Metastatic DTC Research Articles

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Clinical characteristics and long-term outcomes for parapharyngeal metastases of well-differentiated thyroid cancer during 131 I therapy and follow-up.

Parapharyngeal metastases (PPM) are rarely observed in patients with well-differentiated thyroid cancer (WDTC). Radioiodine (131 I) therapy has been the main treatment for metastatic and recurrent DTC after thyroidectomy. This study was performed to evaluate the clinicopathological features and long-term outcomes associated with survival of patients with PPM at the end of follow-up. In total, 14,984 consecutive patients with DTC who underwent 131 I therapy after total or near-total thyroidectomy from 2004 to 2021 were retrospectively reviewed. Therapeutic efficacy was evaluated using the Response Evaluation Criteria in Solid Tumours v1.1 and logistic regression analysis. The disease status was determined using dynamic risk stratification. Disease-specific survival (DSS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. Seventy-five patients with PPM from WDTC were enroled in this study. Their median age at the initial diagnosis of PPM was 40.2 ± 14.1 years, and the patients comprised 32 men and 43 women (male:female ratio, 1.00:1.34). Of the 75 patients, 43 (57.33%) presented with combined distant metastases. Fifty-seven (76.00%) patients had 131 I avidity and 18 had non-131 I avidity. At the end of follow-up, 22 (29.33%) patients showed progressive disease. Sixteen of the 75 patients died; of the remaining 59 patients, 6 (8.00%) had an excellent response, 6 (8.00%) had an indeterminate response, 10 (13.33%) had an biochemical incomplete response, and 37 (49.33%) had a structural incomplete response. Multivariate analysis confirmed that age at initial PPM diagnosis, the maximal size of PPM, and 131 I avidity had significant effects on progressive disease of PPM lesions (p = .03, p= .02, and p < .01, respectively). The 5- and 10-year DSSrates were 98.49% and 62.10%, respectively. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with a poor prognosis (p = .03 and p = .04, respectively). The therapeutic effect for PPM was closely associated with 131 I avidity, age at initial PPM diagnosis, and maximal size of PPM at the end of follow-up. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with poor survival.

Scoring system and a simple nomogram for predicting radioiodine refractory differentiated thyroid cancer: a retrospective study

BackgroundDifferentiated thyroid carcinoma (DTC) originates from abnormal follicular cells and accounts for approximately 90–95% of thyroid malignancies. The diagnosis of radioiodine refractory DTC (RR-DTC) is based on clinical evolution and iodine uptake characteristics rather than pathological characteristics. Thus, it takes a long time to become apparent, and the definition of RR-DTC covers multiple aspects. We aimed to analyze the clinical and molecular imaging characteristics of patients with RR-DTC and identify independent predictors to develop an RR-DTC scoring system and a simple nomogram for predicting the probability of RR-DTC. We reviewed the data of 404 patients with metastatic DTC who underwent both post-RAI WB therapy scintigraphy and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography. Data on the clinical features and molecular characteristics of RR-DTC and non-RR-DTC cases were obtained from medical records. We screened for predictors using univariate analyses, obtained independent predictors through multivariate analyses, and then established a scoring system and a simple nomogram for predicting RR-DTC according to the corresponding odds ratio (OR) values.ResultsDiagnosis at age ≥ 48 years (OR, 1.037; 95% confidence interval [CI], 1.007–1.069), recurrence between the operation and iodine-131 treatment (OR, 7.362; 95% CI 2.388–22.698), uptake of 18F-FDG (OR, 39.534; 95% CI 18.590–84.076), and the metastasis site (OR, 4.365; 95% CI 1.593–11.965) were highly independently associated with RR-DTC. We established a scoring system for predicting RR-DTC, showing that the area under the receiver operating characteristic curve (AUC) with a cutoff value of 10 points (AUC = 0.898) had a higher discernibility than any other single independent predictor. The risk factors of RR-DTC in nomogram modeling include diagnosis at age ≥ 48 years, recurrence between the operation and iodine-131 treatment, uptake of 18F-FDG, and the site of metastasis. The concordance index (c-Index) of the nomogram was 0.9.ConclusionsWe demonstrated that a predictive model based on four factors has a good ability to predict RR-DTC. An index score ≥ 10 points was found to be the optimal index point for predicting RR-DTC. Moreover, this nomogram model has good predictive ability and stability. This model may help establish an active surveillance or appropriate treatment strategy for RR-DTC cases.

Predictive Value of Clinical and Pathological Characteristics for Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma: A 16-year Retrospective Study.

PurposeTo assess predictive value of clinical and pathological characteristics for metastatic radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC) in early stage retrospectively.MethodsWe studied 199 metastatic DTC patients who were divided into two groups (TgAb negative and TgAb positive). The stimulated Tg (Sti-Tg) at the first and second radioiodine therapy (RIT) were defined as Sti-Tg1 and Sti-Tg2, the suppressed Tg (Sup-Tg) were designated as Sup-Tg1 and Sup-Tg2, while the TgAb were defined as TgAb1 and TgAb2, respectively. Univariate analysis and Logistic regression were used to investigate the effects of 13 observed factors to predict RAIR-DTC.ResultsIn TgAb negative group, ROC curve analysis showed that cut-off values of age, Sti-Tg2/Sti-Tg1 and Sup-Tg2/Sup-Tg1 to predict RAIR-DTC were 40 years old, 57.0% and 81.0%, respectively. Age, extrathyroid invasion, Sti-Tg2/Sti-Tg1, Sup-Tg2/Sup-Tg1 and BRAF gene mutation were proved to be independent factors predicting RAIR-DTC. In TgAb-positive group, ROC curve analysis showed that cut-off values of age, TgAb1 and TgAb2/TgAb1 to predict RAIR-DTC were 55 years old, 297 IU/ml (14.8 times higher than the upper limit) and 53.6%, respectively.ConclusionsFor TgAb-negative DTC, age over 40, extraglandular invasion, mutated BRAF gene, Sti-Tg decreased less than 43%, and Sup-Tg decreased less than 19% after the first two courses of RIT were independent predictors for RAIR-DTC. For TgAb-positive DTC, age over 55, extraglandular invasion, mutated BRAF gene, distant metastasis before RIT, TgAb level 14.8 times higher than the upper limit, TgAb dropped less than 46.4% after two courses of RIT were influencing factors.

The potential long-term comparative effectiveness of larotrectinib vs standard of care for treatment of metastatic TRK fusion thyroid cancer, colorectal cancer, and soft tissue sarcoma

BACKGROUND: Larotrectinib is approved for patients with metastatic TRK fusion cancers, including differentiated thyroid (DTC), colorectal cancer (CRC), and soft tissue sarcoma (STS). Given the basket clinical trial design of larotrectinib, direct comparisons against standard of care in each of the mentioned cancers have not been assessed. Also, owing to the limited duration of follow-up in clinical trials, long-term outcomes for treatments are generally not known or estimated. OBJECTIVE: To compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for patients with metastatic DTC, CRC, and STS who are eligible to receive larotrectinib against patients with unknown NTRK gene fusion status receiving standard-of-care therapy. METHODS: We developed a partitioned survival model to estimate the long-term comparative effectiveness of larotrectinib and standard of care for 3 tumor types. Larotrectinib survival data, assessed by independent review committee, were derived from an updated July 2020 analysis of 19, 8, and 23 adult patients (aged ≥ 18 years) with metastatic TRK fusion DTC, CRC, and STS, respectively. The DTC survival data also included 2 patients aged less than 18 years for a total of 21 patients. Survival estimates for standard of care were derived from published clinical trials. Progressionfree and overall survival for all treatments were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Lognormal) fit to the available data. The final exponential form was selected based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the preprogression and postprogression health states by utility weights derived from publicly available literature. RESULTS: Patients receiving larotrectinib experienced more LYs and QALYs compared with those receiving standard-of-care treatments across all 3 assessed cancer types. In DTC, patients receiving larotrectinib had 7.15-8.26 additional LYs (5.87-6.12 QALYs); in CRC, patients receiving larotrectinib had 1.26-1.27 additional LYs (1.00 QALYs); and in STS, patients receiving larotrectinib had 5.56 additional LYs (1.99 QALYs). CONCLUSIONS: Compared with standard of care in metastatic TRK wild-type cancers, larotrectinib is estimated to result in improved LY and QALY outcomes based on parametric extrapolations of intrial survival data. Because patient-level data were unavailable for adjusted analyses, a cross-trial comparison was performed. Given the limitations of this analytic approach and the small sample size for larotrectinib in trials, future studies should reassess the comparative effectiveness of larotrectinib vs standard of care as treated patients accrue and long-term survival data mature. DISCLOSURES: K. Suh, J. Carlson, and S. Sullivan report consulting fees from Bayer US LLC. F. Xia and T. Williamson are employees of Bayer US LLC. This study was funded by Bayer US LLC. The sponsor had no role in the design of the study and did not have any role in the execution, analyses, interpretation of the data, or decision to submit results.

PO-1027 Radioiodine therapy guided by 124I-PET/CT in metastatic DTC: long-term follow-up data

PO-1027 Radioiodine therapy guided by 124I-PET/CT in metastatic DTC: long-term follow-up data

18F]-FDG-PET/CT Correlates With the Response of Radiorefractory Thyroid Cancer to Lenvatinib and Patient Survival.

18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ([18F]-FDG-PET/CT)-positive metastatic lesions in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have a poor prognosis and lenvatinib represents the best therapy. We investigated the role of [18F]-FDG-PET/CT in the evaluation of metabolic response and prediction of the outcome of RAI-R DTC patients treated with lenvatinib. Patients (n = 33) with progressive metastatic RAI-R DTC who were treated with lenvatinib were investigated at baseline and during follow-up with biochemical (thyroglobulin and thyroglobulin antibodies), morphological (whole-body CT scan) and metabolic ([18F]-FDG-PET/CT) evaluation. Nineteen (57.6%) patients showed the greatest metabolic response at the first [18F]-FDG-PET/CT scan, performed after 4 weeks of lenvatinib, while 5/33 (15.1%) patients had this response later. Moreover, 66.7% of patients had both a metabolic response at the first [18F]-FDG-PET/CT scan and a morphological response at the first CT scan. We observed a correlation between the metabolic response at [18F]-FDG-PET/CT scan performed after 4 weeks of treatment and the biochemical response at the same time in 60.6% of patients. The median overall survival (OS) was significantly longer in patients with either a metabolic response at last [18F]-FDG-PET/CT (40.00 vs 8.98 months) or a morphological response at last CT scan (37.22 vs 9.53 months) than in those without response. Moreover, the OS was longer in patients with a metabolic response at [18F]-FDG-PET/CT performed after 4 weeks of treatment (36.53 vs 11.28 months). Our data show that [18F]-FDG-PET/CT can early predict the response to lenvatinib and correlates with the OS of RAI-R DTC patients treated with this drug.

Prevalence and Risk Factors of Developing Fistula or Organ Perforation in Patients Treated with Lenvatinib for Radioiodine-Refractory Thyroid Cancer

Introduction: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. Methods: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. Results: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. Conclusions: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

Determination of thyroglobulin levels by radioimmunoassay method in anti thyroglobulin positive differentiated thyroid patients: One center clinical experience

It is very crucial to determine Tg accurately and precisely in thyroid cancer cases. Although there are many studies on the detection of Tg in thyroid cases in the literature, there are no sufficient clinical studies examining many cases with different features by using RIA methodology. Here, a radiometric and chromatographic method has been studied for the first time to eliminate the interference from anti-Tg positive patients. In this paper, radioimmunoassay (RIA) and immunoradiometric (IRMA) techniques were used for the analysis of 302 sera collected from patients for Tg and TgAb quantification. By the RIA technique, a reliable result was obtained by calculating the real Tg value quantitatively in 41 patients showing TgAb positivity out of 208 patients. Our findings show that the RIA assay is the most suitable approach for detection of changeable (low or undetectable) Tg value and metastases detected by post-therapeutic imaging in early-stage DTC cases showing preoperative and postoperative TgAb positivity. The new immunoradiometric method allows the real (%) Tg value to be reached in a part of TgAb-positive DTC. Even if TgAb positive in the metastatic and nonmetastatic DTC patient group. This allows the accurate clinical follow-up of patients.

1872TiP - Durvalumab plus tremelimumab for the treatment of patients (pts) with refractory and progressive advanced thyroid carcinoma: A phase II multicohort trial (DUTHY / GETNE T1812)

BackgroundPreliminary studies have suggested that the activity of anti-PD-1 immune check-point inhibitors in thyroid cancer is low. However, we hypothesize that combining CTLA-4 and PD-L1 clockade could have a higher effet in the setting of refractory thyroid carcinomas, in which the process of de-differentiation and evasive tumor resistance are associated with increased mutational load. Trial designThis prospective, multi-center, open-label, phase II study will evaluate the efficacy and safety of Durvalumab plus Tremelimumab within three parallel cohorts: differentiated (DTC), medullary (MTC), and anaplastic (ATC) thyroid cancers. Pts will receive Durvalumab 1500mg plus Tremelimumab 75mg every 4 weeks for up to 4 cycles followed by Durvalumab until PD, unacceptable toxicity or patients’ decision. Main end point in cohorts 1 and 2 is progression-free survival (PFS). We hypothesize an increase of 6-months from 25% in historical cohorts up to 45%. A Simon two-stage design will be employed with 17 pts per cohort in the first phase. If 5/17 pts in each cohort (DTC and MTC) are event free and without unacceptable toxicity at 6 months in the first stage, 19 additional pts will be reruited up to 36 pts per cohort. For cohort 3 (ATC), we hypothesize an improvement the probability of being alive at 6 months from 5% in historical cohorts up to 35%. 12 pts are needed in this cohort. Secondary objectives include overall response rate by irRECIST and RECIST, duration of response, safety profile and biomarkers. The main inclusion criteria for the three cohorts are: Cohort 1: Pts with locally advanced or metastatic DTC after PD on multikinase inhibitors (MKIs). Cohort 2: Pts with locally advanced or metastatic MTC after PD to MKIs. Cohort 3: Pts with ATC irrespective of prior therapy. No prior treatment with immune checkpoint inhibitors is allowed. The study is currently recruiting pts with 6 out of 46 planned pts enrolled at time of submission. Clinical trial identificationEudraCT: 2018-001066-42. Legal entity responsible for the studyThe authors. FundingSpanish Group of Neuroendocrine and Endocrine Tumors (GETNE). DisclosureJ. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini; Travel / Accommodation / Expenses: Ipsen, Novartis, AAA, Roche, AstraZeneca, Eisai. M. Taberna Sanz: Advisory / Consultancy: Merck, Nanobiotics, AstraZeneca, MSD and Bristol Myers..A. Carmona Bayonas: Speaker Bureau / Expert testimony: Novartis, Ipsen; Travel / Accommodation / Expenses: Novartis, Ipsen. L. Iglesias: Advisory / Consultancy: Merck Serono, MSD, BMS, Bayer and Sanofi; Speaker Bureau / Expert testimony: Merck Serono, MSD, AstraZeneca and BMS..E. Grande: Advisory / Consultancy: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi, Adacap, Novartis, EUSA Pharma, Pierre Fabre, Lexicon, Celgene; Research grant / Funding (institution): MSD, Roche. J.M. Trigo Perez: Advisory / Consultancy: BMS, MSD, Behringer, GSK; Speaker Bureau / Expert testimony: AstraZeneca, Bayer, Roche; Travel / Accommodation / Expenses: MSD, BMS. T. Alonso Gordoa: Advisory / Consultancy: BMS, MSD, Roche, Astellas, IPSEN, Sanofi; Speaker Bureau / Expert testimony: Pfizer, Ipsen, Janssen, Astellas, Novartis.; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Pfizer, Sanofi. J. Lavernia: Speaker Bureau / Expert testimony: Roche, BMS, Sun Pharma, Sanofi and Merck Serono. J. Capdevila: Advisory / Consultancy: Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, AAA, Amgen, Sanofi, Merck; Honoraria (institution): Eisai, Novartis, Ipsen, AstraZeneca, Pfizer, AAA. All other authors have declared no conflicts of interest.

Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials

Background and aims: Radioiodine-refractory advanced or metastatic thyroid cancer has poor prognosis. We conducted a meta-analysis of randomized controlled trials to evaluate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) for advanced or metastatic thyroid cancer treatment.Methods: Studies published up to April 2017 were selected. The pooled effect size was calculated through meta-analysis by using random effects models. Outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (RR), and adverse events (AEs).Results: Six studies examining 1615 patients were included. TKI treatment significantly improved PFS in patients with differentiated thyroid cancer (DTC; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.23–0.82) and those with medullary thyroid cancer (MTC; HR = 0.36; 95% CI, 0.22–0.58). TKI treatment significantly prolonged OS in patients with DTC (HR = 0.74; 95% CI, 0.58–0.95). The TKI treatment group exhibited a significantly improved partial response rate (risk ratio = 15.8; 95% CI, 1.77–140.69) but a significantly higher number of AEs compared with the control group.Conclusion: TKIs significantly improved PFS and RR in patients with advanced or metastatic DTC or MTC. We recommend thoroughly evaluating patients’ health status and cautiously using TKIs to maximize their benefits and minimize their toxicity.

The placebo effect in thyroid cancer: a meta-analysis.

The natural history of advanced thyroid malignancies is largely unknown. The outcome of patients included in the placebo arm of clinical trials could be reflective of their therapy-free evolution. To analyze the response rate, symptoms and adverse effects of locally advanced or metastatic differentiated (DTC) and medullary thyroid cancer (MTC) in patients treated with placebo in clinical trials. PubMed (MEDLINE) and SCOPUS databases were searched through September 2015 to identify high-quality randomized controlled clinical trials. We included studies that recruited patients with DTC or MTC with a placebo arm. We conducted a meta-analysis for each category of response rate, adherence to treatment, and adverse events. An empirical Bayesian random-effect model was used. We identified five clinical trials. DTC and MTC were independently analyzed. In the placebo arm, no complete response was observed; partial response occurred in 1.6% (0.6-3) and 6.4% (3.4-10.3) of DTC and MTC respectively; stable disease was described in 40.5% (34.6-46.9) and 53.9% (44.3-64.4) of DTC and MTC respectively. DTC reached a disease control rate of 42.3% (36.2-48.9) and MTC of 60.2 (50.1-71.4). Treatment discontinuation rate was 3.5% (1.9-5.5) in DTC and 5.7% (3.0-9.4) in MTC. Rate of dose reduction was 7.3% (4.8-10.5) in DTC and 6.2% (3.3-10.0) in MTC. This meta-analysis provides extensive data on the response rate and adverse effects of locally advanced or metastatic DTC and MTC in patients treated with placebo. These results may be used for comparisons with results from clinical trials without a placebo arm.

Dilemmas in Metastatic Differentiated Thyroid Cancer: To irradiate, medicate, or palliate?

ABSTRACT Aims To explore the challenges in the management of metastatic differentiated thyroid cancer. Introduction Differentiated thyroid cancer (DTC) is the most common form of thyroid cancer. The initial diagnosis of thyroid carcinoma and the distinction between benign and neoplastic disease can be challenging. Radioiodine-refractory metastatic DTC also presents a therapeutic dilemma. Novel targeted agents for advanced radioiodine-refractory metastatic thyroid cancer, such as tyrosine kinase inhibitors (TKIs), are being increasingly used with clinical success, broadening current available therapeutic options. Case report We present the case of a 61-year-old woman with radioiodine-refractory metastatic follicular thyroid carcinoma, which was initially misdiagnosed as benign Hurthle cell adenoma. We focus on the challenges in both the initial diagnosis and the subsequent management of her advanced disease with skeletal dominant metastases. Conclusion The advent of targeted systemic therapies as emerging frontline and salvage therapy is a novel addition to the management of radioiodine-refractory advanced DTC. Further studies to expand the role of sequential and redifferentiation therapy for advanced disease and strategies to reduce skeletalrelated events are still required. How to cite this article Lee MH, Moxey JE, McLachlan S-A, MacIsaac RJ, Sachithanandan N. Dilemmas in Metastatic Differentiated Thyroid Cancer: To irradiate, medicate, or palliate? World J Endoc Surg 2016;8(2):168-171.

Validation of a Simple Thyroid Cancer Dosimetry Model Based on the Fractional Whole-Body Retention at 48 Hours Post-Administration of (131)I.

Standard dosimetric methods to determine the maximum tolerated activity (MTA) of (131)I for the treatment of metastatic, well-differentiated thyroid cancer (DTC) are time-consuming and require complex analysis. As a result, reliable, accurate, and simplified methods are desirable. The objective of this study was to evaluate the validity of a simple regression dosimetry model. Previously, the authors reported a bi-exponential model for estimating the MTA of (131)I for the treatment of metastatic DTC based on a limit of 2 Gy to the blood. This model uses the patient's body surface area (BSA) along with the fractional whole-body retention (WBR) at 48 hours following oral administration of a diagnostic dosage of (131)I. A bi-exponential regression model was developed between the MTA normalized to the patient's BSA and the percent retention value at the 48-hour time point (R): MTA (GBq)/BSA (m(2)) = (13.91 · e(-0.0387R) + 42.33 · e(-0.8522R)). In this study, the same model was applied to a different set of adult patients referred for dosimetry and possible (131)I treatment of DTC under conditions of thyroid hormone withdrawal or recombinant human thyrotropin (rhTSH) stimulation. All patients (n = 170; 96 female) referred to the authors' clinic for dosimetry and possible (131)I treatment for metastatic DTC during the collection period were included in this study, apart from those undergoing renal dialysis. The MTA predicted (MTAp) using the model described above was compared to the measured MTA (MTAm), with statistical analysis performed using ProStat v4.5. In this group, the MTAm ranged from 2.3 to 41.1 GBq. The linear correlation between the MTAp and MTAm was excellent (r = 0.96), with an average deviation of only ± 1.2%. However, to avoid overdosing a patient on the basis of the MTAp, a weighting factor (<1.0) should be applied (e.g., using a value of 0.7 would result in only one patient receiving a prescribed activity of (131)I that exceeded the MTAm [<3%]). The % 48-hour WBR as determined by the bi-exponential function noted herein with reasonable restrictions has been validated as a reliable simplified dosimetry model.

Response to sorafenib treatment in advanced metastatic thyroid cancer.

To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma. Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months). Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%. Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death. These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled.

Current status and future perspectives in differentiated thyroid cancer.

Thyroid cancer is increasing all over the world. The exact cause of this increase is still debated and there are conflicting reports. Sophisticated molecular studies suggest that environmental chemicals may have effects of thyroid carcinogenesis. The development of powerful molecular biology techniques has enabled targeted next-generation sequencing for detection of mutations in thyroid cancer, and this technique can make a specific diagnosis of thyroid cancer in cytologically indeterminate cases. The initial treatment of well-differentiated thyroid cancer (DTC) is surgery followed by radioiodine remnant ablation. However, further studies are needed to determine the optimal dosage of radioactive iodine for DTC patients with lateral neck metastasis. DTC is an indolent tumor and may cause death even decades later. Thus, long-term follow-up is mandatory. Recently, dynamic risk stratification (DRS) has begun to use stimulated thyroglobulin level at 1 year after the initial treatment and restratified the risk in accordance with the response to the initial treatment. This DRS strategy accurately predicts disease free survival and can be widely used in daily clinical settings. For the iodine refractory metastatic disease, redifferentiation therapy and targeted therapy are two promising alternative treatments. Sorafenib is the first approved agent for the treatment of progressive iodine refractory advanced thyroid cancer in Korea and may be very helpful for radioactive-refractory locally advanced or metastatic DTC. Selumetinib may be an effective redifferentiating agent and could be used within several years.

Systemic Therapeutic Approaches to Advanced Thyroid Cancers

Until only recently, few effective systemic therapies were available to treat patients with metastatic thyroid cancers. Recent advances in better understanding the pathogenesis and altered signaling pathways-especially in medullary and differentiated thyroid cancers (MTCs and DTCs)-have begun to change this situation substantially. Vandetanib, an orally bioavailable inhibitor of the RET kinase that is constitutively activated in MTC, has now been approved by the U.S. Food and Drug Administration (FDA) for use in progressive and symptomatic metastatic MTC; it has been shown to delay time to progression relative to placebo in a randomized phase III trial. Further, vascular endothelial growth factor receptor (VEGF-R) inhibitory agents including sorafenib, sunitinib, pazopanib, and axitinib that are already approved in the United States for use in advanced renal cell carcinoma have shown high response rates in treating advanced DTCs in multiple phase II trials, and have become commonly used in progressive radioiodine-refractory metastatic DTC. Yet additional agents are now in development, with several including XL184 (cabozantinib) also showing promise in DTC and MTC. In anaplastic thyroid cancer (ATC), progress has been slower, with the greatest apparent gains resulting more from the application of systemic therapies earlier in the disease course, especially when used in conjunction with initial surgical and radiation therapies. Despite recent progress, additional effective systemic therapeutic approaches remain sorely needed for treating metastatic MTC, DTC, and ATC.

Systemic Therapeutic Approaches to Advanced Thyroid Cancers

Overview: Until only recently, few effective systemic therapies were available to treat patients with metastatic thyroid cancers. Recent advances in better understanding the pathogenesis and altered signaling pathways—especially in medullary and differentiated thyroid cancers (MTCs and DTCs)—have begun to change this situation substantially. Vandetanib, an orally bioavailable inhibitor of the RET kinase that is constitutively activated in MTC, has now been approved by the U.S. Food and Drug Administration (FDA) for use in progressive and symptomatic metastatic MTC; it has been shown to delay time to progression relative to placebo in a randomized phase III trial. Further, vascular endothelial growth factor receptor (VEGF-R) inhibitory agents including sorafenib, sunitinib, pazopanib, and axitinib that are already approved in the United States for use in advanced renal cell carcinoma have shown high response rates in treating advanced DTCs in multiple phase II trials, and have become commonly used in progressive radioiodine-refractory metastatic DTC. Yet additional agents are now in development, with several including XL184 (cabozantinib) also showing promise in DTC and MTC. In anaplastic thyroid cancer (ATC), progress has been slower, with the greatest apparent gains resulting more from the application of systemic therapies earlier in the disease course, especially when used in conjunction with initial surgical and radiation therapies. Despite recent progress, additional effective systemic therapeutic approaches remain sorely needed for treating metastatic MTC, DTC, and ATC.