When it came to avoiding extremes, Goldilocks knew what she was doing as she plumped for the perfect porridge. In fact, her skill in finding the happy medium was immortalised in what we now call the Goldilocks Principle – the suggestion that “just right” usually lies somewhere between two ends of the spectrum.
Doctors use the Goldilocks Principle when deciding how much chemotherapy to give a patient. Too little and the drug won’t hit the cancer hard enough to have an impact, but giving too much of the drug can cause unacceptable side- effects. So how do they figure out which dose is “just right”?
Clinicians usually consider a patient’s size or weight when prescribing chemotherapy, and although this approach is usually effective, it doesn’t always work for everyone. Children can be especially vulnerable to cancer drugs because their bodies are still growing. This means that they can suffer long-term side effects, or their cancer simply doesn’t respond to treatment at all.
Dr Gareth Veal wants to change this situation, by understanding more about the fate of cancer drugs once they’re inside the body. His mission is to improve the way we treat children with cancer so that every child receives a dose of chemotherapy that is “just right”. We recently caught up with Dr Veal at the Northern Institute for Cancer Research in Newcastle, where he told us more about his work.
Cancer Research UK: What’s the aim of your research?
Gareth Veal: Today, we can cure three quarters of children with cancer. But the flip side is that many of these children suffer from side-effects that can affect them for the rest of their lives. We want to maintain these high response rates but minimise the side effects of chemotherapy by tailoring the dose for each child.
Cancer Research UK: Why do some children develop side effects while others don’t?
Gareth Veal: There are many possible reasons but often it may be related to something we call drug exposure. When a child takes a dose of drug the body starts to process it. Drug exposure is basically how much of the drug is present in the body over a period of time. In some children the drug will be removed from the body more quickly, leading to lower exposures, whereas in others the drug will be processed more slowly, resulting in higher exposures. Measuring exposure may give us an idea of how much drug reaches the target tumour and this can vary between patients and even between courses of treatment.
Cancer Research UK: So are some side effects caused by high exposures?
Gareth Veal: That’s certainly the case for a drug called carboplatin which is often used in the treatment of children with solid tumours. Findings from a number of studies, including work done here in Newcastle many years ago by Hilary Calvert and Herbie Newell, showed that people with higher exposures to carboplatin tended to develop side effects.
Cancer Research UK: What things can affect drug exposure?
Gareth Veal: The major organs play a big role. The kidneys are important because they get rid of many drugs from the body. The liver can also be crucial, not only in terms of breaking down drugs but also by activating cancer drugs in some cases.
Cancer Research UK: So why can drug exposure in children be such a different ball game?
Gareth Veal: Children’s organs are still developing so their function is always changing, particularly in infants and younger children. For example, there’s quite a good relationship between kidney function and the age of a child when they’re young, but then things start to level off in adolescence. The kidneys and liver can also be affected by chemotherapy so their function can drop as a child goes through treatment.
Metabolism in a small child may be very different from metabolism in an adult for many reasons, so drug exposure can change dramatically with time. There are also problems arising from the way some drugs are formulated. For example, children with neuroblastoma are often given a drug called 13-cis-retinoic acid which comes as large capsules that they find difficult to swallow. As neuroblastoma is most commonly diagnosed in children 1-5 years of age, the drug is frequently squeezed out of the capsules and mixed with food. All these factors can lead to variations in drug exposure, with some children having much higher exposures than others.
Cancer Research UK: How are you tackling this problem?
Gareth Veal: With 13-cis-retinoic acid, we’re doing something called dose individualisation or adaptive dosing. We’re basically monitoring the exposure in individual patients and tailoring the dose accordingly. So if a child has a very low concentration of the drug in their body, we will increase their dose.
It’s a simple approach but it can be very effective. It helps make sure that the exposure isn’t high enough to cause side effects and it avoids very low exposures which may be less effective at treating the cancer. We can be sure that all the children on the trial get an appropriate dose which gives them the comparable exposures.
Cancer Research UK: Is this approach taken for other cancer drugs used to treat children?
Gareth Veal: Yes, we do it routinely with carboplatin for certain groups of patients in specific circumstances. We also often carry out monitoring when we’re treating very small babies. In both cases, doctors have to be extremely careful about choosing the right dose because you have the potential for serious harm. It can make a real difference to the way we treat these children.
Cancer Research UK: How do you think children with cancer will benefit from your work?
Gareth Veal: We’ll have to follow the children for a few years before we can say anything about actual clinical benefit. But the study has already had an impact. Previously, very young babies were given a lower dose of 13-cis-retinoic acid compared to older children due to concerns over possible side effects. But it was already difficult to give the drug to those children and then on top of that they were given a reduced dose. So we weren’t surprised to find that these children frequently had lower drug exposures, meaning they weren’t actually getting enough of the drug in their systems to treat the cancer effectively.
When we presented these results to the clinical community, it was decided that a standard dose should be given to all patients, rather than giving a lower dose to these very young children. So our early results from this study have already had an impact on the way that children with neuroblastoma are treated.
Cancer Research UK: What’s it like working on children’s cancers?
Gareth Veal: On the one hand doing research into childhood cancer can be incredibly frustrating. If you’re running a trial where you need 100 patients with a specific cancer type and who are receiving a particular drug to get meaningful results for a study, it can take several years to recruit all the patients because children’s cancer is fortunately relatively rare. But when the findings have an impact on how children are treated, it’s really good. The satisfaction of knowing that you’re making a difference to even a small number of children is something that I really value in my job.
Interview conducted by Safia Danovi