Clinical Status and Treatment of Liver Metastasis of Differentiated Thyroid Cancer Using Tyrosine Kinase Inhibitors.

BACKGROUND: Treatment of patients with liver metastasis of differentiated thyroid carcinoma (DTC) has not been sufficiently defined, because liver metastasis of DTC has been described mostly as case reports. Additionally, such patients are considered end-of-treatment responders. A relatively new approach using tyrosine kinase inhibitors (TKIs) may provide opportunities to manage systemic metastasis. This study aims to define the clinical features of DTC patients with liver metastasis and evaluate the benefits of TKIs. METHODS: We retrospectively analyzed clinical features of 29 patients (mean age 67.8 years) diagnosed with liver metastasis of DTC at our institution between January 1981 and May 2017. RESULTS: All patients had distant metastasis at other organ sites upon diagnosis of liver metastasis; 41% of them developed new metastasis afterward. Management after diagnosis of liver metastasis comprised palliative care (48%), radioactive iodine therapy (28%), and TKI therapy (24%). The median survival after diagnosis of liver metastasis was only 4.8 months. Survival rates were significantly better in patients with performance statuses between 0 and 2 on the Eastern Cooperative Oncology Group scale at diagnosis of liver metastasis (n = 22, 76%) treated with TKI compared to those who were not (P = 0.017; log-rank test; hazard ratio 0.19). One-year survival rates were 71.4 and 26.7% for patients treated with or without TKI, respectively. CONCLUSIONS: Patients with liver metastasis had poor clinical prognosis. When other distant metastases existed at diagnosis of liver metastasis, TKI therapy was considered an effective therapeutic option for patients with liver metastasis of DTC.

OPTIMIZING LENVATINIB THERAPY IN PATIENTS WITH METASTATIC RADIOACTIVE IODINE-RESISTANT DIFFERENTIATED THYROID CANCERS.

OBJECTIVE: Lenvatinib is approved for use in advanced radioactive iodine-resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience. METHODS: Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed. RESULTS: The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0-10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response. CONCLUSION: Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy. ABBREVIATIONS: DTC = differentiated thyroid cancer; LASA = linear analog self-assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor.

Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer.

PURPOSE: The aim of this study was to evaluate the efficacy of post-operative radioiodine ablation with 1,850 MBq after recombinant human thyrotropin (rhTSH) administration in patients with differentiated thyroid carcinoma (DTC). We also aimed to assess the prognostic role of several patient features on the outcome of ablation. METHODS: We retrospectively analyzed data from a total of 125 patients with DTC who underwent post-operative radioiodine ablation with 1,850 MBq of ¹³¹I after preparation with rhTSH. One injection of 0.9 mg rhTSH was administered on each of two consecutive days; ¹³¹I therapy was delivered 24 h after the last injection, followed by a post-therapy whole-body scan. Successful ablation was assessed 6-12 months later and defined as an rhTSH-stimulated serum thyroglobulin (Tg) level ≤1.0 ng/ml and a normal neck ultrasound. RESULTS: Patients were stratified according to the American Thyroid Association (ATA) Management Guidelines for Differentiated Thyroid Cancer. Successful ablation was achieved in 82.4 % of patients, with an ablation rate of 95.1 % in low-risk patients and 76.2 % in intermediate-risk patients. Analyzing the correlation between ablation outcome and patient characteristics, we found a statistically significant association between failure to ablate and class of risk based on ATA guidelines (p = 0.025) and a stimulated Tg value at ablation of above 5 ng/ml (p < 0.001). CONCLUSION: The use of 1,850 MBq post-operative radioiodine thyroid remnant ablation in association with rhTSH is effective for low- and intermediate-risk patients. Moreover, in our study, we found a statistical correlation between failure to ablate and class of risk based on ATA guidelines for DTC and a stimulated Tg value at ablation.

Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib.

CONTEXT: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES: Progression-free survival, best response, and median OS were measured. RESULTS: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Rituximab in the treatment of non-Hodgkin's lymphoma--a critical evaluation of randomized controlled trials.

INTRODUCTION: The use of rituximab has led to significant improvements in the outcome of both aggressive and indolent Non-Hodgkin's lymphoma (NHL). It is the first targeted therapy to be developed for the treatment of lymphoma which has been widely adopted. AREAS COVERED: This paper discusses the use of rituximab in NHL, mainly concentrating on diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), with a brief discussion about use in other types of NHL including mantle cell lymphoma (MCL). The use of rituximab in chronic lymphocytic leukemia (CLL) has been recently published in this journal by Robak (Robak T. Rituximab for chronic lymphocytic Leukemia. Expert Opin Biol. Ther. 2012;12(4):503-15). Non hematological indications for rituximab are also not discussed. A Pubmed search was conducted using key words of rituximab, DLBCL, FL, MCL, Burkitt's lymphoma and MALToma. Papers shortlisted for review included randomized control trials and scientific papers discussing CD20. EXPERT OPINION: In conclusion this paper has critically evaluated the use of rituximab in the treatment mainly of DLBCL, FL and MCL both at diagnosis and relapsed disease, and briefly discuses its use in other subtypes of lymphoma. Rituximab has significantly improved the outcome of patients with B cell NHL, in particular those with DLBCL and FL. Patients usually tolerate the treatment well, and studies have shown it to be a cost effective treatment.

Target therapies for radioiodine refractory advanced thyroid tumors.

A small but not irrelevant percentage of differentiated thyroid cancers become refractory to radioiodine treatment either because they lose the ability of taking up iodine over the time or because, despite a persistent uptaking ability, the effect of the radioiodine is lost in terms of tumor burden reduction. These patients receive only few and transient benefits from other conventional therapies and particularly from chemotherapy. In the last decade, several new drugs have been discovered as potentially useful and tested in clinical trials. They are mainly represented by protein kinase inhibitor molecules that should be proposed to advanced and progressive 131I refractory thyroid cancer patients by enrolling them in clinical trials or by the "off label" use of the drug.

Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial.

OBJECTIVE: We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented. PATIENTS AND METHODS: Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity. RESULTS: Median PFS was 18 months (95% confidence interval (95% CI): 7-29 months) and median OS was 34.5 months (95% CI: 19-50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5-39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash. CONCLUSION: Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.

Lac color inhibits development of rat thyroid carcinomas through targeting activation of plasma hyaluronan-binding protein.

Coccid-derived natural food colorants contain active ingredients that potentiate inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In the present study, we examined the effect of lac color (LC) and cochineal extract (CE), representative coccid-derived colorants containing laccaic acid and carminic acid as active ingredients, in an intracapsular invasion model of experimental thyroid cancers using rats. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSIc rats were fed a powdered diet containing 5.0% LC or 3.0% CE during promotion with 0.15% sulfadimethoxine (SDM) in the drinking water for 13 weeks. Capsular invasive carcinomas (CICs) and lung metastases were decreased by LC treatment and accompanied by transcript downregulation on angiogenesis and PHBP-related tissue proteolysis in CICs. In contrast, CE upregulated angiogenesis-related genes in CICs. PHBP was expressed in capsular macrophages and thyroid proliferative lesions with increased intensity in CICs, and LC decreased PHBP-expressing CICs. The size of CICs and their proliferation activity, however, were unchanged compared with those treated with SDM alone. Suppression of cancer by invasion by LC was more evident after an eight-week treatment, exhibiting a profound decrease in tenascin-C-positive early invasive foci and marked reductions in capsular inflammation and fibrosis. These results suggest that LC and CE exerted dissimilar effects on CIC development, the former suppressing the initial step of neoplastic cell invasion into the capsule by targeting PHBP activity of macrophages and neoplastic cells on tissue proteolysis involving inflammatory responses and angiogenesis, and the latter promoting angiogenesis of developed CICs at later stages.

Surgery and radioablation therapy combined: introducing a 1-week-condensed procedure bonding total thyroidectomy and radioablation therapy with recombinant human TSH.

OBJECTIVE: The objective of this study was to determine whether the use of recombinant human TSH (rhTSH) to stimulate radioiodine uptake after thyroidectomy is as efficacious as a period of withholding thyroid hormones, while at the same time avoiding hypothyroidism, reducing sick leave time and shortening the hospital stay. DESIGN: Our aim was to compare the standard procedure of differentiated thyroid cancer treatment, which consists of thyroidectomy followed by 4 weeks of hypothyroidism and a conclusive ablative activity of (131)iodine, with a new shortened treatment in which l-thyroxine (T(4)) medication is initiated a day after thyroidectomy, followed by application of rhTSH stimulation and subsequent ablation a few days after surgery. We presumed our treatment to represent the most sophisticated strategy for the reduction in sick leave days overall without any reduction in safety or the efficacy of ablative therapy. METHODS: Patients (n=25) were randomized either for surgery and rhTSH stimulation or surgery and l-T(4) abstinence before the first application of radioiodine. Ablation success was determined by neck ultrasound and serum thyroglobulin during follow-up. RhTSH receivers were monitored for an average of 635 days (s.d.+/-289) and patients in l-T(4) abstinence for an average of 624 days (s.d.+/-205). Both groups were statistically compared for significant differences in treatment efficacy, safety and overall time of sick leave. RESULTS AND CONCLUSIONS: Our shortened treatment proved to be equally efficacious and safe in comparison with the conventional therapy regimen. At the same time, it showed economic advantages through the reduction in average sick leave time from approximately 29 days (l-T(4) abstinence) down to approximately 6 days (rhTSH stimulation) as well as sustaining the patient's quality of life by the complete avoidance of hypothyroidism.

Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake.

BACKGROUND: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid neoplasia that have lost radioiodine (131I) uptake with heterogeneous results. AIM: Retrospective analysis of the recovery rate of 131I uptake after RA treatment in patients from 11 Spanish hospitals. METHODS: Twenty-seven patients (14 men, 13 women) with papillary [21], follicular [4], and oncocytic [2] thyroid cancer initially treated with total thyroidectomy plus 131I, and with 131I negative metastatic disease, were given 13-cis RA (0.66-1.5 mg/kg for 5-12 weeks) followed by a therapeutic 131I dose (3700-7400 MBq); 3 months later thyroglobulin levels and computed tomography imaging were performed. RESULTS: In 9 out 27 cases (33%) (8 papillary, 1 follicular) optimal positive 131I scan was observed after RA treatment; in the remaining 18, 10 had a suboptimal uptake (7 papillary, 2 follicular, 1 oncocytic) and in the rest there was no 131I uptake recovery (6 papillary, 1 follicular, 1 oncocytic). In 17 positive responses to RA (either optimal or suboptimal) in which image follow-up was available, decrease or stabilization of metastatic growth was observed in 7, while tumor mass increased at short term in the remaining 10. No major side effects were detected. CONCLUSION: Quite a high rate of 131I uptake recovery after RA treatment may be obtained in advanced differentiated thyroid cancer, but the potential modification of the natural course of the disease is uncertain. A better biological characterization of these tumors allowing the identification of potential responders to RA may improve the outcome of RA coadjuvant therapy.

The importance of age over radioiodine avidity as a prognostic factor in differentiated thyroid carcinoma with distant metastases.

BACKGROUND: Differentiated thyroid carcinoma (DTC) usually has a good prognosis and rarely develops distant metastases. Although it might be expected that avid radioiodine uptake in distant metastases would be associated with a favorable outcome, there are few long-term studies regarding this. The present study was performed to evaluate the influence of radioiodine uptake in distant metastases on the disease-specific survival (DSS) in DTC patients. METHODS: This retrospective study included 77 DTC patients with distant metastases (M1) who were treated with (131)I therapy from 1977 to the end of 2000 in our institution. The median follow-up of patients was 6.1 years. Univariate and multivariate analysis were performed using the Kaplan-Meier method and log rank test, and Cox Regression model, respectively. RESULTS: Seventy-seven patients with M1 included 51 (66.2%) women and 26 (33.8%) men; 32 (41.6%) patients were <45 years old and 45 (58.4%) patients were >or=45 years old (range: 8-70 years; mean age: 45.4 years); histologically, there were 54 (70.1%) papillary carcinomas, 22 (28.6%) follicular carcinomas, and one case (1.3%) with an inconclusive histological report. The probability of DSS after appearance of M1 was 57.95% after 5 years, 48.31% after 10 years, and 39.46% after 15 and 20 years. In patients with iodine-avid distant metastases the 5-year DSS was 66.54%, the 10-year DSS was 55.09%, and the 15- and 20-year DSS were 44.99%. In contrast, patients with non-iodine-avid lesions had a 5- and 10-year DSS of 18.33%. This difference relating to the relationship between (131)I uptake in distant metastases and survival was significant (p = 0.0006). The proportion of patients with non-iodine-avid distant metastases that were >or=45 years old was significantly greater than the proportion of patients with non-iodine-avid distant metastases that were <45 years old (p < 0.01). If patients were matched for age, iodine non-avidity significantly shortened the survival in patients <45 years old (p < 0.001). According to multivariate analysis age had significantly greater influence on survival compared with iodine avidity (p < 0.001, p = 0.078, respectively). CONCLUSION: Patients with distant metastases have a long-term survival that depends, in addition to other factors, on age and the degree of radioiodine uptake in distant metastases.

Redifferentiation therapy with 13-cis retinoic acids in radioiodine-resistant thyroid cancer.

Radioiodine (I-131) therapy is of proven efficacy for treatment of differentiated thyroid carcinoma (DTC). However, loss of differentiation in recurrent or metastatic DTC which decrease I-131 uptake may decrease the efficacy of I-131 therapy. Therefore, strategies to improve I-131 uptake are mandatory. This study is an open label clinical study to evaluate the effectiveness of 13-cis retinoic acid (13-cis RA) for improving I-131 uptake in recurrent or metastatic of DTC with defective I-131 uptake. Eleven patients (Age 27-66 years, M : F=4 : 7) were given 13-cis RA (1.5 mg/kg daily for 5 weeks), followed by 200 mCi (7.4 GBq) I-131 treatment. The differences of serum thyroglobulin (Tg) level and I-131 uptake on the post-treatment whole body scan (RxWBS) were compared before and after 13-cis RA therapy. Six out of 11 patients showed significantly increased (above 50%) Tg levels just after RA therapy. However, Tg levels a year after I-131 therapy were increased, stable and decreased in 7, 2 and 1 patients, respectively. Iodine uptake on RxWBS showed marginal improvement in only 2 patients and their Tg levels after one year follow-up increased. Most frequent adverse events were dry skin and lips. 13-cis RA partially restores I-131 uptake in few patients with recurrent or metastatic DTC. The use of 13-cis RA in current protocol has only limited usefulness and is not routinely recommended as currently used protocol.

Diagnostic and therapeutic use of recombinant human TSH (rhTSH) in differentiated thyroid cancer.

Traditionally, withdrawal of thyroid hormone to increase serum levels of thyroid-stimulating hormone (TSH) has been used in patients with differentiated thyroid carcinoma (DTC) to optimize radio-iodine uptake and serum thyroglobulin (Tg) stimulation during follow-up and in preparation for radio-iodine therapy. However, this procedure is associated with signs and symptoms of hypothyroidism which negatively affect the patient's quality of life. Recombinant human thyrotropin (rhTSH) has provided an effective alternative to thyroid hormone withdrawal. After favourable experimental trials in humans, rhTSH obtained regulatory approval in North America and in Europe as a diagnostic tool, and more recently as a preparation for radio-iodine thyroid remnant ablation. Since then, rhTSH has radically changed the diagnostic and therapeutic management of DTC patients. This review will focus on the clinical application of rhTSH in the management of DTC, highlighting current indications and future perspectives.

Serum thyroglobulin determination in thyroid cancer patients.

Serum thyroglobulin determination plays a central role, in combination with neck ultrasonography, in the follow-up of thyroid cancer patients. Its specificity is improved by thyroid remnant ablation, and its sensitivity is optimal following prolonged withdrawal or stimulation with recombinant human thyroid-stimulating hormone (TSH). Modern methods with an improved functional sensitivity may facilitate its use during follow-up.

Rosiglitazone effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-gamma.

BACKGROUND: Thyroid carcinoma patients with high thyroglobulin (Tg) level but negative total body scan (TBS) are difficult to treat with radioiodine (RAI). The objective of this study was to determine if treatment with rosiglitazone (RZ), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, was associated with an increase in RAI uptake in thyroid carcinoma patients with high serum Tg and negative TBSs. We also determined if there was a correspondence between the effect of RZ and the degree of staining for PPAR-gamma within thyroid cancer tissues. METHODS: We prescribed 8 mg of RZ daily for 6 weeks in 23 patients with epithelial cell thyroid carcinoma who previously had negative posttherapeutic I-131 total body scans (post Rx TBSs) with high serum Tg concentrations. Diagnostic total body scans (Dx TBSs) before and 6 weeks after RZ treatment were compared. An ablative dose of I-131 was then given to all patients, and post Rx TBS was performed to evaluate RAI uptake. Immunohistochemical staining of PPAR-gamma expression in thyroid cancer biopsies was done to correlate this with possible effects of RZ on RAI uptake. RESULTS: Seven patients had strong PPAR-gamma-positive staining in thyroid biopsies, nine patients had weakly positive staining, and seven patients had negative staining. Five of seven patients with strong staining had either positive post Rx TBS, or both Dx TBS and post Rx TBS. One of nine patients with weak staining had positive Dx TBS and post Rx TBS. In contrast, none of the seven patients with negative staining had positive TBS. CONCLUSIONS: RZ can increase RAI uptake in thyroid tissue in the majority of patients with epithelial cell thyroid carcinoma whose previous posttherapeutic I-131 scans were negative provided they have high intensity and extent of PPAR-gamma expression in thyroid tissue. Few, if any, patients with weak or no PPAR-gamma expression in thyroid cancer tissue increase RAI uptake after RZ treatment.

Symptomatic hyponatremia in association with a low-iodine diet and levothyroxine withdrawal prior to I131 in patients with metastatic thyroid carcinoma.

BACKGROUND: Strategies to improve I131 uptake in thyroid carcinoma include levothyroxine (LT4) withdrawal or thyrotropin (TSH) administration along with a low-iodine diet. We report five patients with papillary or follicular thyroid carcinoma who developed symptomatic hyponatremia during LT4 withdrawal and low-iodine diet. RESULTS: Four patients had pulmonary and/or brain metastases. All had restricted iodine intakes during LT4 withdrawal. Presenting complaints included weakness, dizziness, fainting spells, lethargy, and/or nausea. Baseline serum sodium levels while on LT4 suppression were normal. During presentation all were hypothyroid and serum sodium ranged from 110 to 121 mmol/L (normal 135-148). Despite hyponatremia, the plasma renin activity and serum aldosterone levels were suppressed, indicating volume expansion. The hyponatremia responded to fluid restriction and normalized after LT4 replacement. Low sodium intake, inappropriate antidiuretic hormone secretion syndrome (SIADH)-like disorder secondary to hypothyroidism and/or lung or cerebral metastases may have contributed to hyponatremia. CONCLUSIONS: The development of hyponatremia during LT4 withdrawal and low-iodine diet in otherwise healthy patients with thyroid carcinoma is extremely rare. However, elderly patients with metastatic thyroid carcinoma need observation during LT4 withdrawal combined with a low-iodine diet and should receive instruction to take iodine-free sodium chloride. Free water restriction may be necessary in some patients.

Overview on the use of recombinant human thyrotropin in thyroid cancer of follicular cell origin.

Stimulation by recombinant human thyroid-stimulating hormone (rhTSH) has gained wide acceptance as an alternative to thyroid hormone withdrawal in the management of patients with differentiated thyroid cancer. RhTSH has the advantage to avoid both the clinical consequences of hypothyroidism, with a positive impact on quality of life and work productivity, and the risk of cancer growth due to the long-lasting endogenous thyrotropin stimulation. RhTSH is a heterodimeric glycoprotein produced by recombinant DNA technology that has the ability to stimulate thyroglobulin production and radioiodine uptake by thyroid cells. RhTSH is now widely used in the follow-up of thyroid cancer patients in order to improve sensitivity of thyroglobulin (Tg) measurement as well as in preparation of (131)I diagnostic whole-body scan. Although initially approved only for diagnostic purposes, rhTSH has been now approved both in Europe and in the United States for remnant ablation in low-risk patients. As far as residual or metastatic cancer treatment, rhTSH has been initially used on a compassionate need basis for elderly and frailer patients and for patients in whom the withdrawal of thyroid hormone was medically contraindicated. Nowadays, there is a trend for widening the use of rhTSH in therapy, in order to avoid hypothyroidism and the concern about the effect of prolonged endogenous thyroid-stimulating hormone stimulation on cancerous cells. Unfortunately, the studies which address the efficacy of rhTSH in cancer treatment are still scarce and the opportunity of its clinical application remains controversial. In addition, rhTSH has been shown to improve the accuracy of [(18)F]-2-fluoro-deoxy-D-glucose positron emission tomography to detect non-functioning thyroid cancer. Although all studies agree on that rhTSH is much better tolerated from the clinical point of view than thyroid hormone withdrawal, there is some controversy about its comparative ability to raise Tg levels and concentrate radioiodine in cancerous thyroid cells. The aim of this paper is to review the performances of rhTSH as compared to hypothyroidism, considering Tg stimulation and diagnostic whole-body scan sensitivity during follow-up, and its effectiveness for normal remnant ablation and for therapy of metastatic disease.

New perspectives on the treatment of differentiated thyroid cancer.

Even though differentiated thyroid carcinoma is a slow growing and usually curable disease, recurrence occurs in 20-40% and cellular dedifferentiation in up to 5% of cases. Conventional chemotherapy and radiotherapy have just a modest effect on advanced thyroid cancer. Therefore, dedifferentiated thyroid cancer represents a therapeutic dilemma and a critical area of research. Targeted therapy, a new generation of anticancer treatment, is planned to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progression. Since many of the tumor-initiation events have already been identified in thyroid carcinogenesis, targeted therapy is a promising therapeutic tool for advanced thyroid cancer. Several new drugs are currently being tested in in vitro and in vivo studies and some of them are already being used in clinical trials, like small molecule tyrosine kinase inhibitors. In this review, we discuss the bases of targeted therapies, the principal drugs already tested and also options of redifferentiation therapy for thyroid carcinoma.