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The Risk of Second Primary Malignancies up to Three Decades after the Treatment of Differentiated Thyroid Cancer

Departments of Radiation Oncology (A.P.B., J.C., Y.J.H., D.C.S., J.D.T.) and Oncological Sciences (A.S.), Huntsman Cancer Hospital, University of Utah, Salt Lake City, Utah 84112

Address all correspondence and requests for reprints to: Dr. Jonathan D. Tward, M.D., Ph.D., Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Salt Lake City, Utah 84112-5560. E-mail: Jonathan.Tward{at}hci.utah.edu.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Background: The 10-yr survival rate of patients with differentiated thyroid cancer exceeds 90%. These patients may be at elevated risk for secondary cancers.

Methods: The risk of nonthyroid second primary malignancies after differentiated thyroid cancer was determined in 30,278 patients diagnosed between 1973 and 2002 from centers participating in the National Cancer Institute’s Surveillance, Epidemiology, and End Results program. Median follow-up was 103 months (range, 2–359 months). Risk was further assessed for the addition of radioisotope therapy, gender, latency to development of secondary cancer, and age at thyroid cancer diagnosis.

Results: There were 2158 patients who developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population [observed/expected (O/E) = 1.09; 95% confidence interval (CI), 1.05–1.14; P < 0.05; absolute excess risk per 10,000 person-years (AER) = 6.39]. A significantly greater risk of second primary malignancies over that expected in the general population was for patients treated with radioisotopes (O/E = 1.20; 95% CI, 1.07–1.33; AER = 11.8) as well as for unirradiated patients (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53). However, the increased risk was greater for the irradiated vs. the unirradiated cohort (relative risk = 1.16; 95% CI, 1.05–1.27; P < 0.05). Gender did not affect risk. The greatest risk of second primary cancers occurred within 5 yr of diagnosis and was elevated for younger patients.

Conclusions: The overall risk of second primary malignancies is increased for thyroid cancer survivors and varies by radioisotope therapy, latency, and age at diagnosis.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
An estimated 25,000 people in the United States are diagnosed with a primary thyroid malignancy every year, and approximately 1,500 of those patients will die of their disease (1). Although thyroid cancer accounts for only approximately 1.5% of cancers diagnosed in the United States, the age-adjusted incidence of thyroid cancer has been steadily rising (2). Women are three times more likely than men to develop thyroid cancer, with a peak incidence seen in people 40–50 yr old (2). Exposure to radiation is a well-established risk factor, and some of the increase may be due to the former practice of treating some benign childhood conditions of the head and neck with radiotherapy (3, 4, 5).

The differentiated papillary and follicular histologies account for approximately 90% of cases and have a 10-yr overall survival exceeding 90% (6). Definitive therapy for these differentiated cancers is complete or partial surgical thyroidectomy, with adjuvant radioiodine ablation/therapy used for residual, unresectable, and/or metastatic disease (7, 8, 9). Radioiodine use in thyroid cancer treatment has caused concern about the potential for development of secondary malignancies. Numerous malignancies are thought to be radiogenic, which have been identified by studies involving environmental, medical, and occupational exposures and most notably in Japanese survivors of nuclear warfare (10, 11, 12, 13, 14). The most prominent among these cancers are leukemia, thyroid, breast, lung, and skin cancers, contrasted with some more radioresistant organs such as the prostate and the central nervous system (15).

Because most survivors of differentiated thyroid cancer have a long life expectancy, it is important to understand how differences in clinical, pathological, and treatment characteristics alter their risk profiles for developing second primary cancers. In this study, we determined how these factors affected the incidence of second primary malignancy in a large U.S. population database over a period of up to three decades.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
The study population was assembled using records from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER program database includes records from patients starting in 1973. A 98% case ascertainment is mandated from 14 population-based registries and three supplemental registries representing approximately 26% of the U.S. population (16). The SEER registries contain information on patient demographics, tumor site, histology, date and source of diagnosis, date of death, and treatment. Each year quality and completeness studies are conducted in SEER areas to ensure high quality data.

The SEER program statistical analysis software package (SEER*Stat, version 6.2.3) was used to identify patients diagnosed with a primary thyroid malignancy of follicular or papillary type from 1973–2002 (the histological subtypes included in analysis were ICD codes 8330, 8331, 8335, 8340–8344, 8260, and 8050). Patients with other thyroid cancer histologies or whose thyroid malignancy was not their first primary cancer were excluded from analysis. Second primary cancers diagnosed within 2 months of the thyroid cancer diagnosis and secondary thyroid cancers were also excluded. The time to development of second primary malignancies was calculated from the date of diagnosis of differentiated thyroid cancer.

From 1973–1987, the SEER registries encoded radioisotope therapy as other radiation. Registrars were also instructed to encode radioactive interstitial implants (brachytherapy) in the other category during that time period. External beam radiation was encoded as its own distinct entity. For our statistical analysis, we considered patients treated from 1973–1987 encoded as other as patients who received radioisotope therapy, because it was unlikely that papillary or follicular thyroid cancer would be treated with brachytherapy. From 1988 onward, radioisotope therapy was specifically encoded. In addition, thyroid ablative radioisotope doses used before the mid-1980s were higher than more modern practices (9, 17, 18). For these reasons, additional analyses with radioisotope therapy as a cohort were performed for the period 1988 onward to provide more statistical certainty.

The SEER*Stat MP-SIR (Multiple Primary-Standardized Incidence Ratio) tool was used to calculate standardized incidence ratios (SIRs) and excess risk for second primary malignancies by comparing these patients’ subsequent cancer profile to the number of cancers that would be expected based on incidence rates for the general U.S. population.

Statistics

The risk of second primary cancers was estimated by compiling person-years (PY) of observation according to age, sex, and calendar-year periods from 2 months after the date of thyroid cancer diagnosis to the date of death, date of last follow-up evaluation, date of diagnosis of second primary cancer, or the end of the study (December 31, 2002), whichever occurred first. Cancer incidence rates specific for 5-yr age groups, gender, and calendar-year intervals were multiplied by the accumulated PY at risk to estimate the number of cancer cases expected. The observed and expected numbers of second cancers were then summed, with the SIR expressed as the ratio of observed-to-expected (O/E) cases. The absolute excess risk per 10,000 PY (AER) was determined by subtracting the expected number from the observed number of second cancers and then dividing the difference by the number of PY at risk. The number of excess second cancers was expressed per 10,000 PY. Risks of second cancers were stratified by sex, age group at thyroid cancer diagnosis, time since diagnosis (latency), and treatment (radiotherapy vs. no radiotherapy). The statistical analysis, including the tests for heterogeneity and linear trend as well as the regression modeling, were conducted using the Poisson modeling method of Breslow et al. (19). This approach is based on the fact that for grouped data, proportional hazards modeling with known baseline hazard is formally equivalent to a Poisson regression.

SIR and AER are two complementary measures of the incidence of an event of interest (in this case second primary cancer) in a subpopulation compared with the entire population. Both are based on comparing the observed number of events in the subpopulation O with the number of events E expected if the risk profile of the subpopulation were identical to that of the full population. Because, as a person ages, his or her risk of an event typically changes (due to both attained age and attained calendar year), the calculation of the expected number of events is adjusted for these variables. Additionally, fixed characteristics affecting event rates, such as gender and race, are incorporated in the calculation of the expected number of events. These adjustments make subpopulations of different structures comparable, for example, longer follow-up in one group. SIR and AER differ in the way they combine O and E; SIR measures the fold difference between the observed and expected number of events (SIR = O/E), whereas AER measures the actual number of excess events normalized to the number of PY observed [AER = (O – E)/PY). Thus, SIR measures the relative risk (RR) of the event on an individual level and does not depend on the frequency of the event in the population, whereas AER measures the population impact, where small increases in the relative risk of a common event affects more people than a large increase in a rare event. It should be noted that the length of follow-up does not affect either measure; the number of observed events O increases, but so do the number of expected events E and the number of person-years PY.

We have also used case-level analysis to examine the effect of latency and age at diagnosis on second primary cancers without categorizing. In this analysis, we considered any nonthyroid second primaries diagnosed at least 2 months after the primary thyroid cancer as an event. We have used SEER*Stat to obtain population rates of nonthyroid cancers by race, gender, and 5-yr age and calendar-year periods. The follow-up period of each case was broken into intervals in which the age group and year group did not change. The expected number of events during each such period was estimated as the length of the interval multiplied by the corresponding risk of cancer. The observed number of events (equal to 0 if the patient survived the interval without an event and 1 if the interval ended with a cancer diagnosis) was modeled using Poisson regression offset by the logarithm of the expected number of events. Because log(SIR) = log(O) – log(E), this approach actually models log(SIR). Gender, race, and treatment group were entered as categorical predictors (including radiotherapy as an independent predictor), and age at diagnosis and latency at the end of the interval were modeled via a restricted cubic spline. An examination of the fitted splines showed that age at diagnosis could be modeled as a linear effect.

The effect of external beam radiation therapy for treatment of thyroid cancer on the development of second primary malignancies was analyzed for cohorts based on age at diagnosis, gender, and the latency period in 5-yr intervals to the development of second cancers.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Overall risk of developing second primary cancers

The demographics of the study population are shown in Table 1. A total of 30,278 patients were evaluable. Of these patients, 2158 patients (7.1%) developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population [O/E = 1.09; 95% confidence interval (CI), 1.05–1.14; P < 0.05; AER = 6.39] (Table 2). There was a significantly increased risk for cancers of the central nervous system (CNS), breast, prostate, kidney, Hodgkin lymphoma, leukemia, myeloma, and salivary gland as well as a significantly decreased risk for cancers of the head and neck (excluding thyroid and salivary gland), lung, esophagus, and bladder.

The ratio of female to male patients was 3.13 (23,059 and 7,219 males, respectively); a distribution consistent with prior reports (2). Both genders had equivalent overall risk of developing second primary cancers (RR = 1.00; 95% CI, 0.92–1.09). For specific cancers, males had an increased risk of developing secondary prostate, kidney, and salivary gland cancers and a decreased risk for other head and neck cancers. Females had increased risk for secondary leukemia, myeloma, breast, kidney, salivary gland, and CNS cancers and a decreased risk for lung and mediastinum (Table 3).

Significantly increased overall risk of second primary cancers was observed in the cohort of patients diagnosed from ages 25–49 yr but not in cohorts of patients 0–24, 50–74, or 75 yr and older (Table 4). However, the risk for several specific cancer sites was elevated in the other age cohorts.

Overall risk of second primary cancers was significantly elevated within the first 10 yr after thyroid cancer diagnosis (yr 0–5: O/E = 1.18; 95%, CI 1.10–1.27; AER = 9.71; yr 6–10: O/E = 1.10; 95% CI, 1.01–1.19; AER = 6.5) but not for longer latency periods.

Interaction of age at diagnosis and latency to development of second primary cancer

A more detailed case-level regression analysis revealed gender, race, and treatment group did not appear to affect the SIR (P = 0.31, P = 0.33, and P = 0.58, respectively). Decreased age at diagnosis resulted in higher SIR; for each decade of age (relative to any comparatively prior decade), SIR is 1.14-fold higher (95% CI, 1.11–1.18; P < 0.0001). The effect of latency is more complicated and is shown in Fig. 1. The SIR is greatly increased immediately after initial diagnosis and treatment; however, this excess risk decreases rapidly and by approximately 5 yr after diagnosis, the effect levels out (at a level dependent on the age at diagnosis). Cancers that show statistically elevated excess risk and represent the largest numbers of newly diagnosed second primaries within 5 yr of diagnosis include breast, prostate, and lymphatic and hematopoietic malignancies.

View larger version (8K): [in this window] [in a new window]   FIG. 1. Fitted estimates of SIR of all nonthyroid malignancies by latency and age at diagnosis (gender, race, and treatment group do not appreciably alter the SIR). The four curves represent fits for four different diagnosis ages (20, 40, 60, and 80 yr old). The thin horizontal line represents a SIR equal to 1.

For the entire study period (1973–2002), patients receiving radioisotope therapy were at increased risk of developing nonthyroid second primary cancers (O/E = 1.21; 95% CI, 1.12–1.30; AER = 13.3) over the general population as well as the nonirradiated survivors (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53), although the nonirradiated group had a risk more similar to the endemic rate. The RR was significantly greater for the irradiated patients than for the nonirradiated patients (RR = 1.16; 95% CI, 1.05–1.27; P < 0.002). When isolating the analysis period from 1988–2002, increased risk was observed in both the isotope-irradiated (O/E = 1.20, 95% CI 1.08–1.34, AER=12.01) and nonirradiated (O/E = 1.12; 95% CI, 1.02–1.23; AER = 7.86) cohorts, but the RR became statistically indistinguishable (RR = 1.08; 95% CI, 0.93–1.24; P = 0.31) overall (Table 5).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Our analysis confirmed some previous reports of increased incidence of breast cancer in thyroid cancer survivors. The risk was significantly elevated only for women ages 25–75 yr at diagnosis and only within 10 yr of thyroid cancer diagnosis. Other authors have postulated that the increased incidence could be due to radioisotope therapy (32, 33). Radioiodine is known to be excreted in breast milk by the sodium iodide symporter, which is also expressed in salivary gland tissue and the stomach (34, 35, 36, 37). Nevertheless, it is unlikely that many women in our study were lactating at the time of radioiodine administration, and this information is not included in the SEER database. In our analysis, both the nonirradiated and irradiated patients had significantly elevated risk for breast cancer, but the relative risk was statistically indistinguishable between the groups. This suggests that the increased risk of breast cancer is likely due to other factors.

The increased diagnosis of prevalent cancers (breast and prostate) within 5 yr of diagnosis of thyroid cancer may be evidence of surveillance bias in our data. Patients who have been diagnosed with a previous malignancy may be more likely to seek routine and follow-up health care resulting in a perceived increase in second primary cancers. To address this issue, we performed an additional analysis using a latency exclusion period of 3 yr as opposed to 2 months, because radiogenic malignancies are thought to have a latency rate of several years before clinical presentation. In this scenario, we still identified an elevated risk of both hematological and solid second malignancies in the irradiated cohort but did not see an overall elevated risk in the nonirradiated group. With some studies reporting reciprocal associations of thyroid with breast, prostate, kidney, and salivary gland cancers (26, 28), we cannot exclude an environmental or genetic mechanism (38) responsible for this correlation. One of the primary molecular changes in papillary, but not follicular, thyroid cancer is mutation of the RET protooncogene (16), which has also been linked to leukemia, prostate cancer, and breast cancer (39, 40, 41, 42). In addition, a missense variant (I157T) of the CHEK2 protein, which participates in DNA repair, is associated with an increased risk of thyroid, breast, prostate, kidney, and colon cancers (43, 44, 45). How these molecular changes may have affected our study population is unknown and beyond the scope of the current work.

Our study also confirmed previous reports of increased risk of prostate cancer. Prostate cancer was the only cancer we analyzed that had statistically increased incidence for patients diagnosed with thyroid cancer after age 75. This could be due to shared molecular-genetic susceptibilities or the potential for surveillance bias, both discussed above. Unfortunately, the SEER database does not track this type of information and is beyond the scope of this work.

Because radioiodine is excreted both fecally and renally, we evaluated these body sites for a radiation effect. Previous studies reported a significantly increased incidence of kidney cancer (29, 46), colorectal cancer (28, 47, 48), and bladder cancer (32, 49) in patients who received radioisotopes. Our analysis did show an increased risk of kidney cancer, but this increased risk was statistically equivalent in both the irradiated and nonirradiated cohorts. We found no increased risk of gastrointestinal malignancies in our study population, with the notable exception of a statistically increased risk for stomach cancer in the radioisotope cohort. The stomach is both strongly avid for ¹³¹I (as measured by nuclear medicine scans) and has some of the greatest expression of the sodium iodide symporter of all body tissues tested (35).

Salivary glands are also known to concentrate and excrete ¹³¹I. Interestingly, in our study, this risk was significantly increased in the nonirradiated patients only. The interpretation of this finding is challenging. Again, one may surmise that the environmental and genetic factors leading to a thyroid cancer are similar to those resulting in salivary tumors. For example, both thyroid and salivary malignancies are known to be induced by radiation (9, 32, 50). However, if it were true that medical or occupational radiation was causing the thyroid and salivary gland tumors, we might expect to see this risk proportionally shared over both the irradiated and nonirradiated cohorts, which we did not. Upon closer review, the excess risk was observed in cases diagnosed between 1973 and 1988, with no excess risk noted for the later time period. This might be attributed to the earlier practice of head and neck irradiation for benign conditions that is a known risk factor for radiogenic malignancies such as thyroid cancer. However, Mehta et al. (4) suggest that these particular malignancies have been dramatically declining since 1970. Our result may simply reflect statistical noise in the setting of multiple subgroup testing.

We observed a decreased risk of smoking-related cancers such as bladder, lung, and nonthyroid head and neck cancers than what was expected in the general population. This decrease could be attributable to smoking cessation among survivors of thyroid cancer, because lifestyle modification in cancer survivors has been documented (51). Alternatively, our study population may represent people less likely to smoke than the general U.S. population. Unfortunately, smoking habits are not encoded by SEER registrars. Sandeep et al. (28) did not observe this decrease and in fact reported an increase in pharyngeal second primaries. This may be explained by different exposures in Sandeep’s study population compared with the U.S. population.

The most frequently reported cancer associated with radioisotope therapy is leukemia (26, 28, 32, 47, 48, 49, 52). Our study confirmed a statistically significant increase of leukemia in patients receiving radioisotope therapy compared with patients who received no radiation therapy (1973–2002: RR = 2.33; 95% CI, 1.38–3.79; P < 0.001; 1988–2002: RR = 3.05; 95% CI, 1.48–8.3; P = 0.004), with greater numbers diagnosed within 10 yr after primary diagnosis. Leukemia, like thyroid cancer, is known to be associated with radiation and chemotherapy and usually occurs within 10 yr of treatment for other cancers (14, 53, 54). The described association of thyroid cancer with leukemia cannot be entirely attributed to treatment, because a reciprocal relationship has been reported (26, 28), indicating other factors separate from treatment effects.

The strengths of our study include the use of a large, high-quality, population database representing diverse sites in the United States and the longest period of follow-up of any study of second primary tumors after thyroid cancer diagnosis. Limitations include the many sources of bias inherent in retrospective studies, particularly surveillance bias that would detect more secondary malignancies in patients with follow-up after thyroid cancer and misclassification bias, as well as the small numbers of relatively rare second primaries and the inability to standardize histology review of malignancies. Some clinical and pathological data known to be of prognostic significance are not available in the SEER database. Specifically lacking is information regarding details about dose and number of courses of radioiodine administration making the investigation of a dose-effect relationship impossible. In addition, the SEER database does not record history of treatment failure or time of relapse. Therefore, we were unable to adjust for these factors in our analyses.

In summary, the overall risk of second primary malignancies is slightly increased for thyroid cancer survivors over that of the general U.S. population. These risks are modified by age at diagnosis, radioisotope use, and latency period. Cancer-specific screening for common second primary cancers, (e.g. leukemia, breast, and prostate) is recommended during follow-up for thyroid cancer survivors. Additional studies investigating molecular-genetic and environmental factors may aid in the identification of specific groups at the greatest risk of developing second primary cancers in the future.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online November 20, 2007

Abbreviations: AER, Absolute excess risk per 10,000 person-years; CI, confidence interval; CNS, central nervous system; O/E, observed-to-expected ratio; PY, person-years; RR, relative risk; SEER, Surveillance, Epidemiology, and End Results; SIR, standardized incidence ratio.

Received May 25, 2007.

Accepted November 9, 2007.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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