Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-014-2760-4

SHORT COMMUNICATION

Thyroid nodules with indeterminate cytology: molecular imaging with 99mTc-methoxyisobutylisonitrile (MIBI) is more cost-effective than the Afirma® gene expression classifier Alexander Heinzel & Dirk Müller & Florian F. Behrendt & Luca Giovanella & Felix M. Mottaghy & Frederik A. Verburg

Received: 20 December 2013 / Accepted: 13 March 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose To compare the cost-effectiveness of 99m Tcmethoxyisobutylisonitrile (MIBI) thyroid scintigraphy and the Afirma® gene expression classifier for the assessment of cytologically indeterminate thyroid nodules. Methods A decision tree model was used. Costs were calculated from the perspective of the German health insurance system. The robustness of the results was assessed with probabilistic sensitivity analyses using a Monte Carlo simulation. Results Life expectancy was 34.3 years (estimated costs per patient €1,459 – €2,224) for the MIBI scan and 34.1 years (estimated costs €3,560 – €4,071) for the molecular test. These results were confirmed by the Monte Carlo simulation. Conclusion MIBI thyroid scintigraphy is more cost-effective than the gene expression classifier.

A. Heinzel (*) : F. F. Behrendt : F. M. Mottaghy : F. A. Verburg Department of Nuclear Medicine, RWTH Aachen University Hospital, 52074 Aachen, Pauwelsstrasse 30, Germany e-mail: [email protected] A. Heinzel Institute for Neuroscience and Medicine (INM-4), Research Centre, Jülich, Germany D. Müller Institute for Health Economics and Clinical Epidemiology, University of Cologne, Cologne, Germany L. Giovanella Department of Nuclear Medicine Oncology, Institute of Southern Switzerland, Belinzona, Switzerland F. M. Mottaghy : F. A. Verburg Department of Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

Keywords 99mTc-Methoxyisobutylisonitrile (MIBI) . Thyroid nodule . Afirma® gene expression classifier . Cost-effectiveness

Introduction Whereas thyroid scintigraphy with 99mTc-pertechnetate can be used to distinguish between hot, intermediate and cold nodules, the further differentiation of cold nodules into benign and malignant lesions is more challenging. To obtain a valid diagnosis, fine needle aspiration (FNA) biopsy is the reference standard. However, in 20 – 30 % of patients FNA will not yield a clinically useful result. Histological analysis of such indeterminate nodules is recommended. As histological analysis of a thyroid nodule involves surgery, patients and physicians alike are often hesitant as to how to proceed. In this situation, nuclear medicine can support the decision by means of 99mTc-methoxyisobutylisonitrile (MIBI) thyroid scintigraphy which has an excellent negative predictive value (NPV) for the presence of malignancy [1, 2]. This method has recently been shown to be cost-effective [2]. A molecular technique involving the analysis of gene expression levels (Afirma®) in cells from FNA has recently been introduced [3], which is also characterized by a high NPV in lesions with indeterminate cytology. This method has specific collection and storage requirements which necessitate a sample for cytopathology and one for the Afirma® analysis collected at the same time. Thus, for one nodule two FNA passes are required (http://afirma.com/for-physicians/library/ resources). This method has also been shown to be costeffective [3]. As the performance data in terms of sensitivity, specificity, NPV and positive predictive value (PPV) reported for Afirma® only marginally differ from those reported in several

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meta-analyses of thyroid MIBI scintigraphy [1, 2], the goal of the present study was to directly compare the costeffectiveness of these two methods.

Materials and methods A decision tree (Fig. 1 and Table 1) was constructed using TreeAge Pro 2009 (TreeAge Inc., Williamstown, MA). The cost analyses were performed from the perspective of the German health insurance (HI) system.

likelihood of a positive or a negative scan. If the scan is negative, no further intervention is performed. N2 shows the likelihood of a true-negative or false-negative test resulting in different life expectancies. If the MIBI scan is positive the scan can be true-positive or false-positive (N3). In both cases thyroidectomy is performed including the possibility of perioperative death (N3a and b). The lower branch is structured equally and represents the decision to perform a molecular test for further diagnosis.

Calculation of the costs Decision tree model Outcome was defined as the life expectancy in years. The starting point of the decision tree model was FNA of a scintigraphically cold nodule with indeterminate cytological findings defined as atypia of undetermined significance, follicular neoplasm/suspicious for follicular neoplasm, or suspicious for malignancy [4]. Based on the literature we assumed a cancer prevalence of 30 % (20 – 35 %) [5]. Applying this, we calculated the PPVand NPV based on the values for sensitivity (0.96, 0.91 – 0.98) and specificity (0.46, 0.42 – 0.51) from a metaanalysis by Wale et al. [2]. Similarly, values for PPV and NPV for the molecular test were based on the values for sensitivity (0.91, 0.7 – 0.95) and specificity (0.75, 0.64 – 0.91) from an analysis by Chudova et al. [6]. We also computed the likelihood of a positive MIBI scan and positive molecular test, as well as the range for each measure, based on these values (Table 1). In Fig. 1, the upper branch represents the decision to perform a MIBI scan for further diagnosis. N1 contains the Fig. 1 The decision tree models the cost of MIBI scintigraphy compared to the molecular test for the diagnosis of thyroid nodules with indeterminate cytological findings on FNA. The outcome represents the life expectancy in years (O chance node, ◄ termination node, # corresponding likelihood 1 − n)

We calculated a baseline scenario with the lowest reimbursement and a severity-adjusted scenario with higher reimbursement. This severity adjustment in calculating reimbursement for medical procedures allows adjustment for various factors such as the difficulty of the procedure or the qualification of health-care staff [7]. The cost of a MIBI scan was obtained from the reimbursement scheme for medical procedures for privately ensured patients (http://www.e-bis.de/goae/defaultFrame.htm, 1 December 2013). We included the following procedures: symptom-based examination (cipher 5: lowest reimbursement €4.66; highest severity-adjusted reimbursement €10.72), consultation (cipher 1: €4.66; €10.72), report on diagnostic findings (cipher 75: €7.58; €17.43), thyroid scintigraphy (cipher 5,401: €75.77; €136.39), and cost for the radiotracer (assuming 13 cents/MBq and an activity of 200 MBq for a typical patient and up to 300 MBq for obese patients), resulting in a total cost ranging from €119 to €214 (rounded).

Eur J Nucl Med Mol Imaging Table 1 Parameters for decision tree analysis and Monte Carlo simulation

Results

Model parameter

Value (range)

Likelihood of negative MIBI scan (N1) MIBI scan NPV (N2) MIBI scan PPV (N3) Likelihood of negative molecular test (N4)

0.33 (0.30 0.96 (0.95 0.43 (0.28 0.56 (0.52

Molecular test NPV (N5) Molecular test PPV (N6) Operative mortality (N3a, b N6a, b) Thyroid cancer diagnosed Missed thyroid cancer Benign thyroid lesion

0.95 (0.90 – 0.97) 0.61 (0.33 – 0.85) 0.002 (0.000 – 0.002) 34.5 years 20.7 years 34.5 years

The deterministic decision tree analysis resulted in a nearly equal life expectancy of 34.3 years for the MIBI scan and 34.1 years for the molecular test. In contrast, the cost per patient was €1,459 for the MIBI scan and €3,560 for the molecular test (baseline scenario), and €2,224 versus €4,071 (severity-adjusted scenario). Results were confirmed by the Monte Carlo simulation (key data in Table 2). In this analysis, the lower limit of the 95 % confidence interval for life expectancy for the MIBI scan (34.23 years) was higher than the upper limit of the 95 % confidence interval for the molecular test (34.19 years).

– – – –

0.41) 0.98) 0.52) 0.78)

The molecular test is offered to non-US residents by Veracyte® Inc. (San Francisco, CA) for $3,500 (= €2,656 applying the average exchange rate for the period November 2012 to October 2013; personal communication by Veracyte®, 14 November 2013). To this, we added the costs of consultation (cipher 1: €4.66; €10.72), report on diagnostic findings (cipher 75: €7.58; €17.43) and FNA (cipher 319: €11.66; €26.81), resulting in a total cost ranging from €2,680 to €2,711 (rounded). The cost of thyroidectomy in case of suspicious nodules is covered by the German HI and are coded within the German DRG System as D44.0. The exact cost for an individual patient depend on many variables such as concomitant disease of the patient or complications of the procedure. Based on typical scenarios, we applied €2,000 for the baseline scenario and €3,000 for the severity-adjusted scenario (e.g. €1,973 – €3,068 at the University Hospital of Münster; http://drg.uni-muenster.de). In order to test the robustness of the results we performed a probabilistic sensitivity analysis using a second-order Monte Carlo simulation with 10,000 samples. Triangular distributions were used for the attribution of probability distributions to variables affecting the results (Table 1) [7].

Table 2 Statistics resulting from the Monte Carlo simulations

Costs are rounded to €1 and life expectancy is rounded to two decimal places

Statistic

Discussion The present analysis is the first to show that molecular imaging with MIBI is cheaper than molecular genetic analysis in the work-up of patients with a nondiagnostic FNA of thyroid nodules, and showed a marginally but significantly higher life expectancy. Although both strategies were cost-effective in the health-care setting in which they initially emerged, there was a marked difference in cost. Considering system-related differences in the cost structure of health-care systems, it is questionable whether Afirma® would be as cost-effective in a European setting as in the American system as demonstrated by Li et al. [3]. A weakness of the present study was the limited quality of the underlying data. All studies on the diagnostic accuracy of MIBI thyroid scintigraphy were retrospective, and there were considerable methodological differences with regard to crucial elements such as timing of scintigraphy and the precise definition of a positive MIBI thyroid scintigraphy scan [8]. In contrast, the data on which the analysis of the Afirma® molecular genetic classifier are based were obtained in a prospective, multicentre study. However, probably also due to the high cost and proprietary nature of this classifier, independent verification of these results are mostly lacking. Interestingly,

MIBI scan

Molecular test

Lowest cost (€)

Severityadjusted cost (€)

Life expectancy (years)

Lowest cost (€)

Severityadjusted cost (€)

Life expectancy (years)

Minimum

1,303

1,986

34.19

3,122

3,378

33.5

10 % Median 90 % Maximum

1,359 1,431 1,482 1,518

2,072 2,183 2,286 2,312

34.25 34.29 34.34 34.4

3,271 3,458 3,574 3,639

3,601 3,879 4,053 4,148

33.78 33.99 34.13 34.25

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the one independent study that we are aware of indicated that the NPV of Afirma® may be lower than suggested in prior literature [9]. In a German retrospective cohort study a PPV of 17.4 % was found [10]. However, in that study the PPV was calculated in a population of patients with hypofunctioning nodules imaged by pertechnetate thyroid scintigraphy. In contrast, our model referred only to nodules with indeterminate cytological findings resulting in a higher cancer prevalence of about 30 %. Recalculating the PPV based on this prevalence and on the values for sensitivity and specificity reported by LeidigBruckner et al. [10] would give a PPV similar to the PPV used in our study. The present results may not apply directly to other healthcare systems. Correct interpretation of a MIBI thyroid scintigraphy scan requires comparison with a pertechnetate thyroid scintigraphy scan. In this study, we assumed that before FNA, all patients had already received a pertechnetate thyroid scintigraphy scan, as is customary practice in Germany. However, in many countries sufficiently large nodules are biopsied without prior pertechnetate scintigraphy; the total cost of the MIBI strategy in these systems would be increased by the cost of pertechnetate scintigraphy, which usually will be similar to the cost of MIBI scintigraphy. The present results may be of considerable importance for clinical practice. MIBI scintigraphy currently is not registered for thyroid nodule diagnostics—its use in this setting remains an off-label use. However, in a direct comparison of the clinical effectiveness and cost-effectiveness of MIBI thyroid scintigraphy and Afirma®, which is a registered product, MIBI scintigraphy performed better in terms of both cost-effectiveness and life expectancy. This should support the cause for obtaining formal registration of MIBI scintigraphy for thyroid nodule diagnostics, although a prospective trial is needed to confirm the diagnostic performance of MIBI scintigraphy.

Conflicts of interest None.

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Thyroid nodules with indeterminate cytology: molecular imaging with ⁹⁹mTc-methoxyisobutylisonitrile (MIBI) is more cost-effective than the Afirma gene expression classifier.

To compare the cost-effectiveness of (99m)Tc-methoxyisobutylisonitrile (MIBI) thyroid scintigraphy and the Afirma gene expression classifier for the a...
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