Pediatric Cancer Survivors and Diabetes: What Are the Risks?

As treatments and outcomes continue to improve in pediatric patients with cancer, it is critical to understand and monitor for potential long-term complications, especially as 5-year survival rates for childhood cancer currently exceed 80%.¹ Diabetes and metabolic syndrome represent two of the most common long-term complications for survivors of childhood cancer.^1,2 Approximately 50% of cancer survivors will be diagnosed with at least 1 hormonal abnormality during their lifetime.³

Friedman Review Article

In pediatric cancer survivors (PCS), there are multiple risk factors for developing diabetes, including treatments started at a younger age, as well as abdominal and total body irradiation (TBI). Abdominal radiation is frequently used to treat pediatric malignancies, including sarcomas, Wilms tumor, and neuroblastoma.² The effects of radiation, specifically on the pancreatic tail, are thought to be one of the primary pathways leading to the development of diabetes. There are conflicting data on the exact impact of cumulative radiation dose on the risk of developing diabetes, with some studies showing a plateau in risk and others not.² In addition to direct cellular damage to the pancreas, radiation may lead to diabetes via decreased blood flow, chromosomal changes, fibrosis, and thrombosis.⁴ Chemotherapy can also induce direct cellular damage, along with oxidative stress and vascular toxicity.^3,4

The mechanism behind diabetes risk and TBI varies slightly from abdominal radiation alone. Total body irradiation has been proposed to promote insulin resistance and hyperinsulinemia, as well as an overall increased level of inflammation.³ Patients undergoing hematopoietic stem cell transplantation can experience altered glucose metabolism, which is independent from obesity and has been linked to TBI, atypical body fat distribution, and sarcopenia.⁵

Pediatric patients with acute lymphoblastic leukemia (ALL) treated with high-dose glucocorticoids represent a specific subtype of PCS that has a relatively established risk of developing diabetes. Williams et al evaluated 1044 patients with at least 10-year survivorship from childhood ALL.⁶ Survivors of pediatric cancer were more likely to have diabetes compared with control patients (odds ratio 2.07 [95% CI, 1.11-3.87]). Development of diabetes was associated with older age, body mass index (BMI) of at least 30 kg/m², and drug-induced diabetes during ALL therapy. This study and others raise the interesting question of whether or not specific subtypes of PCS, such as ALL, should be considered for initiation of prophylactic medications, such as metformin.

Outside of ALL, several studies support the association between PCS and increased diabetes risk, irrespective of the type of cancer. A study conducted by Lega et al reviewed 10,438 survivors of pediatric cancer in Ontario and found they had a 55% increased rate of developing diabetes compared with control participants (hazard ratio [HR] 1.51 [95% CI, 1.28-1.78]).⁷ The overall rate of diabetes during the follow-up period was 1.5% in the pediatric cancer survivor group. Patients diagnosed with cancer between ages 6 and 10 years were found to have the highest risk of developing diabetes (HR 3.89 [95% CI, 2.26-6.68]). Within certain subtypes of PCS, patients with leukemia (HR 2.29 [95% CI, 1.68-3.14]) and lymphoma (HR 1.61 [95% CI, 1.12-2.31]) had the highest risk of developing diabetes. The authors proposed mechanisms of this increased risk, including low physical activity, poor diet, obesity, abdominal radiation, and certain types of chemotherapy. Unfortunately, no treatment-related data were included in this study.

Another study conducted by Meacham et al evaluated 8599 survivors of pediatric cancer and found they were 1.8 (95% CI, 1.3-2.5; P <.001) times more likely to be diagnosed with diabetes compared with their siblings and adjusted for BMI.⁸ Patients receiving radiation were all found to be at increased risk, with TBI (adjusted odds ratio [aOR] 12.6 [95% CI, 6.2-25.3; P <.001]) conferring the highest risk, followed by abdominal irradiation (aOR 3.4 [95% CI, 2.3-5; P <.001]) and cranial irradiation (aOR 1.6 [95% CI, 1-2.3; P =.03]). All chemotherapy agents evaluated — alkylating agents, corticosteroids, and anthracyclines — regardless of adjustment for BMI, were found to increase risk for diabetes. Patients with neuroblastoma, ALL, and AML were all found to have increased risk whereas no statistically significant difference was found in patients with Wilms tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, central nervous system tumor, bone tumor, and soft tissue sarcoma. In addition to the direct cellular damage to the pancreas induced by abdominal irradiation, the authors also proposed that radiation could lead to an alteration in adipose-derived hormones (leptin, resistin, adiponectin) leading to insulin resistance.

Metabolic Syndrome

In addition to diabetes, metabolic syndrome is also a future concern for PCS. Although there are varying definitions of metabolic syndrome, they typically include abdominal/central obesity, elevated blood pressure, elevated blood glucose, and elevated cholesterol/triglycerides, all of which lead to increased risk for cardiovascular disease.³ The underlying pathophysiology explaining the increased risk for metabolic syndrome in PCS is similar to diabetes and may include hormonal changes as well as increases in proinflammatory markers (tumor necrosis factor-α and interleukin-6), resistance to leptin, alteration in satiety signaling, and lower exercise capacity.^3,4 Risk factors for developing metabolic syndrome include TBI, as well as radiation to the chest, abdomen, and/or cranium.^3,4 Cranium irradiation can lead to growth hormone deficiency, which can also contribute to metabolic syndrome, with increased fasting insulin, abdominal obesity, and hyperlipidemia. Patients who undergo surgical resection of their hypothalamus or who have deficits secondary to a malignancy are at risk for obesity and metabolic syndrome.⁵ Pediatric cancer survivors who received radiation therapy or chemotherapy that causes a direct effect on the reproductive system are also at risk for metabolic syndrome via the impact of treatment on sex hormones, specifically testosterone and estrogen.³

Guidelines vary on specific recommendations for screening PCS for diabetes and metabolic syndrome.⁴ Patients who have received radiation therapy are frequently screened at least every 2 years with a fasting lipid profile and fasting blood glucose (and/or hemoglobin A1c). It is important to identify patients at risk and counsel them on adjusting their lifestyle factors, including diet, exercise, and smoking, with a goal of mitigating the risk for these conditions.

References

1. Phillips SM, Padgett LS, Leisenring WM, et al. Survivors of childhood cancer in the United States: prevalence and burden of morbidity. Cancer Epidemiol Biomarkers Prev. 2015;24(4):653-663.
2. Friedman DN, Tonorezos ES, Cohen P. Diabetes and metabolic syndrome in survivors of childhood cancer. Horm Res Paediatr. 2019;91(2):118-127.
3. Brignardello E, Felicetti F, Castiglione A, et al. Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol. 2013;168(3):465-472.
4. Gebauer J, Higham C Langer T, et al. Long-term endocrine and metabolic consequences of cancer treatment: a systematic review. Endocr Rev. 2019;40(3):711-767.
5. Chemaitilly W, Cohen LE, Mostoufi-Moab S, et al. Endocrine late effects in childhood cancer survivors. J Clin Oncol. 2018;36(21):2153-2159.
6. Williams HE, Howell CR, Chemaitilly W, et al. Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: a report from the St Jude Lifetime Cohort Study. Cancer. 2020;126(4):870-878.
7. Lega IC, Pole JD, Austin PC, Lau C, Nathan PC, Baxter NN. Diabetes risk in childhood cancer survivors: a population-based study. Can J Diabetes. 2018;42(5):533-559.
8. Meacham LR, Sklar CA, Li S, et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the Childhood Cancer Survivor Study (CCSS). Arch Inter Med. 2009;169(15):1381-1388.