RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Prevalence of Malignancy and Behavior Under Active Surveillance.

Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes (HRAS, NRAS, KRAS) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS-mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS-mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS-mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS-mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS-mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS-mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS-mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS-mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS-mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

Clinical value of second opinions in oncology: A retrospective review of changes in diagnosis and treatment recommendations.

BACKGROUND: Data on the clinical value of second opinions in oncology are limited. We examined diagnostic and treatment changes resulting from second opinions and the expected impact on morbidity and prognosis. METHODS: This retrospective cohort study included patients presenting in 2018 to a high-volume cancer center for second opinions about newly diagnosed colorectal, head and neck, lung, and myeloma cancers or abnormal results. Two sub-specialty physicians from each cancer type reviewed 30 medical records (120 total) using a process and detailed data collection guide meant to mitigate institutional bias. The primary outcome measure was the rate of treatment changes that were "clinically meaningful", i.e., expected to impact morbidity and/or prognosis. Among those with treatment changes, another outcome measure was the rate of clinically meaningful diagnostic changes that led to treatment change. RESULTS: Of 120 cases, forty-two had clinically meaningful changes in treatment with positive expected outcomes (7 colorectal, 17 head and neck, 11 lung, 7 myeloma; 23-57%). Two patients had negative expected outcomes from having sought a second opinion, with worse short-term morbidity and unchanged long-term morbidity and prognosis. All those with positive expected outcomes had improved expected morbidity (short- and/or long-term); 11 (0-23%) also had improved expected prognosis. Nine involved a shift from treatment to observation; 21 involved eliminating or reducing the extent of surgery, compared to 6 adding surgery or increasing its extent. Of the 42 with treatment changes, 13 were due to clinically meaningful diagnostic changes (1 colorectal, 5 head and neck, 3 lung, 4 myeloma; 3%-17%) . CONCLUSIONS: Second-opinion consultations sometimes add clinical value by improving expected prognoses; more often, they offer treatment de-escalations, with corresponding reductions in expected short- and/or long-term morbidity. Future research could identify subgroups of patients most likely to benefit from second opinions.

What do patients want to know about surgery for low-risk thyroid cancer? A qualitative study.

BACKGROUND: Shared decision-making about treatment for low-risk thyroid cancer requires patients and surgeons to work together to select treatment that best balances risks and expected outcomes with patient preferences and values. To participate, patients must be activated and ask questions. We aimed to characterize what topics patients prioritize during treatment decision-making. METHODS: We identified substantive questions by patients with low-risk (cT1-2, N0) thyroid cancer during audio-recorded consultations with 9 surgeons at 2 unique health care systems. Logistics questions were excluded. Qualitative content analysis was used to identify major themes among patients' questions and surgeon responses. RESULTS: Overall, 28 of 30 patients asked 253 substantive questions, with 2 patients not asking any substantive questions (median 8, range 0-25). Patients were 20 to 71 years old, mostly White (86.7%) and female (80.0%). The questions addressed extent of surgery, hormone supplementation, risk of cancer progression, radioactive iodine, and etiology of thyroid cancer. When patients probed for a recommendation regarding extent of surgery, surgeons often responded indirectly. When patients asked how surgery could impact quality of life, surgeons focused on oncologic benefits and surgical risk. Patients commonly asked about hormone supplementation and radioactive iodine. CONCLUSION: Patient questions focused on the decision regarding extent of surgery, quality of life, and nonsurgical aspects of thyroid cancer care. Surgeon responses do not consistently directly answer patients' questions but focus on the risks, benefits, and conduct of surgery itself. These findings suggest an opportunity to help surgeons with resources to improve shared decision-making by providing information that patients prioritize.

The Influence of Emotions on Treatment Decisions About Low-Risk Thyroid Cancer: A Qualitative Study.

Background: Little is known about the role of emotions in treatment decisions for thyroid cancer. We aimed to characterize the emotional content of patient-surgeon communication during decision-making about low-risk thyroid cancer treatment. Methods: We audio-recorded conversations about treatment for clinically low-risk thyroid cancer or biopsy suspicious for thyroid cancer between patients (n = 30) and surgeons (n = 9) in two diverse, academic hospitals in the United States. Inductive and deductive content analyses were used to characterize the emotional content in verbatim transcripts. Results: Patients' expression of emotion focused on primarily on their diagnosis and treatment outcomes. Patients commonly expressed negative emotions like fear and anxiety about "the C-word" and worried about the cancer growing or spreading. In response, most surgeons used education, as opposed to empathy or validation, to reassure patients, often highlighting low probabilities of adverse events. Surgeons emphasized the "slow-growing" nature and excellent prognosis of thyroid cancer compared with other malignancies. When discussing treatment options, surgeons often described alternatives in terms of their emotional outcomes. Some described total thyroidectomy as providing "peace of mind" or a "sense of completeness," warning that cancer or thyroid tissue remaining in the body with active surveillance or lobectomy might "worry" or "bother" patients. Surgeons supported deliberation by reassuring patients that there are "two right answers" and "no rush" to decide. Conclusions: Patients express negative emotions during treatment decision-making. In response, surgeons often miss opportunities to provide empathy in addition to education. Surgeons and patients both acknowledge patient fear and anxiety as a reason to choose thyroidectomy instead of active surveillance. Peace of mind gained by patients and surgeons as a result of thyroidectomy may lead to overtreatment of patients with low-risk thyroid cancer.

Epidemiology and incidence of HPV-related cancers of the head and neck.

Globally, 4.5% of cancers are due to the human papillomavirus (HPV). In the United States, 80 million people are infected with HPV, and the incidence of HPV oropharyngeal cancer has surpassed HPV cervical cancer. The highest burden of oropharyngeal cancer is seen in middle-aged and increasingly older White men. HPV vaccination promises to change the epidemiology of this disease, but HPV vaccination rates remain too low today to reduce disease transmission.

Travel distance is associated with stage at presentation and laryngectomy rates among patients with laryngeal cancer.

BACKGROUND: The impact of travel distance on stage at presentation and management strategies of laryngeal squamous cell carcinoma (SCC) is unknown. We investigated this relationship. METHODS: Retrospective review of patients with laryngeal SCC in the National Cancer Data Base from 2004 to 2016. Multivariate analysis determined relationships between travel distance, sociodemographic, geographic, and hospital factors. Logistic regression determined the influence of travel distance on T-stage and overall stage at presentation, and receipt of total laryngectomy. RESULTS: Sixty thousand four hundred and thirty-nine patients were divided into groups based on distance to treatment: short (<12.5 miles); intermediate (12.5-49.9 miles); and long (>50 miles). Increased travel was associated with T4-stage (intermediate vs. short OR 1.11, CI 1.04-1.18, p = 0.001; long vs. short OR 1.5, CI 1.36-1.65, p < 0.001), and total laryngectomy (intermediate vs. short OR 1.40, CI 1.3-1.5, p ≤ 0.001; long vs. short OR 2.52, CI 2.28-2.79, p ≤ 0.001). In T4 disease, total laryngectomy was associated with improved survival compared to nonsurgical treatment (HR 0.75, CI 0.70-0.80, p < 0.001) regardless of travel distance. CONCLUSION: Longer travel distance to care is associated with increased stage at presentation, rate of laryngectomy, and improved survival in advanced laryngeal SCC. Health policy efforts should be directed towards improving early access to diagnosis and care.

Disparities and guideline adherence for HPV testing among patients with oropharyngeal squamous cell carcinoma, NCDB, and SEER.

BACKGROUND: Human papilloma virus testing for oropharyngeal squamous-cell carcinoma has been recommended by the National Comprehensive Cancer Network since 2012. We examine disparities, reported rates of human papillomavirus (HPV) testing, and the impact on these findings of limitations with the variable in database registries. METHODS: The HPV variable was queried for patients with oropharyngeal squamous carcinoma (OPSCC) from 2013 to 2016 in National Cancer Data Base (NCDB) and Surveillance, Epidemiology, and End Results (SEER). Multivariable regression was used to identify disparities based on sociodemographic variables. Sensitivity analyses were used to investigate limitations of the variable. RESULTS: Despite limitations in the HPV variable in the databases, there was less than 100% adherence to recommended testing, and there were significant disparities in multiple sociodemographic variables. For example, in NCDB 70% of white versus 60.4% of black patients were tested (odds ratio [OR] 0.75, confidence interval [CI] 0.66-0.85, p ≤ 0.0001); in SEER 59.8% of white and 47.6% of black patients were tested (OR 0.73, CI 0.67-0.81; p ≤ 0.0001). CONCLUSIONS: Disparities exist among patients undergoing testing for HPV-associated OPSCC and adherence to guideline recommended HPV testing has been suboptimal. In addition, the HPV variable definition, especially as it relates to p16 positivity, and use in these two registries should be improved.

Life Expectancy and Treatment Patterns in Elderly Patients With Low-Risk Papillary Thyroid Cancer: A Population-Based Analysis.

OBJECTIVE: Guidelines endorse active surveillance for low-risk papillary thyroid carcinoma (PTC), but this is not commonly utilized. Those with limited life expectancy due to age and comorbidity may be best suited for active surveillance given their higher likelihood of other-cause mortality compared to disease-specific mortality. METHODS: Surveillance, epidemiology, and end results-Medicare was queried for patients >65 years with T1, N0, M0 PTC who received surgery. We evaluated the overall survival, disease-specific survival (DSS), and survival based on tumor size and extent of surgery (hemi- vs total thyroidectomy). We created a competing risk model to identify the cumulative incidence of other-cause mortality to define patient groups with life expectancies of less than 10 and 15 years. RESULTS: A total of 3280 patients were included. The 20-year overall survival and DSS were 38.2% and 98.5%, respectively. DSS was comparable between patients based on tumor size and surgery. The cancer cohort had better survival compared to matched controls (P < .001). Life expectancy was less than 15 years for any patient aged >80 years regardless of Charlson comorbidity score (CCS ≥ 0) and any patient aged >70 years with CCS ≥ 1. Life expectancy was less than 10 years for any patient a >80 years with CCS ≥ 1 and aged >70 years with CCS ≥ 3. CONCLUSION: Older patients with comorbidities have limited life expectancies but excellent DSS from low-risk PTC. Incorporating life expectancy into management decisions and guidelines would likely promote selection of less aggressive management for populations that are most suited for this approach.

NATIONAL SURVEY OF ENDOCRINOLOGISTS AND SURGEONS REGARDING ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER.

OBJECTIVE: Active surveillance for low-risk papillary thyroid cancer (PTC) was endorsed by the American Thyroid Association guidelines in 2015. The attitudes and beliefs of physicians treating thyroid cancer regarding the active surveillance approach are not known. METHODS: A national survey of endocrinologists and surgeons treating thyroid cancer was conducted from August to September 2017 via professional society emails. This mixed-methods analysis reported attitudes toward potential factors impacting decision-making regarding active surveillance, beliefs about barriers and facilitators of its use, and reasons why physicians would pick a given management strategy for themselves if they were diagnosed with a low-risk PTC. Survey items about attitudes and beliefs were derived from the Cabana model of barriers to guideline adherence and theoretical domains framework of behavior change. RESULTS: Among 345 respondents, 324 (94%) agreed that active surveillance was appropriate for at least some patients, 81% agreed that active surveillance was at least somewhat underused, and 76% said that they would choose surgery for themselves if diagnosed with a PTC of ≤1 cm. Majority of the respondents believed that the guidelines supporting active surveillance were too vague and that the current supporting evidence was too weak. Malpractice and financial concerns were identified as additional barriers to offering active surveillance. The respondents endorsed improved information resources and evidence as possible facilitators to offering active surveillance. CONCLUSION: Although there is general support among physicians who treat low-risk PTC for the active surveillance approach, there is reluctance to offer it because of the lack of robust evidence, guidelines, and protocols.

Factors associated with physicians' recommendations for managing low-risk papillary thyroid cancer.

BACKGROUND: The 2015 American Thyroid Association endorsed less aggressive management for low-risk papillary thyroid cancer (LR-PTC). We aimed to identify factors influencing physicians' recommendations for LR-PTC. METHODS: We surveyed members of three professional societies and assessed respondents' recommendations for managing LR-PTC using patient scenarios. Multivariable logistic regression models identified clinical and non-clinical factors associated with recommending total thyroidectomy (TT) and active surveillance (AS). RESULTS: The 345 respondents included 246 surgeons and 99 endocrinologists. Physicians' preference for their own management if diagnosed with LR-PTC had the strongest association with their recommendation for TT and AS (TT: OR 12.3; AS: OR 7.5, p < 0.001). Physician specialty and stated patient preference were also significantly associated with their recommendations for both management options. Respondents who received information about AS had increased odds of recommending AS. CONCLUSIONS: Physicians' recommendations for LR-PTC are strongly influenced by non-clinical factors, such as personal treatment preference and specialty.

Adoption of Active Surveillance for Very Low-Risk Differentiated Thyroid Cancer in the United States: A National Survey.

CONTEXT: Active surveillance (AS) of thyroid cancer with serial ultrasounds is a newer management option in the United States. OBJECTIVE: This work aimed to understand factors associated with the adoption of AS. METHODS: We surveyed endocrinologists and surgeons in the American Medical Association Masterfile. To estimate adoption, respondents recommended treatment for 2 hypothetical cases appropriate for AS. Established models of guideline implementation guided questionnaire development. Outcome measures included adoption of AS (nonadopters vs adopters, who respectively did not recommend or recommended AS at least once; and partial vs full adopters, who respectively recommended AS for one or both cases). RESULTS: The 464 respondents (33.3% response) demographically represented specialties that treat thyroid cancer. Nonadopters (45.7%) were significantly (P < .001) less likely than adopters to practice in academic settings, see more than 25 thyroid cancer patients/year, be aware of AS, use applicable guidelines (P = .04), know how to determine whether a patient is appropriate for AS, have resources to perform AS, or be motivated to use AS. Nonadopters were also significantly more likely to be anxious or have reservations about AS, be concerned about poor outcomes, or believe AS places a psychological burden on patients. Among adopters, partial and full adopters were similar except partial adopters were less likely to discuss AS with patients (P = .03) and more likely to be anxious (P = .04), have reservations (P = .03), and have concerns about the psychological burden (P = .009) of AS. Few respondents (3.2%) believed patients were aware of AS. CONCLUSION: Widespread adoption of AS will require increased patient and physician awareness, interest, and evaluation of outcomes.

Primary tumor volume as a predictor of distant metastases and survival in patients with sinonasal mucosal melanoma.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is an aggressive cancer with high mortality. Identifying patients at risk of distant metastasis assists with management and prognostication. We aimed to define the relationship between volume, survival, and risk of distant metastases. METHODS: A retrospective review of all patients with SNMM treated at a single institution over a 21-year period was conducted. Tumor volume was calculated using cross-sectional imaging and survival analysis was performed. RESULTS: Sixty-one patients were included. Tumor volume was predictive of local progression-free survival (P = .03), distant metastases-free survival (DMFS) (P = .002), and overall survival (OS) (P = .02). It was a better predictor than AJCC stage and T-classification. Tumor volume equal to or greater than 5 cm3 was associated with a significantly worse DMFS and OS (P = .02 and .009, respectively). CONCLUSION: Calculation of tumor volume assists in quantifying the risk of distant metastases and death in SNMM.

The 3 Bs of cancer care amid the COVID-19 pandemic crisis: "Be safe, be smart, be kind"-A multidisciplinary approach increasing the use of radiation and embracing telemedicine for head and neck cancer.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis.

Last-line local treatment with the Quad Shot regimen for previously irradiated head and neck cancers.

OBJECTIVES: Patients with prior irradiated head and neck cancer (HNC) who are ineligible for definitive retreatment have limited local palliative options. We report the largest series of the use of the Quad Shot (QS) regimen as a last-line local palliative therapy. MATERIALS AND METHODS: We identified 166 patients with prior HN radiation therapy (RT) treated with QS regimen (3.7 Gy twice daily over 2 consecutive days at 4 weeks intervals per cycle, up to 4 cycles). Palliative response defined by symptom(s) relief or radiographic tumor reduction, locoregional progression free survival (LPFS), overall survival (OS) and radiation-related toxicity were assessed. RESULTS: Median age was 66 years. Median follow-up for all patients was 6.0 months and 9.7 months for living patients. Overall palliative response rate was 66% and symptoms improved in 60% of all patients. Predictors of palliative response were > 2 year interval from prior RT and 3-4 QS cycles. Median LPFS was 5.1 months with 1-year LPFS 17.7%, and median OS was 6.4 months with 1-year OS 25.3%. On multivariate analysis, proton RT, KPS > 70, presence of palliative response and 3-4 QS cycles were associated with improved LPFS and improved OS. The overall Grade 3 toxicity rate was 10.8% (n = 18). No Grade 4-5 toxicities were observed. CONCLUSION: Palliative QS is an effective last-line local therapy with minimal toxicity in patients with previously irradiated HNC. The administration of 3-4 QS cycles predicts palliative response, improved PFS, and improved OS. KPS > 70 and proton therapy are associated with survival improvements.

Perceived value drives use of routine asymptomatic surveillance PET/CT by physicians who treat head and neck cancer.

BACKGROUND: Why physicians use surveillance imaging for asymptomatic cancer survivors despite recommendations against this is not known. METHODS: Physicians surveilling head and neck cancer survivors were surveyed to determine relationships among attitudes, beliefs, guideline familiarity, and self-reported surveillance positron-emission-tomography/computed-tomography use. RESULTS: Among 459 responses, 79% reported using PET/CT on some asymptomatic patients; 39% reported using PET/CT on more than half of patients. Among attitudes/beliefs, perceived value of surveillance imaging (O.R. 3.57, C.I. 2.42-5.27, P = <.0001) was the strongest predictor of high imaging, including beliefs about outcome (improved survival) and psychological benefits (reassurance, better communication). Twenty-four percent of physicians were unfamiliar with guideline recommendations against routine surveillance imaging. Among physicians with high perceived-value scores, those less familiar with guidelines imaged more (O.R. 3.55, C.I. 1.08-11.67, P = .037). CONCLUSIONS: Interventions to decrease routine surveillance PET/CT use for asymptomatic patients must overcome physicians' misperceptions of its value. Education about guidelines may modify the effect of perceived value.

Elective neck dissection (END) and cN0 hard palate and upper gingival cancers: A National Cancer Database analysis of factors predictive of END and impact on survival.

BACKGROUND AND OBJECTIVES: The reported risk of nodal metastasis in hard palate and upper gingival squamous cell carcinoma (SCC) has been inconsistent with inadequate consensus regarding the utility of neck dissection in the clinically negative (cN0) neck. MATERIALS AND METHODS: Using the National Cancer Database, cN0 patients diagnosed with SCC of the head and neck with the subsites of the hard palate and upper gingiva were identified from 2004 to 2014. RESULTS: A total of 1830 patients were identified, and END was performed on 422 patients with cN0 tumors. Pathologically positive nodes occurred in 14% (59/422) of patients in this cohort. Higher tumor stage, academic hospital type, and large hospital volume (>28 cancer-specific cases/year) were associated with a higher likelihood of END both in univariate and multivariate analyses (P < .05). Patients >80 years of age were less likely to receive END on multivariate analysis (OR 0.52, 0.32-0.84). No variables, including advanced T stage, predicted occult metastases. Cox proportional hazards regression analysis showed that patients who underwent END demonstrated improved OS over an 11-year period (hazard ratio 0.75, P = .002). On subgroup analysis, this improvement was significant in patients with both stage T1 and T4 tumors. CONCLUSIONS: Tumor stage, hospital type, and hospital volume were associated with higher rates of END for patients with cN0 hard palate SCC and after controlling for clinical factors, END was associated with improved overall survival.

Surgical Management Patterns of Sinonasal Malignancy: A Population-Based Study.

Objectives Determining surgical trends and outcomes for sinonasal tumors is challenging given their low incidence and heterogeneous pathology. This study utilized the National Cancer Database (NCDB) to identify trends and outcomes associated with surgical management of sinonasal tumors. Design Retrospective database analysis. Setting National Cancer Database. Participants Patients with sinonasal malignancies identified from the NCDB between 2010 and 2015. Main Outcome Measures The primary outcome was the choice of surgical therapy used for sinonasal tumor resection: endoscopic versus open approach. Each was cohort analyzed with respect to various demographic and clinicopathologic factors. A treatment effect model was used to identify potential differences between surgical approaches. Survival was evaluated using Kaplan-Meier analysis. Results A total of 10,193 patients with sinonasal malignancies were identified in the NCDB database; of these, 2,292 had a documented subsite, histology, and definitive surgical treatment with documented surgical approach and were included in the analysis. About 71.9% of patients had an open approach and 28.1% a purely endoscopic procedures. Tumor histology, treatment facility type, margin status, and length of stay were all variables that were associated with significant differences between the open and endoscopic cohort. Five-year survival rates for the open and endoscopic cohorts were not significantly different (59.6 and 60.8%, respectively). Conclusions Assessment of the NCDB revealed that 28% patients with sinonasal malignancy were selected for endoscopic surgery. These patients had comparable oncologic outcomes to open resection.