1. Iodine uptake and metabolism
The presentations of the 84th Annual Meeting of the American Thyroid Association (ATA), which just concluded, have shed new light on nuclear medicine in the management of thyroid cancer. In this article, we will briefly describe iodine uptake and metabolism, new imaging studies on thyroid cancer, radioactive 131I therapy and pretreatment risk assessment, aggressiveness of thyroid cancer and patient prognosis, iodine-refractory thyroid cancer, and possible updates to the nuclear medicine section of the preliminary draft of the ATA 2014 Guidelines for the Management of Thyroid Nodules and Thyroid Cancer.
In a study of iodine uptake mechanisms in the thyroid, Twyffels et al. identified a follicular cell apical iodine transporter that is different and mediates iodine uptake that is activated by a calcium ion carrier (ionomycin/calcium). The investigators have demonstrated at the cytological level that iodine uptake can be regulated by the expression of anoctamin-specific blockers mainly by thyroid stimulating hormone (TSH). This finding suggests that iodine uptake can be mediated by specific targets other than the sodium-iodine transporter (NIS). It is unclear whether the distribution of anoctamin is as histologically specific as the NIS, but this study leads to the realization that the distribution of 131I in vivo not only represents the distribution of the NIS, but that the presence of anoctamin inhibitors or blockers in nature or in drugs also affects the efficacy of 131I.
A study of urinary iodine excretion and changes in serum thyroid function indicators after iodine contrast agent injection in healthy adults showed that after injection of iodine contrast agents that exceeded the recommended daily iodine dose by more than several thousand times, the peak of urinary iodine excretion occurred 1,1 week after injection and returned to normal at 5,2 weeks. This study answers a long-standing question for nuclear medicine physicians, namely, how soon after enhanced CT is it feasible to perform tests and treatments related to radionuclides such as 131I? Although insight into the course of contrast effects on urinary iodine excretion in hyperthyroid and hypothyroid states is still necessary, this evidence suggests to us that the existing delay of 131I examination or treatment in patients after iodine contrast injection may be too long, and more evidence will hopefully advance the waiting time for 131I treatment in such patients from the previous 2-3 months to 6 weeks.
2. New research on thyroid cancer imaging
At the ATA annual meeting, an Italian scholar reported a study on 99mTc-labeled human recombinant TSH (rhTSH) analogs in poorly differentiated metastatic differentiated thyroid cancer (DTC). The results of the study showed that although dedifferentiated metastatic DTC lose their ability to uptake iodine, they tend to retain their ability to express TSH receptors.
Both in vitro and in vivo tests in this study showed specific high uptake of TSH receptors by 99mTc-TR1401, which makes the application of 99mTc-TR1401 imaging to detect and localize dedifferentiated DTC an alternative imaging when the lesion cannot be detected by positron emission tomography (PET).
3. 131I treatment and pre-treatment risk assessment
131I has been the standard of care for DTC for more than half a century. A study on the correlation between surgery combined with 131I therapy and survival benefit, which included 5000 patients, showed that postoperative 131I therapy in high-risk DTC patients was associated with a survival benefit; while postoperative 131I therapy in low-risk patients did not improve the survival benefit. This result suggests that the best indication for 131I therapy remains a direction for future efforts.
A study by a Canadian researcher with a 6-year follow-up showed that postoperative stimulated thyroglobulin (sTg) levels and neck ultrasound results would help determine whether to proceed with 131I therapy. For example, negative neck ultrasound results plus sTg aided in determining recurrence-free survival (RFS) over the next 6 years in 85% of those with tumors >4 cm in diameter, 89% of those >45 years of age, and 67% of those with central lymph node metastases, thus eliminating the expense of unnecessary follow-up 131I therapy and the risk of radiation exposure in these patients. This pioneering study focuses more on the significance of dynamic assessment and its role in subsequent treatment decisions, and places greater emphasis on the role of therapeutic interventions such as surgery in improving patient prognosis, providing new data for clinicians to individualize the treatment of patients with 131I.
4. Aggressiveness and prognosis of thyroid cancer
Currently, in the study about the relationship between invasiveness and prognosis of thyroid cancer, Johns? Prof. Mingzhao Xing, a Chinese scholar from Johns Hopkins Hospital, has been in the forefront of the world. After revealing the relationship between BRAFV600E gene and thyroid cancer recurrence and survival, Prof. Xing’s group recently found that double abnormalities of telomeric reverse transcriptase will trigger worse clinical outcomes in DTC patients, which has caused people to think about the significance of TERT in thyroid cancer aggressiveness and subsequent therapeutic targets.
5. Disposition of iodine-refractory thyroid cancer
Iodine-refractory thyroid cancer has been a difficult and hot spot for diagnosis and treatment. Rose (Rose) et al. published the results of a phase III randomized double-blind clinical trial on sorafenib for locally advanced and metastatic DTC in The Lancet. The study confirmed that sorafenib prolonged the progression-free survival (PFS) period of patients by almost a factor of 1 compared to the placebo group (10, 8 months versus 5, 8 months).
At this annual meeting, more attention was paid to the indications for the use of tyrosine kinase inhibitors (TKI) such as sorafenib. Given the adverse effects caused by TKI, such as hand-foot syndrome, and the fact that patients can exhibit a longer period of stable disease even in iodine-refractory states, the questions of when to start TKI, whether TKI should be applied earlier, and how to deal with elderly frail patients who cannot use TKI remain unanswered. In response to the question of salvage treatment options for patients who have failed first-line targeted therapy with sorafenib, a study by Dadu et al. suggested that salvage treatment with other TKI such as sunitinib and levatinib would extend the overall survival time of these patients from 28 months to 58 months with sorafenib alone.
In addition, a study from Korea suggests that 131I combined with the application of lithium therapy is expected to improve the responsiveness of iodine-refractory thyroid cancer to 131I therapy and extend the survival of patients (126, 2 months vs. 105, 4 months).
6. Brief description of possible updates to the new guidelines on nuclear medicine
The ATA published guidelines on the diagnosis and treatment of thyroid nodules and thyroid cancer in 2006 and 2009, and their revised versions. In the past 5 years, with the increasing global incidence of thyroid cancer and the growing research evidence on thyroid cancer, the ATA will update the guidelines again in 2014. The first draft of this updated guideline is described and interpreted in this meeting, and is expected to affect the decision making of 131I for DTC in the following ways.
1. Postoperative assessments such as determining postoperative disease persistence or disease-free status will influence 131I decisions more. In the postoperative evaluation, more emphasis is placed on the significance of postoperative Tg levels in assessing disease persistence status, residual thyroid condition and predicting recurrence; and it is proposed that postoperative diagnostic 131I whole-body imaging will help aid in determining residual thyroid condition that cannot be determined by surgery and ultrasound.
In the risk stratification of recurrence before 131I treatment, molecules such as BRAF, which are closely related to aggressiveness and patient prognosis, are expected to be included as important weighting factors in risk assessment and stratification, such as including those with tumors larger than 1 cm with BRAFV600E and TERT mutations in the high-risk stratification, and those with BRAFV600E mutations confined to the thyroid gland in the medium-risk stratification.
3. In terms of 131I dose recommendations, the recommended 131I treatment dose for low- and intermediate-risk patients is 1110 MBq (30 mCi), based on the results of high-quality multicenter clinical trials and recent meta-analyses in recent years.
4. The concept of dynamic assessment after intervention with treatment (including surgery and 131I) and other factors and its significance in guiding patients’ subsequent treatment was emphasized.