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Department of Surgery (K.C., S.A.R., J.A.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Queen’s University School of Medicine (K.C.), Kingston, Ontario, Canada K7L 3N6; Department of Surgery (T.S.W.), Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and Departments of Community Health and Epidemiology and Oncology (H.D.W.), Queen’s University, Kingston, Ontario, Canada K7L 5P9
Address all correspondence and requests for reprints to: Julie Ann Sosa, M.A., M.D., F.A.C.S., Assistant Professor of Surgery and Clinical Epidemiology, Department of Surgery, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208062, New Haven, Connecticut 06520. E-mail: julie.sosa{at}yale.edu.
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Abstract |
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Objective: Our objective was to determine the cost-effectiveness (C/E) of routine calcitonin screening in adult patients with thyroid nodules in the United States.
Settings/Subjects: A decision model was developed for a hypothetical group of adult patients presenting for evaluation of thyroid nodules in the United States. Patients were screened using current American Thyroid Association guidelines only, or American Thyroid Association guidelines with routine serum calcitonin screening. Input data were obtained from the literature, the Surveillance Epidemiology and End Results and Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample databases, and the Medicare Reimbursement Schedule. Sensitivity analyses were performed for a number of input variables.
Main Outcome Measures: C/E, measured in dollars per life years saved (LYS), was calculated.
Results: Addition of calcitonin screening to current American Thyroid Association guidelines for the evaluation of thyroid nodules would cost $11,793 per LYS ($10,941–$12,646). When extrapolated to the national level, calcitonin screening for MTC in the United States would yield an additional 113,000 life years at a cost increase of 5.3%. Calcitonin screening C/E is sensitive to patient age and gender, and to changes in disease prevalence, specificity of fine needle aspiration and calcitonin testing, calcitonin screening level, costs of testing, and length of follow-up.
Conclusion: Routine serum calcitonin screening in patients undergoing evaluation for thyroid nodules appears to be cost effective in the United States, with C/E comparable to the measurement of thyroid stimulating hormone, colonoscopy, and mammography screening.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The majority of patients with sporadic MTC present with a palpable thyroid nodule. Cervical lymph node metastases are common at initial presentation; 10–22% of patients will demonstrate distant metastases (1, 2, 3, 4). Surgical intervention is the mainstay of treatment. The optimal surgical management for patients with clinical evidence of MTC is total thyroidectomy, central lymph node dissection, with possible ipsilateral, or even bilateral, modified radical neck lymphadenectomy. Recent studies have shown that overall survival is associated with patient age, stage of disease, and extent of surgery (1, 2). The prognosis for patients with MTC is worse than that for patients with differentiated thyroid cancer due to early metastasis and the lack of effective systemic therapy.
Multiple European studies have shown that the routine measurement of serum calcitonin in patients with thyroid nodules is effective in the detection of clinically occult MTC (5, 6, 7, 8, 9, 10, 11); Elisei et al. (12) demonstrated that this was associated with an improvement in patient outcome. In 2006, the European Thyroid Association and Cancer Research Network followed the lead of individual European countries and developed a European consensus report on the management of differentiated thyroid carcinoma, including the use of calcitonin screening in patients with thyroid nodules. These guidelines recommended the use of calcitonin measurement in the initial diagnostic evaluation of thyroid nodules (13). In the United States, the American Thyroid Association management guidelines for patients with thyroid nodules could not "recommend either for or against the routine measurement of serum calcitonin" due to unresolved issues of sensitivity, specificity, assay performance, cost-effectiveness (C/E), and lack of pentagastrin availability in the United States (14). We present a formal C/E analysis of the addition of routine serum calcitonin screening to current American Thyroid Association guidelines in the United States.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients with positive calcitonin testing were evaluated for inherited forms of MTC and staged for disease. The Surveillance Epidemiology and End Results system was used for staging: 1) localized (tumor confined entirely to the thyroid gland), 2) regional (extension of tumor beyond the thyroid into directly surrounding tissue or lymph nodes), and 3) distant (metastases to extracervical lymph nodes or organs) (15). Patients with MTC underwent appropriate surgical treatment based on stage of disease at presentation; patients with distant metastases underwent no medical treatment. Patients with false-positive tests were treated like those with local disease; they incurred the same risk of surgical complications and required lifelong thyroid hormone replacement, although annual surveillance for recurrence was unnecessary. Patients with negative tests underwent annual surveillance as recommended by the current American Thyroid Association guidelines. Those assigned to the calcitonin-screening branch received annual serum calcitonin measurements in the base-case analysis. Patients with false-negative tests were appropriately diagnosed and treated at the first follow-up. A proportion of these patients experienced progression of disease to a more advanced stage of MTC and, thereby, reduced life expectancy.
Estimates of the prevalence of thyroid nodules and of MTC were based on a comprehensive literature review. Values used in the base-case and sensitivity analyses are presented in Table 1 (5, 7, 8, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29). The sensitivity and specificity of fine needle aspiration used were 90% and 87%, respectively (27, 28). The sensitivity and specificity of calcitonin screening were 75 and 98%, respectively (5, 7, 8, 10, 11, 12, 16, 17, 18, 19). The probability of a patient presenting at a particular stage of disease was dependent on the screening technique used. For those patients who underwent evaluation of their thyroid nodules based on American Thyroid Association guidelines, 48% of patients presented with local disease, 35% with regional disease, and 17% with distant metastases (1, 2, 12). When screening for MTC was a routine part of the evaluation of thyroid nodules, 69% of patients presented with local disease, 30% with regional disease, and 2% with distant metastases (12).
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Mean natural life expectancy was obtained from the 2000 U.S. census data (30). The probability of survival at 10 yrs for patients with local, regional, and distant MTC is 95.6%, 75.5%, and 40%, respectively (2). Mean life expectancies were calculated using the mean age at presentation and Kaplan-Meier survival curve data for each stage of disease (2, 31, 32, 33). A survival curve for each disease stage was calculated by superimposing the Kaplan-Meier survival data on the natural life expectancy, such that they intersect at the mean age of presentation. Survival data were extrapolated using a Gompertz function, a technique used to fit survival data and describe changes in mortality over time (34). Mean life expectancy for each disease stage is the integral of the resultant curve (Fig. 2).
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Univariate sensitivity analyses were performed to assess the effect of changing the values assigned to the prevalence of MTC, fine needle aspiration sensitivity and specificity, calcitonin sensitivity and specificity, cost of the calcitonin assay, screening interval (6–24 months), number of years of surveillance, 10-yr overall survival rate, and discount rate of future costs (Table 1
). Varying calcitonin test sensitivity and specificity estimated the effect of using different thresholds for a positive basal calcitonin level. C/E also was evaluated for sensitivity to patient age, gender, and nodule size.
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Results |
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Sensitivity analyses demonstrated that the C/E of calcitonin screening was highly dependent on MTC prevalence, specificity of fine needle aspiration and serum calcitonin testing, cost of calcitonin measurements, length of screening interval, and duration of follow-up (Fig. 3). The addition of serum calcitonin screening resulted in improved C/E with higher a prevalence of MTC in this population. For example, when MTC prevalence was increased to 1.28% from the base-case value of 0.78%, C/E decreased to $7,369 per LYS. Conversely, a decrease in MTC prevalence to 0.28% resulted in a C/E of $32,018 per LYS.
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). Each percent increase in fine needle aspiration specificity from the base case of 87% yielded a 15% ($1,780 per LYS) reduction in C/E of calcitonin screening, whereas each percent increase in calcitonin specificity (base case, 98%) resulted in a 11% ($1,288 per LYS) improvement. Using fine needle aspiration specificities of 82 and 88% resulted in a C/E of $3,088 and $14,201 per LYS, respectively. Calcitonin specificities of 96 and 100% resulted in a C/E of $14,841 and $8,746 per LYS, respectively.
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The C/E of calcitonin screening was sensitive to patient age, gender, and nodule size (Fig. 5). It was more cost effective to screen men than women. Screening only men would result in a C/E of $5,759 per LYS (women, $14,878 per LYS). Younger patients were more cost effective to screen than older patients; patients aged 18–40, 41–65, and older than 65 yrs had a C/E of $3,055, $8,224, and $11,081 per LYS, respectively. Calcitonin screening of large nodules was more cost effective than screening smaller nodules. Calcitonin testing of patients with nodules sizes less than 1 cm, and 1–1.9 cm, 2–2.9 cm, 3–3.9 cm, and more than or equal to 4 cm resulted in a C/E of $34,263, $14,575, $4,220, $950, and $829 per LYS, respectively.
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). From the base case of 12-month intervals, C/E improved to –$12,353 per LYS with 24-month screening intervals. When patients were followed longer, the C/E of calcitonin screening decreased as a result. In our model, follow-up was allowed to range from 1–20 yrs (base case, 10 yrs). Patients who underwent 1-yr follow-up had a C/E of –$30,453 per LYS, whereas those who underwent 20-yr surveillance had a decreased C/E to $47,266 per LYS. Sensitivity analyses demonstrated that certain variables had little effect on our model. These included fine needle aspiration and calcitonin measurement sensitivity, overall MTC survival, the discount rate, and cost of treatment for patients with distant stage MTC.
Calcitonin screening with a basal calcitonin threshold of 20 pg/ml (sensitivity 80%, specificity 96%) had a C/E of $14,684 per LYS ($13,999–$15,369) (5, 7, 8, 10, 11, 12, 16, 17, 18, 19). Similarly, a screening program that used pentagastrin stimulation (patients underwent pentagastrin stimulation if basal calcitonin levels were 20–100 pg/ml; sensitivity 80%, specificity 98%) had a C/E of $12,784 per LYS ($11,883–$13,686).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our study demonstrates that the addition of calcitonin screening to current American Thyroid Association guidelines for the evaluation of thyroid nodules would cost $11,793 per LYS ($10,941–$12,646); when extrapolated to the national level, calcitonin screening for MTC would yield an additional 113,000 life years at a cost increase of 5.3%. The C/E of screening programs for breast and colon cancer range from $3,400–$28,700 to $10,000–$25,000 per LYS, respectively (33, 35, 36). Screening for mild hypothyroidism using serum thyroid stimulating hormone measurement has a C/E of $9,223–$20,000 per LYS (24). Calcitonin screening in our model is sensitive to patient age, gender, and changes in disease prevalence, specificity of fine needle aspiration and calcitonin screening, serum calcitonin screening level, test costs, and length of follow-up.
Serum calcitonin is a specific and sensitive marker for MTC (3). The use of serum calcitonin testing for MTC was evaluated by Pacini et al. (5) in 1,385 consecutive patients who presented with thyroid nodules. All patients were evaluated using serum calcitonin measurements and fine needle aspiration cytology. Eight patients had elevated basal serum calcitonin levels; all had MTC on final surgical pathology. Fine needle aspiration was suggestive of MTC in only two patients. The authors concluded that serum calcitonin measurement was superior to fine needle aspiration for diagnosing MTC, and recommended serum calcitonin measurement routinely for evaluating thyroid nodules (5).
This has been corroborated by other European studies (5, 6, 7, 8, 9, 10, 11, 12). Rieu et al. (6) studied 657 patients with and without thyroid nodules. A total of 40 control subjects and all patients without nodules had normal calcitonin levels. Only one of four patients with nodules and elevated calcitonin levels had a fine needle aspiration suggestive of MTC; all four patients had MTC on final pathology. A normal serum calcitonin level precluded the diagnosis of MTC (6).
Vierhapper et al. (8) prospectively studied 1062 patients with thyroid nodules. Basal calcitonin levels were elevated in 55 patients; a pentagastrin stimulation test was performed for levels more than 6 pg/ml. Surgery was recommended for 14 patients with basal and/or stimulated calcitonin levels more than 100 pg/ml. One patient refused surgery, and another, with a basal calcitonin less than 10 pg/ml and marginally elevated stimulated calcitonin level, was histologically negative for MTC. Of the remaining 12 patients, six had C-cell hyperplasia, and six had MTC, including one patient with a transition of C-cell hyperplasia to MTC. The authors concluded that stimulation tests should be performed for a basal calcitonin more than 10 pg/ml, and recommended surgery for patients with basal and/or stimulated calcitonin concentrations of more than 100 pg/ml (8). In a study of 14,000 patients, Vierhapper et al. (10) studied 507 patients who had thyroid nodules and elevated basal calcitonin levels of more than 10 pg/ml. After pentagastrin stimulation, calcitonin levels more than 100 pg/ml were found in 103 patients, including 32 patients with MTC and 43 patients with C-cell hyperplasia. With calcitonin screening, the incidence of MTC increased from 1.1–3.2 cases per 1,000 patients (10).
Elisei et al. (12) compared a group of 10,864 patients with thyroid nodules who underwent calcitonin screening to a historical group of 45 patients with MTC diagnosed before the introduction of calcitonin screening. In the screening group, 47 patients had elevated basal calcitonin levels; one patient refused surgery, and two patients were excluded because the elevated calcitonin level was attributed to chronic renal disease. The remaining 44 patients underwent pentagastrin stimulation and total thyroidectomy with central neck dissection; all had MTC. When compared with the historical group, the group with MTC detected on screening had an earlier stage of disease at diagnosis (P = 0.004), increased frequency of normalization of calcitonin postoperatively (66 vs. 3%, respectively; P < 0.0001), a higher rate of complete remission at last follow-up (59 vs. 3%, respectively; P = 0.0001), and a higher 10-yr survival rate (87 vs. 44%, respectively; P = 0.0005) (12).
In a study of 5817 patients with thyroid nodules, Costante et al. (11) identified 15 cases of MTC and seven cases of C-cell hyperplasia; all MTC was diagnosed in patients with basal calcitonin levels more than 100 pg/ml. The positive predictive value for an elevated preoperative calcitonin level was: 23.1% (
20 pg/ml), 100% (>100 pg/ml), 25% (50–100 pg/ml), and 8.3% (20–50 pg/ml). The overall predictive value for pentagastrin stimulation was 40%. The study confirmed that calcitonin screening was a sensitive tool for detecting MTC in patients with thyroid nodules but emphasized the need for confirmatory stimulation testing in most cases (11).
Based on these data, German evidence-based consensus recommendations were published in 2004, including: 1) serum calcitonin measurement in all patients with thyroid nodules using a two-site immunoassay; 2) pentagastrin stimulation for basal calcitonin more than 10 pg/ml; and 3) thyroidectomy and lymphadenectomy for stimulated calcitonin levels more than 100 pg/ml in patients with a more than 50% risk of MTC, and for all patients with stimulated calcitonin levels more than 200 pg/ml (16). In 2006, the European Thyroid Association and Cancer Research Network published consensus guidelines for the management of patients with differentiated thyroid cancer based on evidence showing that the use of serum calcitonin measurement: 1) allows for detection of MTC in one in 200–300 thyroid nodules; 2) is associated with improved sensitivity compared with fine needle aspiration; and 3) leads to improved patient outcomes, serum calcitonin measurement was recommended as a routine part of the diagnostic evaluation of thyroid nodules (13).
There is disagreement about what calcitonin level should be used to define a positive test for MTC. Pentagastrin for calcitonin stimulation is not readily available in the United States, and the use of calcium infusion as an alternative has not been adequately investigated (11). As a result, U.S. physicians have been reluctant to incorporate routine calcitonin screening in their practices (37). A basal calcitonin level more than or equal to 50 pg/ml was used in this analysis; a lower threshold may detect more subclinical microscopical MTC at the cost of a higher false-positive rate. For patients with calcitonin levels between 20 and 50 pg/ml, follow-up with serial basal calcitonin measurement could be used. The natural history of subclinical microscopical MTC is unknown. Although it can be indolent, MTC is a poorly differentiated cancer with a proclivity for metastasis. Therefore, early detection to facilitate early surgery is essential.
Calcitonin screening is also imperfect in the setting of Hashimoto’s thyroiditis. In a study of 414 patients, Karanikas et al. (9) found that elevated basal calcitonin levels were more frequent among patients with Hashimoto’s thyroiditis (25 vs. 13.3%; P < 0.05).
Borget et al. (38) constructed a cost per life year-saved analysis for a calcitonin-screening program. In a population of 74,000 patients with incidental thyroid nodules, the authors estimated that C-cell hyperplasia and/or MTC would be detected in 280 of the 3,587 thyroidectomies performed. Routine screening, based on a unit cost of 
24 ($36 USDs), would cost 1.8 million ($2.7 million USD); total cost of screening, including cost of thyroidectomy and estimated sick leave, was 21.3 million ($32.3 million USD). The base-case incremental C/E was estimated to be 35,000 ($53,000 USDs); in sensitivity analyses, the most cost-effective strategy was to perform surgery in patients with a calcitonin level more than 50 pg/ml (C/E: 6,000; $9,000 USD). Routine screening would yield an additional 2.2 life years per patient who screened positive. The authors concluded that routine calcitonin screening is highly favorable when compared with several other accepted health interventions (38). Our findings are in line with those of Borget et al. (38): routine serum calcitonin screening in patients undergoing evaluation for thyroid nodules appears to be cost effective.
Thyroid nodules more than or equal to 4 cm have lower fine needle aspiration accuracy, implying a potential increase in sampling error. McCoy et al. (39) studied 223 patients with thyroid nodules more than or equal to 4 cm; preoperative fine needle aspiration failed to identify 24 (34%) follicular lesions, including eight cancers. Sensitivity and specificity of ultrasound and fine needle aspiration vary because both modalities can be operator dependent (40, 41). Our sensitivity analyses demonstrate that calcitonin screening is particularly cost effective when fine needle aspiration specificity is low and when thyroid nodules are large. Therefore, the C/E of calcitonin screening for patients with large nodules is likely to be underestimated in our analyses because we do not account for a corresponding decrease in the accuracy of fine needle aspiration.
Limitations of our study include those inherent to any cost-effective analysis. The analysis involves a hypothetical group of patients and circumstances; the accuracy of our estimates is dependent on the quality of the data available in the literature. We sought to account for this by performing sensitivity analyses at vulnerable points in our model and found that our overall conclusions regarding the C/E of calcitonin screening among patients with thyroid nodules were robust. Health outcomes were measured in life years saved without consideration given to quality of life based on patient utilities.
In the current American Thyroid Association management guidelines, the lack of C/E analysis was cited as one reason for the Taskforce’s inability to recommend for or against routine calcitonin screening for patients with thyroid nodules (14). Our sensitivity analyses demonstrate that routine calcitonin screening would be cost effective for the population as a whole.
This is the first effort to measure the C/E of calcitonin screening in the United States. With the proliferation of practice guidelines intended to standardize quality and cost of care, evidence such as this is essential. We chose to use this methodology because performing a prospective trial would be prohibitively difficult, even at the multi-institutional level, given the relative rarity of MTC, its indolent course, and the idiosyncrasies of the U.S. health care system. We conclude that routine calcitonin screening in the evaluation of patients with thyroid nodules in the United States could be performed with C/E comparable to other widely accepted screening programs. Calcitonin screening appears to be more cost effective in young men with larger thyroid nodules. Therefore, consideration could be given to focusing screening among subgroups of patients.
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Footnotes |
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First Published Online March 25, 2008
Abbreviations: C/E, Cost-effectiveness; LYS, life years saved; MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer; USD, U.S. dollars.
Received November 9, 2007.
Accepted March 14, 2008.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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