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Dr Richard Grundy, BSc MBChB FRCPCH PhD, Clinical Senior Lecturer in Paediatric Oncology, Institute of Child Health, University of Birmingham The
realisation that their child has a Cancer of the brain or spinal cord is
perhaps the most dreaded diagnoses a parent can receive. This fear arises
from a number of different factors some of which I will touch on in this
article. Although
brain tumours are lumped together by
virtue of their anatomical location, they show a wide diversity in terms
of presentation, site of occurrence, their natural history in terms of
growth rate and tumour dissemination. Children with brain tumours present
a great challenge to the multi-disciplinary team (Oncologists,
Neurosurgeons, Paediatricians, Nurses, Psychologists, Physiotherapists,
Speech and Play therapists etc) who are faced with the problem of treating
a diverse group of tumours arising in the developing central nervous
system. Because the Central nervous system is in the process of rapid
development throughout much of childhood the treatment strategies we adopt
must be mindful of the immediate and long-term effects of therapy on this
vital process. It is now clear that brain tumours and their treatment can
have an adverse effects on this normal CNS
development and even when cured a number of children are left with
disability which influences, not only their lives, but also the lives of
their families. Due to the nature of these Central Nervous system tumours
there may have been some delay between the parents’ first significant
concerns and the diagnosis and however slight this delay, it adds to the
initial anxiety and worries. Whether this materially contributes to the
outcome is difficult to determine. The importance of lag-time to diagnosis
is one of the areas we would like to research along with colleagues in
Nottingham. One
of the most important concerns remains the parental and societal
perception of a poor outcome in these tumours. Primary central nervous
system tumours are the leading cause of cancer-related deaths in children
less than 15 years of age in Europe and America. Tumours of the brain and
spine account for 25% of all cancers in children and young people and
although treatments have improved we still only cure 50% of children so
diagnosed. This accounts for the loss of 10,000 life years each year in
England and Wales. By contrast, survival rates for children with acute leukaemia
and many other solid tumours have risen significantly over the last 10
years.
The reasons for the relative lack of progress are multifactorial,
but are now being systematically challenged and I devote the rest of this
article to the improvements these may bring
Surgery remains the mainstay of treatment for most brain tumours. The completeness of surgical resection in many tumours is the factor most clearly related to outcome. In others it is the skill of the surgeon in doing least harm that is important. Until relatively recently the surgical management of children with brain tumours was fragmented throughout the country. Collaboration between Paediatric Neurosurgeons and the United Kingdom Children’s Cancer Study group (UKCCSG) has now ensured that children are only operated on in a few centres such that the surgical expertise can be concentrated increasing the chance that optimal surgery is performed along with the best standards of pre and post-operative care. Most UKCCSG centres now have multidisciplinary teams of physicians, neuro-surgeons, nurses, physiotherapists, psychologists, teachers, speech therapists and other carers supporting the child with a brain tumour optimising their treatment and potential. The brain tumour group is now the largest sub–group within the UKCCSG and is actively tackling the challenge of improving the medical treatment of this diverse group of tumours. Through this group there is increasing International collaboration enabling us to ask important questions about the effectiveness of various treatments. Another
important factor is our poor understanding of the biology of brain tumours,
particularly when compared to other childhood malignancies. There are a
number reasons for our lack of progress in this regard. Unlike Wilms
tumour, a childhood cancer of the kidney, there are few predisposing
conditions to give us genetic clues as to where to look to find the genes
responsible for the initiation or progression of these tumours.
Furthermore, although lumped together, brain tumours are a very diverse
group of tumours with very different behaviours. Although called a solid
tumour, many brain tumours are of a very soft consistency, neurosurgeons
have therefore developed techniques to ‘suck’ rather than cut these
tumours out. Although a biopsy is taken
to make the diagnosis this is often very small resulting in a lack of
tumour samples for scientific study. Increased co-operation between
surgeons and oncologists interested in research (such as myself) has
improved this situation considerably, though clearly the surgeon has to
ensure that this can be done safely. Scientific techniques have now
advanced such that we can start looking for the genetic clues within the
tumours themselves. The
most useful technique is known as comparative genomic hybridisation (CGH).
The methodology is relatively simple and relies on the fact that Human
Deoxyribonucleic acid (DNA) wherever possible will always find its
complementary partner, a process known as hybridisation (DNA carries our
genetic information in the form of genes and chromosomes). To perform CGH
we need DNA, from the tumour and from the blood.
DNA from the tumour of interest is labelled with a green dye and
normal DNA with a red dye. The labelled tumour and normal DNA are
incubated together in the presence of a normal set of human chromosomes, a
process known as co-hybridisation. If the tumour DNA and the normal DNA
are equivalent, that is there are no losses or gains of chromosomal
material in the tumour, the chromosomes will appear to be a uniform colour.
If there is a loss of tumour DNA the underlying chromosome in that region
will appear red and if there is gain of material then the underlying
chromosome appears green. In this way we can look for areas on the
chromosomes in which genes are lost or areas in which genes are amplified.
This technique is very powerful because we can look at all of the
chromosomes in one experiment. If these findings are consistent in a
number of tumours of the same type this suggests that genes in these
regions are involved in the disease process. CGH therefore considerably
increase ones chance of finding the proverbial needle in a haystack. Once
we have defined the genetic regions of interest we can then hone down on
these genes using other techniques.
We
are just starting to get this research underway, but are still looking for
funding to continue and increase this important work. I believe this
research will allow us to gain a greater insight into the genetic
alterations that result in the formation of children’s brain tumours. We
will then look at the information generated by this study to see if it can
help us determine which tumours have ‘good’ biological/prognostic
features. We may then be able to reduce therapy to these tumours and
reserve the most intensive and toxic therapies for those children with
‘adverse’ biological/prognostic features. Any improvement in our
ability to predict outcome and to tailor therapy accordingly would be a
major advance. A greater understanding of the biology of brain tumours
will also allow us in the future to think about ’biological’ therapies
aimed at modulating the cancer causing genes or cascades that result in
the cancer. Although this remains a dream at the moment we have to strive
for better therapies and get away from our current treatments which fight
‘fire with fire’. A greater understanding of the biology of
children’s brain tumours is now needed to allow us to devise new
treatment options for these tumours, which are, at present, difficult to
treat and cure. |
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