Summary Background Before this study started, the standard postoperative chemotherapy regimen for stage II–III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, ...avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II–III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. Methods For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II–III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m2 at weeks 1–8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m2 given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. Findings Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8–79·8). 2 year event-free survival was 92·6% (95% CI 89·6–95·7) for treatment including doxorubicin and 88·2% (84·5–92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4–9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3–98·8) for treatment including doxorubicin and 95·8% (93·3–98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. Interpretation Doxorubicin does not need to be included in treatment of stage II–III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. Funding See Acknowledgments for funders.
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.
Summary Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we ...review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers.
Summary A state-of-the art approach to the debates on ethical issues is key in order to gain guidance on research practices involving sick children and adolescents, as well as to identify research ...avenues in which it might be worth cooperating, to generate better or supplementary evidence. Based on a systematic literature search using MEDLINE, we report the main ethical developments in paediatric oncology clinical trials from 2003–13. The present knowledge about normative and empirical ethical demands in this setting is quantified and summarised in a list of 46 issues. This list primarily aims to provide readers with a comprehensive account of the main decision nodes and professional attitudes that enable families to make a safe, competent, and satisfactory decision about their child's enrolment, or non-participation, in cancer clinical trials. Our systematic Review shows how important it is for professionals to engage in a constant reflection on optimum trial designs, on the effect of offering trial participation on key family dynamics, and on the ways to understand families' needs and values accurately. In view of present scientific developments, we further emphasise the need to enhance societal awareness about research in children and adolescents, to prevent so-called research fatigue in small populations due to multiple solicitations or inadequate legal demands, and to reassess longstanding ethical certainties in the strictest view of promoting sick children's interests. This systematic Review allows a series of questions to be drawn to guide and encourage collective and individual endeavours that should lead to constant improvements in our research practices in paediatric clinical oncology research.
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.
Summary The obtainment, storage, and use of human tissue taken from children for research purposes is an area that is notable for its complexity and legal uncertainties. In the UK, the controversy ...surrounding organ retention prompted radical legislative change in the form of the Human Tissue Act 2004, which came into force from September, 2006. This Review paper explores the effect of the Human Tissue Act on consent, in the context of childhood tissue banking. We take as our case study the UK Children's Cancer Study Group tumour bank. Although the Human Tissue Act provides a new, detailed statutory framework, it does not, by itself, resolve all the relevant issues in this area. Researchers and clinicians must, therefore, continue to work alongside the existing principles of common law relating to this issue. Consent for the removal of tumour tissue during a surgical procedure should be distinguished from consent for the retention of the tissue for future use in research or for other specified uses. Consent to surgery is regulated by the same common law procedures used for consent to treatment. By contrast, the requirements for consent to storage and specified uses of samples are predominantly, but not exclusively, regulated by the Human Tissue Act. Although the Human Tissue Act might, at first, seem to promote clarity, the new legislative provisions and resultant Codes of Practice on consent could possibly lead tumour banks to reassess the nature and process of obtaining consent for the use of samples from children in research.
Summary Paediatric oncology has achieved high cure rates despite the limited availability of drugs that have been specifically studied for use in children with cancer. Efficacy of these drugs has ...received more attention than their safety, but permanent side-effects in growing children need to be considered. An absence of pharmacokinetic data, dose-defining studies, schedules defined by age, and appropriate formulations can lead to underdosing or overdosing in specific age groups, resulting in a potential lack of benefit, development of resistance, and increased adverse drug reactions. These major clinical concerns have promoted initiatives in Europe since 2003 regarding the need for a Paediatric Regulation, aimed at improving the risk–benefit ratio of such drugs in children and providing the legal framework to overcome the limitations of the past. However, to undertake the appropriate studies of these drugs in this setting, financial support is essential. Europe is now showing its commitment to overcome the present difficulties of drug prescribing for children with cancer by introducing measures that will encourage new public–private partnerships. All those involved, including researchers, paediatric oncologists, learned societies, regulatory agencies, national agencies, and pharmaceutical companies, need to become more familiar with the opportunities opened up by the new regulation, which is aimed at providing an increased cooperation between researchers and drug developers for the benefit of children.
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