Appendix F
Screening for Thyroid Cancer: Background Paper

Karen Eden, Ph.D.

Mark Helfand, M.D.

Susan Mahon, M.P.H.

Between 1951 and 1962 the United States Atomic Energy Commission conducted more than 100 aboveground detonations of nuclear weapons at the Nevada Test Site. Parts of Idaho, Montana, Utah, and Colorado had the highest exposure, but radioactive fallout was deposited throughout the United States. Infants and small children who drank milk or ate fresh vegetables contaminated with fallout were exposed to the highest doses of radiation, and as adults these persons are most at risk for developing thyroid abnormalities.

In 1997, the National Cancer Institute (NCI) released a report estimating the amount of radiation exposure Americans received from the nuclear tests (USDHHS, 1997). The report states that the average dose of radiation received by each American was 0.02 gray (Gy). Average exposures in some Western and Midwestern states were higher as much as 0.16 Gy in some areas. In addition to place of residence, the source and quantity of milk consumed by infants and young children can be used to help predict the dosage of the radioactive iodine (I-131) reaching the thyroid gland.

The NCI findings raised concerns that individuals exposed to higher dosages of I-131 might have a high risk of developing thyroid cancer later in life and that early detection and intervention for thyroid cancer could be useful for those persons.

To justify screening, there must be evidence that screening tests can detect thyroid cancer accurately and safely in asymptomatic individuals, that early treatment decreases mortality or morbidity from thyroid cancer when compared with delaying treatment until symptoms occur, and that the benefits of screening clearly outweigh the adverse effects of the screening program itself. Unfortunately, evidence about the ability of early detection to prevent morbidity and mortality from



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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Appendix F Screening for Thyroid Cancer: Background Paper Karen Eden, Ph.D. Mark Helfand, M.D. Susan Mahon, M.P.H. Between 1951 and 1962 the United States Atomic Energy Commission conducted more than 100 aboveground detonations of nuclear weapons at the Nevada Test Site. Parts of Idaho, Montana, Utah, and Colorado had the highest exposure, but radioactive fallout was deposited throughout the United States. Infants and small children who drank milk or ate fresh vegetables contaminated with fallout were exposed to the highest doses of radiation, and as adults these persons are most at risk for developing thyroid abnormalities. In 1997, the National Cancer Institute (NCI) released a report estimating the amount of radiation exposure Americans received from the nuclear tests (USDHHS, 1997). The report states that the average dose of radiation received by each American was 0.02 gray (Gy). Average exposures in some Western and Midwestern states were higher as much as 0.16 Gy in some areas. In addition to place of residence, the source and quantity of milk consumed by infants and young children can be used to help predict the dosage of the radioactive iodine (I-131) reaching the thyroid gland. The NCI findings raised concerns that individuals exposed to higher dosages of I-131 might have a high risk of developing thyroid cancer later in life and that early detection and intervention for thyroid cancer could be useful for those persons. To justify screening, there must be evidence that screening tests can detect thyroid cancer accurately and safely in asymptomatic individuals, that early treatment decreases mortality or morbidity from thyroid cancer when compared with delaying treatment until symptoms occur, and that the benefits of screening clearly outweigh the adverse effects of the screening program itself. Unfortunately, evidence about the ability of early detection to prevent morbidity and mortality from

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications thyroid cancer is incomplete. In contrast to the case of screening for breast cancer, for example, there are no randomized, controlled trials of screening for thyroid cancer, either in the general population or in high-risk groups. Instead, the effect of screening must be inferred from observational studies regarding the prevalence of undiagnosed thyroid cancer and the potential benefit of early detection. In this paper we address whether physicians should screen for thyroid cancer seen in asymptomatic patients thought to have been exposed to I-131. We focus on studies of screening in the general population and in high-risk groups. We examine the accuracy of the tests used for screening, the number of cancer patients detected with screening, and evidence that treatment of cancers found by screening improves outcomes. Definitions Screening is "the application of a test to detect a potential disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done" (Eddy, 1991). Studies of screening can be classified according to the setting in which the decision to screen takes place. In clinic-based screening, or casefinding , a screening test is performed in patients who visit a primary-care physician for an unrelated reason. Studies of casefinding programs provide the most realistic estimates of the effects and costs of screening in a clinic or office practice, but there have been very few studies of casefinding for thyroid cancer. Population-based studies contact, recruit, and follow patients in the context of an epidemiologic research effort. Such studies show the extent of unsuspected thyroid cancer in a population sample, but they do not reflect the yield or costs of screening in clinics or providers' offices. We used population-based studies as a benchmark against which the yield and benefits of clinic-based screening programs could be measured. Finally, studies of monitoring in high-risk groups describe efforts to monitor individuals with occupational exposure to radiation or with a history of head and neck irradiation for benign or malignant conditions. Such studies could be less relevant to screening in populations exposed to the much lower doses of radiation from the Nevada Test Site. Background: Challenges in Developing and Assessing a Screening Proposal Before the consequences of screening can be estimated, it is necessary to formulate the screening problem. To formulate a strategy researchers must specify the intended population for screening; the screening tests, follow-up tests, and treatments that will be used; and the type of outcomes influenced by the tests. In this section, we enumerate the information gaps, and we suggest a strategy for a "baseline" screening program.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications What Is the Target Population? How Can It Be Reached? For screening to be effective, there should be a substantial prevalence of undiagnosed disease in the target population. It is difficult to estimate this prevalence unless the target population for screening is clearly defined and is similar to populations used for published studies. Current age, place of residence as an infant or young child, and current residence might be used as criteria for screening. One approach to identifying patients might be for primary-care providers (or public health agencies) throughout the United States to ask questions designed to identify exposed individuals. If this approach is taken, those questions are the initial test for screening, and their sensitivity and specificity for identifying high-risk individuals would need to be measured to estimate the prevalence of disease in the screened population. Another approach would be to target individuals between the ages 35 and 55 who are current residents of counties that had high exposure to radiation; this would omit individuals who had moved away and could include low risk individuals who had moved to those areas as adults. Estimating the effectiveness of this approach would require information on the rate of migration to and from these areas and areas that received lower doses. A third approach would replicate the efforts of epidemiologic studies to contact and track residents throughout the United States and have them report to a single, organized source of care. Finally, an effort to teach and promote thyroid self-examination could be the primary tool for screening. Studies of screening programs do provide information about screening in a defined geographic area, but little if any information is available about the efficacy of the other approaches. Exposure from the Nevada Test Site detonations occurred more than 30 years ago. Exposed individuals could now be widely dispersed throughout the United States. People who have already been diagnosed and treated for thyroid cancer cannot benefit from screening, so the yield of screening will depend on the probability of having undiagnosed cancer many years after the exposure. What Test Should Be Done? Who Should Do Them? How Should They Be Interpreted? To estimate the effect of screening, the choice and interpretation of screening and follow-up tests must be specified. Either a physical examination or an ultrasound examination can be used to screen for thyroid cancer. Both tests identify thyroid nodules that could be cancerous. If a nodule is found, a fine-needle aspiration (FNA) is done to identify cell types found. Individuals found to have malignant cells, or cells that could be malignant, could undergo surgery and other treatments for thyroid cancer. The interpretation and accuracy of the tests vary. Whether palpation or ultrasound is used, it is necessary to specify how an abnormal result is defined and what action will be taken if the result is normal or abnormal. One variable is the size of the nodule that prompts confirmation by FNA. In some centers most patients

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications with microadenomas are followed with physical examinations (Tan and Gharib, 1997); in other programs, serial ultrasound test or no tests at all might be done. Recommendations for the management of cystic nodules and of small thyroid cancers and protocols for the management of FNA results also vary. No single protocol has been adopted for screening programs. How the tests are performed also can affect results. For ultrasound, relevant characteristics might include the resolution of the image and the qualifications and experience of the personnel who perform and interpret the test. For physical examination, a relevant characteristic might be whether examiners were given special training in examining the thyroid and whether standardized measurements were taken as part of the examination. In general, population-based studies and studies of surveillance for thyroid cancer have used structured interviews and examinations by expert examiners, conditions that could be difficult to replicate throughout the nation. Proficiency is also an important influence on the accuracy and cost of confirmatory FNA (Hall et al., 1989). Which Cancers Require Treatment? What Treatments Should Be Used? To estimate the effectiveness of early treatment for thyroid cancer we must be able to predict what treatment will be done when a cancer or suspicious nodule is found. Recommendations for treatment of thyroid cancers vary among studies and centers. For example, to manage small, localized papillary carcinomas, which are common in individuals exposed to ionizing radiation, some experts prefer total thyroidectomy; others recommend lobectomy with or without adjuvant therapy with ablative doses of I-131. More aggressive therapies could reduce the recurrence rate but cause higher rates of complication. In a nationwide initiative, individual surgeons' recommendations also might vary, making it difficult to estimate the rate of recurrence or complications that would be associated with screening. What Health Outcomes Should Be Considered? How Do Screening Outcomes Compare with Usual-Care Outcomes? Health outcomes relevant to screening for thyroid cancer include mortality and morbidity related to thyroid cancer and to the tests and treatments used in the screening program. Many studies report the number of cases of cancer detected by screening, but few report observed health outcomes in the screened population, and none has made an unbiased comparison of the outcomes of screening with the outcomes of usual care. As a result, the reduction in morbidity and mortality associated with screening can only be inferred from indirect evidence. Figure F.1 illustrates the type of evidence that could be used to make these inferences. Arcs 1 and 2 indicate direct evidence comparing the mortality and morbidity associated with screening against that of usual care; such evidence is

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE F.1 Evidence model. Arcs indicate causal links and lines of evidence. Arcs 1 and 2 represent direct (experimental) evidence linking screening to morbidity and mortality. Arcs 3 to 5 represent evidence from observational studies of screening. Arcs 6-11 represent links for which the available evidence comes from epidemiologic and clinical observational studies not performed in the context of screening. * ''Stage" means any factor that can be used to predict outcome, including patient characteristics (e.g., age) and features of the cancer (size, histologic type, and presence of local or distant metastases). not available. Studies of screening do provide evidence about the number of cancers found in a population (arc 3) and, to a lesser extent, the stages of these cancers at the time of detection (arc 4) and the number of surgical operations performed as a result of screening (arc 5). Does finding these cancers and treating them earlier reduce mortality and morbidity? The stage of cancer at the time of diagnosis, cancer recurrence, and surgery performed are intermediate or surrogate outcomes of screening—they might be related to mortality and morbidity, but they are not a direct measurement of them. Because there is no direct evidence linking screening to health outcome, the effect of screening on mortality and morbidity is inferred. Arcs 6

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications through 12 illustrate causal links between the intermediate measures and health outcomes. Arc 6 is the relationship of cancer stage at the time of detection to mortality. Arc 7 is mortality due to fatal complications of surgery and anesthesia. Arc 8 is the relationship between stage of cancer at the time of detection and the likelihood of developing recurrent cancer. Arc 9 is the effect of recurrence on mortality. Similarly, morbidity depends on morbidity of cancer at the time of detection (arc 10), morbidity due to complications of surgery (arc 11), and morbidity due to recurrent cancer (arc 12). Arcs 10 and 12 are dashed because most studies report results for usual care rather than screening programs, and so they deal with populations that might not be similar to those included in screening programs. Lack of information about current practice also makes it difficult to estimate the effectiveness of not screening; that is, of usual care. Screening identifies cancers that would be detected in usual care after some delay. How much is gained by finding these cancers earlier? In the absence of randomized trials, this benefit must be estimated from the length of the delay, the extent to which the cancer advances during the delay, and the effect of advancement on mortality and morbidity. Information about usual care is needed to estimate the length of delay and the rate of advancement during the delay, but such data are sparse. For this reason, the confidence range about any estimate of the benefit of early detection by screening will be wide. No screening proposal can satisfy all of these concerns completely, and uncertainties do not mean we should not screen for thyroid cancer. Unless a specific proposal is formulated, however, the consequences of screening cannot be estimated. Baseline Strategy and Assumption We examined two alternatives to usual care: screening with palpation and screening with ultrasound examination. We assumed that screening would take place in the primary-care setting among patients seeing a provider for reasons other than thyroid disease. We also assumed that providers, health systems, and public health officers could reliably identify individuals exposed to a specified dose of radiation by asking questions about risk factors identified in the NCI study of the Nevada nuclear test. Figure F.2 depicts the assumptions we made about how screening and follow-up tests would be interpreted and what actions would be taken on test results. For the "palpation" strategy, FNA would be performed if the examiner palpated a nodule. If the FNA result was "malignant" or ''suspicious," the patient would undergo thyroidectomy. If the FNA result was "benign," palpation would be repeated every 6 months. If, over time, the nodule were to enlarge, a repeat FNA would be done. If the FNA result was "insufficient" or "nondiagnostic," FNA would be repeated, possibly under ultrasound guidance. If the FNA was persistently

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE F.2 Screening decision tree. nondiagnostic, a lobectomy would be done to determine whether there was cancer. These assumptions probably underestimate the use of ancillary tests in the follow-up of individuals found to have nodules. For example, in practice, serial ultrasound examinations, trials of levothyroxine, and scintigraphy are commonly used to evaluate or monitor patients with thyroid nodules, but we assumed that these interventions would not be part of a screening protocol and so did not attempt to assess the benefit or harm they produce. In choosing between palpation and ultrasound as the first test for screening, an important issue is whether it is worthwhile to pursue small (<1 cm or <1.5 cm)

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications impalpable nodules found by ultrasound. When palpation is the first test, this issue is moot, because by definition "incidentalomas" or occult thyroid cancers cannot be detected by palpation. The "ultrasound" strategy is similar to the "palpation" strategy, except that the initial management of a nodule depends on its size. As shown in Figure F.2, if ultrasound is the first test, a decision about how to manage small nodules must be made (node 4). Several experts recommend against routine aspiration of all nodules, but their recommendations are intended for nodules found incidentally in individuals who do not exhibit risk factors for thyroid cancer. This recommendation is depicted as node 5 in Figure F.2, in which patients with additional risk factors proceed to aspiration, whereas "low risk" patients might be followed clinically. However, because individuals who have been exposed to radiation usually are considered "high risk,'' it is possible, in a program to screen individuals exposed to radiation, that aspiration with ultrasound guidance would be attempted in patients found to have occult nodules. If malignant or suspected cytology is found, surgical diagnosis and perhaps aggressive treatment are more likely—again because of the history of radiation exposure. Thus, the foremost question in choosing between ultrasound and palpation is this: In patients with low levels of radiation exposure due to exposure to fallout from the Nevada experiments, do the potential benefits of detecting and treating occult thyroid cancers outweigh the potential harm posed by additional monitoring, surgery, and medical treatments that will result from screening? Because ambiguity about these decisions could reduce the benefits of screening, a screening recommendation about thyroid cancer should carefully specify what level of exposure makes a patient "high risk" with respect to the aggressiveness of follow-up of small nodules, what size nodules should prompt a work-up, and when aggressive surgical therapy should be applied. Methods We reviewed studies of screening for thyroid cancer and studies of the accuracy of tests commonly used to screen for thyroid cancer. Data Sources To find relevant articles on screening for thyroid cancer in high-risk populations, we searched the MEDLINE data base for papers published between 1966 and 1998 using the medical subject heading (MeSH) term thyroid neoplasms combined with the MeSH terms mass screening, environmental exposure, radiation-induced neoplasms, power plants, nuclear reactors, radioactive fallout, and nuclear warfare, and the text words screen, screening, power plants, and nuclear reactors. For studies of test performance, we searched the same data base, combining the MeSH terms thyroid neoplasms and sensitivity and specificity. For

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications recent data on incidence and prevalence of thyroid cancer, we searched for papers published since 1987, and we restricted our focus to papers with the MeSH term thyroid neoplasms and the subheading epidemiology . These searches resulted in a total of 1,353 citations: 904 from the screening search, 249 from the test performance search, and 200 from the epidemiology search. To supplement our MEDLINE searches, reference lists from recent reviews were searched and articles recommended by thyroid cancer panel members were retrieved. Papers were excluded unless they included information on at least one of the following areas: controlled studies screening in asymptomatic persons health outcomes screening by physical exam, ultrasound, or FNA recommendations for screening based on test results population-based studies size, stage, or type of nodule. Studies of screening for congenital or familial thyroid disorders were also excluded. Study Selection In all, 56 studies were included in our review: Twenty-six addressed either screening in an exposed or unexposed population or surveillance in an exposed population; 23 addressed the accuracy of palpation, ultrasound, or FNA; and 10 addressed the incidence, natural history, treated history, or predictors of mortality in patients with thyroid nodules or thyroid cancer. (The numbers do not add to 56 because of overlap among paper topics.) We found only one study that attempted to examine whether a delay in the initial treatment of thyroid cancer was associated with decreased survival (Mazzaferri and Jhiang, 1994). We also included well-done review articles and meta-analyses about the epidemiology, course, and treatment of thyroid cancer and about the relationship between radiation exposure and the risk and type of thyroid cancer (Caruso and Mazzaferri, 1991; Fraker et al., 1997; Gharib, 1994; Gharib and Goellner, 1993; Giuffrida and Gharib, 1995; Moosa and Mazzaferri, 1997; Ron and Saftlas, 1996; Ron et al., 1995; Schlumberger, 1998; Tan and Gharib, 1997). Data Extraction We sought to answer several questions about four topics: Yield of screening. How many individuals with thyroid nodules and cancer does screening identify?

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Accuracy of tests. What are the sensitivity and specificity of the initial tests for screening (palpation or ultrasound) and of the confirmatory FNA test? What factors affect sensitivity and specificity? Consequences of a screening program. Given the prevalence of disease and the accuracy of the diagnostic tests, how many individuals with thyroid cancer will screening detect? How many follow-up tests will be performed? How many healthy individuals will have false-positive test results that require additional evaluation? How many surgical operations will be done? Effectiveness. Is there evidence that early treatment reduces the burden of illness? Specifically, how do the outcomes of screening compare with the outcomes of usual care? How might reducing the delay in diagnosis affect the potential complications of thyroid cancer? From each study of screening or surveillance we extracted the following information: the setting in which screening or surveillance was performed, the risk status of the target population, the screening tests used, and the prevalence of thyroid nodules and of thyroid cancer found by screening. When it was available, we abstracted information on the characteristics of the cancers detected by screening (papillary, follicular, undifferentiated, localized, regional, distant metastasis, and so on.) In studies that measured the performance of screening or confirmatory tests, we recorded the tests used, the gold standard determination of disease, the sensitivity and specificity of the tests, and the presence of biases (such as diagnostic-review bias) that could affect the reported results. We also abstracted the number of patients who underwent surgery to establish a final diagnosis. Probability of Developing Thyroid Cancer According to the American Cancer Society, 17,200 new cases of thyroid cancer will be diagnosed in 1998 in the United States (Landis et al., 1998). The incidence of thyroid cancer varies with sex and age. In the SEER registry, the average lifetime risk of being diagnosed with thyroid cancer was 0.27% for males and 0.66% for females (Ries et al., 1997). (For comparison, in a woman of "average risk," the risk of developing colon cancer or breast cancer is 6% or 9.4%, respectively.) In men, the incidence of thyroid cancer gradually increases until age 70-79, at which time the incidence is 8.6 per 100,000 (Ries et al., 1997). For women, the peak incidence, 13.2 per 100,000, is reached in the 50-54 year age group. The probability of developing thyroid cancer depends on the presence of several risk factors. Exposure to ionizing radiation is the most well-established risk factor for thyroid cancer (McTiernan et al., 1984; Ron et al., 1995). In a population-based study done in Connecticut from 1978 to 1980, about 9% of thyroid cancers were attributable to prior irradiation of the head and neck (Ron et

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications al., 1987). Most studies of this risk factor involve patients who had received external radiation to the head and neck for benign conditions (Pottern et al., 1990; Ron et al., 1988, 1989; Schneider et al., 1993; Shore et al., 1993; Tucker et al., 1991). In those studies, an increased incidence of thyroid cancer was observed among people who had received radiation doses as low as 10 rad (0.10 Gy) (Ron et al., 1988; Schneider et al., 1993), and the incidence rose linearly up to a dose of 1,000 rad (10 Gray) (Ron et al., 1989). Mortality and Morbidity of Thyroid Cancer In 1995 all-stage 5-year survival for thyroid cancer was 92.4% for males and 95.9% for females. In 1995 there were 1,120 deaths due to thyroid cancer in the United States (Wingo et al., 1995); 1,200 deaths are expected in 1998 (Landis et al., 1998). In 1994 the lifetime risk of dying from thyroid cancer was 0.04% for males and 0.07% for females. The risk of dying from thyroid cancer is much lower than the risk of developing thyroid cancer because most people with thyroid cancer, die of other causes. The risk of death depends on age and on the characteristics of the thyroid cancer. Longitudinal studies of the treated history of thyroid cancer indicate that age at the time of diagnosis, tumor size, local invasion, tumor cell DNA content, and regional or distant metastasis are associated with mortality from thyroid cancer (Fraker et al., 1997). Because most deaths occur in elderly people who have undifferentiated, metastatic cancers, average rates overestimate mortality in younger and middle-aged individuals, who tend to have papillary and follicular cancers (Ron, 1996). Although distant metastases are present in only 5% of thyroid cancers at the time of diagnosis, patients in this group account for about 60% of deaths. At the other extreme, 56% of cancers are localized to the thyroid gland at the time of diagnosis, but only 4 patients per 1,000 in this group die from thyroid cancer within 5 years (USDHHS, 1997). SCREENING TESTS History and Physical Examination Palpation A thorough clinical evaluation for thyroid disease usually includes ascertainment of age, gender, family history of thyroid disease, history of hormonal problems or prior neck irradiation, and visual inspection and palpation of the thyroid gland by a clinician (Ashcraft and Van Herle, 1981; Brander et al., 1992). The goal of palpation is to detect nodules and to assess the size of the thyroid gland. When a nodule is palpated, the examiner notes its firmness and attachment to underlying structures and attempts to determine whether a single nodule or multiple nodules are present. Additionally, nearby lymph glands are palpated to detect enlargement (Khafagi et al., 1988; Spiliotis et al., 1991). The examiner asks whether the patient has noticed it, how long it has been present, and whether the

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications patients undergoing surgery had cancer (Howard et al., 1997; Inskip et al., 1997). In patients who underwent external radiation for benign medical conditions, the proportion was 0.20 (Ron et al., 1984; Royce et al., 1979; Shimaoka et al., 1982). Effectiveness of Screening Screening in a population is justified if there is evidence that early detection and treatment before clinical symptoms are apparent will reduce mortality and morbidity or improve quality of life. Other issues to be considered include consequences of false-negative and false-positive test results, acceptability of the test to the screened population, and the risks of treatment. There have been no randomized, controlled trials that address the question of whether screening for thyroid cancer improves patient outcomes. Because thyroid cancer is rare and has a long latency period, such trials are unlikely to be done in the future. Case-control studies can be used to judge the effectiveness of screening, but we could find no studies that evaluated screening programs using that model. As shown in Figure F.1, stage is an important intermediate measure used in many studies as a substitute for direct evidence about mortality and morbidity. In theory screening is more likely to find a cancer that it is smaller, that has not yet metastasized, or that has metastasized less widely, than would be likely to be found without screening. In the absence of controlled studies, the only way to estimate the extent of a benefit would be to know how much earlier, compared to usual care, screening will detect cancers. In this context ''earlier" means not only at an earlier time, but also at an earlier stage as judged by size, histology, or extent of spread. The studies of screening we reviewed contained no data on which to base such estimates. Effect of Early Detection on Mortality Three observational studies have attempted to address prognosis with reference to mortality. These papers show that given a particular size, cell type, and extent of spread—and controlling for age—the prognosis of cancers associated with exposure to radiation appears to be similar to that of cancers that occur in unexposed individuals (Schneider et al., 1986), that in an observational study of an unexposed population, the average size of cancers found by screening was smaller than that of a comparison, unscreened group (Ishida et al., 1988), and that in a statistically controlled study, delay in treatment was associated with lower survival-rate in an unexposed cohort (Mazzaferri and Jhiang, 1994). In the observational study, Ishida and co-workers (1988) compared sizes of thyroid cancers found through screening with those found in the course of usual care. In the screened group, made up of healthy Japanese women without exposure to radiation, 58% of palpated tumors were 2 cm or smaller. The comparison group consisted of outpatients at a thyroid cancer clinic. In the clinic patients

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications there were fewer cancers under 2 cm, and more tumors larger than 4 cm. In the screened group, all but 1 of 216 thyroid cancers were differentiated, and 85.5% were papillary. In the comparison group of 229 patients with thyroid cancer, 70.3% of the cancers were papillary, and there were 9 (3.9%) undifferentiated carcinomas. After 1.5-8 years of follow-up, 96.7% of screened patients were disease-free, compared with 85.6% in the comparison group. None of the screened patients died of thyroid cancer, but 12 patients (5.4%) in the clinic group did. Flaws in the selection of the comparison group limit the usefulness of the article (Ishida et al., 1988). It is not clear whether the clinic patients had already been followed for many years. It appears that the investigators reported the sizes of the cancers in the clinic patients at the time of the study, rather than at the time of diagnosis, which could have been years earlier. The mean age of the clinic patients is given, but it is not clear whether the age distribution was similar in the screened group. Finally, the investigators apparently did not study whether cancers or cancer deaths occurred in screened individuals who were not diagnosed to have cancer on the initial and second screenings. Undifferentiated cancers that developed later in screened patients could have been excluded from the "screened" groups and, in fact, might even have been included in the "clinic" group. These flaws make comparison of tumor sizes and follow-up mortality meaningless. In the statistically controlled study of a cohort of patients under the care of U.S. Air Force physicians, Mazzaferri and Jhiang (1994) record the time from the first manifestation of cancer to initial therapy. Patients who died of cancer had a median delay of 18 months, compared with 4 months for those who survived 30 years. A simple linear regression of the logarithm of delay in treatment on cancer death had a correlation coefficient of 0.49. The results suggest that a delay of 1 year increased the probability of dying of cancer by about 5 percentage points (from nearly 0 to 5%); a delay of 10 years instead of 1 year increased the probability of dying of cancer from 5% to approximately 12%. What is the relevance of these findings to screening? First, the average tumor size was 2.5 cm, and the prognosis was inversely related to the size of the nodule at the time of diagnosis. Although the study did not directly estimate the rate of growth of untreated cancerous nodules, it stands to reason that earlier detection of these very large tumors could improve the outcome. Second, the study documents that, in practice, treatment often was delayed for many years. The reasons are not made clear, and may have occurred after a clinical diagnosis was made. Long delays, followed by a poor outcome, could have been the result of the presence of malignant nodules that were inadvertently managed conservatively for many years, perhaps because an accurate diagnosis was not made initially. In any case, this finding argues (as the authors conclude) for more aggressive initial management of large nodules, once they are diagnosed, but it does not necessarily mean that diagnosing these nodules earlier than was done with usual care would substantially improve outcomes.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Third, the benefit of early detection was apparent only in patients with large nodules, and it should not be overgeneralized to patients with occult nodules or even smaller palpable nodules. If true, this finding suggests that screening be focused on finding large (>1.5 cm), potentially palpable, but clinically unsuspected nodules. Effect of Screening on Morbidity Stage at the time of detection, recurrence of cancer, and complications of surgery can affect morbidity (Figure F.1). There are no data from studies of screening about the effect of early detection on recurrence rates or on the frequency of surgical complications in the screened population. Recurrence of Cancer We found no studies that directly compare rates of recurrence in screened versus unscreened populations. Most screening studies involve one-time screening and do not follow patients over time for evidence of recurrence or other outcomes. One follow-up study of surveillance for thyroid cancer in patients exposed to external beam radiation for benign conditions of the head, neck, and thorax (Schneider et al., 1986) reports a lower recurrence rate in patients diagnosed after a screening program was begun compared with those diagnosed through usual care—reflecting factors such as smaller tumor size in cancers discovered through screening. Factors associated with risk of recurrence, such as age at diagnosis (Krausz et al., 1993; Mazzaferri and Jhiang, 1994; Schindler et al., 1991; Schneider et al., 1986; Simpson, 1987; Tubiana et al., 1985), tumor size (Mazzaferri and Jhiang, 1994; Noguchi, 1995; Simpson, 1987; Schindler et al., 1991; Schneider et al., 1986), male sex (Noguchi et al., 1995; Schindler et al., 1991; Tubiana et al., 1985), and local invasion or metastases (Mazzaferri and Jhiang, 1994; Simpson et al., 1987; Schneider et al., 1986; Schindler et al., 1991; Simpson et al., 1987; Tubiana et al., 1985), are generally the same as those associated with increased mortality. Follow-up studies of thyroid cancer patients report recurrence rates of about 10-30%. About two-thirds of recurrences come within 10 years of initial diagnosis, but recurrence can occur throughout a patient's lifetime. A thyroid cancer recurrence does not necessarily mean increased mortality (Krausz et al., 1993). Cure rates remain high even for recurrences, except for patients who have metastases at the time of recurrence (Mazzaferri and Jhiang, 1994). Few studies relate factors at initial diagnosis to mortality at recurrence, but those that do find survival of a recurrence affected most strongly by age. A Japanese study (Noguchi et al., 1995) with follow-up periods of 10-30 years examined risk factors in patients who died after recurrence with patients who survived

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications a recurrence. Only age at initial diagnosis correlated with survival of a recurrence. Similarly, an Israeli study (Krausz et al., 1993) found only that age at initial diagnosis was a significant risk factor for mortality after recurrence. Another study of Japanese patients (Asakawa et al., 1997) found increased mortality of recurrent thyroid cancers to be associated with age at diagnosis and shorter period between initial diagnosis and recurrence. Tumor size and spread at initial diagnosis do not appear to be associated with mortality from recurrence. Even though recurrent thyroid cancers are usually highly curable, Mazzaferri (1987) makes the point that a recurrence, even when cured, is never an insignificant event for the patient, in terms of psychological costs and quality of life. Harms of Screening Uncertainty about effectiveness is of particular concern when significant harms are associated with screening. Almost no information about quality of life or morbidity related to the diagnosis and treatment of thyroid cancer has been published. In general, false-positive test results can cause anxiety. Hypothyroidism, caused by thyroid ablation and treatment for hypothyroidism, unexpected complications of surgery or radioiodine therapy, and even preparation for tests used to find recurrences (Dow et al., 1997a,b), can cause morbidity and affect the quality of life of patients with thyroid cancer, but the consequences of most of these events and conditions have not been systematically studied. The long-term complications of thyroid surgery are hypocalcemia, a serious, difficult-to-treat condition due attendant to hypoparathyroidism; and hoarseness, due to injury to the recurrent laryngeal nerve. The frequency of these complications depends on the extent of the procedure and the experience of the surgeon. Complication rates vary among centers (Fraker et al., 1997). For the most extensive procedure, total thyroidectomy, the risk of hypocalcemia range from 7% to 32% in four surgical series with long-term follow-up (Fraker et al., 1997). In the same study the risk of recurrent laryngeal nerve injury ranged from 0% to 7%. The study reported the experience of highly skilled surgeons at major centers. Major surgery of the thyroid is generally considered difficult, and results of experienced surgeons are thought to be much better than the "average" results of surgeons who perform thyroid surgery only occasionally. Less extensive surgery, such as "near total" and subtotal thyroidectomy, causes fewer complications, but may be associated with higher rates of tumor recurrence and mortality. Summary Table F.5 summarizes the findings of our review. The table shows estimates of relevant probabilities and of the number of significant events per 10,000 individuals screened. Many of the estimates, such as those for test performance and

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications TABLE F.5 Summary of Evidence Regarding the Benefits of Screening for Thyroid Cancer   Probability Palpation Ultrasound References Probability of having a nodule       Table F.3a-b Any size nodule 0.35       0.5-1.0 cm 0.12       1.0-1.5 cm 0.05       >1.5 cm 0.02       Probability that a nodule is cancer       Table F.3a-b nodules smaller than 1 cm 0.03       nodules larger than 1 cm 0.10       Cut-off for a significant nodule   1.0 cm 0.5 cm Figure F.2 Probability of cancer given cut-off   0.0007 0.011   Sensitivity for nodules       Tables F.1, 4 0.5-1.0 cm   0.00 1   1.0-1.5 cm   0.55 1   >1.5 cm   0.65 1   Specificity for nodules       Tables F.1, 4 0.5-1.0 cm     0.98   1.0-1.5 cm   0.98 0.99   >1.5 cm   0.98 1.00   Fine needle aspiration (FNA)       Table F.2a-b Sensitivity for cancer 0.8       False positive rate 0.35       Lobectomy or subtotal thyroidectomy       Fraker et al. Complication (recurrent laryngeal nerve injury) 0.0005       Complication (hypocalcemia) 0.0005       Total thyroidectomy       Fraker et al. Complication (recurrent laryngeal nerve injury) 0.04       Complication (hypocalcemia) 0.1       Morbidity and mortality prevented by screening   — — No data Summary         Events per 10,000 screened         Diagnosed to have a nodule (true positives)   405 1900   Diagnosed to have a nodule (false positives)   386 271   Undergo at least one FNA   791 2171   Undergo FNA but do not have cancer   751 2076   Undergo lobectomy   102 696   Cancers diagnosed   32 85   Cancers missed   38 35   Surgical complications   5 13   Death prevented in 5 years   No data No data  

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications surgical complication rates, are derived from studies performed in specialized settings that are not likely to be representative of the results of a program of screening in the general population. Data were insufficient to estimate the effect of screening on mortality or morbidity from thyroid cancer and from recurrences of thyroid cancer. The information needed to make such a determination involves detailing survival rates by risk category among patients found to have cancer during the course of usual care and estimating the effect of early detection on the distribution cancers among people according to category. As shown in Table F.6a, the SEER study provides estimates of 5-year survival by sex and by the extent of spread (localized, regional, or distant) found among cancers diagnosed in usual care. It also provides estimates of the proportion of cancers found in each risk category. These data can be used to estimate overall survival for males and females with thyroid cancer found in the general population. Although the SEER data provide incomplete information about risk (there are no data by histologic type, for example), these are the only population-based data available about the distribution through risk categories of cancers found during usual care. To determine whether early detection improves outcome, it would be necessary to estimate how often cancers are detected earlier, and how much earlier they are detected. Specifically, it would be necessary to know the average delay in diagnosis through usual care compared with that from screening and the rates of growth or spread of the cancers between the time they would be found by screening and the time they would be found in the usual course of care. Table F.6b shows data elements—but not actual data—in one possible causal chain linking earlier diagnosis to improved survival. The improvement in survival could be estimated if we knew the distribution of tumor sizes in the usual-care population and in a screened population; the average duration of delay in diagnosis in usual care, relative to screening; the rate at which tumors in one size category progress to a larger size category; and the relationship between the size of the cancer and the likelihood that the cancer is localized. Because data about these variables are lacking—studies of screening have not demonstrated to what degree the cancers found by screening have a better prognosis—we could not make a reliable estimate of the benefits of screening. How large is such a benefit likely to be? Table F.6c depicts a hypothetical example showing the potential relationship between earlier detection and 5-year survival for adult females. As shown in Table 6a, in the general population 60% of thyroid cancers were localized at the time of detection; 31% had spread to regional nodes. If screening increased the proportion of cancers that had no regional or distant metastases from 60% to 70%, the overall 5-year survival for thyroid cancer would increase from 0.947 to 0.952. Put differently, 184 people with thyroid cancer would need to be treated to prevent 1 death in 5 years. As seen in Table F.5, 32 cancers would be found per 10,000 people screened. Therefore,

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications TABLE F.6 Hypothetical Relationship Between Efficacy of Early Detection and Five-Year Survival from Thyroid Cancer a. SEER data   Five-year survival Proportion of cancers in each risk category Overall Survival Risk categories Total Males Females   Males Females localized 0.997 0.994 0.998 0.60 0.596 0.599 regional 0.937 0.913 0.947 0.31 0.283 0.294 distant 0.448 0.403 0.475 0.05 0.020 0.024 unstaged 0.766 0.773 0.761 0.04 0.031 0.030 5 year and overall survival       0.931 0.947   b. Consequences of screening (categories of information needed to estimate effect of screening on detection of disease by stage)   c. Hypothetical improvement in survival in relation to risk categories if screening increased proportion of cancers with no metastases from 60% to 70% compared to usual care (adult females only)   Usual Care Screening   Risk categories localized 0.6 0.7   regional 0.31 0.21   distant 0.05 0.05   unstaged 0.04 0.04   Contribution to 5 year survival 0.947 0.952   Number needed to treat to prevent 1 death in 5 years   184 Number needed to screen to prevent 1 death in 5 years   57,445

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