Elsevier

The Lancet Oncology

Volume 14, Issue 3, March 2013, Pages e95-e103
The Lancet Oncology

Series
Sustaining innovation and improvement in the treatment of childhood cancer: lessons from high-income countries

https://doi.org/10.1016/S1470-2045(13)70010-XGet rights and content

Summary

Cancer in children and adolescents is rare and biologically very different from cancer in adults. It accounts for 1·4% of all cancers worldwide, although this proportion ranges from 0·5% in Europe to 4·8% in Africa, largely because of differences in age composition and life expectancy. In high-income countries, survival from childhood cancer has reached 80% through a continuous focus on the integration of clinical research into front-line care for nearly all children affected by malignant disease. However, further improvement must entail new biology-driven approaches, since optimisation of conventional treatments has in many cases reached its limits. In many instances, such approaches can only be achieved through international collaborative research, since rare cancers are being subdivided into increasingly smaller subgroups on the basis of their molecular characteristics. The long-term effect of anticancer treatment on quality of life must also be taken into account because more than one in 1000 adults in high-income countries are thought to be survivors of cancer in childhood or adolescence. The introduction of drugs that are less toxic and more targeted than those currently used necessitates a partnership between clinical and translational researchers, the pharmaceutical industry, drug regulators, and patients and their families. This therapeutic alliance will ensure that efforts are focused on the unmet clinical needs of young people with cancer. Most children with cancer live in low-income and middle-income countries, and these countries account for 94% of all deaths from cancer in people aged 0–14 years. The immediate priority for these children is to improve access to an affordable, best standard of care in each country. Every country should have a national cancer plan that recognises the unique demographic characteristics and care needs of young people with cancer. Centralisation of the complex components of treatment of these rare diseases is essential to improve survival, accelerate research, and train the future specialist workforce. Referral routes and care pathways must take account of the large geographical distances between many patients' homes and treatment centres, and the economic, cultural, and linguistic diversity of the populations served.

Introduction

Since systemic treatment for cancer first became available in the 1950s, the treatment of childhood cancer has become the benchmark for the achievement of successful outcomes for patients. In high-income countries, 5-year survival has improved from 30% in the 1960s to 80% in the 2000s,1, 2 with the expectation that most children with cancer can now be cured (figure 1). This rapid progress was made possible by collaborative work between paediatric cancer specialists within and across national boundaries, who were able to implement clinical trials in these individually very rare diseases. Indeed, for many decades, a comprehensive portfolio of national or international phase 3 clinical trials was available for most newly diagnosed children with cancer, and these trials have underpinned the continuous improvement in survival.3 Progress has depended on sustained international collaborative research to generate the evidence that has set the standards of care, which in turn give both professionals and patients and their families the reassurance that care for children with cancer follows an evidence-based, quality controlled diagnostic and treatment protocol. Enrolment in a clinical trial is viewed as consistent with best practice in many countries, and this contributes to the knowledge base for further improvements in management of these life-threatening diseases.4, 5 However, the historical rate of improvement is unsustainable for several reasons (panel 1).

In high-income countries, we have nearly reached optimisation of present anticancer treatments—the rate of decrease in mortality has slowed substantially since the early 2000s (figure 2).6, 7 New approaches now need to be tested if we are to find effective treatments for the highest risk subgroups of childhood cancers. The introduction of biologically targeted agents into front-line treatment faces several challenges.8 These include the need to identify and validate targets and to develop a new biology-driven approach for the early assessment of novel agents by use of enriched populations of patients selected for the likely molecular drivers of their tumours. Although such an approach has been established for the common adult cancers,9 additional challenges exist in childhood cancers because these diseases are already rare, and biological subgroups might constitute only a handful of patients per year in each country.

The ultimate ambition for our patients is to maximise their chances of survival while minimising the side-effects of treatment, which can sometimes take many years to manifest in the growing child. Cure at the least cost is what our patients demand of us and what we must strive to deliver. The cured childhood cancer survivor has many years ahead of them, during which they wish to achieve their full potential.10 This aim emphasises two further challenges for sustaining improvements in cancer treatment for children and young people around the world.

First, substantial inequality exists in survival from childhood cancers between countries. This inequality is seen both within well-resourced continents such as Europe, where survival can vary by as much as 20% (figure 3), and to a much greater extent in less-developed regions, where the vast majority of the global burden of death from childhood cancer now exists and where it is predicted to remain (figure 4).6, 11 These differences are caused not only by differences in health-care resources, but also by differences in the organisation of care, which contribute to whether prompt diagnosis and uniform access to specified standards of multidisciplinary expert care are available. Because the signs and symptoms of childhood cancer are often non-specific, consideration of appropriate tests might be delayed in some countries, particularly those in which primary care for children is of variable quality or is delivered by non-specialists. Even when symptoms clearly show that a child has a tumour, the community's attitudes about non-disclosure of cancer in the family, or nihilistic beliefs about its curability, can delay or prevent referral for appropriate medical help.

Second, the long-term risks of cancer treatment given during childhood and adolescence are increasingly being recognised. Survivors face major risks, as much due to sequelae of their treatment as to the risk of recurrence of their original cancer. These risks include a continuing excess risk of mortality, second primary neoplasms, neurocognitive defects, cardiovascular disease, other organ dysfunction, and the psychosocial effects of their disease and treatment on both the patients and their families.12 Lifelong follow-up is imperative to prevent or attenuate some of these known risks, and survivors should be empowered to self-manage their health needs as they move into adulthood and often lose contact with their initial treatment centre. The planned incorporation of molecularly targeted agents unfortunately does not preclude the need for long-term follow-up, because of the pivotal roles of signalling pathways in normal human growth and development. With the growing recognition of the total cost to the individual and society of long-term health problems, a major research aim should be to minimise the use of treatments that carry these risks and thus maximise lifelong health and functioning. Substantial innovation in therapeutic approaches in the coming decades will be needed to achieve this goal.

These issues need to be seen in the context of the global challenge of 263 000 new cases of cancer estimated to affect people younger than 20 years annually, two-thirds of which occur in children younger than 15 years. In high-income countries, despite excellent survival, cancer is the most common cause of death from disease in childhood beyond infancy (second only to accidents) and accounts for more than 5000 potentially avoidable deaths every year in people younger than 15 years (figure 5).13 However, almost 90% of the world's children live in parts of the world (low-income and some middle-income countries) where their cancer is often detected too late for effective treatment or not diagnosed at all, and where access to appropriate specialist diagnosis, treatment, and even effective palliative care is poor. As such, about 91 000 deaths from childhood cancer (94% of the global mortality) occur in less-developed countries (figure 4), which presents substantial challenges for the improvement of care.14 In this paper, along with three others in this Series,8, 14, 15 we discuss the policies and approaches needed to improve cancer care for children and adolescents.

Section snippets

Burden of cancer in children and adolescents

The term childhood cancer is usually used to describe cancers that arise before age 15 years; by this definition, about 1 in 400 children in the USA are affected by cancer, according to data for a large population.16 Cancer in children represents about 2% and 0·5% of all cancers in the populations of developing and developed countries, respectively.11 All childhood cancers are individually rare, with incidences that vary from 1·2 cases per million people for very rare cancers such as

Childhood cancer in North America

The long-established model of practice for paediatric oncologists, whereby they work closely with multidisciplinary specialists in the diagnosis, treatment, and long-term follow-up of successfully treated children with cancer, dates back to the early 1950s. The timing coincides with the report of successful, albeit transient, remission induction in acute lymphoblastic leukaemia with the antifolate aminopterin.29 Focused efforts on drug development for cancer in the USA had its origin in the

Childhood cancer in Europe

A similar structured approach to cooperation for the benefit of patients was developed in Europe by early pioneers such as Odile Schweisguth and others who founded SIOP in 1969.18 Under the SIOP umbrella, formal collaborative clinical research was initially undertaken across Europe in common childhood cancers (eg, nephroblastoma, neuroblastoma, lymphomas, and soft-tissue sarcomas) and substantial improvements in survival and reductions in treatment morbidity were achieved. All of these trials

Improving care

In many adult cancers, for which large numbers of patients can be studied, the association between treatment in high-volume hospitals or by high-case-volume clinicians and better outcomes for patients is clear.31, 32, 33 In paediatric oncology, such analyses are more difficult to undertake because all types of childhood cancer are rare, but evidence that centralisation improves outcomes does exist.34 Logically, the same volume-to-outcome relation reported in adult cancers can also be assumed

Survivorship and late effects

As care and treatment in paediatric oncology has evolved during the past 40–50 years, the focus has shifted from a cure at any cost approach to cure at a reasonable cost. The aim now is to provide cure with the least possible cost to patients.10 The number of survivors after cancer in childhood and adolescence is substantial. According to one estimate,45 one person in 1000 in the general population in high-income countries is a survivor of childhood cancer. The number of survivors of childhood

Parent organisations

The International Confederation of Childhood Cancer Parents' Organisations (ICCCPO) is an increasingly influential voice in driving improvements in cancer care for children worldwide. The specific needs of the patients and their families vary widely around the world. The support provided by national parent and patient groups to address local issues ranges from practical help with accommodation and peer support groups to enable centralised specialist care services to function well, to strategic

Conclusions

The single biggest contributing factor to the substantial improvements in survival of children with cancer seen in the past few decades is the longstanding integration of clinical research into front-line care in paediatric oncology. This strong link between quality of care and research activity is dependent on national resources and health-care priorities being aligned to support the improvement of care for children with cancer. The policy of involving parents and children in strategic

Search strategy and selection criteria

Papers published in English since January, 1970 were considered relevant for this Series paper. Cited references are illustrative of the authors' major points and are not meant to be exhaustive. An appropriate search strategy to explore the topics covered in this paper would be: “paediatric” OR “pediatric” OR “child” OR “children” AND “oncology” OR “cancer” OR “malignancy” OR “leukemia” OR “leukaemia” AND “care” OR “pathways” OR “systems” OR “treatment”. We also used data from the UN, WHO, and

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