Have 2006 ATA Practice Guidelines Affected the Treatment of Differentiated Thyroid Cancer in the United States?

Abstract

Background:

There is wide variability in the degree of adherence to guideline recommendations among caregivers. Our aim was to determine the clinical impact of the 2006 guidelines from the American Thyroid Association (ATA) on the management of differentiated thyroid cancer (DTC) in the United States.

Methods:

The Surveillance, Epidemiology and End Results (SEER) database (2004–2009) was employed. Patients were divided into two groups based on receipt of care before (DTC 04–06) and after (DTC 07–09) the release of the 2006 ATA guidelines. Adherence was determined with a chi-square test and binary logistic regression. Survival was analyzed with the Kaplan–Meier method and log-rank test.

Results:

A total of 12,816 patients with DTC were identified between 2004 and 2006, and 14,514 between 2007 and 2009 (DTC 07–09). Adherence to Recommendation 26 (surgery) tended to increase in DTC 07–09 (82.2% vs. 83.2%, p=0.083). Factors associated with discordant practice among the DTC 07–09 group were older age, treatment in the Northeast, having more than one primary cancer, tumor size >4 cm, and follicular and Hürthle cell histologies. Factors associated with accordance were treatment in the Midwest, level II–VI metastases, having lymph nodes examined, AJCC Stage III, and presenting with distant metastases. Patients treated in accordance with Recommendation 26 showed prolonged disease-specific survival (p<0.001). A trend toward more adherence to Recommendation 27 (lymphadenectomy) was observed over time (68.4% vs. 69.7%, p=0.065). Adherence to Recommendation 27 was not associated with disease-specific survival (p=0.539). Less discordance from guidelines was seen for cancers that were 2.1–4 cm, extrathyroidal, and greater than Stage I. Overall accordance with Recommendation 32 (radioactive iodine [RAI] ablation) increased in DTC 07–09 compared to DTC 04–06 (61.7% vs. 57.5% respectively, p<0.001), and this was associated with improved disease-specific survival in DTC 07–09 (p<0.001). Predictors of care discordant with guidelines were patient age ≥65 years, living in the Northeast, and not undergoing total thyroidectomy. Factors associated with RAI use in accordance with guidelines were married status, treatment in the South, and having more than one lymph node examined.

Conclusions:

Care in accordance with evidence-based guidelines for DTC is associated with improved patient outcomes. Ongoing efforts should be undertaken to propagate guidelines to reduce variation in care and improve overall quality of care.

Introduction

Thyroid cancer is the most common endocrine malignancy and the cancer with the fastest increase in incidence in the United States (1 –3). Well-differentiated thyroid cancers (DTC) account for more than 90% of the total number of cases (1). Long-term prognosis for patients who undergo treatment for DTC is excellent, with a 20-year survival rate of >90% (4).

Several guidelines have been published by professional societies, such as the American Association of Endocrine Surgeons/American Association of Clinical Endocrinologists, the American Thyroid Association (ATA), European Thyroid Association, British Thyroid Association, and the National Comprehensive Cancer Network, in order to standardize management of thyroid cancer (5 –8). In 2006, the ATA first published guidelines with recommendations for the extent of surgery, indications for prophylactic central neck lymph-node dissection (pCLND), and use of postoperative radioactive iodine (RAI) ablation (Recommendations 26, 27, and 32 respectively) (9).

Famakinwa et al. studied practice patterns in the United States in existence at the time the initial ATA guidelines were issued for patients with thyroid nodules and DTC (10). Adherence to guidelines has been shown to vary widely across diseases and procedures (10 –20). Our aims were to determine the impact of the 2006 ATA guidelines for DTC on subsequent practice patterns in the United States, and to identify factors associated with accordance with regard to Recommendations 26 (surgical extent), 27 (lymphadenectomy), and 32 (RAI administration).

Materials and Methods

Data sources and study patients

Patients diagnosed with DTC between 2004 and 2009 were identified in the Surveillance, Epidemiology and End Results (SEER) database (21). The International Classification of Diseases for Oncology, Third Edition (ICD-O-3), was utilized as the reference for histology coding (papillary thyroid cancer [PTC], codes 8050, 8340–8344, and 8350; follicular thyroid cancer [FTC], codes 8330–8332, 8335, and 8337; Hürthle cell thyroid cancer [HCTC], code 8290) (22). The SEER database collects data from 18 different registries (San Francisco–Oakland, Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Utah [from 1973], Seattle–Puget Sound [from 1974], metropolitan Atlanta [from 1975], Alaska, San Jose–Monterey, Los Angeles, rural Georgia [from 1992], greater California [excluding San Francisco, Los Angeles, and San Jose]; Kentucky, Louisiana, New Jersey, and greater Georgia [excluding Atlanta and Rural Georgia; from 2000]), collectively representing approximately 28% of the U.S. population (21). Patients <18 years of age were excluded. Study patients were divided into two groups with regard to the release of the 2006 ATA management guidelines: patients diagnosed in the time period immediately prior to publication of the guidelines—2004–2006 (DTC 04–06)—and patients diagnosed in the time period immediately after publication of the guidelines—2007–2009 (DTC 07–09).

Demographic variables of interest included patient sex, age at diagnosis, race/ethnicity, Hispanic origin, marital status, and geography. Age at diagnosis was subdivided into three groups (18–44, 45–64, and ≥65 years) in accordance with the thyroid cancer staging system of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) (23). Race/ethnicity was classified into white, black, and other (American Indian, Alaska Native, Asian, Pacific Islander, and other unspecified); Hispanic origin was “yes” or “no.” Marital status was recoded into married (married and domestic partner) and single (single, divorced, widowed, or separated). Geographic location was categorized as Northeast, South, Midwest, and West.

Clinical information included number of primary tumors per patient, surgical treatment, RAI ablation, and overall and disease-specific survival status. Number of primary tumors per patient was 1, 2, and ≥3; surgical treatment was coded as none, partial thyroidectomy, and total thyroidectomy. RAI administration for patient survival analysis was studied as a binary variable; “no RAI” included none, and forms of radiation other than RAI (e.g., external beam radiation therapy, radiation—not otherwise specified); “yes RAI” included radioisotopes, radioactive implants, a combination of external beam radiation therapy (EBRT), and radioactive implants or radioisotopes. For analysis of compliance with Recommendation 32, “yes RAI” also included patients for whom radiotherapy was recommended but the patient or patient's guardian refused, or where it was unknown if RAI was administered.

Pathologic characteristics were tumor size, histology, extent of tumor, lymph-node metastases, number of lymph nodes examined, number of positive lymph nodes, distant metastases at diagnosis, and AJCC Stage. According to the AJCC staging system, tumor size was divided into ≤2 cm, 2.1–4.0 cm, and >4 cm; tumors >15 cm were excluded due to the possibility of errors in coding (23). Histology was grouped into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and Hürthle cell thyroid cancer (HCTC). Extent of tumor was categorized as intrathyroidal and extrathyroidal. Lymph-node metastases were divided into none, level VI, level II–V, level I, and level VII. Number of lymph nodes examined and number of positive lymph nodes were analyzed as none, 1, 2–4, and ≥5. Lymph-node density was defined as the number of positive lymph nodes divided by the number of lymph nodes examined. Distant metastasis at diagnosis was dichotomously treated as “no” (none present) or “yes” (known distant metastasis). AJCC Stage was I–IV (23).

ATA recommendations

Two levels of recommendation from the ATA guidelines were included in the analysis.

Level A: strongly recommends

The recommendation was based on well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes (9).

Level B: recommends

The evidence was sufficient to determine effects on health outcomes, but the strength was limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes.

Recommendation 26 states that total or near-total thyroidectomy should be the initial surgical procedure for most patients with thyroid cancer. Thyroid lobectomy alone may be considered for small (<1 cm), low-risk, isolated, intrathyroidal papillary tumors in the absence of cervical nodal metastases (level A).

According to Recommendation 27, routine central compartment (level VI) neck dissection should be considered for patients with PTC and suspected HCTC. Near-total or total thyroidectomy without central node dissection may be appropriate for FTC; when followed by RAI therapy, it may provide an alternative approach for PTC and HCTC (level B).

In Recommendation 32, radioactive iodine ablation is suggested for patients with Stages III and IV disease, all patients with Stage II disease aged <45 years, most patients with Stage II disease aged ≥45 years, and selected patients with Stage I disease, especially those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and/or more aggressive histologies (level B).

Statistical analyses

Simple summary statistics were utilized to describe demographic, clinical, and pathologic characteristics; chi-square and analysis of variance (ANOVA) were employed to compare categorical and continuous variables respectively. The Kaplan–Meier method was used for survival analysis, and the log-rank test to determine statistical significance. Binary logistic regression was employed to identify independent factors associated with the outcomes of interest and calculate odds ratios (OR) and confidence intervals.

Statistical Package for the Social Sciences (SPSS) software (v19.0; SPSS Inc., Chicago, IL) was utilized to perform data analyses; all tests were two-sided, and statistical significance was set at a p-value of <0.05. Since SEER data are publicly available and all patient information is de-identified, the current study was granted an exemption from our institutional review board.

Results

A total of 27,330 patients aged ≥18 years with a diagnosis of DTC were identified in the SEER database: 12,816 between 2004 and 2006 (DTC 04–06), and 14,514 between 2007 and 2009 (DTC 07–09).

Characteristics

Sex, race/ethnicity, Hispanic origin, and marital status were equally distributed between the two groups (Table 1). Mean age at diagnosis was 50.6 years for DTC 04–06, and 51.5 years for DTC 07–09 (p<0.001). No significant differences were observed in geographic location; the West accounted for almost half the cases for both DTC 04–06 and DTC 07–09.

Table 1.

Demographic, Clinical, and Pathologic Characteristics of Patients with Differentiated Thyroid Cancer Diagnosed Between 2004 and 2006 (DTC 04–06) and 2007 and 2009 (DTC 07–09), SEER 2004–2009 (DTC 04–06 n=12,816; DTC 07–09 n=14,514)

		DTC 04–06	DTC 07–09
	Patient characteristics	%	%	p-Value
Demographic	Sex			0.977^a
	Male	23.1	23.2
	Female	76.9	76.8
	Age at diagnosis, years (mean±SEM)	50.6±0.1	51.5±0.1	<0.001^b
	18–44	36.5	33.7	<0.001^a
	45–64	43.8	45.7
	≥65	19.7	20.5
	Race/Ethnicity	n=12,713	n=14,377	0.062^a
	White	83.5	82.9
	Black	8.0	7.8
	Other	8.5	9.3
	Hispanic origin			0.056^a
	No	88.0	87.2
	Yes	12.0	12.8
	Marital status	n=12,255	n=13,875	0.979^a
	Single	33.5	33.5
	Married	66.5	66.5
	Geography			0.118^a
	Northeast	23.7	23.2
	South	20.8	21.1
	Midwest	8.1	8.9
	West	47.3	46.9
Clinical	No. of primary tumors/patient			0.002^a
	1	85.3	86.2
	2	12.0	11.8
	≥3	2.7	2.0
	Surgery			0.002^a
	None	2.8	2.2
	Partial thyroidectomy	20.0	19.3
	Total thyroidectomy	77.3	78.5
	Radiation therapy			<0.001^a
	None	51.5	52.0
	Radioactive implants or radioisotopes	46.0	46.4
	Other forms of radiation	2.5	1.6
	Survival at 3 years
	Overall	95.0	96.0	<0.001^c
	Disease-specific	98.5	98.9	0.016^c
Pathologic	Tumor size, cm (mean±SEM)	21.4±0.2	20.3±0.2	<0.001^b
	≤2.0	60.7	63.6	<0.001^a
	2.1–4	26.2	24.3
	>4	13.1	12.1
	Histology			0.001^a
	PTC	80.0	81.4
	FTC	13.4	12.9
	HCTC	6.6	5.6
	Extent of tumor	n=12,545	n=14,280	0.017^a
	Intrathyroidal	86.9	87.9
	Extrathyroidal	13.1	12.1
	Lymph-node metastases			0.040^a
	None	90.4	89.5
	Level VI	5.7	6.5
	Level II–V	3.3	3.3
	Level I	0.6	0.6
	Level VII	0.0	0.1
	Number of lymph nodes examined	n=12,407	n=14,141	<0.001^a
	None	65.8	61.1
	1	13.0	13.1
	2–4	12.2	13.6
	≥5	9.1	12.2
	Number of positive lymph nodes	n=4433	n=5676	0.031^a
	None	69.0	71.3
	1	12.6	10.9
	2–4	10.1	9.3
	≥5	8.4	8.4
	Metastases at diagnosis	n=12,431	n=14,191	0.015^a
	None	97.5	98.0
	Yes	2.5	2.0
	AJCC stage			0.086^a
	I	70.6	70.8
	II	11.1	11.6
	III	11.9	11.9
	IV	6.4	5.7

Percentages have been rounded and so may not total 100.

Chi-square test; ^banalysis of variance (ANOVA); ^clog-rank test.

SEM, standard error of the mean; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; HCTC, Hurthle cell thyroid carcinoma; SEER, Surveillance, Epidemiology and End Results.

DTC 04–06 patients had a slightly lower overall and disease-specific survival at three years than those diagnosed in more recent years (95.0% vs. 96.0%, and 98.5% vs. 98.9%, p<0.001 and 0.016 respectively).

Compared to DTC 04–06 patients, fewer DTC 07–09 patients were diagnosed with FTC and HCTC (p<0.001). DTC 07–09 tumors were smaller than DTC 04–06 tumors, and they were more often intrathyroidal; fewer patients presented with distant metastases at the time of diagnosis in the later time period. When stratified by age, older patients had larger tumors; 16.8% of patients aged ≥65 years had thyroid cancers >4 cm compared with 12.1% and 10.1% of patients aged 18–44 and 45–64 years respectively (p<0.001).

Compared to DTC 04–06 patients, DTC 07–09 patients were more likely to have lymph nodes examined (34.2% vs. 39.9%, p<0.001). However, they had fewer lymph-node metastases (28.7% vs. 31.0%, p=0.031), and a lower lymph-node density (0.54 vs. 0.59, p<0.001). AJCC Stage did not differ between the two time periods; more than 70% of all patients in both time periods presented in Stage I.

ATA Recommendations 26, 27, and 32

Recommendation 26: surgical treatment

For Recommendation 26, 8599 DTC 04–06 and 9572 DTC 07–09 patients met the following inclusion criteria: FTC and HCTC histology, PTC tumors >1 cm, or presentation with extrathyroidal extension or regional/distant metastases (Table 2). Overall compliance with Recommendation 26 tended to increase slightly in the 07–09 time period (82.2% vs. 83.2%), but this failed to reach statistical significance. It appeared that fewer patients underwent no surgery in the later time period. Patients treated in accordance with Recommendation 26 showed a prolonged five-year disease-specific survival (97.8% vs. 95.5%, p<0.001).

Table 2.

Overall Adherence to ATA Guidelines Recommendations 26, 27, and 32

	DTC 04–06	07–09 DTC
Recommendations	%	%	p-Value
Recommendation 26: most patients with DTC should undergo a near total or total thyroidectomy, n=18,171	n=8599	n=9572
Near-total/total thyroidectomy	82.2	83.2	0.083
Less than near total/total thyroidectomy^a
Partial thyroidectomy	15.2	14.6	0.060
No surgery	2.6	2.1
Recommendation 27: central neck dissection (level VI) should be considered for patients with PTC or HCTC treated with near-total or total thyroidectomy; near-total or total thyroidectomy followed by RAI therapy may provide an alternative approach, n=16,496	n=7598	n=8898
Proper management of lymphadenectomy and RAI			0.065
Lymphadenectomy and RAI	22.0	23.6	<0.001
Lymphadenectomy and no RAI	16.2	18.5
No lymphadenectomy and RAI	30.1	27.6
No lymphadenectomy and no RAI^a	31.6	30.3
Recommendation 32: RAI is recommended for patients with stage II–IV disease, and selected stage I patients (extrathyroidal extension, nodal metastases, aggressive histologies), n=8990	n=4214	n=4776
RAI	57.5	61.7	<0.001
No RAI^a	42.5	38.3

Discordant with ATA guidelines.

RAI, radioactive iodine ablation.

Adherence to the guidelines among DTC 07–09 patients was higher in younger, white, and married individuals (Table 3). The Midwest region had the greatest adherence to the guidelines, while the Northeast had the lowest adherence. Patients with smaller tumors received treatment that was more adherent to guidelines; 85.5% of tumors ≤2 cm in size underwent total thyroidectomy compared to 83.5% and 81.3% of individuals with 2.1–4 cm and >4 cm cancers respectively (p<0.001). Greater adherence to guidelines was observed among patients with PTC than among patients with FTC and HCTC. Extrathyroidal lesions were more often managed in accordance with Recommendation 26 than intrathyroidal cancers (89.4% vs. 82.5%), as were DTC 07–09 patients who presented without metastases at diagnosis (83.9% vs. 75.3%). Surgery for patients with AJCC Stage III cancers was more likely to be in accordance with Recommendation 26 compared to patients with Stages I, II, and IV tumors (p=0.001).

Table 3.

Factors Associated with Care in Accordance with ATA Recommendations 26, 27, and 32 After 2006

	Recommendation 26 (n=9572)		Recommendation 27 (n=8898)		Recommendation 32 (n=4776)
Patient characteristics	%	p-Value	%	p-Value	%	p-Value
Sex		0.091		0.056		0.595
Male	82.1		71.6		59.3
Female	83.6		69.2		59.9
Age at diagnosis, years		<0.001		<0.001		<0.001
18–44	86.1		75.5		67.7
45–64	84.2		68.4		61.6
≥65	76.5		62.3		51.7
Race/ethnicity		0.001		<0.001		0.001
White	83.6		70.6		60.2
Black	78.6		58.4		53.3
Others	84.5		70.7		60.9
Hispanic origin		0.343		0.809		0.560
No	83.1		69.7		59.9
Yes	84.2		70.0		58.9
Marital status		<0.001		0.101		<0.001
Single	81.5		68.6		56.7
Married	84.4		70.4		61.8
Geography		<0.001		0.001		<0.001
Northeast	80.8		68.5		50.6
South	82.0		66.6		64.1
Midwest	86.3		70.2		62.5
West	84.4		71.6		61.6
No. of primary tumors/patient		<0.001		0.003		<0.001
1	84.0		70.2		60.7
2	78.2		67.4		55.4
≥3	78.4		58.9		53.1
Surgery		—		—		<0.001
None	—		—		6.5
Partial thyroidectomy	—		—		35.6
Total thyroidectomy	—		—		65.2
Tumor size, cm		<0.001		<0.001		0.002
≤2.0	85.5		66.2		62.9
2.1–4	83.5		80.0		61.1
>4	81.3		76.7		57.8
Histology		<0.001		0.154		<0.001
PTC	86.7		69.5		62.3
FTC	73.2		—		54.7
HCTC	76.9		72.4		52.0
Extent of tumor		<0.001		<0.001		0.003
Intrathyroidal	82.5		67.5		59.0
Extrathyroidal	89.4		86.8		62.2
Lymph-node metastases		<0.001		—		<0.001
None	82.1		—		58.4
Level VI	96.0		—		66.9
Level II–V	93.4		—		65.0
Level I	88.3		—		61.0
Level VII	100.0		—		85.7
Number of lymph nodes examined		<0.001		—		<0.001
None	78.4		—		55.1
1	86.0		—		61.8
2–4	89.9		—		68.3
≥5	94.6		—		66.1
Number of positive lymph nodes		<0.001		—		0.017
None	87.2		—		63.9
1	94.5		—		63.3
2–4	95.3		—		69.7
≥5	98.6		—		67.6
Metastases at diagnosis		0.001		0.052		<0.001
None	83.9		69.6		60.9
Yes	75.3		80.3		43.5
AJCC stage		0.001		<0.001		—
I	84.6		66.2		—
II	80.8		75.4		—
III	85.9		84.0		—
IV	83.6		81.0		—

In multivariate analysis, factors associated with practice that was discordant with ATA management guidelines included older patient age, treatment in the Northeast, having more than one primary cancer, tumor size >4 cm, and FTC and HCTC histologies (Table 4). Factors associated with greater adherence were receiving treatment in the Midwest region, known level II–VI metastases, having lymph nodes examined, AJCC Stage III, and having distant metastases at diagnosis.

Table 4.

Multivariate Analysis of Factors Associated with Care in Accordance with ATA Recommendations 26, 27, and 32 for Patients Diagnosed with Differentiated Thyroid Cancer After 2006

	Recommendation 26 (n=8590)			Recommendation 27 (n=8436)			Recommendation 32 (n=4260)
Patient characteristics	OR	[CI]	p-Value	OR	[CI]	p-Value	OR	[CI]	p-Value
Age 45–64 years	0.82	[0.67–1.00]	0.050	0.57	[0.50–0.65]	<0.001	—	—	—
Age ≥65 years	0.60	[0.48–0.75]	<0.001	0.39	[0.33–0.45]	<0.001	0.68	[0.55–0.84]	<0.001
Marital status	—	—	—	—	—	—	1.24	[1.08–1.42]	0.003
Black	—	—	—	0.57	[0.48–0.68]	<0.001	—	—	—
Northeast	0.79	[0.68–0.92]	0.002	—	—	—	0.62	[0.53–0.74]	<0.001
Midwest	1.33	[1.05–1.68]	0.019	—	—	—	—	—	—
South	—	—	—	—	—	—	1.23	[1.03–1.47]	0.022
2 primary tumors/patient	0.80	[0.67–0.96]	0.015	—	—	—	—	—	—
No surgery	—	—	—	—	—	—	0.06	[0.02–0.14]	<0.001
Partial thyroidectomy	—	—	—	—	—	—	0.31	[0.26–0.37]	<0.001
Size 2.1–4 cm	—	—	—	1.64	[1.35–2.00]	<0.001	—	—	—
Size >4 cm	0.71	[0.57–0.90]	0.004	—	—	—	—	—	—
FTC	0.60	[0.51–0.69]	<0.001	—	—	—	—	—	—
HCTC	0.78	[0.63–0.96]	0.021	—	—	—	—	—	—
Extrathyroidal	—	—	—	1.89	[1.49–2.40]	<0.001	—	—	—
Level VI metastases	2.13	[1.40–3.26]	<0.001	—	—	—	—	—	—
Level II–V metastases	1.91	[1.08–3.38]	0.026	—	—	—	—	—	—
1 LN examined	1.35	[1.12–1.63]	0.002	—	—	—	—	—	—
2–4 LN examined	1.78	[1.45–2.19]	<0.001	—	—	—	1.44	[1.19–1.75]	<0.001
≥5 LN examined	2.50	[1.88–3.32]	<0.001	—	—	—	1.33	[1.11–1.60]	0.002
AJCC stage II	—	—	—	1.39	[1.07–1.79]	0.013	—	—	—
AJCC stage III	1.59	[1.20–2.12]	<0.001	2.79	[2.20–3.53]	<0.001	—	—	—
AJCC stage IV	—	—	—	1.78	[1.15–2.75]	0.009	—	—	—
Distant metastases	2.28	[1.18–4.41]	0.014	—	—	—	—	—	—

Reference groups: age, 18–44; marital status, married; race, white; geography, west; primary tumors/patient, 1; surgery, total thyroidectomy; tumor size, ≤2 cm; histology, PTC; LN metastases, none; LN examined, none; AJCC stage, I; distant metastases, none.

OR, odds ratio (OR<1 indicates more divergence); CI, confidence interval.

Recommendation 27: lymphadenectomy

Overall, 16,496 patients were included in this analysis: 7598 were diagnosed between 2004 and 2006, and 8898 between 2007 and 2009 (Table 2). Criteria for inclusion were PTC or HCTC histology, and undergoing near-total or total thyroidectomy. A trend toward more accordance with Recommendation 27 was observed over time; 68.4 % of DTC 04–06 patients received recommended care compared with 69.7% of DTC 07–09 patients (p=0.065). Compared to DTC 04–06 patients, fewer DTC 07–09 patients were treated with RAI following total/near-total thyroidectomy without central lymphadenectomy, and more patients underwent thyroidectomy with central lymphadenectomy with and without RAI ablation. Adherence to Recommendation 27 had no impact on disease-specific survival (p=0.539).

In univariate analysis of the DTC 07–09 group, treatment in accordance with guidelines was more likely among younger and white patients (Table 3). Treatment in the West was more often in accordance with ATA guidelines, while utilization of central lymphadenectomy was lowest in the South. Patients who had only one primary tumor, larger tumors, and extrathyroidal extension had care that was more often in accordance with Recommendation 27.

Multivariate analysis showed that increasing patient age and black race were associated with treatment that was discordant with the ATA Recommendation regarding lymphadenectomy (Table 4). Accordance was greatest for patients with tumors that were 2.1–4 cm, extrathyroidal, or greater than Stage I.

Recommendation 32: RAI ablation

AJCC Stage II–IV patients and those with aggressive Stage I tumors (extrathyroidal extension, nodal metastases, and aggressive histologies) were included in this subanalysis. A total of 8990 individuals were identified: 4214 DTC 04–06 patients and 4776 DTC 07–09 patients (Table 2). Overall adherence to the guideline was 57.5% in the former group and 61.7% in the latter group (p<0.001).

We analyzed the trend of RAI use over time since 1988. We found that every three years, RAI use increased by an average of 1.5%. Over the period 04–06 and 07–09, there was only a 0.5% increase for all patients with PTC. However, for patients included in Recommendation 32, the increase in RAI in the same time period was 4.2% (p<0.001). Patients who underwent RAI ablation in accordance with the ATA recommendations appeared to have a better five-year disease-specific survival in the univariate analyses as compared to those who did not (97.2% vs. 91.3%, p<0.001). However, this did not remain significant in multivariate analysis.

Adherence to guidelines after 2006 was lower among elderly patients and higher among patients who were white or married. The Northeast provided treatment that was more often discordant from Recommendation 32, while the South had the highest rate of accordance. Presenting with distant metastases was associated with decreased adherence to Recommendation 32, whereas regional lymph-node involvement implied higher agreement with care described in the recommendation.

In multivariate analysis, predictors of discordant care were patient age ≥65 years, living in the Northeast, and not undergoing near-total or total thyroidectomy, and predictors of care in line with the RAI recommendation were married status, living in the South, and having more than one lymph node examined (Table 4).

A separate analysis of RAI use in low-risk Stage I patients was performed. The ATA guidelines do not recommend RAI for these patients, but there was no decrease in use of RAI after 2006 (42.6% vs. 41.2% received RAI, p=0.062).

Discussion

To our knowledge, the current study is the first to analyze practice patterns and potential changes in clinical practice associated with the publication of the 2006 ATA guidelines for the management of patients with thyroid nodules and DTC. Overall, accordance with recommended care between 2007 and 2009 increased slightly compared to the practice patterns prior to ATA guidelines publication. Overall, lower adherence was observed among elderly patients, those undergoing treatment in the Northeast, and patients with Stage I cancers. Discordance with guidelines was associated with slightly decreased disease-specific survival. This was observed in the analyses regarding each recommendation individually, and in the modest overall and disease-specific survival improvement observed after the ATA 2006 guidelines' release. However, the DTC 07–09 patient group included patients with cancers with better prognostic factors, such as smaller tumors, lower incidence of FTC and HCTC, and less extrathyroidal extension, which may have an impact on survival.

Haymart et al. surveyed 944 physicians involved in thyroid cancer care from 251 hospitals affiliated with the U.S. National Cancer Database (17). Their findings revealed variation in several aspects of thyroid cancer management, including the role of central lymph-node dissection, particularly for small thyroid cancers, the optimal extent of surgery, and the role of radioactive iodine treatment. In line with the results of our study, this article demonstrated that standardized management of thyroid cancer still needs to be pursued. Variation in thyroid cancer care has been observed in other countries too (18). In 2006, Walsh et al. published the results of a questionnaire containing a hypothetical case (similar to the one above) sent to both endocrinologists and endocrine surgeons in Australia. Again, significant differences were noted between the two groups of professionals in the management of a solitary thyroid nodule (19).

Using data from SEER, Famakinwa et al. analyzed 26,157 DTCs between 1988 and 2005 and found that patients with small tumors who were young and white appeared to receive care that was more often in accordance with the 2006 ATA guidelines (10). In a SEER study of 2033 patients with medullary thyroid carcinoma, Panigrahi et al. identified elderly patients as a vulnerable population that more often received care out of line with ATA guidelines (20). Our study demonstrates that three years after the release of the ATA guidelines for thyroid nodules and DTC, certain vulnerable populations still appear to exist who undergo thyroid cancer care that is discordant with guidelines, and this appears to be associated with compromised survival.

The Level VI (central compartment) encompasses prelaryngeal, paratracheal, perithyroidal, and inferior laryngeal lymph nodes (24). In the 2006 ATA guidelines, routine central neck compartment lymph-node dissection (CLND) was “considered” for PTC and HCTC, with evidence supporting this rated as level B. The revised ATA guidelines published in 2009 divided Recommendation 27 into three subgroups, differentiating between therapeutic and prophylactic CLND and assessing different levels of the recommendation: B and C (based on expert opinion) respectively (25). Lang et al. recently published a systematic review and meta-analysis of prophylactic CLND among 3331 patients with PTC (26). The authors suggested that patients who undergo total thyroidectomy and prophylactic CLND may have a 35% reduction in risk of locoregional recurrence in the short term (<5 years) compared to those who undergo total thyroidectomy alone. However, it was unclear how much of the risk reduction observed was related to increased use of RAI ablation and potential selection bias in some of the studies examined. Other investigators have explored the role of prophylactic CLND with contrasting results. Barczyński et al. analyzed 640 patients treated with/without CLND between 1993 and 2002, finding an improvement in 10-year disease-specific survival and loco-regional control (27). Gyorki et al. reviewed the value of prophylactic CLND and found no convincing evidence that prophylactic CLND improves rates of recurrence or overall survival when applied broadly to all patients with DTC (28). They concluded that resection of clinically negative lymph nodes may not be beneficial for low-risk DTC. Our results showed that lymph-node density decreased after 2006: more lymph nodes are being examined surgically, and fewer were found to be metastatic on final pathology. This may suggest that more patients are undergoing prophylactic lymphadenectomy. However, this did not confer any survival benefit. This finding could be due to the fact that DTC has excellent five-year disease-specific survival, and longer follow-up would be necessary to identify a potential difference.

There are several limitations to our study, including those inherent to using any large clinical database, such as errors in coding and sampling. However, SEER registries have extensive data quality profiles, which help ensure overall accuracy. Moreover, the SEER database has been well validated by numerous studies (29,30). There are no data in SEER regarding patient comorbidities, intent of surgery, rates of recurrence, and pertinent serologic and molecular laboratory tests. Given the lack of a widely accepted definition of “lymphadenectomy,” the SEER coding for this variable may be inconsistent. With regard to CLND, Recommendation 27 says that such procedure “should be considered.” The authors were not able to determine whether the patient and the surgeon “considered” doing a neck dissection and then decided not to do it. Therefore, it was assumed that not receiving it was equal to not considering it.

In conclusion, this is the first study to show that evidence-based guidelines for DTC are associated in a positive way with improved disease-specific survival. A trend toward increasing compliance with ATA guidelines was observed in the clinical management of patients with thyroid cancer over the study period. Ongoing efforts should be undertaken to propagate evidenced-based guidelines, particularly for certain geographic areas and vulnerable populations, in order to reduce variation in care and thereby hopefully improve overall quality of care.

Footnotes

Author Disclosure Statement

The authors have nothing to declare.

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