothyroidism is observed in 10– 20% of patients treated with 131I alone [19], the percentage rises to 36–65% in patients pre-treated with rhTSH [10,17]. 3. TSH stimulation to enhance PET scanning and chemotherapy treatment 18
Fluoro-2-deoxyglucose (FDG) PET scanning has been shown to be useful in patients with thyroid carcinoma, elevated Tg levels and negative 131I Total Body Scan. Since the sensitivity of diagnostic techniques such as Tg determination and iodine concentration is enhanced by TSH stimulation, some Authors hypothesized that TSH would also increase FDG uptake by increasing glucose transport and/or glycolytic activity, in thyroid cancer patients [1,13]. With this aim, stimulated scans were performed after two 0.9 mg i.m. doses of rhTSH, while patients continued the same L-thyroxine dose. The results were encouraging since all lesions seen on the basal scans during TSH suppression were also visualized on the rhTSH stimulation studies. Moreover, after rhTSH stimulation additional lesions, not seen on TSH suppression, were identified and, in a minority of cases, PET was positive on rhTSH stimulation alone. The mean and maximum lesions to background ratios were significantly higher with rhTSH stimulation, compared with TSH suppression. Interestingly, no correlation was observed between the appearance of additional foci
221
on rhTSH-stimulated PET scans and the difference between basal and rhTSH-stimulated thyroglobulin levels. Authors concluded that rhTSH-stimulation improves the detectability of occult thyroid metastases with FDG-PET, compared with scans performed on TSH suppression, suggesting a potential role for rhTSH-stimulated FDG-PET scanning in the detection of persistent disease. The rationale for the use of rhTSH in chemotherapy is to evaluate whether increasing the metabolic rate of thyroid cancer cells by TSH stimulation might result in higher response rate to chemotherapy in patients with poorly differentiated thyroid carcinoma and nonfunctioning metastases detected at computed tomography scan. In a study by Santini and coworkers [16] a combination of carboplatinum and epirubicin was administered and TSH stimulation achieved either by reduction of the daily dose of L-thyroxine resulting in mild hypothyroidism or by administration of rhTSH. At each course, patients received 1 injection of 0.9 mg rhTSH for consecutive 2 days and chemotherapy was administered on day 3. The overall rate of positive responses was 37% that rose to 81% when including patients with stable disease. Serum Tg after chemotherapy declined more than 50% in about half of patients, with respect to basal levels. Apparently, no difference in the response rate was observed between exogenous or endogenous TSH stimulation. After 21 months of chemotherapy, 64.3% were still alive, most of them showing a stable disease. Authors concluded that the response rate of poorly differentiated thyroid cancer to chemotherapy after rhTSH stimulation was favorable and promising. 4. RhTSH in the differential diagnosis of congenital hypothyroidism Another important application of rhTSH is the differential diagnosis of congenital hypothyroidism (CH) (Table 1). The differential diagnosis of CH is mainly aimed to distinguish between transient and permanent hypothyroidism in order to avoid unnecessary prolongation of treatment and psychosocial problems due to continuous monitoring. On the other hand, an Table 1 Diagnostic and therapeutic uses of recombinant human TSH (Thyrogen®, Genzyme Corp., Cambridge, MA, USA). The dosage (i.m. administration) required for each use is also reported Diagnostic Evaluation of stimulated Tg with or without TBS in the follow-up of differentiated thyroid cancer; in alternative to THW Differentiated thyroid cancer (central hypothyroidism) FDG-PET Differential diagnosis of CH Therapeutic Remnant ablation Treatment of thyroid cancer metastases; in alternative to THW; compassionate programme Non-toxic nodular goiter Enhancement chemotherapy THW: thyroid hormone withdrawal.
Dose 0.9 mg × 2 days
0.9 mg × 2 days 0.9 mg × 2 days 0.004 mg/kg × 2 days or × 3 days Dose 0.9 mg × 2 days 0.9 mg × 2 days 0.45 mg or 0.01 mg or 0.03 mg × 1 day 0.9 mg × 2 days
222
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
Fig. 1. The proposed protocols for the differential diagnosis of congenital hypothyroidism by rhTSH testing during L-thyroxine replacement treatment, according to the ultrasonographic diagnosis at enrolment.
accurate definition of the defect is required to undertake appropriate genetic investigations and family counseling. The etiologic diagnosis of CH is based on clinical examination, biochemical tests, thyroid ultrasound and scintigraphy (99mTc, 131I or preferably 123I uptake with or without perchlorate discharge test). A complete clinical evaluation, and in particular thyroid scintigraphy and discharge test, can be performed before the early start of L-thyroxine in neonates only in specialized centers. In other settings, due to the lack of adequate facilities for the management of these neonates, these examinations are postponed during infancy in order to allow early therapy. Thus, tests are completed at 2–4 years of age, after 1 month of L-thyroxine withdrawal [18]. The resulting hypothyroid state is associated with particular concern by several parents and with untoward effects including rapid and great thyroid enlargement if the underlying CH cause is defective hormonogenesis. With the aim to verify the efficacy and safety of new protocols for rhTSH testing in the etiologic diagnosis of CH during L-thyroxine replacement, we tested new protocols in an pilot group of adult patients [2] and more recently in a cohort of pediatric patients (age range 15–144 months) with different forms of CH [3]. All patients remained on L-thyroxine therapy and underwent new protocols for rhTSH testing. In the first study on adult patients, a standard protocol was used with the administration of 4 μg/kg per day of rhTSH during 3 days and thyroid scintiscan on days 3 and 4. At variance, in the study on pediatric patients, children underwent distinct rhTSH protocols depending upon the CH classification of the defect made at birth (Fig. 1). Patients with ultrasonographic diagnosis of gland in situ underwent 2 rhTSH injections (4 μg/kg per day, i.m.) on days 1 and 2. A thyroid scintigraphy with 123I and a perchlorate discharge test were performed on day 3. In particular, 123I was administered intravenously and counts were obtained at 1 and 2 h. For the discharge test, 200 or 400 mg of potassium perchlorate were administered orally and uptake was calculated after 1, 2 and 3 h. In the patients with hemiagenesis or apparent agenesis at the ultrasound examination performed at enrolment, 3 rhTSH injection were given on days 1–3 in order to enhance testing sensitivity for the disclosure of small tissue remnants. On day 3, 123I was given (9.25 MBq) and head, neck and mediastinum uptakes were
measured after 2 and 24 h. In order to make the most of each rhTSH vial, patients were divided in groups and each vial reconstituted in 4 ml sterile water. After rhTSH injections, TSH levels peaked to 33.5–68.2 mU/l on day 4 in the “adult study” and to 10.9–59.2 mU/l, on days 3 or 4 in the “children study”. Free thyroid hormones levels were always in the normal range and anti-thyroid autoantibodies were negative in all cases. Thyroglobulin peaks varied according to the diagnosis. Indeed, a mean of 3-folds elevation was observed in patients with a final diagnosis of total iodide organification defect (TIOD), while blunted Tg responses were observed in cases with a final diagnosis of agenesia or resistance to TSH action. Interestingly, extremely variable Tg responses were observed in the cases of ectopy, ranging from very mild elevations up to 15-folds increases. Nevertheless, the present rhTSH testing protocols have been proved to stimulate thyroid uptake and to cause Tg increases even in the presence of minimal amounts of responsive thyroid cells that could not be visualized at scintiscan or ultrasound. All protocols for rhTSH testing allowed the accurate definition of the underlying defect in each patient, providing useful information about the defective step in thyroid development or function in all the patients. In particular, considering the adult and pediatric patients studied, the accuracy of rhTSH testing was demonstrated in a considerable number of patients for the different CH categories (7 with ectopia, 3 with agenesis, 3 with TIOD, 4 with TSH resistance and 3 transient forms). Testing by rhTSH is particularly useful in patients with the clinical suspicion of a dyshormonogenic defects. Indeed, the discontinuation of L-thyroxine needed to perform the discharge test is not recommended since hypothyroidism can induce a dramatic thyroid enlargement in these cases. Moreover, rhTSH test may be performed very early in postnatal life, thus allowing the selection of candidates for Lthyroxine withdrawal. This would finally prevent the unnecessary prolongation of replacement treatment in transient CH. Thanks to the accurate classification of the disorder; targeted genetic analyses could be performed in many patients, leading to the identification of TPO mutations in three cases. As far as the cost benefit analysis of the present protocols is concerned, it must be underlined that the doses of rhTSH used are extremely low. Indeed, the dose for the differential diagnosis in one CH patient is 6-folds lower than that used to test one patient with thyroid cancer. This is obviously possible only by appropriate grouping of patients. In conclusion, emerging uses for recombinant human TSH have been reported. In the diagnosis and treatment of thyroid cancer, rhTSH has the advantage to avoid both hypothyroidism, with a major impact on the quality of life, and the side effects on tumor growth related to the long-lasting TSH increase. In benign thyroid diseases, rhTSH administration increases thyroid uptake resulting in a more homogeneous distribution of the tracer, and allows reducing the dose of 131I maintaining the same effects on thyroid shrinkage. Finally, rhTSH testing has been proved to be safe and to lead, in association with ultrasound, to the differential diagnosis of congenital hypothyroidism during L-thyroxine, allowing the appro-
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
priate clinical/genetic management of the disease and thus representing a valuable alternative to L-thyroxine withdrawal.
[11]
References [12] [1]
Chin BB, Patel P, Cohade C, Ewertz M, Wahl R, Ladenson P. Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab 2004;89:91–5. [2] Fugazzola L, Persani P, Mannavola D, et al. Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during L-thyroxine replacement. Clin Endocrinol (Oxf) 2003;59:230–6. [3] Fugazzola L, Persani L, Vannucchi G, et al. Thyroid scintigraphy and perchlorate test after recombinant human TSH in paediatric age: a new tool for the differential diagnosis of congenital hypothyroidism during L-thyroxine replacement therapy. Eur J Nucl Med Mol Imaging 2007 [doi:10.1007/s00259-007-0377-6]. [4] Haugen BR, Pacini F, Reiners C, et al. Comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877–85. [5] Hegedus L, Hansen BM, Knudsen N, Hansen JM. Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goiter. BMJ 1988;297:661–2. [6] Huysman DA, Hermus AR, Corstens FH, Barentsz JO, Kloppenborg PW. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994;121:757–62. [7] Ladenson PW. Recombinant thyrotropin versus thyroid hormone withdrawal in evaluating patients with thyroid carcinoma. Semin Nucl Med 2000;30:98–106. [8] Lippi F, Capezzone M, Angelini F, et al. Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH. Eur J Endocrinol 2001;144:5–11. [9] Mazzaferri EL, Kloos RT. Using recombinant human TSH in the management of well-differentiated thyroid cancer: current strategies and future directions. Thyroid 2000;10:767–78. [10] Nieuwlaat WA, Huysmans DA, Van Den Bosch HC, et al. Pretreatment with a single, low dose of recombinant human thyrotropin allows dose
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
223
reduction of radioiodide therapy in patients with nodular goiter. J Clin Endocrinol Metab 2003;88:3121–9. Nygaard B, Hegedus L, Gervil M, Hjalgrim H, Soe-Jensen P, Hansen JM. Radioiodine treatment of multinodular non-toxic goiter. BMJ 1993;307: 828–32. Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab 2006;91:926–32. Petrich T, Borner AR, Otto D, Hofmann M, Knapp WH. Influence of rhTSH on [(18)F]fluorodeoxyglucose uptake by differentiated thyroid carcinoma. Eur J Nucl Med Mol Imaging 2002;29:641–7. Robbins RJ, Tuttle RM, Sharaf RN, et al. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:619–25. Robbins RJ, Larson SM, Sinha N, et al. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002;43:1482–8. Santini F, Bottici V, Elisei R, et al. Cytotoxic effects of carboplatinum and epirubicin in the setting of an elevated serum thyrotropin for advanced poorly differentiated thyroid cancer. J Clin Endocrinol Metab 2002;87:4160–5. Silva MNC, Rubio’ IGS, Romao R, et al. Administration of a single dose of recombinant human thyrotropin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol 2004;60:300–8. Toublanc JE. Guidelines for neonatal screening programs for congenital hypothyroidism. Working Group for Neonatal Screening in Paediatric Endocrinology of the European Society for Paediatric Endocrinology. Acta Paediatr 1999;88(Suppl):13–4. Vannucchi G, Chiti A, Mannavola D, et al. Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium. Eur J Nucl Med Mol Imaging 2005;32:1081–8. Wesche MFT, Tiel-V Buul MMC, Lips P, Smits NJ, Wiersinga WM. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic non-toxic goiter. J Clin Endocrinol Metab 2001;86: 998–1005.
Expanding use of recombinant hTSH L. Fugazzola Endocrine Unit and Department of Medical Sciences, Fondazione Policlinico IRCCS and University of Milan, Italy Available online 08 August 2007
Abstract The clinical benefits of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen®, Genzyme Corp., Cambridge, MA, USA) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the follow-up of thyroid cancer patients. rhTSH has the advantage to avoid both hypothyroidism, with a major impact on the quality of life, and the side effects on tumor growth related to the longlasting TSH increase. More recently, alternative uses have been proposed, including treatment of nodular goiter, TSH stimulation to enhance PET scanning and chemotherapy treatment, and differential diagnosis of congenital hypothyroidism. In benign thyroid diseases, rhTSH administration increases thyroid uptake resulting in a more homogeneous distribution of the tracer, and allows to reduce the dose of 131I maintaining the same effects on thyroid shrinkage. Moreover, rTSH stimulation improves the detectability of occult thyroid metastases with FDG-PET, and promising results have been obtained in the response rate of poorly differentiated thyroid cancer submitted to chemotherapy after rhTSH stimulation. Finally, rhTSH testing has been proved to be safe and to lead, in association with ultrasound, to the differential diagnosis of congenital hypothyroidism during L-thyroxine, allowing the appropriate clinical/genetic management of the disease and thus representing a valuable alternative to L-thyroxine withdrawal. © 2007 Elsevier Masson SAS. All rights reserved. Keywords: Recombinant human TSH; Congenital hypothyroidism; Nodular goiter; Radioiodine uptake
1. Introduction The clinical benefits of recombinant human thyroidstimulating hormone (rhTSH; Thyrogen®, Genzyme Corp., Cambridge, MA, USA) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the follow-up of thyroid cancer patients. Indeed, it has been demonstrated that rhTSH administration (0.9 mg/die in following 2 days) is effective in the stimulation of 131I uptake and thyroglobulin (Tg) production by normal residual tissue, local relapse or metastases and comparable to thyroxine withdrawal [4,7,9,14]. Main advantages of rhTSH are the higher reliability of the diagnostic investigations and the possibility to avoid periods of hypothyroidism. Consequently, patients do not suffer from a decreased quality of life and keep their ability to work. More recently, successful thyroid ablation has been reported after rhTSH preparation using 131I activity determined by individual dosimetry [15], or after a fixed dose of 3700
E-mail address: [email protected] (L. Fugazzola). 0003-4266/$ - see front matter © 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ando.2007.06.010
MBq [12]. The latter procedure has been approved in 2005 in Europe for the preparation to the administration of 131I to lowrisk patients. When using rhTSH for thyroid ablation, the patient should receive one i.m. injection of 0.9 mg rhTSH on consecutive 2 days and receive radioiodine 24 h after the second injection. Finally, though not yet approved for this purpose, rhTSH has been successfully used in a compassionate use program for the preparation to 131I therapy of patients with distant metastases [8]. Although the majority of the literature regarding the diagnostic uses of rhTSH relates to thyroid cancer detection and treatment, alternative uses have been proposed, including treatment of nodular goiter, TSH stimulation to enhance PET scanning and chemotherapy treatment, and differential diagnosis of congenital hypothyroidism. 2. RhTSH in the radiometabolic treatment of non-toxic nodular goiter Patients with large non-toxic nodular goiters (MNG) frequently suffer with symptoms of neck compression. These symptoms can include dysphagia, odynophagia and sensations of throat compression. Additionally, these patients can have
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
extrathoracic airway obstruction resulting in impaired airflow. Although treatment of these large, compressive nontoxic nodular goiters is usually accomplished by surgical resection, radioiodine has been used to reduce goiter volume, particularly in patients who are poor surgical candidates due to other comorbid conditions. In the last 15 years, a growing interest in 131 I treatment of MNG has been recorded. Several studies demonstrated that 131I treatment is followed by a significant and permanent thyroid volume reduction (typically 50–60% reduction at 2–5 years) and improvement of obstructive symptoms [5,6,11,19,20]. Nontoxic nodular goiters usually have relatively low radioiodine uptake values and high treatment doses of 131I are often required to induce substantial goiter size reduction. Pretreatment of patients with rhTSH may enhance radioiodine uptake and improve efficacy of 131I to reduce goiter volume. Different doses of rhTSH have been used to this purpose, ranging from very low doses (0.01 and 0.03 mg, [10]) up to higher doses (0.45 mg, [17]). In all cases, two or more folds increased thyroid uptake and a more homogeneous uptake was observed. Moreover, it has been demonstrated that the administration of rhTSH before radiodiodine treatment allows reducing the dose of 131I to be administered, without compromise of efficacy [10]. Alterations in thyroid function constitute the main side effects of 131I treatment. In particular, transient thyrotoxicosis has a prevalence varying between 3 and 27%, while hypothyroidism has been reported after a follow-up of 1–2 years in 21– 48% of treated patients, depending on the dose of 131I employed and on the thyroidal uptake [5,6,11,19,20]. In this context, a major disadvantage of the pretreatment with rhTSH is the high prevalence of 131I-induced hypothyroidism. Indeed, while radioiodine induced hypothyroidism is observed in 10– 20% of patients treated with 131I alone [19], the percentage rises to 36–65% in patients pre-treated with rhTSH [10,17]. 3. TSH stimulation to enhance PET scanning and chemotherapy treatment 18
Fluoro-2-deoxyglucose (FDG) PET scanning has been shown to be useful in patients with thyroid carcinoma, elevated Tg levels and negative 131I Total Body Scan. Since the sensitivity of diagnostic techniques such as Tg determination and iodine concentration is enhanced by TSH stimulation, some Authors hypothesized that TSH would also increase FDG uptake by increasing glucose transport and/or glycolytic activity, in thyroid cancer patients [1,13]. With this aim, stimulated scans were performed after two 0.9 mg i.m. doses of rhTSH, while patients continued the same L-thyroxine dose. The results were encouraging since all lesions seen on the basal scans during TSH suppression were also visualized on the rhTSH stimulation studies. Moreover, after rhTSH stimulation additional lesions, not seen on TSH suppression, were identified and, in a minority of cases, PET was positive on rhTSH stimulation alone. The mean and maximum lesions to background ratios were significantly higher with rhTSH stimulation, compared with TSH suppression. Interestingly, no correlation was observed between the appearance of additional foci
221
on rhTSH-stimulated PET scans and the difference between basal and rhTSH-stimulated thyroglobulin levels. Authors concluded that rhTSH-stimulation improves the detectability of occult thyroid metastases with FDG-PET, compared with scans performed on TSH suppression, suggesting a potential role for rhTSH-stimulated FDG-PET scanning in the detection of persistent disease. The rationale for the use of rhTSH in chemotherapy is to evaluate whether increasing the metabolic rate of thyroid cancer cells by TSH stimulation might result in higher response rate to chemotherapy in patients with poorly differentiated thyroid carcinoma and nonfunctioning metastases detected at computed tomography scan. In a study by Santini and coworkers [16] a combination of carboplatinum and epirubicin was administered and TSH stimulation achieved either by reduction of the daily dose of L-thyroxine resulting in mild hypothyroidism or by administration of rhTSH. At each course, patients received 1 injection of 0.9 mg rhTSH for consecutive 2 days and chemotherapy was administered on day 3. The overall rate of positive responses was 37% that rose to 81% when including patients with stable disease. Serum Tg after chemotherapy declined more than 50% in about half of patients, with respect to basal levels. Apparently, no difference in the response rate was observed between exogenous or endogenous TSH stimulation. After 21 months of chemotherapy, 64.3% were still alive, most of them showing a stable disease. Authors concluded that the response rate of poorly differentiated thyroid cancer to chemotherapy after rhTSH stimulation was favorable and promising. 4. RhTSH in the differential diagnosis of congenital hypothyroidism Another important application of rhTSH is the differential diagnosis of congenital hypothyroidism (CH) (Table 1). The differential diagnosis of CH is mainly aimed to distinguish between transient and permanent hypothyroidism in order to avoid unnecessary prolongation of treatment and psychosocial problems due to continuous monitoring. On the other hand, an Table 1 Diagnostic and therapeutic uses of recombinant human TSH (Thyrogen®, Genzyme Corp., Cambridge, MA, USA). The dosage (i.m. administration) required for each use is also reported Diagnostic Evaluation of stimulated Tg with or without TBS in the follow-up of differentiated thyroid cancer; in alternative to THW Differentiated thyroid cancer (central hypothyroidism) FDG-PET Differential diagnosis of CH Therapeutic Remnant ablation Treatment of thyroid cancer metastases; in alternative to THW; compassionate programme Non-toxic nodular goiter Enhancement chemotherapy THW: thyroid hormone withdrawal.
Dose 0.9 mg × 2 days
0.9 mg × 2 days 0.9 mg × 2 days 0.004 mg/kg × 2 days or × 3 days Dose 0.9 mg × 2 days 0.9 mg × 2 days 0.45 mg or 0.01 mg or 0.03 mg × 1 day 0.9 mg × 2 days
222
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
Fig. 1. The proposed protocols for the differential diagnosis of congenital hypothyroidism by rhTSH testing during L-thyroxine replacement treatment, according to the ultrasonographic diagnosis at enrolment.
accurate definition of the defect is required to undertake appropriate genetic investigations and family counseling. The etiologic diagnosis of CH is based on clinical examination, biochemical tests, thyroid ultrasound and scintigraphy (99mTc, 131I or preferably 123I uptake with or without perchlorate discharge test). A complete clinical evaluation, and in particular thyroid scintigraphy and discharge test, can be performed before the early start of L-thyroxine in neonates only in specialized centers. In other settings, due to the lack of adequate facilities for the management of these neonates, these examinations are postponed during infancy in order to allow early therapy. Thus, tests are completed at 2–4 years of age, after 1 month of L-thyroxine withdrawal [18]. The resulting hypothyroid state is associated with particular concern by several parents and with untoward effects including rapid and great thyroid enlargement if the underlying CH cause is defective hormonogenesis. With the aim to verify the efficacy and safety of new protocols for rhTSH testing in the etiologic diagnosis of CH during L-thyroxine replacement, we tested new protocols in an pilot group of adult patients [2] and more recently in a cohort of pediatric patients (age range 15–144 months) with different forms of CH [3]. All patients remained on L-thyroxine therapy and underwent new protocols for rhTSH testing. In the first study on adult patients, a standard protocol was used with the administration of 4 μg/kg per day of rhTSH during 3 days and thyroid scintiscan on days 3 and 4. At variance, in the study on pediatric patients, children underwent distinct rhTSH protocols depending upon the CH classification of the defect made at birth (Fig. 1). Patients with ultrasonographic diagnosis of gland in situ underwent 2 rhTSH injections (4 μg/kg per day, i.m.) on days 1 and 2. A thyroid scintigraphy with 123I and a perchlorate discharge test were performed on day 3. In particular, 123I was administered intravenously and counts were obtained at 1 and 2 h. For the discharge test, 200 or 400 mg of potassium perchlorate were administered orally and uptake was calculated after 1, 2 and 3 h. In the patients with hemiagenesis or apparent agenesis at the ultrasound examination performed at enrolment, 3 rhTSH injection were given on days 1–3 in order to enhance testing sensitivity for the disclosure of small tissue remnants. On day 3, 123I was given (9.25 MBq) and head, neck and mediastinum uptakes were
measured after 2 and 24 h. In order to make the most of each rhTSH vial, patients were divided in groups and each vial reconstituted in 4 ml sterile water. After rhTSH injections, TSH levels peaked to 33.5–68.2 mU/l on day 4 in the “adult study” and to 10.9–59.2 mU/l, on days 3 or 4 in the “children study”. Free thyroid hormones levels were always in the normal range and anti-thyroid autoantibodies were negative in all cases. Thyroglobulin peaks varied according to the diagnosis. Indeed, a mean of 3-folds elevation was observed in patients with a final diagnosis of total iodide organification defect (TIOD), while blunted Tg responses were observed in cases with a final diagnosis of agenesia or resistance to TSH action. Interestingly, extremely variable Tg responses were observed in the cases of ectopy, ranging from very mild elevations up to 15-folds increases. Nevertheless, the present rhTSH testing protocols have been proved to stimulate thyroid uptake and to cause Tg increases even in the presence of minimal amounts of responsive thyroid cells that could not be visualized at scintiscan or ultrasound. All protocols for rhTSH testing allowed the accurate definition of the underlying defect in each patient, providing useful information about the defective step in thyroid development or function in all the patients. In particular, considering the adult and pediatric patients studied, the accuracy of rhTSH testing was demonstrated in a considerable number of patients for the different CH categories (7 with ectopia, 3 with agenesis, 3 with TIOD, 4 with TSH resistance and 3 transient forms). Testing by rhTSH is particularly useful in patients with the clinical suspicion of a dyshormonogenic defects. Indeed, the discontinuation of L-thyroxine needed to perform the discharge test is not recommended since hypothyroidism can induce a dramatic thyroid enlargement in these cases. Moreover, rhTSH test may be performed very early in postnatal life, thus allowing the selection of candidates for Lthyroxine withdrawal. This would finally prevent the unnecessary prolongation of replacement treatment in transient CH. Thanks to the accurate classification of the disorder; targeted genetic analyses could be performed in many patients, leading to the identification of TPO mutations in three cases. As far as the cost benefit analysis of the present protocols is concerned, it must be underlined that the doses of rhTSH used are extremely low. Indeed, the dose for the differential diagnosis in one CH patient is 6-folds lower than that used to test one patient with thyroid cancer. This is obviously possible only by appropriate grouping of patients. In conclusion, emerging uses for recombinant human TSH have been reported. In the diagnosis and treatment of thyroid cancer, rhTSH has the advantage to avoid both hypothyroidism, with a major impact on the quality of life, and the side effects on tumor growth related to the long-lasting TSH increase. In benign thyroid diseases, rhTSH administration increases thyroid uptake resulting in a more homogeneous distribution of the tracer, and allows reducing the dose of 131I maintaining the same effects on thyroid shrinkage. Finally, rhTSH testing has been proved to be safe and to lead, in association with ultrasound, to the differential diagnosis of congenital hypothyroidism during L-thyroxine, allowing the appro-
L. Fugazzola / Annales d’Endocrinologie 68 (2007) 220–223
priate clinical/genetic management of the disease and thus representing a valuable alternative to L-thyroxine withdrawal.
[11]
References [12] [1]
Chin BB, Patel P, Cohade C, Ewertz M, Wahl R, Ladenson P. Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab 2004;89:91–5. [2] Fugazzola L, Persani P, Mannavola D, et al. Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during L-thyroxine replacement. Clin Endocrinol (Oxf) 2003;59:230–6. [3] Fugazzola L, Persani L, Vannucchi G, et al. Thyroid scintigraphy and perchlorate test after recombinant human TSH in paediatric age: a new tool for the differential diagnosis of congenital hypothyroidism during L-thyroxine replacement therapy. Eur J Nucl Med Mol Imaging 2007 [doi:10.1007/s00259-007-0377-6]. [4] Haugen BR, Pacini F, Reiners C, et al. Comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877–85. [5] Hegedus L, Hansen BM, Knudsen N, Hansen JM. Reduction of size of thyroid with radioactive iodine in multinodular non-toxic goiter. BMJ 1988;297:661–2. [6] Huysman DA, Hermus AR, Corstens FH, Barentsz JO, Kloppenborg PW. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994;121:757–62. [7] Ladenson PW. Recombinant thyrotropin versus thyroid hormone withdrawal in evaluating patients with thyroid carcinoma. Semin Nucl Med 2000;30:98–106. [8] Lippi F, Capezzone M, Angelini F, et al. Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH. Eur J Endocrinol 2001;144:5–11. [9] Mazzaferri EL, Kloos RT. Using recombinant human TSH in the management of well-differentiated thyroid cancer: current strategies and future directions. Thyroid 2000;10:767–78. [10] Nieuwlaat WA, Huysmans DA, Van Den Bosch HC, et al. Pretreatment with a single, low dose of recombinant human thyrotropin allows dose
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
223
reduction of radioiodide therapy in patients with nodular goiter. J Clin Endocrinol Metab 2003;88:3121–9. Nygaard B, Hegedus L, Gervil M, Hjalgrim H, Soe-Jensen P, Hansen JM. Radioiodine treatment of multinodular non-toxic goiter. BMJ 1993;307: 828–32. Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab 2006;91:926–32. Petrich T, Borner AR, Otto D, Hofmann M, Knapp WH. Influence of rhTSH on [(18)F]fluorodeoxyglucose uptake by differentiated thyroid carcinoma. Eur J Nucl Med Mol Imaging 2002;29:641–7. Robbins RJ, Tuttle RM, Sharaf RN, et al. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:619–25. Robbins RJ, Larson SM, Sinha N, et al. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002;43:1482–8. Santini F, Bottici V, Elisei R, et al. Cytotoxic effects of carboplatinum and epirubicin in the setting of an elevated serum thyrotropin for advanced poorly differentiated thyroid cancer. J Clin Endocrinol Metab 2002;87:4160–5. Silva MNC, Rubio’ IGS, Romao R, et al. Administration of a single dose of recombinant human thyrotropin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres. Clin Endocrinol 2004;60:300–8. Toublanc JE. Guidelines for neonatal screening programs for congenital hypothyroidism. Working Group for Neonatal Screening in Paediatric Endocrinology of the European Society for Paediatric Endocrinology. Acta Paediatr 1999;88(Suppl):13–4. Vannucchi G, Chiti A, Mannavola D, et al. Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium. Eur J Nucl Med Mol Imaging 2005;32:1081–8. Wesche MFT, Tiel-V Buul MMC, Lips P, Smits NJ, Wiersinga WM. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic non-toxic goiter. J Clin Endocrinol Metab 2001;86: 998–1005.