When less is more

The conventional approach to chemotherapy treatment for cancer is to give the patient a cocktail of different chemo drugs at the maximum tolerated dose (MTD). The idea of MTD treatment is to hit the cancer with the most toxic treatment the patient can stand in the hope that it causes the maximum damage to the disease. Normally a treatment consists of a number of cycles of chemo using a mix of drugs, with the idea that each drug will attack the tumour in a different way – reducing the chance of the tumour surviving the onslaught. And it’s an onslaught for the person receiving the treatment too – most chemotherapy drugs are toxic to a wide range of cells, not just cancer cells. Hence the hair loss, the nausea, the immune suppression, fatigue and the rest of the side effects that makes chemo so hard.

Of necessity a person needs recovery time after each cycle of chemotherapy. Blood counts need to recover, sickness needs to pass, people need to regain some strength. Unfortunately that’s recovery time that tumours can also use to recover. The highest rates of tumour kill tend to be at the least cycles, the later cycles tend to be less effective, particularly if resistance starts to kick in.

However, this isn't the only way of delivering treatment. An alternative approach to chemotherapy has been developing for some time. Low dose metronomic chemotherapy involves many of the same drugs as MTD chemo, but delivered at low doses, often in tablet form, but with no treatment breaks. The continuous dosing is possible because at these low doses the drugs work in very different ways to when they are delivered at MTD levels. The side effects are minimal as the drugs are no longer acting as potent toxins to massively kill cells.

Saatchi Bill and Medical Anecdotes

Opponents of the Medical Innovation Bill (aka as the Saatchi Bill), such as Sarah Wollaston MP, have been very vocal in attacking the Bill by making a number of false claims about what the Bill will do. One such argument is that the Bill will undermine medical progress by doing away with clinical trials, and that instead we will just have to rely on individual anecdotes that arise from doctors using innovative off-label treatments on patients. In fact Sarah Wollaston even referred to the Bill as the ‘Medical Anecdotes Bill’ in her recent speech in the House of Commons.

There are a number of points that to raise in response to this false assertion.

First, there is no intention to replace clinical trials. The Bill is about treating patients with no place left to turn – these are people who have exhausted standard therapies and for whom there are few options left to explore. If a clinical trial is open and the patient is eligible then that is the place to go if it is in the patient’s best interest. There may be cases where it is the right thing to do, just as there are cases when it will not benefit the patient who is offered the additional choice of an non-standard treatment (for example an off-label drug with evidence of clinical activity in the patient’s illness). This will be decided on a case by case basis, what it will not do is force doctors to ignore clinical trials or undermine the trials process.

Not All Journals Are Created Equal

An increasing hazard in science publishing is the increasing number of 'predatory journals'. The term refers to low-quality scientific journals which exist solely to make easy money under the 'author pays' model of publishing. These journals pretend to do peer review and they look and feel like proper academic journals, but in reality they will publish anything to harvest those publication fees. It's a scam, and a successful one given the growth of the number of these journals. The way the scam works is for these journals to solicit papers, to claim they do peer review, then to accept the papers. The authors are billed the article processing and publication fees, and then the paper is published online.

There are multiple dangers in this process. The first and most obvious is that the authors are ripped off - they have effectively just paid for someone to turn there text into a web page. There has been no peer review, no proper scrutiny of the content and the chances are that the paper will be ignored by other academics. If you have a limited budget for publication fees you've just wasted it. If you are starting out in your research career publishing in these journals may seem an easy route to getting some papers to your name, but more knowledgeable colleagues will know what you've done and so the risk is that you damage your career, not enhance it. It is also possible that unscrupulous academics will deliberately use predatory journals to beef up a CV to impress people who don't know about predatory journals - all of which sound eminently respectable to the unsuspecting.

However, the biggest danger is not with academics, but with the general public. Most people are impressed by a paper that is published in a scientific journal. Scammers and snake-oil salesmen can use this to peddle fake medical treatments to desperate patients. Shoddy papers that sound scientifically plausible can be published in predatory journals and then used to convince people that there's some real science behind the scam. If you're not a scientist or someone versed in the medical literature a paper that claims to treat late stage cancer patients and to have miraculous results can be very convincing. The best examples of this are the scammers selling GcMAF as a miracle cure for cancer, autism, AIDS and just about everything else.

How can you, as a reader, verify that the journal paper you are reading is not a piece of junk published in exchange for a few hundred dollars?

Alveolar Soft Part Sarcoma - The Reverse Warburg Effect In Action?

Alveolar soft part sarcoma (ASPS) is a rare cancer - rare even among soft tissue sarcomas - that is slow growing but hard to treat. When the disease metastasises the prognosis is generally grim and there are few options for treatment if surgical resection is not possible. A new paper, published in the journal Cancer Cell, describes work in a mouse model of the disease which may ultimately have important therapeutic consequences.

A team at the University of Utah have created a mouse model of ASPS, by fusing two strands of DNA to create a fusion gene which forms tumours in the mice in which it is implanted. What's more the resulting disease behaves very much like ASPS in humans, including producing very similar genetic profiles. Intriguingly the mouse tumours formed preferentially in areas of the body which had high concentrations of lactate. In humans this tends to be in the skeletal muscles as lactate is a by-product when our muscles are straining for energy in low oxygen conditions. In the mice the areas with the highest lactate concentrations were in the skull.

Generally tumours are believed to generate excess lactate as a by-product of their metabolism - this is known as the Warburg effect. And yet here the tumours seem to be feeding off the lactate produced by non-cancer cells. As one of the researchers, Kevin Jones explains: "It's unusual to find a cancer using lactate this way. The ASPS cells grow preferentially where they are bathed in high concentrations of lactate."

The most likely explanation is that this is yet another example of the reverse Warburg effect, first described by Michael Lisanti and his team. This is a topic of huge importance as it revises what has been seen as a core component of our understanding of cancer. In this model of cancer, the tumour cells act on non-cancer cells to change their metabolism so that they emit lactate and glutamine, which the tumour cells use as a more powerful fuel source.

This does open up opportunities for intervention, however. If we can interrupt that 'metabolic shuttle' between lactate consuming tumour cells and stromal cells they are 'farming' then we can starve the cancer cells and so slow - or possibly even halt - tumour growth.

Cimetidine as an anticancer drug - New ReDO paper

The latest paper from the ReDO project has just been published. Our focus for this paper is the well-known antacid cimetidine (trade name Tagamet, but now available as a generic). The paper summarises the extensive pre-clinical and clinical evidence that shows cimetidine has huge potential in cancer treatment. It has multiple mechanisms of action and there is clinical trial evidence that it is associated with a survival in colorectal cancers.

The paper is published as open access at the journal ecancer.

The press release provides a few more details:

How a common antacid could lead to cheaper anti-cancer drugs

The cancer solution in your medicine cabinet

A popular indigestion medication can increase survival in colorectal cancer, according to research published in ecancermedicalscience. But in fact, scientists have studied this for years - and a group of cancer advocates want to know why this research isn't more widely used.

"Cimetidine is an interesting drug as it's very safe, very well-known, and has clinical results in cancer that have been confirmed in a number of trials," says Pan Pantziarka, lead author of the paper and member of the Repurposing Drugs in Oncology (ReDO) project.

Fecal Transplants In Medicine

I've mentioned on here before that fecal transplants represent a potential new addition to medical practice. The idea is that we can transfer whole ecosystems of gut bacteria from one individual to another, and in doing so transfer the beneficial side effects that 'good bacteria' can bring to the immune system.

I take a much wider look at the topic in an article at the science and technology website The Register.

Bisphosphonates in non-bone tumours

Bisphosphonates are a class of bone-targeted drug that act to slow the turn-over of bone (bone resorption). These drugs, including zoledronate, ibandronate and others, are standard treatments for osteoporosis and other bone diseases. And, as I have mentioned previously on this blog they have increasingly found use in cancer treatment to help control bone-related problems - both from metastatic disease to the bone and in primary bone tumours. There is also increasing evidence that as well as controlling bone pain and reducing fractures, these drugs have some very positive effects on overall survival. For example there is now evidence that zoledronate (also called Zometa or zoledronic acid) gives a survival advantage even in early stage breast cancer. Now this is something of a surprise because the effects are there even when there are no bone metastases, so the drug must be acting on non-bone tumour tissue - how is this possible?

New light has been shed on the matter by some recent work that convincingly shows that zoledronic acid is taken up by cancer associated cells outside of bony metastases. Some clever lab work has shown that zoledronic acid attaches itself to tiny crystals of calcium (microcalcifications) outside of the bone. These microcalcifications are then eaten up by tumour associated macrophages, immune cells that actively encourage and support tumour growth. Once these macrophages have swallowed the microcalcifications with the zolderonic acid attached the drug can get to work and interfere with their function. In other words, the drug doesn't affect tumour cells directly, it affects the cells that provide some of the life-support that tumours require. The lab work on mice was also confirmed on a tumour sample from a breast cancer patient.

Book Review - p53 : The Gene That Cracked The Cancer Code

Keywords: Cancer, p53, Li Fraumeni Syndrome Title: p53 : The Gene That Cracked The Cancer Code Author: Sue Armstrong Publisher: Bloomsbury Sigma ISBN: 978-1472910516

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If any single gene deserves a biography, it’s TP53 (more commonly known as p53). This is the gene, memorably christened the ‘guardian of the genome’ by David Lane, one of its co-discoverers, which is the tumour suppressor that is most commonly lost or mutated in cancer. It’s also the gene most commonly mutated in the rare and deadly cancer predisposition condition called Li Fraumeni Syndrome. Science writer Sue Armstrong has crafted that biography, delivering a book that is engaging, interesting and has a real page-turning quality that you might not expect for a book on the workings of a single gene.

Adopting a largely historical narrative, the book explores the evolution of our understanding of cancer via our expanding knowledge of p53. Early on, before the structure of DNA was unravelled, scientists explored the viral transmission of cancer in animal models – sarcoma viruses could reliably infect animals with tumours. If it worked for animals, they reasoned, why not for people? How did the virus create tumours? Investigations showed that these viruses triggered changes in cells that eventually developed into cancers. Individual genes and pathways were discovered that were termed oncogenes – these were the culprits that caused cancer.

But of course most cancers that develop in people are not virally transmitted, but as technology and scientific tools expanded the theories developed and changed. Our understanding of DNA spawned a revolution in our thinking, including our thinking about cancer and the role of genetic change. When it was first discovered – independently by multiple groups – p53 was assumed to be just another oncogene, a driver of cancer development.

The Burzynski Con

There is a lot wrong with current oncology practice and the research that underpins it. The pace of change is slow. Promised breakthroughs fail to deliver what they initially promised. The clinical trials process is slow and getting slower. Patient needs remain unmet and patients are dying while regulations multiply and conspire against change. But with that in mind, that doesn't mean that science is wrong, that clinical trials are wrong or that there are 'cures' out there which the drug companies are suppressing. As I have written before, there is no such thing as a miracle cure.

Unfortunately there are some people who take what are valid criticisms of the clinical trials process or the lack of progress in oncology and then imagine that there are conspiracies at work to deliberately stop progress happening. And of course there are some people out there who will use that to their advantage. Probably the most notorious example of this is a man called Stanislaw Burzynski.

Burzynki came up with the idea that there were chemicals in the body, which he called antineoplastons, which could be effective against cancer. His idea was that people with cancer were deficient in these antineoplastons, and that by taking them externally they could mount an effective defence against cancer. It's a simple idea, but rather than go through the normal process of testing, Burzynski set up a clinic and began treating patients very early on. He has been doing this for decades, and still there is no proof that his treatment works. In the years that he has been operating his Burzynski Clinic in Texas, he has treated many thousands of patients, at great financial cost to them. It's not a cheap treatment. And, despite what he says, it's not non-toxic either, patients have died from the side effects of his treatment. And still there is no evidence that this stuff works.

For The Love of George - Book

The starting point for this blog was a conversation with my son, George, in the middle of his battle with osteosarcoma. I’d had been immersed in reading about treatments, supplements, theories and he thought that it would be good to share that knowledge with other people. We talked about it for a while and he came up with some ideas for a logo, we talked about the domain name and so on. It was typical George, thinking about the future, coming up with plans and schemes. The other web site he was really keen on starting was eat positive, that was one he was really keen on and I’m glad that I’ve managed to kick that off in a very low key sort of way too. Unfortunately not every story has a happy ending, and George did not live to see either of these sites become real. And of course after his death we created the George Pantziarka TP53 Trust to support other individuals and families afflicted with Li Fraumeni Syndrome in the same way that he was.

But for all this activity, I do sometimes worry that people will lose sight of who George was. He was a kid who suffered three different cancers, and who tried just about every treatment available before finally succumbing to the disease at the age of 17. It’s a painful story, but one that is common to families with LFS, or to families with a child with cancer. It’s a story that needs telling. And to that end my wife, Irene Kappes, has written a book called ‘For The Love of George’. I’ll be honest, it’s not an easy read. It doesn’t have a happy ending, though we all hope that what we are doing in his name can make something positive out of what he went through.

We worry that the book is harrowing and will scare some people, but then how can we make clear what families with LFS have to go through if we’re not honest? The only way is to show what George was like. To show what a fantastic kid he was, how we had good times even when the medical situation was grim, and to hope that there things in the book that people can learn from.

A portion of the proceeds from the book will go into the Trust.

The book is available on Kindle and as hard copy from Amazon.

In the UK: Kindle or Paperback

In the US: Kindle or Paperback

Book Review - Surviving 'Terminal' Cancer

Keywords: Cancer, glioblastoma, drug cocktails Title: Surviving Terminal Cancer Author: Ben Williams, PhD Publisher: Fairview Press ISBN: 978-1477496510

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While there are some cancers for which we have made progress in treatments and consequent survival, there are also some for which progress has been pretty much non-existent. Glioblastoma multiforme (GBM) is one of the latter – the survival statistics are abysmal and have remained unchanged for many years. Which is why this book, by professor of Psychology Ben Williams, is so inspirational. When faced with this terrifying diagnosis, he got through the shock and then decided he was going to do more than just sit back and accept the standard of care treatment that was almost guaranteed to fail. Instead he took matters into his own hands and sought out other options, whatever and wherever they might be. He is, therefore, one of the few very long-term survivors of GBM. What is more, he has done more than just seek out something for himself, and he has dedicated the last twenty years to helping others do the same. This book is his story and it is, without doubt, one of the most inspirational and yet practical books in the vast literature of cancer.

Written in three sections, ‘Surviving Terminal Cancer’ is more than just a memoir, it also includes a section on the need for change in the system of clinical trials and drug development and a final section on some of the specific treatments and supplements that Williams has found to be useful. In all this is a comprehensive range of material that moves far beyond a memoir and becomes more of a manual for the activist patient who wants to go beyond what the standard treatments.

The book starts, however, with Ben William’s own story. He describes the terrifying diagnosis and his initial shock and paralysis in the face of it. But this changes as he responds by using his skills as a scientist to understand the disease and to look at what was being researched. Over time he expands this to develop an approach to his treatment that incorporates multiple additional treatments over and above the standard treatments in place. In the process he comes face to face with an oncological community unwilling to experiment or offer additional choices even when they know that outcome will be dismal. If people are going to die then why is it unethical to treat them with non-standard drugs?

The memoir is profoundly moving and also disturbing in that it reveals a degree of conservatism in the oncology profession that does no favours for patients. 

The next section of the book picks up on many of the issues that his own direct experience raised regarding medical institutions, clinical practice and the clinical trials process. The issues raised are not unique to Ben Williams, nor specific to glioblastoma or even cancer in general come to that. The system is clearly not optional, and it actively inhibits change. It is a system designed for regulators and bureaucrats and the needs of patients are low on the list of priorities. The clinical trials process in particular has continued to evolve towards very large Phase III trials that are expensive, time-consuming and often lead to minor incremental changes in outcomes, if at all. Ben Williams does not argue for doing away with trials completely, instead he argues for smaller and more focused trials leading to changes in clinical practice in a way that is more responsive to good results.

In the final section of the book – suitably entitled ‘What your oncologist won’t tell you’ – the attention turns to ‘alternative’ medicine, supplements, and the current state of play in cancer research.  The arguments about what counts as ‘alternative’ are well-rehearsed, and there is an examination of some well-known controversies regarding laetrile, iscador, the case of Stanislaw Burzynski. The pros and cons of each are discussed, in some detail with regards to Burzynski, but what is more important than the details of each is the process of sifting out the details that Ben Williams goes through. In a world where there are numerous scammers promising miracle cures, arming people with the tools to recognise junk science is essential.

In all this is a fantastic read. It’s thought-provoking, polemical, honest and hopeful. What is more, the approach that Ben Williams is suggesting applies to more than glioblastoma and other brain tumours, it applies across the board to cancer.

Fecal Transplants And Cancer

Fecal transplantation is probably one of the most disgusting medical procedures in existence. It literally means taking a sample of fecal material (poop, in other words) from one person and transplanting it into another. Like I said, it's a pretty disgusting idea, but one that is receiving increasing attention. The more we learn about the role of our gut bacteria the more we understand that having a healthy gut ecosystem is essential to health. Gut bacteria play a big part in how we digest our food, with possibly a role in causing obesity, and in the development of our immune systems. It's the latter that has been explored the most in inflammatory bowel diseases - which is where fecal transplants have been used to treat conditions like Crohn's Disease and similar conditions.

When it comes to cancer there is also a possible role for our gut bacteria. I have previously written about the study that showed mice with a genetic predispostion to cancer and fed with a probiotic had fewer tumours and later onset of disease than similar mice not fed probiotic. Note that these mice were developing breast cancers, not colon, so the effect of feeding probiotics was systemic, not just restricted to the colon. This is really a stunning result and worth taking note of. But I think there is room to take this further...

There is now strong evidence that our gut bacteria are essential for a good response to chemotherapy - again this has been something of a surprising result, but the evidence is that without the right gut bacteria chemotherapy response is severely blunted. And we also know that having the wrong bacteria - gut dysbiosis in the terminology - is also associated with the development of colon cancer.

Where am I going with this? Well, if we know that fecal transplants can be effective in inflammatory bowel conditions, and we know that gut dysbiosis is a factor in colorectal and other cancers, then shouldn't we now be considering looking at fecal transplants as a possible cancer treatment?

Nitroglycerin and cancer drug therapy

Following on from the paper on the anti-parasitic drug mebendazole (which I first discussed on this site a while ago) and the antacid cimetidine (paper not yet published), I've been working on another ReDO paper on the drug nitroglycerin. Like all the repurposed drugs we're looking at in the ReDO project this one is commonly used clinically for non-cancer uses, in this case it's a drug used to treat heart problems and blood pressure. Available as tablet you stick under the tongue, or a spray or even a transdermal patch, nitroglycerin is a drug that has been used for over a 100 years as a vasodilator - in other words it relaxes the blood vessels. It's partly this property that makes it interesting in terms of anti-cancer treatment.

Like other tissues, tumours need a blood supply for food and oxygen, and it is well-known that they release chemical signals that cause new blood vessels to form. This is the process called angiogenesis, and for many years scientists have been looking at ways to disrupt the process - with drugs like avastin (bevacizumab) developed to stop this happening. The idea is that with no blood supply tumours can't grow. However, even when angiogenesis does take place and tumours sprout the blood vessels they need, the vessels that are formed aren't normal. The blood supply is chaotic and the vessels are much leakier than normal. Back in the late 1980s some scientists started looking at how we could use this to our advantage. The idea is that you take advantage of the leakiness by using drugs that leak out into the tumours rather than spreading throughout the body (as normal chemo does). Hiroshi Maeda and his co-workers termed this the 'enhanced permeability and retention' (EPR) effect.

Nitroglycerin enters the picture as a way of making the leakiness worse by relaxing the blood vessels, thus encouraging large drug molecules to leak into the tumours. And once they've leaked out, the chaotic structure of the vessels means the drugs are retained in the tumour where they can have an effect. It is, in theory at least, a way of targeting anti-cancer drugs to the tumours and not to the rest of the body. It's an elegant idea and has lots of experimental evidence going for it. And the evidence includes some small trials in humans - primarily in lung and prostate cancers. There are more clinical trials on-going, and we can but hope that their results encourage more work in this area. To really work well we need to team up the nitroglycerin with some reworked chemotherapy drugs that are specifically designed to work with the EPR effect.

Gina Pantziarka 1964 - 1994

Everyone has a cancer story. Mine started in the summer of 1994. My wife, Gina, had given birth to our second child – George – a year previously and had been suffering a bit from the blues. She’d been feeling tired, low, generally out of sorts. It was hard to pin down any particular thing that was wrong, she just felt exhausted all the time and there were these odd symptoms that seemed to come and go. For example her menstrual cycle seemed to be out of whack, or at least there were a couple of times when there were unexpected bleeds mid-cycle. Was that the sort of thing that happened after giving birth, didn’t it just take time for things to settle down again? In any event a couple of visits to the GP didn’t suggest anything other than a mild bout of post-natal depression. In the summer we were due to go on holiday to Cyprus, it was where she was born and we always holidayed there so that she could get to see her parents and her sister.

Normally she really looked forward to going on holiday, but this time she was just feeling worn down. Something wasn’t right, but she was only 29 years old and had no history of illness. She’d put on a fair bit of weight in the previous few years but other than that there was nothing to cause concern. A week before we were due to leave I suggested she go back to the GP and explain what was going on. The doctor seemed to be a bit perplexed and hesitant and suggested that some investigations might be in order. It was all a bit tentative. How urgent should these investigations be? Gina wasn’t really sure how concerned the doctor was, so I called the GP to ask the question directly: did we need to postpone our holiday? And the answer was clear enough, there was no reason not to go on holiday.

We spent two or three weeks in Cyprus. Gina’s parents were over-joyed at their new grandson and thoroughly besotted with their grand-daughter, now seven. It was a tiring holiday in many respects. We did a grand tour of family on both sides and for a while Gina seemed back to her old self – always smiling, chatting and enjoying company. Towards the end the tiredness was edging forward again, not that she complained much, though she did let on to one of her cousins that it had been a bad year so far and she couldn’t wait for it to finish and a better year to start.

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.

The Case of Dr Henry Mannings

It was back in December 2012 that I first wrote about the case of Dr Henry Mannings, the founder of Star Throwers, a charity in Norfolk that helps late stage cancer patients with nowhere else to go. Let me state at the outset that I am a Trustee of Star Throwers and proud to be one. Henry Mannings treated my son George when we had no place else to go. In the many years of treatment that my poor son endured before his death, we met few doctors as dedicated, concerned and open minded as Henry Mannings. George was the first patient that Henry treated with Coley’s Toxins, but by then the disease was so advanced that nothing could stop it – but George, and the rest of the family, appreciated the care and advice from Henry, and the hope that the treatment gave us when there was no place else to turn. And, let me add, Henry made no promises, he did not give us false hope and everything he said or recommended he backed up with evidence and reasoning. In the years since George’s death I have come to know Henry Mannings well and I know that the trust he inspired in us he continues to inspire in the many patients who come to Star Throwers.

However, his popularity with his patients, and his open-minded approach to oncology, makes him unpopular with some of the powers that be. And so in late 2012 a complaint was made by a senior oncologist in Norwich to the General Medical Council. The complaint alleged that Dr Mannings was prescribing chemotherapy drugs in an unsafe manner that put patients at risk, with specific mention of two cases. In neither case was the complaint made by the patient or the patient’s family. In fact the complaint was made without first asking the people concerned whether they had any complaints to make against Dr Mannings.

Based on these complaints the GMC instituted proceedings against Dr Mannings, and initially took the step of taking away his power to prescribe treatment at Star Throwers. This meant that patients who were being actively treated had to stop treatment, even if these treatments were successfully keeping cancer at bay. In response there was an outpouring of support from patients and patient families, from other clinicians familiar with Dr Mannings and his work and from experts in the field who could see no wrong in the work that he was doing or the scientific rationale behind it. He wasn’t offering miracle cures or ripping patients off or acting in any way unethically. The restriction on prescribing was removed in January 2013 but in many senses the damage had been done - doubt had been cast on Dr Mannings competence and the work he did to fund himself while working for free at Star Throwers dried up. More than that, it put him under great personal strain and incredible levels of stress that no amount of public support from patients and friends could quite counteract.

Organic Food and Cancer Risk

There is a theory popular in certain alternative and complementary medicine circles that cancer is caused by environmental toxins, radiation, microwaves, mobile phones and just about every modern convenience in the household. While there's little evidence for any of this, the idea that there are 'chemicals' lurking in the environment has become common-place, particularly when it comes to food. Hence one of the most common questions from newly diagnosed cancer patients: should I switch to an organic diet? There are enough people out there pushing the idea that 'organic' food is healthier than conventionally grown food, so it should be no surprise that people naturally feel that food grown 'without chemicals' will help them in the fight against cancer. After all conventional crops depend on 'chemicals' and organic food doesn't. And we all know that chemicals, in this case mainly pesticides, are bad for you. Therefore organic food should be healthier, and the strong growth in organic food sales in the last ten or fifteen years shows how popular opinion has accepted this assertion. 

However, the results of a new UK study that looked at cancer risk and the consumption of organic food seems to suggest that popular opinion is pretty much wrong in this case (http://www.nature.com/bjc/journal/v110/n9/full/bjc2014148a.html). While organic food and alternative medicine advocates have pushed organics as a way of reducing cancer risk, the study shows that it makes little difference one way or another. The study in question appears in the British Journal of Cancer and is by Oxford University cancer epidemiologist Dr Kathryn Bradbury and co-workers. Part of the Million Women Study funded by Cancer Research UK and the Medical Research Council, this particular bit of research tracked 623 080 middle-aged British women for almost ten years and looked at their pattern of organic food consumption and the incidence of sixteen different cancer types, as well as overall cancer incidence.

Based on their reported eating habits the women were put into three groups: never, sometimes, or usually/always eating organic food. The headline result showed that eating organic was not associated with overall cancer incidence one way or another (in fact there was a tiny increased overall risk of about 3%, but it’s the sort of noisy result one can ignore). The results for the different types of cancer are mixed, with some showing increased or decreased risks, but no overall pattern or anything too dramatic. These results, in contrast to the myths of wholesome organic, have upset some people, especially the British Soil Association, the guardian of all things organic in the UK (including being the premier organic certification body in the country). 

Guest Post - Genetic Alliance UK: The My Condition, My DNA Project

 My Condition, My DNA

Would you be willing to take part in a research study to help us understand what patients affected by genetic conditions and their families think about the use of genomic sequencing in the NHS?

When the first person had their entire DNA sequenced as part of the Human Genome Project back in the 1990s, it took over 12 years. Today it is possible to have your entire genome sequenced in just a matter of weeks. A new technique has been developed which means it is faster and cheaper to do this, and as a result has the potential to dramatically change the way that conditions may be diagnosed and treated.

The aim of this research is to find out what patients and families think about genomic sequencing. This will involve exploring the ethical, societal and practical issues raised by the NHS using genomic sequencing to collect large amounts of an individual’s genetic information with the view to improving healthcare. As the ease of genomic sequencing and its potential uses becomes greater, people working in the NHS and other healthcare providers will be thinking about these issues and making decisions. By being a part of this research, you can help to bring the perspective of patients into the decision making process and form a key part of shaping how genomic sequencing could be used in UK healthcare to benefit patients.

What is the purpose of this project?

To help patients and their families understand what genomic sequencing is and how it might be used in a healthcare setting; and to understand from them their opinion of the ethical, societal and practical issues raised by using genomic sequencing in the NHS.

Who can take part?

If you or a member of you family has a diagnosed or suspected genetic condition we would like to hear from you. We are particularly interested in having families take part. This may include children under the age of 18, although an individual under 18 cannot take part without a parent or guardian.