European Journal of Endocrinology (2002) 146 283–294 ISSN 0804-4643

CLINICAL STUDY Managing toxic thyroid adenoma: a cost-effectiveness analysis Gwenae¨lle M Vidal-Tre´can, James E Stahl1 and Isabelle Durand-Zaleski2 De´partement de sante´ publique, CHU Cochin Port Royal, Assistance Publique-Hoˆpitaux de Paris, Universite´ Rene´ Descartes, Paris, France, 1Decision Analysis and Technology Assessment Group, Massachusetts General Hospital, Boston, Massachusetts, USA and 2Sante´ publique, CHU Henri Mondor, 51 avenue du Mare´chal de Lattre de Tassigny, 94010 Cre´teil Cedex, France (Correspondence should be addressed to G M Vidal-Tre´can, De´partement de sante´ publique, CHU Cochin Port Royal, 24, rue du faubourg Saint Jacques, 75014 Paris, France; Email: [email protected])

Abstract Objective: To examine the cost-effectiveness of therapeutic strategies for patients with toxic thyroid adenoma. Design: A decision analytic model was used to examine strategies, including thyroid lobectomy after a 3-month course of antithyroid drugs (ATDs), radioactive iodine (RAI), and lifelong ATDs followed by either RAI (ATD-RAI) or surgery (ATD-surgery) in patients suffering severe drug reactions. Methods: Outcomes were measured in quality-adjusted life years. Data on the prevalence of co-incident thyroid cancer, complications and treatment efficacies were derived from a systematic review of the literature (1966–2000). Costs were examined from the health care system perspec- tive. Costs and effectiveness were examined at their present values. Discounting (3% per year), variations of major cost components, and every variable for which disagreements exist among studies or expert opinion were examined by sensitivity analyses. Results: For a 40-year-old woman, surgery was both the most effective and the least costly strategy (e1391),while ATD-RAI cost the most (e5760). RAI was more effective than surgery if surgical mor- tality exceeded 0.6% (base-case 0.001%). RAI become less costly for women of more than 72 years (more than 66 in discounted analyses). For women of 85, ATD-RAI may be more effective than RAI and have an inexpensive marginal cost-effectiveness ratio (e4975) if lifelong follow-up results in no decrement in quality of life. Conclusions: Age, surgical mortality, therapeutic costs and patient preference must all be considered in choosing an appropriate therapy.

European Journal of Endocrinology 146 283–294

Introduction injury resulting from RAI remain, at this time, only theoretical concerns. Finally, some authors consider Toxic thyroid adenoma causes thyrotoxicosis in RAI to be the least expensive treatment for hyper- European populations, particularly in cases of thyroidism and encourage its greater use (16). Long- iodine deficiency (1–6). In European countries, term therapy with antithyroid drugs (ATDs) is seldom patients with thyroid toxic adenoma represent used because, while surgery and RAI will cure the 7–11% of thyrotoxic patients (7). Treatment patient, ATDs will never do so due to the intrinsic options are surgery and radioactive iodine (RAI) nature of the adenoma (neoplasm generally due to a (5, 8–10). The most common surgical procedure somatic mutation of the thyrotropin (TSH) receptor). is unilateral thyroid lobectomy (11–15). Advocates Moreover, withdrawal of ATD therapy will generally for surgery claim that surgery rapidly controls the end up in relapse. While intra-lesional injection of thyrotoxicosis and lowers the risk of missing ethanol has also been proposed (10), this treatment incidental thyroid cancers associated with the remains experimental (17). Although surgery and adenoma, while having negligible mortality and RAI are time-honored treatments, they have never morbidity. Advocates for RAI note that it is effec- been compared in a randomized trial; choice of therapy tive and carries no immediate risk of mortality. In has typically depended upon locally available facilities addition, hypothyroidism resulting from RAI is rare and expertise. Our objective was to compare the costs and relapse of the toxic adenoma is uncommon. and the outcomes (survival and quality of life) of Furthermore, long-term carcinogenic risk or genetic therapeutic strategies for thyroid adenoma.

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Methods resulted in hospitalization, the discontinuation of ATDs, or death. Patients who survived underwent Case definition either lobectomy or treatment with RAI. Some minor A toxic solitary thyroid nodule was defined as one adverse effects such as rash, urticaria and arthralgias which demonstrated uptake with suppressed uptake (8) possibly led to discontinuation of ATDs. in the surrounding thyroid tissue in a thyroid scinti- scan in an individual with clinical hyperthyroidism Quality of life (9, 18, 19). Patients with non-toxic autonomously functioning nodules were not considered. Since toxic We adjusted LE for both acute and chronic morbidities. thyroid adenomas are most common in women These quality-adjustment factors were mostly based on between 30 and 50 years of age (17, 19–21) we con- published data supplemented by expert judgment sidered the base-case of a 40-year-old woman. We (Table 1) (31). QALE for chronic morbidities were have assumed that all toxic thyroid adenomas must modeled as quality of life coefficients multiplied by the be treated. total LE while acute morbidities were subtracted from LE. Continued monitoring for euthyroidism, hypothy- roidism and permanent dysphonia resulted in Description of decision analytic model decreased quality of life (31). We examined the cost-effectiveness of four mutually exclusive strategies. (A) Primary RAI. (B) Primary sur- Resource use gery – thyroid lobectomy once euthyroidism has been The costs for each strategy were estimated for two achieved with ATDs. (C) Lifelong medical therapy periods: (A) the initial year following diagnosis and with ATDs followed by either surgery (ATD-surgery) (B) the subsequent remaining years of life (Table 2). or (D) RAI (ATD-RAI) in the event of a serious drug reaction. We used Decision Maker (22, 23), a decision Surgical treatment Patients received a 3-month analysis software program to model these strategies course of ATDs prior to surgery (14, 20, 32). as a recursive decision model (24) with a lifetime Hematoma resulted in a longer hospitalization and an horizon. (The decision tree is available on request associated decrement in quality of life. Transient vocal from G M Vidal-Tre´can.) cord palsies required vocal cord re-education; perma- nent hypothyroidism required long-term treatment Effectiveness and follow-up. In the base-case we assumed lobectomy to be 100% effective and patients were followed for only Outcomes were expressed both as overall life expect- 1 year. If a thyroid cancer was detected, a total thyroid- ancy (LE) and as quality-adjusted life expectancy ectomy was performed and 3700 MBq RAI was (QALE), using a declining exponential approximation prescribed. Patients required lifelong surveillance for of the ‘DEALE’ (25). Population-based mortality rates treatment with TSH-suppressive levothyroxine and were derived from tables of vital statistics. Mortality recurrent thyroid cancer or metastases that were not rates for patients with co-incident thyroid cancer modeled. The cost components of thyroid cancer treat- (Table 1) detected during surgical procedure and trea- ment were drawn from expert opinion. Guidelines for ted have been estimated to be 0.002 per year (5-year treatment of patients with hyper- and hypothyroidism survival: 99%) for patients under the age of 50 years (Agence Nationale d’Accreditation et d’Evaluation en and 0.023 per year (5-year survival: 89%) for patients Sante´) were used to establish the periodicity of clinical 50 years of age or older (26). Primarily undetected visits and laboratory tests. thyroid cancer might progress in all non-surgical strat- egies and increase mortality. Excess mortality from Medical treatments Patients initially treated with those cancers was estimated from treated patients RAI were pretreated with b-blockers, received outpatient who developed locally extensive or metastatic thyroid RAI and required lifetime follow-up. Transient hyperthy- cancer (27, 28). Long-term complications of RAI roidism following RAI required a course of ATDs. included recurrent hyperthyroidism, permanent Failure to control hyperthyroidism resulted in the hypothyroidism, and radiation-induced thyroid cancer. administration of up to three courses of RAI. Patients The prognosis of radiation-induced thyroid cancer with hyperthyroidism after three courses of RAI was modeled as being equivalent to undetected thyroid underwent surgery. In the base-case, a high dose of cancer. Short-term complications of surgery included RAI was used (i.e. 555–1850 MBq (15–50 mCi)) hematoma and transient vocal cord paralysis, transient because it is considered more effective than low-dose hypothyroidism, and anesthesia-related death. Major therapy (11, 20, 33–39). complications of ATD therapy including agranulocyto- The follow-up of lifelong therapy with ATDs required sis, hepatitis and vasculitis (9, 29, 30) occurred at both four ambulatory visits during the first year, and two in 7 weeks and 6 months after the start of therapy. They subsequent years.

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Table 1 Probabilities and utilities used in the baseline and in the sensitivity analyses for cost-effectiveness analysis of managing toxic thyroid adenoma. References are given in parentheses.

Extreme values or 95% Quality of life adjustment factor* Probabilities confidence intervals of Event and rates probabilities and rates Short term† (days) Long term‡

Short term† Antithyroid drugs Hyperthyroidism, treatment, first year (31) 9 Agranulocytosis (29, 81) 0.003 0.001–0.010 30 Delayed agranulocytosis (70) 0.0007 30 146 Other adverse reactions (29) 0.010 0.010–0.050 30 Death from agranulocytosis (71) 0.001 NA Radioactive iodine (555 MBq–1850 MBq) 7 Failure of a first RAI dose to control hyperthyroidism 0.080 0–0.157 95 (13, 31, 33, 35, 39, 79) Hyperthyroidism (31) 0.080 NA 4.5 Surgery 15 Death related to anesthesia (51) 0.00001 0.000005–0.00008 Hematoma (12–15, 32) 0.020 0.01–0.03 0.25 Transient dysphonia (12) 0.060 0.0–0.083 0.25 Transient hypothyroidism (13–15, 32, 39, 50) 0.040 0.014–0.071 0.25 Long term‡ Co-occurring thyroid cancer (11–15, 20, 32, 33, 42, 44–49) 0.007 0.003–0.012 Excess mortality rate For undetected thyroid cancer (31) 0.058/year 0.83

For diagnosed thyroid cancer (age ,40) (31) 0.002/year 0.92 analysis decision a adenoma: thyroid Toxic For diagnosed thyroid cancer (age $40) (31) 0.023/year 0.92 Antithyroid drugs (31) 0.95 Radioactive iodine 0.999 Hypothyroidism (11, 33, 34, 36–38) 0.185 0.064–0.306 0.99 Recurrent hyperthyroidism (11, 31, 33–36, 38) 0.014 0–0.045 95 Radio-induced thyroid cancer (31, 43, 61, 63) 0.000 (0–0.008)§ 0.83

Downloaded fromBioscientifica.com at09/30/202108:22:07AM Surgery Dysphonia (12, 15, 32, 50) 0.030 0.015–0.040 0.98 Hypothyroidism (11–15, 32, 39) 0.040 0.020–0.054 0.99

* Quality-adjustment factors reflect the relative desirability of each health state or event. They usually result from expert judgment, values from the literature or values from measurements on a sample of subjects (40). † For short-term outcomes, quality-adjustment factor is expressed in days and subtracted from life expectancy. ‡ For long-term outcomes, quality-adjustment factor is multiplied by life expectancy. § Range of rates examined in the sensitivity analyses. NA, not applicable. www.eje.org 285 via freeaccess 286 G M Vidal-Tre´can and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 146

Table 2 Average costs of therapy for toxic adenoma*.

First-year Subsequent outpatient outpatient cost costs per year Event (e) (e)

ATD treatment Methimazole Acute phase (40 mg/day) 18† NA Maintenance period (10 mg/day) 32 38 Out-patient specialist visits (6) (2)† 137 46 Complete blood count (1/10 days during acute phase) 85 NA Hormonal measurements Acute phase (2)‡ 41 NA Maintenance period (4) (2)‡ 83 41 Total 396 125 RAI first treatment Propranolol 4 NA Outpatient specialist visits before RAI (1)† 23 NA 99mTC-pertechnetate scan before RAI (1)† 131 NA Hormonal measurements before RAI (1)‡ 35 NA Patient evaluation and treatment (1)† 171 NA Total 364 Each RAI following treatment 99mTC-pertechnetate scan before RAI (1)† 131 Patient evaluation and treatment (1)† 171 NA Total 302 Follow-up after RAI Outpatient specialist visits (3) (1)† 68 23 Hormonal measurement (1)‡ 97 21 Total 166 43 Hypothyroidism Out-patient specialist visits (4) (1)† 91 23 Hormonal measurements (4) (1)‡ 84 21 Levothyroxine 34 34 Total 209 77

Inpatient First-year Outpatient cost cost outpatient cost per year Event (e) (e) (e)

Surgical therapy Out-patient specialist visits before surgical procedure (3)† NA 68 NA Hormonal measurements before surgical procedure (1)‡ NA 35 NA Surgery§ 796 NA NA Out-patient specialist visits after surgical procedure (4)† NA 91 NA Hormonal measurements after surgical procedure (1)‡ NA 140 NA Total 796 335 NA Agranulocytosis 2889 NA NA Vocal cord palsy Medical evaluation of a speech problem (2)† NA 46 NA Laryngoscopy (1)† NA 29 NA Vocal cord re-education sessions (20)† NA 219 NA Total NA 293 NA Thyroid cancer Detected during surgery 4656 283 158 Primary undetected or radiation induced 4745 283 561

* All costs are in 2001 Euros; NA indicates not applicable. † The number of visits, examinations or sessions is indicated between parentheses; two numbers between parentheses denote number during the first year and the following years. ‡ Denotes the cost of free thyroxine (FT4) and TSH at the first evaluation and of TSH for follow-up; the number of measurements is indicated between parentheses. § Includes professional fees, anesthesia, surgery and an average of 4 days in a hospital.

Costs total inpatient costs were derived from the cost accounting system of the Assistance Publique-Hoˆpitaux Costs were estimated from the perspective of the health de Paris (AP-HP). The AP-HP is a hospital network of care system and are expressed in 2001 Euros. Average 50 non-profit university hospitals in the Paris region.

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Non-healthcare costs such as losses in productivity or contained the cancer. Co-incident thyroid cancers costs outside the health system (e.g. family time) were found at surgery were mostly intrathyroidal and of not considered. Hospital costs included all personnel the microcancer type. costs, supplies, drugs and blood products, tests, house- keeping and hospital overheads. Ambulatory costs were Complications from surgery Local complications estimated using the national reimbursement schedule from lobectomy (11–15, 32, 39, 50) included transient provided by the Social Security, prices for drugs were vocal cord palsies (5.8%; extreme values: 0.0–8.3%) derived from the French Red Book (Dictionnaire and hematoma (2.0%; 95% CI: 1.0–3.0%). Transient Vidal). Costs and health benefits in the remaining hypothyroidism (4.2%, 95% CI: 1.4–7.1%) was usually years of life were examined at their present value mild and early recovery was common. (40). The cost of treating localized thyroid cancer dis- Potential long-term complications from lobectomy covered at surgery was the sum of the costs of a hospi- included persistent dysphonia (2.8%; 95% CI: talization for total thyroidectomy, an evaluation for 1.5–4.0%) and permanent hypothyroidism (3.7%; thyroid cancer, and one course of ablative radioiodine 95% CI: 2.0–5.4%). Anesthesia-related death ranged therapy (e4939) and ambulatory visits each year to from 1/13 207 to 1/185 000 (51). No surgical deaths confirm the absence of progression of disease (e158). were reported when patients were pretreated with Information provided by Eeckhoudt et al. (41) was ATDs. used to estimate the cost of a primarily undetected Recurrence never happened after total lobectomy. In thyroid cancer. For the first year this was estimated as the sensitivity analyses, the risk of complications was the costs from one surgical hospitalization and from assumed to be same as for the primary lobectomy one hospitalization for the administration of except for the risk of hypoparathyroidism which was 3700 MBq RAI (e5028). Lifetime costs included those estimated to be respectively 6% for transient and of one surgical hospitalization for recurrent thyroid 0.6% for permanent hypoparathyroidism (52). cancer, ambulatory visits to evaluate the progression of disease each year, and four hospitalizations each RAI dosing and complications Results were for the administration of 3700 MBq RAI (on average stratified into those of high-dose RAI (555–1850 MBq e561 each year). In both cases, the lifetime cost for or 15–50 mCi) and low-dose RAI (40–554 MBq or hypothyroidism was included. In sensitivity analyses, 1mCi– , 15 mCi) therapy. The first dose failure rate the cost of permanent hypoparathyroidism was for high doses was 7.8% (95% CI: 0.0–15.7%), for estimated to be e353 for the first year and e309 for low-doses it was 14.1% (95% CI: 8.7–19.5%) (11, subsequent years including the cost of therapy and 13, 14, 33, 35, 36, 39, 53–58). We used expert follow-up. opinion to estimate the risk of transient mild hyperthy- roidism due to RAI and assumed that this could not be Cost-effectiveness analysis more frequent than failure to control hyperthyroidism. In most published studies, the incidence of hypothyroid- Incremental cost-effectiveness ratios were computed ism increased over time after treatment with RAI. In a using the costs and the outcomes of both strategies. subset of studies where patients with high-dose therapy were followed beyond 10 years (11, 33–38) the Data used in the model average rate of hypothyroidism was 18.5% (95% CI: 6.4–30.6%) while the average rate of recurrent We reviewed both the English and the French language hyperthyroidism was 1.4% (95% CI: 0.0–4.5%). In medical literature from 1966 to 2000 using a struc- follow-up studies of patients receiving low-dose therapy tured Medline search supplemented by manual (14, 36, 53–55, 59) these figures were 5.6% (95% CI: searches of bibliographies of selected articles. Studies 1.8–9.4%) and 5.4% (95% CI: 1.6–9.1%) respectively. were excluded if they did not report separate results Three of seven published studies evaluating thyroid for both autonomously functioning adenomas, and/or cancer risk following RAI treatment for benign lesions toxic nodular goiters. If the same patient series was (43, 60–65) demonstrated an increased relative risk published in more than one journal, only data from (60, 64, 65). Considering the average latency period the latest publication were included. Mean estimates for thyroid cancer induced by external radiation (12 for each variable in the model were used for the years or longer) (66–68), we modeled occurrence of base-case analysis (Table 1). thyroid cancer 12 years after RAI administration. However, the data in Franklyn et al. (65) indicate that Prevalence of thyroid cancer in association with thyroid cancer could be diagnosed 7.5 years after RAI toxic adenoma Thyroid carcinoma was associated therapy. In the base-case analysis, we assumed no with toxic adenoma in 0.7% of patients undergoing increased risk of thyroid cancer in patients receiving thyroidectomy (95% confidence intervals (CI): RAI. RAI exposure after the 10th week of gestation 0.3–1.2%) across studies (11–15, 20, 32, 33, 35, may cause fetal hypothyroidism and may be an 39, 42–49). The toxic thyroid nodule itself seldom indication for therapeutic abortion (16, 69).

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Adverse reactions of ATD therapy In patients were examined. Most authors consider that if costs treated with methimazole, 0.3% developed agranulo- are discounted then medical outcomes such as life cytosis (70). The risks of drug-induced hepatitis, years gained must also be discounted (75). Treatment vasculitis and other adverse effects leading to discon- with RAI is an absolute contraindication to tinuation of ATDs were estimated at 1% (8). In our pregnancy and lactation during the year following base-case analysis, we used a mortality rate from RAI administration. The reduction in quality of life major complications of ATDs of 0.1% (71). Rarely, for women of childbearing age was only considered in infant defects may be associated with the use of sensitivity analyses of short-term morbidity. methimazole in pregnancy (9), leading to the use of propylthiouracil in this circumstance. This was assumed not to change the rates of adverse effects Results and the medication costs. Base-case analysis In the base-case of a 40-year-old woman (Table 3A), Other medical therapy Studies of patients with toxic thyroid adenoma, primary thyroid lobectomy receiving lifelong replacement levothyroxine therapy after a 3-month course of ATDs was the least expensive (72, 73) after thyroid ablative therapy did not show and the most effective strategy, resulting in a gain of increased mortality except in the cases when doses 0.24 QALYs, as compared with RAI. ATD-surgery or were higher than those used for substitution therapy. ATD-RAI cost more and were less effective than surgery and RAI. Sensitivity analyses Sensitivity analyses Sensitivity analyses were performed on every variable for which disagreements among studies or expert All sensitivity analyses were performed using present opinions had been found in the literature. The extreme values for both costs and effectiveness unless otherwise values of reported data or the estimated 95% CI were noted. used (Table 1). In addition, we also tested the effects of variations in value of major cost components (i.e. Patient age We examined the effect of age in other- length of hospitalization, frequency of ambulatory wise healthy women between 15 and 85 years (Table follow-up). 4). Surgical mortality related to anesthesia was Recurrence of toxic thyroid adenoma was considered adjusted accordingly, from 0.001% in patients less after a delay and resulted in a course of ATDs and con- than 60 years of age, to 0.002% between the ages of tralateral lobectomy. These treatments may result in 60 and 80, and to 0.003% over the age of 80. Surgery the same short-term or long-term complications as was the most effective strategy for women of all ages the previous surgical procedure; the risk of transient studied. Only for women of more than 72 did RAI or permanent hypoparathyroidism should be added to become less costly. these risks. Both costs and effectiveness discounted at 3% per Mortality from surgery RAI was more effective year to account for time preference and inflation (74) than surgery when the surgical mortality risk exceeded

Table 3 Base-case analysis (40-year-old woman) of (A) cost and effectiveness of management strategies and (B) discounted cost and effectiveness strategies for thyroid toxic adenoma*.

Cost QALE† D cost D effectiveness D cost-effectiveness Strategy (e) (QALYs‡) (e) (QALYs) ratio (e/QALYs)

(A) Surgery 1391 42.58 RAI 2826 42.34 1435 20.24 DS{ ATDs-surgery 5741 40.39 2915 21.95 DS ATDs-RAI 5760 40.38 19 20.01 DS (B) Surgery 1378 23.04 RAI 1784 22.97 406 20.07 DS{ ATDs-surgery 3254 22.38 1470 20.59 DS ATDs-RAI 3260 22.38 6 0 DS

* All costs are in 2001 Euros and in (B) are discounted at 3% per year. † QALE denotes quality-adjusted life expectancy (effectiveness) expressed in QALYs in (A) and discounted at 3% per year in (B). ‡ QALYs are quality-adjusted life years. { DS denotes dominated strategy, i.e. the strategy in this row is both less effective and more costly than the one in the row above.

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Table 4 Cost-effectiveness of competing strategies for management of thyroid toxic adenoma by age group*.

QALE† D cost D effectiveness D cost-effectiveness Strategy Cost (e) (QALYs‡) (e) (QALYs) ratio (e/QALYs)

15-year-old-woman Surgery 1490 66.50 RAI 4081 66.05 2591 20.45 DS{ ATDs-surgery 8767 62.99 4686 23.06 DS ATDs-RAI 8801 62.98 34 20.01 DS 55-year-old-woman Surgery 1332 28.71 RAI 2096 28.55 764 20.16 DS ATDs-surgery 3981 27.24 1885 21.31 DS ATDs-RAI 3991 27.24 10 0 DS 70-year-old-woman Surgery 1279 15.93 RAI 1424 15.86 145 20.07 DS ATDs-surgery 2359 15.13 935 20.73 DS ATDs-RAI 2361 15.13 2 0 DS 85-year-old-woman RAI 905 6.05 ATDs-RAI 1104 5.79 199 20.26 DS ATDs-surgery 1108 5.79 4 0 DS Surgery 1238 6.08 333§ 0.03§ 11 100§

* All costs are in 2001 Euros. † QALE denotes quality-adjusted life expectancy (effectiveness) expressed in QALYs. ‡ QALYs are quality-adjusted life years. { DS denotes a dominated strategy, i.e. the strategy in this row is both less effective and more costly than the one in the row above. § Differences in cost, effectiveness and marginal cost-effectiveness ratio of surgery versus RAI.

0.6%. This threshold decreased slightly with age from Prevalence of a co-incident thyroid cancer The 0.7% for a 15-year-old woman to 0.5% for an prevalence of thyroid cancer varied from 0.3% to 85-year-old woman. When the risk of death exceeded 1.2% in sensitivity analyses. Throughout this range, 0.7%, the marginal cost-effectiveness of RAI versus sur- surgery was preferred, resulting in a gain of 0.15 gery was relatively inexpensive from 40 and decreased QALYs for a prevalence of 0.3%, and 0.35 QALYs for with age until 72 years old and with increment of risk a prevalence of 1.2%. The difference in costs of surgery of death from surgery (Fig. 1). versus RAI administration increased from e1369 to e1518. Efficacy and other complications of surgery Quality of life adjustment factors Quality of life Surgery remained the most effective strategy unless adjustment factors for most morbidities were derived the risk of permanent hypothyroidism exceeded 61% from expert opinion. The model was relatively insensi- and the risk of permanent dysphonia exceeded 31% tive to these factors. Sensitivity analyses over reason- and the least costly unless the risk of permanent able ranges for these variables did not change the hypothyroidism exceeded 49%. All these thresholds outcomes of the strategies significantly whatever the decreased slightly with age (Table 5) but never reached age of the patients (Table 5). levels contained in the estimated 95% CI or published For our base-case, lobectomy should result in a loss extreme values. of 0.31 QALYs (113 days) to be less effective than RAI. For women of 85, if lifelong surveillance and RAI dosing, efficacy and complications The effi- therapy result in no decrement in quality of life, then cacy and complication rates of RAI were different for ATD-RAI is more effective than RAI administration high- and low-dose treatments. Low-dose RAI resulted and has a marginal cost-effectiveness ratio of e4975 in 0.05 more quality-adjusted life years (QALYs) than compared with RAI. high-dose therapy in our base-case with an estimated If we perform our analysis using quality-unadjusted average lifetime cost of e2644. Thus low-dose RAI outcomes then surgery provides a gain of 0.16 years dominated high-dose RAI. over RAI. Surgery remained the most effective strategy Lowering the risk of RAI complications did not make unless surgical risk exceeded 0.4%, at which point RAI this strategy less costly than surgery. When the risk of became more effective. developing a radio-induced thyroid cancer was con- sidered, the cost of RAI increased and its effectiveness Costs In undiscounted analyses, the only situations decreased. where surgery is more expensive than RAI are those in

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Figure 1 Marginal cost-effectiveness of RAI versus surgery as a function of patient age according to variations in the threshold of risk of death from surgery.

Table 5 Thresholds in probabilities of events, quality of life adjustment factors and costs that render RAI more effective or less costly than surgery for women of various ages.

RAI preferred if ... 40 years 55 years 70 years

Effectiveness Probability of death from surgery .0.006 .0.006 .0.005 Probability of permanent dysphonia after surgery .0.314 .0.306 .0.284 Probability of permanent hypothyroidism after surgery .0.607 .0.591 .0.548 Quality of life adjustment factor for permanent dysphonia ,0.79 ,0.80 ,0.81 Quality of life adjustment factor for surgery .103 days .73 days .45 days Cost Length of follow-up after surgery .35 years .19 years .3.5 years Inpatient cost of lobectomy .e 2119 .e 1910 .e 1278 Cost of annual follow-up after RAI ,e 0.16 ,e 9 ,e 31 Probability of permanent hypothyrodism after surgery .0.497 .0.403 .0.166 Probability of hyperthyroidism recurrence after surgery .0.406 .0.306 .0.094

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Downloaded from Bioscientifica.com at 09/30/2021 08:22:07AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 146 Toxic thyroid adenoma: a decision analysis 291 which the cost of lobectomy exceeds e2596 (187% cost of surgery. Finally, the high lifetime costs of more than the base-case) or if the cost of the life-long follow-up and therapy also explained the higher cost ambulatory follow-up after RAI administration is less of the medical strategies. The average lifetime cost in than e0.16. These differences varied with age and the least expensive ATD strategy (i.e. ATD-surgery) were possible for a 70-year-old woman (Table 5). The exceeded the cost of RAI by e2915 in our base-case. model is insensitive to variations in costs of thyroid Our results also showed that the patient’s age is an cancer treatment and follow-up. In discounted ana- important consideration when choosing treatment. lyses, the costs of RAI administration and of the Surgery is the less costly strategy for patients under medical strategies (Table 3B) were lower than in non- the age of 72 years and of 66 years in discounted ana- discounted analyses because of the longer term effects lyses, but RAI was preferred when the risk of surgical of RAI. Above 66 years of age RAI became the least mortality exceeded 0.6% which is not unlikely in costly. patients with multiple co-morbidities. For women of 85 years of age, lifelong treatment with ATDs (followed by RAI in case of an adverse reaction) was preferred to Discussion RAI. We also assumed in our analysis that women would The choice between RAI and lobectomy for toxic avoid pregnancy during the year following RAI thyroid adenoma has until now largely depended on administration, and that they would receive propyl- expert opinion. This is because outcomes in thyroid dis- thiouracil as the ATD of choice. However, compliance eases have seldom been evaluated using randomized may be poor. Since radiation exposure after the 10th clinical trials and, to our knowledge, only three (26, week of gestation may cause fetal hypothyroidism, 76, 77) decision analyses for thyroid diseases have leading to therapeutic abortion (16), lobectomy may been published, none of which examined toxic thyroid be favored even more strongly in women under 50 adenoma. Our analysis comparing thyroid lobectomy years of age. with 555 MBq RAI and the unusual lifelong therapy Our model was relatively insensitive to variations in with ATDs showed that for an otherwise healthy procedural and follow-up costs for our typical patient. 40-year-old woman lobectomy is the preferred strategy. Surgery would become more expensive than RAI This result is explained by the high effectiveness and administration only if the cost of lobectomy were low anesthesia-related risk of surgery compared with 187% over our base-case cost estimation and if the alternative strategies (11–15, 20, 32, 33, 35, 39, cost of ambulatory follow-up after RAI were very low. 42–49, 51). This result is robust for rates of anesthe- Estimating the probability of post-radiation morbidity sia-related mortality under 0.5%. Another element of from small series was difficult (11, 14, 20, 33–39, the high effectiveness of surgery is the prevalence of 53–56, 58, 59, 79) The frequency of permanent co-incident thyroid cancers, which are definitively hypothyroidism due to RAI increased over time. Both removed. We estimated, from surgical series, that the the efficacy and the prevalence of post-RAI hypo- prevalence of co-incident thyroid cancers is 0.7% thyroidism varied with the size of the radiation dose. (95% CI: 0.3–1.2%) (11–15, 20, 32, 33, 35, 39, Low-dose RAI was both less expensive and slightly 42–49); we assumed that missing thyroid cancer more effective than high-dose RAI. It provided 18 during surgery was unlikely which may have biased days more of QALE than high-dose therapy due to our analysis slightly in favor of surgery. The other the lower frequency of hypothyroidism. The risk of strategies were assumed to occasionally miss thyroid radiation-induced cancer in patients treated with RAI cancer, delaying diagnosis and resulting in a small for benign thyroid diseases remains controversial. In risk of disseminated disease and a higher risk of death our base-case analysis we assumed there was no risk and higher costs. Differences in the unadjusted long- of radiation-induced thyroid cancer. Three reports term health outcomes between all the strategies were (60, 64, 65) have found an increased relative risk smaller than the quality-adjusted health outcomes. while others (43, 61, 63) have not. Furthermore, The modest decrement in quality of life associated some of them (60, 63) have noted a small increased with the lifelong clinical follow-up that is required risk of other cancers. We explored this in sensitivity with either ATDs or RAI strategies explained their analyses. If the probability of developing a radio- lower QALE when compared with lobectomy. induced thyroid cancer were considered, the differences In the base-case, surgery was less costly than RAI in effectiveness and in cost of RAI with surgery would administration. The differences were explained mostly slightly increase. by higher lifetime follow-up costs rendered necessary Our study has some limitations. Risk aversion for by the delayed risk of hypothyroidism after RAI admin- surgery was not considered. As thyroid toxic adenoma istration, even if the annual costs of follow-up and cannot be considered as a chronic disease, we designed hypothyroidism treatment are low (11–14, 32, 35, a simple recursive tree to model outcomes and costs of its 44, 78). The lower costs of follow-up for surveillance management. However, therapeutic choices may result or management of hypothyroidism offset the higher in long-term consequences, such as radio-induced

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Downloaded from Bioscientifica.com at 09/30/2021 08:22:07AM via free access 292 G M Vidal-Tre´can and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 146 hypothyroidism or thyroid cancer. Therefore, using a 8 Cooper DS. Antithyroid drugs. New England Journal of Medicine Markov model may have provided more precise results 1984 311 1353–1362. 9 Franklyn JA. The management of hyperthyroidism (published (80). However, we did not find data describing the erratum appears in New England Journal of Medicine 1994 331 time-dependent function for radio-induced hypothy- 559). New England Journal of Medicine 1994 330 1731–1738. roidism specifically in patients with toxic thyroid ade- 10 Hermus AR & Huysmans DA. Treatment of benign nodular noma and thyroid radiation-induced cancer. Quality thyroid disease. New England Journal of Medicine 1998 338 1438–1447. of life following therapy is an important concern, 11 O’Brien T, Gharib H, Suman VJ & van Heerden JA. 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