This presentation described the occurrence of late side effects (commonly described as ‘late effects’) in childhood cancer survivors (CCS), and how paediatric oncology healthcare professionals and researchers across the world have worked together to reduce or eliminate their impact on the long- term health of survivors.
The long-term overall survival of childhood cancer or leukaemia is now at 80%, but this modern-day success story has created an ever-increasing number of long-term survivors, many of whom have a high-risk of late effects of their cancer and especially of its treatment. Large cohort studies have shown that 15–30 years after diagnosis of their initial malignancy, approximately 60–75% of CCS suffer from at least one late effect, 25–45% from at least two late effects, and 25–40% from a severe, life-threatening, or disabling late effect. The range of late effects observed in CCS is very wide. Most are due to damage to the function, or structure, of organs, organ systems, or tissues; for example: cardiovascular, gonadal/reproductive, neurological/sensory, renal/urinary tract, and respiratory toxicities. Some late effects lead to impaired quality of life or neurocognitive function, whilst others have more general consequences such as the development of the metabolic syndrome, accelerated ageing (frailty), or secondary malignancies.
Late effects have many different causes, most commonly chemotherapy drugs, radiotherapy, and major surgical procedures. In some children, particularly those with brain tumours, the site and nature of the primary tumour may affect the risk of developing late effects and determine their consequences. Genetic susceptibility may also play an important role, for example genetic polymorphisms may modify the risk of late effects by influencing drug pharmacokinetics and pharmacodynamics, whilst cancer predisposition syndromes can increase the risk of second or subsequent malignancies. By their very nature, most late effects are persistent, causing chronic medical, psychological, or social problems. Nevertheless, late effects vary greatly in their timing of onset, with some, such as chemotherapy induced renal toxicity, initially presenting during or soon after treatment, whilst others, for example secondary malignancies, may occur decades later. Some late effects appear to be largely or entirely due to one cause, for example sensorineural hearing loss due to platinum drugs, whilst others are complex and multifactorial, such as cardiac damage which may be due to anthracycline drugs or radiotherapy to a field, including the heart, or both. The impact of late effects is also very variable, ranging from easily correctable subclinical organ dysfunction, such as compensated hypothyroidism, to life-threatening consequences, such as secondary malignancies, or even late (but still very premature) mortality.
The risks of late effects have led to the development of long-term follow-up (LTFU) for CCS, seeking to manage existing late effects, undertake surveillance to allow earlier detection or ideally prevention of potentially severe late effects, and provide information for CCS about their current and future late effects risks and what steps they can take to optimise their health. Alongside this development of clinical LTFU care, several large cohorts of CCS have been constructed in North America (for example, the Childhood Cancer Survivor Study) and especially in Europe (such as the British Childhood Cancer Survivor Study). These cohorts have allowed detailed epidemiological study of the nature and outcomes of late effects in CCS and have identified which survivors are at highest risk due to personal, genetic (in some cases), disease, and treatment-related factors. This can allow development and evaluation of risk stratification approaches to guide surveillance for clinically important late effects. Ongoing research is needed to inform optimal management which may comprise both medical treatment of incipient or existing late effects and pharmacological and/or lifestyle interventions to reduce the risk of future effects.
International collaboration also continues to play a vital role in efforts to improve the longevity and quality of life of CCS. PanCareSurFup (Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies) is a landmark Pan-European study investigating the risk factors for cardiotoxicity, second malignancies, and premature mortality in unprecedented detail. Furthermore, PanCareSurFup is developing evidence-based clinical practice guidelines for models of LTFU care, transition to age-appropriate care in adolescence and young adulthood, and health promotion which are all important components of LTFU. Reassuringly, large-scale international randomised clinical trials are now including late effects as important study outcomes in an effort to reduce long-term toxicities of curative treatment.