Overall all-cause mortality risk
This large Israeli population-based historical cohort study demonstrated a higher all-cause mortality rate among TC survivors than among individuals without any thyroid disease or any type of cancer from the same population, matched by sex and age. The difference remained statistically significant after adjusting for age, sex, baseline cardiovascular risk factors, and cardiovascular and cerebrovascular diseases at study onset. The novel findings of this study are the association between cardiovascular risk factors at the end of follow-up and the higher mortality among Israeli TC survivors compared to non-TC individuals. In contrast, there was no association between mortality and the presence of a second primary malignancy in the former group and the presence of a primary malignancy in the latter group at the end of follow-up.
The majority of the TC survivors in the current cohort were female (79%). Stratification by sex showed that the mortality HR for male TC survivors was higher than that of females. Similarly, analysis of the SEER data revealed a higher mortality rate among male TC survivors than among females.2 Moreover, during the last three decades, age-adjusted mortality attributed to TC was reported to remain stable among Israeli men and to decrease among Israeli women.4
Interestingly, there were nearly 10% more current smokers in the non-TC group compared with the TC group. That inverse association between smoking and the development of TC was present in both females (HR=0.54, 95% CI: 0.35-082) and males (HR=0.31, 95% CI: 0.09-1.04), suggesting that smoking may be a protective factor, as observed by Meinhold et al.13
Surprisingly, female sex and a diagnosis of dyslipidemia at the beginning of the follow-up for the entire cohort were associated with a lower risk for mortality. This finding may be explained at least in part by statin treatment.
Mortality Risk by Age
There was a significant and pronounced age-related increased mortality risk for TC survivors compared to the non-TC group, particularly from age 55 years onwards. Our findings concur with a recent study that found 55 years to be a valid cutoff age for risk assessment in TC survivors.14 Another recent publication concluded that the increasing age risk should be considered along a continuum.15 The SEER study also reported that the 5-year and 10-year probability of death increased with age among TC survivors.8 The lower relative mortality risk among younger TC survivors is supported by the results of a German study that disclosed no reduced life expectancy among DTC survivors who were under 45 years of age at DTC diagnosis and with tumor-node-metastasis (TNM) stages I, II, or III compared to the general population.16
Factors Contributing to Increased Mortality among TC Survivors
The interpretation of our results should take into account the various factors that may contribute to increased mortality in TC survivors. First, despite the excellent prognosis and the low and decreasing fatality rates, the small proportion of TC survivors who die of their disease naturally increases the general mortality rate in TC survivors, particularly in the long term during which recurrence is a factor. In a Dutch study,10 progression or recurrence of TC was the cause of mortality for 39% of TC survivors who died during a mean follow-up of 8.5 years. An increased risk of second primary cancers, compared to the general population, may also increase overall mortality. Such risk has been documented in Israel17 and elsewhere.18 Although a second primary cancer also worsens the prognosis of TC survivors,19 a second primary cancer was not more common among the TC survivors who died than a de novo primary cancer among the individuals who died in the non-TC group in the current study. However, analyses of the current findings revealed a direct association between the number of cardiovascular risk factors and mortality risk among the TC patients.
Increased mortality due to non-cancer causes must also be considered in relation to TC. SEER data showed that the risk of dying from a cause other than the primary disease in TC survivors is nearly 2-fold than that of dying from TC.8 In that study, the 10-year probabilities of death from TC, from other cancers, and from non-cancer causes were 3.0%, 2.0% and 3.9%, respectively. In the current study, increased mortality persisted after controlling for baseline cardiovascular risk factors and morbidity, in addition to age and sex. At the time of TC diagnosis, the anthropometric and clinical characteristics of the TC survivors were very similar to those of the non-cancer individuals, with the exception of hypertension, which was slightly more prevalent among the TC survivors. Similarly, a Dutch population-based study reported a higher than expected prevalence of hypertension among TC survivors.20 In the current study, the prevalence of diabetes mellitus at baseline was similar between the TC group and the non-TC group. This concurs with a recently published Israeli study that was based on a nationwide cohort and which found no association between diabetes mellitus and TC.21 Nevertheless, diabetes mellitus may still affect TC prognosis. For example, TC survivors with type 2 diabetes mellitus and DTC were found to be more likely to have an advanced TNM stage at the time of diagnosis as well as increased disease-specific mortality.22 The prevalence of hypertension, dyslipidemia, and cardiovascular disease at the end of the follow-up were higher for the individuals in the TC group who died during the follow-up period of the current study than among those in the non-TC group who died. These differences between the groups at study closure were greater than those recorded at baseline.
The treatment of TC may affect the mortality risk in a number of ways. The majority of the Israeli TC survivors were treated according to a standard of care consisting of thyroidectomy, radioactive ablation, and thyroid hormone suppression treatment. Several studies have shown a greater risk of second primary cancer among TC survivors treated with radioactive ablation than among those who did not undergo such treatment.18,19 This increased risk was shown to also prevail among low-risk TC survivors23 and only when the cumulative radioactive iodine dose was ≥37.0 GBq.24 The mortality risk was also higher for the 5-15% of TC survivors who become refractory to radioactive iodine therapy.25,26
Thyroid hormone suppression is a component of TC treatment, both for those who respond and for those who are refractory to radioactive iodine therapy. Associations have been reported among thyroid hormone suppression treatment and atrial fibrillation,27 impaired small and large artery elasticity,28 increased left ventricular mass,28 abnormalities of heart morphology related to impaired exercise performance,29 a prothrombotic condition,30 and myocardial strain.31 In the absence of data on thyroid hormone treatment, we do not know the degree to which subclinical hyperthyroidism was achieved in the TC survivors, or the proportion of individuals in the TC group that may have had endogenous subclinical hyperthyroidism. However, subclinical hyperthyroidism not in the setting of TC has been shown to be associated with atrial fibrillation32,33 worse physical capacity,34 increased risk of heart failure, and cardiovascular morbidity.33,35 Moreover, endogenous subclinical hyperthyroidism was associated with increased risks of total and cardiovascular mortality in a pooled analysis from 10 cohorts of individuals not treated with thyroxine.32 A Danish population-based study found increased heart failure and increased cardiovascular and all-cause mortality among patients with subclinical hyperthyroidism compared to euthyroid individuals.36 In contrast with these reports, a recently published small study with up to a 9-year follow-up showed no impairment in cardiac function and structure among individuals who received thyroid hormone suppression treatment.37 However, the patients’ thyroid-stimulating hormone (TSH) levels in that study were <0.1 mU/L in the intermediate-risk-of-recurrence group and <0.3 mU/L in the lower-risk-of-recurrence group, which is higher than the recommendations for TSH suppression. Having no data on TSH levels during the follow-up in our cohort, we were unable to compile the effects of treatment on mortality.
Health-related quality of life (HRQoL) is an additional factor that may affect health and long-term mortality in cancer survivors. A recent publication reported that 14-17 years after diagnosis, almost half of DTC survivors who filled in a HRQoL questionnaire expressed anxiety about disease recurrence, and that this negatively impacted their HRQoL.38 Poor HRQoL has been found to be related to all-cause mortality in various populations.39,40
Stage at diagnosis2,16 and genetic variance41 have been shown to affect mortality. The current study did not distinguish between types of TC. DTC, which comprised the vast majority of TCs in our population, confers considerably better prognosis than do the less common types of TC.1
The strengths of this study are the long-term follow-up findings of a large population-based cohort, which are based on the computerized data file of the largest healthcare fund in Israel (covering around 52.3% of the total Israeli population). They take into account baseline pathological conditions and those diagnosed during the follow-up period of the study (including dyslipidemia, hypertension, diabetes mellitus, cardiovascular and cerebrovascular diseases, and new malignancies). A significant limitation of this study is the lack of data on the cause of death, as well as on other variables, such as the histological variant of the TC, the stage of the TC, the doses of radioactive iodine treatment, and the TSH levels during the follow-up period.