Decision Regret Following the Choice of Surgery or Active Surveillance for Small, Low-Risk Papillary Thyroid Cancer: A Prospective Cohort Study.

Background: It is important to understand cancer survivors' perceptions about their treatment decisions and quality of life. Methods: We performed a prospective observational cohort study of Canadian patients with small (<2 cm) low-risk papillary thyroid cancer (PTC) who were offered the choice of active surveillance (AS) or surgery (Clinicaltrials.gov NCT03271892). Participants completed a questionnaire one year after their treatment decision. The primary intention-to-treat analysis compared the mean decision regret scale total score between patients who chose AS or surgery. A secondary analysis examined one-year decision regret score according to treatment status. Secondary outcomes included quality of life, mood, fear of disease progression, and body image perception. We adjusted for age, sex, and follow-up duration in linear regression analyses. Results: The overall questionnaire response rate was 95.5% (191/200). The initial treatment choices of respondents were AS 79.1% (151/191) and surgery 20.9% (40/191). The mean age was 53 years (standard deviation [SD] 15 years) and 77% (147/191) were females. In the AS group, 7.3% (11/151) of patients crossed over to definitive treatment (two for disease progression) before the time of questionnaire completion. The mean level of decision regret did not differ significantly between patients who chose AS (mean 22.4, SD 13.9) or surgery (mean 20.9, SD 12.2) in crude (p = 0.730) or adjusted (p = 0.29) analyses. However, the adjusted level of decision regret was significantly higher in patients who initially chose AS and crossed over to surgery (beta coefficient 10.1 [confidence interval; CI 1.3-18.9], p = 0.02), compared with those remaining under AS. In secondary adjusted analyses, respondents who chose surgery reported that symptoms related to their cancer or its treatment interfered with life to a greater extent than those who chose AS (p = 0.02), but there were no significant group differences in the levels of depression, anxiety, fear of disease progression, or overall body image perception. Conclusions: In this study of patients with small, low-risk PTC, the mean level of decision regret pertaining to the initial disease management choice was relatively low after one year and it did not differ significantly for respondents who chose AS or surgery.

Gender Differences in Fears Related to Low-Risk Papillary Thyroid Cancer and Its Treatment.

Importance: Fear is commonly experienced by individuals newly diagnosed with papillary thyroid cancer (PTC). Objective: To explore the association between gender and fears of low-risk PTC disease progression, as well as its potential surgical treatment. Design, Setting, and Participants: This single-center prospective cohort study was conducted at a tertiary care referral hospital in Toronto, Canada, and enrolled patients with untreated small low risk PTC (<2 cm in maximal diameter) that was confined to the thyroid. All patients had a surgical consultation. Study participants were enrolled between May 2016 and February 2021. Data analysis was performed from December 16, 2022, to May 8, 2023. Exposures: Gender was self-reported by patients with low-risk PTC who were offered the choice of thyroidectomy or active surveillance. Baseline data were collected prior to the patient deciding on disease management. Main Outcomes and Measures: Baseline patient questionnaires included the Fear of Progression-Short Form and Surgical Fear (referring to thyroidectomy) questionnaires. The fears of women and men were compared after adjustment for age. Decision-related variables, including Decision Self-Efficacy, and the ultimate treatment decisions were also compared between genders. Results: The study included 153 women (mean [SD] age, 50.7 [15.0] years) and 47 men (mean [SD] age, 56.3 [13.8] years). There were no significant differences in primary tumor size, marital status, education, parental status, or employment status between the women and men. After adjustment for age, there was no significant difference observed in the level of fear of disease progression between men and women. However, women reported greater surgical fear compared with men. There was no meaningful difference observed between women and men with respect to decision self-efficacy or the ultimate treatment choice. Conclusions and Relevance: In this cohort study of patients with low-risk PTC, women reported a higher level of surgical fear but not fear of the disease compared with men (after adjustment for age). Women and men were similarly confident and satisfied with their disease management choice. Furthermore, the decisions of women and men were generally not significantly different. The context of gender may contribute to the emotional experience of being diagnosed with thyroid cancer and its treatment perception.

Risk of Adverse Cardiovascular Outcomes in Differentiated Thyroid Cancer Survivors: A Systematic Review and Meta-Analysis.

Introduction: Long-term cardiovascular (CV) risk is a concern for differentiated thyroid cancer (DTC) survivors. Methods: We performed a systematic review and meta-analysis evaluating the risks of CV mortality and morbidity in DTC survivors compared with the general population. Respective meta-analyses were conducted for data that were adjusted for relevant confounders and crude data. We searched five electronic databases from inception to October 2021, supplemented with a hand search. Two reviewers independently screened citations, reviewed full text articles, extracted data, and critically appraised the studies, with discrepancies resolved by a third reviewer. The primary outcome was CV mortality. Secondary outcomes included atrial fibrillation, ischemic heart disease, stroke, and heart failure. We estimated the relative risk (RR) and confidence intervals [CI] of outcomes using random-effects models (adjusted for age and gender), compared with the general population. Results: We reviewed 3409 unique citations, 65 full text articles, and included 7 studies. CV mortality risk was significantly increased in DTC survivors in one study adjusted for confounders-adjusted RR (aRR) 3.35 ([CI 1.66-6.67]; 524 DTC, 1572 controls). The risk of CV morbidity in DTC survivors, adjusted for risk factors, was estimated as follows: atrial fibrillation-aRR 1.66 [CI 1.22-2.27] (3 studies, 4428 DTC, I2 = 75%), ischemic heart disease-aRR 0.97 [CI 0.84-1.13] (2 studies, 3910 DTC, I2 = 0%), stroke-aRR 1.14 [CI 0.84-1.55] (2 studies, 3910 DTC, I2 = 69%), and heart failure-aRR 0.98 [CI 0.60-1.59] (2 studies, 3910 DTC, I2 = 79%). In meta-analyses of unadjusted data, the risks of CV mortality were not significantly increased but the CV morbidity risks were similar to adjusted data. Conclusions: There is limited evidence suggesting that DTC survivors may be at an increased risk of CV death and atrial fibrillation (after adjustment for confounders). We did not observe a significantly increased risk of ischemic heart disease, stroke, or heart failure. Most analyses were subject to significant heterogeneity and further research, with careful attention to CV risk factors, is needed to clarify CV risk in DTC survivors. Registration: PROSPERO CRD42021244743.

Women and thyroid cancer incidence: overdiagnosis versus biological risk.

PURPOSE OF THE REVIEW: Our aim is to discuss the concepts of sex and gender in the context of thyroid cancer epidemiology. RECENT FINDINGS: It has been long-established in global epidemiologic data that thyroid cancer incidence rates are higher in women than men. However, what has been less well understood is whether this reflects sex disparities in cancer susceptibility, gender disparities in detection, or a combination. A recent meta-analysis of autopsy data from individuals who were not known to have thyroid cancer in their lifetime demonstrated no difference in the prevalence of thyroid cancer in women and men, suggesting that gender differences may be the reason for gender-based differences in thyroid cancer detection. This finding, and sex differences in auto immunity and other factors that may affect cancer susceptibility are explored. SUMMARY: Additional research to explore gender- and sex-specific data on thyroid cancer would inform our understanding of the differences and similarities between men and women in susceptibility and detection of thyroid cancer and help to optimize disease management for all genders and both sexes.

A Quantitative Analysis Examining Patients' Choice of Active Surveillance or Surgery for Managing Low-Risk Papillary Thyroid Cancer.

Background: It is important to understand patient preferences on managing low-risk papillary thyroid cancer (PTC). Methods: We prospectively followed patients with low-risk PTC <2 cm in maximal diameter, who were offered the choice of thyroidectomy or active surveillance (AS) at the University Health Network (UHN), in Toronto, Canada. The primary outcome was the frequency of AS choice (percentage with confidence interval [CI]). Univariate and multivariable analyses were performed to identify predictors of the choice of AS. Results: We enrolled 200 patients of median age 51 years (interquartile range 42-62). The primary tumor measured >1 cm in 55.5% (111/200) of participants. The AS was chosen by 77.5% [71.2-82.7%, 155/200] of participants. In a backwards conditional regression model, the clinical and demographic factors independently associated with choosing AS included: older age (compared with referent group <40 years)-age 40-64 years-odds ratio (OR) 2.78 [CI, 1.23-6.30, p = 0.014], age ≥65 years-OR 8.43 [2.13-33.37, p = 0.002], and education level of high school or lower-OR 4.41 [1.25-15.53, p = 0.021]; AS was inversely associated with the patient's surgeon of record being affiliated with the study hospital-OR 0.29 [0.11-0.76, p = 0.012]. In a separate backwards conditional logistic regression model examining associations with psychological characteristics, AS choice was independently associated with a fear of needing to take thyroid hormones after thyroidectomy-OR 1.24 [1.11-1.39, p < 0.001], but inversely associated with fear of PTC progression-OR 0.94 [0.90-0.98, p = 0.006] and an active coping mechanism ("doing something")-OR 0.43 [0.28-0.66, p < 0.001]. Conclusions: Approximately three-quarters of our participants chose AS over surgery. The factors associated with choosing AS included older age, lower education level, and having a surgeon outside the study institution. Patients' fears about either their PTC progressing or taking thyroid hormone replacement as well as the level of active coping style were associated with the decision. Our results inform the understanding of patients' decisions on managing low-risk PTC. Registration: Clinicaltrials.gov NCT03271892.

Ultrasonography and Fine-Needle Aspiration in Indeterminate Thyroid Nodules: A Systematic Review of Diagnostic Test Accuracy.

OBJECTIVES/HYPOTHESIS: Sonographic risk criteria may assist in further prognostication of indeterminate thyroid nodules (ITNs). Our aim was to determine whether sonographic criteria could further delineate the post-test probability of malignancy in ITNs. STUDY DESIGN: Meta-analysis of diagnostic test accuracy. METHODS: A systematic review of Web of Science, MEDLINE, EMBASE, and CINAHL was performed from inception to April 15, 2021. Eligible studies included those which reported ultrasonographic evaluations with the American Thyroid Association (ATA) or the Thyroid Imaging Reporting and Data System (TIRADS) in adult patients with ITNs. ATA or TIRADS were scored as low (negative) or high (positive) malignancy risk using a previously validated binary classification. Primary outcomes included pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratio for all sonographic criteria. Studies were appraised using Quality Assessment of Diagnostic Accuracy Studies and the data were pooled using bivariate random-effects models. RESULTS: Seventeen studies were included in the analysis. For Bethesda III, ATA had a specificity (0.90, 95% confidence interval (CI): 0.74-0.94), but a sensitivity of 0.52 (95% CI: 0.25-0.77). Conversely, K-TIRADS had the highest sensitivity (0.78, 95% CI: 0.62-0.89) with a specificity of 0.53 (95% CI: 0.31-0.74). Furthermore, American College of Radiology and EU TIRADS had specificities of 0.60 (95% CI: 0.36-0.80) and 0.81 (95% CI: 0.73-0.87) with sensitivities of 0.70 (95% CI: 0.37-0.90) and 0.38 (95% CI: 0.20-0.60), respectively. There were few studies with Bethesda IV nodules. CONCLUSIONS: Though dependent on malignancy rates, Bethesda III nodules with low-suspicion TIRADS features may benefit from clinical observation, whereas nodules with high-suspicion ATA features may require molecular testing and/or surgery. LEVEL OF EVIDENCE: NA Laryngoscope, 132:242-251, 2022.

Surgical Case Volume has an Impact on Outcomes for Patients with Lateral Neck Disease in Thyroid Cancer.

BACKGROUND: This study aimed to assess whether surgical case volume for lateral neck dissection has an impact on the survival of patients who have well-differentiated thyroid cancer (WDTC) with lateral cervical node metastases. The authors used a population-based cohort study design. METHODS: The study cohort consisted of WDTC patients in Ontario Canada who underwent thyroidectomy and lateral neck dissection. These patients were identified using both hospital- and surgeon-level administrative data between 1993 and 2017 (n = 1832). Surgeon and hospital volumes were calculated based on the number of cases managed in the year before the procedure by the physician and at the institution managing each case, respectively, and divided into tertiles. Multilevel Cox regression models were used to estimate the effect of volume on disease-free survival (DFS). RESULTS: A crude model without patient or treatment characteristics demonstrated that DFS was associated with both higher surgeon volume tertiles (p < 0.01) and higher hospital volume tertiles (p < 0.01). After control for clustering, patient/treatment covariates, and hospital volume, the lowest surgeon volume tertile (range, 0-20/year; mean, 6.5/year) remained an independent statistically significant negative predictor of DFS (hazard ratio, 1.71; 95 % confidence interval, 1.22-2.4; p < 0.01). CONCLUSION: Surgeon lateral neck dissection case volume is a predictor of better DFS for thyroid cancer patients, with the lowest surgeon volume tertile (<20 neck dissections per year) demonstrating poorer DFS.

Ultrasound in active surveillance for low-risk papillary thyroid cancer: imaging considerations in case selection and disease surveillance.

Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly studied in prospective observational studies. Ultrasound is the primary imaging modality for case selection. While researchers have put forward selection criteria for PTCs based on size, absence of suspicious lymph nodes and tumor location, there are limited reported data highlighting inherent ultrasound limitations and guidelines for case selection and follow-up. We report our experience including imaging limitations encountered in the ongoing AS prospective observational study for PTCs measuring < 2 cm at our institute. We define disease progression as an increase in size of > 3 mm in the largest dimension of nodule or evidence of metastatic disease or extrathyroidal extension. Accurate, consistent and reproducible measurements of PTCs are essential in risk stratifying patients for the option of AS or disease progression. Interobserver discrepancy, shadowing from coarse calcification and background parenchyma heterogeneity or thyroiditis can limit accurate PTC size assessment and therefore hinder patient eligibility evaluation or AS follow-up. Following the ACR Thyroid Imaging, Reporting and Data System (TI-RADS) protocol of three-axes technique to measure a thyroid nodule enables reproducibility of measurements. In patients with multi-nodular goiter, accurate identification and labeling of the PTC is important to avoid mistaking with adjacent benign nodules at follow-up. Ultrasound assessment for extrathyroid extension of PTC, and relationship of PTC to trachea and the anatomic course of the recurrent laryngeal nerve are important considerations in evaluation for AS eligibility.

A Protocol for a Pan-Canadian Prospective Observational Study on Active Surveillance or Surgery for Very Low Risk Papillary Thyroid Cancer.

Background: The traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference. Methods: This is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient's choice. Our primary objective is to determine the rate of 'failure' of disease management in respective AS and surgical arms as defined by: i) AS arm - surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes. Discussion: The results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer. Registration details: This prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery.

Proceedings of the Canadian Thyroid Cancer Active Surveillance Study Group 2019 national investigator meeting.

Active surveillance (AS) in the management of small, low risk papillary thyroid cancer (PTC) as an alternative option to thyroidectomy, is an area of active research. A national Canadian study is proposed to evaluate the long-term outcomes of patients with small, low risk PTC who choose AS or surgery. This letter describes the proceedings of a national investigator meeting to plan the study.

Online Public Interest in Cancer During the COVID-19 Pandemic.

PURPOSE: Health care priorities of individuals may change during a pandemic, which may, in turn, affect health services utilization. We examined Canadians' online relative search interest in five common solid tumors (breast, colon, lung, prostate, and thyroid) during the COVID-19 pandemic to that observed in the same months in the prior 5 years. METHODS: We conducted a cross-sectional retrospective study using Google Trends aggregate anonymous online search data from Canada. We compared the respective relative search volumes for breast, colon, lung, prostate, and thyroid cancers for the months March-November 2020 with the mean for the same months in 2015-2019. Welch's two-sample t tests were performed and the raw P values were then adjusted using Benjamini-Hochberg procedure to correct for multiple comparisons. The level of statistical significance was defined by choosing false discovery rate at .05 for the primary analysis. RESULTS: We observed temporary statistically significant reductions in Canadians' relative search volumes for various cancers, largely early in the pandemic, in the spring of 2020. Specifically, significant reductions (after adjustment for multiple comparisons) were observed for breast cancer in April, May, and October 2020; colon cancer in March and April of 2020; lung cancer in April and September 2020; and prostate cancer in April and May 2020. Thyroid cancer relative search volumes were not significantly different from those observed prior to the pandemic. CONCLUSION: Although Canadians' online interest in various cancers temporarily waned early in the COVID-19 pandemic, recent relative search volumes for various cancers are largely not significantly different from prior to the pandemic.

Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease.

Background: Glucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD. Methods: The retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency. Results: Of 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease. Conclusions: CC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.

BACKGROUND: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. METHODS: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. RESULTS: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. DISCUSSION: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC. Methods: The specific clinical questions and topics addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of the Task Force members (authors of the guideline). Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues, including end of life. The guidelines include 31 recommendations and 16 good practice statements. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of ATC. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with ATC.

Decision-making in Surgery or Active Surveillance for Low Risk Papillary Thyroid Cancer During the COVID-19 Pandemic.

We describe our experience conducting a prospective observational cohort study on the management of small, low risk papillary thyroid cancer during the COVID-19 pandemic. Our study participants are given the choice of active surveillance (AS) or surgery, and those in the AS arm are followed at the study center, whereas surgical patients undergo usual care. During the pandemic we have transitioned from in-person research patient visits to largely virtual care of patients under AS. As of 30 October 2020, we had enrolled 181 patients enrolled in our study (including 25 during the pandemic), of which 92.3% (167/181) consented to telephone communication and 79.0% (143/181) consented to secure videoconferencing communication. Prior to the pandemic, 74.5% (117/157) of our patients chose AS over surgery, whereas during the pandemic, 96.0% (24/25) chose AS. Of the 133 study patients who were under AS within the timeframe from 12 March 2020, to 30 October 2020, the percentage of patients who missed appointments was 8.3% (11/133, for neck ultrasound and physician visits, respectively) and delayed appointments was 23.3% (31/133). This preliminary data suggests that prospective observational research on AS of thyroid cancer can safely continue during the pandemic.