rhTSH Stimulation Research Articles

Practice trends in patients with persistent detectable thyroglobulin and negative diagnostic radioiodine whole body scans: a survey of American Thyroid Association members.

Management of patients with thyroglobulin (Tg)-positive/scan-negative thyroid cancer remains challenging. American Thyroid Association (ATA) guidelines recommend potential use of empiric (131)I therapy and various scanning modalities, but no standard for managing such cases exists. We surveyed ATA members to assess current practice in management of patients with Tg-positive/scan-negative disease. Members participated in a web-based survey of six case scenarios of Tg elevations but iodine scan negativity. A total of 288 ATA members (80% male) participated. Patient age, sex, and basal and stimulated Tg varied between the cases. Respondents were asked their opinion regarding empiric (131)I therapy use, including (131)I dose, use and duration of low-iodine diet, thyroxine withdrawal or recombinant human thyrotropin (rhTSH), and utilization of additional imaging (neck ultrasound (US) or positron emission tomography/computed tomography (PET/CT)) and reconsideration of (131)I therapy. Between 16% and 51% recommended initial use of empiric (131)I for the various scenarios. The majority chose a (131)I dose between 75 and 150 mCi, and 73% employed a low-iodine diet for two or more weeks. Preference between thyroxine withdrawal versus rhTSH was evenly split. More than 98% obtained a neck US if empiric (131)I was not given; 52-89% would proceed to PET/CT if US was negative. Only 44% used rhTSH stimulation in PET scan preparation. (131)I use was more common with stimulated Tg significantly >10 ng/mL. (131)I therapy was slightly more likely with PET-positive (56%) than PET-negative status (45%). Respondents were split regarding empiric (131)I if basal and stimulated Tg increased ≥150% over two years. Providers in North America less commonly utilized (131)I treatment than those from other areas. In the face of possible heterophilic antibody interference in the Tg assay, the majority did not recommend (131)I therapy. Empiric (131)I therapy is still utilized for patients with Tg-positive/scan-negative disease. Neck US is frequently used to further evaluate such cases as (18)FDG-PET/CT, albeit the latter is used somewhat less often. Use of (131)I therapy correlated with the degree of Tg elevation or development of Tg antibodies, and was recommended more commonly with PET-positive than PET-negative status in patients with lower Tg levels. (131)I was less commonly used by providers within North America.

Effects of recombinant human thyrotropin administration on 24-hour arterial pressure in female undergoing evaluation for differentiated thyroid cancer.

Objective. Thyroid-stimulating-hormone (TSH) receptors are expressed in endothelial cells. We investigated whether elevated TSH levels after acute recombinant TSH (rhTSH) administration may result in alterations in blood pressure (BP) in premenopausal women with well-differentiated thyroid carcinoma (DTC). Designs. Thirty euthyroid DTC female patients were evaluated by rhTSH stimulation test (mean age 40.4 ± 8.6 years). A 24 h ambulatory systolic and diastolic blood pressure (SBP, DBP) monitoring (24 hr ABPM) was performed on days 2-3(D2-3). TSH was measured on day 1(D1), day 3(D3), and day 5(D5). Central blood pressure was evaluated on D3. Twenty-three patients were studied 1–4 weeks earlier (basal measurements). Results. TSH levels were D1: median 0.2 mU/L, D3: median 115.0 mU/L, and D5: median 14.6 mU/L. There were no significant associations between TSH on D1 and D3 and any BP measurements. Median D5 office-SBP and 24 h SBP, DBP, and central SBP were correlated with D5-TSH (P < 0.04). In those where a basal 24 h ABPM had been performed median pulse pressure was higher after rhTSH-test (P = 0.02). Conclusions. TSH, when acutely elevated, may slightly increase SBP, DBP, and central SBP. This agrees with previous reports showing positive associations of BP with TSH.

RhTSH-aided low-activity versus high-activity regimens of radioiodine in residual ablation for differentiated thyroid cancer

The effects of low-activity versus high-activity radioiodine regimens in thyroid remnant ablation for patients with differentiated thyroid carcinoma (DTC) under recombinant human thyrotropin (rhTSH) stimulation have been widely quoted but there has been no systematic review of the evidence. We undertook a systematic review of randomized controlled trials to assess the effects of low-activity radioiodine in thyroid remnant ablation in patients with DTC under rhTSH stimulation compared with high-activity radioiodine. Studies were obtained from computerized searches of MEDLINE, EMBASE, and the Cochrane Library (all until September 2012). Randomized controlled trials were included. Altogether, 637 patients with DTC who participated in three trials for residual ablation were included. Overall, studies had a low risk of bias. We found no statistically significant differences between low-activity (1.11/1.85 GBq) and high-activity (3.7 GBq) radioiodine treatment aided by rhTSH in terms of successful ablation rates on the basis of diagnostic scans [odds ratio (OR) 0.85, 95% confidence interval (CI) 0.49–1.47, P=0.56], thyroglobulin levels (OR 0.66, 95% CI 0.38–1.15, P=0.14), and health-related quality of life (mean difference 0.07, 95% CI −0.96 to 1.09, P=0.9). In addition, the subgroup analysis of 1.11 versus 3.7 GBq (OR 0.83, 95% CI 0.46–1.49, P=0.53) and 1.85 versus 3.7 GBq (OR 1, 95% CI 0.23–4.35, P=1) also showed no significant differences. The lower activity of 1.11 GBq showed significant benefit in terms of reduction in adverse events including neck pain, radiation gastritis, and salivary dysfunction during and after ablation (OR 0.63, 95% CI 0.42–0.93, P=0.02). Limited data from three randomized controlled trials suggested that an rhTSH-aided low radioiodine activity level of as low as 1.115 GBq may be sufficient for thyroid remnant ablation when compared with 3.7 GBq, with fewer common adverse effects in patients with metastasis-free DTC. Further evidence is needed to confirm the effects of low-activity radioiodine for thyroid remnant ablation. Radioiodine treatment of 1.11 GBq showed significant benefit in terms of reduction in adverse events including neck pain, radiation gastritis, and salivary dysfunction during and after ablation (OR 0.63, 95% CI 0.42–0.93, P=0.02). rhTSH-aided low radioiodine activity levels of 1.11 and 1.85 GBq are sufficient for thyroid remnant ablation as compared with 3.7 GBq, with fewer common adverse effects in patients with metastasis-free DTC. A well-designed study that compares low-activity with high-activity radioiodine ablation is needed to fully understand the long-term adverse effects and relapse or metastases.

Potential Use of Recombinant Human Thyrotropin in the Treatment of Distant Metastases in Patients with Differentiated Thyroid Cancer

In order to effectively treat differentiated thyroid cancer (DTC) with radioiodine (RAI) it is necessary to raise serum TSH levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of recombinant human TSH (rhTSH). The goal of this review is to present current data on the relative efficacy and side effects profile of rhTSH-aided versus THW-aided RAI therapy for the treatment of patients with distant metastases of DTC. We have searched the PubMed database for articles including the keywords "rhTSH", "thyroid cancer", and "distant metastases" published between January 1, 1996 and January 7, 2012. As references, we used clinical case series, case reports, review articles, and practical guidelines. Exogenous stimulation of TSH is associated with better quality of life because it obviates signs and symptoms of hypothyroidism resulting from endogenous TSH stimulation. The rate of neurological complications after rhTSH and THW-aided RAI therapy for brain and spine metastases is similar. The rate of leukopenia, thrombocytopenia, xerostomia, and pulmonary fibrosis is similar after preparation for RAI treatment with rhTSH and THW. There is currently a controversy regarding RAI uptake in metastatic lesions after preparation with rhTSH versus THW, with some studies suggesting equal and some superior uptake after preparation with THW. Analysis of available retrospective studies comparing survival rates, progression free survival, and biochemical and structural response to a dosimetrically-determined dose of RAI shows similar efficacy after preparation for therapy with rhTSH and THW. The rhTSH stimulation is not presently approved by the FDA as a method of preparation for adjunctive therapy with RAI in patients with metastatic DTC. Data on rhTSH compassionate use suggest that rhTSH stimulation is as equally effective as THW as a method of preparation for dosimetry-based RAI treatment in patients with RAI-avid metastatic DTC.

Prevalence of Thyroglossal Duct Cyst Carcinoma in Adults Having Surgery for Thyroglossal Duct Cysts

Thyroglossal duct cyst (TGDcyst) is the most common developmental abnormality of the thyroid gland (1). It usually presents as an asymptomatic, soft swelling in the midline and has characteristic ultrasound features. TGDcysts are usually benign lesions but a few cases of TGDcyst carcinoma (TGDcyst-Ca), approximately 250, have been reported (2). The data regarding the prevalence of TGDcyst-Ca in adults with clinically evident TGDcysts is sparse (3). In an attempt to estimate this, at least for patients with TGDcysts that demanded intervention, we carried out a retrospective review of the patients in our hospital who underwent surgical excision of TGDcysts between 2001 and 2011. Overall there were 23 patients who were surgically treated for TGDcysts and these were either large or rapidly increasing in size TGDcysts. Among them, there were three patients with TGDcyst-Ca. The first patient was a 37-year-old woman who in October 2001 was diagnosed with a 20-mm papillary thyroid carcinoma (PTC) within a TGDcyst (pT3N0Mx). The diagnosis was based on histopathology following surgical excision of the cyst by Sistrunk procedure. A total thyroidectomy (tTx) was subsequently performed and the thyroid itself was free of PTC. Following thyroid removal, because of persistently elevated recombinant human thyrotropin (rhTSH)-stimulated serum thyroglobulin (Tg), she received five treatments with I (RAI) for a cumulative dose of 15.91 GBq, between 2002 and 2009. She was prepared for these treatments with rhTSH. PostRAI whole body scans (WBS) revealed persistent low uptake in the left hemithorax. She declined further RAI treatments. The second patient was a 42-year-old man who underwent Sistrunk surgical excision of a cystic lesion of the neck in November 2001. Histological examination revealed a 14-mm PTC within a TGDcyst. It infiltrated surrounding tissues (pT3N0Mx). In March 2002, following tTx, a 3-mm PTC was found in the left thyroid lobe, and a second 1-mm PTC focus in the contralateral lobe (pT1bN0Mx). Six months after tTx, 3.7 GBq of RAI with rhTSH preparation was administered. The post-RAI WBS was negative and serum Tg concentrations after rhTSH administration were undetectable. The third patient was a 21-year-old woman underwent surgical excision of a TGDcyst by Sistrunk procedure in March of 2010. Histopathology showed a follicular variant of PTC within the TGDcyst (pT1N0Mx). A tTx was subsequently performed and no malignancies were noted in the thyroid gland. She was treated with 4.5 GBq RAI and serum Tg concentrations after rhTSH stimulation were consistently undetectable. In our series of 23 patients who had surgery for TGDcyst, the prevalence of TGDcyst-Ca was 13%. A similar study by Patel et al. (3) of patients who had surgery for TGDcyst at a large cancer center obtained a prevalence of 14%. In our small series of three patients with TGDcyst-Ca, the thyroid gland was free of PTC in two patients. This supports the hypothesis that PTC can arise from ectopic thyroid tissue, but can remain confined to its site of origin. None of the patients with TGDcyst-Ca in our series had follicular thyroid carcinoma, squamous cell carcinoma, Hurthle cell carcinoma, or anaplastic carcinoma. This is consistent with other reports indicating that PTC is the most common cancer to occur in TGDcysts but these other tumors have also been reported (1). There is considerable controversy regarding the role of thyroidectomy in the management of TGDcyst-Ca (4). We believe that tTx should be performed on all patients in whom TGDcyst-Ca is confirmed by histopathology of the TGDcyst specimen in order to rule out occult thyroid carcinomas that might have metastasized to the TGDC, even though it is evident that not all TGDcyst-Ca are associated with carcinoma within the thyroid gland itself. Moreover, the prognosis of TGDcyst-Ca is generally good. A very large prospective study would be needed to adequately address this issue. Although all three of our patients received radioactive iodine ablation the value of this treatment is unclear; future guidelines should address this issue. In summary, most patients who present with a large or clearly growing TGDcyst have a good prognosis, not only because most such lesions do not harbor cancer, but also because in many of them who do harbor cancer, this is confined to the TGDcyst. Nevertheless, we advocate that such lesions have prompt surgical treatment.

Undetectable Sensitive Serum Thyroglobulin (&amp;lt;0.1 ng/ml) in 163 Patients with Follicular Cell-Derived Thyroid Cancer: Results of rhTSH Stimulation and Neck Ultrasonography and Long-Term Biochemical and Clinical Follow-Up

Surveillance of patients with differentiated thyroid cancer (DTC) is achieved using serum thyroglobulin (Tg), neck ultrasonography (US), and recombinant human TSH (rhTSH)-stimulated Tg (Tg-stim). Our primary aim was to assess the utility of rhTSH Tg-stim in patients with suppressed Tg (Tg-supp) below 0.1 ng/ml using a sensitive assay. Our secondary aims were to assess the utility of US and to summarize the profile of subsequent Tg-supp measures. This is a retrospective study conducted at two sites of an academic institution. A total of 163 patients status after thyroidectomy and radioactive iodine treatment who had Tg-supp below 0.1 ng/ml and rhTSH Tg-stim within 60 d of each other were included. After rhTSH stimulation, Tg remained below 0.1 ng/ml in 94 (58%) and increased to 0.1-0.5 in 56 (34%), more than 0.5-2.0 in nine (6%), and above 2.0 ng/ml in four (2%) patients. Serial Tg-supp levels were obtained in 138 patients followed over a median of 3.6 yr. Neck US were performed on 153 patients; suspicious exams had fine-needle aspiration (FNA). All positive FNA were identified around the time of the initial rhTSH test. Six of seven recurrences were detected by US (Tg-stim >2.0 ng/ml in one, 0.8 in one and ≤ 0.5 in four). One stage IV patient had undetectable Tg-stim. In patients with DTC whose T(4)-suppressed serum Tg is below 0.1 ng/ml, long-term monitoring with annual Tg-supp and periodic neck US are adequate to detect recurrences. In our experience, rhTSH testing does not change management and is not needed in this group of patients.

Letter to the Editor: Lymph nodes thyroglobulin measurement after rhTSH stimulation

Letter to the Editor: Lymph nodes thyroglobulin measurement after rhTSH stimulation

Radioiodine Thyroid Remnant Ablation after Recombinant Human Thyrotropin or Thyroid Hormone Withdrawal in Patients with High-Risk Differentiated Thyroid Cancer

To supplement limited relevant literature, we retrospectively compared ablation and disease outcomes in high-risk differentiated thyroid carcinoma (DTC) patients undergoing radioiodine thyroid remnant ablation aided by recombinant human thyrotropin (rhTSH) versus thyroid hormone withdrawal/withholding (THW). Our cohort was 45 consecutive antithyroglobulin antibody- (TgAb-) negative, T3-T4/N0-N1-Nx/M0 adults ablated with high activities at three referral centers. Ablation success comprised negative (<1 μg/L) stimulated serum thyroglobulin (Tg) and TgAb, with absent or <0.1% scintigraphic thyroid bed uptake. “No evidence of disease” (NED) comprised negative unstimulated/stimulated Tg and no suspicious neck ultrasonography or pathological imaging or biopsy. “Persistent disease” was failure to achieve NED, “recurrence,” loss of NED status. rhTSH patients (n = 18) were oftener ≥45 years old and higher stage (P = 0.01), but otherwise not different than THW patients (n = 27) at baseline. rhTSH patients were significantly oftener successfully ablated compared to THW patients (83% versus 67%, P < 0.02). After respective 3.3 yr and 4.5 yr mean follow-ups (P = 0.02), NED was achieved oftener (72% versus 59%) and persistent disease was less frequent in rhTSH patients (22% versus 33%) (both comparisons P = 0.03). rhTSH stimulation is associated with at least as good outcomes as is THW in ablation of high-risk DTC patients.

Particularités méthodologiques et interprétation du dosage de thyroglobuline sérique

Thyroglobulin (Tg) is a large glycoprotein produced and excreted by thyrocytes exclusively. Thus, Tg is a central marker for the follow-up of differentiated thyroid cancer (DTC). This review presents recent analytical and related clinical advances in Tg assay. Indeed, recent advances in Tg assay challenge the previous use of the assay in the management of DCT. Indeed, a recent assay seems sensitive enough to be used to predict DTC differentiated recurrences without stimulation of thyrocytes by rhTSH. This improvement in analytical sensitivity is combined with international standardisation and reduced interferences by Tg autoantibodies. Such assays could reduce the cost of DCT follow-up by associating echography with a single assay, reducing the need of rhTSH stimulation to rare ambiguous cases.

Decreased serum vascular endothelial growth factor‐D levels in metastatic patients with differentiated thyroid carcinoma

Vascular endothelial growth factor-D (VEGF-D) has been identified as one of the lymphangiogenic growth factors involved in metastatic diffusion. The aim of this study is to evaluate the serum VEGF-D levels in patients with differentiated thyroid cancer at different conditions of disease. We studied prospectively the VEGF-D plasma levels in 96 subjects affected by differentiated thyroid cancer. The patients were divided into three groups according to the clinical and biochemical findings: patients with no evidence of disease (Cured), patients with pathological (>1 ng/ml) stimulated thyroglobulin (Tg) (Path-Tg/rhTSH) levels only after rhTSH and patients with elevated basal Tg levels (Path-Tg/LT4). The serum VEGF-D concentrations in patients of group Cured were not different from the controls, while group Path-Tg/rhTSH showed baseline serum VEGF-D levels significantly lower than group Cured and controls (P < 0·001 and P < 0·01, respectively). Moreover, the patients of group Path-Tg/LT4 showed median serum cytokine concentrations at baseline not significantly different from the patients of group Path-Tg/rhTSH. The rhTSH stimulation did not modify the difference in serum VEGF-D levels in patients of group Cured and group Path-Tg/rhTSH. Our data demonstrate that the VEGF-D serum levels are reduced in patients with metastases of differentiated thyroid cancer, regardless of the degree of metastatic spread. It is possible that some other molecule produced by the tumoral tissue could affect the VEGF-D physiologically produced of from different tissues, thus conducting to a decrease in the VEGF-D found in blood of patients with evidence of metastatic differentiated thyroid cancer.

Usefulness of repeated recombinant human thyrotropin-stimulated thyroglobulin test in the post-surgical follow-up of very low-risk patients with differentiated thyroid carcinoma.

The European Thyroid Association (ETA) and the American Thyroid Association (ATA) guidelines identify subgroups of patients affected by thyroid carcinoma in whom, due to a low risk of recurrence, radioiodine ablation is not indicated. These patients are referred to as "very low-risk" according to the ETA consensus and "low-risk" patients according to the ATA guidelines. The recommended post-surgical follow-up of these patients is based upon periodical measurements of serum thyroglobulin (Tg) on levothyroxine therapy and neck ultrasound (US). To evaluate the usefulness of recombinant human (rh)-TSH Tg test and its repetition 2-3 yr afterwards in very low-risk patients. We consecutively enrolled 32 patients with undetectable anti-Tg antibodies. Basal serum Tg levels was undetectable in all patients. Following rhTSH serum Tg remained undetectable in 23 (71.9%) patients (UP) and was >1.0 ng/ml in 9 (DP). US and whole body scan, revealed lymph node metastasis in 4/9 DP patients. A second rhTSH stimulation test (36.9±3.5 months later) was performed in all UP and in 5 DP patients without proven recurrences. All the UP and 4/5 formerly DP patients showed undetectable Tg stimulation. Our results suggest that rhTSH Tg test may be helpful in very low-risk patients, given its ability to differentiate those who may be considered "free of disease" from those who require further investigation and treatment. Repeated rhTSH Tg tests may be indicated only in patients with detectable serum Tg at prior stimulation testing.

Radioiodine for remnant ablation and therapy of metastatic disease

Radioiodine is considered an effective and low-risk therapy modality of advanced differentiated thyroid cancer. For patients without lymph-node or distant metastases and low stages of the primary tumor, debate is ongoing about the necessity of thyroid remnant tissue ablation in an adjuvant setting. On the basis of evidence from retrospective studies, and until results of ongoing controlled prospective randomized trials become available, (131)I ablation of remnant thyroid tissue in patients with primary tumors >1 cm is advisable. For thyroid remnant ablation, individual dosimetry is not obligatory. By contrast, the effectiveness of (131)I therapy of locally advanced and/or metastatic disease can be improved by individual dosimetry. For practical reasons, an approach delivering the maximal possible radiation dose to the tumor without exceeding a critical blood dose of approximately 2 Gy seems advantageous. The availability of recombinant human TSH (rhTSH) has improved the quality of life of patients and reduces the radiation exposure of healthy nonthyroid tissue compared with TSH stimulation through levothyroxine withdrawal. In patients with distant metastases, rhTSH stimulation is possible only in off-label use, from which especially elderly and frail patients may benefit, as they most severely suffer from hypothyroidism caused by thyroid hormone withdrawal.

Thyroglobulin measurement in fine‐needle aspiration biopsy of metastatic lymph nodes after rhTSH stimulation

Thyroglobulin measurement in the washout of the needle used in fine-needle aspiration cytology (FNAC) has been proposed for the early detection of lymph node metastasis both in patients with or without serum thyroglobulin antibodies; however, up to now, there have been no reports that recombinant human thyrotropin (rhTSH) stimulation modifies thyroglobulin measurement in lymph node aspirates. We described, after rhTSH stimulation, the switching from undetectable to detectable levels of thyroglobulin in fine-needle aspiration fluid from a suspected metastatic lymph node in 2 patients. We hypothesized that thyroglobulin levels in the lymph node increased after rhTSH stimulation. The excess thyroglobulin saturates all thyroglobulin antibody binding sites and becomes detectable, explaining why it was undetectable when TSH was suppressed. On the basis of our experience, we suggest submitting to thyroglobulin measurement in the washout of the needle used in FNAC all patients with detectable serum thyroglobulin antibody after rhTSH stimulation.

Five-Year Survival Is Similar in Thyroid Cancer Patients with Distant Metastases Prepared for Radioactive Iodine Therapy with either Thyroid Hormone Withdrawal or Recombinant Human TSH

Context:Elevated levels of TSH markedly enhance the effectiveness of radioiodine (RAI) therapy in metastatic thyroid cancer.Objective:The objective of the study was to compare short-term overall survival in thyroid cancer patients with RAI-avid distant metastases prepared for RAI therapy with either traditional thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) stimulation.Design:This was a retrospective chart review.Setting:The study was conducted at a tertiary care comprehensive cancer center.Patients:Patients included 175 patients with RAI avid metastatic disease to lung and/or bone.Interventions:In 58 patients, all RAI treatments (remnant ablation and therapy of metastatic disease) were done with rhTSH stimulation. In 35 patients, all RAI treatments were done after THW. In 82 patients, THW was used for initial RAI treatment(s) with subsequent administered activities given after rhTSH stimulation.Main Outcome Measure:Overall survival was measured.Results:After a median follow-up of 5.5 yr, there were no significant differences in overall survival between patients prepared for RAI therapy with rhTSH alone, THW alone, or THW followed by rhTSH (Kaplan-Meier analysis,P = 0.80). In a multivariate analysis that included clinicopathological features and method of preparation (rhTSH or TWH), only age at diagnosis was an independent predictor of overall survival.Conclusions:Preparation for RAI therapy using either THW or rhTSH stimulation was associated with similar 5-yr overall survival rates in patients with RAI avid thyroid cancer metastases to lung or bone.

The use of ultrasensitive thyroglobulin assays reduces but does not abolish the need for TSH stimulation in patients with differentiated thyroid carcinoma.

Measurement of serum Tg using ultrasensitive assays is proposed to replace TSH-stimulated Tg measurement in the follow-up of differentiated thyroid cancer (DTC). Aim of our study was to verify this possibility using two ultrasensitive Tg assays. We selected 215 DTC patients with undetectable (<1 ng/ml) basal serum Tg at the time of a recombinant human TSH (rhTSH) stimulation. According to standard criteria, 173 (80.4%) patients were considered free of disease, 17 (7.9%) had documented disease and 25 (11.7%) had no evidence of disease but detectable serum rhTSH-stimulated Tg (biochemical disease). The sera of these patients were re-assayed with two commercial ultrasensitive assays and the results were compared with the clinical data. Basal Access and E-Iason Tg assays were able to distinguish patients with persistent disease or free of disease with a sensitivity of 82.3 and 82.3%, specificity of 85.5 and 86.1%, positive predictive value (PPV) of 35.8 and 36.8%, negative predictive value (NPV) of 98 and 98.6%, respectively. With both assays the addition of neck ultrasound to basal Tg increased the sensitivity and the NPV to 100% and decreased the false negative rate to 0%. In patients with detectable basal Tg without evidence of disease, serum Tg converted from detectable to undetectable in about 80% of the cases during 2-yr follow-up. Our study indicates that the combination of neck ultrasound and basal ultrasensitive Tg allows to identify all patients free of disease and can decrease the need for rhTSH stimulation in nearly 80% of the patients.

Heath-related quality of life in thyroid cancer patients following radioiodine ablation

BackgroundThere is limited information about the medium to long-term health-related quality of life (QOL) in thyroid cancer patients after initial therapy and the existing studies suffer from limitations. The aim of the study was to assess the determinants of medium-term QOL after the initial therapy.MethodsFollowing a total thyroidectomy, 88 thyroid cancer patients received either rhTSH or hypothyroid-assisted radioiodine ablation (RRA) using 3.7 GBq (100 mCi) of radioiodine. QOL evaluation of the patients using the validated Functional Assessment of Chronic Illness & Therapy (FACIT) was performed at the time of inclusion (t0) and later at the 9-month post-RRA (t1).Results83 patients were eligible for the final evaluation. Medium-term FACIT scores were not statistically different between t0 and t1 patients. All but one domain of the QOL score was similar between t0 and t1. Using a multivariate analysis, only age and immediate postoperative QOL scores were found to be determinants of the overall medium term 9-month QOL scores. Analysis showed that 'high QOL levels' (baseline and 9-month) and 'no depression', 'low anxiety levels', were associated with '<45yrs', 'men', 'partner', and 'rhTSH stimulation'.ConclusionsThe use of radioiodine ablation does not seem to affect the medium term QOL scores of patients. Medium-term QOL is mainly determined by pre-ablation QOL. The assessment of baseline QOL might be interesting to evaluate in order to adapt the treatment protocols, the preventive strategies, and medical information to patients for potentially improving their outcomes.

Does an undetectable rhTSH‐stimulated Tg level 12 months after initial treatment of thyroid cancer indicate remission?

Routine monitoring after the initial treatment of differentiated thyroid cancer (DTC) includes periodic cervical ultrasonography (US) and measurement of serum thyroglobulin (Tg) during thyrotrophin (TSH) suppression and after recombinant human TSH (rhTSH) stimulation. The aim of our study was to evaluate the utility of repeated rhTSH-stimulated Tg measurements in patients with DTC who have had no evidence of disease at their initial rhTSH stimulation test performed 1 year after the treatment. A retrospective chart review of 278 patients with DTC who had repeated rhTSH stimulation testing after an initial undetectable rhTSH-stimulated serum Tg level. The number of rhTSH stimulation tests performed on individual patients during the follow-up period (3-12 years, mean 6·3) varied from two to seven. Biochemical and/or cytological evidence of potential persistent/recurrent disease based on detectable second or third rhTSH-stimulated Tg values and US findings was observed in 11 (4%) patients. Subsequent follow-up data revealed that in five cases, the results of the second stimulation were false positive, in one case - false negative. Combined with the negative neck US, the negative predictive value for disease-free survival was 98% after the first undetectable rhTSH-stimulated Tg and 100% after the second one. In patients with DTC, the intensity of follow-up should be adjusted to new risk estimates evolving with time. The first rhTSH-stimulated Tg is an excellent predictor for remission, independent of clinical stage at presentation. Second negative rhTSH-Tg stimulation is additionally reassuring and can guide less aggressive follow-up by the measurement of nonstimulated Tg and neck US every few years.

Recombinant human thyrotropin (rhTSH) aided radioiodine treatment for residual or metastatic differentiated thyroid cancer.

For patients with differentiated thyroid cancer (DTC) following thyroidectomy, thyroid hormone withdrawal (THW) for four to six weeks has been used for decades to increase serum thyroid-stimulating hormone (TSH) concentrations in order to enhance iodine-131 uptake by normal thyroid cells and differentiated thyroid tumour cells. Exogenous stimulation with recombinant human thyroid-stimulating hormone (rhTSH) offers an alternative to THW while avoiding the morbidity of hypothyroidism. However, the efficacy of rhTSH-aided iodine-131 treatment for residual or metastatic DTC has not been prospectively assessed. To assess the effects of rhTSH-aided radioiodine treatment for normal residual or metastatic DTC. We obtained studies from computerised searches of MEDLINE, EMBASE and The Cochrane Library (all until November 2009), and paper collections of conferences held in Chinese. Randomised controlled clinical trials and quasi-randomised controlled clinical trials comparing the effects of rhTSH with THW on iodine-131 treatment for residual or metastatic differentiated thyroid cancer with at least six months of follow up. Two authors independently assessed risk of bias and extracted data. Altogether 223 patients with DTC participated in four trials. Overall, studies had a high risk of bias. We found no statistically significant differences between rhTSH and THW treatment in terms of successful ablation rate but significant benefits in radiation exposure to blood and bone marrow. One trial reported on benefits in some domains of health-related quality of life. There were no deaths and no serious adverse effects in DTC patients treated with either rhTSH or THW. Maximum follow up was 12 months. None of the included trials investigated complete or partial remission of metastatic tumour, secondary malignancies or economic outcomes. We did not find sufficient data comparing rhTSH with THW-aided radioiodine treatment for metastatic DTC. Results from four randomised controlled clinical trials suggest that rhTSH is as effective as THW on iodine-131 thyroid remnant ablation, with limited data on significant benefits in decreased whole body radiation exposure and health-related quality of life. It is still uncertain whether lower iodine-131 doses (1110 MBq or 1850 MBq versus 3700 MBq) are equally effective for remnant ablation under rhTSH stimulation. Randomised controlled clinical trials are needed to guide treatment selection for metastatic differentiated thyroid cancer.

On the effectiveness of recombinant human TSH as a stimulating agent for 131I treatment of metastatic differentiated thyroid cancer

Radiotherapy with I is the most effective treatment of iodine-avid metastases of differentiated thyroid cancer. Early diagnosis of metastases and repeated treatment with high activities of I improve outcome and allow complete remission in a substantial percentage of metastatic patients [1, 2]. However, treatment efficacy is subordinated to the ability of cancer cells to concentrate I. In patients whose metastases show no initial I uptake, the 10-year survival can be as low as 10% [3]. Therefore, before I administration, it is necessary to achieve high serum thyroid-stimulating hormone (TSH) levels in order to induce cancer cells to overexpress the sodium-iodide symporter, and thus enhance their iodine-trapping ability. Traditionally, high TSH levels (at least 30–50 mIU/l) have been achieved endogenously through several weeks of thyroid hormone withdrawal. However, the ensuing clinical hypothyroidism may lead to important morbidity and reduced quality of life. Recombinant human TSH (rhTSH) was developed to elevate serum TSH exogenously in euthyroid patients, thus obviating hypothyroid morbidity. In the therapeutic setting, the use of rhTSH has been approved as a preparation method for remnant ablation with 3.7 GBq (100 mCi) I by both the US Food and Drug Administration and the European Medicine Agency in welldifferentiated thyroid cancer without evidence of distant metastases. Although rhTSH has not undergone phase III study for the treatment of known distant metastases, it has been used off-label since the 1990s to treat frail patients in whom thyroid hormones could not be interrupted. It has also been used in patients unable to raise an adequate endogenous TSH response, either because of hypopituitarism or continued production of thyroid hormones by thyroid remnants or metastatic tumour [4]. Although rhTSH does have a stimulating effect on cancer cells [4], there are only a few studies comparing the respective efficacy of rhTSH stimulation and hormone withdrawal to enhance radioiodine uptake into metastatic lesions. The large study by Freudenberg and colleagues in the present issue of the European Journal of Nuclear Medicine and Molecular Imaging [5] provides important insights into the biological efficacy of rhTSH to stimulate iodine concentration in cancer cells. The authors compared dosimetric data from two groups of metastatic thyroid cancer patients, in whom stimulation was achieved either by traditional thyroid hormone withdrawal or by rhTSH injection. I PET/CT, the state-of-the-art method of measuring radioiodine kinetics in thyroid cancer lesions, was used to calculate the dose that would be absorbed in metastases after administration of a normalized activity of I. The authors found that the mean absorbed dose for the rhTSH group was only 60% of that of the withdrawal group (30.6 Gy/GBq vs 51.8 Gy/GBq). Themean difference was not statistically significant, but 85% of the confidence interval encompassed differences favouring hormone withdrawal. Although these findings are suggestive of a better efficacy of hormone withdrawal at concentrating I in cancer cells, they should still be considered with caution, as this is a retrospective, non-randomized study, in which the criteria for choosing the stimulation method were subjective, decided case by case and not systematically recorded. As a consequence, the two populations in this study differ to some P. Zanotti-Fregonara (*) Medecine Nucleaire, Hopital Saint Antoine, Assistance Publique-Hopitaux de Paris, 184 Rue du Fbg St. Antoine, 75571 Paris Cedex 12, France e-mail: fregonara@hotmail.com

Serum Basal Thyroglobulin Measured by a Second-Generation Assay Correlates with the Recombinant Human Thyrotropin–Stimulated Thyroglobulin Response in Patients Treated for Differentiated Thyroid Cancer

Recombinant human thyrotropin (rhTSH) stimulation is frequently used to assess the disease status of patients treated for differentiated thyroid cancer (DTC) when basal (unstimulated) thyroglobulin (b-Tg) is below the assay sensitivity limit. The objective of this study was to determine relationships between the b-Tg and the 72-hour rhTSH-stimulated Tg (rhTSH-Tg) using a second-generation immunochemiluminometric assay with a functional sensitivity of 0.05 ng/mL (microg/L). Serum Tg was measured in paired b-Tg and rhTSH-Tg specimens from 1029 rhTSH tests performed on 849 TgAb-negative patients during long-term monitoring for DTC. Basal Tg correlated with rhTSH-Tg across b-Tg concentrations ranging from 0.05 to 1000 ng/mL (microg/L) (r = 0.85, p < 0.0001). The b-Tg concentration was unrelated to age, sex, basal TSH, 72-hour TSH, or the Tg fold response (rhTSH-Tg/b-Tg). Further, only 2/655 (0.3%) tests with b-Tg below 0.1 ng/mL (microg/L) had rhTSH-Tg above 2.0 ng/mL (microg/L) (2.9 and 3.8 ng/mL [microg/L], respectively). Thirty-three patients with three or more rhTSH tests performed over a 2- to 5-year period displayed high indexes of individuality for both the 72-hour TSH and the Tg fold response (indexes of individuality = 0.30 and 0.38, respectively). Basal Tg measured using a first-generation assay with a functional sensitivity of 0.9 ng/mL (microg/L) failed to reliably detect an rhTSH-Tg response above 2.0 ng/mL (microg/L). An rhTSH-Tg response above 2.0 ng/mL (microg/L) was highly unlikely when b-Tg was below 0.1 ng/mL (microg/L). Second-generation b-Tg measurements correlated with the degree of rhTSH-Tg stimulation and thus the likelihood of having rhTSH-Tg above the customary cut-off of 2.0 ng/mL (microg/L), whereas b-Tg measured by a first-generation assay did not. Correlations between four different assays showed that the use of a fixed Tg cut-off was influenced by assay selection. Patients receiving repetitive rhTSH tests had highly reproducible rhTSH-Tg/b-Tg fold responses, suggesting that repetitive testing is unnecessary and that second-generation measurement of b-Tg trends without rhTSH stimulation would be satisfactory for the long-term monitoring of most patients with DTC.