Decreased health-related quality of life in disease-free survivors of differentiated thyroid cancer in Korea

The study involved consecutive disease-free patients with DTC who visited the outpatient clinic of the Thyroid Cancer Center, Samsung Medical Center between July 2008 and October 2008. All patients older that 18 years of age were asked to participate and to complete the written questionnaires by themselves at the outpatient clinic. Inclusion criteria were having undergone thyroid surgery with or without radioiodine therapy, the use of T4 replacement continuously for at least six months, absence of clinical or laboratory evidence of DTC at the time of the study, and no further planned therapy for thyroid cancer except T4 replacement. Exclusion criteria were any other acute or chronic co-morbidity which required medical or surgical treatment and could influence their HRQOL, and the administration of RAI within less than six months either for diagnostic or therapeutic purposes since the recent recovery from hypothyroidism could affect the patient's answers. The most commonly listed medical co-morbidities were: diabetes mellitus, hypertension, coronary artery disease, liver disease, kidney disease, lung disease and psychiatric problem. Patients who had detectable thyroglobulin (Tg) levels during TSH suppression or stimulation were also excluded because these patients had a high likelihood for requiring further treatment, which could be a cause of anxiety. Data on patient age and sex were derived from the medical files: the patients were also asked for additional data on marital status (married vs. not-married), highest level of education achieved (graduated from elementary school, middle school, high school, college or university), employment status (employed vs. not employed), religious status (religious vs. non-religious) and subjective financial status (low, middle, or high economic class) using written questionnaire. Data on disease severity parameters were derived from medical records as follows: histology, disease stage, type of operation, number and cumulative dose of RAI, TSH and free T3 level, and time since remission at the time the questionnaire was administered. This study was approved by the Institutional Review Board of Samsung Medical Center. Written consent was obtained from all participants.

Sex- and age- matched control group was adopted from a previously published large-scale epidemiologic study to provide reference data for HRQOL in the general Korean population [12, 13]. In summary, 1000 members (F:M = 1:1) of the general population from over 15 sites in Korea were surveyed according to probability-proportional-to-size technique. Eligibility criteria for control included being physically and mentally well enough to fill out a questionnaire of communicate with the interviewer.

The EORTC QLQ-C30 was scored according to the EORTC scoring manual. Incomplete questionnaires were handled as per the developer's recommendations. BFI and HADS questionnaires with missing values were not used. We used descriptive statistics for the socio-demographic and clinico-pathologic features of the subjects. Differences in continuous variables between participants and non-participants for the survey were tested by independent samples t-test. Differences between groups in categorical variables were tested by chi-square test and for small cell variables, Fisher`s exact test. The one-sample t-test was used to compare the means of each domain of questionnaires between disease-free survivors of DTC and the general population controls. We used an analysis of covariance with a generalized linear model to determine significant differences between the groups according to the mode of treatment of thyroid cancer. Multiple regression analysis was used to evaluate the predictors of HRQOL. The independent variables used to predict each of the EORTC QLQ-C30 domains included demographic features (age at diagnosis, age at evaluation, gender, marital status, level of education, employment, religion, and financial status), clinical parameters (type of operation, cancer stage, TSH level, cumulative RAI dose, and time since remission), BFI scores, and the psychological status of the patient (HADS-D and HADS-A scores). The variables that were P < 0.2 in univariate analysis of variance tests or were known to be important determinants that affect the HRQOL in other previously published studies on this topic were included in these multiple regression analysis [6‐11, 22‐26]. P values of < 0.05 were considered statistically significant.

We identified 681 consecutive patients at our outpatient clinic who were potentially disease-free survivors of DTC. Two hundred eighty (40.9%) of these patients were excluded either because of a co-morbidity or because it was less than six months after last the administration of RAI. Eighty-five of the 401 (21.1%) disease-free survivors of DTC who were eligible declined participation, and lack of time or inconvenience were the most commonly stated reasons. There were no differences in the demographic and clinico-pathologic characteristics between the participants and the non-participants (Table 1). Three hundred sixteen (78.9%) disease-free survivors of DTC ultimately participated in the study (Figure 1).

The baseline clinical characteristics for the participants are summarized in Table 2. Two hundred eighty-seven of the 316 participants were female (90.8%). The mean age (± SD) at the time of diagnosis was 41.2 years (± 9.8). Most of the patients were married (91.9%, 274/298). Two hundred fourteen of the 300 patients (71.3%) were religious, and 93.2% of the patients reported a subjective financial status as middle class or higher. A majority of the participants had papillary thyroid carcinoma (97.5%, 308/316) and eight (2.5%) had follicular thyroid carcinoma. A total thyroidectomy was performed in 89.9% (284/316) of the patients, and 10.1% (32/316) had a subtotal thyroidectomy or lobectomy. Based on TNM staging, 223 (70.6%) of the patients had stage I disease, five (1.6%) had stage II disease, 82 (25.9%) had stage III disease, and six (1.9%) had an unknown stage. The mean TSH level (± SD) at the time of the survey was 0.49 (±5.74) , free T3 was 3.77 (± 0.93) . The mean time since disease remission (± SD) was 37.3 months (28.8). RAI therapy was performed in 92.0% (291/316) of the patients, with a mean cumulative RAI dose (± SD) of 134.0 (± 101.0) mCi, and the mean number (± SD) of RAI therapy treatments was 2.6 (± 1.4).

Results from the EORTC QLQ-C30 of the disease-free survivors of DTC and the control group are compared in Figure 2. The disease-free survivors of DTC showed significantly lower scores in all of the functional domains (physical, role, cognitive, emotional, and social), as well as on the global health/QOL scale at the EORTC QLQ-C30 survey (P < 0.05). Furthermore, the proportion of problematic groups according to EORTC QLQ-C30 was significantly higher in disease-free survivors of DTC than controls for all functional domains and global health/QOL scale except physical functioning domain (Table 3). HADS-A, HADS-D, and BFI scores for the disease-free survivors of DTC and the control group are shown in Table 4. Disease-free survivors of DTC had greater levels of distress according to the HADS-A and BFI scores. Interestingly, the disease-free DTC patients showed less distress in the HADS-D score compared with the control group.

The functioning scales for the EORTC QLQ-C30, HADS-A, HADS-D, and BFI did not show any differences between patients who underwent surgery alone and patients who underwent surgery combined with RAI therapy. The cumulative dose of RAI also did not affect the HRQOL in our study group (Table 5).

Anxiety, depression and fatigue emerged as the strongest determinants for most of the domains in the EORTC QLQ-C30 in disease-free survivors of DTC according to the multiple regression analysis. Fatigue had negative influence on global health and QOL scale (β = -0.50), physical functioning (β = -0.34), role functioning (β = -0.57), emotional functioning (β = -0.25), cognitive functioning (β = -0.17), and social functioning (β = -0.37). Anxiety had negative influence on physical functioning (β = -1.02), emotional functioning (β = -3.45), cognitive functioning (β = -1.92) and social functioning (β = -1.36). Depression had negative influence on global health and QOL scale (β = -1.82), role functioning (β = -1.41) and cognitive functioning (β= -1.52).

Increasing age at diagnosis (β = -0.27) and female gender (β = -12.11) had a negative influence on the physical functioning domain. Increasing age at evaluation had negative influence on the physical functioning (β = -0.37) and cognitive functioning (β = -0.23) and positive influence on the emotional functioning (β = 0.20).

Patients who were employed at the time of evaluation showed significantly better role functioning (β = 6.66) and social functioning (β = 5.00). The frequency of RAI therapy, cumulative dose of RAI, and level of TSH suppression had no significant impact on the HRQOL of the disease-free survivors of DTC. The regression coefficient of each variables, adjusted R² and significant P values are described in Table 6.