Background

In order to conduct the study, the country was divided into 10 regions (Figure 2), each being the responsibility of a single epidemiological centre, and ethical approvals were obtained from all local ethics committees across Great Britain. Ethical approval was consolidated and updated in 2005 with the Northern and Yorkshire Multi-Centre Research Ethics Committee - now the North East- York Research Ethics Committee under reference 05/MRE03/022.

A common protocol was agreed by the Management Committee at the beginning of the study, and data on cases and controls were collected from multiple sources. The parents of children were interviewed, medical notes were abstracted (mother’s obstetric, child’s neonatal, and mother’s, father’s and child’s primary care), household radiation measurements were taken (ionising and non-ionising), birth certificates were obtained, and residential postcodes were linked to small area census data. For case children, diagnostic information was obtained from treatment trials, pathological review, cytogenetic databases and hospital records; and pre-treatment and remission blood samples were taken and stored.

UKCCS recruitment and data collection finished in the late 1990s, and data were centralised at the study’s data management and analysis centre: the Epidemiology & Cancer Statistics Group (ECSG) in the Department of Health Sciences at the University of York. Analyses have been ongoing since that time, and over 80 original papers containing UKCCS data have been published (1–82).

Since the study’s inception UKCCS researchers have worked closely with other investigators from around the world, many of whom modelled their own studies on the UKCCS design (46). However, because the UKCCS is predicated on NHS infrastructures that cannot be replicated in other healthcare settings, it remains unique in several important respects; most notably in relation to its inbuilt methodological design features and medical note abstraction procedures – both of which have enabled the UKCCS to address key research issues more rigorously than any other similar investigation. In brief, the UKCCS was specifically designed to make maximum use of routinely compiled administrative data; linking all childhood cancer cases and their potential controls to birth notifications using NHS numbers, and area-based census measures using residential postcodes (1,43,47–50). In addition, rather than relying solely on information reported by parents at interview, the study accessed medical records to answer key questions relating to prescription drugs, illness histories and co-morbidities. Importantly, such contemporaneously recorded information, which by its nature is free from differential recall bias, often produced very different results from those emanating from studies that were reliant on self-report (10,18,21,24,29,34,36–38,51).

Hitherto, the UKCCS’s main body of work has related to its original objectives, namely to investigate the potential causes of childhood cancer, alongside certain methodological issues. However, like many epidemiological studies of its type, where families of affected individuals give their time to contribute to research, the rich resource of information gathered has also been used for other health service research, including investigating the pattern of health attendances and symptoms that precede the diagnosis of cancer (24,51). Furthermore, whilst UKCCS data have mostly been used to investigate the potential aetiological impact of events that happened before the child was diagnosed with cancer, they have also be used to investigate health outcomes and patterns further along the patient pathway (52–54,83); and it is this aspect of the study that offers particular promise for future research.

Aims and objectives

The UKCCS remains one of the largest and most comprehensive case-control studies of childhood cancer ever undertaken. Our continued work on events and exposures preceding the diagnosis of cancer, and new proposals for research in the years following diagnosis encompass three overarching objectives:

1. to continue to investigate the potential causes of childhood cancer, both within the UKCCS and with international collaborators
2. to investigate factors potentially involved in childhood cancer survival
3. to study the long-term health, and healthcare needs, of childhood cancer survivors

1) Causes of childhood cancer

Childhood cancer is exceedingly rare; accounting for less than 1% of all newly diagnosed malignancies in developed regions of the world (84,85). Hence, in order to increase statistical power, several important international collaborative pooling initiatives have been established within which the UKCCS has played a key analytical role; examples include studies examining the potential aetiological role of neonatal intramuscular vitamin K administration (6,10), residential exposure to electromagnetic fields (4,17,54), intrauterine growth (44,45) and genetic susceptibility (55–75).

UKCCS investigators are active members of the Childhood Leukaemia International Consortium (CLIC), which involves over 20 similar epidemiological studies of childhood leukaemia setup to share anonymised data and exchange ideas among researchers from different disciplines (46). CLIC represents a large subset of childhood leukaemia studies including most of the large case-control studies worldwide; some of which, like the UKCCS, included all childhood cancers (Figure 3).Current topics for pooled analyses within CLIC include birth characteristics, environmental and occupational exposures, family history, genetic studies, and infection and immunity; and CLIC has already reported on specific exposures under these categories (25,26,28,31,44,81). Following the model of other successful international consortia, CLIC’s coordinating group approves pooled projects proposed by its members, and a data coordinating centre - hosted by the World Health Organization’s (WHO’s) International Agency for Research on Cancer (IARC), Lyon, France- collates and harmonises the studies’ anonymised data ready for statistical analyses. Hence, as well as maintaining our own analysis programme, the UKCCS contributes anonymised data to the CLIC Data Coordinating Centre for the purposes of conducting pooled analyses.

2) Childhood cancer survival

Although cancer in children is rare, in economically developed countries it remains a leading cause of death; around one in every five children with cancer do not survive beyond five years after diagnosis (84,86,87). Furthermore, whilst treatment trials for childhood cancer tend to have a higher coverage than those among adults, not all children participate – either because there is no trial or because they are not enrolled. In this regard, we have demonstrated the utility of the UKCCS’s population-based national data; examining survival variations by cancer type and socio-demographic characteristics (52,53). Indeed, it is recognised that epidemiological case-control studies like the UKCCS can be used to deepen the understanding of those at high risk of poor outcomes (83,88), and to investigate risk factors that may be involved in cancer progression (54). Accordingly, UKCCS conduct survival analyses, incorporating data on other factors including co-morbidities (16,43,51).
 

3) Health of childhood cancer survivors

Over the last 30 years, survival rates for children diagnosed with cancer have improved dramatically, exceeding 80% in the UK and other economically developed countries (89,90). By 2020, it is estimated that there will be half a million childhood cancer survivors in Europe alone; a number that will increase as therapeutic advances continue to be made and populations age (91).

The majority of cancers that occur in children are more responsive to chemotherapy than those that occur in adults; but treatments are aggressive and, for some individuals, adverse health problems may occur several years later; including second malignancies, cardiovascular problems, respiratory conditions and fertility issues (92–95). To investigate the long-term health outcomes of childhood cancer survivors, a number of childhood cancer cohorts and registries have been established to examine health complications and quality of life among childhood cancer survivors (96–99). Whilst some have relied on survivors’ participation and self-reported outcomes others, using similar methods to the ones proposed by the UKCCS, have exploited electronic health records to provide coverage that is more comprehensive. In both instances, in order to interpret findings, information on background levels of the health events of interest in the population are required, the ideal being an “unexposed” comparator cohort. This design feature is, however, missing from existing UK studies which have tended to use hospital admission data to generate comparison populations, meaning that individuals with no admissions are excluded (99,100). Hence, with a view to providing a unique and valuable resource for childhood cancer survivorship studies, cases and controls from the UKCCS are followed as two cohorts by linking individuals to routinely compiled NHS data. This enables the UKCCS to put the health of childhood cancers into the context of their peers as they age, making it uniquely placed to investigate the long-term healthcare needs of UK childhood cancer survivors.