NON-OPERATIVE MANAGEMENT OF DIFFERENTIATED THYROID CANCER IN CALIFORNIA: A POPULATION LEVEL ANALYSIS OF 29,978 PATIENTS

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP OR NON-OPERATIVE MANAGEMENT OF DIFFERENTIATED THYROID CANCER IN CALIFORNIA: A POPULATION LEVEL ANALYSIS OF 29,978 PATIENTS Eric J. Kuo MD 1 ; James X. Wu MD 1 ; Ning Li PhD 2 ; Kyle A. Zanocco MD 1 ; Michael W. Yeh MD 1 ; Masha J. Livhits, MD 1 From: 1 Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095; 2 Department of Biomathematics, UCLA David Geffen School of Medicine, Los Angeles, CA Running title: Non-operative management of DTC Corresponding address: Dr. Masha J. Livhits, MD Section of Endocrine Surgery Le Conte Ave, CHS Los Angeles, CA mlivhits@mednet.ucla.edu

2 Key words: thyroid cancer, active surveillance, non-operative, California Word count (max 2,500): 2,499 Abstract word count (max 250): 246 Number of tables: 3 Number of figures: 2 Number of references: 22 Disclosures: None

3 ABSTRACT (250 word maximum) Objective. There has been increasing interest in active surveillance of papillary thyroid microcarcinoma (mptc). The objective of this study was to characterize the incidence and outcomes of non-operatively managed differentiated thyroid cancers (DTCs) in California. Methods. Biopsy-proven DTCs from the California Cancer Registry (CCR) were linked to data from the California Office of Statewide Health Planning and Development ( ). Low-risk tumors were defined as localized disease measuring < 4 cm without extrathyroidal extension, nodal involvement, or distant metastasis. Results. Of 29,978 patients with DTC, 318 patients (1.1%) were managed non-operatively. Compared to operatively managed patients, patients managed non-operatively were older with more comorbidities, larger tumors (mean size 2.9 vs. 2.0 cm), and an increased rate of distant metastasis (20.4 vs. 3.4%). Independent predictors of non-operative management included increasing age, larger tumor size, papillary histology, and distant metastases. Of 10,795 patients with low-risk tumors, 161 patients (1.5%) were managed non-operatively with tumor size as follows: < 1 cm (15.5%), 1-2 cm (50.3%), >2-3 cm (24.3%), and >3-4 cm (9.9%). There were no disease-specific deaths in the low-risk, non-operative group (median follow-up [interquartile range], 21.3 [ ] months). The proportion of patients managed non-operatively remained relatively stable over the study period (mean increase 0.1% per year, P=0.09). All P values were < 0.05 unless otherwise stated. Conclusion. The vast majority of patients with DTCs were treated surgically, suggesting active surveillance was rarely practiced in California. Although follow-up was limited, no disease-specific mortality in non-operatively managed, low-risk DTCs was observed. Abbreviations: mptc = papillary thyroid microcarcinoma; DTC = differentiated thyroid cancer; CCR = California Cancer Registry; PTC = papillary thyroid carcinoma; FTC = follicular thyroid carcinoma; HCC = Hurthle cell carcinoma; OSPHD = Office of Statewide Health Planning and Development; ATA = American Thyroid Association; CCI = Charlson Comorbidity Index; SD = standard deviation; HMO = Health Maintenance Organization; PPO = Preferred Provider Organization.

4 INTRODUCTION Differentiated thyroid cancer (DTC) represents approximately 95% of thyroid malignancies. 1 Characterized by well-differentiated histology and uptake of radioactive iodine, DTCs include papillary (PTC), follicular (FTC), and Hurthle cell carcinomas (HCC). Surgery is the mainstay of treatment, and prognosis is generally favorable, with disease-specific survival in excess of 90% among patients with American Joint Committee on Cancer (AJCC) stage I-III disease. 1 Papillary thyroid microcarcinoma (mptc) accounts for approximately 80% of thyroid cancers and has a particularly favorable prognosis, with disease-specific survival exceeding 99% at 10 years. 2 Many studies show mptcs to be indolent lesions most commonly identified incidentally or at the time of autopsy. 3-5 Studies primarily from Japan have demonstrated no mortality and low rates of progression with active surveillance. 6 In the United States, mptc is currently the most common thyroid cancer diagnosed in patients > 45 years of age. 5 Trials of active surveillance for patients with low-risk PTC are underway. 7 Published reports of active surveillance for low-risk PTC have been limited to prospective studies from academic referral centers. The extent to which non-operative management is practiced on a population level is unknown. The aim of our study was to evaluate current practice patterns and outcomes of non-operative management of DTC in California. We hypothesized that most non-operatively managed patients fell into one of two groups: (1) patients who would be considered high risk surgical candidates (older with more comorbid conditions), and (2) patients with low-risk tumors who may be potentially undergoing active surveillance. METHODS Study participants The data source for this study was a linked dataset from the California Cancer Registry (CCR) and the California Office of Statewide Health Planning and Development (OSPHD) from 2004 through ,9 CCR is a statewide cancer surveillance system that collects information on all cancers diagnosed in California and can be linked to data from California s OSPHD utilizing individual patient identifiers. OSPHD collects data on inpatient and ambulatory surgery encounters from all licensed hospitals and ambulatory surgery clinics in California. Cases of DTCs were identified from CCR using thyroid site code C739 in combination with ICD-O-3 histology codes reflecting PTC (8050, 8260, 8340, 8341, 8450), FTC (8330, 8331, 8332), and HCC (8290). Cases of cancer are

5 identified by CCR through physician statement of malignancy followed by microscopic confirmation, either by fine needle aspiration or core needle biopsy. 10 Our study was restricted to patients 18 years of age. Cases diagnosed at autopsy or using death certificate information were excluded, as were patients with unknown tumor size or stage. Study protocol CCR surgery codes were used to identify patients who underwent surgery. Demographic and clinical variables extracted from CCR included age at diagnosis, gender, socioeconomic status, tumor size, presence of extrathyroidal extension as defined by imaging or pathology when available, nodal metastasis, and summary stage. Racial and ethnic categories were grouped as White, Black, Latino, Asian/Pacific Islander, and Other/Unknown in accordance with the Office of Management and Budget Socioeconomic status is a variable reported by CCR as determined by Yost et al. 11 Summary stage categorizes disease stage as localized (confined to thyroid), regional (extrathyroidal extension or nodal metastasis), or distant. CCR variable NOSURG summarizes the reason why surgery was not performed. Patients with the following characteristics were classified as low-risk in approximation of ATA guidelines 12 : tumors 4 cm, absent extrathyroidal extension, nodal metastasis, and distant metastasis, localized summary stage, and no chemotherapy or radiation administered. In patients who did not undergo surgery, clinical staging was used as opposed to pathologic staging. The tumor and vital status at last follow-up were also obtained from CCR. Variables extracted from OSPHD included comorbid conditions and hospital volume. Patients listed comorbidities were used to calculate the Charlson Comorbidity Index (CCI). 13 Hospital volume was defined by the annual volume of thyroid surgery and categorized into quintiles. Tumor status and vital status in combination with cause of death variables were used to determine disease-specific mortality. Statistical analysis Summary statistics were used to describe baseline characteristics. Standardized differences were used to represent differences in effect sizes between groups. 14 Standardized differences of 0.2, 0.5, and 0.8 represent small, medium, and large effect sizes, respectively. 15 Linear regression was used to analyze trends in incidence. Binary logistic regression was used to identify factors independently associated with non-operative management. Multivariate regression was performed with backwards elimination with retention of covariates with P < 0.2. All

6 tests were two-sided, and P<0.05 was considered statistically significant. Statistical analysis was performed with SAS version 9.4. The study was approved the institutional review board. RESULTS Total cohort Of 29,978 patients with DTC, 318 patients (1.1%) were managed non-operatively. The median follow-up was 50.5 months (interquartile range [IQR] months). The number of patients managed non-operatively increased by 4.1% per year (P<0.01) over the study period. However, adjusting for the increasing incidence of operatively-managed DTCs, the proportion of non-operative management remained relatively stable over the study period (mean annual increase of 0.05%, P=0.09) (Figure 1). Compared to patients who had surgical treatment, patients managed non-operatively were more frequently >65 years of age (46.9% vs. 17.2%, P<0.01) and had more comorbidities (mean CCI 1.0 vs. 0.5, P<0.01) (Table 1). Additional differences in baseline demographics included a higher percentage of male patients (33.3% vs. 22.1%, P<0.01) and Asian/Pacific Islander race/ethnicity (23.0% vs. 16.0%, P=0.01) in the non-operatively managed group. Patients managed non-operatively were also more frequently uninsured (9.3 vs. 2.1%, P<0.01) and in the lowest quintile of socioeconomic status (16.0 vs. 12.4%, P=0.01). Patients treated at facilities in the two highest hospital volume categories were less likely to undergo non-operative management (18.9% vs. 29.8%, P<0.01). Patients managed non-operatively had larger tumors (mean size 2.9 vs. 2.0 cm, P<0.01) that were more frequently associated with distant metastases (20.4% vs. 3.4%, P<0.01) compared to patients who had surgical treatment. The rate of nodal metastasis was lower in patients managed non-operatively compared to those who underwent surgery (17.6% vs 25.0%, P<0.01) (Table 2). In patients managed non-operatively, rates of chemotherapy (2.2%) and radiation treatment (9.4%) were low. The most frequent reason specified for no surgery performed was that it was not recommended as part of the planned first course of treatment (79%). Advanced age or medical comorbidities (4.1%) and patient refusal (5.7%) were uncommon reasons why surgery was not performed. Independent predictors of non-operative management included age 65 years (odds ratio [OR] 2.3, 95% confidence interval [CI] ), Asian/Pacific Islander race/ethnicity (OR 1.5, 95% CI ), uninsured status (OR 6.3, 95% CI ), CCI > 1 (OR 1.6, 95% CI ), and distant metastases (OR 4.6, 95% CI ). Increasing tumor size was also predictive of non-operative management: 1-2 cm, OR 4.1 (95% CI ); 2.1-3

7 cm, OR 4.8 (95% CI ); cm, OR 4.6 (95% CI ); > 4 cm, OR 7.8 (95% CI ). Patients with follicular (OR 0.2, 95% CI ) or Hurthle cell histology (OR 0.3, 95% CI ) and nodal metastasis (OR 0.03, 95% CI ) were less likely to undergo non-operative management (Table 3). Low-risk patients Of 10,634 patients with low-risk tumors, 161 patients (1.5%) underwent non-operative management, comprising 50.6% of total non-operatively managed tumors (Figure 2). The median follow-up was 21.3 (IQR, ) months. The proportion of low-risk patients managed non-operatively remained stable over the study period (mean annual increase of 0.04%, P=0.34) (Figure 1). The majority of low-risk tumors managed non-operatively were less than 2 cm in size: < 1 cm (15.5%), 1-2 cm (50.3%), 2-3 cm (24.3%), and >3-4 cm (9.9%). Among low-risk microcarcinomas (< 1 cm), 0.4% underwent non-operative management with a median age of 52 years (interquartile range [IQR] years) and CCI of 0 (IQR 0-1). Among low risk tumors 1-2 cm in size, 2.8% underwent nonoperative management with a median age of 49 years (IQR years) and CCI of 0 (IQR 0-1). The disease-specific mortality for patients with low-risk tumors treated surgically was 0.1% (median follow-up [interquartile range] 47.9 [ ] months). There were no disease-specific deaths in the non-operative group (median follow-up [interquartile range], 21.3 [ ] months). DISCUSSION This study analyzed patients with non-operatively managed thyroid cancers in California, with a particular emphasis on low-risk tumors to capture patients potentially undergoing active surveillance. We found that the rate of non-operative management was low (1.1%), and remained stable over the study period. Patients managed nonoperatively had more medical comorbidities and a higher rate of distant metastatic disease. They were also older, more frequently uninsured, in the lowest quartile of socioeconomic status, and less frequently were treated at high volume hospitals. Furthermore, we identified a subpopulation of patients with low-risk disease who were managed non-operatively and had favorable outcomes with limited follow-up. Non-operative management of DTC may reflect a variety of clinical scenarios, including an unfavorable risk-benefit ratio in the setting of advanced age or comorbid conditions, underutilization of surgery, or active surveillance. Indeed, we found patients with non-operatively managed DTCs were more frequently elderly and had more comorbid conditions. In such cases it may be reasonable to forgo surgery for an indolent malignancy.

8 However, non-operative management may also be a reflection of underutilization or barriers to access of care. In a national study of resectable pancreatic cancer, Bilimoria et al. showed that after controlling for age, comorbid conditions, and patient refusal, 54.7% of patients did not have an identifiable reason for why they did not undergo surgery. 16 These patients were disproportionately older, black, less educated, had lower annual incomes, and were on Medicare or Medicaid, suggesting that many patients with resectable pancreatic cancer did not undergo surgery due to health care disparities. Our study of non-operatively managed thyroid cancers mirrored several of these findings, as non-operatively managed patients were older, more frequently uninsured, and in the lowest quintile of socioeconomic status. However, the low rate of non-operative management overall observed in our study suggests that underutilization of thyroidectomy in patients with DTC is low in comparison to those with pancreatic cancer. In contrast to poor outcomes observed in pancreatic cancer, DTC is often incidentally identified and associated with a favorable prognosis. In Japan, active surveillance for low-risk mptc has been practiced since 1993 with promising outcomes year rates of disease progression are low, and no disease-specific mortality has been observed. 17 This has lead to an increasing interest in active surveillance of mptc in the United States culminating in the initiation of several American clinical trials. 7,18 However, long-term outcomes from American trials of active surveillance have yet to be published. Our study hypothesized the existence of a hidden trial of active surveillance within California Cancer Registry data, and aimed to evaluate outcomes in patients with ATA low-risk tumors managed non-operatively. We found that within low-risk tumors, non-operative management was rare, even among microcarcinomas. Furthermore, no significant trends in non-operative management with time were observed. This suggests acceptance of active surveillance as a viable strategy to manage mptc was low and not increasing during the study period. Although active surveillance is only under investigation for mptc, our study broadly analyzed DTC to evaluate differences in practice patterns between papillary and follicular or Hurthle cell histologies. Amongst DTC, PTC is associated with a more favorable prognosis in comparison with FTC and HCC. 1 While disease specific survival in mptc exceeds 99% at 10 years, 2 surgery for follicular and Hurthle cell microcarcinomas is recommended based on high rates of distant metastasis. 19 Although patients with follicular and Hurthle cell histologies more frequently underwent non-operative management in our cohort, this was likely due to associated increased rates of distant metastasis. After adjustment for disease stage, papillary histology as expected was independently associated with non-operative management.

9 With respect to outcomes, no disease-specific deaths have been reported in Japanese trials of active surveillance. 17 In our cohort of low-risk DTCs which includes microcarcinomas, no disease-specific deaths were observed. This finding must be interpreted in the setting of short follow-up and an inability to distinguish whether patients were receiving active surveillance, or were non-operatively managed for other reasons. Furthermore, the short follow-up in this group in the setting of an eight year study period may indicate that these patients may have limited access to care rather than being actively surveilled. Nevertheless, we did not observe compromised outcomes in non-operatively managed low-risk tumors. Additional follow-up studies are needed to define long-term outcomes in patients who have undergone non-operative management of DTC in California. Defining candidates for active surveillance is challenging. A framework has been proposed classifying candidates as ideal, appropriate, or inappropriate based on tumor size and the likelihood of extrathyroidal extension among other factors. 20 Non-operative management of PTCs > 2 cm has been cautioned due to a significant potential for disease-specific mortality. 21 Current protocols for active surveillance in the United States accept tumors up to 1.5 cm in size, and the upper limit of acceptable size is undefined. 7 We observed no disease-specific deaths in our analysis of low-risk tumors < 4 cm, which precluded analysis of a potential size threshold of active surveillance. The main limitation of our study is the lack of knowledge as to why patients did not have surgical treatment. Non-operative management is distinct from active surveillance, which entails close follow-up (with ultrasound performed at least annually) and consideration of surgery if there is disease progression. 22 There is no specific code for active surveillance in CCR, and the data in CCR that reports why surgery was not performed is limited. Follow-up in the low-risk, non-operative cohort was limited, however, this may reflect (1) poor access to care and potentially poor follow up or (2) less frequent follow up given the low risk nature of the disease. Cancer registries outside California send data on California residents treated out of state annually, and therefore, patients who have surgery out of state would be captured in our cohort. However, our study would not capture patients who were initially surveilled but ultimately underwent surgery for disease progression or other reasons. Finally, determinants of low-risk DTC which would preclude active surveillance such as posterior location of the tumor in proximity to the recurrent laryngeal nerve or suspicion of tracheal invasion are not captured by cancer registries. Although statewide cancer reporting in California was initiated in 1988, the quality of data prior to 2004 precluded analysis.

10 The purpose of our study was to more clearly define patterns and outcomes of non-operative management in California. We found that while most patients managed non-operatively were older, had more comorbidities and a higher rate of distant metastasis, there was a subpopulation of patients with low-risk disease who had favorable outcomes in short-term follow-up. This may represent patients who are undergoing active surveillance, or alternatively patients with poor access to care. The proportion of patients managed non-operatively remained stable over the study period, suggesting that surgical management remains the standard of care even for low-risk DTC outside of a clinical trial. With minor modifications, cancer registries may have more utility in reporting outcomes of patients undergoing active surveillance. Increased education of patients and physicians in the community may expand the role of active surveillance. This must be done cautiously in appropriately selected patients and with close follow-up. Future studies may more clearly define population-level outcomes in thyroid cancers undergoing active surveillance. ACKNOWLEDGEMENTS This publication was supported in part by the H H Lee Research Program.

11 REFERENCES 1. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., [see commetns]. Cancer. 1998;83: Yu XM, Wan Y, Sippel RS, Chen H. Should all papillary thyroid microcarcinomas be aggressively treated? An analysis of 18,445 cases. Ann Surg. 2011;254: Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A "normal" finding in Finland. A systematic autopsy study. Cancer. 1985;56: Ahn HS, Kim HJ, Welch HG. Korea's Thyroid-Cancer Epidemic Screening and Overdiagnosis. New England Journal of Medicine. 2014;371: Hughes DT, Haymart MR, Miller BS, Gauger PG, Doherty GM. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid. 2011;21: Miyauchi A. Clinical Trials of Active Surveillance of Papillary Microcarcinoma of the Thyroid. World J Surg. 2016;40: Ho A. Active Surveillance of Papillary Thyroid Microcarcinoma. 2017; 8. California Cancer Registry. Accessed September 6, Office of Statewide Health Planning and Development. Accessed September 6, California Cancer Registry. Q-Tips on Thyroid Cancer 2017; Accessed February 8, Yost K, Perkins C, Cohen R, Morris C, Wright W. Socioeconomic status and breast cancer incidence in California for different race/ethnic groups. Cancer Causes Control. 2001;12: Haugen BR, Alexander EK, Bible KC, et al American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133.

12 13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40: Thomas LE, Pencina MJ. Do not over (p) value your research article. JAMA Cardiology. 2016;1: Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale, N.J.: L. Erlbaum Associates; Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007;246: Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid. 2014;24: Tuttle M. Treatment Decision-Making Among Patients Diagnosed With Papillary Microcarcinoma and Their Significant Others. 2011; Kuo EJ, Roman SA, Sosa JA. Patients with follicular and Hurthle cell microcarcinomas have compromised survival: a population level study of 22,738 patients. Surgery. 2013;154: ; discussion Brito JP, Ito Y, Miyauchi A, Tuttle RM. A Clinical Framework to Facilitate Risk Stratification When Considering an Active Surveillance Alternative to Immediate Biopsy and Surgery in Papillary Microcarcinoma. Thyroid. 2016;26: Nilubol N, Kebebew E. Should small papillary thyroid cancer be observed? A population-based study. Cancer. 2015;121: Ito Y, Miyauchi A, Inoue H, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010;34:28-35.

13 Table 1. Clinical characteristics of non-operatively vs. operatively managed DTCs ( ) Non-operative, n (%) n=318 Operative, n (%) n=29,660 P-values Age (years) <0.01 Mean (SD) (19.4) (15.0) (23.3%) 11,643 (39.4%) (29.9%) 12,917 (43.6%) > (46.9%) 5,100 (17.3%) Gender <0.01 Male 106 (33.3%) 6,540 (22.0%) Female 212 (66.7%) 23,120 (78.0%) Race/Ethnicity a 0.01 White 141 (44.3%) 15,147 (51.2%) Black 13 (4.1%) 1,138 (3.8%) Latino 82 (25.8%) 7,494 (25.4%) Asian/Pacific Islander 73 (23.0%) 4,742 (16.0%) Other 9 (1.8%) 1,139 (3.9%) Socioeconomic Status 0.02 Lowest 51 (16.0%) 3,674 (12.4%) Lower-middle 69 (21.7%) 5,107 (17.2%) Middle 56 (17.6%) 6,040 (20.5%) Higher-middle 58 (18.2%) 6,987 (23.6%) Highest 84 (26.4%) 7,852 (26.5%) Insurance <0.01 Uninsured 29 (9.3%) 622 (2.1%) Managed care/hmo/ppo/private 118 (37.8%) 20,019 (68.6%) Medicare/Medicaid/County 128 (41.0%) 6,027 (20.6%) Other 37 (11.9%) 2,535 (8.7%) Charlson Comorbidity Index <0.01 Mean (SD) 1.03 (1.68) 0.52 (1.09) Hospital volume <0.01 Lowest 80 (25.3%) 6,314 (21.3%) Lower-middle 54 (17.0%) 4,893 (16.5%) Middle 36 (11.3%) 3,656 (12.3%) Higher-middle 36 (11.3%) 5,191 (17.5%) Highest 24 (7.6%) 3,647 (12.3%) Chemotherapy <0.01 No 310 (97.8%) 29,524 (99.5%) Yes 7 (2.2%) 118 (0.4%) Unknown 0 (0%) 18 (0.1%) Radiation <0.01 No 287 (90.3%) 14,290 (48.2%) Yes 30 (9.4%) 15,325 (51.7%) Unknown 1 (0.3%) 11 (0.1%) DTC, differentiated thyroid cancer; SD, standard deviation; HMO, Health Maintenance Organization; PPO, Preferred Provider Organization a Racial and ethnic categories were grouped as White, Black, Latino, Asian/Pacific Islander, and Other/Unknown in accordance with the Office of Management and Budget 2015

14 Table 2. Pathologic characteristics of non-operatively vs. operatively managed DTCs ( ) Non-operative, n (%) n=318 Operative, n (%) n=29,660 P-values Histology 0.03 Papillary 286 (89.9%) 27,718 (93.5%) Follicular 22 (6.9%) 1,228 (4.1%) Hurthle cell 10 (3.1%) 714 (2.4%) Tumor size (cm) <0.01 Mean (SD) 2.86 (2.10) 1.97 (2.51) 2cm 150 (47.2%) 19,583 (66.0%) 2.1-4cm 88 (27.7%) 9,155 (24.1%) > 4cm 80 (25.2%) 2,922 (9.9%) Nodal metastasis <0.01 None 227 (71.4%) (73.8%) Present 56 (17.6%) 7410 (25.0%) Unknown 35 (11.0%) 359 (1.2%) Summary stage <0.01 Localized 217 (68.2%) 19,670 (66.3%) Regional 36 (11.3%) 8,981 (30.3%) Distant 65 (20.4%) 1,009 (3.4%) SD, standard deviation

15 Table 3. Multivariate analysis identifying independent predictors of non-operative management of DTCs in California ( ) Odds Ratio 95% Confidence Limits p-value Age years Reference years years <.0001 Gender Female Reference Male Race/Ethnicity a White Reference Black Latino Asian/Pacific Islander Other/Unknown Socioeconomic Status Lowest Reference Lower middle Middle Higher middle Highest Insurance Managed care/hmo/ppo/private Reference Uninsured <.0001 Medicaid/Medicare/County Military Other Unknown Charlson Comorbidity Index 0 Reference Histology Papillary Reference Follicular <.0001 Hurthle cell Tumor size < 1cm Reference 1-2cm < cm < cm <.0001 > 4cm <.0001 Nodal metastasis None Reference Present <.0001 Unknown <.0001 Number of lymph nodes examined Lymph nodes examined Lymph nodes not examined Examined, no nodal metastasis Examined, yes nodal metastasis

16 Distant metastasis None Reference Present <.0001 Unknown HMO, Health Maintenance Organization; PPO, Preferred Provider Organization a Racial and ethnic categories were grouped as White, Black, Latino, Asian/Pacific Islander, and Other/Unknown in accordance with the Office of Management and Budget 2015

17 Figure legends Figure 1. Percent of DTCs in California managed non-operatively from DTC, differentiated thyroid carcinoma Figure 2. Patients with non-operatively managed DTC by ATA risk stratification and tumor size (n=29,978) Pie of pie chart displaying non-operatively managed DTCs by ATA risk stratification and low-risk DTCs by size; DTC, differentiated thyroid carcinoma; ATA, American Thyroid Association; low-risk tumors were 4 cm, absent extrathyroidal extension, nodal metastasis, and distant metastasis, localized summary stage, and no chemotherapy or radiation administered

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