Elsevier

The Lancet Oncology

Volume 9, Issue 4, April 2008, Pages 392-399
The Lancet Oncology

Personal View
Improving recruitment to clinical trials for cancer in childhood

https://doi.org/10.1016/S1470-2045(08)70101-3Get rights and content

Summary

Clinical trials have underpinned progress in the treatment of cancer in childhood: about 75% of children newly diagnosed with cancer can expect to be long-term survivors. This success has been achieved because most children with cancer have participated in available clinical trials. This high level of engagement of the childhood-cancer community relies on the so-called therapeutic alliance that begins between doctors and families when a child is diagnosed with cancer. More research is needed to understand how to present most effectively the unfamiliar idea of a randomised clinical trial at a stressful time. High overall survival using current regimens presents challenges for future trial design—to secure further incremental increases in survival or to show survival equivalence from targeted agents that might have reduced side-effects. Small subgroups of children with cancers defined by molecular signatures mean that international recruitment is essential to do trials in a reasonable timeframe. Such collaboration across linguistic and cultural boundaries presents not only legal and regulatory hurdles, but also challenges the childhood-cancer research community to reappraise individual treatment preferences. The introduction of new paediatric regulations in Canada and the USA and Europe should encourage manufacturers of new anticancer drugs to lend support to clinical trials of cancer in childhood.

Introduction

When a parent is faced with the diagnosis of a life-threatening disease in their child, the normal reaction is shock and perhaps disbelief.1 Parents are desperate to give their child the best possible chance of cure and to understand what their child will have to endure. At this stressful time, the idea of entry into a clinical trial can be very challenging (figure 1).

Importantly, clinical trials lie behind the story of remarkable scientific progress in the treatment of cancer in childhood. Sidney Farber's 1948 study2 famously showed temporary remission of leukaemia in childhood—once almost invariably a fatal disease. Since then, clinical trials have addressed questions about the role of various intensities of chemotherapy, the need for radiotherapy, and the timing and extent of surgical treatment. For example, current survival from acute lymphoblastic leukaemia is associated with a successive series of collaborative clinical trials that spanned 35 years, during which 10-year survival increased from less than 10% to 80%.3 Treatment protocols for most cancers of childhood are highly complex, needing expert management by multidisciplinary teams. Overall, the results of high-quality well-coordinated trials mean that about 75% of children in developed countries who are diagnosed with cancer will survive the illness.4

Despite the enviable success in the treatment of cancer in childhood, a pressing need for further research and development remains. Many children die from such illness, and reduction of mortality is an important goal. Moreover, survival is not the only objective in the study of cancer in childhood: the long-term and short-term iatrogenic effects of current cytotoxic drugs and radiotherapy present substantial hazards, including toxicity-related problems in later life. The need to identify and assess treatments that are safer and at least as efficacious as current treatments is ongoing. New therapeutic strategies that optimise existing treatment regimens and that use new agents are needed.5 Development of such strategies is likely to benefit from recent advances in cancer biology and from the new generation of molecularly targeted agents that are emerging in the treatment of adults with cancer.

High rates of participation in clinical trials of patients and established networks of clinicians who care for children with cancer have made possible multicentre (and indeed national and international) collaborative clinical trials of rare diseases. Although more than 70% of children who are diagnosed with cancer currently enter national or international phase III clinical trials in most western European countries,6 recruitment and randomisation for different trials vary substantially. For example, UK studies of children with acute lymphoblastic leukaemia7 have recruited more than 85% of eligible children (with >90% accepting randomisation), whereas only 39% of eligible cases accepted randomisation in a concurrent trial in Wilms' tumour.8 These variations raise important questions about how the quality of trial recruitment might be improved. Improvement does not necessarily mean maximisation of recruitment, but rather engaging families and patients as informed partners who can make appropriate choices.

This Personal View focuses on the challenges associated with improving recruitment to phase III trials of cancer in childhood, which is the option generally offered to newly diagnosed patients. These trials usually compare current, best known treatment (ie, the standard group) against a modification of that treatment (ie, the experimental group), and are designed to test whether there is either improved efficacy or equal efficacy with reduced toxic effects. Phase III trials are designed to be low risk to participants in terms of not compromising the chance of cure, and the best interests of the child are prioritised above any research objectives. Although the interests of the child are of course prioritised in phase I and II trials, these early studies raise additional questions and require separate discussion.

Section snippets

Clinical trials of cancer in childhood: design and implementation

It is essential for optimum recruitment that a clinical trial asks a question that is important to the eligible community, and that the design seems reasonable and acceptable both to physicians who will be recruiting and to the families of children who will be candidates (Panel 1, Panel 2).

The history of cancer in childhood highlights these issues.9 Throughout the 1960s, children with leukaemia in the UK were treated with antibiotics (and sometimes steroids) only, with invariably fatal

Ethical issues

An ongoing dilemma in clinical research is the desire for patients to benefit from progress in medical care realised by scientific research while avoiding the risk of harm from such research for any individual. The overarching ethical principle is that physicians must act in the best interests of every child. If there is substantial uncertainty—ie, clinical equipoise25—over which treatment is likely to be best for a child, it is not only defensible to offer the child the opportunity of a

Conclusion

Clinical trials of cancer in childhood have substantially improved the survival and wellbeing of thousands of children worldwide. National groups who develop and apply treatment protocols, whether randomised or not, and evaluate and publish their results lend support to a culture of evidence-based treatments. Children who are treated in such settings are ensured a scientifically sound approach to care and are generally offered treatment under conditions of best clinical practice. The tendency

Search strategy and selection criteria

This Personal View reflects the personal experience of the authors. Relevant research articles were identified from the authors' knowledge of the subject and by searching PubMed by use of the keywords “clinical trials”, “recruitment”, “randomisation”, “cancer”, “children”, and “childhood”. Further papers were chosen from the reference lists of relevant articles.

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