Advanced Differentiated Thyroid Cancer Research Articles

Ten years' real-life experience on the use of multikinase inhibitors in patients with advanced differentiated thyroid cancer.

To evaluate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) associated with tyrosine kinase inhibitors (TKIs) in patients with radioiodine refractory differentiated thyroid cancer (RR-DTC). Additionally, to compare: (i) ORR and PFS among patients treated with lenvatinib and sorafenib; (ii) ORR and PFS among patients receiving lenvatinib as first-line vs. second-line and; (iii) adverse effects (AEs) observed in patients treated with these medications. Retrospective analysis of RR-DTC adult patients treated with TKIs at the Division of Endocrinology, Hospital de Clinicas, University of Buenos Aires (March 2011-November 2023). Among 43 patients included in the study, 32 received sorafenib (30 as first-line and 2 as second-line), while 29 received lenvatinib (12 as first-line and 17 as second-line). The median PFS and OS for the entire cohort were 32.7 and 39.0 months, respectively. Lenvatinib demonstrated a significantly higher ORR compared to sorafenib (37.9% vs. 9.4%, p = 0.008). However, both drugs exhibited similar median PFS (23.2 vs. 16.0 months, p = 0.419). No significant difference was observed in ORR and PFS between patients receiving first-line vs. second-line lenvatinib. Sorafenib-treated patients experienced higher rates of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018), whereas lenvatinib-treated patients had higher rates of proteinuria (31% vs. 0%, p < 0.001) and grade 3 hypertension (31% vs. 9%, p = 0.034). TKIs demonstrated efficacy and tolerability comparable to real-world data in RR-DTC. PFS was not statistically different between sorafenib and lenvatinib. Our study will help guide physicians in making informed decisions regarding treatment sequencing with TKIs in these patients.

Targeting miR-31 represses tumourigenesis and dedifferentiation of BRAFV600E-associated thyroid carcinoma.

BRAFV600E is the most common genetic mutation in differentiated thyroid cancer (DTC) occurring in 60% of patients and drives malignant tumour cell phenotypes including proliferation, metastasis and immune-escape. BRAFV600E-mutated papillary thyroid cancer (PTC) also displays greatly reduced expression of thyroid differentiation markers, thus tendency to radioactive iodine (RAI) refractory and poor prognosis. Therefore, understanding the molecular mechanisms and main oncogenic events underlying BRAFV600E will guide future therapy development. Bioinformatics and clinical specimen analyses, genetic manipulation of BRAFV600E-induced PTC model, functional and mechanism exploration guided with transcriptomic screening, as well as systematic rescue experiments were applied to investigate miR-31 function within BRAFV600E-induced thyroid cancer development. Besides, nanoparticles carrying miR-31 antagomirs were testified to alleviate 131I iodide therapy on PTC models. We identify miR-31 as a significantly increased onco-miR in BRAFV600E-associated PTC that promotes tumour progression, metastasis and RAI refractoriness via sustained Wnt/β-catenin signalling. Mechanistically, highly activated BRAF/MAPK pathway induces miR-31 expression via c-Jun-mediated transcriptional regulation across in vitro and transgenic mouse models. MiR-31 in turn facilitates β-catenin stabilisation via directly repressing tumour suppressors CEBPA and DACH1, which direct the expression of multiple essential Wnt/β-catenin pathway inhibitors. Genetic functional assays showed that thyroid-specific knockout of miR-31 inhibited BRAFV600E-induced PTC progression, and strikingly, enhanced expression of sodium-iodide symporter and other thyroid differentiation markers, thus promoted 131I uptake. Nanoparticle-mediated application of anti-miR-31 antagomirs markedly elevated radio-sensitivity of BRAFV600E-induced PTC tumours to 131I therapy, and efficiently suppressed tumour progression in the pre-clinical mouse model. Our findings elucidate a novel BRAF/MAPK-miR-31-Wnt/β-catenin regulatory mechanism underlying clinically BRAFV600E-associated DTC tumourigenesis and dedifferentiation, also highlight a potential adjuvant therapeutic strategy for advanced DTC.

The methodological and reporting quality of randomized controlled trials of tyrosine kinase inhibitors for advanced differentiated thyroid cancer: Meta-research study.

Clinical trials on tyrosine kinase inhibitors (TKI) treatment have shown an improvement in overall and progression-free survival in patients with advanced differentiated thyroid cancer. However, it is necessary to evaluate these studies to assess methodological biases and inconsistencies that may impact the effects. To map and assess the methodological quality of randomized clinical trials (RCTs) regarding randomization, allocation concealment, blinding, and selective reporting bias. RCTs assessing the efficacy and safety of TKI for the treatment of advanced differentiated thyroid cancer were included. The search was performed in the MEDLINE database. The included RCTs were assessed for the adequacy of the methodological steps, as recommended by the Cochrane Risk of Bias tool. Nine studies were analyzed, of which 77.7% were classified as low risk of bias regarding selective reporting and 33.3% as high risk of reporting bias. The mean time between protocol registration and study publication was approximately 5.11 years. Moreover, 66.7% were classified as low risk of bias for randomization and allocation concealment, and 33.3% did not specify the randomization process and allocation concealment in a way that would allow the identification of occurrences of bias. Concerning blinding of participants and outcome assessors, 77.8% of the RCTs reported adequate blinding and were classified as having a low risk of bias, 11.1% had a high risk of bias, and 11.1% had insufficient information and were classified as having unclear risk of bias. Regarding the blinding of the outcome assessors, 33.3% did the blinding correctly, 11.1% did not blind, and 55.6% did not provide enough information. Overall, the assessed RCTs were predominantly at low risk of bias. The critical evaluation of these studies is essential to have confidence in the treatment estimated effect that will support clinical decision-making and provide information to preclude future clinical study flaws.

How to Manage Advanced Differentiated Thyroid Cancer: Step-by-Step Analysis from Two Italian Tertiary Referral Centers

Background: Differentiated thyroid carcinoma (DTC) has an excellent prognosis; however, advanced disease is associated with a worse prognosis and is relatively common. Surgery followed by RAI treatment remains the mainstream treatment for a large majority of patients with high- and intermediate-risk DTC, but its benefits should be carefully weighed against the potential for harm. The aim of this paper is to critically review the experience in treating advanced DTC at two tertiary referral centers in Italy. Methods: Retrospective analysis of 300 patients who underwent surgery for ADTC over 30 years. Results: The complication rate was 50.33%. A total of 135 patients (45%) remained at regular follow-up, 118 (87.4%) were alive, while 17 (12.6%) were deceased. The mean overall survival at 12 years was 84.8% with a mean of 238 months. Eleven patients (8.1%) experienced a relapse after a median of 13 months. Conclusions: ADTC patients adequately treated can achieve prolonged survival even in the case of metastasis or disease relapse. Patients with ADTC should be referred to high-volume centers with the availability of an extended multidisciplinary team to receive tailored treatment.

A New Twist on a Classic: Enhancing Radioiodine Uptake in Advanced Thyroid Cancer.

Advanced differentiated thyroid cancer that is resistant to radioactive iodine therapy may become responsive with a unique treatment combination of chloroquine and vorinostat. This treatment was demonstrated in cellular and animal models of thyroid cancer to inhibit endocytosis of the plasma membrane-bound iodine transporter, NIS, and restore iodine uptake. See related article by Read et al., p. 1352.

Expert consensus on management strategies for locally advanced differentiated thyroid cancer involving the laryngeal nerve

The laryngeal nerve is the most commonly involved peripheral structure of locally advanced differentiated thyroid carcinoma, which often requires larger resection range and corresponding reconstruction, resulting in a series of complications and sequelae. Therefore, treatment strategies must not only guarantee survival benefits, but also take into account functional protection or reconstruction. Comprehensive and detailed evaluation should be conducted before surgery, and a thorough treatment plan should be made according to scientific stratification in different situations. This consensus aims at thyroid surgeons, voice physicians, anesthesiologists, rehabilitators, nurses and other groups, and standardizes the diagnosis, treatment and rehabilitation technical standards and procedures of advanced differentiated thyroid cancer involving laryngeal nerve, so as to benefit the majority of thyroid cancer patients.

Hashimoto Thyroiditis and Mortality in Patients with Differentiated Thyroid Cancer: The National Epidemiologic Survey of Thyroid Cancer in Korea and Meta-Analysis.

Many studies have shown that Hashimoto's thyroiditis (HT) acts as a protective factor in differentiated thyroid cancer (DTC), but little is known about its effects on mortality. Therefore, this study was performed to reveal the prognosis of HT on mortality in patients with DTC. This study included two types of research. retrospective cohort study using the National Epidemiologic Survey of Thyroid cancer (NEST) in Korea and meta-analysis study with the NEST data and eight selected studies. Of the 4,398 patients with DTC in NEST, 341 patients (7.8%) died during the median follow-up period of 15 years (interquartile range, 12.3 to 15.6). Of these, 91 deaths (2.1%) were related to DTC. HT was associated with a smaller tumor size and less aggressive DTC. In Cox regression analysis after adjusting for age and sex, patients with HT showed a significantly lower risk of all-cause death (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96) and DTC-related death (HR, 0.33; 95% CI, 0.14 to 0.77). The analysis with inverse probability of treatment weight data adjusted for age, sex, and year of thyroid cancer registration showed similar association. The meta-analysis showed that patients with HT showed a lower risk of all-cause mortality (risk ratio [RR], 0.24; 95% CI, 0.13 to 0.47) and thyroid cancer-related mortality (RR, 0.23; 95% CI, 0.13 to 0.40) in comparison with patients without HT. This study showed that DTC co-presenting with HT is associated with a low risk of advanced DTC and presents a low risk for all-cause and DTC-related death.

Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer

Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. A significant correlation was found between RAI-R development and genetic alterations (P= 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P= 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P= 0.006). Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.

Pharmacokinetics/Pharmacodynamics of Dabrafenib and Trametinib for Redifferentiation and Treatment of Radioactive Iodine-Resistant Mutated Advanced Differentiated Thyroid Cancer.

Background: BRAF and MEK inhibitors are cornerstones of the redifferentiation strategy in metastatic radioactive iodine (RAI)-resistant mutant thyroid cancers. We explored the exposure-toxicity relationship for dose-limiting toxicity (DLT) onset in patients treated with dabrafenib and/or trametinib and investigated whether plasma exposure was associated with RAI reuptake. Methods: We conducted a retrospective monocentric study in which we reviewed the electronic medical records of patients treated in our institution with a tumor redifferentiation strategy, for whom plasma concentration of dabrafenib, its active metabolite hydroxy-dabrafenib, and trametinib was measured. Trough concentrations (Cminpred) and total plasma drug exposure (area under the curve, AUC) of dabrafenib (AUCDAB), hydroxy-dabrafenib (AUCOHD), and trametinib (AUCTRA) were estimated. Results: Of the 22 patients treated in a redifferentiation strategy between March 2014 and December 2021, 15 were included in this study. A dabrafenib- or trametinib-related DLT was experienced by 8 (62%) and 9 (64%) patients, respectively. Patients who experienced a trametinib-related DLT exhibited a significantly higher last AUCTRA than the average AUCTRA of patients who had no DLT (390, IQR: 67 vs. 215, IQR: 91 ng/mL·h-1, respectively; p = 0.008). Patients who experienced a dabrafenib-related DLT had a higher AUCDAB than observed in other patients (9265 ng/mL·h-1 vs. 6953 ng/mL·h-1, respectively; p = 0.09). No clinical and demographical characteristic was associated with the DLT onset. Overall, 9 of 15 (60%) patients demonstrated tumor redifferentiation. Patients in whom RAI reuptake was achieved had significant lower AUCDAB (6990 ng/mL·h-1 vs. 9764 ng/mL·h-1, p = 0.014; respectively) compared with patients who did not. Moreover, the relative exposure ratio of AUCOHD/DAB was significantly higher in patients who achieved RAI reuptake (1.11 vs. 0.71, respectively; p = 0.0047). Conclusions: Our data suggest a relationship between DLT onset and trametinib plasma exposure, as well as an association between achievement of RAI reuptake and dabrafenib plasma exposure (AUC and ratio of AUCOHD/DAB). These data imply that the use of plasma drug monitoring could be helpful in guiding clinical practice in redifferentiation treatment.

SAT526 Limited Utility of Routine Neck Ultrasound Follow-up in Advanced Stage Differentiated Thyroid Cancer

Abstract Disclosure: V. Munro: None. S. Mustafa: None. F.S. Siddiqi: None. M. Rajaraman: None. S.A. Imran: None. Background: Most guidelines recommend periodic cervical ultrasound (US) for ongoing surveillance of differentiated thyroid cancer (DTC). While recent studies do not support routine US surveillance in low-risk DTC, to date, no study has assessed the clinical utility of cervical US in advanced DTC. Methods: We conducted a retrospective study of our hospital DTC registry using the following criteria: a) AJCC stage III and IV, b) minimum follow-up of &amp;gt;4 years since total thyroidectomy +/-I-131 ablation, and c) at least one US per 3 years of follow-up. Patients with hemithyroidectomy only or positive anti-thyroglobulin antibody at the initial visit were excluded. Two years after initial treatment, patients were categorized by Dynamic Risk Stratification (DRS) as excellent, indeterminate, biochemically incomplete, or structurally incomplete response. Data obtained at each visit included: treatment response, thyroglobulin (TG) level, and US findings. Results: A total of 114 patients (85 AJCC stage III and 29 stage IV patients) met the inclusion criteria. Mean age (yrs) at diagnosis was 59, and 67% were female. Mean duration of follow-up was 8.5 years. Based on DRS, 73 patients had excellent response, 28 indeterminate, 8 biochemically incomplete, and 5 structurally incomplete. Recurrence or progression was detected in 20 patients (17.5%): 5 excellent response, 6 indeterminate, 5 biochemically incomplete, and 4 structurally incomplete. Recurrence sites included cervical region (14), distant metastases (5) and both (1). The TG rose from a mean of 4.76 ng/mL at baseline to 40.37 ng/mL at time of recurrence/progression. In those with structurally incomplete disease, US demonstrated progression in all 4 patients. However in other DRS categories, only 5/10 had definite US abnormalities. Of those without recurrence, 4 patients (4.3%) had false positive TG (mean baseline TG 0.08 rose to 11.8 ng/ml) without clinical/radiologic recurrence whereas the rate of false positive US abnormalities was 32% (37/114). The sensitivity and specificity of US vs. TG in diagnosing recurrence was 45% and 60% vs 100% and 95.7%, respectively. Conclusion: Our study suggests that routine cervical US surveillance after initial DRS does not improve the detection of recurrence in patients with excellent, indeterminate, or biochemically incomplete disease, and has a high false positive rate. Therefore, we suggest TG should be considered the mainstay of surveillance and any further imaging guided by DRS status and change in TG. Presentation Date: Saturday, June 17, 2023

SAT510 I-131 Therapy with Dosimetry for Advanced Thyroid Carcinoma: Recombinant TSH vs Thyroid Hormone Withdrawal

Abstract Disclosure: D. Awad: None. J. Hamsa: None. A. Fingeret: None. C. Johnson: None. F. Rutar: None. C. Carson: None. A. Kotwal: None. A. Patel: None. A. Thornburg: None. W.S. Goldner: None. Background: Dosimetry can be used to calculate an optimal and safe dose of Iodine-131 (I-131) for treatment of advanced differentiated thyroid cancer (DTC). Thyroid hormone withdrawal (THW) is the preferred method of TSH elevation for I-131 therapy with dosimetry. At our institution, Recombinant TSH (RhTSH) is used in patients in whom prolonged hypothyroidism is deemed clinically unsafe or cannot tolerate THW. We aim to evaluate if RhTSH and THW are equivalent methods of preparation for I-131 therapy using dosimetry (I-131D). Methods: This is a single institution retrospective cohort study evaluating all patients who received I-131D from 2010-2022. Demographic, clinical variables were assessed and dosimetric calculations were obtained. Statistical analysis was performed with Mann Whitney U, Kruskal Wallis, Chi-squared and Fisher’s exact testing. Results: Fifty-one unique patients were included with a total of fifty-five I-131D treatments, with 55% being female. Median (IQR) age at time of treatment was 60.3 years (42.8-70.4), and BMI kg/m2 was 29.3 (24-33.8). Of these patients 13% were stage I, 18.5% stage II, and 68.5% stage III/IV AJCC 7th ed. Sixty percent underwent THW and 40% received RhTSH. Gamma camera and blood activity measurements, at several time points following the pre-therapeutic I-131 dose, were taken to calculate the residence times and effective half-lives in whole body and blood. All patients demonstrated a monophasic elimination of I-131 activity in both the whole body and blood. Patients receiving RhTSH exhibited a slower elimination of the I-131 in the whole body than THW patients (effective half-life of 22 hrs vs 17 hrs) resulting in a higher fraction of I-131 activity remaining in the whole body 48 hours post-dose (25% vs 16%, p= 0.025). The effective half-life in the blood was also higher in the RhTSH group (p=0.025) resulting in a higher amount of activity remaining in the blood. As a result, the median (IQR) RAI dose was lower for those who received RhTSH (187.5 mCi (167-198)) vs those who underwent THW (260 mCi (202-306)) (p&amp;lt;0.001). As expected, TSH at the time of treatment was higher in the RhTSH group (p=0.0038). Thyroglobulin was higher at the time of treatment in the RhTSH group (p=0.031), but thyroglobulin drop at three months was not statistically different (p=0.0682) between groups. Conclusion: RhTSH administration is non-inferior to THW as a method of TSH elevation and preparation for I-131D for patients with advanced DTC. RhTSH, in comparison to THW, results in a significantly longer half-life in the whole-body and blood resulting in a lower calculated RAI dose. More studies are needed to confirm these findings. Presentation Date: Saturday, June 17, 2023

SAT518 Real World Use of Systemic Therapy for Treatment of Advanced Thyroid Cancer

Abstract Disclosure: D. Chen: None. M. Banerjee: None. T. Xu: None. F.P. Worden: None. M.R. Haymart: None. Background. Since 2011, the United States Food and Drug Administration (FDA) has approved eight small-molecule kinase inhibitors (SMKIs) for the treatment of advanced thyroid cancer (i.e., radioiodine-refractory metastatic differentiated thyroid cancer, metastatic medullary thyroid cancer, and anaplastic thyroid cancer). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend use of 15 SMKIs, of which eight are FDA-approved and seven are commercially available, for the treatment of advanced thyroid cancer. However, little is known about how these medications are used in the real-world setting for treatment of patients with advanced thyroid cancer. Methods. This descriptive study used data from Optum Clinformatics Data Mart, a de-identified commercial claims database of a large national health insurance provider. We identified patients with thyroid cancer who had prescription claims for at least one of the 15 SMKIs of interest (axitinib, cabozantinib, dabrafenib, entrectinib, everolimus, larotrectinib, lenvatinib, pazopanib, pralsetinib, selpercatinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib). Lines of therapy were defined by the date of SMKI claims. We describe changes in usage patterns over time with a focus on the demographics of patients who were newly initiated on treatment of advanced thyroid cancer, and on the medications used for each line of therapy. Results. Between 2013-2021, 886 patients were treated for advanced thyroid cancer with at least one of the 15 SMKIs of interest. Median age was 65.1 years. Most patients were female (54.6%), non-Hispanic White (62.1%), and had supplementary Medicare insurance (60.6%). Between 2013 and 2016, there was an increase in the proportion of Hispanic patients and a corresponding decrease in the proportion of non-Hispanic White patients treated for advanced thyroid cancer. Although most patients were initiated on an FDA-approved SMKI as first line therapy, 23.1% (N=205) were initiated on a commercially available SMKI. Sorafenib was the most prescribed first-line therapy in 2013 (24.4%) and 2014 (48.3%). Lenvatinib was the most prescribed first-line therapy between 2015-2021 when prescriptions for lenvatinib constituted 38.3-55.6% of all SMKIs prescribed for the treatment of advanced thyroid cancer. Between 2017-2021, a minority of patients were treated with up to a fifth line of therapy although the majority (81.8%) were treated with only a first line agent. Conclusions. Since 2015 when lenvatinib was approved by the FDA for treatment of advanced differentiated thyroid cancer, it has become the most commonly prescribed SMKI for treatment of advanced thyroid cancer. However, variation exists in which SMKIs are used to treat patients with advanced thyroid cancer, with almost one-quarter of patients initiated on commercially available SMKIs. Presentation Date: Saturday, June 17, 2023

Fusion Oncogenes in Patients With Locally Advanced or Distant Metastatic Differentiated Thyroid Cancer.

Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. We aimed to investigation between fusion oncogenes and clinicopathological characteristics involving a large-scale cohort of patients with advanced DTC. We collected 278 tumor samples from patients with locally advanced (N1b or T4) or distant metastatic DTC. Targeted next-generation sequencing with a 26-gene ThyroLead panel was performed on these samples. Fusion oncogenes accounted for 29.86% of the samples (72 rearrangement during transfection (RET) fusions, 7 neurotrophic tropomyosin receptor kinase (NTRK) fusions, 4 anaplastic lymphoma kinase (ALK) fusions) and occurred more frequently in pediatric patients than in their adult counterparts (P = .003, OR 2.411, 95% CI 1.329-4.311) in our cohort. DTCs with fusion oncogenes appeared to have a more advanced American Joint Committee on Cancer (AJCC)_N and AJCC_M stage (P = .0002, OR 15.47, 95% CI 2.54-160.9, and P = .016, OR 2.35, 95% CI 1.18-4.81) than those without. DTCs with fusion oncogenes were associated with pediatric radioactive iodine (RAI) refractoriness compared with those without fusion oncogenes (P = .017, OR 4.85, 95% CI 1.29-15.19). However, in adult DTCs, those with fusion oncogenes were less likely to be associated with RAI refractoriness than those without (P = .029, OR 0.50, 95% CI 0.27-0.95), owing to a high occurrence of the TERT mutation, which was the most prominent genetic risk factor for RAI refractoriness in multivariate logistic regression analysis (P < .001, OR 7.36, 95% CI 3.14-17.27). Fusion oncogenes were more prevalent in pediatric DTCs than in their adult counterparts and were associated with pediatric RAI refractoriness, while in adult DTCs, TERT mutation was the dominant genetic contributor to RAI refractoriness rather than fusion oncogenes.

Role of gender on adverse events in a consecutive series of 28 patients with advanced differentiated thyroid cancer receiving lenvatinib

Role of gender on adverse events in a consecutive series of 28 patients with advanced differentiated thyroid cancer receiving lenvatinib

ASO Author Reflections: Targeted Therapy Combined with Immunotherapy as Neoadjuvant Treatment for Locally Advanced Differentiated Thyroid Cancer.

ASO Author Reflections: Targeted Therapy Combined with Immunotherapy as Neoadjuvant Treatment for Locally Advanced Differentiated Thyroid Cancer.

The Efficacy and Safety of Surufatinib Combined with Anti PD-1 Antibody Toripalimab in Neoadjuvant Treatment of Locally Advanced Differentiated Thyroid Cancer: A Phase II Study.

Surgery is the primary treatment for locally advanced differentiated thyroid cancer (DTC). However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced DTC. Surufatinib targets multiple kinases, which is efficient, tolerable, and safe in patients with radioiodine-refractory DTC. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity in advanced solid tumors. This study was designed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced DTC in the neoadjuvant setting. In this single-arm, phase II study, patients with pathologically confirmed unresectable or borderline resectable DTC were eligible and received a combination of 250mg of surufatinib (orally daily) with 240mg of toripalimab (intravenous, every 3weeks). Treatment continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity, or investigator decision. Primary endpoint was objective response rate (ORR). Secondary endpoints included R0/1 resection rate, adverse events (AEs), etc. RESULTS: Ten patients were enrolled and received at least 4 cycles of treatment. The ORR was 60%. Nine patients received R0/1 resections after neoadjuvant treatment. The median best percentage change in the sum of the target lesion diameter was 32%. Most adverse events (AEs) were grade 1 or 2. Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced DTC was feasible, and the majority of patients achieved R0/1 resection. It represents a new option for locally advanced DTC and needs further investigation.

The efficacy and safety of sequential use of anlotinib and 131I for locally advanced or metastatic differentiated thyroid cancer: A single-arm phase II clinical trial.

e18102 Background: Locally advanced or metastatic differentiated thyroid cancer (DTC) commonly responds poorly to radioiodine (131I) treatment alone. Tyrosine kinase inhibitors, however, have exerted promising antitumor activity in multiple advanced solid tumors. This study aimed to investigate the efficacy and safety of sequential use of anlotinib and 131I for the treatment of locally advanced or metastatic DTC. Methods: This is a single-arm phase II open-label clinical trail. The key eligibility criteria included locally advanced or metastatic 131I-avid DTC, ECOG PS of 0-1, and at least one measurable lesion. Previous tyrosine kinase inhibitor was not allowed. Patients initially received anlotinib (12 mg QD, 2 weeks on/1 week off ) for 4 cycles. At the beginning of 13th week when levothyroxine had been discontinued for 4 weeks, diagnostic 131I whole body scan (Dx-WBS) was performed, and those with 131I-avid lesions were immediately identified to undergo 131I treatment. The primary endpoint was objective response rate (ORR) . The secondary endpoints included disease control rate (DCR), biochemical response rate (BRR), time-to-response (TTR), progression-free survival (PFS), and safety. Results: From June 2021 to December 2022, a total of 16 patients with locally advanced or metastatic DTC were included. At the data cut off, 8 patients (4 males and 4 females) were withdrawn from the trial due to negative Dx-WBS, and the remaining 8 patients were subsequently treated with 131I. Six patients who had completed at least one cycle of sequential treatment were eligible for data analysis. Partial response and stable disease were found in 2 (33.33%) and 3 (50%) patients, respectively. An ORR of 33.33% [95% CI, 4.33-77.72], a DCR of 83.33% [95% CI, 35.88-99.58], a BRR of 100% [95% CI, 54.07-100.00], and a TTR of 6.34 months [95% CI, 5.85-NE] were achieved. Median PFS was not reached. Grade 3 adverse events occurred in 2 (33.33%) of the 6 subjects, including pain owing to skeletal metastasis in one patient and drug-related hypertention in the other. Conclusions: This study firstly demonstrates the favorable efficacy and safety of sequential therapy with tyrosine kinase inhibitor and 131I, suggesting anlotinib as a adjuvant option for 131I treatment of locally advanced or metastatic DTC. Randomized controlled studies on sequential therapy versus 131I treatment are warranted. Clinical trial information: ChiCTR2100045178 .

A phase 2 study of neoadjuvant lenvatinib in locally advanced invasive thyroid cancer.

TPS6105 Background: Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor that has demonstrated meaningful benefit in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). In SELECT, lenvatinib significantly prolonged progression-free survival (PFS) and was associated with an overall response rate (ORR) of 65% in patients with RAI-refractory DTC, with the greatest degree of tumor shrinkage occurring in the first 2 cycles. The robust activity of lenvatinib in DTC suggests that neoadjuvant treatment in patients presenting with bulky neck disease may make surgery more feasible, allows for optimal surgical outcomes and less aggressive surgical management. Neoadjuvant lenvatinib to improve surgical outcomes in locally advanced DTC has not been studied to date. This phase 2 study will examine the efficacy and safety of lenvatinib prior to thyroidectomy, with the goal of achieving more favorable surgical outcomes. Methods: This is a Simon two-stage Phase 2 open-label multicenter clinical trial for adult patients who meet the following criteria: have been diagnosed with locally advanced or persistent/recurrent thyroid and/or cervical nodal DTC, deemed at risk for R2 resection (surgical margins with macroscopic tumor) (as evident by vocal cord paralysis by laryngoscopic exam, imaging documenting extrathyroidal/extranodal extension, or major vessels involvement), have measurable disease per RECIST v1.1, have an ECOG performance status ≤ 1, and no contraindication to surgery. A total of 28 patients will be enrolled from three centers (Massachusetts General Hospital/Massachusetts Eye &amp; Ear Infirmary (MGH/MEEI), Memorial Sloan-Kettering Cancer Center (MSKCC), and MD Anderson Cancer Center (MDACC)). Participants will receive up to 6 cycles of lenvatinib prior to surgery depending on response. Participants will undergo restaging at the end of cycle 2, 4, and 6. Participants with sufficient response to treatment who projected to achieve an R0 or R1 resection will stop lenvatinib and proceed to surgery within 7-10 days from the last dose. Participants who do not have a sufficient response who are tolerating treatment, will receive an additional 2-4 cycles of lenvatinib, followed by surgery. The primary objective is the R0 (surgical margins free from tumor)/R1 (surgical margins free from macroscopic tumor) resection rate. Secondary outcome measures include R0/R1 resection rates in each of 5 pre-specified anatomic target interfaces (perithyroid muscles, cartilage, esophagus, recurrent laryngeal nerve, major vessels), evaluation of the change in surgical morbidity complexity MGH/MEEI-MSKCC-MDACC (MMM) score and the Invasive Thyroid Class, ORR prior to surgery per RECIST v1.1, and the safety of lenvatinib in this patient population. The study is currently accruing with 11 patients enrolled at time of submission. Clinical trial information: NCT04321954 .

Neoadjuvant tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a single centre case series.

Primary surgical resection remains the mainstay of management in locally advanced differentiated thyroid cancer. Tyrosine kinase inhibitors have recently shown promising results in patients with recurrent locally advanced differentiated thyroid cancer. This study discussed four patients with locally advanced differentiated thyroid cancer managed with tyrosine kinase inhibitors used prior to surgery in the 'neoadjuvant' setting. Prospective data collection through a local thyroid database from February 2016 identified four patients with locally advanced differentiated thyroid cancer unsuitable for primary surgical resection commenced on neoadjuvant tyrosine kinase inhibitor therapy. All cases had T4a disease at presentation. Three cases tolerated tyrosine kinase inhibitor therapy for more than 14 months while the last case failed to tolerate treatment at 1 month. All patients subsequently underwent total thyroidectomy to facilitate adjuvant radioactive iodine treatment. Disease-specific survival remains at 100 per cent currently (range, 29-75 months). Neoadjuvant tyrosine kinase inhibitors in locally advanced differentiated thyroid cancer can be effective in reducing primary tumour extent to potentially facilitate a more limited surgical resection for local disease control.

Neutrophil-to-lymphocyte ratio as an independent factor for worse prognosis in radioiodine refractory thyroid cancer patients.

This study aimed to evaluate neutrophil to lymphocyte ratio (NLR) as a laboratory biomarker in radioactive iodine-refractory (RAIR) locally advanced and/or metastatic differentiated thyroid cancer (DTC) and determine its correlation with overall survival (OS). We retrospectively included 172 patients with locally advanced and/or metastatic RAIR DTC admitted between 1993 and 2021 at INCA. Age at diagnosis, histology, presence of distant metastasis (DM), DM site, neutrophil-to- lymphocyte ratio (NLR), imaging studies such as PET/CT results, progression free survival (PFS) and overall survival (OS) data were analyzed. NLR was calculated at the time of locally advanced and/or metastatic disease diagnosis and the cutoff value was 3. Survival curves were established using the Kaplan-Meier method. The confidence interval is 95%, and a p-value of less than 0.05 was considered statistically significant RESULTS: Out of 172 patients, 106 were locally advanced, and 150 presented DM at some point during follow-up. Regarding NLR data, 35 had NLR over 3 and 137 had NLR under 3. Higher NLR at was associated with shorter OS (6 vs. 10; p = 0.05) and with highest SUV on FDG PET-CT (15.9 vs. 7.7, p = 0.013). We found no association between higher NLR and age at diagnosis, DM or final status. NLR higher than 3 at the time of locally advanced and/or metastatic disease diagnosis is an independent fator for shorter OS in RAIR DTC patients. Noteworthy higher NLR was also associated with highest SUV on FDG PET-CT in this population.