Body composition and bone density during and after childhood cancer therapy: The flip side of therapy

Abstract

In the Netherlands, there are approximately 8000 childhood cancer survivors, and this population of survivors is expanding due to improved therapy. However, therapy has a consequent flip side, namely their inherent side effects. Approximately 75% of the CCS will develop one or more severe chronic health conditions. The primary aim of this thesis was to investigate determinants of side effects which occur during and after childhood cancer treatment, with special focus on body composition and skeletal toxicity. Methotrexate is an effective drug in the treatment of acute lymphoblastic leukaemia (ALL). The optimal patient specific dosage scheme remains under debate, as it is unpredictable which patients develop methotrexate-induced side effects. Mucositis occurred in 20% of the patients and was the most frequently occurring side effect. Mucositis occurred more frequently in patients with a higher erythrocyte-folate, and in those whom carried the wild-type variant of SNP rs7317112 in the ABCC4 gene. Previous studies have suggested that BMI at diagnosis and change in BMI during treatment may influence the outcome of paediatric ALL patients. In a national Dutch cohort, it was found that paediatric ALL patients whom were underweight at diagnosis exhibited an increase in the likelihood of relapse, and that BMI loss during 32 weeks of treatment was associated with a decreased overall survival. There is still a need for concise nutritional support for paediatric patients and their parents, based on evidence based guidelines. In this same cohort information on bone mineral density (BMD) and osteonecrosis was collected. BMD is an estimation of bone strength and fracture risk. We showed that symptomatic osteonecrosis and BMD decline during anti-leukemic therapy co-occur in paediatric ALL patients.We believe that osteonecrosis is a risk factor for low BMD and therefore we advocate that these patients could benefit from extra follow-up to prevent impaired BMD in adult life. The magnitude of low BMD in cancer survivors is unknown. We had the opportunity to measure BMD in adult survivors of childhood cancer, with a median time of 15 years after therapy. The occurrence of impaired BMD was associated with ages below 12 years at diagnosis of cancer, male gender, age above 30 years at follow-up, treatment with radiotherapy or steroids and lower body weight at the time of DXA assessment. In addition, the GG genotype of rs2504063 in the ESR1 gene, and the GG genotype of rs599083 in the LRP5 gene were associated with impaired BMD. Screening for osteogenic side effects needs attention in survivors of childhood cancer. This thesis has addressed the importance of studying a number of early and late side effects. With continuing efforts and collaboration between research groups, childhood cancer therapy will ultimately be refined into limiting un-wanted side effects.