Differentiated thyroid cancer mortality by disease stage in northern England.

OBJECTIVE: Mortality from thyroid cancer is reported to be higher in the UK compared with several other European countries, though UK data on mortality by disease stage have not been published. The aim of this study was to ascertain disease-specific mortality by stage in our centre. DESIGN, PATIENTS AND MEASUREMENTS: This was a cohort study of all patients presenting to a single centre. Four hundred and twenty patients treated between 2000 and 2010 were identified. The medical records and causes of deaths were reviewed and analysed. RESULTS: Overall disease-specific mortality at 5 and 10 years was 1.4% and 5.8%, respectively. The observed mortality was 58 against 66.3 expected deaths (CI 43.8-75.4) thus yielding an age-standardized mortality rate of 0.87. There were no deaths due to thyroid cancer in patients with stage I disease at 5 or 10 years. The 10-year disease-specific mortality rose with stage (stage II 3.1%, stage III 28.6%, stage IV 30%). CONCLUSIONS: Thyroid cancer mortality of patients treated at our centre was lower than the official national UK registry and most European figures.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.

BACKGROUND: Two large randomised trials of patients with well-differentiated thyroid cancer reported in 2012 (HiLo and ESTIMABL1) found similar post-ablation success rates at 6-9 months between a low administered radioactive iodine (131I) dose (1·1 GBq) and the standard high dose (3·7 GBq). However, recurrence rates following radioactive iodine ablation have previously only been reported in observational studies, and recently in ESTIMABL1. We aimed to compare recurrence rates between radioactive iodine doses in HiLo. METHODS: HiLo was a non-inferiority, parallel, open-label, randomised controlled factorial trial done at 29 centres in the UK. Eligible patients were aged 16-80 years with histological confirmation of differentiated thyroid cancer requiring radioactive iodine ablation (performance status 0-2, tumour stage T1-T3 with the possibility of lymph-node involvement but no distant metastasis and no microscopic residual disease, and one-stage or two-stage total thyroidectomy). Patients were randomly assigned (1:1:1:1) to 1·1 GBq or 3·7 GBq ablation, each prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or thyroid hormone withdrawal. Patients were followed up at annual clinic visits. Recurrences were diagnosed at each hospital with a combination of established methods according to national standards. We used Kaplan-Meier curves and hazard ratios (HRs) for time to first recurrence, which was a pre-planned secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT00415233. RESULTS: Between Jan 16, 2007, and July 1, 2010, 438 patients were randomly assigned. At the end of the follow-up period in Dec 31, 2017, median follow-up was 6·5 years (IQR 4·5-7·6) in 434 patients (217 in the low-dose group and 217 in the high-dose group). Confirmed recurrences were seen in 21 patients: 11 who had 1·1 GBq ablation and ten who had 3·7 GBq ablation. Four of these (two in each group) were considered to be persistent disease. Cumulative recurrence rates were similar between low-dose and high-dose radioactive iodine groups (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 5·9% vs 7·3%; HR 1·10 [95% CI 0·47-2·59]; p=0·83). No material difference in risk was seen for T3 or N1 disease. Recurrence rates were also similar among patients who were prepared for ablation with rhTSH and those prepared with thyroid hormone withdrawal (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 8·3% vs 5·0%; HR 1·62 [95% CI 0·67-3·91]; p=0·28). Data on adverse events were not collected during follow-up. INTERPRETATION: The recurrence rate among patients who had 1·1 GBq radioactive iodine ablation was not higher than that for 3·7 GBq, consistent with data from large, recent observational studies. These findings provide further evidence in favour of using low-dose radioactive iodine for treatment of patients with low-risk differentiated thyroid cancer. Our data also indicate that recurrence risk was not affected by use of rhTSH. FUNDING: Cancer Research UK.

131I activity for remnant ablation in patients with differentiated thyroid cancer: A systematic review.

CONTEXT: Radioiodine ablation of the thyroid remnant after thyroidectomy is commonly performed in the management of patients with differentiated thyroid cancer. Although many centers administer an activity of 100 mCi, there is uncertainty over using a lower activity. OBJECTIVE: A systematic review of the published literature was used to compare the success rates of remnant ablation using approximately 30 mCi with approximately 100 mCi (1.1 vs. 3.7 GBq). DATA SOURCES: Data were obtained from MEDLINE and EMBASE for the years 1966 to March 2006. STUDY SELECTION: All studies that reported rates of successful ablation associated with approximately 30 or approximately 100 mCi of radioiodine were reviewed. DATA EXTRACTION: Studies were based on reviews of patient case notes (n = 41), prospective cohorts (n = 12), and randomized trials (n = 6). We obtained the success of thyroid remnant ablation according to different administered activities of radioiodine. Where a study reported on two or more activities, the risk ratio of having a successful ablation (approximately 30 vs. approximately 100 mCi) was calculated and combined in a meta-analysis. DATA SYNTHESIS: Observational studies confirmed the high ablation success rate ( approximately 80%) using approximately 100 mCi, although 22% of studies reported a rate of 90% or greater. The pooled ablation success rate in these studies was 10% lower using 30 mCi compared with 100 mCi (95% confidence interval, 3-17%; P = 0.01). The meta-analysis of the randomized trials produced equivocal results. For example, the rate of successful ablation in patients given 30 mCi was 8% lower compared with 100 mCi (95% confidence interval, 29% lower or up to 20% greater, P = 0.58), consistent with there being no difference or that 30 mCi is much less effective. CONCLUSIONS: From the published data, it is not possible to reliably determine whether ablation success rates using 30 mCi are similar to using 100 mCi. Large randomized trials are needed to resolve the issue and guide clinical practice.

Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.

CONTEXT: Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. OBJECTIVE: The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action. Design, Setting, Patients, and Interventions: Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data. PRIMARY OUTCOME MEASURE: Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays. RESULTS: Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells. CONCLUSION: Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement.

Discordant serum thyroglobulin results generated by two classes of assay in patients with thyroid carcinoma: correlation with clinical outcome after 3 years of follow-up.

BACKGROUND: Serum thyroglobulin measurement is an integral part of monitoring patients with thyroid carcinoma, but analytic problems pose serious difficulties in the utility of this test. METHODS: Between 1997 and 1998, serum samples from 83 patients with differentiated thyroid carcinoma were collected. Serum thyroglobulin was assayed by both radioimmunoassay and by an immunoradiometric assay. The disease status of patients with discordant serum thyroglobulin results was assessed in June 2001. Therefore, the predictive value of a single thyroglobulin measurement was assessed by evaluating the clinical status of patients 3 years later. RESULTS: Discordant serum thyroglobulin results were noted in 17 (20.4%) patients. Of the 17 patients with discordant results, 16 had adequate clinical follow-up data. Of these 16 patients, 11 patients had detectable levels of serum thyroglobulin by immunoradiometric assay (range, 1.4-350 microg/L) whereas levels were undetectable by radioimmunoassay (< 1 microg/L). All 11 patients had evidence of metastases 3 years later. Two patients had undetectable serum thyroglobulin levels using the immunoradiometric assay (< 1 microg/L), whereas they had detectable levels using radioimmunoassay (serum thyroglobulin 7.2-30 microg/L). The serum samples from both patients had normal recoveries and positive antithyroglobulin antibodies. Both patients developed metastases 3 years later. CONCLUSIONS: False-negative serum thyroglobulin results were significantly higher with the radioimmunoassay method compared with the immunoradiometric assay. The immunoradiometric assay is more reliable than the radioimmunoassay, particularly in patients who have no thyroglobulin antibodies. This finding is novel in that traditional immunoradiometric assay systems compared with radioimmunoassays usually have a higher incidence of false-negative results when assessed against clinical status. The immunoradiometric assay is subject to false-negative results in some patients with thyroglobulin antibodies, even when recovery experiments indicate the absence of interference. Thyroglobulin antibodies should be measured in all patients with differentiated thyroid carcinoma and if positive, results should be interpreted with extreme caution.