Endocrine long-term side effects in childhood cancer survivors

Because of increasing survival rates of childhood cancer, long-term side effects have become more prominent. These include several endocrine consequences, such as metabolic syndrome, growth hormone deficiency, low bone mineral density, frailty, and osteonecrosis, which can lead to low quality of life and early mortality. Prevention, early diagnosis and treatment of these late effects can enhance quality of childhood cancer survival.
These studies are part of the nationwide Dutch LATER study. This is a cross-sectional study that was initiated in all seven pediatric oncology centers in The Netherlands, for which the national cohort of all survivors treated between 1963 and 2002 was invited to participate, from 2017 until 2020. Data for a great number of long-term side-effects have been collected, including metabolic syndrome, growth hormone deficiency, bone density, and frailty. Individuals who survived at least five years after diagnosis of histologically confirmed malignancies defined in the International Classification of Childhood Cancer, edition 3, or Langerhans cell histiocytosis treated with chemotherapy and/or radiotherapy, who were between 0 and 17 years of age at diagnosis, are invited. Data for all studies have been collected at the time of their regular care visit to the late-effects clinic. The entire cohort contained 6165 eligible CCS. The cleaned cohort was frozen in 2016, leaving 5160 subjects eligible who were alive at that time point, and were invited to participate. About 2500 survivors participated in the Dutch LATER study.
Detailed data on cancer diagnosis and treatment, including chemotherapy regimens and doses, radiotherapy fields and (fractionated) dose, stem cell transplantation and corticosteroids, have been collected in a web-based central database for all eligible CCS. This includes primary diagnosis as well as, if applicable, recurrences and secondary malignancies.
Normative data from the Dutch Lifelines cohort will serve as control. All data is stored pseudonymized in a central database. In this database, data on previous treatment, length and weight at cancer diagnosis and comorbidity are available. In the general health questionnaire, survivors are asked about medication use, smoking and alcohol habits, family history of diabetes mellitus and cardiovascular disease, and physical activity.
Metabolic syndrome
Potential late effects of childhood cancer include adiposity, insulin resistance, dyslipidemia and hypertension, which cluster together as metabolic syndrome (MetS). MetS is associated with a higher risk of diabetes mellitus, and cardio- and cerebrovascular morbidity and mortality later in life.
Studies in childhood cancer survivors (CCS) have reported a prevalence of MetS of over 30% after 25 years follow-up, compared to 15% in the general young-adult population. This is in addition to the risk by cardiotoxic and endothelium damaging therapies, such as anthracyclines, irradiation and alkylating agents. The mortality due to cardiovascular disease in CCS is up to 12.7 times higher than the general population.
MetS risk can be the result of having been treated for a brain tumor, been treated with radiotherapy, nephrectomy, or adrenalectomy. There are conflicting results on the influence of other potentially harmful treatments, for example corticosteroids and stem cell transplantation, and patient-related factors such as sex, age, BMI at diagnosis, and lifestyle.
Adequate assessment of MetS in CCS using the classic definitions can be difficult, particularly after abdominal radiotherapy. It has been shown that BMI and waist circumference underestimate adiposity, due to deformation of spine, muscles and fat, particularly in past treatment eras with higher radiotherapy doses and larger treatment portals. Similarly, adiposity can be underestimated due to sarcopenic obesity after stem cell transplantation. Serum biomarkers may be more cost-effective surrogate markers for MetS, but have so far not been studied in large cohorts of CCS.
So far, studies on MetS in CCS have yielded heterogeneous and conflicting results and can be difficult to compare. This is due to generally small patient cohorts, suboptimal study design such as retrospective and questionnaire studies, insufficient treatment data, heterogeneity of malignancies and treatments, short follow-up, and lack of a control group. In addition, comparison of study outcomes can be difficult due to the use of different MetS definitions. Currently, no studies in national cohorts on prevalence and determinants of MetS in childhood cancer survivors including biomarkers and genetic predisposition are available.
Growth hormone deficiency
Growth hormone deficiency (GHD) is the most common long term complication of patients who received cranial radiotherapy. The radiation-induced damage to the hypothalamic-pituitary axis is both dose and time dependent and may only become apparent after a latency of many years until in advanced adulthood. GHD has several unfavorable effects on health status in children as well as in adults. GHD in adults is associated with decreased quality of life, fatigue, impaired cognitive functioning, decreased mass of muscle and bone, components of the metabolic syndrome and (most likely) cardiovascular disease. Symptoms of GHD can be reversed by growth hormone substitution therapy. The gold standard for the diagnosis of GHD is the insulin tolerance test, which is time consuming, inconvenient to the patient and contraindicated in certain instances. In such cases an arginine stimulation test is recommended. Traditionally, screening for GHD is performed by measurement of IGF-1 and reduced concentrations of IGF-1 levels are highly suggestive of GHD. But a normal IGF-1 does not rule out GHD, especially after cranial irradiation and in patients with characteristics of the metabolic syndrome. The latter is very common in childhood cancer survivors, and contributes to the low sensitivity of IGF-1 to detect patients with GHD. Measurement of free/bioactive IGF-1 may circumvent the shortcomings of the (total) IGF-1 assay, but its diagnostic accuracy for this patient group remains to be proven. Identification of patients with GHD is essential because this offers an evidence based treatment option, with among other effects, an improvement in quality of life. This study aims to investigate the frequency of GHD in our Dutch national cohort, and aims to investigate the role of biomarkers such as IGF-1 and sKlotho and to compare different assays in evaluation of GHD.
Accelerated aging (low bone mineral density and frailty)
Childhood cancer survivors carry an increased risk of morbidity, including poor bone health, sarcopenia (low muscle mass and strength), poor physical performance and low energy levels that appear not only more frequently, but also decades earlier than expected. This accelerated aging is a phenotype that among older persons is referred to as frailty. The risk of (very) low bone mineral density (BMD), which is associated with fractures and frailty in elderly, also seems to be increased in childhood cancer survivors. Risk stratification, timely diagnosis and preventive strategies of (pre)frailty and (very) low BMD are of importance to prevent osteoporotic fractures and early mortality and to improve quality of life. Enhanced insights in treatment-related and genetic risk factors and the prognostic value of biomarkers may improve identification of survivors at risk.
Follow-up of patients who experienced osteonecrosis
Osteonecrosis is a serious toxicity occurring during or shortly after acute lymphoblastic leukemia (ALL) treatment. Symptoms (such as severe pain and impaired range of motion of the joints) may resolve completely with conservative therapy, or may persist even years after ALL treatment. Also, osteonecrosis is associated with BMD decline. Little is known about the symptoms and radiological features of children who experienced osteonecrosis during treatment at the very long-term, and risk factors for persisting disease remain unclear. These insights could guide clinical decision-making for children who develop osteonecrosis during ALL treatment in the future.