The decades of investment and research into more effective cancer treatments is beginning to pay off in a big way. While a cancer diagnosis might have been a virtual death sentence in the past, today it is in many cases highly treatable and survivable, with the development of combined therapies and targeted treatments contributing to steadily improving mortality and survival rates in countries with developed healthcare systems.
A particularly encouraging statistic was announced by Cancer Research UK in September. Over the last decade, the mortality rate for children with cancer in the UK has dropped by 22%, from around 330 deaths a year in 2004 to around 260 today. There has been a particularly marked decline in leukaemia death rates, which have almost halved in the last ten years.
For a dedicated childhood leukaemia specialist like Josef Vormoor, the Sir James Spence professor of Child Health at Newcastle University ‘s Northern Institute for Cancer Research and honorary consultant in paediatric oncology at the Great North Children’s Hospital, statistics like these are a positive and exciting validation for years of work.
Nevertheless, these heartening figures represent the beginning of a long road of iterative improvement, a platform on which to build to ensure more children get the optimal treatment plan, delivered in the optimal way. We speak to Vormoor to get some insight on the opportunities and challenges that remain in the complex field of paediatric oncology.
Chris Lo: How central have new combined drug therapies been in improving treatment for children with cancer?
Josef Vormoor: Well, [combined therapy in] childhood cancer is actually not new; I think since the ’70s, when the pioneers of the field started to use combination therapies, we have been making progress with combination therapies. But so far, it’s not actually new drugs, we have just been improving the way we use drugs that have been around for 30 or 40 years. There are actually very few new drugs that have found their way into paediatric practice.
CL: Is there a need for new, innovative drugs in particular?
JV: So far, it has been about improving how we deliver therapy, how we combine drugs, how we dose drugs, in combination with better supportive care. We are much better at detecting and treating infections. There are surgical and imaging advantages now. So it’s a whole package that has driven this progress.
An interesting question is why is combination chemotherapy so much more successful in paediatric cancers than in adult cancers? It’s not because we paediatricians are better doctors. Most importantly, and this is why combination therapy works, is that childhood cancers are generally much more genomically stable than adult cancers. Just to give you an example, if you take a typical prognostically favourable ALL [acute lymphoblastic leukaemia], if you do whole-exome sequencing you will probably see about 20 molecular aberrations, point mutations or structural abnormalities. If you take lung cancer or renal cancer in adults, there are thousands. So with a clever combination, our types of tumours are much less likely to escape our treatment and become able to develop resistance, because there isn’t the genomic complexity and the clonal complexity for drug-resistant clones to emerge.
A pioneering study combining existing therapies to slow down cancer is showing encouraging results.
I think for the introduction of the novel agents, which I think will bring the next step change in the way we treat childhood cancers over the next ten years, paediatric tumours may lead the way because they are so much more genomically stable. By combining two or three of the right drugs, we may be able to cure childhood cancers while lots of the more genomically unstable adult cancers will very easily find mechanisms to escape, even with the combination therapies.
CL: Leukaemia mortality rates for children have seen a particularly marked decline – what factors have contributed to this improvement?
JV: Yeah, one is what we call stratified medicine; again, in paediatrics we have been doing this for quite a while. We are trying to adapt the intensity of the treatment to the risk of relapse by looking at response to therapy. This has made a huge difference, because we can now identify sub-groups that have a 95% cure rate, and we can identify the patients who need more intensive treatment, who need a bone marrow transplant. So identifying those at risk and intensifying treatment has helped us to improve treatment by better applying the drugs we’ve had all the time.
CL: What types of childhood cancers still cause high mortality and need to be the focus of increased study in the future?
JV: Well, there are two kinds of challenges. One challenge is for curable disease, and the other is the challenge of high-risk disease. This is mainly metastatic disease; it’s metastatic sarcomas, it’s relapsed leukaemia, it’s high-risk neuroblastoma. Those are the patients who at the moment often have a very low cure rate, often still below 20%. It is for those patients we very clearly need new and novel drugs, because they do not respond to the portfolio of drugs available.
If I go back to the example of relapsed ALL, for example, I really expect that we will see a big change in the way we treat relapsed ALL. We have new immunotherapies coming through, which are specific to ALL; blinatumomab is one example, the BiTE [bispecific T cell engager], a bispecific antibody that recognises an antigen on lymphatic leukaemic cells, and then on the other side it recognises the T cells, so basically it drags T cells and brings them into close proximity to the leukaemic cells, and then the cytotoxic T cells kill the leukaemic cells.
The other good results are CARs, which are the chimeric antigen receptor T cells, again mainly with CD19, which is a surface marker on ALL cells. So I think it looks like immunotherapy will be able to rescue a significant proportion of relapsed leukaemias.
So there are new drugs coming through for relapsed ALL in particular, where I expect we’ll see quite a big change in the way we can treat relapsed leukaemia. In the metastatic sarcomas and the neuroblastoma, I think at the moment we struggle a little bit more, and we really need new drugs.
CL: What can be done with targeted treatments and other measures to increase the tolerability of paediatric cancer treatments?
JV: Generally, I think at the moment it’s actually children who usually tolerate much more intensive treatment than even adolescents and adult patients, so that’s again one of our advantages because we can give much more intensive chemotherapy to a young child than you can give to a 50 or 60-year-old. But I agree that if you look at the impact of the treatment, even if you cure childhood leukaemia it’s two to three years of treatment – there are lots of side effects. About two thirds of survivors of childhood cancer treatment have one chronic health problem, and one third have either multiple or severe chronic health problems, not as a consequence of their cancer but as a consequence of their treatment.
We clearly need to introduce novel therapies to the treatment of childhood cancer, both for the ones that at the moment we can’t cure, and for the ones we can cure. It’s really about reducing the toxicity and side effects of treatments. But then again, we need to really be careful that the targeted drugs we give don’t affect other organ systems, because the targets we have are signal transduction pathways in cancer cells, but those signal transduction pathways will play a role in other contexts in other organs. So we need to be very careful that we don’t just exchange one problem for another.
CL: How is your own work progressing in Newcastle to develop a new drug to treat children with relapsed leukaemia?
JV: You’re probably referring to the trial where I was the chief investigator, the AT9283 trial. That one hasn’t been a very successful trial, because none of the patients we treated really had a response. Because of that, eventually the recruitment was very poor, because patients who qualify for really novel drugs are at the moment patients who are in a palliative situation, so it’s very difficult to move a family with a child around the country to go to a centre where this trial is open, if you don’t really have the promise that this drug makes a difference.
We have a large team; at the moment we have pre-clinical work that has just been published. Dr. Julie Irving just had an interesting blood paper out, where they show that if you combine a MEK inhibitor, selumetinib, with dexamethasone, you will see pre-clinically, in mouse models and in vitro, excellent ways of controlling this leukaemia. So we are having discussions with pharma and our funders at the moment to establish a trial for targeting leukaemias which have RAS pathway mutations; about a third of leukaemias that relapse will have RAS pathway mutations. They often have CNS [central nervous system] involvement, so disease in the brain. The mice, at least, did not develop CNS leukaemia when they were treated with the combination. Whether this actually translates – you have to be very careful not to raise false hope. It works nicely in our pre-clinical models, but we now have to do the studies to see whether this translates into a benefit for patients.
CL: With these sorts of projects on the horizon, are you confident that enough money is coming through via fundraising and grants to fund the work?
JV: Yeah, I’m very optimistic about this at the moment. The key thing nationally that we’re trying to establish in the UK is an infrastructure so that we can introduce advanced genomics into clinical practice for childhood cancers, particularly for patients who have relapsed, and then look at whether there are actionable activations of pathways and mutations that we can then use in those patients who have relapsed. Very similar discussions and infrastructures are being built up in France, in Germany and in the United States. So we are at the moment looking into how we establish those platforms and create that infrastructure so we can do this.
Our key funders in that space are Cancer Research UK and Leukaemia and Lymphoma Research, and I think they are very keen to work with the community to get these things going.
CL: With the research situation going forward, what are your hopes for further reducing children’s cancer mortality rates in the next ten years?
JV: At the moment we cure eight out of ten patients with cancer, specifically in children and young people. I think we will probably never get to a situation where we will cure everyone. One needs to be realistic. But with the new drugs coming in, my hope would be that we would at least get to nine out of ten patients. So I really hope that the new drugs will help us to make significant progress in successfully treating children that we can’t cure at the moment.
My main hope is that we can actually improve treatment for the majority of cancer patients in a way that they get fewer side effects while on treatment, and fewer long-term chronic health problems. We really want to reduce chemotherapy and get rid of some of the drugs that we currently have to use. I’m actually quite optimistic that the new drugs that are coming through and being made available by pharma will make a huge difference in the next ten years. One of our advantages in childhood cancer is that we have a genomically stable disease in most cases, so I really think that with the right combination, there are good chances.