0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(6):2859–2866 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2003-031127 The Economic Implications of Three Biochemical Screening Algorithms for Pheochromocytoma ANNA M. SAWKA, AMIRAM GAFNI, LEHANA THABANE, AND WILLIAM F. YOUNG, JR. Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine (W.F.Y.), Mayo Clinic, Rochester, Minnesota 55905; Department of Internal Medicine and Division of Endocrinology (A.M.S.), St. Joseph’s Healthcare, Hamilton, Ontario, Canada L8N 4A6; Department of Internal Medicine and Division of Endocrinology (A.M.S.), McMaster University, Hamilton, Ontario, Canada L8N 3Z5; Centre for Evaluation of Medicines (L.T.), St. Joseph’s Healthcare, Hamilton, Downloaded from https://academic.oup.com/jcem/article/89/6/2859/2870332 by guest on 24 September 2021 Ontario, Canada L8N 1G6; and Department of Clinical Epidemiology and Biostatistics (L.T., A.G.), McMaster University, Hamilton, Ontario, Canada L8N 3Z5 Pheochromocytoma is a rare, life-threatening condition. Using offs would undergo 24-h urinary measurements (total meta- a modeling technique, we studied the economic implications of nephrines and fractionated catecholamines) and be imaged if detection strategies for pheochromocytoma (third-party payer positive. We determined that, if 100,000 hypertensive patients perspective). The diagnostic efficacy of biochemical tests was (including 500 patients with pheochromocytoma) were tested, based on Mayo Clinic Rochester data. In all hypothetical algo- algorithm A (measurement of fractionated plasma metaneph- rithms, positive biochemical tests were followed by abdominal rines alone) would detect 489 pheochromocytoma patients at computerized tomography and, if negative, metaiodobenzylgua- a cost of 56.6 million dollars, whereas B (24-h urinary mea- nidine scintigraphy. surements) would detect 457 pheochromocytoma patients for In each hypothetical algorithm, imaging would be indi- 39.5 million dollars, and C (combination of measurements of cated after positive biochemical testing as follows: algorithm fractionated plasma metanephrines and urines) would detect A, fractionated plasma metanephrine measurements above 478 patients for 28.6 million dollars. None of the screening the laboratory reference range; or algorithm B, abnormal strategies for pheochromocytoma described are affordable if measurements of 24-h urinary total metanephrines or cat- implemented on a routine basis in extremely low-risk pa- echolamines. In algorithm C, subjects with fractions of plasma tients. However, algorithm C may be the least costly, and at a metanephrine at or above 0.5 nmol/liter or normetanephrine reasonable level of sensitivity, for subjects in whom the sus- at or above 1.80 nmol/liter would undergo imaging, whereas picion of disease is moderate. (J Clin Endocrinol Metab 89: those with values between the reference range and these cut- 2859–2866, 2004) ATECHOLAMINE-SECRETING TUMORS are rare ical screening strategies (and subsequent imaging) for de- C neoplasms of chromaffin cells (estimated incidence, tection of pheochromocytoma. 1.55–8 per million persons per year) that arise from the adrenal medulla (pheochromocytoma) or paraganglia (para- Subjects and Methods ganglioma) (1–5). Catecholamine-secreting tumors are some- Subjects who underwent biochemical tests times sought as part of an evaluation for secondary causes of We reviewed the medical records of 416 outpatients (including 47 hypertension, unexplained spells, or incidental adrenal patients with histologically confirmed pheochromocytoma or paragan- masses, or in patients with rare genetic predispositions to glioma) who had concurrent measurements of fractionated plasma pheochromocytoma. There is no standardized approach to metanephrines, 24-h urinary total metanephrines, and 24-h urinary cat- echolamines between January 1, 1999, and November 29, 2001, to esti- biochemical screening for catecholamine-secreting tumors mate the diagnostic efficacy of biochemical tests (updated published between or within institutions. series) (Fig. 1) (11). Indications for testing in patients without pheo- Although recent reports have suggested that measure- chromocytoma included hypertension in 148 patients, spells with or ments of fractionated plasma metanephrines may be a con- without sustained or paroxysmal hypertension in 126, adrenal mass(es) on an imaging study in 57, and high-risk group (including patients with venient biochemical test for pheochromocytoma, an optimal high-risk familial syndromes, pheochromocytomas, or paragangliomas strategy for dealing with mildly elevated (borderline) ele- cured surgically previously) in 38 subjects (Fig. 1). Of the 47 pheochro- vations of these measurements is needed (6–10). The eco- mocytoma patients, 30 had an adrenal pheochromocytoma, 17 had at nomic implications of different biochemical testing strategies least one extra-adrenal pheochromocytoma, 17 had malignant pheo- chromocytoma, and 6 had a genetic syndrome predisposing to pheo- and subsequent imaging of positive screens have not been chromocytoma (those with genetic syndrome screened before Novem- explored. Our aim was to explore, using a modeling tech- ber 27, 2001) (Fig. 1). After November 27, 2001, subjects with a known nique, the economic implications of three proposed biochem- genetic predisposition to pheochromocytoma were excluded from the study to prevent excessive representation of subjects with rare familial syndromes who are prone to being seen in quaternary care centers (36 Abbreviations: CI, Confidence interval; CT, computerized tomogra- subjects, including 4 subjects with pheochromocytoma excluded). An- phy; MIBG, metaiodobenzylguanidine. other 47 subjects were excluded because of an abnormal spectral curve, indicating drug interference in measurement of 24-h urinary total JCEM is published monthly by The Endocrine Society (http://www. metanephrines. endo-society.org), the foremost professional society serving the en- All catecholamine-producing tumors were histologically confirmed. docrine community. In terms of extra-adrenal paragangliomas, only catecholamine-secreting 2859 2860 J Clin Endocrinol Metab, June 2004, 89(6):2859–2866 Sawka et al. • Cost Effectiveness of Pheochromocytoma Screening FIG. 1. Description of subjects from whom diag- nostic efficacy data of biochemical tests were ob- tained. “Syndromic pheochromocytoma” refers to patients that have a genetic disorder that in- creases their risk to harbor a catecholamine- secreting tumor (e.g. familial paraganglioma, neurofibromatosis type 1, von Hippel-Lindau dis- ease, Carney triad, and multiple endocrine neo- plasia type 2). “Hx pheochromocytoma” refers to patients that had prior resection of a catechol- amine-secreting tumor. Downloaded from https://academic.oup.com/jcem/article/89/6/2859/2870332 by guest on 24 September 2021 paragangliomas were included. All subjects without pheochromocy- TABLE 1. Charges to the third-party payer (in U.S. dollars) toma were assigned a different clinical diagnosis by their treating phy- sician at the completion of their evaluation. The Institutional Review Variables Costs Board of the Mayo Foundation approved the study, and signed consent was verified for all patients whose medical records were reviewed. Venipuncture $ 20.50 There was no sponsor involvement, nor funding for the study. (added to plasma metanephrine cost) Fractionated plasma metanephrines $ 105.00 Biochemical assays (not including venipuncture) 24-h urinary total metanephrines $ 110.00 ($121.00)a a Liquid chromatography with electrochemical detection was used for 24-h urinary fractionated catecholamines $ 170.00 ($187.00) a measurement of fractionated plasma metanephrines (reported as meta- 24-h urinary creatinine $ 32.50 ($35.75) nephrine and normetanephrine fractions) and 24-h urinary cat- CT scan of abdomen $1460.00 echolamines (reported as norepinephrine, epinephrine, and dopamine (with and without iv contrast) 123 fractions), whereas urinary total metanephrines were measured by spec- [ I]MIBG scan $1875.00 trophotometry (12–15). All biochemical assays were performed at the (with and without SPECT) Mayo Medical Center. In the case of multiple measurements of the same SPECT, Single-proton emission CT. metabolite for the same patient, only the first concurrent measurement a Costs inflated by 10% for urinary measurements to adjust for of plasma and urinary analytes was included in the study. Fractionated need for repeat collections because of drug interference or incomplete plasma metanephrine measurements were performed via venipuncture collections. in the sitting posture, either fasting or nonfasting. Interpretation of biochemical tests egy. The outcome of interest was the number of patients with pheo- chromocytoma expected to be detected by each strategy. The costs of For fractionated plasma metanephrines, the upper limits of the 95% false-positive biochemical tests were reflected only in the costs of sub- reference range established by Mayo Medical Laboratories were 0.5 sequent imaging and not in potential costs of needless surgery or its nmol/liter (98 pg/ml) for the metanephrine fraction and 0.9 nmol/liter possible complications. (165 pg/ml) for the normetanephrine fraction, and measurements at or A decision analysis model of screening of hypertensive patients solely above either of these levels were considered positive in algorithm A. A by measurement of fractionated plasma metanephrines was