Rural-Urban Disparities in the Continuum of Thyroid Cancer Care: Analysis of 92,794 Cases.
Thyroid : official journal of the American Thyroid Association
Rurality is associated with higher incidence and higher disease-specific mortality for most cancers. Outcomes for rural and ultrarural ("frontier") patients with thyroid cancer are poorly understood. This study aimed to identify actionable deficits in thyroid cancer outcomes for rural patients. We queried linked California Cancer Registry and California Office of Statewide Health Planning and Development databases for patients diagnosed with thyroid cancer (1999-2017). We analyzed time from disease stage at diagnosis, time from diagnosis to surgery, receipt of appropriate radioactive iodine ablation, surveillance status, and overall and disease-specific mortality for urban, rural, and frontier patients. Cox and logistic regression models controlled for clinical and demographic covariates a stepwise manner. All incidence figures are expressed as a proportion of newly diagnosed cases. Our cohort comprised 92,794 subjects: (65,475 women [70.6%]; mean age 50.0 years). Compared to urban patients, rural and frontier patients were more likely to be American Indian, White, uninsured, and from lower quintiles of socioeconomic status ( < 0.01). Distant disease at diagnosis was more common in rural (56.0 vs. 50.4 cases per 1000 new cases, < 0.01) and frontier patients (80.9 vs. 50.4 per 1000, < 0.01) compared to urban patients. The incidence of medullary thyroid cancer was greater in rural patients (17.9 vs. 13.6 cases per 1000, < 0.01) and frontier patients (31.0 vs. 13.6 per 1000, < 0.01) compared to urban patients. The incidence of anaplastic thyroid cancer was higher in frontier versus urban patients (15.5 vs. 7.1 per 1000, < 0.01). When compared to urban patients, rural and frontier patients were more often lost to follow-up (odds ratio [OR] 1.69 [confidence interval, CI 1.54-1.85], and OR 3.03 [CI 1.89-5.26], respectively) and had higher disease-specific mortality (OR 1.18 [CI 1.07-1.30], and OR 1.92 [CI 1.22-2.77], respectively). Rural and frontier residence was independently associated with being lost to follow-up, suggesting that it is a key driver of disparities. Compared to their urban counterparts, rural and frontier patients with thyroid cancer present with later-stage disease and experience higher disease-specific mortality. They also are more often lost to follow-up, which presents an opportunity for targeted outreach to reduce the observed disparities in outcomes.
10.1089/thy.2023.0357
Fusion Oncogenes in Patients With Locally Advanced or Distant Metastatic Differentiated Thyroid Cancer.
The Journal of clinical endocrinology and metabolism
CONTEXT:Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. OBJECTIVE:We aimed to investigation between fusion oncogenes and clinicopathological characteristics involving a large-scale cohort of patients with advanced DTC. METHODS: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. RESULTS: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). CONCLUSION: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.
10.1210/clinem/dgad500
Beneficial Role of Multi-Disciplinary Treatment for Anaplastic Thyroid Cancer with Initial Distant Metastasis.
International journal of radiation oncology, biology, physics
PURPOSE/OBJECTIVE(S):Anaplastic thyroid cancer (ATC) is a rare, highly aggressive tumor, with median survival around 5 months. Approximately half of the ATC patients presents with distant metastases at diagnosis, showing even more devastating prognosis, yet no outcome analysis had been reported. In this study, we aim to evaluate the clinical outcome of M1 ATC patients, and to define the group of patients who would benefit from local treatment based on multi-disciplinary approach. MATERIALS/METHODS:A total of 133 histology-confirmed ATC patients underwent protocol-based multidisciplinary treatment including surgery and chemoradiotherapy (CRT) between May 2016 and January 2022. Patients received intensity-modulated radiotherapy of 30 fractions concurrently with paclitaxel on days 1, 8 and 15 every 4 weeks, and lenvatinib was added upon progression. After 18 fractions of CRT, interim response analysis using modified RECIST was conducted for adaptive treatment planning. We reviewed 58 patients with distant metastasis at diagnosis (stage IVC). Overall survival (OS) and progression-free survival (PFS) were measured from the day of diagnosis. RESULTS:Most common metastatic site was lung (91.4%), followed by bone (31.0%) and brain (5.2%). Lenvatinib was added for 35 patients after any sign of progression. Fourteen patients received upfront surgery (16 debulking and 5 total) followed by adjuvant CRT in 16 patients. Thirty-one patients received upfront CRT with 2 patients receiving total resection after sufficient down-staging. Six (10%) patients could not complete radiotherapy but continued receiving systemic treatment. The median follow-up was 5.9 months. The median and 1-year OS were 6.2 months and 20.5%, and PFS were 3.7 months and 3.5%. Total RT dose over 60 Gy significantly improved median OS (7.5 vs 4.1 months, p = 0.012) and median PFS (4.4 vs 3.0, p = 0.010). Patients with less than 10 initial metastatic tumors showed better median OS (9.1 vs 4.6 months, p = 0.002) but not PFS (5.1 vs 3.6, p = 0.485). At interim analysis, early response (CR, PR and SD) of primary tumor was not associated with survival, while progression of distant metastases showed significantly worse median OS (9.8 vs 4.6 months, p = 0.001). More than 10 metastatic tumors (HR 2.73, 95% CI 1.32-5.66) and stable metastasis at interim analysis (HR 2.39, 95% CI 1.04-5.48) remained as significant factor in the multivariable cox regression analysis. Median OS and PFS of patients with less than 10 metastases showing no progression at interim analysis were 9.1 months, and 5.1 months. CONCLUSION:Local treatment combined with chemotherapy for M1 ATC patients showed outcome comparable to those of non-metastatic ATC results. Active local treatment should be considered especially for patients with less than 10 metastases, and patients without distant progression in early response evaluation.
10.1016/j.ijrobp.2023.06.1996
Differentiated Thyroid Cancers in Young Adults Versus Children: Clinical Characteristics and 10-year Follow-up Outcomes.
The Journal of clinical endocrinology and metabolism
BACKGROUND:Differentiated thyroid cancer (DTC) in young adults has been steadily rising in incidence over the decades. However, data on long-term outcomes in this specific cohort remain limited. In this study, we intended to evaluate young adults with DTC with regard to their clinical characteristics and treatment outcomes and compare the same vis-à-vis pediatric patients with DTC. METHODS:Data of pediatric (≤18 years) and young adult (19-39 years) patients with DTC, from 1971 to 2016, were sequentially extracted and analyzed for clinical characteristics, treatment responses, rates of recurrent/persistent disease, and disease-free survival (DFS). RESULTS:A total of 1803 patients with DTC were included (pediatric cohort: n = 176; young adult cohort: n = 1627). Pediatric patients with DTC had more frequent adverse baseline features including extrathyroidal extension (P = .040), nodal and distant metastases, and American Thyroid Association high-risk disease (P < .001 each). At 2 years posttreatment, young adult patients with DTC had significantly lower incomplete responses compared with pediatric patients with DTC (223/1627; 13.7% vs 94/176, 53.4%, respectively; P < .001). Over a median follow-up of 10.7 years, 120/1627 (7.4%) young adult patients with DTC had recurrent/persistent disease vs 23/176 (13.1%) pediatric patients with DTC (P = .012). The 10-year DFS probability was 93.6% for the young adult patients with DTC vs 88.7% for the pediatric patients with DTC (P = .007). American Thyroid Association high-risk disease and incomplete response at 2 years were independent predictors of significantly worse DFS in the young adult cohort (P < .001 each). CONCLUSIONS:Young adult DTCs behave less aggressively compared with their pediatric counterparts with excellent long-term outcomes. Appropriate initial and dynamic risk stratification can help optimize treatment decisions and follow-up strategies.
10.1210/clinem/dgad343
A New Twist on a Classic: Enhancing Radioiodine Uptake in Advanced Thyroid Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
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.
10.1158/1078-0432.CCR-23-3503
Emerging therapeutic options for follicular-derived thyroid cancer in the era of immunotherapy.
Frontiers in immunology
Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.
10.3389/fimmu.2024.1369780
Advances and challenges in thyroid cancer: The interplay of genetic modulators, targeted therapies, and AI-driven approaches.
Life sciences
Thyroid cancer continues to exhibit a rising incidence globally, predominantly affecting women. Despite stable mortality rates, the unique characteristics of thyroid carcinoma warrant a distinct approach. Differentiated thyroid cancer, comprising most cases, is effectively managed through standard treatments such as thyroidectomy and radioiodine therapy. However, rarer variants, including anaplastic thyroid carcinoma, necessitate specialized interventions, often employing targeted therapies. Although these drugs focus on symptom management, they are not curative. This review delves into the fundamental modulators of thyroid cancers, encompassing genetic, epigenetic, and non-coding RNA factors while exploring their intricate interplay and influence. Epigenetic modifications directly affect the expression of causal genes, while long non-coding RNAs impact the function and expression of micro-RNAs, culminating in tumorigenesis. Additionally, this article provides a concise overview of the advantages and disadvantages associated with pharmacological and non-pharmacological therapeutic interventions in thyroid cancer. Furthermore, with technological advancements, integrating modern software and computing into healthcare and medical practices has become increasingly prevalent. Artificial intelligence and machine learning techniques hold the potential to predict treatment outcomes, analyze data, and develop personalized therapeutic approaches catering to patient specificity. In thyroid cancer, cutting-edge machine learning and deep learning technologies analyze factors such as ultrasonography results for tumor textures and biopsy samples from fine needle aspirations, paving the way for a more accurate and effective therapeutic landscape in the near future.
10.1016/j.lfs.2023.122110
The Effect of Thyrotropin Suppression on Survival Outcomes in Patients with Differentiated Thyroid Cancer: A Systematic Review and Meta-Analysis.
Thyroid : official journal of the American Thyroid Association
Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; = 0%). Significant study heterogeneity was noted for primary outcomes. TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. PROSPERO #252396.
10.1089/thy.2023.0711
Response to Surgery Assessments for Sparing Radioiodine Remnant Ablation in Intermediate-Risk Papillary Thyroid Cancer.
The Journal of clinical endocrinology and metabolism
CONTEXT:Using response to surgery when tailoring radioiodine (RAI) therapy for papillary thyroid cancer (PTC) is valued but lacks prospective validation. OBJECTIVE:To spare RAI thyroid remnant ablation among patients with intermediate-risk PTCs using 3-tiered assessments with response to surgery highlighted, in addition to the risk of the recurrence stratification and TNM staging. METHODS:Patients with no evidence of disease (NED) identified as excellent response (ER) or indeterminate response (IDR) to surgery were spared from RAI thyroid remnant ablation after informed consent and prospectively enrolled under active surveillance. Those involved in other trials or without sufficient follow-up data were excluded. Dynamic responses were followed and compared longitudinally. The main outcome measures were NED presenting as durable ER or IDR for over 12 months. RESULTS:Of the enrolled 215 patients, 47.4% (102/215) ER and 52.6% (113/215) IDR were identified regarding RAI decision-making. After a median of 23.6 (interquartile range 13.8-31.6) months, the share of ER increased to 82.8% (178/215) and IDR decreased to 16.3% (35/215), with 85 patients shifting from IDR to ER over time, only 0.5% (1/215) structural incomplete response and 0.5% (1/215) biochemical incomplete response observed. Successful remnant ablation was observed in 27.7% (26/94) of the patients completing 2 diagnostic whole-body scans after a median interval of 13.0 months, indicating a theranostic effect. In the 173 patients followed for over 12 months, the NED rate did not differ between ER and IDR subgroups (100% vs 97.9%, P = .20). CONCLUSION:Through the 3-tiered assessments with response to surgery highlighted, postoperative ER and IDR spared from RAI remnant ablation may indicate similar favorable responses in intermediate-risk patients with PTC during 23.6 months of follow-up.
10.1210/clinem/dgac745
Thirty years of active surveillance for low-risk thyroid cancer, lessons learned and future directions.
Reviews in endocrine & metabolic disorders
Active Surveillance is a non-invasive strategy designed to identify a minority of patients with low-risk papillary thyroid carcinoma who might experience clinical progression and benefit from additional definitive treatments. Global experience suggests that these tumors typically show minimal changes in size during active surveillance, often demonstrating very slow growth or even size reduction. Moreover, the rate of lymph node metastases is low and can be effectively managed through rescue surgery, without impacting cancer-related mortality. However, despite 30 years of experience demonstrating the safety and feasibility of active surveillance for appropriately selected patients, this approach seems to have limited adoption in specific contexts. This limitation can be attributed to various barriers, including disparities in access to accurate information about the indolent nature of this disease and the prevalence of a maximalist mindset among certain patients and medical settings. This review aims to revisit the experience from the last three decades, provide current insights into the clinical outcomes of active surveillance trials, and propose a systematic approach for its implementation. Furthermore, it intends to emphasize the importance of precise patient selection and provides new perspectives in the field.
10.1007/s11154-023-09844-y
Analysis of risk factors for lymph node metastasis in 241 patients with thyroid carcinoma and establishment of a prediction model.
American journal of cancer research
This study aimed to identify risk factors for cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) and develop a clinical prediction model. Retrospectively, data were collected from 348 PTC patients treated at the Second Affiliated Hospital of Nanchang University between January 2019 and December 2022, with 241 patients included in the final analyses. Patients with lateral cervical LNM were categorized into a metastasis group, and those without were in a non-metastasis group. The patients were divided into a training set (n=169) and a validation set (n=72) in a 7:3 ratio. Logistic and least absolute shrinkage and selection operator (LASSO) regression models were used to identify key factors associated with lateral cervical LNM and prognosis, enabling the construction of a predictive model. The model's validity was assessed via the Hosmer-Lemeshow Test, calibration curves, ROC curves, and decision curve analysis. The metastasis group exhibited higher proportions of males, multiple lesions, bilateral involvement, tumor diameter ≥1 cm, and elevated levels of PLR, LMR, and NLR (P<0.05). Logistic regression analysis revealed that gender, multiple lesions, affected side, and tumor diameter were associated with lateral cervical LNM (P<0.05). The predictive Nomogram model, which included factors like affected side, tumor diameter, capsular invasion, central LNM, PLR, and NLR, demonstrated strong predictive accuracy and clinical utility. Thus, this study provides a practical clinical tool through an accurate Nomogram model to assess lateral cervical LNM risk in PTC patients using logistic and LASSO regression analyses.
10.62347/HDNA2969
Health-Related Quality of Life and Thyroid Cancer-Specific Symptoms in Patients Treated for Differentiated Thyroid Cancer: A Single-Center Cross-Sectional Survey from Mainland China.
Thyroid : official journal of the American Thyroid Association
The incidence of differentiated thyroid cancer in Mainland China has increased rapidly in recent years, yet the number of studies focusing on health-related quality of life (HR-QOL) is still limited. Additionally, some of the quality-of-life (QOL) issues specific to thyroid cancer have not been adequately described. The aims of this study were to assess the generic and disease-specific HR-QOL of differentiated thyroid cancer survivors and to identify the associated factors. A cross-sectional survey including 373 patients was conducted in Mainland China. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Thyroid Cancer-Specific Quality of Life Questionnaire (THYCA-QOL), and a questionnaire on patient demographics and clinical characteristics. The QLQ-C30 global mean score was 73.12 (standard deviation [SD] = 11.95), while the THYCA-QOL summary mean score was 34.50 (SD = 12.68). The two QLQ-C30 functional subscales with the lowest scores were the social functioning and role functioning subscales. The five symptom subscales of the THYCA-QOL with the highest scores were the subscales regarding less interest in sex, problems with scar, psychological problems, voice problems, and sympathetic problems. Factors associated with worse global QOL on the QLQ-C30 included a shorter time since completing primary treatment (≤6 months), a history of lateral neck dissection, and a lower current thyrotropin (TSH) level (≤0.5 mIU/L). Higher cumulative activities of radioiodine (RAI; >100 mCi), gender (women), postoperative hypoparathyroidism, and a history of lateral neck dissection were associated with worse thyroid cancer-specific QOL. In contrast, higher monthly household income (>5000￥) and a history of minimally invasive thyroid surgery were associated with better thyroid cancer-specific QOL. Thyroid cancer patients experience multiple health-related problems and disease-specific symptoms after completing primary treatment. Patients with a duration ≤6 months from the completion of primary treatment, those with a history of lateral neck dissection, and a current TSH level ≤0.5 mIU/L may be more likely to have impaired generic QOL. More thyroid cancer-specific symptoms may be associated with higher cumulative activities of RAI, gender (women), postoperative hypoparathyroidism, a history of lateral neck dissection, lower monthly household income, and conventional surgery.
10.1089/thy.2022.0490
Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer.
ESMO open
BACKGROUND: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. MATERIALS AND METHODS: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. RESULTS: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). CONCLUSIONS: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.
10.1016/j.esmoop.2023.102039
Leveraging molecular targeted drugs and immune checkpoint inhibitors treat advanced thyroid carcinoma to achieve thyroid carcinoma redifferentiation.
American journal of cancer research
Thyroid cancer can be classified into three different types based on the degree of differentiation: well-differentiated, poorly differentiated, and anaplastic thyroid carcinoma. Well-differentiated thyroid cancer refers to cancer cells that closely resemble normal thyroid cells, while poorly differentiated and anaplastic thyroid carcinoma are characterized by cells that have lost their resemblance to normal thyroid cells. Advanced thyroid carcinoma, regardless of its degree of differentiation, is known to have a higher likelihood of disease progression and is generally associated with a poor prognosis. However, the process through which well-differentiated thyroid carcinoma transforms into anaplastic thyroid carcinoma, also known as "dedifferentiation", has been a subject of intensive research. In recent years, there have been significant breakthroughs in the treatment of refractory advanced thyroid cancer. Clinical studies have been conducted to evaluate the efficacy and safety of molecular targeted drugs and immune checkpoint inhibitors in the treatment of dedifferentiated thyroid cancer. These drugs work by targeting specific molecules or proteins in cancer cells to inhibit their growth or by enhancing the body's immune response against the cancer cells. This article aims to explore some of the possible mechanisms behind the dedifferentiation process in well-differentiated thyroid carcinoma. It also discusses the clinical effects of molecular targeted drugs and immune checkpoint inhibitors in thyroid cancer patients with different degrees of differentiation. Furthermore, it offers insights into the future trends in the treatment of advanced thyroid cancer, highlighting the potential for improved outcomes and better patient care.
Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities.
Biochimica et biophysica acta. Reviews on cancer
Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.
10.1016/j.bbcan.2023.188928
Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Preliminary Latin American Experience.
Thyroid : official journal of the American Thyroid Association
Surgical resection is not always achievable in thyroid cancer patients. Neoadjuvant therapy is rarely used, but recent trends favor multikinase inhibitors or selective tyrosine kinase inhibitors. These aim to reduce tumor volume, enabling previously unfeasible surgeries. Consecutive patients with locally advanced malignant thyroid tumors who received systemic therapies with a neoadjuvant intention were included in this retrospective multicenter case series conducted in five Latin American referral centers. Primary outcomes were pre- versus postneoadjuvant response evaluations using the Response Evaluation Criteria in Solid Tumors, feasibility of surgery, and completeness of resection. Secondary outcomes were mortality and status at the last visit. Twenty-seven patients were included in this analysis. Patients with unresectable differentiated thyroid cancer (DTC) or poorly differentiated thyroid cancer (PDTC) received sorafenib ( = 6) or lenvatinib ( = 12), those with medullary thyroid cancer (MTC) were treated with vandetanib ( = 5) or selpercatinib ( = 1), and those with anaplastic thyroid cancer (ATC) harboring a mutation ( = 3) received dabrafenib and trametinib. The median patient age was 66 years (range 12-82), and 52% of the patients were female. In patients with PTC and PDTC, the median reduction in the diameter of the primary tumor was 25% (range 0-100%) after a median of 6 months of treatment. Surgical intervention was performed in 10 (55%) of the patients. Among these, six patients (60%) achieved R0/R1 resection status. Six patients with MTC had a median reduction in tumor diameter of 24.5% (range 1-49) after a median treatment time of 9.5 months. Only one patient receiving selpercatinib, with a tumoral reduction of 25% could undergo surgery, resulting in an R2 resection due to extensive mediastinal extension. Three patients with ATC showed a median tumor diameter reduction of 42% (range 6.7-50) after a median treatment time of 2 months. Two patients underwent surgical intervention and achieved R1 and R2 resection, respectively. While neoadjuvant therapy achieved tumoral responses, surgical resection was feasible in 55% of DTC, 33% of ATC, and 16% of MTC patients, with R0/R1 resection in 26% of the cohort, underscoring the need for patient selection and further research in this area.
10.1089/thy.2024.0090
Definitive Radiotherapy for Oligometastatic and Oligoprogressive Thyroid Cancer.
International journal of radiation oncology, biology, physics
PURPOSE/OBJECTIVE(S):Local consolidative radiotherapy (LCT) for oligometastatic disease is a promising paradigm improving outcomes for various malignancies but has been underexplored for metastatic thyroid cancer. We hypothesize that LCT to distant sites with definitive RT doses can yield favorable outcomes and defer systemic therapy escalation for these patients. MATERIALS/METHODS:We reviewed 96 thyroid cancer patients who received 175 LCT courses from 2010-2022 to 228 metastatic sites, including: thorax (45%), bone (40%), brain (6%), head/neck (5%), and abdomen (3%). Common prescriptions were 50-55Gy/4-5fxs or 56-70Gy/8-10fxs for lung; 52.5-60Gy/15fxs for mediastinum; and 18-24Gy/1fx or 27-30Gy/3fxs for bone. RECIST v1.1 and CTCAE v5.0 were used to define progression and toxicities, respectively. Outcomes were evaluated via Kaplan-Meier and associations examined via Cox proportional hazards modeling. RESULTS:Median age was 63 years (range: 26-92), with 62 oligometastatic cases (total 1-5 sites) and 34 oligoprogressive (with 1-5 growing sites). Primary disease was controlled in all patients, with 39% receiving post-op RT and 66% prior RAI. Histologies included papillary (40%), anaplastic (25%), follicular (12%), medullary (9%), Hurthle (7%), and poorly-differentiated (7%). Median time from initial diagnosis to LCT was 3 yrs (IQR 1-8), and median follow-up from 1st LCT was 21 mos (IQR 9-51). Patients received an average 2 LCT courses (range 1-8) treating 1-4 sites. Median survival (OS) from 1st LCT was 9 yrs (95% CI = 5-14). On multivariable analysis (MVA), worse OS was associated with anaplastic histology (HR 4.6, p<.01), but longer OS was associated with prior RAI (HR 0.33, p = .02) and oligometastatic disease (HR 0.3, p = .01). For anaplastic histology, median OS was 1.2 years vs. 9.3 years for non-anaplastic; 3-yr OS was 36% vs. 88% (log-rank, p<.01). Five-year OS for oligometastatic cases was 75% vs 53% for oligoprogressive (log-rank, p = .04). Median progression free survival (PFS) from 1st LCT was 15.5 mos (95% C I = 11-20). On MVA for all LCT courses, time to any progression (TTP) was negatively associated with anaplastic histology (HR 1.7, p = .02) and 2nd or higher LCT course (HR 1.45, p = .05), but favorably associated with thoracic site (HR 0.49, p<.01). Following later LCT courses, median TTP was 11 mos vs 17 mos for initial LCT course (log-rank, p = .03). After LCT to lung/chest, TTP was 18.6 mos vs 9.5 mos for non-thoracic sites (log-rank, p<.01). Only 6% of failures occurred at previously treated lesions. Most LCT courses (67%) were without ongoing chemotherapy, while 25% entailed continuing the same regimen and 9% had planned treatment post-RT. There were 2 Grade 3 toxicities (pneumonitis and esophagitis) and no Grade 4-5 events. CONCLUSION:With high local control rates and minimal toxicity, LCT can be a feasible strategy to defer systemic therapy escalation for oligometastatic and oligoprogressive thyroid cancer.
10.1016/j.ijrobp.2023.06.1918
Prevalence of Differentiated High-Grade Thyroid Carcinoma Among Well-Differentiated Tumors: A Systematic Review and Meta-Analysis.
Thyroid : official journal of the American Thyroid Association
The current edition of the World Health Organization (WHO) classification of endocrine tumors introduced grading for follicular cell-derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling the Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. In this study, we performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022378716). In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 [95% confidence interval, CI, = 0.045-0.113]. The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC; 0.146 [CI = 0.101-0.205]) than in papillary thyroid carcinoma (PTC; 0.059 [CI = 0.036-0.097]). Diffuse sclerosing, follicular, and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018 [CI = 0.004-0.084]; 0.036 [CI = 0.010-0.124]; and 0.042 [CI = 0.027-0.066], respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154 [CI = 0.067-0.314] and 0.168 [CI = 0.108-0.252], respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136 [CI = 0.058-0.287] and 0.152 [CI = 0.086-0.254], respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence), the proportion of DHGTC was 0.287 [CI = 0.155-0.469]. Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular, and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.
10.1089/thy.2023.0350
Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.
European journal of endocrinology
OBJECTIVE:Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS:We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS:We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION:The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.
10.1093/ejendo/lvad061
Harnessing Immunity to Treat Advanced Thyroid Cancer.
Vaccines
The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5-10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.
10.3390/vaccines12010045
NTRK fusions in thyroid cancer: Pathology and clinical aspects.
Critical reviews in oncology/hematology
Thyroid cancer is the most common endocrine cancer. Neurotrophic tyrosine receptor kinase (NTRK) fusions are oncogenic drivers in multiple solid tumors, including thyroid cancer. NTRK fusion thyroid cancer has unique pathological features such as mixed structure, multiple nodes, lymph node metastasis, and a background of chronic lymphocytic thyroiditis. Currently, RNA-based next-generation sequencing is the gold standard for the detection of NTRK fusions. Tropomyosin receptor kinase inhibitors have shown promising efficacy in patients with NTRK fusion-positive thyroid cancer. Efforts to overcome acquired drug resistance are the focus of research concerning next-generation TRK inhibitors. However, there are no authoritative recommendations or standardized procedures for the diagnosis and treatment of NTRK fusions in thyroid cancer. This review discusses current research progress regarding NTRK fusion-positive thyroid cancer, summarizes the clinicopathological features of the disease, and outlines the current statuses of NTRK fusion detection and targeted therapeutic agents.
10.1016/j.critrevonc.2023.103957
Progress in Thyroid Cancer Genomics: A 40-Year Journey.
Thyroid : official journal of the American Thyroid Association
Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.
10.1089/thy.2023.0045
The Frequency of Differentiated Thyroid Cancer Recurrence in 2302 Patients With Excellent Response to Primary Therapy.
The Journal of clinical endocrinology and metabolism
CONTEXT:Discrepant data on the recurrence rate of differentiated thyroid cancer (DTC) are reported. OBJECTIVE:To evaluate the frequency and risk factors of true recurrence in DTC patients with excellent responses (ExR) to initial therapy. METHODS:A retrospective analysis of the 2302 consecutive DTC patients with ExR to primary therapy, treated during 24 years at single center. The percentage of recurrence and cumulative recurrence rate (CRR) were analyzed. Risk factors for recurrence for patients with papillary thyroid cancer (PTC) were investigated and methods for establishing a diagnosis of recurrence were evaluated. RESULTS:Of DTC patients, 32 (1.4%) experienced recurrence. PTC patients with recurrence were more likely to have younger age (P = .0182), larger tumor size (P = .0013), lymph node metastases (P = .0013), incomplete resection (P = .0446), higher ATA risk (P = .0002), and had more frequently been treated with 131I (P = .0203). CRRs at 5, 10, 15, 20, and 24 years after surgery were 1.2%, 1.9%, 2.5%, 2.9%, and 2.9%, respectively. The CRRs according to histological type were highest for poorly differentiated thyroid cancer (PDTC), lower for oncocytic (OTC) and follicular thyroid cancer (FTC), and lowest for PTC. Most recurrences occurred within the first 5 years of observation. The most effective method for detecting local recurrence was ultrasonography with fine needle aspiration cytology, and for distant metastases, 18F-FDG PET. CONCLUSION:True recurrence is rare in DTC patients. PTC patients with ExR to primary therapy and N0/Nx can be dismissed from oncological follow-up. Despite ExR to primary therapy, DTC patients with N1, and PDTC, OTC, FTC should remain under oncological follow-up.
10.1210/clinem/dgad571
Redifferentiation of Differentiated Thyroid Cancer: Clinical Insights from a Narrative Review of Literature.
Thyroid : official journal of the American Thyroid Association
Patients who have metastatic differentiated thyroid cancer (mDTC) frequently have negative diagnostic and/or post-therapy radioiodine scans. As a result, I therapy is frequently no longer considered a therapeutic option for these patients. However, with the knowledge of genomic alterations of patients with mDTC, the use of selected agents in specific patient groups may be used with the intention to re-establish I uptake (i.e., ) and additional I therapy. The objectives of this narrative review are to present definitions of related terminology, a brief overview of the molecular mechanisms of redifferentiating agents, and a narrative review of the literature for in patients who have radioiodine refractory mDTC. We searched multiple electronic databases and reviewed the relevant English-language literature reported after 2010. Fourteen articles were included in this narrative review. Preliminary data suggest that select agents may offer potential for re-establishing I uptake in selected patients with radioiodine refractory mDTC (e.g., negative diagnostic and/or post-therapy radioiodine scans). These agents may also enhance uptake (e.g., ) in patients who have I uptake in mDTC on a diagnostic and/or post-therapy radioiodine scan. As a result, this may facilitate higher absorbed dose delivered (Gy (rad]) per I activity administered [GBq (mCi)]. This in turn may increase the likelihood of a better therapeutic effect for the planned administered I activity or a reduction in the originally planned administered I activity, while achieving the same intended therapeutic effect with potentially less untoward effects. Further studies are warranted to confirm these preliminary observations and to confirm acceptable subsequent I therapy responses after redifferentiation and/or uptake enhancement.
10.1089/thy.2022.0632
Definitive Radiotherapy for the Treatment of Gross Disease in Unresected Differentiated Thyroid Cancer.
International journal of radiation oncology, biology, physics
PURPOSE/OBJECTIVE(S):While surgery (with or without radioactive iodine (RAI)) is the mainstay of locoregional control in differentiated thyroid cancer (DTC), patients with unresectable disease present a clinical challenge. Uncontrolled disease in the neck can lead to substantial morbidity and mortality in DTC and obtaining locoregional control is vital to preserving quality of life and longevity. High dose definitive radiotherapy (RT) for gross disease in DTC is understudied. This study examines the efficacy of definitive RT in this setting. MATERIALS/METHODS:From an IRB-approved registry of head and neck cancer cases treated at a tertiary care center over a period of 8 years (2014-2022), patients with incompletely resected or unresectable DTC including papillary, follicular, mixed, medullary, and poorly differentiated types were identified. All patients were treated to the neck and/or thyroid regions with visible gross disease to a definitive dose of radiation. The primary endpoint was local control within the radiated portal with a secondary endpoint of locoregional control within the neck. RESULTS:A total of 31 patients were identified, of whom 74.2% were Caucasian. Fourteen were female (45.2%), and 17 (54.8%) were male. The median age was 68 years (range 26-90) and the median follow-up was 31 months. Histologically, 19 (61.3%) cases were papillary, 4 (12.9%) were follicular, 2 (6.5%) were mixed, 3 (9.7%) were medullary, and 3 (9.7%) were poorly differentiated. Among patients with non-medullary DTC 18 (69.2%) received prior RAI. Twelve patients were treated with radiation at initial diagnosis, while 19 patients were treated at the time of recurrence; two patients received concurrent chemotherapy. Twenty-eight patients (90.3%) were treated with IMRT and 3 (9.7%) were treated with SBRT. The median dose to the gross disease was 66 Gy (range 30-70.4) in 32 fractions (range 5-35). Overall, 5 patients (16.1%) experienced a locoregional failure after RT and all experienced failure in the RT portal. The actuarial infield control/locoregional control of radiation therapy at 3 and 5 years was 84.8% and 74.2%, respectively. Overall survival at 3 and 5 years was 68.5% and 47.4%, respectively. Among patients who had a locoregional failure after RT, 2 patients were salvaged with systemic therapy, 2 patients with surgery, and 1 patient with SBRT re-irradiation (40 Gy/5 fractions). The patient salvaged with SBRT remains without disease 8 months post-RT. CONCLUSION:Definitive radiotherapy is a highly effective strategy to obtain durable control of unresected DTC. It should be standard for unresected disease and considered as a viable alternative for patients with borderline resectable disease for whom resection would be highly morbid.
10.1016/j.ijrobp.2023.06.1895
Longitudinal Changes in Quality of Life Before and After Thyroidectomy in Patients With Differentiated Thyroid Cancer.
The Journal of clinical endocrinology and metabolism
OBJECTIVE:The objective of this prospective study was to assess longitudinal variations in health-related quality of life (HR-QOL) in patients diagnosed with differentiated thyroid cancer (DTC) before and after thyroidectomy. METHODS:A cohort of 185 DTC patients who underwent thyroidectomy between January 2013 and December 2017 and who completed all necessary questionnaires was evaluated. Their HR-QOL was gauged using the University of Washington Quality of Life questionnaire (UW-QOL) and the City of Hope Quality of Life-Thyroid Version questionnaire (QOL-TV) both prior to surgery and at 3 months, 6 months, 1 year, 2 years, 3 years, and 5 years postoperatively. RESULTS:Out of 185 patients, 150 (81.1%) were female, with an average age of 48.7 ± 12.9 years. For both UW-QOL and QOL-TV, the total composite QOL scores notably declined from preoperative levels to 3 months postoperatively, then gradually improved over 5 years, ultimately exceeding preoperative scores. Factors such as total thyroidectomy, radioactive iodine (RAI) ablation, and postoperative hypoparathyroidism were associated with lower physical composite QOL scores. Patients who underwent remote-access thyroidectomy expressed significantly higher satisfaction with appearance compared with those who had conventional thyroidectomy. Mood and anxiety were major clinical concerns both before and after surgery, showing considerable improvement postoperatively. CONCLUSION:For DTC patients, HR-QOL experienced a significant drop 3 months postsurgery, subsequently showing gradual improvement, surpassing preoperative QOL by 5 years. Factors contributing to improved physical QOL included the utilization of remote-access thyroidectomy, less extensive thyroidectomy, and the absence of RAI ablation and hypoparathyroidism.
10.1210/clinem/dgad748
Urban and Rural Surgical Practice Patterns for Papillary Thyroid Carcinoma.
Thyroid : official journal of the American Thyroid Association
The 2015 American Thyroid Association (ATA) guidelines shifted recommendations toward less aggressive management of papillary thyroid cancer (PTC). Subsequently, several studies demonstrated a trend in performing thyroid lobectomy (TL) over total thyroidectomy (TT). However, regional variation has persisted without a clear indication of what factors may be influencing practice variation. We aimed to evaluate the surgical management of PTC in patients in rural and urban settings to assess trends of TL compared with TT following the implementation of the 2015 ATA guidelines. A retrospective cohort analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2019 of patients with localized PTC <4 cm who underwent TT or TL. Patients were classified as living in urban or rural counties based on the 2013 Rural-Urban Continuum Codes. Procedures performed from 2004 to 2015 were categorized as preguidelines, while those performed from 2016 to 2019 were categorized as postguidelines. Chi-square, Student's -test, logistic regression, and Cochran-Mantel-Haenszel test were used. A total of 89,294 cases were included in the study. Eighty thousand one hundred and fifty (89.8%) were from urban settings and 9144 (9.2%) were from rural settings. Patients from rural settings were older (52 vs. 50 years, < 0.001) and had smaller nodules ( < 0.001). On adjusted analysis, patients in rural areas were less likely to undergo TT (adjusted odds ratio 0.81, confidence interval [CI] 0.76-0.87). Before the 2015 guidelines, patients in urban settings had a 24% higher odds of undergoing TT compared with those in rural settings (odds ratio 1.24, CI 1.16-1.32, < 0.001). There was no difference in the proportions of TT and TL based on setting following guideline implementation ( = 0.185). The 2015 ATA guidelines led to a change in overall practice in surgical management of PTC toward increasing TL. While urban and rural practice variation existed before 2015, both settings had an increase in TL following the guideline change, emphasizing the importance of clinical practice guidelines to ensure best practice in both rural and urban settings.
10.1089/thy.2022.0711
Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAF Mutant Anaplastic Thyroid Cancer: A Single-Center Retrospective Cohort Study.
Thyroid : official journal of the American Thyroid Association
The aim of this study was to describe the oncologic outcomes of patients with BRAF-mutated anaplastic thyroid cancer (ATC) who had neoadjuvant BRAF-directed therapy with subsequent surgery. For context, we also reviewed patients who received BRAF-directed therapy after surgery, and those who did not have surgery after BRAF-directed therapy. This was a single-center retrospective cohort study conducted at a tertiary care cancer center in Texas from 2017 to 2021. Fifty-seven consecutive patients with BRAF-mutated ATC and at least 1 month of BRAF-directed therapy were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). All patients had stage IVB (35%) or IVC (65%) ATC. Approximately 70% of patients treated with BRAF-directed therapy ultimately had surgical resection of residual disease. Patients who had neoadjuvant BRAF-directed therapy followed by surgery ( = 32) had 12-month OS of 93.6% [confidence interval (CI) 84.9-100] and PFS of 84.4% [CI 71.8-96.7]. Patients who had surgery before BRAF-directed therapy ( = 12) had 12-month OS of 74.1% [CI 48.7-99.5] and PFS of 50% [CI 21.7-78.3]. Finally, patients who did not receive surgery after BRAF-directed therapy ( = 13) had 12-month OS of 38.5% [CI 12.1-64.9] and PFS of 15.4% [CI 0-35.0]. Neoadjuvant BRAF-directed therapy reduced tumor size, extent of surgery, and surgical morbidity score. Subgroup analysis suggested that any residual ATC in the surgical specimen was associated with significantly worse 12-month OS and PFS (OS = 83.3% [CI 62.6-100], PFS = 61.5% [CI 35.1-88]) compared with patients with pathologic ATC complete response (OS = 100%, PFS = 100%). We observed that neoadjuvant BRAF-directed therapy reduced extent of surgery and surgical morbidity. While acknowledging potential selection bias, the 12-month OS rate appeared higher in patients who had BRAF-directed therapy followed by surgery as compared with BRAF-directed therapy without surgery; yet, it was not significantly different from surgery followed by BRAF-directed therapy. PFS appeared higher in patients treated with neoadjuvant BRAF-directed therapy relative to patients in the other groups. These promising results of neoadjuvant BRAF-directed therapy followed by surgery for BRAF-mutated ATC should be confirmed in prospective clinical trials.
10.1089/thy.2022.0504
Outcomes of Conversion Surgery for Patients With Low-Risk Papillary Thyroid Carcinoma.
JAMA otolaryngology-- head & neck surgery
Importance:The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined. Objective:To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma. Design, Setting, and Participants:In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score-matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States. Exposures:Surgery. Main Outcomes and Measures:Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). Results:Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group. Conclusions and Relevance:In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.
10.1001/jamaoto.2024.1699
Advances in the management of anaplastic thyroid carcinoma: transforming a life-threatening condition into a potentially treatable disease.
Reviews in endocrine & metabolic disorders
Anaplastic thyroid cancer (ATC) is an infrequent thyroid tumor that usually occurs in elderly patients. There is often a history of previous differentiated thyroid cancer suggesting a biological progression. It is clinically characterized by a locally invasive cervical mass of rapid onset. Metastases are found at diagnosis in 50% of patients. Due to its adverse prognosis, a prompt diagnosis is crucial. In patients with unresectable or metastatic disease, multimodal therapy (chemotherapy and external beam radiotherapy) has yielded poor outcomes with 12-month overall survival of less than 20%. Recently, significant progress has been made in understanding the oncogenic pathways of ATC, leading to the identification of BRAF V600E mutations as the driver oncogene in nearly 40% of cases. The combination of the BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) showed outstanding response rates in BRAF-mutated ATC and is now considered the standard of care in this setting. Recently, it was shown that neoadjuvant use of DT followed by surgery achieved 24-month overall survival rates of 80%. Although these approaches have changed the management of ATC, effective therapies are still needed for patients with BRAF wild-type ATC, and high-quality evidence is lacking for most aspects of this neoplasia. Additionally, in real-world settings, timely access to multidisciplinary care, molecular testing, and targeted therapies continues to be a challenge. Health policies are warranted to ensure specialized treatment for ATC.The expanding knowledge of ATC´s molecular biology, in addition to the ongoing clinical trials provides hope for the development of further therapeutic options.
10.1007/s11154-023-09833-1
Active Surveillance of Differentiated Thyroid Cancer Metastatic Cervical Lymph Nodes: A Retrospective Single-Center Cohort Study.
Thyroid : official journal of the American Thyroid Association
The most frequent site of recurrence of differentiated thyroid cancer (DTC) is cervical lymph nodes (LNs), which often necessitates repeated surgical interventions and morbidity in a generally indolent disease. Data on active surveillance (AS) of small cervical nodal metastasis are still scarce, particularly in real-world clinical settings. In this study, we evaluated the DTC outcomes of AS of metastatic cervical LNs and explored factors associated with disease progression. We conducted a retrospective cohort study, including DTC patients with biopsy-proven metastatic cervical LNs, who were followed on AS in a tertiary care, university-based institution in Brazil. The inclusion criteria were cervical metastasis ≤2.0 cm and an AS duration of at least 6 months. We excluded lesions with aggressive histology, those in close proximity to or invading local structures. The primary outcome was disease progression (enlargement ≥3 mm in any diameter or a new cervical metastasis). Data from 40 patients were analyzed. Most were female (77.5%) and had papillary thyroid cancer (97.5%). The mean age was 47.0 (± standard deviation 15.8) years. The 8th edition of the tumor, node, metastasis stage (TNM8) staging for DTC was as follows: 29 in stage I (74.4%), 8 in stage II (20.5%), and 2 in stage IV (5.0%). The median maximum LN diameter was 0.9 (interquartile range [IQR], 0.8-1.3) cm, and the median AS follow-up duration was 27.5 (IQR, 16.5-47.3) months. Disease progression occurred in 14 (35%) patients: 7 (17.5%) due to enlargement ≥3 mm, and 7 (17.5%) had new cervical metastasis. The cervical progression-free survival was 51.0 (confidence interval, 47.0-55.0) months. No demographic, oncological, or biochemical factors were associated with disease progression. Of the 14 patients with disease progression, 8 were referred for surgery. No permanent surgical complications were reported. Of the six patients who remained on AS despite disease progression, five showed no further progression during subsequent follow-up (range 6-40 months). We observed that most small metastatic cervical LNs remained stable and were safely managed with AS. Nevertheless, these observations are limited by the retrospective design, small sample size, and short follow-up. Further prospective and long-term studies are warranted.
10.1089/thy.2022.0542
Reoperation Rates After Initial Thyroid Lobectomy for Patients with Thyroid Cancer: A National Cohort Study.
Thyroid : official journal of the American Thyroid Association
The 2015 American Thyroid Association (ATA) guidelines recommended thyroid lobectomy (TL) as an alternative to total thyroidectomy (TT) for the surgical treatment of low-risk differentiated thyroid cancer. Increasing use of TL has since been reported despite concerns for an increased risk of disease recurrence and need for reoperation. This study sought to compare reoperation rates among patients who underwent initial TL or TT for malignancy, characterize trends at centers based on operative volume, and examine factors associated with reoperation. We queried the Vizient Clinical Data Base for TL and TT performed preguideline change (pre-GC = 2013-2015) and postguideline change (post-GC = 2016-2021). Reoperations included reoperative thyroid surgery (RTS) and neck dissection (ND); timing was defined as early (≤180 days), thought to indicate inadequacy of initial operative choice, or late (>180 days), suggesting potential disease recurrence. Of 65,627 patients, 31.8% underwent initial TL and 68.2% underwent initial TT; TL increased from 21.4% of total cases pre-GC to 37.0% post-GC ( < 0.001). Among TL patients, early RTS declined from 33.9% to 14.2% and ND declined from 0.8% to 0.4% ( < 0.001). Among TT patients, early RTS remained 0.2%, while ND increased from 0.4% to 0.7% ( < 0.001). TL-associated late RTS declined from 2.0% to 1.7%, while ND increased from 0.6% to 0.8% ( = 0.17). In TT patients, both late RTS and ND increased, from 0.2% to 0.3% ( = 0.04) and 1.7% to 2.1% ( < 0.01), respectively. There was no difference in the late reoperation rate for TL compared with TT post-GC (+0.2%, = 0.18). TL volume grew annually by 12.5% [8.9-16.2%] at high-volume centers (HVCs) and 8.3% [5.6-11.1%] at low-volume centers (LVCs). TL-associated reoperations at HVCs declined annually by 12.6% [5.6-19.0%] and 10.8% [2.7-18.1%] at LVCs. Uninsured status and more recent initial operation were associated with an increased risk of late reoperation (HR = 1.84 [1.06-3.20] and HR = 1.30 [1.24-1.36], respectively). The type of index operation performed, however, was not predictive of late reoperation. The rate of early reoperations declined for TL after the 2015 ATA guideline release, but late reoperations remained unchanged despite a significant shift in practice patterns towards initial lobectomy. Patients appear to be receiving less aggressive, guideline-concordant care without a significant increase in the late reoperation rate for TL compared with TT.
10.1089/thy.2024.0128
Health-Related Quality of Life in Patients with Low-Risk Differentiated Thyroid Cancer: A Systematic Review Examining the Extent of Thyroidectomy.
Thyroid : official journal of the American Thyroid Association
Total thyroidectomy (TT) and hemithyroidectomy (HT) are acceptable surgical options for the treatment of low-risk differentiated thyroid cancer (DTC). While previous data suggest similar disease-free and disease-specific survival regardless of initial surgical treatment, the effect of the extent of surgery on health-related quality of life (HRQOL) is less clear. This systematic review aimed to examine HRQOL in low-risk DTC survivors after TT compared with HT. A search of PubMed, CINAHL, Cochrane, PsycINFO, and Scopus databases was conducted to identify studies published between January 1, 2011, and December 31, 2022, that assessed HRQOL predominantly in patients with low-risk DTC who underwent open thyroid surgery. Covidence™ software was used to apply the inclusion criteria, and a validated instrument was used to assess study quality. Sixteen of the 1402 identified studies were included: 5 prospective and 11 retrospective cohort studies. The majority of included studies were of good quality ( = 14) and were from Asia and the Middle East ( = 11). Overall, six studies concluded that HT led to a better HRQOL than TT, two concluded that HT only resulted in better HRQOL compared with TT with central neck dissection (CND), and two concluded HT resulted in better short-term HRQOL that dissipated by 6 months postoperatively. The HRQOL domains found across all studies to be most consistently improved after HT included physical health, psychological/emotional, and social function. Factors found to be associated with HRQOL in more than one study included age, stage, and marital status. Differences in HRQOL after HT and TT tended to favor HT particularly when measured <6 months after surgery or when compared with TT with CND. Additional prospective and ideally randomized data are needed to fully determine the impact of the extent of surgery on HRQOL in patients with low-risk thyroid cancer.
10.1089/thy.2023.0328
Partial Thyroidectomy With Incidental Metastatic Lymph Nodes.
JAMA otolaryngology-- head & neck surgery
Importance:The need for completion thyroidectomy in patients with incidental metastatic lymph nodes after partial thyroidectomy is unclear. Objective:To investigate the outcomes of patients with incidental metastatic lymph nodes following partial thyroidectomy. Design, Setting, and Participants:A retrospective review of a prospectively maintained thyroid cancer database from 1985 to 2015 was carried out at a head and neck surgery practice at a tertiary referral cancer center. A total of 74 patients who underwent thyroid lobectomy or thyroid isthmusectomy between 1985 and 2015 and were found to have incidental metastatic lymph nodes on final pathologic analysis and were selected to be observed without immediate completion thyroidectomy were included. A separate group of additional 11 patients who underwent immediate completion thyroidectomy was also identified and reviewed. Main Outcome and Measure:Analysis took place from February to May 2022. Recurrence-free survival outcomes of patients found to have incidental metastatic lymph nodes on final pathologic analysis following partial thyroidectomy with no immediate completion thyroidectomy. Results:A total of 74 patients were observed, with a median (IQR) age of 39 (28-49) years; 44 (59%) were women. Sixty-four patients underwent thyroid lobectomy and 10 patients had isthmusectomy. Classic papillary thyroid carcinoma was the most common histologic type (34 [46%]). Vascular invasion and microscopic extrathyroidal extension were present in 11 patients (16%) and 22 patients (30%), respectively. Positive margins were identified in 5 patients (7.8%). Size of metastatic lymph nodes ranged between 0.07 cm and 1.2 cm. No extranodal extension was reported. A total of 52 patients (70%) were classified as intermediate risk for recurrence based on the American Thyroid Association risk stratification system. The median (IQR) follow up was 48.15 (15.4-86.1) months, during which only 1 patient had a regional recurrence. Another patient underwent delayed completion thyroidectomy for a contralateral lobe malignant abnormality. Recurrence-free survival, disease-specific survival, and overall survival were 97.4%, 100%, and 96.2%, respectively. A separate group of 11 patients who underwent immediate completion thyroidectomy were reviewed. These patients were more likely to have tall-cell papillary thyroid carcinoma (6 [55%] vs 13 [18%]), multifocality (9 [82%] vs 28 [41%]), microscopic extrathyroidal extension (8 [73%] vs 22 [30%]), and positive margins (3 [30%] vs 5 [7.8%]) compared with patients who were under observation only. Conclusion and Relevance:Completion thyroidectomy may not be necessary in appropriately selected patients who are found to have incidental metastatic lymph nodes (N1a) after partial thyroidectomy for localized well-differentiated thyroid cancer.
10.1001/jamaoto.2023.3668
Quality of life in thyroid cancer.
Best practice & research. Clinical endocrinology & metabolism
To explore the impact of differentiated thyroid cancer (DTC) on quality of life (QoL) a clinical analytical framework was developed. Based on the clinical analytical framework, a systematic literature search was performed to identify studies applying patient-reported outcomes (PRO) instruments among patients with DTC. Subsequently, the scope was narrowed down to studies comparing scores on the Medical Outcomes Study (MOS) Short form 36 (SF-36) to a reference population (clinical interpretability criterion). Further, the currently available thyroid cancer (TC) specific QoL PROs were review in accordance with the standards of the International Society of Quality of Life Research. In the initial search, 213 studies were included. The additional 'clinical interpretability'-criteria, limited the final study sample to 16 studies, 13 cross-sectional and 3 longitudinal. QoL was impacted across all SF-36 scales. The impact was generally modest and the impact was impeded by time since diagnosis and treatment. Four TC specific instruments were identified. Generally, the documentation of their measurement properties, particularly content validity and clinical validity, including substantial quantitative validation, was scarce. As was the cross-cultural applicability of the currently available instruments. This restricted, focused, clinically founded review showed an impact on a broad range of QoL issues. There is a need for large-scale measurement of QoL outcome longitudinally, using well-validated PRO instruments in order to identify with certainty the impact on subgroups.
10.1016/j.beem.2023.101732
Current practice in intermediate risk differentiated thyroid cancer - a review.
Reviews in endocrine & metabolic disorders
Although the overall prognosis for differentiated thyroid cancer (DTC) is excellent, a subset of patients will experience disease recurrence or may not respond to standard treatments. In recent years, DTC management has become more personalized in order to enhance treatment efficacy and avoid unnecessary interventions.In this context, major guidelines recommend post-surgery staging to assess the risk of disease persistence, recurrence, and mortality. Consequently, risk stratification becomes pivotal in determining the necessity of postoperative adjuvant therapy, which may include radioiodine therapy (RIT), the degree of TSH suppression, additional imaging studies, and the frequency of follow-up.However, the intermediate risk of recurrence is a highly heterogeneous category that encompasses various risk criteria, often combined, resulting in varying degrees of aggressiveness and a recurrence risk ranging from 5 to 20%. Furthermore, there is not enough long-term prognosis data for these patients. Unlike low- and high-risk DTC, the available literature is contradictory, and there is no consensus regarding adjuvant therapy.We aim to provide an overview of intermediate-risk differentiated thyroid cancer, focusing on criteria to consider when deciding on adjuvant therapy in the current context of personalized approach, including molecular analysis to enhance the accuracy of patient management.
10.1007/s11154-023-09852-y