Report from Metronomic Chemotherapy Conference

Chemotherapy remains at the core of much current cancer treatment. Along with radiotherapy and surgery, it’s one of the big three that nearly every cancer patient has to face in the treatment of disease. Many of the ‘classical’ chemotherapy drugs have been in clinical use for decades now, and you would think we would know all there is to know about how best to use them. Unfortunately it appears not... 

The most common approach to chemotherapy is the multi-drug maximum tolerate dose (MTD) protocol. Here you take a set of drugs that work in slightly different ways and then blast them into the patient in a fixed pattern and at the highest possible dose. These cocktails are incredibly toxic – they knock out cancer cells but at considerable collateral damage. Patients lose hair, suffer sickness, loss of immune system, suffer damage to the heart and other organs. It’s a horror and nobody looks forward to chemo. On the plus side there is often a considerable amount of tumour kill, at least at the beginning. But very often tumours develop resistance, the drugs stop being effective and the side effects continue.

However, there is an alternative approach to using these drugs called metronomic chemotherapy. This involves giving considerably lower doses of these drugs but much more frequently. Here, instead of blasting the patient with chemo and then leaving them for a couple of weeks while they recover from the blast – time in which the tumour can also recover – you give a steady drip-drip of the drugs instead. The side effects are considerably lower and quality of life is much higher – especially as the drugs are usually given in tablet form on an out-patient basis.

A new surgical technique for bone cancers

When it comes to bone cancers – such as osteosarcoma or Ewings sarcoma – surgical removal of the tumour-bearing bone is part of the standard treatment. Chemotherapy is part of the treatment, and sometimes radiotherapy, but resection of the bone is at the core of any curative program.  In days gone by this used to mean amputation of a limb, but these days a lot of work goes into limb-sparing surgery. And of course for those cases where the tumour is not in a limb, amputation isn’t an option any way.

In practice this means that very often surgery involves not just the removal of the effected bone, but also taking bone from another part of the body and slotting it into place a replacement. In my son’s case, George had three separate operations to treat the osteosarcoma in his jaw. The second and third time the ‘new’ mandible had to be replaced with a ‘newer’ one – in the end bone taken from his leg, his hip and a rib all to craft new jaw bones. While his was an extreme case, it shows what surgeons are capable off – but also gives an idea of how much trauma is involved to the patient. Some of the operations took more than 12 hours to complete. 

But what if there is a way to reduce the scale of the operation? What if the surgeons didn’t need to harvest new bone to replace the diseased one?

Surprisingly, such an approach does exist. It involves removing the diseased bone – making sure there are good margins as normal – and then the bone is treated to definitively kill the tumour cells. This is achieved by placing the resected bone in liquid nitrogen or bombarding it with very high doses of radiotherapy. Then the treated bone, now stripped of disease, is replaced in its original position. No need therefore to operate on other parts of the body to harvest bits of bone. No need for extensive remodelling.

Does this radical new treatment work? Recent papers show that the results are very good – there are lower rates of complications, low rates of disease recurrence, and of course lower risks of infection and faster recovery times.  For example in one study, published in the Bone and Joint Journal (http://www.bjj.boneandjoint.org.uk/content/96-B/4/555.abstract), no recurrences are reported at all in the grafted bones. 

That’s the good news. For patients in the UK the bad news is that this procedure, which was first used in Japan about 10 years ago, is not available. I remember asking for this for George, but got a blank look in return. So far as I know this is still not available in the UK – though I’d love to find out that someone, somewhere in the NHS has started doing this. It would make a huge difference to those people who’ve got primary bone cancers or bony metastases.

The Case of Ashya King

The sad case of Ashya King, the five year old with a brain tumour who was taken from hospital by his parents, has generated huge amounts of publicity in the UK and has focused attention on the issue of cancer treatments available abroad that are not easily accessed or available in the UK. I write as someone who has faced this problem with my own child, George, and as someone who has helped other parents access treatment abroad. In this country it’s extremely difficult to criticise the NHS, it’s seen as a betrayal somehow, yet there are serious problems which have to be discussed. I’ve written before about the abysmal figures for osteosarcoma in this country, figures which lag behind some of the other countries in Europe. It’s a similar story with some other cancers, particularly some of the rarer cancers.

In the case of Ashya King, the family wanted their child treated with proton beam therapy, but it’s not the only instance of treatments which are available abroad but not in the UK. There are numerous kinds of ablation treatments in use in other parts of the world which are not often used in the UK – cryoablation, radiofrequency or microwave ablation and so on. In some cases there is treatment in the UK at one or two centres and only for one or two cancer types, whereas in the other countries they treat a wide range of cancers and at more centres.

The hard part comes for parents who’ve identified a treatment and then try to get approval and funding to get that treatment. This is incredibly hard to do. Socially we are not used to demanding things from doctors – we are brought up to be respectful and not to question. It takes a lot of guts to actually disagree and make a demand. If you are lucky you’ll get a hearing, but more often than not you’ll be turned down, fobbed off or made to feel stupid. Persuading your doctors is one thing, assuming that you get through that hurdle – and many people don’t – the next step is to get funding. Again there are some fantastic cases where everything works and people are referred abroad for treatment. In many more cases there’s no funding. In which case people have to fall back on savings, on family and friends, even on taking out loans and new mortgages. Not only is this hard on families financially, it takes time and energy that should be focused on the child not fighting the system.

So, never let anyone tell you that everything is wonderful in children’s oncology in the UK. Especially now, with this case in the news and at the start of Childhood Cancer Awareness month. There are some fantastic people there, some great doctors and nurses, but also a system that is monolithic, moves at a snail’s pace and is resistant to change. And don’t underestimate the bravery and courage required to be a parent of a child with cancer who has to fight that system.

ReDO - Repurposing Drugs in Oncology

A theme that I have covered here many times is the potential use of common non-cancer drugs as parts of anticancer drug protocols. Examples that I have covered have included the anti-hypertension (high blood pressure) drug losartan, the anti-fungal itraconazole and the anti-parasitic mebendazole. For the last few months I have been working on a project called Repurposing Drugs in Oncology (ReDO), looking precisely at how we can make more progress in getting these common and low-cost drugs into use clinically against cancer.


I’m happy to report that the first two papers from the ReDO project have been published today, in the open access journal ecancermedicalscience, along with an editorial making the argument for repurposing. The first paper describes the rationale of the project and outlines our thinking in the selection of the candidate drugs, what we hope to achieve in the project and some of the social and political implications involved:

The Repurposing Drugs in Oncology (ReDO) Project

The second paper looks in detail at the first drug on our list – mebendazole. It summarises the evidence for an anti-cancer action of the drug at clinically relevant dosages. Additionally the paper proposes a series of drug combinations for specific types of cancer:

Mebendazole as an anti-cancer agent

The editorial that accompanies the two papers is also online:

Recycling existing drugs for cancer therapy: delivering low cost cancer care

More details on this, including links to some of the clinical trials my colleagues are involved in supporting and links to additional articles, can be found at the project web site:

www.redo-project.org

These papers are just the first, and we hope that in the months to come there will be more publications and a greater intervention in public debates about health policy and drug development in cancer.

Li Fraumeni Syndrome and Cellular Metabolism

A while ago I wrote about the trial of the anti-diabetic drug metformin  in individuals with Li Fraumeni Syndrome (LFS) and the importance of starting to look beyond the idea that LFS is just about a defects in the self-destruct mechanism of damaged cells. Another clinical trial in LFS, also at the National Institutes of Health in the United States, is also taking place and this one too is about looking at a different aspect of LFS. The ‘Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome’ study (http://www.clinicaltrials.gov/ct2/show/NCT00406445) is looking specifically at whether a mutated TP53 gene causes metabolic changes in humans, as it does in mice and in test tube studies.

This is not just an academic question – ultimately we are looking to see whether there are factors that can change the cancer risk in individuals with LFS. This is the key idea in my own research on LFS, see for example the paper on ‘Li Fraumeni syndrome, cancer and senescence: a new hypothesis’.

Dr Paul Hwang, one of the investigators on this new trial kindly agreed to respond to a few questions on his work:

Pan: In your experiments you have found that mice with a mutated TP53 gene show different patterns of cellular metabolism compared to mice with non-mutated TP53. How would this difference manifest itself day to day? For example, would you expect to see different responses to exercise and diet?

PH: In a preliminary study of individuals carrying mutations in the TP53 gene (encoding p53 protein), we have observed evidence of increased muscle oxidative metabolism which is carried out by sub-cellular compartments of the cell called the mitochondria. In a mouse model of LFS, where genetic and environmental variables between individuals can be well controlled, we see a marked increase in aerobic exercise capacity which is also dependent on muscle mitochondria. Thus, in individuals with LFS this intrinsic characteristic could manifest itself as higher baseline endurance exercise capacity. Additionally, with exercise training, it could be possible to see a more robust improvement in fitness compared to individuals who do not carry the TP53 alteration. However, it should be noted that there are many different mutations of TP53 that can cause LFS, and it is not known whether our finding of increased oxidative metabolism is applicable to all individuals with LFS. With respect to diet, we have observed that some p53 mutations result in unresponsiveness to nutrient deprivation at the cellular level but how this affects the relationship between diet and cancer in people would only be speculative at this time.

The LDN Research Trust - Q & A Linda Elsegood

The LDN (Low Dose Naltrexone) Research Trust is at the forefront of raising awareness of the potential of low dose naltrexone as a treatment in auto-immune diseases and cancer. Not just in the UK, the LDN Research Trust has done an outstanding job on the international as well as the national stage. At the heart of this hive of activity – with multiple projects on-going at any one time – is Linda Elsegood, who founded the Trust in February 2004. Ahead of a busy schedule in organising the 2014 LDN Research conference, Linda was kind enough to answer a few questions on LDN and cancer.

Pan: There seems to have been a real rise in the level of interest in LDN and cancer, what’s driving that?

Linda: It’s been incredible really, there is so much interest coming from all areas now – not just in this country but internationally too. Social media has made a huge difference to this. People can access information much more easily than when we started more than 10 years ago. And it’s not just from patients. We get a lot more interest from doctors too. People want to know. And we’re really busy at the LDN Research Trust. We’ve got seven projects on the go at the moment, including the filming of a documentary, there’s the conference which we really want to live stream to everyone for free, to achieve this we have to raise the money. Again, social media is making the difference to this sort of thing.

Pan: In terms of this level of interest, how much is it driven directly by doctors, and how much is it doctors pushed to find out by their patients?

Osteosarcoma - A Proposal for Reducing the Relapse Rate

As has been mentioned on this site before, there has been little progress in the treatment osteosarcoma – the disease that killed my son,George – in the last twenty-five to thirty years. The actual figures vary by country, but generally the five year disease free survival is around 60% - 70%, though in the UK the last published figures were an absolutely appalling 43%. But these figures mask what’s really going – osteosarcoma of the extremities (the long bones in the arms and legs) has a much higher disease free survival rate than osteosarcoma at other sites. So the figures for England show that the rate is 48% for osteosarcoma of the extremities and only 16% for other sites. And, regardless of site, the prognosis for relapsed disease (whether it’s a local recurrence or a distant metastasis) is truly grim.

Looking at the patterns of relapse however shows us something really interesting and, hopefully, significant. The vast majority of relapses occur within 18 months of surgical resection (and in osteosarcoma the only way for definitive cure is to surgically remove the tumour). What is more, most of these relapses take the form of distant metastases, the majority appearing as new tumours in the lungs. This begs the question as to why this pattern? It suggests that there’s something systemic going on – and it’s a similar pattern to the relapse/recurrence of breast, lung, head and neck and other cancers. 

One possible mechanism involves the surgery itself. The body responds to the trauma of surgery by releasing different growth factors, cytokines and other inflammatory responses. This is necessary for wound healing, but it also creates an environment that is conducive to cancer growth – there are pro-angiogenic growth signals, immune suppression and so on. It all adds up to an environment that gives any microscopic pockets of cancer cells the chance to expand and grow into new tumours, particularly in the lungs.