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The challenges of improving outcomes for children with cancer

January 10, 2015

An article by Prof. Roger Reddel, Head, Cancer Research Unit and Lorimer Dods Professor and Director, Children’s Medical Research Institute; and Dr Luciano Dalla-Pozza, Head, Oncology Unit, Children’s Hospital Westmead.

Childhood cancer has a major impact on families and the broader community.

Although it is relatively rare compared with cancer in adults, childhood cancer remains the leading cause of disease-related death in children aged 1 to 15 years. In fact, based on US data, the number of years of life lost through childhood cancer is about the same as for breast cancer.

The relative rarity of childhood cancer poses unique challenges for researchers:

  • Opportunities to participate in clinical trials that define more effective, efficient and less toxic therapies are often stifled by low patient numbers as well as lack of funding, but clinical trials are considered the standard of care that should be offered to children and their families;
  • Enrolling sufficient patients into clinical trials requires the participation of multiple paediatric cancer centres;
  • The difficulties faced by researchers are compounded by the lack of incentive for pharmaceutical companies to invest actively in new treatments;
  • And finally, government agencies have a tendency to direct priority-driven research funding to the more common adult cancers.

Paediatric cancer researchers have in part addressed these challenges by forming international clinical trials consortia. As a result, a substantial number of patients are now enrolled in clinical trials, allowing meaningful, statistically significant outcomes to be achieved.

Most paediatric oncology centres in Australia have well-developed clinical trials infrastructure, almost all of which is funded through philanthropy. We meet world-class standards in our methods, resources, and ethics processes. This capacity allows centres to enrol a large proportion of their patients – even if they have rare forms of childhood cancer – in relevant clinical trials, a situation that is essentially impossible in most adult cancer centres.

Consequently, childhood cancer centres provide a clinical care environment for childhood cancer patients which is research-intensive. This approach has been a major factor in driving the improvements in the long term survival rate which, in developed countries, now stands at over 80%.

It is now estimated that about 1 in 650 adults between 20 and 40 years of age is a survivor of childhood cancer and, given that survival was less than 10% in the 1950s, this is a great success.

It has been achieved, however, at some cost to patients, their families and the community. Current therapies are intensive and produce both acute and long term toxicities. A substantial proportion of adult survivors of childhood cancer have significant long term side effects of their therapies and they require ongoing care and support. The impact on the health care system is substantial.

Prevention of childhood cancer is currently not a feasible strategy because the causes are largely unknown, but it may become possible in future.

The positive effects of interventions and life style changes on cancer incidence are largely seen in adult cancer. For example the widespread adoption of the human papilloma virus vaccine will result in reduction of specific adult-onset cancers such as cervical cancer. Similarly, immunization against Hepatitis B and C viruses will translate into reduction in hepatocellular carcinoma rates in susceptible populations. Although such measures will have no or negligible impact on childhood cancer incidence, we can hope to apply these learnings to a significant proportion of children with an underlying genetic predisposition to cancer. Increasing our knowledge about genetic predisposition will facilitate surveillance measures for early detection as well as potential preventive measures.

Since we are currently limited in our capacity to prevent childhood cancer, research needs to focus on devising treatments that are less toxic, shorter in duration, and more targeted to the specific malignancy. Quality of life – both short and long term – is a goal that all researchers should prioritise.

As a means to this end, further entrenching research into clinical care remains an essential prerequisite to increasing survival and improving quality of life.

Clinical trials overseen by paediatric cancer units or centres should universally become the standard of care. Without government intervention (through legislation or incentives), pharmaceutical companies are unlikely to invest in developing specific and novel therapies for childhood cancer. The onus of undertaking effective research therefore must remain with academic institutions tied to major paediatric teaching hospitals.

Recent enhancements in research technologies are already assisting the process of developing treatment approaches that are both disease- and patient-specific. The cost of DNA sequencing has fallen rapidly, which may make it possible in the not-too-distant future to obtain whole genome sequencing of every child’s cancer, and of their normal DNA. There have also been parallel advances in the analyses of RNA and proteins.

Already, a major consequence of these technologies is the sheer volume of available data. This requires major computing and bioinformatics resources and, most importantly, careful interpretation. Given the elevated rate of mutation in cancers, many of the changes will be random and of no consequence whereas others will be critically important drivers of the cancer. The knowledge required to make precise clinical decisions on the basis of molecular analyses currently has many gaps, which urgently need filling.

In the short term, these technologies will make the current complex situation even more complicated. Cancers, such as medulloblastoma, which were previously regarded as a single disease, are now known to be clearly heterogeneous. They can be subdivided into different biological categories based on detailed molecular analyses and these molecular differences translate into differences in cancer behaviour and responses to treatment.

Even within the same class of cancers, molecular heterogeneity will thwart the development of a universal treatment approach. However, research on one class of cancer may reveal potential therapies for other types. It is clear already that treatments developed and trialled for one type of cancer (paediatric or adult) might be just as useful for other types. For example, changes in a gene known as ‘ALK’ occur in various cancers including specific types of lung cancer and lymphoma. A drug treatment that targets ALK has shown benefit in the relevant lymphoma subtype and is being tested in children with neuroblastoma containing ALK mutations.

In the medium term, these technologies are providing researchers the tools to develop solutions. For decades, many cancer researchers have concentrated on developing therapies that are directed to specific molecular targets, and the flood of new molecular data should accelerate this effort. Technological developments now make it possible to manipulate genomes (the genetic makeup) of live cells, which has greatly increased our ability to analyse the functional consequences of newly discovered genetic changes. We are also able to better design and create experimental tools in the laboratory which can be used to pinpoint weaknesses in cancers, and to identify existing therapies or develop new drugs that specifically counteract the adverse consequences of these mutations. Moreover, our increasing ability to analyse the molecular determinants of how normal tissues handle drugs, including cancer treatments, means it should be increasingly feasible to tailor treatments more precisely to the individual patient.

The challenges remain enormous, but the knowledge base and technologies required to successfully overcome childhood cancer are developing at an unprecedented rate.

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