Abstract
Context
Childhood cancer survivors experience chronic health conditions that impact health-related quality of life (HRQOL) and participation in optimal physical activity.
Objective
The study aimed to determine independent effects of endocrine and metabolic disorders on HRQOL and physical activity.
Design, Setting, and Patients
Retrospective cohort with longitudinal follow-up of survivors of childhood cancer enrolled in the North American Childhood Cancer Survivor Study.
Main Outcome Measures
Medical Outcomes Short Form-36 estimated HRQOL, and participation in physical activity was dichotomized as meeting or not meeting recommendations from the Centers for Disease Control and Prevention. Log binomial regression evaluated the association of each endocrine/metabolic disorder with HRQOL scales and physical activity.
Results
Of 7287 survivors, with a median age of 32 years (range, 18 to 54 years) at their last follow-up survey, 4884 (67%) reported one or more endocrine/metabolic disorders. Survivors with either disorder were significantly more likely to be male, older, have received radiation treatment, and have experienced other chronic health conditions. After controlling for covariates, survivors with any endocrine/metabolic disorder were more likely to report poor physical function risk ratio (RR, 1.25; 95% CI, 1.05 to 1.48), increased bodily pain (RR, 1.27; 95% CI, 1.12 to 1.44), poor general health (RR, 1.49; 95% CI, 1.32 to 1.68), and lower vitality (RR, 1.21; 95% CI, 1.09 to 1.34) compared with survivors without. The likelihood of meeting recommended physical activity was lower among survivors with growth disorders (RR, 0.90; 95% CI, 0.83 to 0.97), osteoporosis (RR, 0.87; 95% CI, 0.76 to 0.99), and overweight/obesity (RR, 0.92; 95% CI, 0.88 to 0.96).
Conclusion
Endocrine and metabolic disorders are independently associated with poor HRQOL and suboptimal physical activity among childhood cancer survivors.
Chronic endocrine and metabolic conditions adversely affected health-related quality of life and physical activity among adult survivors of childhood cancers followed in a large North American cohort.
Significant improvements in the treatment of childhood cancer have led to a 5-year overall survival of >80%, leaving >420,000 survivors alive in the United States (1, 2) at risk for early onset of cancer or therapy-related chronic health conditions. Survivors are also at risk for poor health-related quality of life (HRQOL) (3) and are less likely than peers to meet recommended guidelines for physical activity (4, 5). Previous research has identified cranial radiation exposure as a risk factor for reduced HRQOL, as well as less than optimal participation in physical activity (5). However, not all survivors with this exposure experience these adverse outcomes. Given that exposures among adult survivors of childhood cancer who have lived for years after treatment are remote to both perceived quality of life and health behaviors, examination of the impact of potentially treatable organ-specific chronic health conditions on these outcomes is warranted; however, research in this area is limited (6–9).
Endocrine and metabolic disorders are among the most common chronic health conditions experienced by survivors (10–22), and often one condition contributes to additional conditions across the endocrine system. For example, GH deficiency is associated with obesity, and sex-hormone deficiency is associated with low bone mineral density. In the Childhood Cancer Survivor Study (CCSS), ∼40% to 50% of survivors reported at least one endocrine disorder, a rate significantly higher compared with siblings (22). In that study and other work from the CCSS, metabolic conditions such as obesity and overweight were grouped together with other endocrinopathies. Endocrine and metabolic disorders have been associated with lower levels of physical activity and difficulties managing self-care and activities of daily living (6, 9, 23). However, the individual contribution of specific endocrinopathies or overweight/obesity on HRQOL and physical activity are unknown. Consequently, the primary aim of this study was to investigate the independent effects of the most common endocrine disorders and overweight/obesity on HRQOL and physical activity and, as a secondary aim, to examine whether treatment of these disorders improved these outcomes.
Subjects and Methods
Participants
The CCSS is a retrospective cohort study with longitudinal follow-up of adult survivors of childhood cancer. The study design and cohort characteristics have been previously described in detail (10, 24). Briefly, eligible participants were 5-year survivors of leukemia, brain tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, soft tissue sarcoma, or a malignant bone tumor diagnosed prior to age 21 years at one of 26 institutions across the United States and Canada between 1970 and 1986. These analyses included survivors who completed the baseline survey (administered in the mid-1990s) and two follow-up surveys (beginning in 2003 and 2007, respectively), and who were ≥18 years of age at the time of the 2003 survey.
Outcome measures
The Medical Outcomes Short Form-36 (SF-36) embedded in the 2003 survey was used to measure HRQOL (25). Participants answered a 36-item questionnaire about their general health, well-being, and quality of life during the previous 4 weeks. The SF-36 has two summary scales (physical and mental components) and eight individual subscales (physical function, role physical, bodily pain, general health, vitality, role emotional, social function, mental health). Each scale is presented as a T-score with a general population mean of 50 (SD of 10). Lower scores indicate worse HRQOL. Poor HRQOL was defined as a T-score of ≤40 (3, 25). Physical activity levels were determined based on self-reported frequency, duration, and intensity of moderate and/or vigorous physical activity, including participation in an organized activity during the previous 4 weeks (26). Survivors who reported participating in recent organized physical activity were considered to have an active lifestyle. Survivors who met the equivalent of 150 minutes of moderate activity per week were classified as meeting the guidelines of the Centers for Disease Control and Prevention (CDC) (4).
Independent variables
Survivors reported the presence of the following categories of endocrinopathies (grades 1 to 4 per the common terminology of adverse events CTCAE version 4.03) (10, 27): thyroid disorders (hypothyroidism, hyperthyroidism, thyroid cancer, and thyroid nodules), growth disorders (short stature, GH deficiency), gonadal dysfunction, osteoporosis, diabetes mellitus, and other endocrine disorders as previously described (22). They also reported on current height (cm) and body weight (kg), from which the body mass index (BMI; kg/m2) was calculated to assess metabolic disorders of overweight/obesity. Overweight was defined as BMI of ≥25 kg/m2 but <30 kg/m2 or a BMI at or above the 85th percentile but less than the 95th percentile per age and sex for participants <18 years of age, and obesity was defined as a BMI >30 kg/m2 or BMI higher than the 95th percentile per age and sex for participants younger than 18 years of age. Two follow-up questionnaires were used to ascertain the presence of endocrine/metabolic disorders and whether survivors were being treated for the condition from the time of study entry until last follow-up. Responses to both surveys were used to define the endocrine condition because the first survey only recorded medications used to treat hormone deficiencies as a proxy for endocrine conditions, whereas the subsequent survey specifically asked survivors to report each endocrinopathy, and the year of onset of that condition, regardless of whether they were receiving treatment. Only survivors where the onset of endocrine conditions and replacement therapy for that condition occurred prior to the outcome measures were included in the analyses.
Psychological measures of anxiety, depression, and somatization were assessed using the Brief Symptom Inventory-18, an 18- item scale that was embedded in the 2003 survey with a T-score ≥63 indicating emotional distress within the preceding 7 days (28). Task efficiency, a neurocognitive construct related to initiating and completing tasks in a rapid manner and associated with lower physical activity, was measured by the CCSS neurocognitive questionnaire (29), a self-reported measure in the 2003 survey. Both were used as adjustment variables when analyzing the physical activity outcomes.
Statistical analysis
Demographic and treatment characteristics were compared between survivors with and without self-reported endocrine and metabolic disorders using χ2 tests for categorical variables and a t test for continuous variables. We repeated this analysis with the exclusion of overweight/obesity as an outcome so that it focused only on endocrinopathies. Log binomial regression was used to evaluate the association of having any endocrine/metabolic disorder, as well as the association of each individual endocrine/metabolic disorder with HRQOL and physical activity, followed by similar analyses after excluding overweight/obesity. Specific endocrine disorder therapy (replacement therapy for hypothyroidism, testosterone therapy, and hormone replacement therapy for gonadal dysfunction among females), and the total number of endocrine disorders with the probability of a poor score (≤40) for each component of HRQOL, and each of the two measures of physical activity were analyzed using log binomial regression. All models were adjusted for sex, race, education, marital status, household income, health insurance, employment status, radiation therapy, amputation, and grade 3 to 4 (severe or life-threatening or disabling) chronic health conditions other than endocrine disorders. The analysis of physical activity outcome was also adjusted for emotional distress and task efficiency (28, 30).
Results
Characteristics of study population
Of the 7287 survivors who completed the baseline and follow-up surveys and were ≥18 years of age at the time of the last follow-up survey, 4884 (67%) had one or more endocrine or metabolic disorder. Survivors with these disorders were more likely than those without to be male, older at cancer diagnosis and at the time of each survey, and less likely to be employed. They were also more likely to have other grade 3 to 4 chronic health conditions as well as poor emotional health, and more likely to have received any radiation treatment compared with those without these conditions (Table 1).
Table 1.
Demographic and Treatment Characteristics of Adult Survivors of Childhood Cancer With and Without Endocrine and Metabolic Disorders
| Characteristics | Total Survivors (N = 7287) | Survivors With and Without Endocrine and Metabolic Disorders | ||
|---|---|---|---|---|
| With Endocrine Disorders, n (%) (n = 4884)a | Without Endocrine Disorders, n (%) (n = 2276)a | P Valueb | ||
| Sex | <0.001 | |||
| Male | 3566 (48.94%) | 2504 (51.3%) | 1011 (44.4%) | |
| Female | 3721 (51.06%) | 2380 (48.7%) | 1265 (55.6%) | |
| Race | <0.001 | |||
| White, non-Hispanic | 6586 (90.38%) | 4386 (89.8%) | 2086 (91.7%) | |
| Black, non-Hispanic | 205 (2.81%) | 134 (2.7%) | 66 (2.9%) | |
| Hispanic | 287 (3.94%) | 226 (4.6%) | 57 (2.5%) | |
| Other | 209 (2.87%) | 138 (2.8%) | 67 (2.9%) | |
| Age at diagnosis, y (mean ± SD) | 8 (2–14) | 9 (3–15) | 8 (2–14) | <0.001 |
| Age at survey, y (mean ± SD) | 32 (24–40) | 33 (25–40) | 31 (23–38) | <0.001 |
| Interval between cancer diagnosis and assessment of endocrine function, y (mean ± SD) | 24 (19–28) | 24 (19–28) | 23 (19–28) | <0.001 |
| Diagnosis | <0.001 | |||
| Leukemia | 2506 (34.39%) | 1765 (36.2%) | 684 (30%) | |
| Central nervous system tumors | 896 (12.30%) | 680 (14%) | 203 (8.9%) | |
| Hodgkin lymphoma | 952 (13.06%) | 764 (15.6%) | 183 (8.0%) | |
| Non-Hodgkin lymphoma | 546 (7.49%) | 369 (7.6%) | 168 (7.4%) | |
| Wilms tumor | 664 (9.11%) | 296 (6.1%) | 354 (15.6%) | |
| Neuroblastoma | 469 (6.44%) | 257 (5.3%) | 199 (8.7%) | |
| Soft tissue sarcoma | 648 (8.89%) | 419 (8.6%) | 219 (9.6%) | |
| Ewing sarcoma | 191 (2.62%) | 116 (2.4%) | 75 (3.3%) | |
| Osteosarcoma | 390 (5.35%) | 205 (4.2%) | 180 (7.9%) | |
| Other | 25 (0.34%) | 13 (0.3%) | 11 (0.5%) | |
| Health insurance | 0.47 | |||
| Yes | 6494 (89.82%) | 4363 (90.0%) | 2020 (89.5%) | |
| No | 736 (10.18%) | 484 (10.0%) | 238 (10.5%) | |
| Employed | <0.001 | |||
| Yes | 6391 (87.70%) | 4215 (86.3%) | 2095 (92.0%) | |
| No | 896 (12.30%) | 669 (13.7%) | 181 (8.0%) | |
| Amputation | <0.001 | |||
| Yes | 384 (5.27%) | 200 (4.1%) | 175 (7.7%) | |
| No | 6903 (94.73%) | 4684 (95.9%) | 2101 (92.3%) | |
| Chemotherapy or radiation | <0.001 | |||
| No chemotherapy and no radiation | 526 (7.68%) | 285 (6.2%) | 231 (10.9%) | |
| With chemotherapy or radiation | 6319 (92.32%) | 4309 (93.8%) | 1898 (89.1%) | |
| Any chemotherapy | 0.004 | |||
| Yes | 5362 (79.19%) | 3549 (78.2%) | 1711 (81.2%) | |
| No | 1409 (20.81%) | 992 (21.8%) | 395 (18.8%) | |
| Alkylating agents | 0.03 | |||
| Yes | 3356 (49.56%) | 2294 (50.5%) | 1004 (47.7%) | |
| No | 3415 (50.44%) | 2247 (49.5%) | 1102 (52.3%) | |
| Alkylating cumulative equivalent dose, mg/m2 (mean ± SD) | 9974 (1782–18,167) | 10,303 (2066–18,540) | 9375 (1214–17,536) | 0.005 |
| Steroids | <0.001 | |||
| Yes | 3286 (48.53%) | 2320 (51.1%) | 901 (42.8%) | |
| No | 3485 (51.47%) | 2221 (48.9%) | 1205 (57.2%) | |
| Stem cell transplant | 0.001 | |||
| Yes | 295 (4.06%) | 233 (4.8%) | 59 (2.6%) | |
| No | 6976 (95.94%) | 4639 (95.2%) | 2213 (97.4%) | |
| Any radiation therapyc | <0.001 | |||
| Yes | 4480 (65.68%) | 3318 (72.5%) | 1089 (51.3%) | |
| No | 2341 (34.32%) | 1256 (27.5%) | 1035 (48.7%) | |
| Brain radiation therapy | <0.001 | |||
| Yes | 2301 (34.37%) | 1834 (40.9%) | 417 (20.2%) | |
| No | 4394 (65.63%) | 2654 (59.1%) | 1668 (80.0%) | |
| Brain radiation therapy dose, cGy (mean ± SD) | 3003 (1527–4480) | 3063 (1569–4557) | 2772 (1380–4165) | <0.001 |
| Chest radiation therapy | <0.001 | |||
| Yes | 1743 (26.05%) | 1358 (30.3%) | 374 (17.9%) | |
| No | 4947 (73.95%) | 3125 (69.7%) | 1711 (82.1%) | |
| Chest radiation therapy dose, cGy (mean ± SD) | 2945 (1742–4148) | 3032 (1852–4212) | 2643 (1407–3879) | <0.001 |
| Abdominal or pelvic radiation therapy | <0.001 | |||
| Yes | 1803 (26.95%) | 1327 (29.6%) | 452 (21.7%) | |
| No | 4888 (73.05%) | 3157 (70.4%) | 1633 (78.3%) | |
| Maximum radiation therapy dose to abdominal and pelvic, cGy (mean ± SD) | 2810 (1616–4004) | 2905 (1712–4099) | 2564 (1429–3700) | <0.001 |
| Total body irradiation | <0.001 | |||
| Yes | 92 (1.38%) | 79 (1.8%) | 12 (0.6%) | |
| No | 6596 (98.62%) | 4402 (98.2%) | 2073 (99.4%) | |
| Grade 3 to 4 chronic health condition (other than endocrine) | <0.001 | |||
| Yes | 5433 (74.56%) | 3808 (78.0%) | 1536 (67.5%) | |
| No | 1854 (25.44%) | 1076 (22.0%) | 740 (32.5%) | |
| Brief Symptom Inventory-18 | 0.02 | |||
| Yes | 600 (9.57%) | 426 10.2%) | 163 (8.3%) | |
| No | 5668 (90.43%) | 3771 (89.8%) | 1804 (91.7%) | |
| Neurocognitive status (mean ± SD) | 54 (40–67) | 54 (41–68) | 52 (40–64) | <0.001 |
There are 127 survivors with missing value of endocrine disorders.
Unknown value is not considered when calculating the P value except for household income.
Childhood cancer survivors could belong to more than one radiation therapy category.
Characteristics of endocrine and metabolic disorders
The most common condition was overweight/obesity, which was present in 50.7% of survivors (Table 2). Thyroid disorders were the most common endocrinopathy (22.9%), followed by growth disorders (19%). Females were more likely to report gonadal dysfunction than males.
Table 2.
Proportion of Adult Survivors of Childhood Cancers With Specific Endocrine and Metabolic Disorders
| Endocrine Disorder | CTCAE Grade (Version 4.03) | Number (%) |
|---|---|---|
| Hyperthyroidism | 1 | 66 (0.91%) |
| 2 | 139 (1.91%) | |
| Hypothyroidism | 1 | 138 (1.89%) |
| 2 | 792 (10.87%) | |
| Thyroid nodules | 2 | 140 (1.92%) |
| 3a | 329 (4.51%) | |
| Thyroid cancer | Nongradable | 67 (0.9%) |
| Short stature | Nongradable | 821 (11.3%) |
| GH deficiency | 1 | 211 (2.90%) |
| 2 | 353 (4.84%) | |
| Gonadal dysfunction (males): testicular failure | 1 | 29 (0.81%) |
| 2 | 1 (0.03%) | |
| 3 | 53 (1.49%) | |
| Gonadal dysfunction (females): ovarian failure | 1 | 4 (0.11%) |
| 3 | 247 (6.64%) | |
| Osteoporosis or osteopenia (low bone mineral density) | 2 | 376 (5.16%) |
| Diabetes mellitus | 1 | 51 (0.70%) |
| 2 | 63 (0.86%) | |
| 3 | 60 (0.82%) | |
| 4 | 1 (0.01%) | |
| Overweight/obesity | Nongradable | 3699 (50.7%) |
| Other endocrine disorders | 1 | 112 (1.54%) |
| 3 | 19 (0.26%) |
Grade 3 thyroid nodules are those that resulted in surgery leading to a subtotal or total thyroidectomy.
Relationship between type and number of endocrine and metabolic disorders and HRQOL
Survivors with female gonadal dysfunction risk ratio (RR, 1.26; 95% CI, 1.08 to 1.46), osteoporosis (RR, 1.45; 95% CI, 1.29 to 1.63), diabetes mellitus (RR, 1.23; 95% CI, 1.08 to 1.40), or overweight/obesity (RR, 1.25; 95% CI, 1.12 to 1.38) had an elevated risk of a poor physical component summary score on the SF-36. Thyroid disorders (RR, 1.16; 95% CI, 1.01 to 1.34) and male gonadal dysfunction (RR, 1.67; 95% CI, 1.25 to 2.24) were associated with an elevated risk of a poor mental component summary score. The association between additional specific endocrinopathies and poor scores on the subscales of the SF-36 are displayed in Table 3.
Table 3.
HRQOL by Type of Endocrine/Metabolic Disorder Among Adult Survivors of Childhood Cancers
| SF-36 Scale or Component Summary Score | Endocrine Disorder (Reference Group Is Survivors With No Endocrine Disorder) [RR (95% CI)] | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Any Thyroid Disorder | Any Growth Disorders | Gonadal Dysfunction (Males): Testicular Failure | Gonadal Dysfunction (Females): Ovarian Failure | Osteoporosis | Diabetes | Overweight/Obesity | Other Endocrine Disorders Not Specified | Any Endocrine Disorder | |
| Physical function | 1.03 (0.92–1.15) | 1.14 (0.99–1.32) | 1.52 (1.10–2.10) | 1.44 (1.18–1.76) | 1.29 (1.12–1.50) | 1.37 (1.04–1.79) | 1.20 (1.04–1.38) | 1.57 (1.19–2.06) | 1.25 (1.05–1.48) |
| Role physical | 1.25 (1.10–1.43) | 0.96 (0.82–1.14) | 1.13 (0.67–1.92) | 1.06 (0.84–1.36) | 1.41 (1.20–1.65) | 1.28 (1.09–1.50) | 1.00 (0.89–1.13) | 1.37 (1.00–1.87) | 1.09 (0.95–1.27) |
| Bodily pain | 1.00 (0.88–1.14) | 0.79 (0.68–0.93) | 1.58 (1.20–2.09) | 1.31 (1.06–1.62) | 1.37 (1.18–1.61) | 1.36 (1.09–1.70) | 1.28 (1.15–1.42) | 0.99 (0.71–1.38) | 1.27 (1.12–1.44) |
| General health | 1.27 (1.15–1.40) | 0.98 (0.87–1.11) | 1.17 (0.80–1.71) | 1.50 (1.32–1.70) | 1.45 (1.30–1.61) | 1.50 (1.30–1.72) | 1.26 (1.15–1.39) | 1.14 (0.91–1.43) | 1.49 (1.32–1.68) |
| Vitality | 1.21 (1.09–1.35) | 0.95 (0.83–1.08) | 1.59 (1.13–2.25) | 1.13 (0.94–1.36) | 1.20 (1.04–1.39) | 1.46 (1.28–1.68) | 1.19 (1.08–1.30) | 1.40 (1.15–1.71) | 1.21 (1.09–1.34) |
| Role emotional | 1.21 (1.06–1.38) | 0.89 (0.77–1.04) | 1.57 (1.07–2.30) | 1.06 (0.83–1.34) | 1.25 (1.04–1.49) | 0.93 (0.66–1.32) | 1.03 (0.92–1.15) | 1.04 (0.75–1.44) | 1.03 (0.91–1.17) |
| Social function | 1.13 (0.97–1.32) | 0.84 (0.70–0.99) | 1.63 (1.21–2.20) | 1.48 (1.17–1.87) | 1.19 (0.96–1.47) | 1.47 (1.12–1.92) | 1.03 (0.90–1.17) | 1.07 (0.75–1.52) | 1.07 (0.92–1.24) |
| Mental health | 1.04 (0.90–1.19) | 0.87 (0.75–1.02) | 1.44 (1.08–1.91) | 1.24 (0.99–1.56) | 1.28 (1.06–1.54) | 1.19 (0.88–1.60) | 1.05 (0.94–1.17) | 1.09 (0.80–1.47) | 1.09 (0.96–1.24) |
| Physical component summary | 1.09 (0.95–1.24) | 0.99 (0.83–1.18) | 1.01 (0.55–1.85) | 1.26 (1.08–1.46) | 1.45 (1.29–1.63) | 1.23 (1.08–1.40) | 1.25 (1.12–1.38) | 1.51 (1.15–1.99) | 1.30 (1.11–1.52) |
| Mental component summary | 1.16 (1.01–1.34) | 0.76 (0.64–0.90) | 1.67 (1.25–2.24) | 1.04 (0.80–1.34) | 1.03 (0.83–1.29) | 0.99 (0.70–1.41) | 0.99 (0.88–1.10) | 1.07 (0.77–1.50) | 0.98 (0.87–1.11) |
Adjusted for sex, race, education, marital status, household income, health insurance, employment status, radiation (yes/no), amputation, and other grade 3 to 4 chronic conditions.
Bold type indicates significant results.
Survivors with more than two endocrine/metabolic disorders had an elevated risk of poor physical component summary scores of HRQOL compared with those without a disorder (RR, 1.7; 95% CI, 1.3 to 2.4). Additionally, these survivors had a higher risk of limitations in performing physical activities (RR, 1.8; 95% CI, 1.2 to 2.7), showing lower scores in physical functioning, increased bodily pain, poor general health, and lower vitality compared with those without any endocrine disorder. Details of the number of endocrine disorders including overweight/obesity and poor scores on the subscales of SF-36 are shown in Table 4.
Table 4.
Effect of Number of Endocrine and Metabolic Disorders on SF-36 Subscales Among Adult Survivors of Childhood Cancers
| SF-36 Scale or Component Summary Score | No. of Endocrine and Metabolic Disordersa [RR (95% CI)] | |||||
|---|---|---|---|---|---|---|
| 1 vs None | 2 vs None | >2 vs None | 2 vs 1 | >2 vs 1 | >2 vs 2 | |
| Physical function | 1.2 (0.9–1.6) | 1.6 (1.1–2.2) | 1.8 (1.2–2.7) | 1.3 (0.96–1.8) | 1.4 (0.99–2.1) | 1.1 (0.7–1.7) |
| Role physical | 1.0 (0.8–1.2) | 1.3 (1.1–1.6) | 1.3 (0.99–1.6) | 1.3 (1.1–1.6) | 1.3 (1.03–1.6) | 1.0 (0.8–1.2) |
| Bodily pain | 1.2 (1.1–1.4) | 1.3 (1.1–1.5) | 1.4 (1.2–1.8) | 1.0 (0.9–1.2) | 1.2 (0.9–1.4) | 1.1 (0.9–1.4) |
| General health | 1.3 (1.2–1.5) | 1.7 (1.5–2.0) | 2.0 (1.7–2.4) | 1.3 (1.1–1.5) | 1.5 (1.3–1.7) | 1.1 (0.98–1.3) |
| Vitality | 1.1 (0.99–1.3) | 1.4 (1.2–1.6) | 1.6 (1.3–1.9) | 1.2 (1.1–1.4) | 1.4 (1.2–1.7) | 1.2 (0.97–1.4) |
| Role emotional | 1.0 (0.9–1.1) | 1.1 (0.97–1.3) | 1.2 (0.9–1.4) | 1.2 (1.01–1.3) | 1.2 (0.98–1.5) | 1.0 (0.8–1.3) |
| Social function | 1.0 (0.9–1.2) | 1.1 (0.9–1.3) | 1.3 (1.04–1.6) | 1.0 (0.9–1.2) | 1.3 (1.03–1.6) | 1.2 (0.97–1.5) |
| Mental health | 1.1 (0.9–1.2) | 1.1 (0.9–1.3) | 1.3 (1.02–1.5) | 1.0 (0.8–1.1) | 1.2 (0.96–1.4) | 1.2 (0.97–1.5) |
| Physical component summary | 1.2 (0.9–1.5) | 1.6 (1.3–2.1) | 1.7 (1.3–2.4) | 1.4 (1.1–1.8) | 1.5 (1.1–2.0) | 1.1 (0.8–1.4) |
| Mental component summary | 1.0 (0.8–1.1) | 1.0 (0.9–1.2) | 1.0 (0.8–1.3) | 1.1 (0.9–1.3) | 1.0 (0.8–1.3) | 1.0 (0.8–1.2) |
Bold type indicates significant results.
Adjusted for sex, race, education, marital status, household income, health insurance, employment status, other grade 3 to 4 chronic condition, radiation (yes/no), amputation, and task efficiency. The adjusted number of outcomes and percentages were calculated based on the survivors with endocrine information.
Relationship between the types and numbers of endocrine and metabolic disorders and physical activity
As shown in Table 5, participation in recent physical activity consistent with an active lifestyle was lower among those with growth disorders (RR, 0.95; 95% CI, 0.91 to 0.99) or diabetes mellitus (RR, 0.84; 95% CI, 0.74 to 0.96) compared with those without these endocrine disorders. The likelihood of meeting the CDC guidelines for physical activity was lower among survivors who had a growth disorder (RR, 0.90; 95% CI, 0.83 to 0.97), osteoporosis (RR, 0.87; 95% CI, 0.76 to 0.99), or overweight/obesity (RR, 0.92; 95% CI, 0.88 to 0.96). Table 6 demonstrates that self-reported participation in recent physical activity was less likely among those with more than two endocrine/metabolic disorders compared with those with none (RR, 0.90; 95% CI, 0.83 to 0.97) or one (RR, 0.92; 95% CI, 0.85 to 0.99). Similarly, survivors with increasing number of endocrine/metabolic disorders were less likely to report meeting the CDC guidelines for physical activity compared with those without these disorders. Those with more than two endocrine or metabolic disorders were less likely to meet CDC physical activity recommendations compared with two (RR, 0.84; 95% CI, 0.73 to 0.96) or fewer (RR, 0.82; 95% CI, 0.72 to 0.94).
Table 5.
Physical Activity Among Adult Survivors of Childhood Cancer and Type of Endocrine/Metabolic Disorder
| Endocrine or Metabolic Disorder | Value | Recent Participation in Any Organized Physical Activities [n (%)]a | Meets CDC Guidelines for Physical Activity [n (%)]a |
|---|---|---|---|
| Thyroid disorders | Yes (n = 1247) | 966 (77.5%) | 653 (52.4%) |
| No (n = 6042) | 4738 (78.4%) | 3382 (56.0%) | |
| RR of yes vs no | 1.02 (0.99–1.06) | 1.04 (0.97–1.10) | |
| Growth disorders | Yes (n = 1121) | 798 (71.2%) | 517 (46.1%) |
| No (n = 6118) | 4867 (79.6%) | 3489 (57.0%) | |
| RR of yes vs no | 0.95 (0.91–0.99) | 0.90 (0.83–0.97) | |
| Gonadal dysfunction (males): testicular failure | Yes (n = 83) | 59 (72.0%) | 41 (50.6%) |
| No (n = 3485) | 2775 (79.9%) | 2114 (61.8%) | |
| RR of yes vs no | 0.93 (0.81–1.06) | 0.96 (0.77–1.19) | |
| Gonadal dysfunction (females): ovarian failure | Yes (n = 251) | 183 (72.9%) | 106 (43.1%) |
| No (n = 3470) | 2687 (77.7%) | 1774 (51.8%) | |
| RR of yes vs no | 0.95 (0.88–1.04) | 0.88 (0.75–1.03) | |
| Osteoporosis | Yes (n = 376) | 269 (71.5%) | 164 (43.6%) |
| No (n = 6913) | 5435 (78.6%) | 3871 (56.0%) | |
| RR of yes vs no | 0.94 (0.87–1.01) | 0.87 (0.76–0.99) | |
| Diabetes | Yes (n = 175) | 114 (65.1%) | 72 (41.1%) |
| No (n = 7114) | 5590 (78.6%) | 3963 (55.7%) | |
| RR of yes vs no | 0.84 (0.74–0.96) | 0.82 (0.67–1.0008) | |
| Overweight/obesity | Yes (n = 3699) | 2834 (76.6%) | 1969 (53.2%) |
| No (n = 3389) | 2732 (80.6%) | 1979 (58.4%) | |
| RR of yes vs no | 0.97 (0.95–1.00) | 0.92 (0.88–0.96) | |
| Other endocrine disorders | Yes (n = 131) | 100 (76.3%) | 56 (42.7%) |
| No (n = 7158) | 5604 (78.3%) | 3979 (55.6%) | |
| RR of yes vs no | 1.02 (0.92–1.13) | 0.82 (0.65–1.03) |
Bold type indicates significant results.
Adjusted for sex, race, education, marital status, household income, health insurance, employment status, other grade 3 to 4 chronic condition, emotional health (Brief Symptom Inventory-18), radiation (yes/no), amputation, and task efficiency. The adjusted number of outcomes and percentages were calculated based on the survivors with endocrine information.
Table 6.
Effect of Number of Endocrine and Metabolic Disorders on Physical Activity Among Adult Survivors of Childhood Cancer
| Value | Recent Participation in Any Organized Physical Activities [n (%)]a | Meets CDC Guidelines for Physical Activity [n (%)]a | |
|---|---|---|---|
| No. of endocrine and metabolic disorders | 1 (n = 3257) | 2547 (78.2%) | 1819 (55.8%) |
| 2 (n = 1176) | 887 (75.4%) | 587 (49.9%) | |
| >2 (n = 451) | 309 (68.5%) | 181 (40.1%) | |
| No endocrine/metabolic disorder (n = 2278) | 1868 (82.0%) | 1385 (60.9%) | |
| RR (95% CI) | |||
| 1 vs no endocrine/metabolic disorder | 0.98 (0.96–1.005) | 0.93 (0.89–0.98) | |
| 2 vs no endocrine/metabolic disorder | 0.96 (0.92–1.001) | 0.91 (0.85–0.98) | |
| >2 vs no endocrine/metabolic disorder | 0.90 (0.83–0.97) | 0.76 (0.67–0.85) | |
| 2 vs 1 | 0.98 (0.94–1.02) | 0.98 (0.92–1.06) | |
| >2 vs 1 | 0.92 (0.85–0.99) | 0.82 (0.72–0.94) | |
| >2 vs 2 | 0.93 (0.86–1.01) | 0.84 (0.73–0.96) | |
Bold type indicates significant results.
Adjusted for sex, race, education, marital status, household income, health insurance, employment status, other grade 3 to 4 chronic condition, emotional health (Brief Symptom Inventory-18), radiation (yes/no), amputation, and task efficiency. The adjusted number of outcomes and percentages were calculated based on the survivors with endocrine information.
We did not find any major differences in clinical characteristics, HRQOL subscales, or physical activity between survivors with and without endocrine disorders after exclusion of overweight/obesity (31).
Treatment effect and HRQOL outcomes
As shown in Table 7, among survivors with hypothyroidism who reported use of thyroid hormone replacement, there was a significantly lower risk of general mental health morbidities (RR, 0.58; 95% CI, 0.36 to 0.93) compared with those not reporting thyroid hormone replacement. Male survivors with gonadal dysfunction who reported use of testosterone had a lower risk for poor physical health (RR, 0.19; 95% CI, 0.04 to 0.88), role limitations due to emotional problems (RR, 0.38; 95% CI, 0.15 to 0.98), poor social functioning (RR, 0.22; 95% CI, 0.05 to 0.97), and poor mental health (RR, 0.22; 95% CI, 0.06 to 0.86) compared with those who did not report taking testosterone replacement.
Table 7.
Adjusted RRs of SF-36 Outcomes Between Survivors With Endocrine Conditions Reporting Medication Use for Hormone Replacement Compared With Those Not on Hormone Replacement Therapy
| SF-36 Scale or Component Summary Score | Survivors with Hypothyroidism on Replacement Therapy at 2003 Survey Compared With Survivors With no Replacement (n = 110)a | Males With Gonadal Dysfunction on Testosterone Therapy at 2003 Survey Compared With Survivors With No Replacement (n = 51)a | Females With Gonadal Dysfunction on HRT at 2003 Survey Compared With Survivors With No Replacement (n = 168)a |
|---|---|---|---|
| Physical function | 1.00 (0.96–1.04) | 0.19 (0.04–0.88) | 0.90 (0.53–1.55) |
| Role physical | 1.23 (0.61–2.50) | 0.71 (0.71–2.53) | 1.01 (0.57–1.80) |
| Bodily pain | 1.08 (0.64–1.81) | 0.47 (0.15–1.50) | 0.84 (0.55–1.26) |
| General health | 0.81 (0.50–1.32) | 0.40 (0.14–1.19) | 0.85 (0.62–1.15) |
| Vitality | 0.78 (0.50–1.22) | 0.54 (0.25–1.18) | 0.72 (0.48–1.09) |
| Role emotional | 0.74 (0.48–1.13) | 0.38 (0.15–0.98) | 1.02 (0.58–1.82) |
| Social function | 0.89 (0.46–1.69) | 0.22 (0.05–0.97) | 0.99 (0.71–1.38) |
| Mental health | 0.58 (0.36–0.93) | 0.22 (0.06–0.86) | 1.07 (0.65–1.77) |
| Physical component summary | 0.77 (0.45–1.32) | 0.16 (0.02–1.56) | 1.09 (0.62–1.91) |
| Mental component summary | 0.75 (0.41–1.36) | 0.48 (0.16–1.43) | 1.16 (0.62–2.20) |
Bold type indicates significant results.
Abbreviation: HRT, hormone replacement therapy.
Adjusted for sex (only for testosterone therapy and HRT), race, education, marital status, household income, health insurance, employment status, radiation (yes/no), amputation, and other grade 3 to 4 chronic condition.
Discussion
In this study of >7000 survivors, we demonstrated an independent association of endocrine and metabolic disorders and reduced HRQOL and physical activity, even after adjusting for factors known to negatively influence these outcomes such as other chronic health conditions, cranial radiation therapy, and neurocognitive deficits. Two-thirds of survivors had at least one endocrine or metabolic disorder. These disorders significantly affected both the physical and mental components of HRQOL and were associated with reduced physical activity. In a previous study, an amputation or cranial radiation (5) significantly affected HRQOL and physical activity. However, we demonstrated that even when adjusting for these treatment variables, endocrine/metabolic disorders have an incremental negative impact on HRQOL and physical activity, suggesting that these disorders may be associated with pathophysiological changes that decrease HRQOL.
Compared with survivors without any endocrine or metabolic disorders, most survivors with these disorders reported significant limitations in physical functioning that included difficulties with activities of daily living, pain that limited their physical well-being, and a perception that their general health was poor. They also experienced symptoms of fatigue. The endocrine system integrates a complex set of physical and psychological signals that influence a variety of body systems, allowing individuals to adapt to their environment. Although it was previously known that survivors with endocrine disorders are at risk for physical limitations, this analysis elucidated the impact of individual endocrinopathies. For example, survivors with thyroid disorders reported significant limitations in work and activities of daily living due to their physical health, were more likely to feel weak and tired at all times, and perceived their general health as poor and likely to get worse. Although these survivors did not have increased symptoms of anxiety and depression, they did report that emotional problems interfered with their work or daily activities. Similar findings were observed in a Swiss study of childhood cancer survivors in which thyroid disorders were shown to impact all elements of HRQOL (6). Impairments in HRQOL have been reported in adult, noncancer populations with thyroid disorders (32–35). Given the critical role played by thyroid hormones in growth, development, and energy metabolism, as well as the long latency of developing thyroid disorders after cancer treatment, these finding support the need to remain vigilant for signs or symptoms of thyroid dysfunction in at-risk patients throughout the survivorship trajectory. This is particularly important because survivors who reported taking thyroid hormone replacement showed better overall mental health, an important aspect of HRQOL.
We observed that male survivors with gonadal dysfunction reported more problems at work and performing physical activities of daily living due to poor physical health, more somatic pain, and a general feeling of being fatigued and worn out. Similar to previous reports of males with gonadal dysfunction (36–38), these members of our cohort experienced greater functional impairment due to emotional problems, interference in social activities due to these problems, and an increase in symptoms of anxiety and depression. Testosterone deficiency may have limited physical development, such as low muscle mass, and sexual health and function, such as poor libido and infertility. Encouragingly, survivors who reported taking testosterone replacement reported higher physical, social functioning, and mental health on the SF-36 than did those not receiving replacement. Female survivors with gonadal dysfunction reported limitations in performing physical activities and increased body pain and feelings of poor physical health, which may be related to poor bone health due to estrogen deficiency (39, 40).
Survivors with diabetes mellitus and overweight/obesity also reported impairment in physical activity, increased and functionally limiting pain, increased feelings of fatigue, and decreased perception of general health and well-being without a significant impact on mental health. Careful and targeted counseling for weight reduction and other lifestyle changes are needed so that improvement in HRQOL can be achieved in these survivors.
The negative impact of endocrine and metabolic disorders on physical domain subscales of the HRQOL was first reported by Ness et al. (9). To our knowledge, our study is the first to show that among survivors with endocrine disorders, those with growth and bone disorders were less likely to report adherence to the CDC physical activity guidelines. These disorders when untreated affect lean muscle mass, muscle and bone strength, and may lead to poor exercise tolerance (23). Additionally, survivors with growth disorders also reported an inactive lifestyle. This is significant, as it is well known that subjects with GH deficiency are at risk for poor cardiovascular outcomes (41). Survivors with diabetes mellitus and those who were overweight/obese also reported poor compliance with CDC guidelines. Targeting exercise interventions to this group could produce significant health benefits that may potentially alter the underlying disease trajectories of diabetes and obesity. Our results also showed that it was harder to maintain physical activity with cumulative effects of more than one endocrine/metabolic disorder. These results should prompt exercise interventions for survivors with multiple endocrinopathies.
There are several limitations to this study. First, the diagnosis of endocrine and metabolic disorders was obtained from a self-reported survey. This might underestimate the proportion of survivors with these disorders in our study, as previous studies have shown that screenings and risk-based assessment frequently detect endocrine disorders that survivors are not aware of (42, 43). The physical activity outcomes in this study were a self-reported measure and were not validated against known objective measurements such as resting energy expenditures or accelerometers. Owing to the study design, we were not able to determine whether survivors were receiving optimum treatment or were compliant with medications prescribed to treat an endocrinopathy, and so we cannot determine whether poorer HRQOL and lower physical activity were associated with having an untreated endocrinopathy, or whether even adequately treated endocrinopathies negatively influence these outcomes. However, we observed better outcomes in many aspects of the HRQOL among those survivors reporting taking thyroid and male sex hormones compared with those who were not on these replacement medications. Further investigations are required in the setting of a prospective study design to confirm and validate these findings.
In summary, childhood cancer survivors with endocrine and metabolic disorders are more likely to have functional impairment, decreased physical activity, and an inactive lifestyle. To our knowledge, this study provides the first evidence of how each of the more common endocrine and metabolic disorders affects HRQOL and physical activity. Prospective studies designed to evaluate the treatment interventions of these disorders on HRQOL and physical activity are needed to optimize improvement in these outcomes.
Acknowledgments
Financial Support: This work was supported by National Cancer Institute Grant CA55727 (to G.T.A.). Support to St. Jude Children’s Research Hospital was also provided by Cancer Center Support (CORE) Grant CA21765.
Additional Information
Disclosure Summary: K.R.P. is employed by Eli Lilly and Company. The remaining authors have nothing to disclose.
Data Availability: All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.
Glossary
Abbreviations:
- BMI
body mass index
- CCSS
Childhood Cancer Survivor Study
- CDC
Centers for Disease Control and Prevention
- HRQOL
health-related quality of life
- RR
risk ratio
- SF-36
Medical Outcomes Short Form-36
References and Notes
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