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Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.
Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed 1970–1986, and 2936 randomly selected siblings of CCSS survivors. The main outcome was self-reported DM.
Survivors and siblings had mean ages of 31.5 years (range, 17.0–54.1) and 33.4 years (range, 9.6–58.4), respectively. DM was reported in 2.5% of survivors and 1.7% of siblings. Adjusting for body mass index (BMI), age, sex, race/ethnicity, household income, and insurance, survivors were 1.8 times more likely to report DM (95% confidence interval [CI], 1.3–2.5; P<0.001) than siblings, with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2–25.3; P<0.001), abdominal irradiation (OR, 3.4; 95% CI, 2.3–5.0; P<0.001) and cranial irradiation (OR, 1.6; 95% CI 1.0–2.3; P=0.03) at increased risk. In adjusted models, increased risk of DM was associated with: total body irradiation (OR 7.2; 95% CI, 3.4–15.0; P<0.001); abdominal irradiation (OR 2.7; 95% CI, 1.9–3.8; P<0.001); alkylating agents (OR 1.7; 95% CI, 1.2–2.3; P<0.01); and younger age at diagnosis (0–4 years; OR 2.4; 95% CI 1.3–4.6; P<0.01).
Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.
Secondary to their curative therapies, childhood cancer survivors face an increased risk of morbidity and mortality. We recently reported that by thirty years after diagnosis, almost three-fourths of survivors will have a chronic health condition, including 42.4% with a severe, disabling, or life-threatening condition or death due to a chronic condition.1 Further, survivors frequently suffer from multiple conditions. Among long-term childhood cancer survivors, Mertens and colleagues reported a standardized mortality ratio of 7.0 for deaths due to cardiovascular disease.2 Importantly, most childhood cancer survivors worldwide are still relatively young, with only a small percent beyond their fifth decade of life.
In the general population, DM is strongly associated with an increased risk of cardiovascular disease and all-cause death.3 We can anticipate that DM in long-term survivors of childhood cancer will further increase their risk of adverse health outcomes. Importantly, the risk of type 2 DM is potentially modifiable. Thus, it is important to determine if childhood cancer survivors are at increased risk of DM, identify treatment exposures or other factors that may affect risk, and alert clinicians and survivors regarding these risks.
Recent studies suggest that cancer survivors whose treatment included bone marrow transplantation may have an increased prevalence of DM, particularly those who were treated with total body irradiation (TBI).4–9 Two small studies suggested a possible increased risk of DM following abdominal irradiation for Wilms tumor.10,11 In addition, acute lymphoblastic leukemia (ALL) and brain tumor survivors who were treated with cranial irradiation, particularly females treated at a young age, have an increased risk of obesity in adulthood.12,13 Obesity is a strong predictor of insulin resistance and type 2 DM and thus it can be anticipated that these subpopulations of childhood cancer survivors may develop type 2 DM at an increased rate.
The purpose of this cross-sectional study was to further elucidate the risk of DM in long-term survivors of childhood cancer, using a large, diverse and well characterized cohort of survivors and a comparison group of siblings. Additionally, we sought to identify treatment exposures and other factors that modify the risk of DM.
The methodology of the Childhood Cancer Survivor Study (CCSS) and a description of participants have been published in detail previously.14 Briefly, the CCSS cohort consists of survivors of specific childhood cancers (leukemia, central nervous system [CNS] malignancies, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas or bone tumors) who were diagnosed before the age of 21 years at one of 26 participating centers between 1970 and 1986, and who were alive at least five years from their original diagnosis. The eligible cohort consisted of 20,720 patients, of whom 14.6% were deemed lost to follow-up after intensive tracing. Of the 17,703 who were successfully contacted, 14,366 (81.2%) enrolled in the study. Comparisons of demographic and cancer-related characteristics of participants and non-participants did not demonstrate significant differences with regard to gender, cancer type, age at diagnosis, age when the cohort was assembled (e.g., 1993–4), and type of cancer treatment.14,15 To allow comparisons with a representative of the general population without cancer, a random sample of participating survivors was asked to identify his or her nearest-age living sibling. Of 4,782 eligible siblings, 3,846 (80.4%) participated.
Since the time of enrollment (1995–1996 for most participants) a series of questionnaires have been administered. Eligibility for this analysis was limited to participants who completed the CCSS 2003 Follow-up Survey, which included questions about medication use for diabetes mellitus (available at www.stjude.org/ccss). The study methodology was approved by the Institutional Review Board of each participating institution and written informed consent was obtained from each participant or his or her parent or guardian. Participating CCSS institutions are provided in the appendix.
Information regarding original cancer diagnoses was obtained for eligible cases from treating institutions. For all CCSS participants returning signed medical releases, information regarding primary cancer therapies was collected, including initial treatment, treatment for relapse, and (where applicable) preparatory regimens for bone marrow transplantation. Qualitative information was abstracted from medical records for 42 specific chemotherapeutic agents, for which quantitative dose information was abstracted on 22. Copies of radiation therapy records were obtained and centrally reviewed, including doses of cranial and craniospinal radiotherapy and total body irradiation. The treatment abstraction forms employed in data collection are available at www.stjude.org/ccss.
In the CCSS 2003 Follow-up Survey, participants were asked if they had taken insulin or an oral medication for DM for more than one month in the preceding two years. To prompt participants, common examples of oral DM medications and forms of insulin were provided. Participants were asked to specify the name of the medication(s). They were considered to have DM if they listed an oral DM medication and/or a form of insulin.
Socio-demographic characteristics of the participants included gender, race/ethnicity, highest level of educational attainment, household income, and health insurance status. Race/ethnicity was included to account for racial and ethnic disparities in the prevalence of DM.16,17 Body mass index (BMI; kg/m2) was calculated from self-reported heights and weights. Based upon questions in the 2003 Behavioral Risk Factor Surveillance System (BFRSS), conducted through the Centers for Disease Control and Prevention (CDC), two measures of physical activity were included in the 2002–2003 CCSS Survey.18 First, participants who reported either ≥ 30 minutes of moderate-intensity physical activity on ≥ 5 days per week or ≥ 20 minutes of vigorous-intensity physical activity on ≥ 3 days per week were classified as meeting the CDC recommendation for physical activity.19 Second, participants were considered ‘inactive’ if they reported no leisure-time physical activity in the month preceding the survey. Additional risk factors assessed among survivors included: cancer diagnosis, age at diagnosis, interval from diagnosis to study, and cancer therapy.
Characteristics of survivors and siblings (age, sex, race/ethnicity, education, household income, health insurance, physical activity, BMI) were compared using nonparametric bootstrap by resampling families 1000 times so that we take potential within-family correlation into account in the comparison.20 The prevalence of DM was estimated for survivors and siblings. Logistic regression analysis was conducted to estimate the odds ratios (OR) and associated 95% confidence intervals (CI) for having DM in survivors compared to siblings, adjusting for age at interview, sex, race/ethnicity, household income, and health insurance. Because of the influence of BMI on the risk of DM, a second model was fitted, adjusting for BMI in addition to the above variables. Similarly, models adjusting for being inactive or not meeting the CDC recommendations for physical activity were assessed. Specific subgroups of survivors, depending upon cancer type or therapy, were compared with siblings, with respect to the prevalence of diabetes. Generalized Estimating Equations with non-independent working correlation were used to modify the logistic regression accounting for potential within-family correlation.21 Note there is only one possible non-independent working correlation as there is at most one sibling per family.
To further assess the independent effects of different cancer therapies on diabetes, a logistic regression analysis was performed among survivors only, adjusting for BMI, not meeting the CDC recommendations for physical activity, age at interview, sex, race/ethnicity, household income, and health insurance. Treatment exposures within the first five years from the original cancer diagnosis were considered. All statistical analyses were performed using SAS Version 9.1 (SAS Institute Inc., Cary, NC, USA) and 2-sided statistical inferences were employed throughout the analyses.
At the time of the CCSS 2003 Follow-up Survey, there were 11,465 survivors who were alive and eligible for medical records abstraction. Of the 11,465 survivors, 1751 (15.3%) were passive or active non-respondents, and 406 (3.5%) could not be located. Furthermore, 709 patients with second malignancy (SMN) and/or a recurrence after 5 years since diagnosis were excluded from the analysis (32 had SMN and recurrence, 391 SMN only, 286 late recurrence only). Participants did not differ from non-participants by diagnosis, original cancer treatment, or age at diagnosis. However, participants were slightly more likely to be female (48.5% female in the participants vs. 43.4% in the nonparticipants, p <0.001) and slightly younger at the first contact (mean age at baseline contact 23.7 years vs. 24.3 years, p <0.001). There were 3599 siblings in the cohort who were alive when the CCSS 2003 Follow-up Survey was administered, of which 597 (16.6%) were an active or passive non-respondent and 51 (1.4%) could not be located. Additionally, 12 siblings who developed cancer were excluded. Thus, there were 8,599 survivors and 2,936 siblings available for this analysis.
Table 1 shows the characteristics of survivors and siblings. The mean age of survivors was 31.5 years (range, 17.0 to 54.1) and the mean interval from cancer diagnosis to the CCSS 2003 Follow-up Survey was 23.5 years (range, 16.0 to 35.2). The mean age of siblings was 33.4 years (range, 9.6 to 58.4). In comparison with survivors, siblings were slightly more likely to be female (53.6% vs 48.5%, P<0.001), white, non-Hispanic (91.8% vs 85.3%, P<0.001), to have a household income of $20,000 or more (92.6% vs 86.7%, P<0.001), and to have health insurance (90.6% vs 87.4%, P<0.001).
Of the 8,599 survivors, 218 (2.5%) reported being on a medication for DM; of the 2,936 siblings, 49 (1.7%) reported being on a medication for DM. Fifty-seven percent of the survivors with DM were less than 35 years old, in contrast to only 35% of the siblings (Figure 1a and 1b). Of the 218 survivors with DM, 45 (20.6%) were on insulin only; the remainder were on oral medications with or without insulin. Similarly, 20.4% of the siblings (10/49) were on insulin alone. Thus, at least 79% of survivors and 80% of siblings with DM suffered from type 2 DM.
Compared to siblings and adjusted for age at interview, sex, race/ethnicity, household income, and health insurance, survivors were 1.6 times as likely to have DM (95% CI, 1.2–2.2; P<0.01) [Table 2]. This estimate was slightly higher when also adjusted for BMI (OR=1.8; 95% CI, 1.3–2.5; P<0.001). Findings were not significantly different when adjusting for either not meeting the CDC recommendation for physical activity or being inactive. Compared with siblings, the adjusted ORs (including BMI) were significantly increased for the following cancer groups: acute myeloid leukemia (AML; OR=5.7; 95% CI, 3.1–10.6; P<0.001), neuroblastoma (OR=2.9; 95% CI, 1.5–5.6; P<0.01), Wilms tumor (OR=2.2; 95% CI, 1.2–3.9; P=0.01), and ALL (OR=1.8; 95% CI, 1.2–2.6; P<0.01).
The relationship of different chemotherapy and radiation therapy exposures was assessed, adjusting for age at interview, sex, race/ethnicity, household income, and having health insurance. Treatment with an alkylating agent, corticosteroid, or anthracycline was associated with an increased prevalence of DM (Table 2). For both alkylating agents and anthracyclines, survivors with higher cumulative doses were not more likely to have DM than those with lower doses, so these treatment exposures were collapsed into yes/no variables. In survivors not treated with radiation, there was no association between alkylating agents and DM. There was no difference in the association of individual corticosteroids (dexamethasone, hydrocortisone, or prednisone) and DM, so these agents were grouped into a single corticosteroid category. Other chemotherapeutic agents, including asparaginase, were not associated with DM. Three types of radiation therapy were associated with DM: total body irradiation (TBI), abdominal irradiation, and cranial irradiation.
To further investigate the relationship between radiation and DM, we compared survivors to siblings, stratified by diagnosis (neuroblastoma, Wilms tumor, Hodgkin lymphoma, AML, ALL, CNS tumor) and type of radiation (Table 3). Survivors who were treated with abdominal irradiation (neuroblastoma, OR=6.9; 95% CI, 3.5–13.9; P<0.001; Wilms tumor, OR=2.1; 95% CI, 1.1–4.0; P=0.03; Hodgkin lymphoma, OR=2.1; 95% CI, 1.2–3.5; P<0.01) were significantly more likely to be diabetic than siblings. When adjusted for BMI, these point estimates were further increased. In contrast, survivors of these three cancer groups who were not treated with abdominal irradiation were not more likely to have DM than siblings. AML survivors treated with and without TBI were more likely to be diabetic than siblings (with TBI, OR=17.7, 95% CI, 6.4–49.4; P<0.001; without TBI, OR=2.8; 1.2–6.3; P=0.01). Adjusting for BMI increased both of these estimates. ALL survivors who were treated with cranial irradiation were 1.8 times as likely to report DM as the siblings (95% CI, 1.2–2.8; P<0.01), with a decrease in the estimate to 1.6 (95% CI, 1.0–2.5; P=0.06) when adjusted for BMI.
As noted above, we could not ascertain whether or not patients who were on insulin had type 1 or 2 DM. When the above analyses were repeated, excluding all survivors and siblings who were on insulin only, the findings were not different (data not shown).
A multivariate logistic regression model (Table 4) was used to estimate the odds of having DM among survivors and included socio-demographic factors that are associated with DM in the general population (age, sex, race/ethnicity, household income, insurance, physical inactivity, BMI category). Survivors treated with abdominal irradiation were 2.7 times as likely to report DM (95% CI, 1.9–3.8; P<0.001) in comparison with survivors who were not treated with abdominal irradiation or TBI; those treated with TBI were 7.2 times as likely to report DM (95% CI, 3.4–15.0; P<0.001). In this final model, cranial irradiation was not associated with DM.
When adjusted for radiation therapy, previous treatment with an alkylating agent also increased risk of DM (OR=1.7; 95% CI, 1.2–2.3; P<0.01). However, there was not a significant interaction between alkylating agent exposure and either abdominal irradiation or TBI. In the adjusted multivariate model with different treatment exposures, previous therapy with corticosteroids or asparaginase was not associated with DM.
Age at cancer diagnosis modified the risk of DM, with survivors who were diagnosed prior to the age of five being 2.4 times (95% CI, 1.3–4.6; P<0.01) as likely to report DM as those who were diagnosed in late adolescence (age 15–20 years). As in the general population, older age, Black or Hispanic/Latino background, lower household income, physical inactivity, and increased BMI were associated with increased risk of DM. The final model was not significantly different when survivors who were on insulin only were excluded (data not shown).
From this large and diverse cohort of young adult survivors of childhood cancer, we report an almost two-fold increased risk of self-reported DM, primarily of probable type 2, in comparison with their siblings. This risk was most evident for AML, neuroblastoma, Wilms tumor, and Hodgkin lymphoma survivors who were treated with TBI or abdominal irradiation. Importantly, this risk was independent of obesity and physical inactivity. Survivors of ALL who were treated with cranial irradiation were also more likely to be diabetic than the siblings, but this was in part related to increased BMI and physical inactivity. The relationship between cranial irradiation and insulin resistance has been well described 7, 22–24 and is an expected outcome of the increased prevalence of obesity following CRT in this population.13,25 Further, Mohn and colleagues suggest that impaired β-cell function may persist following chemotherapy for ALL.26 Thus, the following discussion focuses on the less well characterized association between DM and abdominal and total body irradiation. Indeed, the diabetes observed among this irradiated cancer population may represent a form of therapy induced diabetes and be the result of an impairment of insulin release and specific β-cell lesions.27
Diabetes following abdominal irradiation for neuroblastoma has not previously been reported. Neuroblastoma survivors who were treated with abdominal irradiation had a nine-fold increased likelihood of being diabetic in comparison with siblings, after adjusting for BMI. In contrast, those who were not treated with abdominal irradiation did not have an elevated risk of DM. This pattern was also seen in the two other groups of survivors commonly exposed to abdominal irradiation. For both Wilms tumor and Hodgkin lymphoma survivors, a significantly increased risk of DM in comparison with siblings was observed only in those who were treated with abdominal irradiation. To date, there are a few studies that have assessed the risk of DM following abdominal irradiation. In a small retrospective chart review of 121 Wilms tumor survivors, 8 (6.6%) developed DM, 6 of whom were controlled on either diet or oral medication.11 Conversely, among 4387 childhood cancer survivors who were a median age of 29.8 years, Hawkins et al did not find an increased prevalence of DM associated with abdominal irradiation.28
There are several mechanisms by which abdominal irradiation may lead to DM. The pancreas is in the field of left-sided (or bilateral) abdominal irradiation. Small animal studies suggest that following radiation, the pancreatic islet cells show evidence of degranulation, vacuolization, mitochondrial destruction, and impaired insulin secretion.29,30 Pancreatic insufficiency, relative or absolute, may result following irradiation. Of note, however, most survivors in our study who had DM following abdominal irradiation were either on oral medication or combination therapy, suggesting that if they have β-cell dysfunction, it is not absolute. Thus, there are likely other mechanisms by which abdominal irradiation leads to DM. Alterations in adipose-derived hormones following radiation may lead to insulin resistance. Adipose tissue, originally thought only to have an energy storage function, is now recognized as an endocrine organ, producing and secreting a variety of factors including leptin, resistin and adiponectin.31,32 Perhaps the production of adiponectin or other adipose-derived hormones are radiosensitive processes and decreased levels may be a late effect of therapeutic abdominal irradiation.
Our finding of an association between TBI and DM confirms other recent studies.4–9 Generally, these studies suggest that DM following TBI is secondary to hyperinsulinemia rather than B-cell insufficiency.6,7,9 It is likely that the development of DM following TBI is multifactorial. Needless to say, the mechanisms described above with abdominal irradiation may apply also to patients who have been treated with TBI. Notably, though, the radiation dose to the abdomen is lower with TBI (12–15 Gy) than with abdominal irradiation in neuroblastoma or Wilms tumor treatment (20–30 Gy). Growth hormone deficiency (GHD) is common among childhood cancer survivors who are treated with TBI, particularly those treated at a young age.33,34 In non-cancer populations, GHD is associated with insulin resistance.35,36 GHD is likely one of the primary pathways by which ALL survivors become insulin resistant.22,37 Neville et al did not find an association between GHD and insulin resistance.7 Rather, they found that untreated hypogonadism and abdominal obesity were predictive of insulin resistance or hyperinsulinemia. The relationship of hypogonadism and insulin resistance among childhood cancer survivors has been reported by others.6,9 In the general population, men with androgen insufficiency have increased prevalence of insulin resistance and metabolic syndrome.38–40 However, this has not been reported in women with ovarian failure.
Interestingly, both GHD and androgen deficiency contribute to abdominal obesity.38,40 Abdominal obesity, particularly an increase in visceral adipose tissue, is strongly associated with the development of insulin resistance.41–43 It is thought that visceral fat is the more metabolically active fat and its ability to challenge the liver directly with free fatty acids (FFA) may play a crucial role in insulin resistance.41,44 Elevated levels of intrahepatic FFAs delivered directly through the portal system can lead to increased hepatic glucose production and reduced insulin sensitivity. Of note, recent studies within the HIV-infected population reported redistribution of adipose tissue in patients on a protease inhibitor. In these patients with HIV-associated adipose redistribution syndrome (HARS), there is an increase in visceral adipose tissue that is strongly correlated with insulin resistance and dyslipidemia.45
When interpreting the findings of this study, there are several limitations that need to be recognized. Diabetes was attributed to subjects who stated they were on a medication commonly used to treat DM or hyperinsulinemia. Misclassification resulting from reporting medications for DM is likely low. There is, however, a greater probability of misclassification resulting from undiagnosed DM. In addition, survivors who are aware of their increased risk for chronic health problems might be more likely to seek medical care than their siblings and therefore more likely to be diagnosed with a condition such as DM, leading to potential ascertainment bias and overestimates of risk. The sibling cohort is intended to represent a general, non-cancer population. While some outcomes may be different between siblings and the general population, we previously did not find any difference between the siblings and age- and gender-matched participants in national surveys with respect to BMI or meeting the CDC recommendations for physical activity.46–48 Non-participation may have introduced a selection bias in the study; 19% of the eligible survivors did not participate in this survey. Notably, participants did not differ from non-participants by diagnosis, original cancer treatment, or age at cancer diagnosis. Lastly, the cross-sectional design of this study precludes inferences of temporality, causality, and risk.
In summary, the prevalence of DM was almost twice as high in childhood cancer survivors compared to siblings, with risk being markedly elevated in those who were treated with either TBI or abdominal irradiation. It is likely that this additional chronic disease in childhood cancer survivors, who frequently also sustain damage to the heart, kidneys, and endocrine system,1 will lead to further morbidity and premature mortality. Thus, it is imperative that clinicians recognize this risk, screen for diabetes and pre-diabetes when appropriate, and approach survivors with aggressive risk-reducing strategies. Moreover, further research is warranted to understand the pathways by which these two modes of radiation therapy lead to diabetes.
Funding/Support: This work was supported by Grant U24-CA-55727 (L.L. Robison, Principal Investigator) from the Department of Health and Human Services, funding to the University of Minnesota from the Children’s Cancer Research Fund, and funding to St. Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities (ALSAC).
Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Competing Interest Statement: All authors declare that the answers to the questions on your competing interest form are all no and therefore have nothing to declare.
Ethical Approval: Institutional Review Board at all 26 participating institutions.
Contributors: Drs. Oeffinger and Robison had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Meacham, Sklar, Gimpel, Robison, Oeffinger
Acquisition of data: Whitton, Meacham, Sklar, Stovall, Robison, Oeffinger
Analysis and interpretation of data: Li, Liu, Yasui, Whitton, Meacham, Sklar, Oeffinger, Gimpel
Drafting of the manuscript: Meacham, Oeffinger
Critical revision of the manuscript for important intellectual content: Meacham, Oeffinger, Sklar, Yasui, Gimpel, Stovall, Robison
Obtained funding: Robison
Study supervision: Oeffinger, Robison