Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma - a critical review and evaluation of the existing evidence.

PURPOSE: Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. METHODS: An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose-response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: For the outcome "SPM", the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome "SHM", reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was "very low" regarding SPM after RAI and regarding a dose-response relationship, and "low" for SHM after RAI. CONCLUSION: Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small.

High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy.

Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500-800 mGy, subclinical hypothyroidism has been detected in 3%-6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.

Hypothyroidism after radiation exposure: brief narrative review.

The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10-20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 "internal radiation therapy" of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3-5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.

The time point of completion thyroidectomy has no prognostic impact in patients with differentiated thyroid cancer.

BACKGROUND: After partial resection of the thyroid gland, a second operation referred to as "completion thyroidectomy" may be required if histopathological analysis indicates the presence of differentiated thyroid cancer (DTC). Although there is little evidence, it is assumed that the time point of completion thyroidectomy is not critical for oncological prognosis of patients with DTC. We assessed whether patients with total thyroidectomy (TTx) in a two-step procedure have an equal long-term prognosis with regard to disease-specific survival (DSS) compared to patients immediately undergoing total thyroidectomy in a one-step procedure. METHODS: A database study using the Würzburg thyroid cancer database with 2258 patients with pT1a-pT4b tumours DTC who were operated between 1980 and 2016 was carried out. RESULTS: A total of 277 patients with papillary microcarcinoma pT1aN0M0 were treated by hemithyroidectomy. TTx as one-step procedure was performed in 1114 patients compared to 867 with TTx as a two-step procedure. Patients with papillary thyroid cancer more frequently had a TTx as one-step procedure than follicular thyroid cancer patients (59.4% vs 47%; P < 0.001). Compared to a one-step thyroidectomy, overall complication rate was not different compared to patients undergoing a single operation. Multivariate analysis showed that the presence of distant metastases, T-stage and age at diagnosis were the only independent determinants for DTC-specific survival, regardless of a one- or two-time thyroidectomy. CONCLUSION: The present study on the largest of such patient collectives provides evidence that a delayed completion operation does not affect DSS in DTC, nor does it lead to a significant increase in complication rates.

The effects of the Union for International Cancer Control/American Joint Committee on Cancer Tumour, Node, Metastasis system version 8 on staging of differentiated thyroid cancer: a comparison to version 7.

OBJECTIVE: To assess the changes resulting from the changes from UICC/AJCC TNM version 7 to version 8 and to subsequently determine whether TNM version 8 is an improvement compared to previous iterations of the TNM system and other staging systems for differentiated thyroid cancer (DTC) with regard to prognostic power. DESIGN: Database study of DTC patients treated in our centre between 1978 up to and including 1 July 2014. Results were compared to our previous comparison of prognostic systems using the same data set. PATIENTS: 2257 DTC patients. MEASUREMENTS: Staging in accordance with TNM 7 and TNM 8. Thyroid cancer-specific mortality; comparison was based on p-values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). RESULTS: There is a redistribution from stage 3 to lower stages affecting 206 (9.1%) patients. DTC-related mortality according to Kaplan-Meier for younger and older patients in TNM 7 had a slightly lower prognostic power than that in accordance with TNM 8 (P = 8.0 10-16 and P = 1.5 10-21 , respectively). Overall staging is lower in 627/2257 (27.8%) patients. PVE (TNM 7: 0.29; TNM 8: 0.28) and the P-value of Cox regressions (TNM 7: P = 7.1*10-52 ; TNM 8: P = 3.9*10-49 ) for TNM version 8 are marginally lower than that for TNM version 7, but still better than for any other DTC staging system. CONCLUSION: TNM 8 results in a marked downstaging of patients compared to TNM 7. Although some changes, like the change in age boundary, appear to be associated with an improvement in prognostic power, the overall effect of the changes does not improve the predictive power compared to TNM 7.

Only a Rapid Complete Biochemical Remission After 131I-Therapy is Associated with an Unimpaired Life Expectancy in Differentiated Thyroid Cancer.

The objective of the work was to investigate the relationship between thyroglobulin doubling time (TgDT) as a marker of speed of response to 131I-therapy and the differentiated thyroid cancer (DTC) recurrence rate, DTC specific mortality rate, and relative survival rate in a DTC population followed over a long period of time after 131I-therapy. From our database, data of 1354 patients were reviewed. TgDT could be calculated in 174 patients, however, 376 patients did not have sufficient Tg values available for TgDT calculation and 804 patients reached biochemical remission before a sufficient number of Tg measurements for TgDT calculation was acquired. Main outcome measures were recurrence-free, DTC specific, and relative survival rates. In patients<45 years, TgDT in multivariate analysis was identified as the solitary significant determinant of DTC specific and relative survival. In patients≥45 years of age at diagnosis, TgDT is an independent, but not the only determinant of recurrence free, DTC specific, and relative survival. Importantly, in this age group life expectancy is normal in patients reaching rapid biochemical remission (i. e., before TgDT can be calculated); it was reduced in patients with a negative TgDT, which normally is deemed a marker of response to therapy. Only DTC patients with a rapid biochemical remission have a very good prognosis with a normal life expectancy. If no rapid biochemical remission occurs, both biochemically progressive disease and a slower biochemical remission of disease are associated with a reduced prognosis, especially in older DTC patients.

Exercise-Induced Hypoxemia in Juvenile Thyroid Carcinoma With Lung Metastases.

PURPOSE: Exercise-induced arterial hypoxemia (EIAH) has been reported in patients with juvenile thyroid cancer treated with radioiodine for lung metastases. This retrospective study tested the hypothesis that EIAH is due to ventilation-perfusion-mismatch in this rare pulmonary condition. METHOD: 50 patients (age 13-23 years) treated for juvenile thyroid carcinoma and lung metastasis with 131I and 24 controls with thyroid cancer but without lung metastases and prior 131I-treatment were assessed in a state of acute hypothyroidism by com-puted tomography of the lungs, pulmonary function testing, cardiopulmonary exercise test with measurements of gas exchange, oxygen saturation, alveolar-arterial difference in pO2 (p(A-a)O2) and pCO2 (p(ET-a)CO2). RESULTS: 10 of the 50 patients with lung metastases showed EIAH. They had more pronounced pulmonary fibrosis on computed tomography, a widened p(A-a)O2, and p(ET-a)CO2, a lower DVE/DVCO2-slope, a lower respiratory rate and no increased dead space ventilation. A more pronounced EIAH was associated with male gender, younger age, lower diffusion capacity, higher p(ET-a)CO2 during exercise and a higher peak exercise tidal volume over vital capacity ratio. CONCLUSION: EIAH in patients with thyroid carcinoma and pulmonary metastases is not related to ventilation-perfusion mismatch but to alveolar hypoventilation, possibly related to an increased work of breathing with pulmonary fibrosis.

Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.

Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case-control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC.

The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer.

OBJECTIVE: Many prognostic systems have been developed for differentiated thyroid cancer. It is unclear which one of these performs 'best'. Our aim was to compare staging systems applicable to our patient database to identify which best predicts DTC-related loss of life expectancy and DTC-specific mortality. DESIGN: Database study of patients with DTC treated in our centre between 1978 (earliest available data) up to and including 1 July 2014. All were staged in accordance with the AMES, Clinical Class, Memorial Sloan Kettering, Ohio State University, TNM versions 5 and 6/7, University of Alabama, University of Münster and qTNM systems. PATIENTS: A total of 2257 patients with differentiated thyroid cancer. MEASUREMENTS: Loss of life expectancy expressed as relative survival and thyroid cancer-specific mortality. Comparison was based on P values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). RESULTS: Median available follow-up time was 7·2 years (range: 0-35·1 years). Three hundred and twenty-seven patients died, 149 of whom died of DTC. Version 7 of the TNM system was best for predicting DTC-related mortality (P = 7·1 × 10-52 ; PVE = 0·296), followed by TNM version 5 (P = 6·7 × 10-44 ; PVE = 0·255). For prediction of loss of life expectancy, version 7 of the TNM system was also best, closely followed by the Clinical Class system (P both < 2 × 10-16 ). CONCLUSIONS: The UICC/AJCC TNM system version 7 outperforms other prognostic classification systems based on extent of disease at the start of treatment both for prediction of differentiated thyroid cancer-related death and for prediction of loss life expectancy.

Endogenous TSH levels at the time of 131I ablation do not influence ablation success, recurrence-free survival or differentiated thyroid cancer-related mortality.

PURPOSE: Based on a single older study it is established dogma that TSH levels should be ≥30 mU/l at the time of postoperative 131I ablation in differentiated thyroid cancer (DTC) patients. We sought to determine whether endogenous TSH levels, i.e. after levothyroxine withdrawal, at the time of ablation influence ablation success rates, recurrence-free survival and DTC-related mortality. METHODS: A total of 1,873 patients without distant metastases referred for postoperative adjuvant 131I therapy were retrospectively included from 1991 onwards. Successful ablation was defined as stimulated Tg <1 µg/l. RESULTS: Age, gender and the presence of lymph node metastases were independent determinants of TSH levels at the time of ablation. TSH levels were not significantly related to ablation success rates (p = 0.34), recurrence-free survival (p = 0.29) or DTC -elated mortality (p = 0.82), but established risk factors such as T-stage, lymph node metastases and age were. Ablation was successful in 230 of 275 patients (83.6 %) with TSH <30 mU/l and in 1,359 of 1,598 patients (85.0 %) with TSH ≥30 mU/l. The difference was not significant (p = 0.55). Of the whole group of 1,873 patients, 21 had recurrent disease. There were no significant differences in recurrence rates between patients with TSH <30 mU/l and TSH ≥30 mU/l (p = 0.16). Ten of the 1,873 patients died of DTC. There were no significant differences in DTC-specific survival between patients with TSH <30 mU/l and TSH ≥30 mU/l (p = 0.53). CONCLUSION: The precise endogenous TSH levels at the time of 131I ablation are not related to the ablation success rates, recurrence free survival and DTC related mortality. The established dogma that TSH levels need to be ≥30 mU/l at the time of 131I ablation can be discarded.

Determinants of successful ablation and complete remission after total thyroidectomy and ¹³¹I therapy of paediatric differentiated thyroid cancer.

PURPOSE: In adult differentiated thyroid cancer (DTC) patients, successful ablation and the number of (131)I therapies needed carry a prognostic significance. The goal was to assess the prognosis of DTC in children and adolescents treated in our centre in relation to the number of treatments needed and to establish the determinants of both complete remission (CR) and successful ablation. METHODS: Seventy-six DTC patients <21 years of age at diagnosis were included. Recurrence and death rates, rates of CR (=negative stimulated thyroglobulin, negative neck ultrasound and negative (131)I whole-body scintigraphy) and successful ablation (=CR after initial (131)I therapy) were studied. RESULTS: No patients died of DTC. Seven patients were treated by surgery alone and did not show signs of recurrence during follow-up. Of the 69 patients also treated with (131)I therapy, 47 patients achieved CR, 25 of whom had successful ablation. In multivariate analysis, female gender and the absence of distant metastases were independent determinants of a higher CR rate. Female gender, lower T stage and higher (131)I activity (successful ablation, median activity 3.1 GBq, unsuccessful ablation 2.6 GBq) were determinants of a higher rate of successful ablation. After (131)I therapy no patient showed recurrence after reaching CR or disease progression if CR was not reached. CONCLUSION: In our paediatric DTC population prognosis is extremely good with no deaths or recurrences occurring regardless of the number of (131)I therapies needed or whether CR was reached. The determinants of CR and successful ablation can be used to optimize the chance of therapy success.

Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation.

Long-term management of patients with differentiated thyroid cancer (DTC) commonly includes TSH-suppressive therapy with L-T4 and, in case of postsurgical hypoparathyroidism, Calcium-D3 supplementation, both of which may affect skeletal health. Experience with female patients treated for DTC at a young age and who were then receiving long-term therapy with L-T4 and Calcium-D3 medication is very limited to date. This cross-sectional study set out to investigate effects of Calcium-D3 supplementation and TSH-suppressive therapy on bone mineral density (BMD) in 124 young female patients treated for DTC at a mean age of 14 years and followed-up for an average of 10 years. BMD was found to be significantly higher in patients receiving Calcium-D3 medication than in patients not taking supplements. The level of ionized calcium was the strongest factor determining lumbar spine BMD in patients not receiving Calcium-D3 supplementation. Pregnancy ending in childbirth and HDL-cholesterol were associated with a weak adverse effect on spine and femoral BMD. No evidence of adverse effects of L-T4 and of radioiodine therapies on BMD was found. We conclude that Calcium-D3 medication has a beneficial effect on BMD, and that TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up.

The number of 131I therapy courses needed to achieve complete remission is an indicator of prognosis in patients with differentiated thyroid carcinoma.

PURPOSE: To assess the risk of differentiated thyroid cancer (DTC) recurrence, DTC-related mortality and life expectancy in relation to the number of courses of (131)I therapy (RIT) and cumulative (131)I activities required to achieve complete remission (CR). METHODS: The study was a database review of 1,229 patients with DTC, 333 without and 896 with CR (negative TSH-stimulated thyroglobulin and negative (131)I diagnostic whole-body scintigraphy) after one or more courses of RIT. RESULTS: The median follow-up was 9.0 years (range 0.1 - 31.8 years) after CR. Recurrence rates at 5 years, 10 years and the end of follow-up were 1.0 ± 0.3%, 4.0 ± 0.7 % and 6.2 ± 1.1 %, and DTC-related mortality was 0.1 ± 0.1%, 0.5 ± 0.3% and 3.4 ± 1.1%, respectively. Recurrence rates also increased with an increasing number of RIT courses required (p = 0.001). DTC-related mortality increased from four RIT courses. In patients with CR after one RIT course, there were no differences in recurrence or DTC-related mortality rates between low-risk and high-risk patients. In patients requiring two RIT courses these rates remain elevated in high-risk patients. Recurrence and DTC-related mortality rates were only significantly elevated in those requiring a cumulative activity over 22.2 GBq (600 mCi) from multiple RIT courses for CR. Regardless of the number of RIT courses or activity needed, life expectancy was not significantly lowered. CONCLUSION: If more than one RIT course is needed to achieve CR, higher recurrence and DTC-related mortality rates are observed, especially in high-risk patients. Patients requiring >22.2 GBq (131)I for CR should be followed in the same way as patients in whom CR is never reached as long-term mortality rates are similar.

Potassium iodide (KI) to block the thyroid from exposure to I-131: current questions and answers to be discussed.

Thyroid cancer in children and adolescents has to be considered as the most severe health consequence of a nuclear reactor emergency with release of radioiodine into the atmosphere. High doses of potassium iodide are effective to block radioiodine thyroid uptake and to prevent development of thyroid cancer years later. However, there are controversies concerning thyroid cancer risk induced by radioiodine exposure in adults. Further, the interaction of nutritional supply of potassium iodide and radioiodine uptake as well as the interaction of radioiodine with certain drugs has not been addressed properly in existing guidelines and recommendations. How to proceed in case of repeated release of radioiodine is an open, very important question which came up again recently during the Fukushima accident. Lastly, the side effects of iodine thyroid blocking and alternatives of this procedure have not been addressed systematically up to now in guidelines and recommendations. These questions can be answered as follows: in adults, the risk to develop thyroid cancer is negligible. In countries, where nutritional iodine deficiency is still an issue, the risk to develop thyroid cancer after a nuclear reactor emergency has to be considered higher because the thyroid takes up more radioiodine as in the replete condition. Similarly, in patients suffering from thyrotoxicosis, hypothyroidism or endemic goitre not being adequately treated radioiodine uptake is higher than in healthy people. In case of repeated or continued radioiodine release, more than one dose of potassium iodide may be necessary and be taken up to 1 week. Repeated iodine thyroid blocking obviously is not harmful. Side effects of iodine thyroid blocking should not be overestimated; there is little evidence for adverse effects in adults. Newborns and babies, however, may be more sensitive to side effects. In the rare case of iodine hypersensitivity, potassium perchlorate may be applied as an alternative to iodine for thyroid blocking.

Application of the American Thyroid Association Risk Assessment in Patients with Differentiated Thyroid Carcinoma in a German Population.

BACKGROUND: The American Thyroid Association (ATA) uses criteria to assess the risk for persistent disease in differentiated thyroid carcinoma (DTC) after radioiodine therapy (RAI). There are no data available showing that this classification can be adopted unadjusted by Germany. AIM: The aim of our study is to investigate whether the ATA classification can be applied to a German population for short-term prognosis. Furthermore, we investigated the influence of an age cutoff value. METHODS: We retrospectively analyzed 121 patients who were referred to our tertiary referral center. Patients were classified into risk categories, and the therapy response was determined according to ATA. RESULTS: A total of 73/83 (88%) ATA low-risk patients and 12/19 (63%) intermediate-risk patients showed an excellent response; 2/19 (11%) high-risk patients had a biochemical, and 6 (31%) had a structural incomplete response. Of all 39 patients ≥55 years, 84% had an excellent response. Using a cut off of 50 years, 50/62 (81%) of the older patients showed an excellent response. CONCLUSION: The ATA risk classification is able to estimate the response to RAI therapy in a German population. A shift from 55 to 50 years as an age cutoff value does not result in any relevant change in the treatment response.

Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

OBJECTIVE: Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS: We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS: We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION: The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Changes within the thyroid axis after long-term TSH-suppressive levothyroxine therapy.

OBJECTIVE: The effects of long-term TSH-suppressive levothyroxine (LT4) therapy on thyroid hormone metabolism in patients with differentiated thyroid carcinoma (DTC) are unknown. The aim of the study was to investigate the changes in thyroid hormone metabolism after long-term TSH-suppressive LT4 therapy in patients with DTC. PATIENTS AND METHODS: Sixty one patients with DTC were followed. For each patient, frozen remnant sera from two time points were selected: time1 (drawn within 1 year of I-131 ablation; TSH on file <0·3 mIU/l; recruitment period 1999-2002) and time2 (last available sample with TSH on file <0·3 mIU/l; minimum of 3 years of continuous TSH-suppressive LT4-therapy on record). TSH, reverse triiodothyronine (rT3), total triiodothyronine (TT3) and total thyroxine (TT4) levels were measured at both time1 and time2, and relationships between these parameters were analysed. RESULTS: Total triiodothyronine, TT4 and TSH levels were significantly reduced at time2 (P < 0·001), whereas LT4 dose, bodyweight and rT3 levels remained constant between time1 and time2. There were no significant changes in the relationship between the dose of LT4/kg bodyweight and TT4 levels (P = 0·14). TT4/TT3 was increased at time2 (P < 0·001), whereas TT4/rT3 and TT3/rT3 were significantly decreased at time2. There appeared to be no relationship of the effects found and advancing age. CONCLUSION: After long-term TSH-suppressive LT4 therapy for DTC, there are significant changes in thyroid hormone metabolism, which are best explained by a combined downregulation of deiodinases subtypes 1 and 2 and an upregulation of deiodinase subtype 3.

Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma.

OBJECTIVES: To assess (i) the influence of Thyrotropin (TSH) suppression at a level of <0·1 mU/l and (ii) whether FT3 and FT4 levels have a prognostic significance independently of TSH values with regard to survival in patients with differentiated thyroid carcinoma (DTC) and distant metastases. PATIENTS AND METHODS: In a retrospective patient chart study, we reviewed survival in 157 DTC patients with distant metastases treated between September 1985 and 1 July 2010. Patients with at least three available FT3 and FT4 values during TSH suppression were eligible. RESULTS: Fifty-three of 157 patients died from DTC. DTC-specific survival was significantly better in patients with a median TSH level ≤0·1 mU/l (median survival 15·8 years) than those with a non-suppressed TSH level (median survival 7·1 years; P < 0·001). However, there was no further improvement in survival caused by TSH suppression to a level ≤ 0·03 mU/l (P = 0·24). FT3 and FT4 levels were also significantly associated with poorer survival; of these, only the prognostic value of FT3 was independent from that of TSH levels. CONCLUSION: The care of patients with DTC and distant metastases is like walking an endocrinological tightrope: non-suppressed TSH levels, that is, >0·1 mU/l, are associated with an impaired prognosis. There is, however, no prognostic benefit from suppressing TSH to levels lower than 0·1 mU/l. On the contrary, an improvement in prognosis might be achieved by keeping FT3 levels as low as possible.