Abstract
The risk of cataracts after 131I therapy for cancer is unknown. The objective of this study was to evaluate the association between 131I therapy for thyroid cancer and risk of receiving cataract surgery in Taiwan. Methods: This was a nationwide population-based cohort study of patients with thyroid cancer diagnosed during the period 1998–2008. The data were obtained from the Taiwan National Health Insurance Research dataset. The cumulative 131I activity in each patient was calculated. Hazard ratios were calculated using a time-dependent survival analysis to estimate the effect of 131I therapy on the risk of receiving cataract surgery. Results: A total of 8,221 patients were eligible for the final analysis (mean age, 43.2 y; mean follow-up, 5.9 y); 69% received 131I with a median cumulative activity of 3.7 GBq. Two hundred patients received cataract surgery. The adjusted hazard ratios were 0.77 (95% confidence interval, 0.54–1.09), 0.92 (95% CI, 0.64–1.31), and 1.06 (95% CI, 0.58–1.94) for cumulative 131I activities of 0.1–3.6, 3.7–7.3, and 7.4 GBq or more, respectively, compared with a cumulative activity of 0. No trend was noted (P = 0.85). No interaction between 131I activity and age or between 131I activity and sex was noted (all P > 0.05). Conclusion: 131I treatment for thyroid cancer did not increase the risk of receiving cataract surgery up to 10 y after treatment. However, further research with direct lens examination and a longer follow-up period is needed to assess subtle and late adverse effects beyond 10 y.
A cataract is opacity of the ocular lens that results in visual impairment. It is a leading cause of blindness and accounts for 51% of global blindness, about 20 million people (1). In the United States, the prevalence of cataracts was estimated to be 22% for people aged 65–69 y and up to 71% for those older than 80 y (2). The number of cataract surgeries continues to rise steadily and poses a substantial financial burden (3). In Taiwan, the prevalence of cataracts was estimated to be 51% for people older than 50 y (4) and 59% for those older than 65 y (5).
Aging is the most common cause of cataracts, which also develop more frequently after uveitis (6), intraocular cancer, ocular trauma (7), and intraocular surgery. Well-established risk factors include diabetes, smoking, exposure to ionizing radiation or ultraviolet B light, and use of steroids (8–10). Less well-established risk factors include myopia, drinking, obesity, hypertension, nutrition, exogenous estrogen, and statin use (8,10,11). Children with congenital cataracts are usually diagnosed at birth and receive combined lens extraction and posterior capsulectomy (12). Patients with myotonic dystrophy are more likely to develop cataracts at a much earlier age (13).
Radiation cataracts used to be classified as a deterministic effect with a threshold of 2 Gy for acute exposure and 5 Gy for chronic exposure (14). Recent epidemiologic studies on atomic bomb survivors (15,16), Chernobyl accident clean-up workers (17), interventional cardiologists and staff (18–20), radiologic technologists (21), astronauts and airline pilots (22,23), and Taiwanese residents in radiocontaminated buildings (24) suggested a linear no-threshold relationship at low doses for radiation cataracts. Accordingly, a new occupational exposure guideline has considerably lowered the radiation cataract threshold to 0.5 Gy and the occupational lens equivalent exposure limit to a mean of 20 mSv per year over a 5-y period and less than 50 mSv in any 1 y (25).
Radiation cataracts had not been considered as an important adverse long-term effect of 131I therapy probably because radiation cataracts had been regarded as a deterministic effect and a dose to the lens, estimated to be about 60 mGy per 3.7 GBq (26), was well below the old threshold of 2–5 Gy (14). However, as mentioned above, the new threshold has recently been revised to 0.5 Gy and there may be a linear no-threshold relationship (25). Furthermore, some thyroid cancer patients received repeated 131I therapy for recurrence or metastases, giving a lens dose of hundreds of mGy. Currently there is no information on radiation cataracts after 131I therapy for thyroid cancer, despite being clinically and scientifically important for the assessment of treatment safety.
Lens extraction surgery is the only effective treatment for cataracts and indicates late stage of cataracts when vision is severely affected. In this study, a nationwide cohort of thyroid cancer patients from the Taiwan National Health Insurance (NHI) database was used to investigate the association between 131I therapy for thyroid cancer and risk of receiving cataract surgery.
MATERIALS AND METHODS
Taiwan NHI Research Database
The database used was from the NHI reimbursement system of Taiwan, which was launched in March 1995 and covers more than 98% of the population. Detailed information concerning health care services, including up to 3 or 5 diagnoses coded by the International Classification of Diseases, Ninth Revision (ICD-9) (27), prescription drugs and doses, orders, and dates, were obtained for each outpatient visit or hospital admission. This database has been used for epidemiologic research, and information on prescription use, diagnoses, and hospitalizations is of high quality (28–30). The authors have previously used this database to assess the link between 131I therapy for thyroid cancer and primary hyperparathyroidism (31).
The NHI reimbursement data of Taiwan is anonymized and maintained by the National Health Research Institute with strict confidentiality in accordance with the Personal Electronic Data Protection Law. This study was also approved by the Ethics Review Board of the National Taiwan University College of Public Health.
Study Design and Population Selection
This was a nationwide population-based cohort study. A total of 18,111 patients with a diagnosis of thyroid cancer (ICD-9 code 193) made between 1997 and 2008 were identified from the Registry of Catastrophic Illnesses Patients, which includes people diagnosed with cancer, serious autoimmune diseases, end-stage renal disease, and chronic mental disorders. Patients with such illnesses are exempt from medical costs, so the registry database is comprehensive, with excellent validity.
Figure 1 shows population selection. The date of the first inpatient diagnosis of thyroid cancer, typically at the date of the first cancer surgery, was used as the index date. We excluded patients who had a diagnosis of thyroid cancer before 1998 and those who had no thyroidectomy on the index date or had undergone any 131I whole-body scanning before the index date, because they were more likely to be prevalent cases.
Population selection. Fluoroscopy includes coronary angiography, aortography/noncardiac angiography, procedures related to biliary system (t-tube cholecystography, operative cholangiography, endoscopic retrograde cholangiopancreatography, endoscopic retrograde pancreas drainage, percutaneous transhepatic cholangiography, percutaneous transhepatic cholangiography-drainage, and percutaneous gallbladder drainage), percutaneous transluminal angioplasty, transarterial embolization, percutaneous nephrostomy, hysterosalpingography, myelography, percutaneous vertebroplasty, and venography.
Patients were excluded if they had received first 131I activity before, or more than 6 mo after, the index date; had missing information on sex or address; had been followed up 2 y or less from the index date; or had received extraction surgery before or within 2 y after the index date. Patients who had received radiotherapy, chemotherapy, or certain kinds of fluoroscopic examination (32) (the footnotes of Fig. 1 provide details) 2 y or more before cataract surgery or last clinical visit were also excluded. This was to minimize confounding and to ensure that the main radiation source was 131I therapy.
We further excluded patients who had been diagnosed as muscular dystrophy or other dystrophy; had received capsulectomy for congenital cataract; had been diagnosed as inflammatory disorders of uvea, intraocular tumor, or ocular trauma; or had received intraocular surgery 2 y or more before cataract surgery or last clinical visit. ICD-9 codes, the Anatomic Therapeutic Chemical codes of drugs, and drug or order codes used in the Taiwan NHI dataset are listed in Supplemental Tables 1–3 (supplemental materials are available at http://jnm.snmjournals.org).
Statistics
All statistical analyses were performed using SAS software (release v.9.4; SAS Inc.). P values were 2-sided, and a value of less than 0.05 was considered statistically significant. A Cox proportional hazards model was used to estimate the effect of 131I therapy on the risk of receiving extraction surgery using a time-dependent covariate for cumulative 131I activity by the SAS PHREG procedure. A latency of 2 y was used to calculate cumulative 131I activity and person-years at risk. Cumulative 131I activity was treated as a 4-level covariate (0, 0.1–3.6, 3.7–7.3, ≥ 7.4 GBq). Patients with 0 GBq were used as the reference group.
The potential confounding factors considered in the primary analysis (model 1) included sociodemographic characteristics (sex, age and calendar year at diagnosis of thyroid cancer, income, and urbanization degree of a residential area). We also considered comorbidities that would affect the risk of developing cataracts, particularly diabetes. Prescription drugs that could potentially confound the association between 131I therapy and cataract risk were identified, including statin, estrogen, and steroid use. Other radiation sources from diagnostic radiation examinations were controlled for, including diagnostic radiology (head x-ray and CT) and nuclear medicine examinations (99mTc-methyldiphosphonate bone scan, 201Tl whole-body scan, 67Ga scan, 99mTc-labeled red blood cell scan, 18F-FDG PET scan, parathyroid scan, sialoscintigraphy, 131I thyroid scan, 99mTc thyroid scan). Each diagnostic radiation examination was treated as a binary variable (0 = no, 1 = yes). Slit-lamp examination was included in the model to consider potential detection bias. A trend was assessed by treating 131I activity as a continuous covariate. Interaction between 131I activity and age and between 131I activity and sex was examined.
Sensitivity analyses were performed to investigate bias. First, an alternate analysis (model 2) was performed for cataracts with less visual impairment: at least 1 inpatient admission or 3 outpatient visits with diagnosis coded as ICD-9 366, prescription of relevant eye drops (pirenoxine, azapentacene), or receiving extraction surgery. Second, the analysis (model 3) was repeated, focusing on patients younger than 50 y only because younger patients exposed to radiation were likely to be at more risk (16,21,24). Third, the analysis (model 4) was conducted focusing on patients receiving only 1 131I ablation therapy. Fourth, the analysis (model 5) was repeated using a latency of 5 y (rather than 2 y) to investigate possible later biologic effects of 131I activity. Lastly, we repeated the analysis (model 6), treating both cumulative 131I activity and age as time-dependent variables to consider a possible aging effect.
RESULTS
In total, there were 8,221 thyroid cancer patients eligible for the primary analysis. Their characteristics are shown in Table 1. Sixty-nine percent of patients received 131I. The median cumulative 131I activity was 3.7 GBq, and 131I was given on average 1.5 mo after the index date. The mean follow-up period was 5.9 y. Compared with patients with zero 131I activity, those with 131I activity were followed up for a slightly longer period (6.1 vs. 5.5 y, P < 0.001), were slightly younger (42.9 vs. 44.0 y, P < 0.001), had a slightly lower female-to-male ratio (men % = 21% vs. 16%, P < 0.001), had thyroid cancers that were diagnosed earlier in the decade (48% vs. 56% in 2003–2008, P < 0.001), were more likely to have hyperlipidemia (19% vs. 16%, P = 0.01), were less likely to have chronic kidney disease (2% vs. 3%, P < 0.001), were less likely to take oral steroids (2% vs. 3%, P = 0.01), and were more likely to receive CT scanning (37% vs. 32%, P < 0.001) and many nuclear examinations particularly 99mTc-methyldiphosphonate bone scanning (13% vs. 8%, P < 0.001) and 201Tl whole-body scanning (14% vs. 6%, P < 0.001).
Characteristics of Patients with Thyroid Cancer by 131I Activity
Figure 2 shows the incidence rate and adjusted hazard ratios (HRs) in the primary analysis (model 1) and sensitivity analyses (models 2–6). Of the 8,221 patients, 200 received cataract extraction surgery during the 31,512 person-years. There were 72 patients receiving cataract extraction surgery during 9,354 person-years for a cumulative 131I activity of 0 GBq and 128 patients receiving cataract extraction surgery during 22,158 person-years for more than 0 GBq. The overall rate of receiving cataract extraction surgery was 635 per 105 person-years (770 and 578 per 105 person-years for 131I activity = 0 and > 0 GBq, respectively).
Incidence and adjusted HRs of cataracts associated with 131I treatment in patients with thyroid cancer and sensitivity analyses. Model 2: different cataract definition—cataract defined as at least 1 inpatient admission or 3 outpatient visits with diagnosis coded as ICD-9 366, prescription of relevant eye drops (pirenoxine, azapentacene), or receiving extraction surgery. HR adjusted for sex, age, and calendar year at diagnosis of thyroid cancer, income, degree of urbanization, comorbidities (diabetes, hypertension, hyperlipidemia, chronic kidney disease, chronic obstructive pulmonary diseases, alcohol-related diseases), drug use (estrogen, statin, oral steroid, steroid eye drops), receiving radiologic examinations (head x-ray, computerized tomography), nuclear medicine examinations (99mTc-methyldiphosphonate bone scan, 201Tl whole-body scan, 67Ga scan, 99mTc labeled red blood cell scan, 18F-FDG PET scan, parathyroid scan, sialoscintigraphy, 131I thyroid scan, 99mTc thyroid scan), and slit-lamp examination. Cumulative 131I activity was used as continuous variable in trend test.
In the primary analysis (model 1), the adjusted HRs were 0.77 (95% confidence interval [CI], 0.54–1.09), 0.92 (95% CI, 0.64–1.31), and 1.06 (95% CI, 0.58–1.94) for cumulative 131I activity of 0.1–3.6, 3.7–7.3, and 7.4 GBq or more, respectively, compared with a cumulative activity of 0. No trend with dose was noted (P = 0.85). No interaction between cumulative 131I activity and age or between 131I activity and sex was noted (all P > 0.05, data not shown). In the sensitivity analyses (models 2–6), the findings remained negative.
DISCUSSION
Although radiation-induced lens opacities with varying degrees of severity were found in many epidemiologic studies, whether such opacities affect vision is rarely reported (16,21). In this study, we assessed clinically relevant visual impairment as quantified by the risk for receiving cataract surgery and obtained negative findings for patients receiving 131I therapy (median, 3.7 GBq) in an average of 5 y of follow-up per patient using the NHI claims dataset.
Our negative findings were not consistent with the results of the studies using cataract surgery as an outcome among atomic bomb survivors (lens dose, range = 0 to > 3 Gy) (16) and radiologic technologists (occupational lens dose, median = 28.1 mGy) (21). From the study of 6,066 atomic bomb survivors exposed at age 20 y, the RR per Gy was 1.32 (95% CI, 1.17–1.52) after a follow-up period of 50 y. After a nearly 20-y follow-up of 35,705 radiologic technologists aged 23–44 y, the risk of self-reported cataract extraction for those with number of x-rays 25 or greater was 1.5 times that for those with number of x-rays less than 5 (95% CI, 1.09–2.06). Explanations for the disparity between these studies and the current analysis might relate to differences in the radiation dose received, in the age at exposure, or in the follow-up period.
Several methodologic issues need to be clarified before any conclusion can be made. There is a concern that patients receiving 131I therapy usually had more advanced-stage thyroid disease and may have been examined more by diagnostic radiology and nuclear medicine, which would be a source of additional and unmeasured radiation exposure. Lens dose from head CT was estimated to be 50 mGy (33). However, additional radiation exposure would tend to overestimate the effect of 131I therapy and cannot explain the negative results found.
There is an issue whether the negative findings reported result from a long latency period because the latency seems to be inversely related to dose (9,34). An average latency of 2–3 y, ranging from 6 mo to 35 y, was noted for radiation-induced lens opacities after acute low-dose x-ray exposure (35). We used latencies of 2 and 5 y in the analyses, and the results remained similar. We were not, however, able to examine the long-term effects beyond 10 y in this dataset.
We recognize that the administered 131I activity used in our study could not be a precise indicator of absorbed doses to lenses. Doses may depend on different clinical situations, such as recombinant human thyroid-stimulating hormone use, presence of thyroid remnants or metastases, renal clearance, and use of techniques to increase 131I excretion such as lemon juice intake, hydration, frequency of urination, and laxative use. Such misclassification would be nondifferential, and its effect would tend to move the effect estimate toward null. Information on the type of cataract was not available in the NHI dataset, so that the effects on specific radiation-induced types—posterior subcapsular cataract and cortical cataract (9,34,36)—could not be further analyzed. Also, several potential confounders such as smoking, alcohol, diet, sunlight exposure, and use of self-paid radiation modalities were not measured, and myopia was not validly coded in the NHI reimbursement dataset, raising concern about uncontrolled confounding.
Cataract surgery was used as the main outcome in this study and although a different definition was used in the sensitivity analysis we recognize that this was not as sensitive as diagnosis using direct eye slit-lamp examination. Therefore, we could not rule out the possibility that 131I therapy induces mild cataracts. Our final concern was that the follow-up period of up to 10 y might be too short for occurrence of late-stage cataracts.
Having considered limitations, we recognize that this study had several strengths. The large sample size in this nationwide study gave excellent statistical power, minimized the problem of losing cohort members at follow-up, and allowed accurate calculation of 131I activity. Treatment of patients at different hospitals was not an issue because the NHI database includes more than 98% of the population in Taiwan. Because cataract surgery was validly coded due to the nature of insurance reimbursement, misclassification bias was minimized. In addition, the NHI database allowed us to deal with as many potential confounders as possible to obtain unbiased results. Last, because the study was prospective, we were able to investigate the causal relationship between radiation exposure from 131I therapy and the risk of receiving cataract surgery.
CONCLUSION
Overall, we did not find that 131I treatment for thyroid cancer in Taiwanese patients increased their risk of receiving cataract surgery up to 10 y after treatment. Our negative findings indicate that medical costs spent on cataract surgery would not increase after 131I therapy and may have clinical implications for assessing the safety of 131I therapy. However, further research with direct lens examination and a longer follow-up period is needed to assess subtle and late adverse effects beyond 10 y.
DISCLOSURE
The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. No potential conflict of interest relevant to this article was reported.
Footnotes
Published online Feb. 2, 2016.
- © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
REFERENCES
- Received for publication September 21, 2015.
- Accepted for publication January 7, 2016.
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