INTRODUCTION MATERIALS AND METHODS

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1 ORIGINAL ARTICLE Demographic and socioeconomic factors predictive of compliance with American Thyroid Association guidelines for the treatment for advanced papillary thyroid carcinoma Ashley E. Wenaas, MD, 1 Celeste Z. Nagy, BA, 1 Yin Yiu, MD, 1 Li Xu, PhD, 2 Kelsey Horter, BS, 1 Jose P. Zevallos, MD, MPH 3 * 1 Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, 2 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 3 Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC. Accepted 29 June 2014 Published online 25 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The American Thyroid Association (ATA) publishes evidence-based guidelines for the treatment of papillary thyroid carcinoma (PTC). We sought to identify factors associated with receiving treatment compliant with the 2006 ATA guidelines for advanced-stage PTC. Methods. The 2006 ATA guideline compliance was examined in patients with stage III and IV PTC extrapolated from Surveillance, Epidemiology, and End Results (SEER). Results. Sixty percent of patients received ATA-compliant treatment. A stepwise increase in compliance occurred between 2006 and 2009 (p-value trend ). Age 45 to 64 years versus 65 (odds ratio [OR] ; 95% confidence interval [CI] ; p <.0001) and higher income (p trend 5.012) were associated with an increased likelihood of receiving ATA-compliant care. African Americans (OR ; 95% CI ; p ) and single patients (OR ; 95% CI ; p 5.02) were less likely to receive ATA-compliant care. Conclusion. This study highlights specific populations at risk for receiving non ATA-compliant care for PTC and underscores the need to further implement guideline-based practice. VC 2014 Wiley Periodicals, Inc. Head Neck 37: , 2015 KEY WORDS: thyroid cancer, papillary thyroid carcinoma, American Thyroid Association (ATA) guidelines, disparities, socioeconomic status INTRODUCTION Thyroid carcinomas are the most common endocrine malignancies in the United States with a prevalence of over 450,000 and an estimated incidence of 60,220 new cases in Over the last 20 years, there has been a sharp increase in the incidence of thyroid cancer. A Surveillance, Epidemiology, and End Results (SEER) study from Davies and Welch 2 showed that thyroid cancer has nearly tripled from 1975 to 2009, with almost the entire increase being attributable to increased incidence of papillary thyroid carcinoma (PTC). There is significant variability in the management of thyroid cancer across the United States. Controversy exists with respect to the required extent of primary thyroid surgery, the need for lymph node dissection, and the use of adjuvant radioactive iodine. 3 This degree of variability has led the American Thyroid Association (ATA) to periodically publish evidence-based guidelines for the *Corresponding author: J. P. Zevallos, Bobby R. Alford Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, 170 Manning Drive, Box 7070, Chapel Hill, NC jose_zevallos@med.unc.edu This work was accepted for oral presentation at the International Federation of Head and Neck Oncologic Societies 5th World Conference (abstract number: 58163). treatment of thyroid cancer. In 2006, the ATA published guidelines including recommendations on the extent of primary surgery, indications for prophylactic central lymph node dissection, and use of postoperative radioactive iodine ablation (recommendations 26, 27, and 32, respectively). 4 It has been demonstrated that care compliant with the ATA guidelines results in improved oncologic outcomes. 5 Goffredo et al 5 published a population-level SEER analysis of compliance with the 2006 ATA guidelines for all well-differentiated thyroid cancers in order to determine the impact these guidelines had on disease-specific outcomes. They found a statistically significant improvement in disease-specific survival for patients who underwent treatment compliant with the 2006 ATA guidelines. The purpose of this study was to identify demographic and socioeconomic factors associated with receiving care compliant with the 2006 ATA guidelines for advanced PTC in order to assess the impact these guidelines had on health care delivery on a national scale. MATERIALS AND METHODS The study design was a retrospective cohort analysis utilizing the SEER database, a registry maintained and updated annually by the National Cancer Institute. Specifically, we used the dataset named Incidence SEER 18 Regs Research Data 1 Hurricane Katrina Impacted 1776 HEAD & NECK DOI /HED DECEMBER 2015

2 COMPLIANCE WITH AMERICAN THYROID ASSOCIATION GUIDELINES FOR PTC Louisiana Cases, Nov 2011 Sub ( varying). The SEER registry is the main source of cancer incidence statistics in the United States. This particular database contains incidence research records for 18 geographic areas that collectively span approximately 28% of the U.S. population. Eligible patients were identified using the International Classification of Diseases for Oncology, third edition histology codes encompassing the clinically relevant subtypes of PTC. Thyroid cancer codes included were those for papillary carcinoma (8050) and papillary adenocarcinoma ( ). We further selected cases with adequate data regarding staging, primary surgery, nodal management, and use of radioactive iodine. Case characteristics of patients with PTC treated between 2006 and 2009 were extrapolated from the SEER database. Characteristics extrapolated from SEER included demographic variables, such as patient age, sex, year of treatment, marital status at presentation, and race/ ethnicity (non-hispanic white, African American, Hispanic, and Asian). Clinicopathologic characteristics of the tumors included American Joint Committee on Cancer (AJCC) stage, histologic classification, and number of examined and subsequently positive lymph nodes. County-level data on socioeconomic status (SES) was collected using SEER*Stat software. Specifically, 2 county SES indicators (cost-of-living-adjusted median household income and percentage of population with health insurance) were coded in quartiles. For the purposes of this study, we assessed compliance with the 2006 ATA guidelines for the treatment of stage III and IV PTC. Specifically, we evaluated recommendations 26, 27, and 32 of the 2006 ATA guidelines that focus on primary surgery, central compartment lymph node dissection, and radioactive iodine, respectively. 4 Each of these recommendations is based on the patient s AJCC stage and is accompanied by a rating specifying the strength of the recommendation using the schema proposed by the U.S. preventative services task force. Recommendation 26 states that a near-total or total thyroidectomy is recommended for all patients with a preoperative diagnosis of thyroid cancer (level A). They did specify that a thyroid lobectomy was sufficient for patients with small (<1 cm), low-risk, isolate, and intrathyroidal papillary carcinomas. Because all the patients in this SEER analysis had stage III or IV tumors, a thyroid lobectomy was considered noncompliant with ATA guidelines. Recommendation 27 states that routine central lymph node dissection, even in the absence of identifiable pathologic lymph nodes, should be strongly considered for patients with PTC (level B), but that a total thyroidectomy followed by radioactive iodine was an acceptable alternative. We considered all patients who did not have lymph node dissection or radioactive iodine to be noncompliant. Recommendation 32 focused on the postoperative use of radioactive iodine. They recommended radioactive iodine for all patients with stage III and IV disease (level B). If patients did not receive lymph node dissection or radioactive iodine, we considered them to be noncompliant with recommendation 32 alone, instead of noncompliant with both recommendations 28 and 32. The chi-square test was used to compare demographic data and clinical characteristics by ATA compliance. A trend test was performed to determine interval differences in ATA compliance between 2006 and 2009, as well as to determine differences between income quartiles. To determine individual predictors of ATA compliance, multivariable analyses were performed and used to estimate odds ratio (OR) and 95% confidence interval (CI) for each socioeconomic, demographic, and clinicopathologic variable. The cutoff p value for inclusion into the multivariable analysis was set at <.05. All analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC). RESULTS A total of 2447 patients fit the criteria of this study. Overall, 60% of patients (n ) received treatment compliant with ATA guidelines. A stepwise increase in the rate of ATA compliance was noted between 2006 and 2009 (54% 2006; 60% 2007; 62.4% 2008; and 63.8% 2009; p trend ). Demographic characteristics of patients in this study and their effect on ATA compliance can be found in Table 1. African Americans were less likely to receive ATA-compliant treatment compared to non-hispanic whites (p ), as well as single versus married patients (p ). Age was divided into 2 categories, 45 to 64 years and 65 years. An inverse relationship between increasing age and ATA compliance was noted (p trend <.0001). In regard to the SES indicators examined, as county-level median household income increased, there was a similar increase in ATA compliance (p trend 5.012), but no significant association was noted between percent insured by county and rates of ATA compliance (p trend 5.309). Compliance was also noted to be higher for stage III versus stage IV tumors (p ). On multivariable analysis (Table 2), age 65 years (OR ; 95% CI ; p ) was associated with a decreased likelihood of receiving ATA-compliant care. As county-level median household income increased, ATA compliance increased (p trend 5.011). African Americans (OR ; 95% CI ; p ) and single versus married patients (OR ; 95% CI ; p 5.023) were less likely to receive ATA-compliant care, independent of income and insurance status. A total of 40% of patients in this study received treatment that was not compliant with ATA guidelines. Among those patients, the vast majority were not compliant with ATA guidelines regarding the lymph node dissection or the use of radioactive iodine: 44.8% did not receive radioactive iodine of lymph node dissection when either was recommended by the guidelines, and 39.7% did not receive radioactive iodine when radioactive iodine alone was recommended. An additional 14.4% did not undergo a total thyroidectomy and were therefore noncompliant with respect to extent of primary surgery. DISCUSSION In the present study, we sought to assess socioeconomic and demographic factors that are predictive of receiving treatment compliant with the 2006 ATA guidelines for stage III and IV PTC, with the intent to identify possible barriers to the delivery of ATA-compliant care. Forty percent of patients in this study did not receive treatment HEAD & NECK DOI /HED DECEMBER

3 WENAAS ET AL. TABLE 1. Patient demographic and treatment characteristics based on American Thyroid Association compliance. ATA compliant ATA noncompliant Variables No. of patients % No. of patients % Chi-square test p value Trend test p value Age, y < Sex Male Female Marital status Married Single/separated Race Asian or Pacific Islander Black Spanish, Hispanic, Latino White AJCC stage III IV Year of diagnosis Income Q Q Q Q Insurance Q Q Q Q Abbreviations: ATA, American Thyroid Association; AJCC, American Joint Committee on Cancer; Q, quartile. compliant with ATA guidelines, demonstrating variability in thyroid cancer treatment patterns and significant barriers to the delivery of new health care standards. We noted a significant increase in ATA guideline compliance between 2006 and As the strongest level of evidence in the 2006 ATA guidelines is for advanced stage PTC, we focused specifically on compliance with recommendations for advanced stage tumors. All 3 recommendations that were assessed (recommendations 27, 29, and 32) were either level A or B recommendations, which are based on strong evidence and not expert opinion. A statistically significant increase in treatment compliance was noted with each passing year after publication of the 2006 guidelines. Although compliance in the final year of this analysis only reached 63.8%, these findings support at least some success in the dissemination of the guidelines to practitioners in the community. The impact of SES on thyroid cancer incidence has been well established. Li et al 6 recently reported that high SES counties had a significantly higher increase in incidence of well-differentiated thyroid cancer over a 28-year period in comparison to low SES counties. In a separate population level assessment of PTC, Zevallos et al 7 noted that low SES patients were more likely to present with advanced stage, positive lymph nodes, and multifocal disease. Although SES has an important impact on thyroid cancer incidence and presentation, its impact on thyroid cancer management and health care delivery has not been clearly elucidated. This study suggests that SES plays a complex and multifaceted role in patients receiving guideline-compliant care and in dissemination of new guidelines. We noted a significant association between higher median household income and likelihood of receiving ATA-compliant care. We also found that there was no association between ATA compliance and county-level insurance rate, suggesting that insurance status may play a limited role in the dissemination of guidelines and patient management once a diagnosis has been obtained. As further research is done at an individual level to assess the role SES plays in guideline dissemination and treatment compliance, each socioeconomic factor should be evaluated individually to determine which disparities in care are due to health care access versus financial burden. There is conflicting data in previous studies in regard to the role that race plays in thyroid cancer incidence and presentation. In an article aimed at assessing the difference in presentation of thyroid cancer between racial groups, Morris et al 8 reported that African American 1778 HEAD & NECK DOI /HED DECEMBER 2015

4 COMPLIANCE WITH AMERICAN THYROID ASSOCIATION GUIDELINES FOR PTC TABLE 2. Multivariable analysis of compliance with 2006 American Thyroid Association guidelines. Variables OR 95% CI p value Trend test p value Age, y vs Marital status Single vs married Race Asian/Pacific Islander vs white Black vs white Spanish/Latino vs white Income Q2 vs Q Q3 vs Q Q4 vs Q AJCC stage 4 vs Year of diagnosis 2007 vs vs vs Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; Q, quartile; AJCC, American Joint Committee on Cancer. patients with thyroid cancer were more likely to present later in life and with larger tumors, but the authors felt that this difference was more likely attributable to variability in thyroid cancer detection related to SES. In a subsequent SEER database study, Yu et al 9 demonstrated that African Americans had a lower 5-year overall survival (91.5%) for PTC compared to other racial/ethnic groups (non-hispanic whites 95.3%; Hispanics 94.5%; Asian/Pacific islanders 94.4%; and American Indians 96.2%), although it is unclear whether this observed difference in survival was related to thyroid cancer or other causes of mortality. In an analysis of patients with thyroid cancer using the California cancer registry, Herrari et al 10 also found that minority racial/ethnic groups were more likely to present with advanced stage thyroid cancer, but this may have been related to the under diagnosis of smaller low-risk thyroid cancers. The causes of the disparities in thyroid cancer incidence, presentation, and treatment among racial minority groups continue to be controversial. In particular, the role that adherence to treatment guidelines plays in this controversy has not be well elucidated. In the present study, African Americans were significantly less likely to receive ATA-compliant care compared to non-hispanic whites. This difference was independent of the SES variables that were included. These findings suggest a true disparity that may explain, in part, the survival differences for PTC that have been noted previously Further research is needed to elucidate these findings and identify reasons for this disparity in thyroid cancer care. Age is an important prognostic factor in thyroid cancer, but it has not been fully examined in terms of delivery of thyroid cancer care. Age has been demonstrated to impact the quality of care, compliance with institutional standards, and the likelihood of receiving curative therapy in multiple other cancer sites Our study also demonstrated variability in the delivery of ATA-compliant care by age. Age 65 was associated with a lower likelihood of receiving ATA-compliant treatment independent of other demographic factors. This is consistent with previously published population-based studies on ATA compliance. 5,17,18 Famakinwa et al 18 assessed adherence to the 2006 ATA guidelines regarding the treatment of 31,486 patients with well-differentiated thyroid cancer and reported that patients >65 showed the lowest accordance with guidelines. Gofreddo et al 5 also noted that increasing patient age was a factor in discordance which each 3 of the 2006 ATA guidelines analyzed. Marital status has also been shown to impact one s ability to receive compliant care for a variety of cancers. Aizer et al 19 recently published a large SEER populationbased study of 1.2 million patients with numerous types of cancer. They found that married patients were more likely to receive definitive therapy and less likely to die of their cancer than unmarried patients after adjusting for tumor stage, treatment, and demographic variables. Similarly, married patients in the present study were more likely to receive ATA-compliant treatment compared to single patients regardless of age, other demographic factors, and SES. In this study, we assessed compliance with 2006 ATA guidelines despite the fact that more recent guidelines were published in Although this may be considered a limitation, using the 2006 guidelines allowed for an assessment of compliance trends for 5 years after publication of the guidelines, which provided a platform for assessing delivery of these guidelines on a national basis. A statistically significant increase in treatment compliance was noted with each passing year after publication of the 2006 guidelines with a 10% overall increase in compliance between 2006 and Changes between the 2006 and 2009 guidelines included more specific recommendations for central neck dissection for patients with clinically involved central or lateral lymph nodes, and prophylactic central neck dissection for patients with T3 or T4 tumors. The new guidelines also refined the indications for radioactive iodine. Although previously recommended for all patients with stage III and IV PTC, radioactive iodine is now recommended for patients with PTC with T3 or T4 tumors, extrathyroidal extension, or known distant metastases. For stage III or IV patients with tumors between 1 and 4 cm but without nodal metastases, radioactive iodine is recommended when the combination of the patient s age, tumor size, lymph node status, and histology give them an intermediate or high risk of recurrence or death from thyroid cancer. The new, more specific recommendations in 2009 for central neck dissection and radioactive iodine do point out that some of the patients in our study who received treatment compliant with the 2006 guidelines were likely overtreated at that time, and a follow-up study may be warranted to assess compliance with the 2009 guidelines. The purpose of the present study was not to assess treatment outcomes, but to assess the success of dissemination of the 2006 guidelines and the barriers to health care delivery. This study had several limitations inherent of population-based studies using a large national database. SEER does not provide individual-level data on SES. HEAD & NECK DOI /HED DECEMBER

5 WENAAS ET AL. County-level data may mask individual variability and presents the potential for ecologic bias. However, previous studies have reported that regional measures of SES correlate well with individual measures There also may be nonmeasurable differences in patients who receive treatment versus patients who do not, which is a weakness of doing a SEER-based study in which limited information regarding the specific patients is available. There are also limitations with respect to treatment details. Specifically, it is not clear whether patients receiving lymphadenectomy underwent a central neck dissection, a lateral neck dissection, or a sampling of a few nodes. It is also unclear whether some patients were upstaged to stage III when surgical pathology revealed microscopic extrathyroidal extension. These patients would have been labeled as noncompliant in this study if they had not undergone a prophylactic central neck dissection at the time of surgery or received adjuvant radioactive iodine after final pathology revealed extrathyroidal extension. Even though these patients would have been labeled as noncompliant, they should not have received differential treatment based on race or SES and, therefore, would not affect our analysis on factors influencing the dissemination and implementation of the ATA guidelines. In conclusion, this population-level assessment demonstrates that a large percentage of patients with advanced stage PTC did not receive treatment that complies with the 2006 ATA guidelines. These findings highlight specific patient populations at risk for receiving noncompliant PTC care, underscores the variability in healthcare delivery patterns, and the need to further implement guideline-based practice into the care of patients with thyroid cancer. 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