Monday, 23 December 2013

Opiates, Surgery and Prostate Cancer

My son, George, showed no fear when it came to the surgical treatment of his osteosarcoma. He had multiple major operations, some lasting more than 12  hours, in which his bones were moved from one place to the next, tissues cut out from one place and refashioned and repurposed elsewhere. With a tumour in his jaw, the surgeons at St George's Hospital in London worked absolute miracles. And, in the end, it wasn't the tumour in the jaw that killed him, but the metastatic spread to the pelvis and elsewhere. To this day I am astounded at the courage my son showed in facing those long, complex operations, but he had every confidence in Nick Hyde and the maxillofacial team at St Georges. And for George the thing that made it bearable was that there was something definitive about surgery - it lead to the physical removal of the tumour assuming that the margins were clear. In this he was not alone, many cancer patients would rather opt for a surgical option rather than rounds of toxic chemotherapy or being blasted with radiotherapy.

However, it is becoming increasingly clear that surgery itself could well be contributing to the metastatic spread of disease, no matter how good the surgeon or how clear the margins are. It is not the surgery itself that seems to be at issue, but the use of opiate-based pain relief (morphine, fentanyl and so on). It's a topic that I have covered a number of times on this site already:

The culprit is the mu-Opioid Receptor (MOR) pathway that is the main target of the opiate-based pain-killers and which cause increased levels of tumour growth and metastases. We know this from epidemiological studies (looking at what happened to cancer patients after surgery based on what pain relief they had), from studies in animals and from studies in the test tube. The effect is likely due to a number of factors, including the fact that the opiates increase angiogenesis, cause immune suppression and activate a number of pro-cancer pathways.

Another epidemiological study has just been published which looks at the rate of disease progression and overall mortality in prostate cancer patients who have had a radical prostatectomy. The study, 'Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study' has been published in the British Journal of Anaesthesia. The authors used a large sample of patients, matched for age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease and type of anaesthesia - those treated with neuraxial anaesthesia (which has lower use of opiates) and general anaesthesia (using the 'normal' amount of opiate-based pain relief).

The results are clear and in line with the previous studies I have written about. Increased use of opiates is associated with increased risk of disease progression and higher overall mortality.

The question we need to be asking ourselves now is not whether opiates in surgery are risky for cancer patients, the evidence is there in plain sight. The question we need to be asking now is how can we ensure that clinical practice changes and changes soon? One step in the right direction is the clinical trial being run by Dr Patrice Forget in breast cancer patients:

But at the same time, if I was a cancer patient about to have surgery I know that I would be wanting to speak to my surgical team and pointing them in the direction of these various results. At the very least I would be wanting to explore the use of methylnaltrexone if there is no option but opiate-based pain relief.

Tuesday, 29 October 2013

Osteosarcoma - A Small Step Forward?

In the past I have written about Dr Stefano Fais in Italy and his work on the use of anti-acid drugs in relation to cancer, for example here and here.In particular his work using proton pump inhibitors (PPI), some of them over-the-counter drugs, to change the tumour micro-environment shows huge potential for therapeutic benefit to patients. One example of this was work done using lansoprazole and standard chemotherapy to treat pets afflicted with cancer, to quote from my previous article:
...this study uses a cheap and readily available drug that is widely used, thus short circuiting many years of safety testing. It is part of a welcome trend in using existing drugs for tackling cancer and cancer-related conditions – other notable examples include the anti-diabetic drug metformin, beta blockers, celecoxib and aspirin. Finally, as with many of the other off-label drugs listed, the target here isn't cancer cells directly, but the tumour microenvironment.  Without a supportive microenvironment, cancer cannot thrive and prosper, which is exactly what we want. In this case, by attacking the microenvironment it means that existing chemotherapy drugs can work more effectively and kill the cancer cells. The hope now is that these results can be replicated in a wide range of human cancers, making them susceptible again to the chemotherapy that all too often stops working.
In a new paper Dr Fais and colleagues report a small clinical trial that combined a PPI drug with the standard treatment for osteosarcoma (the bone cancer that killed my son, George). Now the standard treatment for osteosarcoma is multi-drug chemotherapy followed by surgical resection of the bone tumour. A key prognostic marker for this treatment is to look at the degree of cancer cell death in the tumour after it has been removed. A good response is normally when there is greater than 90% tumour necrosis, less than 90% is counted as a poor response to the chemotherapy. So, for this trial Dr Fais and colleagues added pre-treatment with the anti-acid drug Esomeprazole to the standard four drug chemotherapy treatment for osteosarcoma.

The results show that there was a higher rate of good responses in patients taking the esomeprazole prior to chemotherapy compared to historical controls. In the case of the chondroblastic subtype of osteosarcoma the difference in the number of good responders is truly striking. Overall though across all types of osteosarcomas the difference was 47% good responders in the control group versus 57% in the PPI group.

This was a small study, not randomised (due to the fact that osteosarcoma is a relatively rare cancer), and it was looking at response to chemotherapy and not overall survival, but with those caveats this is an important step forward. It adds significantly to the evidence that adding PPI to existing treatments can have positive effects. And, in terms of osteosarcoma, it shows that there is something that can be done to incrementally improve treatments for a disease that remains stubbornly hard to treat.

Monday, 14 October 2013

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.

Monday, 7 October 2013

Campaign For Earlier Bone Cancer Diagnosis

I have written before about the poor record we have in the UK regarding osteosarcoma, the disease that ultimately killed my son George. It  is a scandal that survival rates have not improved for more than 25 years in this country, and that the figures are lower than for comparable countries in Europe and North America, (see for example my article on dismal bone cancer statistics). Figures from Cancer Research UK suggest that survival for many common cancers has doubled in the last 40 years, but there has been no change in the 54% overall survival rates for bone cancers (osteosarcoma and Ewings sarcoma) in 25 years. I don't know about you, but I find that shocking.

In a bid to address this the Bone Cancer Research Trust, in alliance with the Royal College of GPs, has launched a new e-learning module to help doctors recognise and diagnose bone cancers earlier. The idea being that earlier disgnosis will lead to better outcomes as there is less disease and lower risk of metastates at diagnosis. I know from our own experience with George that it took many weeks of visits to a number of oncology departments before even the experts were able to diagnose osteosarcoma of the jaw. Admittedly this is a rare cancer, but too many doctors were not alerted to the possibility that a numbness of the lips is a warning of cancer in the jaw. Bone cancers are more common in the long bones of the arms and legs, but we know from other parents that we met that even in the more common cases there were long delays in their children being diagnosed.

While we should welcome the campaign to get earlier diagnosis and improve the recognition of the key symptoms, we also need to make sure we do more to research on new treatments. As with many cancers, it is often metastatic disease that kills, not the primary tumour. So it's with some interest that we note that one of the cancers that has a bimodal pattern of recurrence is osteosarcoma. As with breast cancer, there is a spike of metastases/recurrence in the first couple of years after surgical treatment. This is the trigger for the work of Dr Patrice Forget, who has found that treatment with the anti-inflammatory pain-killer ketorolac at the time of surgery massively reduces the rate of recurrence in breast cancer patients. Perhaps it's time we looked at osteosarcoma in the same way. Can the pattern of metastases/recurrence be massively reduced by the use of ketorolac (or other similar drugs) before and during surgery?

Wednesday, 25 September 2013

Q & A With Dr Patrice Forget: Ketorolac and Breast Cancer

In the previous article on this site I wrote about recent work that showed that the use of a cheap, safe and generally available anti-inflammatory pain killer (ketorolac) had the potential to massively reduce the incidence of cancer relapse following surgery. This extraordinary result was discovered by a Belgian anaesthesiologist Dr Patric Forget and colleagues. Now working on a clinical trial to put this finding under test, Dr Forget kindly agreed to respond to a short interview to give us more of background to his research.

PP: What prompted your initial investigations - did you expect to find the results that you found?

PF: The diverse long term effects of anaesthetic techniques and analgesic medications have been suspected for many years. Discrepancies exist about the effect on outcome in humans. Concerning opioids, many data exist, but results are inconsistent. Concerning NSAIDs, animal data are consistent, but no human data are available. Therefore, we investigated it in the prospective patients listing existing in our Cancer Centre. Nevertheless, the magnitude and the repetition of the NSAIDs data were relatively unexpected.

PP: What are the clinical factors that influence the choice of ketorolac versus other medications?

PF: The anaesthesiologists have to make choices for which there are not always evidence-based guidelines. This is the case with single NSAIDs dose in the perioperative period. The usefulness of this single dose in terms of analgesia improvement is still matter of debate. The American Society of Anesthesiology has no definitive recommendations about it. Consequently, in many centres, including ours, some anaesthesiologists use it systematically, and others not.

PP: Your findings suggest that other interventions - such as taking a surgical biopsy - could also have a negative influence on cancer outcomes. What is your view on this?

PF: Inflammatory pathways are implicated in the development of cancer. It is probable that the degree of tissue injury during surgery is associated with cancer outcome. Nevertheless, whether  this effect is mediated by an influence on tumours cells, tumours cells spreading and/or immune suppression is not clear. In all cases, many arguments exist to limit as far as possible the extent of tissue attrition and surgical procedures in cancer patients.

PP: Although the emphasis of your work is on breast cancer, there is evidence that a similar bimodal pattern of relapse occurs in other cancers. Do you think that peri-operative ketorolac can have a similar reduction in relapse in these cancers?

PF: Yes. We have done the same observation in non-small cell lung cancer (NSCLC) (Forget et al, Ann Surg Oncol 2013). In NSCLC, the bimodal pattern of relapse was shown by Demicheli et al. Out data shows that the NSAIDs effect is also present. In contrast, in prostate cancer, no NSAIDs effect was observed (Forget et al, Eur J Anaesthesiol 2011). Concommitantly, no bimodal patter of relapse was shown, in my knowledge, arguing for a different pre-, intra- and/or postoperative cancer pathophysiology.

Wednesday, 18 September 2013

Ketorolac and Breast Cancer

Most cancer papers, even the ones with really interesting and important results, are not exactly an easy read. Aside from the technical content, they’re written in a deliberately dry and unemotional style that suggests objectivity and cautiousness. Which is why the paper ‘Promising development from translational or perhaps anti-translational research in breast cancer’, published in the journal Clinical and Translational Medicine stands out from the crowd. It’s an open access paper available here: If you only ever read one cancer paper make it this one. It’s written a highly accessible style, raises key questions and contains a result that, if confirmed, could reduce breast cancer mortality by 25% - 50%. That would be a massive step forward, truly massive.

And what is this finding that holds the promise of reducing breast cancer deaths by such a massive amount? It’s not a new drug, not a new form of therapy not even a new type of treatment. It’s simple, cheap and easily available and, best of all, easy to slot into place in existing treatment protocols. The starting point for all of this is the observation that the pattern for cancer recurrence following mastectomy occurs in two waves (it’s bimodal in stats jargon). The first wave happen in the immediate period (the first four years), and then there is a second peak of relapses that happens much later, around six years and stretching out to 10 – 15 years. This pattern of relapse has been confirmed in numerous countries and studies now, and seems to also be common in some other cancers, including prostate, lung, and pancreatic cancer, as well as osteosarcoma and melanoma.

This pattern of relapse could not easily be explained by existing theories of cancer growth. In fact, it was a down-right inconvenient finding with huge and controversial implications. Chief among these was that it suggested that surgery to remove the primary tumour was often triggering spurts of metastatic disease. To quote from the paper directly: Between 50% and 80% of relapses result from surgery initiated growth. That is a truly shocking result. It means that many breast cancer deaths are caused by the surgery meant to remove the initial small tumours.

Wednesday, 11 September 2013

Aspirin To Treat Liver Tumours?

There were a number of really interesting papers that popped up over the summer, and I'll be blogging about them in the next few days. For today though I'll focus on an open-access paper in the World Journal of Hepatology (and in case you're wondering, hepatology is the branch of medicine focused on the liver, pancreas and gall bladder). The paper is entitled 'In vivo assessment of intratumoral aspirin injection to treat hepatic tumors' and looks at what happens when you inject aspirin directly into liver tumours. Given the very high levels of interest in the anticancer properties of aspirin, taking it to the next level and injecting it directly rather than swallowing it seems such an obvious idea that it's a suprise that no one has tried this. But then it's often the case that it's the simple, obvious ideas that get over-looked.

And the results? Stunning, to be honest. The experiment took place in rabbits implanted with liver tumours and then injected with a solution of sodium bicarbonate and aspirin. Firstly there seemed to be no ill-effects - the rabbits showed no physical changes aside from changes in the tumours injected. And here the results were clear - the tumours collapsed and seven days after the treatment had disappeared completely, whereas in the control group the tumours continued to grow as expected. Furthermore, there was no evidence that the tumours started to recur or regrow.

Clearly this is a small study in rabbits and not humans, but the result is really striking and it cries out for follow up research. Given the low toxicity of aspirin, the obvious follow-up is for a small human trial. If the results are as fast and as positive we should know very quickly whether this is a viable treatment option to explore further.

Unfortunately I've not been able to contact the researchers (in Brazil), but hopefully this isn't destined to be one of those interesting results that sits languishing on the shelves and goes no where.

Thursday, 8 August 2013

Li Fraumeni Syndrome - A New Hypothesis

In the last year or so I have been working on developing some new ideas on cancer development in Li Fraumeni Syndrome. The results so far are a paper in a peer-reviewed oncology journal (Cancer Cell International), and a follow up article (aimed at clinicians rather than researchers) in Oncology News. Both of these are open access publications:

My paper is available here:

And the less technical version is here::

But this isn't the end of the story - I am continuing to develop these ideas and follow up on the clinical implications.

Tuesday, 16 July 2013

Omega 3s and cancer - confusing results

I had been planning on writing a follow up to the last article on omega 3s and chemotherapy with a piece on new research that looked at a protective effect of omega 3s on breast cancer. However, the big news of the moment is the result of a study that found that an increased risk of prostate cancer from omega 3s. So what gives? For those wanting to know whether to increase or decrease omega 3 intake, these conflicting results are just down-right confusing and a bit scary too.

Let’s deal with the prostate cancer results first. The paper in question is called ‘Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial’ and was published in the Journal of the National Cancer Institute (unfortunately not an open access publication). The abstract is available here: The authors looked at the relative percentages of different omega 3s fatty acids in blood samples from men with and without prostate cancer who had been enrolled in the Selenium and Vitamin E Cancer Prevention Trial. Men were ranked into four groups according to relative plasma omega 3 content and then the group with the lowest 25% were compared with the highest 25%. The results of this analysis showed that the men in the highest group had greater risk of prostate cancer than those in the lowest group. This was true for total omega 3 measurement as well as for individual omega 3s (e.g. DHA, DPA and EPA). On the face of it this looks like a pretty solid finding. But there are some puzzling things about this result. The first and the most obvious is that there’s no causal mechanism offered to explain a result that the authors themselves admit is puzzling and contrary to expectations. Omega 3s have many different effects in the body, for example they are strongly anti-inflammatory, but none of them known to be pro-carcinogenic or pro-tumour. Stranger still, the study found that some omega 6 fatty acids, which are known to be pro-inflammatory and often associated with being pro-cancerous, were associated with lower cancer incidence in this study.

Friday, 5 July 2013

Book Review: Mammography Screening: Truth, Lies and Controversy

Keywords: Cancer, screening, medicine, public policy, science
Title: Mammography Screening: Truth, Lies and Controversy
Author: Peter C. Gotzsche
Publisher: Radcliffe Publishing Ltd
ISBN: 978-1846195853
On the face of it the case for increased breast cancer screening is clear. Cancers caught sooner are easier to excise or to treat with chemotherapy. Earlier diagnosis means a lower likelihood of metastases, which are the real killers in cancers of all kinds. So who could argue against increased screening? Unfortunately this simple picture, seductive though it is, is just too simplistic and obscures a bitter controversy that has raged across the medical literature but which barely registers in public consciousness.

Peter Gøtzsche, a Danish medical researcher, Professor of Clinical Research Design and Analysis and the director of the Nordic Cochrane Centre, is a key player in the controversy and is highly sceptical of the value of breast screening in the general population. As an expert in clinical trial design and results analysis he came to the topic with no real experience of breast oncology, chemotherapy or surgery. But it was from this position of independence that he looked at the data from the studies that had been performed on breast screening and decided, based on the evidence that he and his colleagues uncovered, that far from being an unalloyed good, there were real and significant harms being perpetrated on women taking part in breast cancer screening programs.

As Gøtzsche outlines in considerable detail in this book, his findings were not greeted with open arms by breast screening advocates, the medical establishment and numerous well-placed political and academic figures. In fact the reaction was extremely hostile and remains so to this day, many years after his initial research findings. Gøtzsche and his colleagues were attacked from all sides for straying from the 'consensus' view that screening saved lives. His results, methods and motives were all attacked and continue to be attacked, though few seem to actually dispute the core of what he has found.

And what is it that makes Gøtzsche and a few others like him dispute the simple narrative that regular screening saves women's lives? The fly in the ointment is simple - over-diagnosis. If you go looking for cancer then cancer is what you'll find. Mammography screening will find all kinds of lumps and abnormalities. Some of these will become invasive and dangerous cancers, many will not. The difficulty is that at this stage we don't know which will melt away and which will turn into killers. Given that we can't tell the difference the only thing to do is to aggressively treat all the tumours that we find. And, let's be honest, this treatment is often brutal - mastectomy, radiotherapy and chemotherapy.

In analysing the data Gøtzsche focuses on overall all-cause mortality. And his key finding is truly shocking - while some women might be saved by early diagnosis and treatment, others will die from over-diagnosis and the results of over-treatment. In their latest advice, Gøtzsche and his co-workers state that:
Screening produces patients with breast cancer from among healthy women who would never have developed symptoms of breast cancer. Treatment of these healthy women increases their risk of dying, e.g. from heart disease and cancer.
This is not a trivial finding it's a scandal that ought to have anti-cancer activists up in arms. Unfortunately many activists are so wedded to the idea of mammography being the panacea that they campaign for increases in screening rather than wanting to subject the programs in place to the critical scrutiny they deserve.

For those of us familiar with that other science war - climate-change - some of what Gøtzsche describes will be eerily similar: well-entrenched 'consensus' science subjecting sceptical voices to attack, subversion of peer review, ad hominen attacks, endless dissimulation and the knocking down of strawman arguments that sceptics do not make. The parallels between this and what goes on in 'climate science' are strong, obvious and depressing. Even more depressing is the fact that Gøtzsche himself seems to have fallen for the party line when it comes to climate change, not realising that scientists sceptical of the 'consensus' view of man made climate disaster are also subject to subverted peer review, ad hominen attack, accusations of working for commercial interests etc. Where he is accused of killing patients, anthropogenic global warming sceptics are accused of wanting to kill the planet.

Gøtzsche describes in great detail the many controversies and arguments that have ensued since going public with his results. There is a degree of repetition throughout the book, but at its core is a simple story based not on complex statistical analysis or mathematical modelling but on the raw data of what happens to women taking part in screening programs.

Where he comes back again and again to the inevitable fact of over-diagnosis, the advocates of screening focus on the fact that earlier diagnosis leads to improved outcomes for the women diagnosed. Both these things are true. But in terms of women in general, it means that large numbers of women are being turned into cancer patients unnecessarily, and that some of these will die because of the treatment they receive.

This isn't to say that screening is a bad idea per se. For women with genetic predisposition, with family histories of breast cancer or who are in other high risk groups then screening make sense. However, for the vast majority of women who are not at high risk, especially younger women, screening does not make sense and will lead to harm to a number of them. In fact Gøtzsche and the Nordic Cochrane group have published a leaflet for women, setting out the benefits and risks of screening, leaving it to women to make up their own minds based on a clear exposition of the data. It can be downloaded here:

And, despite the accusations of his opponents, Gøtzsche is not alone. For example, Michael Baum, who worked for 30 years as a surgeon specialising in breast cancer, and is now professor emeritus of surgery at University College London, recently stated:
If we stopped screening today, the incidence of breast cancer would fall at a stroke by about 25 per cent.
In the end Gøtzsche's book is like the cancer version of Andrew Montford's 'The Hockey Stick Illusion'. Both books look at contentious areas of science. Both books cut through often obscure statistical arguments to get to the core of the issue. And both books describe a situation where you have tightly knit and entrenched groups of scientists with institutional backing, political support and significant funding doing their level best to lock out those who refuse to bow down to a 'consensus' that is not grounded in solid science.
Or as Gøtzsche puts it:
The screening literature has been polluted to an extraordinary degree by statistical modelling of raw data, often combined with wishful thinking and the use of favourable, but unrealistic assumptions for variables that cannot be measured. This has helped conceal inconvenient facts and has yielded results people wanted to see.
To conclude, this is essential reading for everyone interested in science, medicine and public health policy. Most of all it is essential reading for women being emotionally blackmailed into taking part in screening programs without being given all the facts.

Wednesday, 26 June 2013

Omega 3 Fish Oils and Chemotherapy

While chemotherapy remains the mainstay of treatment for most types of cancer, there will be a need to improve what’s called the ‘therapeutic index’. Simply put this is a measure of the good a drug does versus the bad. Chemotherapy causes all kinds of toxic side effects while killing cancer cells, and generally it could kill more if given at a higher dose, but to do so ends up causes a lot more damage. One way of improving chemo is through the use of new generation drugs that target tumour cells rather than the indiscriminate slaughter of the older drugs.

Another way to do this is to find ways of protecting normal cells in some way and/or making cancer cells more susceptible to the effect of the existing chemo drugs. Can this be done safely? According to some researchers the answer is a qualified yes. And the magic drugs that can spare normal cells but make cancer cells more susceptible to chemo are…omega 3 fish oils. There is mounting evidence that omega 3 fish oils, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can indeed work in this way.

A new paper ‘Selective sensitization of tumours to chemotherapy by marine derived lipids: A review’, published in the journal Cancer Treatment Reviews (abstract here:, goes over the evidence from cell cultures, animal experiments and clinical trials. And there is a lot of evidence to go over. The authors summarise it quite nicely, showing that the positive effect is there across many tumour types (including breast, prostate, colon, lung, lymphomas and more), and across chemo types (nearly all of the main classes of chemotherapy drug are listed).

One very encouraging aspect of this story is the number of active clinical trials looking at this now. The pre-clinical results and first analyses from those human trials that have taken place have all been positive. And when you factor in the other positive effects of EPA and DHA, such as helping to cope with stress (, or a reduction in side effects (, then it really does begin to seem as though high dose omega 3s should be the one supplement that every cancer patient takes.

Tuesday, 11 June 2013

Cancer research - Surrey University

Interesting news on cancer research can come from all sorts of unexpected sources (and I don't mean the daily press or the BBC...). One recent example comes from 'Forever Surrey', the magazine for alumni and supporters of Surrey University (where I did my PhD in computer science). The latest issue carries a few interesting snippets on cancer research at the university.

First up is news of a new urine test for prostate cancer. Current testing for the test is geared around Prostate-Specific Antigen (PSA), which is produced by all prostate cancer cells, not just cancerous ones. This means a high PSA value may not necessarily be connected to cancer but be caused by other conditions. It's better than no test at all, but it's not ideal. It also makes it hard to distinguish between slow-growing prostate cancers that can be safely let alone or monitored over time, and those that are fast-growing, aggressive and have to be treated immediately. Professor Hardev Pandha, a professor at the university and a consultant oncologist at the Royal Surrey County Hospital, and his team have come up with a new test that is much more cancer-specific.

Targeting a protein called Engrailed-2 (EN2), which is produced by prostate cancer cells and present in urine, they have developed a test that is much more specific, faster and easier to use. For starters this is a urine test rather than a blood test (which is what the PSA test is), and the researchers are working on a version of the test that can be done using a dipstick (like a pregnancy testing kit). A more faster and more accurate test that can really pin-point cancer rather than just generic prostate problems would be a great step forward.

But it's not just a new and improved biomarker test that's being developed at Surrey. The same research team are also working on a new treatment for prostate cancer. Dr Richard Morgan, one of Professor Pandha's team, has been working on a drug that targets a protein called HXR9 which is only active in cancer cells. By being able to switch off this protein with a new drug it can safely treat prostate cancer - without the damaging side-effects of existing treatments.

Interestingly, the same drug seems to have activity in a range of other cancers, including ovarian, breast and melanoma. This is definitely one to keep an eye on in the future...

Wednesday, 24 April 2013

George - Second Anniversary

One of the many doctors who treated George described him as a miracle child. And it was true. He had survived a rhabdomyosarcoma diagnosed at two and which was aggressively treated for about a year, followed by a few months in remission. When the disease recurred it was treated hard again but the last scan showed there was still evidence of disease. With no options left on the table we were sent home to prepare for the worst. George was just four years old. We refused to accept the news, and he was just a kid who wanted to play. And play he did, for the next eleven years. He really was a miracle child. But when he was fifteen he was diagnosed first with a basal cell carcinoma and then, a little later, with osteosarcoma. For us the miracle ended two years ago, when the osteosarcoma finally defeated our wonderful, lovely child, after the hard years of battle.

On this second anniversary it’s time to take stock of where we are with the Trust formed in his name. One of the things we wanted to focus when we started was on encouraging more research in Li Fraumeni Syndrome. We never imagined that we would be responsible for some of that research, but that is precisely what has happened. Over the last year I have developed a new theory about cancer initiation in LFS, one that is subtly different from the mainstream view. The first test of a new theory is to see if it can stand the peer review process and be published in a reputable peer-reviewed scientific journal. I am happy to report that the paper ‘Li Fraumeni Syndrome, cancer and senescence: a new hypothesis’ has been published in the journal ‘Cancer Cell International’. There will be more to say in the coming weeks and months about this paper, but for now it’s available for download at the journal’s website.

Friday, 12 April 2013

Ablation of bone tumours

For patients with advanced cancer bone tumours, (whether from primary bone cancers like osteosarcoma or metastases from other types of cancer, such as breast or prostate), can be a cause of persistent and hard to treat pain. A standard treatment in many such situations is radiotherapy, which can have unpleasant side-effects, and, in the case of Li Fraumeni Syndrome patients, might also have long-term implications regarding further cancers. Additionally, treating cancer pain with opiate-based pain-killers, such as morphine, can also be problematic given the evidence that opioids can cause further cancer progression (though this can be reversed with the use of naltrexone).

In which case there’s some encouraging news being reported at the 29th Annual Meeting of the American Academy of Pain Medicine. A group of French clinicians have reported on treating patients with tumour pain, including bone tumours, with micro-wave ablation (MWA).

One of the doctors, Adrian Kastler of the Centre Hospitalier Universitaire, in Besançon, France, is reported as saying:
"This technique may be applied to any patient suffering from bone tumour pain, mainly in patients suffering from bone metastases, refractory to conventional therapies. The main advantage of ablation techniques is the fast pain relief obtained - immediately after the procedure - as opposed to delayed pain relief obtained with radiation therapy… Our research showed that the use of MWA in bone and soft-tissue tumours is feasible and effective concerning pain palliation. However, MWA needs to be studied in order to apply the same procedure in a curative intention." 
The last point is certainly one that needs urgent attention. Bone tumours are notoriously hard to treat, so any new treatment that shows signs of being effective needs to be researched as a matter of priority. And, given that primary bone cancers are often unresponsive to chemotherapy, any physical treatments that can be used alongside surgery are urgently needed.

Thursday, 21 March 2013

Milk, cancer and hype

The headlines were striking enough, for example the Daily Mail declared that 'Breast cancer patients who eat cheese, yogurts or ice cream could HALVE their chances of survival', while the Daily Mirror ran the headline 'High-fat dairy food increases risk of death in breast cancer patients'. The question is are these scary headlines warranted?

The source of the headlines is a study that looked at dairy intake in women after they had been diagnosed with early-stage invasive breast cancer between 1997 and 2000. These women were asked to fill in questionnaires about their diet, and these were followed up five or six years later. The researchers then looked at the associations with dairy intake and outcomes. The reported outcome was that intake of high-fat dairy was associated with a great risk of death, both from cancer and other causes.

The first thing to say is that this paper is not open access. It's published in the Journal of the National Cancer Institute (JNCI), which is a tax-payer funded body, and it's outrageous that scientific research like this is kept away from the public. When there's a story as potentially important as this then there's no excuse for keeping the data behind a pay-wall. US tax-payers should be demanding that the JNCI switch to open access publishing immediately.

That said, and without access to the full paper, there are some comments to make on what's reported in the abstract of the paper. Firstly this is a study that depends on questionnaires. This is one of the most unreliable sources of information on long term diet that there is. It depends on people being able to accurately remember what they eat and drink, and that they're not lying to themselves or trying to impress the people running the survey. In a long time frame, it also means the researchers have to make assumptions about the long periods between questionnaires. Remember, the researchers are trying to establish the cumulative intake of dairy.

Tuesday, 12 March 2013

Itraconazole - Anti-fungal and anti-cancer

One of the common themes of this site is the use of existing drugs as anti-cancer agents. Given the many years and millions of dollars it takes to get new drugs from the lab and into early phase human trials, it makes a lot of sense to re-look at existing, approved drugs to see if they can be re-purposed as anti-cancer therapies. Prominent examples of such drugs include metformin (used in diabetes), aspirin (pain killer), beta blockers (used for treating hypertension) and mebendazole (used as an anti-parasitic agent).

The latest example is the anti-fungal drug Itraconazole. A Phase II trial has just been reported in a paper in the Oncologist - freely accessible to all here: The drug was used to treat advanced prostate cancer (metastatic castration-resistant prostate cancer to be exact). Two dosing schedules were used, low-dose (200 mg/day) or high-dose (600 mg/day), and the men were treated for 24 weeks and then assessed for a reduction in PSA and, more importantly, for progression free survival.

The low dose arm of the trial was abandoned early because of the low levels of response, however the higher dose arm continued to completion. The results were fairly impressive. The primary end-point of the study was stopping the increase in PSA levels, and this was acheived in 48% of men on the high dose (12 of 25 men). The main secondary end point was freedom from disease progression (which is the more important measure overall), and here the result was that 24-week PFS rate was estimated to be 61.6%.

Wednesday, 6 March 2013

The 2-Day Diet

It may seem odd to find a review of a diet book on a web site devoted to cancer, but there are good reasons for looking at this book. Firstly, it's an accepted fact that there is a strong link between obesity, metabolism and cancer. Secondly, there is an increasing view among some researchers that cancer is a metabolic syndrome, and that cancers are associated with a whole set of metabolic changes, both in the tumour and the surrounding tissues. Cancer and metabolism, and therefore diet, are inextricably linked. And, as discussed on this site in the past, there is evidence that altering diet can impact cancer treatments as in the work that looked at chemo response and fasting. There is another reason for looking at this book - the authors (Professor Tony Howell and Dr Michelle Harvie) are both working in breast cancer research, and are involved specifically in helping patients reduce their chances of getting the disease or reducing the risk of recurrence. One of the authors, Tony Howell, is well known to regular readers of this site for his work on the reverse Warburg effect and his association with Michael Lisanti and the development of new theories that link cancer with metabolism.

That said, this is primarily a book about diets and losing weight rather than a book specifically about cancer. Although the links to cancer are there in the text, and many of the patient stories include mention of cancer, the main aim is to help readers lose weight and keep it off. And, in doing so, to reap the overall health benefits across the board.

So, what is the 2-day Diet, and how does it differ from the thousands of other diet books on the market? A key point to make up front is that this is a diet that's been backed up by clinical data. There are no celebrity endorsements, no one selling expensive supplements or foods, no hand waving or bold claims unsupported by evidence. This is a diet that has been shown to work, it's that simple. Simple too is the basic idea behind the diet - it's simpler to stick to a strict diet for two days per week than it is for seven. And, importantly, the changes induced by a strict two day a week diet are significant enough to cause changes in body weight, glucose tolerance, mood and so on.

Wednesday, 27 February 2013

PDT Norfolk

The mainstays of cancer treatment remain chemotherapy, surgery and radiotherapy. These are the big three treatment modalities and have, largely, remained in place as the core weapons in the arsenal of oncologists despite the advent of a number of newer treatments. However, there is a class of treatments called ablative therapies that really need to become the fourth big weapon in the anti-cancer arsenal. Ablative therapies include photodynamic therapy (PDT), cryoablation, radio-frequency or microwave ablation and the new kid on the block, irreversible electroporation (which I have previously written about here).

Of these treatments, which all take the approach of directly and physically attacking tumours rather indirectly using drugs or radiation, it is PDT which is the most mature and most widely used. PDT works by injecting a light sensitive drug (called a photosensitiser) into a patient and then letting the drug accumulate in tumour cells – normal cells do not take up the drug to the same extent. Once the drug has been absorbed by the tumour light is applied to it – usually by a surgeon operating to gain access to the tumour and then shining a laser or LED directly on to the tumour. The photosensitive drug in the tumour cells reacts to the light and in the process kills the cell. In this way PDT can be used to destroy solid tumours directly.

While PDT is the most mature of the ablative treatments, it’s still not used widely enough in the UK, and even many oncologists remain unaware that it is available and that it’s a viable treatment option for their patients. This is a treatment that works, can be used against a wide variety of tumour types and does not produce the long-term side-effects of radiotherapy or chemotherapy. If ever there was a treatment that needed to become more widely known and available to more patients it’s this one. And, luckily, there are people around who are actively campaigning to raise awareness of PDT amongst the medical profession, amongst patients and the general public.

One such group is PDT Norfolk (take a visit to their site here: Recently I travelled up from London to meet with the team at PDT Norfolk to discuss some of the science, some strategy and ways that we could work together. It was a good meeting and I think some very positive ideas came out of it. I think this is a campaign that has the potential to advance research in PDT as well as to raise the profile of the treatment, provide resources for patients and help to bring this treatment to a wider range of patients.

Tuesday, 19 February 2013

Of Mice and Men

I’ve written about the state of cancer research on a number of occasions in the past, in particular focusing on the use of different models of cancer – for example here: and here: and here: So I hope it’s not getting repetitive to raise the subject again in the light of an important new paper in the Proceedings of the National Academy of Sciences (PNAS). The paper, Genomic responses in mouse models poorly mimic human inflammatory diseases is not about cancer as such, but it’s as important and relevant as any paper on cancer.

The opening line of the paper makes plain why these results are important:
A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials.

And it’s true enough in most areas of medicine, but none more so than in cancer research, where the mouse model is king. But the only problem is that mouse models don’t always match human disease profiles at all well. In the specific case that this paper outlines, it turns out that mouse models of massive inflammatory responses in critically ill patients are miles apart. To quote from the paper again:
The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed.

The reason for this divergence turns out to be because the relationship between genes changed in human patients bears little relationship to the genes expressed in the mouse models of the diseases – the relationship is pretty much random. However, for years scientists who have been studying these diseases have focused on drugs that work for mice and then these drugs have subsequently failed in humans. Not only has this cost millions, it also means that much research effort has been wasted in targeting genes that have nothing to do with human diseases. It also means that potentially useful drugs have been abandoned precisely because they failed to do anything in mice.
And it’s not just inflammatory diseases at stake – the same is true in cancer research. We can only speculate on how much money, effort and intellectual energy has been wasted on research that doesn’t apply to people. The reliance on test tubes and mouse models means that much time and effort has been for nothing.

Something needs to change.

Wednesday, 13 February 2013

LFS SIGNIFY Trial Looking for Volunteers

This just in from the people running the SIGNIFY trial for Li Fraumeni Syndrome:

We are conducting a small scale pilot study to investigate the use of whole body magnetic resonance imaging (MRI) in families with Li Fraumeni Syndrome.

We would like to enrol individuals in the trial who are between 18 and 60 years old and are known to have a genetic mutation (alteration) in the P53 gene as well as unrelated people who do not carry the gene mutation whose scan results can be used as controls.

All study participants will undergo a whole body MRI scan at the Royal Marsden Hospital, Sutton, Surrey.

If you are interested please contact SIGNIFY study coordinator Dr Emma Killick or another member of the SIGNIFY team at the Institute of Cancer Research on 0208 661 3375.

Tuesday, 29 January 2013

More On Stress and Cancer

A new open access research paper, 'Behavioural Stress Accelerates Prostate Cancer Development in Mice' (, adds more detail to the emerging picture of the relationship between stress and cancer. In this case the research team used mouse models to investigate the effect of stress on the development and progression of prostate cancer. And, as expected, those mice subjected to a stressful environment had greater incidence of cancer and higher rates of disease progression. And, just as importantly, some of the ill-effects of a stressful environment could be prevented through the use of drugs that interfere with the stress response to raised adrenalin and noradrenaline (i.e. like beta blockers).

From a science point of view this paper uncovers some of the molecular mechanisms at play here, which further advances our understanding of the relationship between psycho-social stresses, the resulting hormone stress response and the process of cancer initiation and progression.

However, it's the human angle that is of direct interest to me, (and to most readers of this article I would guess). What this new paper does is point out the horrible vicious circle that is at play here. As we know a cancer diagnosis is an incredibly frightening and stressful experience. It shakes your world up completely. The body responds to this stress by releasing adrenaline and other stress hormones. These can drive the cancer forward, causing even more stress as the disease progresses. It's not just the bad news. Cancer treatments are stressful too. Physically they are hard to take - there are side effects of drugs, radiotherapy and surgery. But there's also the stress induced by the whole process - the endless waiting, the delays, the uncertainty, the feeling of being disempowered.

Tuesday, 15 January 2013

Statement from Star Throwers

Dr Henry Mannings Restrictions Lifted After Review Hearing

Star Throwers are delighted to declare that all restrictions placed on Dr Henry Mannings imposed after an initial Interim Orders Panel (IOP) hearing on the 27th November 2012 have been revoked.

Back in November, an Interim Orders Panel imposed an order on Dr Mannings to restrict him from prescribing any medication.

At the IOP review hearing on Monday 14th January 2013, Dr Mannings, who represented himself, produced additional scientific evidence to the panel to prove the efficacy and safety of his approach in the cases of the two patients in question. He also reiterated the testimonials from eminent specialists which disagreed with and challenged the allegations made. Furthermore, the petition which has garnered approximately 3000 signatories so far was brought to the panel's attention, along with the hundreds of letters of support written from patients and families of patients.

In their conclusion, the Interim Orders Review Panel wrote: "The scientific papers to which the Panel has been referred indicate that the treatment which you gave was minimally toxic in the dosage you prescribed.

“In light of this additional information it does not consider that you present a risk to the public which makes it necessary to impose an interim order. It considers that an interim order could have a serious impact on you and the patients in your care and the risk posed does not justify these consequences.

“In all the circumstances, the Panel has determined that it is no longer necessary for the protection of members of the public, in the public interest or in your own interests for your registration to be subject to an order. The previous interim order is therefore revoked."

The hearing was held in public at the request of Dr Mannings in order to have full transparency, and was attended by members of the press and supporters of Dr Mannings.

Dr Mannings said after the hearing: "I am obviously very pleased with the common sense shown by the interim panel and their realisation of all the good work that is done at Star Throwers, based on all the evidence that was shown, including the petition and letters of support.

He continued: “We are exceptionally pleased that we will now be treating patients again, but can only hope that the time lost whereby they had not received any treatments will not have any long term consequences. "

The GMC will continue their investigations into the veracity of the allegations and a full hearing may still ensue. In the meantime, however, it is a very positive result for Dr Mannings and his patients.

Star Throwers manager Steven Ho said: “We are delighted at this common sense outcome as we can now go back to work giving the best service we possibly can to our patients and continue our important work looking after people affected by cancer.

“Once again, we would like to thank every single person who signed our petition, wrote a letter of support or helped to spread the word through their friends, families, and the media. We did it!”

Monday, 14 January 2013

Henry Mannings - Successful Appeal

It's with great pleasure that I can report that Dr Henry Manning's appeal to the GMC's Interim Orders Panel has been successful and that all restrictions have been lifted. This is great news as it means that Henry can pick up where he left off treating patients at Star Throwers.

While we all should all be pleased, I can't help but feel angry at the whole affair. Effectively treatment was interrupted for cancer patients with no other options. And, just as importantly it cast a cloud over Dr Mannings professional reputation - one that effected his ability to earn a living in the short term and which may have damaged his reputation permanently in the long term. And why? Because one other doctor took it upon himself to make a complaint that had no foundation. As anyone who reads the transcripts can see, this lone doctor pretended to speak on behalf of his colleagues when in fact he was speaking for no one but himself. Will there be any come back? I'm not holding my breath, but if this doctor had any integrity he'd make a public apology.

Thursday, 10 January 2013

More On Beta Blockers

Back in October 2011 I wrote about the increasing evidence that beta blockers – normally prescribed for high blood pressure – might have some significant anti-cancer effects. A recently published paper, this time looking at people treated with radiotherapy for non-small cell lung cancer (NSCLC), examined what effect taking beta blockers had. And, it has to be said that the results were very positive.

Specifically, those taking beta blockers had better distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), even after taking account of age, disease staging and previous treatments. This suggests that taking beta blockers is independently associated with better overall survival. Mostly the effect seems to be related to stopping metastatic spread of the disease, as there was little evidence that it had much effect on the primary tumour. However, it’s worth keeping in mind that very often it’s the metastases that ultimately kill rather than the primary tumour.

This was a retrospective study, which means the data for it came from previously treated patients, but it was reasonably large (722 patients, of whom 155 were taking beta blockers). So, while this is solid evidence it’s not the same as a randomised clinical trial. There are lots of questions still to be explored, for example does the effect of beta blockers depend on prior exposure (i.e. do you have to have been taken them for a long time before diagnosis), is the effect still there if beta blockers are started after diagnosis, and at what dosage?

The hope is that this additional study adds to the weight of evidence and that it helps make a really strong case for some controlled clinical trials.

The paper reporting the trial can be downloaded here.

Monday, 7 January 2013

Dr Mannings - Case Review

We start the year with some good news regarding Dr Henry Mannings. The General Medical Council's Interim Orders Panel has granted an early review of his case. A new panel will sit on Monday Jan 14th, and will decide whether to uphold, amend or revoke the restriction on Dr Mannings ability to prescribe medication. We hope, of course, that the restriction is completely lifted. And, in time, we hope that a full investigation will reveal the dishonest and political nature of the allegations against him. In the meantime the petition and other activities in support of Dr Mannings can only help his case.