2016 has been a big year for me. I’m a research scientist from the UK and this year I published my first scientific paper from an idea which was of my own design. It also marks 22 years since I was diagnosed with childhood acute lymphoblastic leukaemia (ALL). Two separate bits of information, which are uniquely linked. My treatment regimen 22 years ago was similar to protocols that children undergo across the world even now. Although the cure rates for childhood ALL have increased dramatically in the last 22 years, the chemotherapy drugs used remain very similar, as do the side effects from treatment. I remember hating painful asparaginase injections and horrible mood swings and pica caused by steroids, but the worst side effect I personally experienced was after methotrexate.
The day after a hospital visit, I was at home with my family and I began feeling a little clumsy, weak and slightly delirious. I went to bed and the next morning when I awoke, I was paralysed down my left side. I was rushed to hospital with my panicked parents and several doctors were called in to the hospital to try and figure out what had happened to me. I wasn’t in pain, but I could sense the anxiety of everyone around me and I was scared. I was told I had a rare side effect caused by methotrexate called stroke-like syndrome (SLS), which looks like a stroke, but without blockage of blood vessels in the brain. I forget exactly how long it was before feeling started to come back in my fingertips and I regained some strength, perhaps a couple of days – but thankfully I eventually made a full recovery and completed the rest of my treatment without serious incident.
I grew up and studied for a degree in biomedical sciences and eventually my PhD in leukaemia biology, before working as a postdoctoral research scientist here in the UK at Newcastle University. I had always wondered why I had SLS after treatment and after speaking to the parent of a local survivor who was treated just a few years previously, I realised it was not as rare as I thought. I did some reading and found that in the two decades since I had SLS, nobody had worked out why some children experience it whereas most do not. Although my professional expertise was not looking at toxic side effects of treatment nor neuroscience, I decided to try to learn more about why it happened. I started by emailing my doctor from when I was on treatment to ask if she would be willing to meet to catch up and discuss my ideas as well as let me look at my medical records to search for clues as to why I had SLS when most patients do not. We had a wonderful catch up just outside the hospital where she worked in London, and my own notes gave a bit of evidence to my theory about why some patients experience neurotoxicity, whereas most don’t.
I thought that other medications might have combined with the methotrexate to increase the risk of SLS. One in particular – nitrous oxide (laughing gas) is sometimes used as an anaesthetic during procedures such as lumbar punctures and central line insertions. Nitrous oxide reduces the amount of vitamin B12 in the body, which in a normal healthy person probably wouldn’t make much difference on their B12 levels, but children with leukaemia are different. A small, but helpful study coordinated by one of the doctors I worked with on the project suggested that a quarter of patients are B12 deficient during treatment. Low B12 levels alone can cause various health problems, but we were more concerned about what low B12 levels in combination with methotrexate might do.
Methotrexate works on cancer cells by reducing the amount of folate in a cell and blocking DNA division, but to some extent will affect healthy cells too. B12 is also needed for this process to run smoothly. We feared that if methotrexate was reducing folate levels in healthy cells, which already didn’t have enough B12, it would be especially toxic. Nerve cells such as those in the brain and spinal cord likely get a particularly big dose of methotrexate as it is used for intrathecal injections to get rid of any leukaemia cells hiding in the central nervous system. Our research showed that methotrexate might be particularly toxic to certain types of nerve cells by reducing their production of an amino acid called methionine. Methionine is very important in producing myelin, the insulating material for all of our nerves. When there is not enough of it, nerve impulses do not travel correctly and symptoms such as paralysis can result. I wondered whether this was at all related to my experience.
I worked with some fantastic clinicians in Newcastle and across the UK to further develop this idea that perhaps other medications which children with leukaemia are often on, might increase the chances of neurotoxic side effects from methotrexate. Through the network of doctors we created, we encountered a patient with severe stroke like syndrome and were able to test the B12 levels for the first time, showing that they were low. Our research is certainly at an early stage, but the potential interaction we described between nitrous oxide and methotrexate was considered plausible enough to change the treatment protocol for children with leukaemia in the UK to make sure patients never get nitrous oxide anaesthesia at the same time as methotrexate. We published the research last month and hope that it will inspire debate and discussion globally amongst healthcare professionals working in the field.
My doctor who kindly met me for coffee and to discuss my notes at the very beginning of this project sadly passed away unexpectedly in January of this year. She never saw the published research, but I have her to thank, not only for treating me 22 years ago, but for working with me as a fellow scientist to help future patients. Her passion and drive for helping children with cancer has always inspired me and will continue to do so for the rest of my career.
Dr Vicky Forster is a postdoctoral cancer research scientist with interests in paediatric cancers and the long- and short-term side effects of treatment. She’s also a 22 year survivor of childhood leukaemia and an advocate for childhood cancer survivorship and patient involvement in research. She currently works at the Northern Institute for Cancer Research, Newcastle upon Tyne, UK on a project investigating neurotoxic side effects of methotrexate treatment in children with leukaemia. Early next year, she is excited to be moving to Toronto to work at The Hospital for Sick Children (SickKids) on rare paediatric brain tumours. She is passionate about science communication and keeping the whole paediatric oncology community up to date with her research progress.