Whether due to improved detection or unknown environmental factors, the incidence of thyroid cancer is on the rise. People are twice as susceptible to this cancer today as they were in 1990. The American Cancer Society estimates that more than 56,000 Americans will be diagnosed with thyroid cancer by the end of the year. Three out of four cases will be in women. A common and successful treatment for thyroid cancer is radioactive iodine (RAI), but this therapy is not without its risks and can cause leukemia and impaired fertility. Furthermore, some thyroid cancers are resistant to radioiodine. In this Tri-Point article, a clinical practitioner discusses what factors to consider when selecting patients for radioiodine therapy; a clinical researcher weighs the therapy’s general benefits and risks; and two basic researchers unveil possible future therapies to fight resistant thyroid cancers.
Clinical Practitioner Perspective
By Martin Schlumberger, M.D.
Professor Schlumberger is chair of nuclear medicine at Institut Gustave Roussy, Villejuif, France.
Radioiodine is widely used in thyroid cancer patients. Its administration is easy and is usually well tolerated. However, its cost and potential side effects should restrict its use to patients for whom a benefit is expected. When indicated, the lowest effective activity should be administered.
Side effects of radioiodine include swelling of the salivary glands and subsequent dry mouth, lacrimal disturbances, nausea, and loss of taste. Long-term adverse events include the occurrence of secondary cancers and leukemias. However, the risk is significantly increased after the administration of a cumulative activity of 22 GBq or more. No evidence exists of increased risk to pregnancies following radioiodine exposure when conception occurs more than six months after the last exposure. On the other hand, benefits of radioiodine treatment have been shown in only some subgroups of thyroid cancer patients and its use should be selective, after initial surgery, during follow-up, and in patients with persistent or recurrent disease. Indications are well-defined, except after initial surgery, a situation for which prospective trials are needed.
Post-operatively, radioiodine may be administered with three aims: first, to irradiate any persistent neoplastic focus in order to decrease the risk of subsequent recurrence; second, to eradicate normal thyroid remnants in order to obtain an undetectable serum thyroglobulin (Tg) in the absence of anti-Tg antibodies; and third, to perform a whole body scan (WBS) 2–5 days after the administration of radioiodine to detect metastatic disease. Benefits of radioactive iodine remnant ablation on outcome have been demonstrated for high-risk patients and for those with persistent disease who are treated with high activities (≥ 100 mCi or 3.7 GBq). Radioiodine is not indicated in very low-risk patients with tumors of less than 1 cm and with no lymph node metastases, and no evidence is currently available that it improves the outcome of low-risk patients (with tumors larger than 1 cm and no or limited lymph node involvement) who have no evidence of disease after total thyroidectomy.
Not All Thyroidectomy Patients Require Radioiodine
Prospective trials are warranted in these latter patients, to identify those who should receive post-operative radioactive iodine remnant ablation. In the absence of prospective trials, retrospective studies have shown that serum Tg may already be undetectable after total thyroidectomy and before any radioiodine administration, and only 3 percent of such patients had persistent disease on WBS, and all had lymph node metastases. After total thyroidectomy, patients with no lymph node metastases at a prophylactic lymph node dissection or with no evidence of lymph node metastases on neck ultrasonography may not require any radioiodine.1–4 In these low-risk patients, some questions remain unresolved and, because initial treatment includes several steps that are still not validated, successive prospective randomized trials are needed to answer these questions: (1) What is the optimal protocol for post-operative radioiodine administration? (2) Which low-risk patients should receive radioactive iodine remnant ablation? (3) When should prophylactic neck dissection be performed?
To answer the first question, two prospective randomized trials on large series of patients who had been treated with total thyroidectomy have demonstrated that the ablation rate is over 90 percent following either 1.1 GBq or 3.7 GBq and after a preparation using either rhTSH or withdrawal.5, 6 Thus, the use of 1.1 GBq after rhTSH stimulation is recommended when radioiodine ablation is indicated in these lowrisk patients: this will avoid any hypothyroidism, maintain the quality of life, and decrease the radiation dose to the body by 5-fold compared to the previous protocol, which used 3.7 GBq following withdrawal. When radioiodine has not been administered, follow-up is based on serum Tg determination on levothyroxine (LT4) treatment and on neck ultrasound at one year. Indeed, with this new standard, we are launching another randomized trial in low-risk thyroid cancer patients after total thyroidectomy, with 1.1 GBq following rhTSH compared to no radioiodine, to define in which patients it may be beneficial.
Diagnostic WBS has no routine indication and ablation is currently assessed by neck ultrasound and serum Tg determination, obtained either using a sensitive method on LT4 treatment7 or following rhTSH injections. Diagnostic WBS may be performed during follow-up in patients with any abnormality, including an elevated serum Tg, in those with high uptake in large thyroid remnants on post-ablation scan and in those with anti-Tg antibodies.
In patients with persistent or recurrent disease, radioiodine is indicated for the treatment of neoplastic foci in the two-thirds of patients with tumor uptake. In patients with persistent or recurrent disease in the neck, radioactive iodine remnant ablation may eradicate small neoplastic foci (less than 1 cm in diameter), but rarely larger foci. Radioiodine is useful to localize any neoplastic foci on SPECT/CT in addition to other imaging modalities (neck ultrasonography, CT scan, FDG-PET scan) and to enable their pre-operative localization with a probe. This is the rationale for the administration of a large dose of radioiodine several days before surgery, which enabled the resection of all tumor foci in 92 percent of patients.
Radioiodine Should be Used Only in Selected Cancer Patients
In patients with distant metastases, various treatment dosages are administered depending on the center. However, no evidence exists that any protocol based on dosimetry or using high activities may be more effective than repeated treatments with a standard activity of 3.7 GBq administered following thyroid hormone withdrawal. Complete responses are obtained in 40 percent of distant metastases with radioiodine uptake, and predictive factors for cure are younger age at discovery of the metastases, small size of metastases, well differentiated cancer histotype, and low uptake of FDG on PET scan. Almost all complete responses were obtained with a cumulative activity of 22 GBq or less, and few progressions have been observed after complete remission.
These findings led to the definition of refractory thyroid cancers, which are observed in patients with: (1) at least one target lesion with no detectable iodine uptake, (2) progression during the 12 months following radioactive iodine remnant ablation, or (3) persistent disease after the administration of 22 GBq. Indeed, radioiodine should not be given to patients who meet one of these criteria. They may be candidates for other treatment modalities in case of documented progression.
In conclusion, the use of radioiodine is easy and is usually well tolerated, but it should be used only in selected thyroid cancer patients for whom benefits have been demonstrated.
Clinical Researcher Perspective
Bryan R Haugen, M.D., F.A.C.P.
Dr. Haugen is a professor of medicine and pathology and head of the Division of Endocrinology at the University of Colorado School of Medicine.
Consideration in choosing patients to receive radioactive iodine remnant ablation
The goals of primary therapies, including radioiodine treatment, for any cancers are: (1) to improve cancer-related survival, (2) to minimize the risk of disease recurrence and metastatic spread, (3) to permit accurate long-term surveillance for disease recurrence, (4) to permit accurate staging of disease, and (5) to minimize treatment-related morbidity.1 In order to choose the appropriate patients who may benefit from radioiodine remnant ablation, we must first stratify these patients by risk. The American Joint Commission Against Cancer/Tumor, Nodes, Metastases (AJCC/TNM) staging system is used to determine overall survival and disease-specific survival. To estimate risk of disease persistence or recurrence, the American Thyroid Association Guidelines classified patients into three risk categories: low, intermediate, and high. These categories appear to be quite good at predicting persistent or recurrent structural disease.2 Patients in the low-, intermediate-, and high-risk categories have a 2 percent, 19 percent, and 67 percent risk of recurrence. The tumor marker serum thyroglobulin, measured at its nadir under levothyroxine (LT4) suppression therapy, may help further define which low- to intermediate-risk patients may benefit from radioiodine therapy and those who may not.
Radioactive iodine remnant ablation is recommended for all patients with thyroid cancer metastases that can concentrate and respond to radioiodine, patients with gross extra thyroidal extension, and patients with tumors greater than 4 cm.5 Radioiodine ablation is recommended for selected patients with primary tumors between 1 and 4 cm that are confined to the thyroid and who have higher risk features for recurrence (high-risk subtypes of differentiated thyroid cancer, extensive lymph node metastases). Radioiodine remnant ablation is not recommended for patients with unifocal cancer less than 1 cm or for patients with multifocal papillary thyroid carcinoma when each of the foci are less than 1 cm in the absence of other higher risk features.
Benefits and risks of radioactive iodine remnant ablation
The goals of initial radioiodine therapy are to ablate all residual thyroid cells, both normal and cancerous, remaining after surgery. The results of many retrospective studies looking at the benefit of radioiodine remnant ablation in patients with low- and intermediate-risk thyroid cancer have been mixed. A systematic review of the literature indicates that disease recurrence can be reduced by approximately 50 percent with radioiodine in a large non-risk stratified group of patients.3 No survival benefit was observed. A prospective multi-center database analysis showed survival benefit of radioiodine therapy for high-risk patients (stage 3 and stage 4) and that radioiodine therapy improved overall survival in stage 2 patients. However, no benefit was observed of radioiodine remnant ablation in the broad group of stage 1 patients.
Multiple risks are associated with radioiodine therapy, including dental caries, watery eyes, gonadal dysfunction, marrow suppression, and secondary malignancies.
Preparation and administered doses of radioiodine for remnant ablation
Many studies have now shown that patients can be adequately prepared for radioactive iodine remnant ablation using recombinant human TSH.8, 9 If one is considering withdrawal therapy, many experts suggest three-week withdrawal of LT4 without the addition of liothyronine because this does not appear to improve quality of life. This is a shorter, simpler way to prepare patients for radioactive iodine remnant ablation.
Two ways to reduce potential risks of radioiodine therapy are to deliver radioiodine in the euthyroid state so that whole body clearance is higher, and administer the lowest dose of I that can achieve successful remnant ablation. Two recent prospective randomized trials comparing 30 mCi (1.11 GBq) with 100 mCi (3.7 GBq) of I, each in combination with recombinant human TSH, or thyroid hormone withdrawal preparation showed no difference among the subgroups, suggesting that preparation of low-risk patients with recombinant human TSH and 30 mCi of 131I is likely sufficient for remnant ablation in most patients. Older studies have shown mixed success in patients receiving doses as low as 30 mCi of I. This may be due in part to less complete thyroidectomies performed years ago.
Summary
Radioactive iodine remnant ablation should have limited use in many of our low-risk patients, particularly those with stage 1 disease who are younger, with smaller primary tumors, no lymph node involvement, and no extrathyroidal invasion. We can use a serum thyroglobulin approximately six to eight weeks after thyroidectomy on LT4 suppression to further stratify risk in these patients. We should consider selected use in our low- to intermediate-risk patients and primarily reserve radioactive iodine remnant ablation for those older patients with larger tumors, more extensive lymph node involvement, and patients with higher risk subtypes of differentiated thyroid cancer (tall cell, insular, etc.). Most low- to intermediate-risk patients who warrant radioiodine remnant ablation can be prepared with recombinant human TSH. Furthermore, the smallest dose possible to achieve successful remnant ablation (30–50 mCi 131I) should be considered.
Basic Researcher Perspective
Determinants of response to RAI in metastatic
thyroid cancer
Stephanie Fish, M.D., and James A. Fagin, M.D.
Dr. Fish is an associate member, Endocrinology Service at Memorial Sloan-Kettering Cancer Center in New York, New York. Dr. Fagin is the chief of the Endocrinology Service and a member of the Human Oncology and Pathogenesis Program at Memorial SloanKettering Cancer Center in New York, New York.
Most cases of thyroid cancer can be treated effectively with total thyroidectomy, in some cases followed by adjuvant RAI therapy. Mortality from thyroid cancer is primarily associated with metastatic disease. The 10-year survival of patients with metastatic thyroid cancer that retains RAI avidity is approximately 60 percent, whereas it is only 10 percent if the metastases are refractory to RAI therapy. This has prompted many efforts to develop therapies to restore the ability of RAI-refractory thyroid cancers to trap iodide and respond to this therapy. Iodide uptake and storage in the form of thyroid hormone precursors are complex and highly regulated processes that require the function of key proteins such as the sodium-iodide symporter (NIS), pendrin, the potassium channel subunits KCNQ1 and KCNE2, thyroglobulin (Tg), and thyroid peroxidase (TPO). A subset of thyroid cancers loses expression and function of these genes. The mechanisms that account for this have been extensively investigated and will be discussed here, with particular emphasis on those that have also been tested in the clinic.
Nuclear receptor ligands in RAI refractory
thyroid cancer
Retinoids act by binding to the retinoic acid (RAR) and the retinoid X (RXR) nuclear receptors, through which they regulate gene transcription by direct interaction with the regulatory regions of a diverse set of genes. Retinoids have key effects on cell differentiation and in development, and are used as cancer therapies. The most notable use of retinoids in cancer is for acute promyelocytic leukemia, more than 95 percent of which are caused by a translocation that juxtaposes the PML gene on chromosome 15 and the RARα gene on chromosome 17. Retinoids induce expression of the type I iodothyronine 5’-deiodinase isoenzymes and NIS mRNA in follicular thyroid cancer cell lines. Based on these observations, numerous clinical studies of retinoids in patients with advanced thyroid cancer were initiated, mostly with isotretinoin (13-cis-retinoic acid). About 20–40 percent of patients showed some response to isotretinoin therapy, including reduced tumor size and increased RAI uptake. However, more recent reports have shown that few patients had a clinically meaningful response, suggesting that retinoid monotherapy is not effective in RAI-resistant metastatic thyroid cancer.
The peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear hormone receptor superfamily. Thiazolidinediones (TZDs), PPARγ agonists that have been used historically and primarily in the treatment of type 2 diabetes, inhibit cell proliferation and induce re-differentiation of different cancer cell types, including follicular thyroid cancer cell lines. Based on these observations, 20 patients with metastatic non-RAI-avid thyroid cancer were treated with the TZD rosiglitazone, but none had significant clinical responses.
Effects of chromatin remodeling and demethylating
agents in thyroid cancer
Histone acetylation decreases chromatin compaction, which is permissive for gene transcription. Conversely, when the acetyl groups are removed, electrostatic interactions between DNA and histones compact the chromatin, inhibiting transcription. Histone deacetylase (HDAC) inhibitors, such as depsipeptide, increase TG and NIS mRNA levels and RAI uptake in poorly differentiated thyroid cancer cells. Unfortunately, these preclinical data did not translate into the clinic, as neither depsipeptide nor vorinostat conferred clinical benefit in patients with RAI-refractory thyroid cancer.7, 8 The relatively poor record of preclinical studies in predicting the activity of compounds designed to reactivate iodine incorporation in clinical trials of thyroid cancer may be due in part to the fact that some of the in vitro studies used cancer cell lines that were later found to have been misidentified, and were not of thyroid origin. Moreover, the magnitude of the effects in vitro was, in general, quite modest compared to the iodine uptake of well differentiated, non-transformed thyroid cells.
DNA methylation of key gene regulatory elements decreases gene transcription. Cancer cells often exhibit aberrant gene methylation patterns, which accounts for some of the global abnormalities in their gene expression patterns. Many of the key genes required for thyroid hormone biosynthesis have been reported to be silenced through hypermethylation in thyroid cancer.10 This provided the rationale for a pilot clinical trial of the demethylating agent 5-azacytidine to restore RAI responsiveness, but the results were reportedly negative, according to Kenneth Ain, M.D.
Molecular mechanisms of loss of iodine uptake
in thyroid cancer
Recent discoveries on the genetic basis of thyroid cancer have provided novel insights into the mechanisms contributing to loss of RAI uptake in the disease. Papillary thyroid cancers (PTC) are associated with mutually exclusive mutations of oncogenes encoding effectors of the mitogenactivated protein kinase (MAPK) signaling pathway (i.e., RET, NTRK, RAS, and BRAF).11 Oncogenic BRAF signals as a monomer and promotes higher levels of MAPK activity than other lesions in the pathway because normal feedback events controlling MAPK become disabled. Unrestrained MAPK activation in thyroid cells leads to loss of expression of genes required for thyroid hormone biosynthesis, including NIS and TPO. 12, 13 The activating BRAFV600E mutation is the most frequent genetic alteration in PTC and confers a poor prognosis.14 BRAF is associated with tumors with lowered NIS expression, which likely explains the clinical observation that PTCs with BRAF mutations are often particularly resistant to RAI therapy.15 The mechanisms by which BRAF inhibits differentiated function in thyroid cells, and NIS expression and iodide uptake in particular, may involve a BRAF-induced TGFβ1 autocrine loop.
Loss of NIS expression is restored in vitro by treatment with MAPK kinase (MEK) inhibitors.12, 17 Mice with doxycycline-inducible expression of BRAFV600E in thyroid cells develop invasive lesions that are histologically consistent with papillary thyroid cancers, showing profound decreases in expression of thyroid-specific genes and of radioactive iodide uptake in vivo. Iodide uptake is restored when doxycycline is discontinued, and when the mice are treated with RAF or MEK inhibitors.18 Based on these results, drugs of this class are currently being tested in phase 2 clinical trials of patients with RAI-refractory thyroid cancer.
Conclusion
The prognosis of patients with metastatic RAI-refractory thyroid cancer is poor. A better understanding of the basic mechanisms accounting for the loss of iodine incorporation in cancer cells points to ways by which this process can be reversed, at least in a subset of patients. MAPK activation in thyroid cells leads to loss of thyroid-specific gene expression. Agents that can effectively block this pathway in a sustained manner have had promising results in mouse models of thyroid cancer, and are now being tested in clinical trials.
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