Ottobre-Dicembre 2013 • Vol. 43 • N. 172 • Pp. 233-237
ONCologia pediatrica
Children with cancer in Europe: challenges and
perspectives
Kathy Pritchard-Jones
University College London, Institute of Child Health, 30 Guilford Street, London, UK
Summary
Cancer in children and adolescents is rare and biologically different from cancer in adults. 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.
Further improvements must entail new biology-driven approaches since optimization of conventional treatments has in many cases reached its limits. This
will be achieved by the access to drugs thar are less toxic and more targeted than those currently used and through international collaborative research,
since rare cancers are being subdivided into increased smaller subgroups. Finally 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.
Riassunto
I tumori del bambino e adolescente sono malattie relativamente rare e biologicamente differenti dai tumori dell’età adulta. Nei paesi con risorse economiche
elevate, la sopravvivenza dei tumori infantili ha raggiunto oggi l’80%. Ciò si è realizzato attraverso l’arruolamento dei pazienti in protocolli clinici come
standard di cura di prima linea. Il progressivo miglioramento è probabile possa essere ottenuto con approcci innovativi basati sulle conoscenze biologiche
e molecolari, poiché l’ottimizzazione dei trattamenti con i farmaci convenzionali ha raggiunto ormai il massimo delle sue potenzialità. L’accesso a farmaci
meno tossici e diretti contro target molecolari più specifici dei chemioterapici convenzionali e la collaborazione internazionale per far fronte all’identificazione e trattamento di gruppi di pazienti sempre più piccoli, sono due degli aspetti da cui dipenderà l’ulteriore miglioramento della sopravvivenza dei pazienti.
Infine l’impatto a lungo termine dei trattamenti chemio-radioterapici sulla qualità di vita è divenuto sempre più rilevante, considerando che si stima che
circa 1 adulto su 1000 sia stato affetto da tumore in età pediatrica.
Key words: childhood cancer, clinical research, SIOP Europe
Parole chiave: cancro infantile, ricerca clinica, SIOP Europa
Introduction
Cancer in children is a significant health challenge for our society,
even though it is relatively rare, affecting about 1 in 600 children
before their 15th birthday, and comprises only 1% of all cancers in
high income countries (Pritchard-Jones et al., 2013). In this setting,
overall survival has increased to approximately 80% at 5 years. This
means that current estimates of the proportion of the young adult
population (aged 18-40 years) who has survived childhood cancer
stands at 1 in a thousand. This proportion is set to continue to rise
rapidly.
Despite these good overall survival rates, there remain subgroups
of childhood cancers with much worse outcomes, such as high risk
neuroblastoma, high grade gliomas and metastatic sarcomas. Also,
for those children who are cured with current treatments, many will
have received unpleasant, prolonged therapy that disrupts schooling
and family life and may cause permanent side effects that compromise normal functioning in adult life. Hence, clinical research that
aims to improve survival rates and quality of survival for the total
population afflicted by childhood cancer remains an important goal
for our society.
The spectrum of the mainly embryonal cancer types seen in children is very different from the predominantly epithelial types seen
in adults and from the spectrum of cancers seen in adolescents and
young adults (Fig. 1). However, the number of major subtypes is just
as complex as in adult cancer (Fig. 2). Once biological risk stratifica-
tion is incorporated, whereby tumours are risk-stratified according
to their molecular subtype, then each childhood cancer category becomes individually rarer still. Hence, it is essential that clinical trials
specific to the cancers that affect children and adolescents are conducted in a timely and efficient manner if we are to continue to make
progress at a European level. These inevitably require multi-national
co-operation due to the small numbers of cases in each country.
Since the beginning of the new millenium, the rate of improvement
in overall survival rates has slowed for most childhood cancers (Fig.
3). It is becoming clear that we have reached the limits of optimising
currently available treatments through dose intensification or rapid
scheduling, and that new approaches are needed (Pritchard-Jones
et al., 2013). These can include introduction of biomarkers to improve the accuracy of risk-stratification or response assessment,
and use of new, molecularly targeted drugs that have mostly been
developed for adult cancers (Vassal et al., 2013). Indeed, there are
now more than 400 biologically targeted drugs available for clinical
use in adult cancers, but few of these have yet been tested for their
safety or efficacy in childhood cancers, even though there may be a
strong biological rationale if the same molecular target is disrupted
in cancer in both age groups.
The other major challenge is the inequality in survival rates seen
between different geographical regions of Europe. The differences
measured by comparative cancer registry research in the 1990s
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K. Pritchard-Jones
Age groups (years)
Mortality
Figure 2.
Proportion of the 12 main tumor groups in children and adolescents in Europe (with permission of Lancet Oncology, Pritchard-Jones et al., 2013).
Years
Figure 1.
Cancer incidence by type in three age groups (with permission of Lancet Oncology, Pritchard-Jones and Sullivan, 2013).
showed an approximately 15-20% difference in survival rates,
even though the rate of improvement was similar in Eastern and
Western European regions (Fig. 4). Whilst there is recent evidence
that this difference is decreasing in the 2000s (Gatta et al, 2013),
it must be remembered that this improvement is only known with
any confidence in those countries with cancer registration in place
at a population level. There may be persisting outcome differences
in countries without specific cancer control resources in place. For
these reasons, outcomes research must also focus on the broader
aspects of health services delivery and models of care.
The Europe perspective
To address the challenges faced by children and young people with
cancer at a European level, the ENCCA project (European Network for
Cancer research in Children and Adolescents) was developed with funding from the 7th framework programme of the European Commission
(www.encca.eu). Due to the requirements of European grant funding,
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Figure 3.
Child cancer mortality (per million person-years) (aged 0-14 years) in
three European countries (Ireland, Netherlands and UK (combined) (blue
line) and the USA (red line) (modified from Lancet Oncology, PritchardJones et al., 2013).
ENCCA was created at relatively short notice in 2009 by the collaborative efforts of a relatively limited number of specialist centres active in
treatment and clinical research into childhood and/or adolescent cancers. However, it was always planned from the very beginning that ENCCA would unite the multinational clinical trial groups and national childhood cancer organisations into the building blocks of a future «virtual
institute» of paediatric haemato-oncology research, that would involve
every major treatment and research centre across Europe.
To summarise the need in numbers, every year there are 15,000
new cases of cancer in children and adolescents in Europe. Whilst
80% can be cured with current multidisciplinary treatments, 3,000
will die. There are more than 60 different disease types histologically and clinically, from newborns to teenagers. There are hundreds
of subtypes when biomarkers are considered. These children and
young people receive their diagnosis and treatment at one of about
250 public specialised treatment centres in the EU, each seeing only
a handful of each individual cancer type each year.
Childhood cancer in Europe: problems and perspective
Mortality
agreeing common goals and priorities and then working in partnership to deliver these in a timely fashion. Everyone will benefit from
such sharing of resources – most importantly the patients who will
see the fruits of the research being applied in clinical care more
quickly and with greater confidence from the robust sample size
involved in each trial question.
Years
Figure 4.
Child cancer mortality (per million person-years) (aged 0-14 years) in
former socialist economies (red line) compared with other European
countries (blue line) (modified from Lancet Oncology, Pritchard-Jones
et al., 2013).
The challenges of clinical research
Since the 1970’s, there have been networks conducting clinical trials across many institutions, all working to a common protocol with
standards for diagnosis, pathology review, response assessment
and event free and overall survival. Many of these clinical trial groups
started as national entities, often conducting single arm studies that
laid the evidence base for the standard of care. However, soon either
the numbers required for statistically meaningful trial design, or the
intellectual rigor and pleasure of working with like-minded individuals with a common understanding and passion for improvement in
outcomes, led to most clinical trial groups working across national
boundaries. By the late 1990s, approximately 40% of patients were
treated within trials (phase I to III), a further 40% were treated according to recognised standards within prospective studies, but less
than 5% were enrolled in pharma-sponsored trials of new drugs.
However, since the introduction of the well-intentioned EU Clinical
Trials Directive (EU-CTD), the proportion of children treated in clinical trials or prospective studies has dropped dramatically. This is not
because the trials are no longer needed, but rather because the time
taken and expense incurred to open a trial has increased massively
due to new bureacracy and need for formal sponsorship with insurance (Pritchard-Jones, 2008).
How to make progress
The challenge for childhood cancer in the current millenium must
be to gain a better understanding of the biological basis of the different childhood cancers and to work in partnership with the pharmaceutical industry to obtain better access to molecularly targeted
drugs that may offer chances for improved or safer cure (Vassal et
al., 2013, Pritchard-Jones, 2008). This will require extensive translational research, with comprehensive tissue banking from current
patients linked to their clinical diagnosis, treatment and outcome
data. Only in this way can biomarkers for risk prediction, response
assessment and signposting to existing therapies be developed and
assessed prior to routine use in standard care.
How do we achieve all of this with the limited resources available to
us? The answer has to lie in much wider and stronger collaboration,
Through the ENCCA project and its workstreams, many high-level
research teams dedicated to paediatric tumour biology have forged
stronger links and are sharing tissue samples and genomic analysis data. A series of ‘biology-driven drug development workshops’
have been held to bring together experts in drug development, the
relevant tumour biology and clinical trial groups and representatives
of parents and regulators (http://www.ema.europa.eu/docs/en_GB/
document_library/Regulatory_and_procedural_guideline/2013/02/
WC500139182.pdf;http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2013/02/
WC500139183.pdf; Perotti et al., 2013).
Here the discussion has been about understanding the driver biological targets or pathways for each tumour type or subtype and
prioritising the drugs for testing in early phase trials in high risk
tumours. The ultimate output of each workshop is a proposal for a
model ‘Paediatric investigation plan’ that can stimulate more appropriate drug development plans that match the clinical unmet needs
of children with these forms of cancer.
Working with the clinical trial groups and the innovative therapies for
children with cancer consortium (www.itcc-consortium.org), several
workpackages within ENCCA are prioritising this biology-driven approach to new drug development, aiming to open at least one trial
of a suitably targeted new agent. The resources to run the trial do
not come from ENCCA, rather it provides the catalyst that has allowed groups to bid successfully for further funding or to present a
united front to an industry partner to make the drug and sometimes
sponsorship available.
This partnership approach to improving outcomes for children and
young people with cancer across Europe requires us all to think in a
different way to the traditional institutional and national loyalties we
were brought up with. We need to agree on the best structures and
relationships in order to build a sustainable, safe and high quality
network for clinical care and research that benefits all of the children and young people with cancer in Europe. This is the only way
we can truly tackle the unacceptable variation we find now in access to ‘state of the art’ treatment and best outcomes. SIOP Europe
has therefore created a ‘European Clinical Research Council’ (ECRC)
to be the common, harmonised voice for advocacy and lobbying at
the European level on paediatric and adolescent cancer clinical and
research activities. The ECRC comprises representatives of each of
the National Paediatric Haemato-Oncology Societies (NAPHOS) and
of the multi-national clinical trial groups.
Many EU member states have established NAPHOS that have links
to health policy makers and have introduced quality standards
for specialist centres to care for children with cancer and for the
training of the staff who work there. In the UK, for example, there
are 17 specialist centres designated to provide services for a total
population of about 60 million. Quality standards were published in
2005 (http://www.nice.org.uk/nicemedia/pdf/C&YPManual.pdf) and
centres have been externally quality assessed since 2012. However,
not all countries in Europe have yet achieved this, and the degree
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K. Pritchard-Jones
Table I.
The 7 priority areas for a Virtual Institute of Paediatric Haematology Oncology to make progress in:
Introducing safe and effective innovative treatments (new drugs, new technologies) in multidisciplinary standard care.
Driving therapeutic decision by improved risk classification and use of molecular characteristics (tumour, patient) – personalized medicine
Increasing knowledge on tumour biology and speeding up translation to the patients
Increasing equal access across Europe to standard care and clinical research
Addressing the specific needs of adolescents and young adults jointly with adult oncology
Addressing long-term toxicity and cancer treatment consequences including the genetic background/risk – quality of survivorship
Understanding the causes of paediatric cancers and setting prevention where possible
Table II.
Challenges and proposed solutions to make progress in childhood cancers.
Summary of Challenges
Increasing complexity of risk stratification
Proposed Solutions
We have to work together across Europe to design and implement clinical
trials – the European Clinical Trials Council, co-ordinated by SIOPE
– single countries only have a handful of cases in each category e.g. very
high risk Wilms: 5 pts and 1-2 relapses/yr in Italy
Optimisation of intensive use of present treatments has reached its limits
European virtual institute for translational research in childhood and
adolescent cancer to promote a biology-driven approach
- Need for biology-driven approach to risk stratification and response
assessment in front line treatment
Unaffordable & unnecessarily complex regulatory bureaucracy for
international investigator-led clinical trials
Professionals, parents and patients need to establish a “Therapeutic
Alliance” with industry & regulators
- Need to influence revision of EU CTD to a Regulation
Insufficient commercial interest from Phama
of development of standards and quality assurance remains variable. Hence, an important project has been launched through SIOP
Europe, the European Standards of Care for children with cancer
(http://www.siope.eu/european-research-and-standards/standards-of-care-in-paediatric-oncology/). This is now being disseminated through a partnership with EPAAC (European Partnership for
Action Against Cancer). It should be noted that a key component of
the expected standard for any childhood cancer treatment centre is
the ability to offer patients participation in clinical trials and to contribute clinical data to cancer registration processes. This is based
on the clear observation that patients who are treated within clinical
trials or at institutions that are active in research have better outcomes (Stiller et al., 2012). The life threatening diseases that make
up childhood cancer and the serious side effects of the necessary
treatments mandate that the clinical teams should be constantly
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Professionals, parents and patients need to establish a “Therapeutic
Alliance” with industry & regulators
learning and improving through clinical research and well designed
prospective studies and audit.
Conclusions
SIOP Europe and ENCCA are currently working on creating a sustainable solution to the challenges we face together in continuing
to make improvements for children and young people with cancer
in Europe. This group has identified 7 priority areas that we need
to focus on (Tab. I). Whilst the challenges are immense, solutions
have been identified (Tab. II). We now need to coordinate our efforts in each country so that we can work together most effectively
to ensure we are ready to win the opportunities that we expect to
be available in Horizon 2020 and other funding sources in the near
future.
Childhood cancer in Europe: problems and perspective
Box di orientamento
Che cosa si sapeva prima
I tumori pediatrici, rappresentando solo l’1-2% di tutti i casi registrati di tumore, sono un evento relativamente raro. Nonostante ciò, queste malattie
hanno un grande impatto sui pazienti, sulle loro famiglie e sulla società in generale, e costituiscono la seconda causa di morte in età infantile dopo
traumi ed avvelenamenti. La diminuzione del tasso di mortalità dei tumori pediatrici (in particolare leucemie, malattia di Hodgkin e sarcomi) è stato
uno dei successi più importanti della medicina negli ultimi 30 anni. Tale risultato è stato ottenuto principalmente grazie all’arruolamento dei pazienti
in protocolli clinici di diagnosi e trattamento, come standard di cura, al miglioramento delle terapie di supporto e ai risultati del trapianto di cellule
staminali emopoietiche.
Cosa sappiamo adesso
Nei paesi con elevate risorse economiche, il trend di miglioramento ha raggiunto una stabilità ed è difficile prevedere che un ulteriore successo possa avvenire con l’ottimizzazione dei chemioterapici fino ad ora utilizzati. La genomica sta progressivamente modificando il paradigma di cura verso
l’utilizzo di farmaci diretti contro le alterazioni genetiche dei diversi tipi di tumore. L’aspettativa è quella di poter disporre di farmaci meno tossici e
più efficaci, perché diretti principalmente contro la cellula tumorale. Un ulteriore aspetto di novità è costituito dai “guariti” o “lungo sopravviventi” (si
stima che circa 1 adulto su 1000 sia stato affetto da tumore in età pediatrica) e dalla necessità di sviluppare risposte a nuove domande di salute, di
inserimento sociale e di qualità di vita.
Quali ricadute sulla pratica clinica
Il successo terapeutico dei tumori in età pediatrica rende ancora più necessario il diretto coinvolgimento del Pediatra e Medico di famiglia nel percorso
di diagnosi e cura per poter divenire senza soluzione di continuità il referente diretto di nuovi bisogni di salute che il bambino/adolescente “guarito”
esprimerà a conclusione del suo percorso terapeutico.
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procedural_guideline/2013/02/WC500139182.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_
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Corrispondenza
Kathy Pritchard-Jones, University College London, Institute of Child Health, 30 Guilsford Street, London, UK. E-mail: [email protected]
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