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Porter
Coming up in today’s programme: Radiotherapy – it’s a crucial part of modern cancer treatment, so why does it get so little attention compared to other therapies like drugs? An injustice one of our listeners thinks Inside Health should address. So we do by visiting the department where she works.
Smoking – we all know it’s detrimental to health but new research highlights just how important it is for patients undergoing radiotherapy to kick their habit. Radiation and tobacco making particularly poor bedfellows.
And we’ve an update on the latest research into using daily low dose aspirin to protect against cancer – so called chemo-prevention.
But first, growing concerns about the widespread use of PPIs – the acid suppressing family of drugs that includes omeprazole and lansoprazole used to treat indigestion, and now among the most prescribed drugs in the world.
Since their introduction in the ‘80s the number of people taking a PPI in the UK has soared from around 1 in 500 in 1990, to over 1 in 10 today. And while NICE advises limiting courses of treatment to weeks in typical cases of heartburn, most people, myself included, take them for months or years. But at what cost to our health? Well, PPIs have now been linked to a number of problems – ranging from fragile bones to an early grave. Dr Margaret McCartney has been looking at the evidence.
McCartney
So I remember when these drugs were brought in and it was quite exciting at the time, they were very powerful drugs. And because they were very expensive they were mainly prescribed by specialists in hospitals and it took a few years before they were rolled out to people, like me, GPs prescribing them, but of course you don’t get something for nothing and lots of people have raised concerns about some side effects, quite rare side effects so uncommon that you only really pick up in a population, day to day most people put up with these tablets pretty well. So in 2003 there was concerns that people who were taking PPIs long term had a higher risk of a nasty gastric infection called clostridium and since then there was also another concern that people were at higher risk of another infection – pneumonia. In 2006 people started to notice that long term use of PPIs led to a higher risk of lower magnesium in the blood. And then there was a concern that this might lead to hip fractures, to the bones being thinner than you would expect. We’ve also had concern about a type of kidney disease and there’s now been at least two studies saying that there is an increase in mortality, death rates, when people are taking PPIs in the longer term. There’s also been a study that seems to have found an association between long term PPI taking and an increased risk of being diagnosed with dementia.
Porter
The one that’s going to catch people’s eye there obviously is that if you take a long term PPI you’re more likely to die earlier.
McCartney
Well yes, so this was a big study, an enormous cohort study, that was published earlier this year in BMJ Open, looking at a core of army and military service veterans who’d been taking PPIs for a long time. And the researchers found that for every 500 people taking these drugs for a year there was one extra death that they say would not have otherwise occurred. Now there’s big problems with this kind of study, I absolutely think it’s important that we should pay attention to it but what we don’t know is why people were being prescribed them. Were they being prescribed them because they were already ill with another disorder that was then going to cause their demise or were these tablets somehow leading to their death? That’s what we don’t know and we don’t have a study that tells us that we can reduce death rates if we take people off them or if we don’t prescribe them, that’s the problem.
Porter
Because is there a plausible mechanism to explain why there might be these associations? You can imagine with things like clostridium difficile – C. diff – that we’re affecting the acidity in the gut and that might have an impact on the bacteria that live there for instance. But people dying early, non-specifically, seems odd.
McCartney
Well the cause hasn’t been established, nobody really knows. One theory is that it may change the chemical balances in your body, particularly magnesium, which we need for our hearts and for our lungs and for our brains, so it could be something like that. But the bottom line is we just don’t know. And what’s really important to note is that these big cohort studies tell us there’s an association, it tells us there’s a link but it doesn’t tell us what is cause and what is effect.
Porter
Looking at your own practice, I presume like any other GP you’re prescribing an awful lot of these?
McCartney
Well we are, there’s absolutely no question about that and I do wonder if we’re prescribing more of them because they actually work quite well. So of course if you have gastric symptoms that’s caused by too much alcohol, being overweight, smoking, the motivation to perhaps change your lifestyle when you’ve got a drug that works so well perhaps isn’t there. And so they have become very popular drugs and of course the more popular they are the more widely they’re prescribed, the more you’re going to see relatively rare side effects becoming more common.
Porter
Margaret McCartney.
Dr Matthew Banks is Consultant Gastroenterologist at University College London Hospital NHS Trust.
Banks
If you have a look at the evidence we know that up to 70% of patients on PPIs don’t have a very clear indication. Not only that when patients come into hospital approximately 20% of them are taking PPIs when they arrive, when they’re there 40% are prescribed PPIs and when they leave 50% are on PPIs. But not only that if you have a look through the notes of those patients 90% of them haven’t got a clear indication.
Porter
And by a clear indication what you mean is some documented reason that you should be taking these drugs?
Banks
Absolutely, patients on ITU are often put on PPIs for no good reason.
Porter
Well there must be a reason.
Banks
Yes if they are very sick then they have a higher risk of developing ulcers and they are, for good reason, put on it but then they’re not reviewed when they come off ITU or discharged. So if a patient is put on a PPI for good reason, such as acid reflux, then they should be reviewed within four to eight weeks. And at that stage the treatment should be either discontinued or tapered off and then they should be re-reviewed.
Porter
But I know both from personal experience, I’ve been on these drugs on and off for eight years now for reflux, it’s about the only thing that seems to control my symptoms and I’ve got lots of patients who are just taking these drugs day in day out, there must be some people who need to continue taking these drugs. Are you happy? Do you think that’s safe?
Banks
Well the evidence for the risk of these drugs is not very clear and therefore the whole community, gastroenterologists, are a little bit worried about what they should be doing. By not clear there are risk associations and I just saw an article a few weeks ago about fizzy drinks reducing your life expectancy or making you older by five years and that may not have been because you’re on fizzy drinks, it may be because you never exercise or because you’re overweight, there are many other reasons. And that holds true with most of the studies that have been undertaken with PPIs. Yes there are lots of associations but we have no idea whether these are causative effects. So we don’t really know the dangers yet.
Porter
What about if I wanted to try coming off my PPI and have been on it for a long time, months or maybe even years? One of the problems you often hear discussed amongst doctors is that when you come off a PPI there’s some sort of rebound excess production of acid that makes your symptoms much, much worse and drives you back to the pills again. Is there any science behind that?
Banks
You’re describing patients who abruptly stop PPIs and then their perception is that their symptoms are far worse than they ever were and there is very little evidence for rebound and probably my belief is patients are experiencing symptoms as they had done before they went on to PPIs or they’ve picked up bad habits on PPIs, for example going to bed after a heavy meal or drinking too much alcohol, that they’re able to do when they’re on PPIs but not able to do before they started. And what I suggest with most patients is they slowly taper off the PPIs and get used to the feeling of some of their symptoms coming back and either to reduce the dose initially and then take alternate days for a week or so and then finally stop.
Porter
And what happens to these people if their symptoms do come back and affecting their quality of life on a day to day basic, presumably they’re going to have to go back on them aren’t they?
Banks
This is something that we need to discuss with the patients and we need to make it very clear there might be some long term side effects but as yet we don’t know. But there are alternatives, there are being careful with your diet, so food that’s fried or very high in oil or fat will increase the risk of acid reflux. There are certain irritants such as citrus, chillies and alcohol. Losing weight helps. And finally using Gaviscon relatively regularly or antacids, of which there are many on the market, probably all equally effective. So there are other alternatives.
Porter
If you’re looking after somebody who has significant reflux and you want them to be on a PPI long term are there any investigations, any monitoring, that we need to do to keep an eye on what’s going on?
Banks
So there are an increasing number of case reports with magnesium.
Porter
And this is an important salt which we can measure using a blood test.
Banks
It is but we do know there are very clear case reports of patients who had low magnesium on PPIs, having not had low magnesium before, stop the PPIs the magnesium returns to normal, restarted the PPIs and the magnesium dropped again. So I think there’s a causative effect there rather than an association. But it’s so rare you can’t justify monitoring everyone on PPIs, it would cost the earth and I don’t think it would be effective.
Porter
The other one that you often hear mentioned is Vitamin B12, that the reduction in acid somehow affects the absorption of that, is there any evidence for that?
Banks
There’s some evidence but again it’s conflicting. I’m not convinced with the body of evidence so far. And perhaps the only people you should possibly monitor are vegetarians or those who have low dietary intake of B12.
Porter
Who are going to be more at risk anyway.
Banks
Exactly.
Porter
Gastroenterologist Matthew Banks who has persuaded me to have another go at coming off my PPI.
But it’s not all bad news. One reason why PPIs are being prescribed so widely these days is that they are increasingly being used to protect the lining of the gut from other drugs. Drugs like aspirin. And combining a PPI with aspirin may have other benefits too.
A 10 year UK study – the ASPECT trial – is investigating whether the combination can reduce the long term risk of cancer of the oesophagus in people with Barrett’s syndrome – a condition where changes in the lining of the lower oesophagus resulting from acid reflux, that’s acid splashing up from the stomach, can occasionally turn cancerous.
Professor Janusz Jankowski is ASPECT’s lead investigator.
Jankowski
The best way to think about aspirin is like a speed regulator in a high speed truck. It stops the speed of the cycling of the cells getting out of control. And aspirin is an important physiological molecule which dampens the signalling generally within the cell.
Porter
Using your truck metaphor, it’s careering down a road from normality towards cancer and aspirin is applying the brake – is that a fair analogy?
Jankowski
Yes that’s exactly right, it slows down the cells so that they all start working in synchrony. The important aspect of aspirin is that there’s already quite compelling data, which has already been approved by the United States preventative services taskforce to give limited approval for low dose aspirin cancer prevention in people with heightened risk of colorectal cancer. And that’s a common condition that has high risk of going to cancer. The condition we’re studying is actually Barrett’s Oesophagus which has mild to moderate risk of going to cancer – 97-98% of people with Barrett’s Oesophagus will never have oesophageal cancer. So it’s a much more useful condition because it’s more generalizable to the population and that’s why we’re hoping – in fact I think the whole community in chemo prevention is hoping if we can get clear results in the ASPECT trial it actually will help national guidelines and policy change about how we prescribe low dose aspirin for the general population.
Porter
Earlier in the series we talked about using aspirin alongside acid suppressing drugs to protect the lining of the stomach against the side effects of aspirin, which can include quite significant bleeds, but that’s not why you’re using this combination together in the case of Barrett’s?
Jankowski
Partly true. The most important reason we’re using it is because the problem with oesophageal reflux is it’s abnormal acid coming up the oesophagus and causing the damage. So the premise of this study is actually to switch off the causative factor in the first place, which is the acid reflux disease and then actually deal with the aspirin as chemo prevention to actually slow down the process once it’s developed. But there is actually a good synergy between the two agents there where the Proton Pump Inhibitors also prevent the incidence of aspirin complications in the upper GI tract.
Porter
Because if aspirin was to prove effective in preventing cancer of the gullet in cases like this the downside would be at what price and the price is normally significant bleeds from the stomach, which can be fatal. But by prescribing with these anti-ulcer drugs, like omeprazole and lansoprazole and esomeprazole, have you actually negated that risk?
Jankowski
No not completely but we do decrease the risk by at least 50% and some of the studies say up to 85%.
Porter
Can you explain where you are at with your research now, when will we know?
Jankowski
The main findings of the ASPECT trial won’t be published until early or mid-next year but I can share some preliminary findings presented recently at the British Society of Gastroenterology. What we were able to show there is in a highly selected patients with Barrett’s Oesophagus when we followed up 100% of these patients at baseline who were randomised to aspirin we found out that 22% of these patients actually had the aspirin stopped in agreement with their local physician, simply because of increasing potential complications – peptic ulcer disease, gastrointestinal bleed, vomiting, nausea and in one or two cases haemorrhagic strokes.
Porter
I mean that’s a high proportion.
Jankowski
Oh absolutely. In the vast majority of these individuals, in fact the complications were mild to moderate, so stopping the aspirin they went back to relatively near normal life expectancy again. And in some of the individuals there was very serious complications indeed. In fact what was interesting from our preliminary results is that another 13% had other reasons for stopping aspirin, probably because they were tired of taking it, so this is only after five years you have to remember or maybe it was interfering with some of the other medications. So when you add that together after five years of taking aspirin 35% of our population were no longer on it and it’s a question of whether your glass is half full or half empty. Sixty five percent were still taking aspirin but we know to get the maximum benefits you need a minimum of five years, probably six years, and the average length for most of the case cohort studies shows that in fact probably 10 years is where you get your medium benefit from. So even if you do want to take aspirin most people run out of enthusiasm after a period of time. What we would like to do is trying to target who’s going to respond to aspirin better so we can actually give them therapies to actually maintain their enthusiasm.
Porter
Janusz Jankowski on using aspirin and PPIs to reduce the risk of cancer which, albeit exciting, has its fair share of problems too. And we will invite Janusz back when the final results of ASPECT are published next year. More details, as ever, on the Inside Health page of the Radio 4 website.
Now I’ve left the studio and I’m standing next to the fountain in the centre of Bart’s Hospital Square in London and I’ve come to see a Christine Usher. Christine emailed us, she’s the Head of Radiotherapy Physics here at the hospital, she emailed us after listening to our programme in the last series talking about thyroid cancer when the surgeon I interviewed made what she regarded as a throwaway comment that thyroid therapies were not like radiotherapy that cause lots of unpleasant side effects. She says that she can’t remember when we did a decent programme on radiotherapy, that’s because we’ve probably never done a programme on radiotherapy, and she says it’s about time we did and put that right. So we’ve come to Bart’s to meet Christine.
Usher
Hello Mark, welcome to our radiotherapy department. So this is one of our linear accelerators, so they’re high energy x-ray machines, they deliver x-rays a 1,000 more than a diagnostic x-ray would be that people might have a chest x-ray.
Porter
A 1,000 times more powerful. So to give us some idea of the scale – the machine itself has got to be nine or 10 foot tall. I mean it looks like a massive sewing machine, if you don’t mind me saying so, with the – the bit where the needle would come out was where the x-rays are coming through and the patient is slid in on a – well it looks like an operating table doesn’t it.
Usher
So the patient would like on the couch which moves under the beam of x-rays and then we can rotate the machine around the patient. That machine will rotate around a sphere of less than a millimetre in diameter. External beam radiotherapy is highly targeted. If you give somebody a pill, be it chemotherapy or radioiodine, it goes throughout the whole body. In 40% of the patients who are cured of cancer they have radiotherapy as part of their treatment.
Porter
Do you think people are aware of that?
Usher
No I don’t.
Porter
I get the impression – I mean we might have touched on a raw nerve and there’s a good reason for that and that’s because radiotherapy – people think of chemotherapy, new drugs, surgery of course when we’re talking about cancer but radiotherapy plays a key role.
Usher
It does but I think people are generally a bit cautious or afraid of radiation. It’s not had a good press for some quite good reasons. But the thing we need to understand about radiotherapy is it’s very controlled and it’s a high technology that model the way the radiation is delivered to the patient.
Conibear
So my name is John Conibear and I’m a Consultant Clinical Oncologist in Bart’s Hospital. There’s no doubt in my mind that pharmaceutical drugs takes a much more prominent view in the public gaze which is really unfortunate because we know that radiotherapy actually offers patients a curative option for cancer whereas the systemic treatments that we use, whether it’s chemotherapy or newer drugs that we term biological therapies, they really only help to control cancers rather than cure them. So I treat breast cancer and I treat lung cancer. Under certain circumstances the radiotherapy might be being used as a belt and braces approach to reduce the risk of cancer recurrence but also at the same time for certain patients we use the radiotherapy as their prime modality for curative treatment. A good example would be patients who I treat with lung cancer.
Goddard
My name’s Alex Goddard and I was diagnosed with stage four lung cancer getting on for two years ago. I’m a 45 year old woman who I’d considered myself to be in pretty good health until I presented at my GP’s surgery with worsening headaches over a four week period that led to admission to the Royal London Hospital, within a few days of that I knew that I’d got lung cancer which had metastasised to my brain. So I had four brain tumours and one tumour in my lung. I was having oral chemotherapy and it was very successful, ostensibly got rid of three of them which left one that was still of significant size and has proved to be in an ongoing sense rather stubborn. So I’ve had radiotherapy on two occasions here.
Porter
Describe to me what was actually involved in your radiotherapy.
Goddard
So three sessions, I think about an hour in duration, on consecutive days. You lie down in what I can only describe as the most 21st Century facility that you can possibly imagine, so something out of a science fiction film.
Porter
Because when you’re actually having the treatment you’re in the room on your own.
Goddard
It’s like nothing I’d ever experienced before.
Porter
Were you scared?
Goddard
I tried not to be but it’s difficult not to be because when somebody’s sort of pointing something, particularly at your head, it’s hard not to be a little bit scared.
Porter
Did you have any problems with side effects after the treatments?
Goddard
Really hardly anything. I was a bit tired. I took the bus home, as I always do from the hospital, I felt tired but then that could be just mental fatigue of going through the process. I was astonished really at how little side effects I was feeling.
Conibear
Tumours come in all shapes and sizes. Thirty, forty years ago my predecessors when they were doing radiotherapy planning they’d be armed with a ruler and a pen to draw a box round what they thought was the tumour on an x-ray. With the advent and introduction of CT into radiotherapy planning my role now as a modern clinical oncologist is to actually sit down in front of a computer and actually I can help to define my tumour target ever more precisely and we now have the radiation equipment which is able to conform the radiation dose around the borders of that target that I’ve defined.
Porter
What’s actually happening at a cellular level, I think most people understand that radiation’s not a good thing for us generally, so presumably it’s toxic to the tumour, but what’s it doing?
Conibear
Through the science of radiobiology over the last century and a half we’ve helped to better understand the processes that take place in the cell when it’s struck with exposure to radiation. And there’s two ways in which it works. One is it causes direct damage to the DNA contained within that cell. The second is that the radiation leads to the creation, if you like, of what we call free radicals, which are toxic little molecules that again damage the cell. We understand now that tumour cells don’t have the same reparability as normal cells, so that the cancer cells when we damage them with radiation because we treat these tumours every day the tumour never has an opportunity to fully repair itself, whereas our normal cells that the radiation passes through to reach that tumour they are able to repair. And so when the patient goes home at the end of their day of treatment and they go to bed and they have dinner and watch TV it’s their normal cells in their body that’s repairing that DNA damage where their cancer cells aren’t able to.
Porter
The sort of radiation you’re using – the rays, if we can call them that – are highly penetrative, that’s what makes them such a useful tool for you, you can get to things that are deep inside the body but it also means you can’t stop them – so they go through the tumour and they go into the tissue beyond – I’m thinking for the breast for instance – they’re going into the heart and the lung. What sort of collateral damage do you see with radiotherapy?
Conibear
Breast cancer again is a very good example. So if you’re curing a patient of cancer they have to live with the consequences of that treatment. And it became clear in the literature for patients who have had breast cancer and had radiotherapy for their breast cancer that over the course of their next 20, 30, 40 years of their lives that there was a much higher incidence of cardiovascular disease particularly in patients who’d had left breast cancers, because the heart is predominantly contained within the left side of the chest. What we’ve done to try and minimise that effect now is we’ve used the human anatomy to our advantage, so we now use something called deep inspiration breath hold, it became clear that women or men with breast cancer if they take a deep breath in, during the course of their treatment, their lungs increase in volume and it actually pushes their chest wall and their breast away from the heart so that you can effectively do heart sparing radiotherapy.
Porter
Dr John Conibear. But the heart is not the only organ that can be damaged. Carolyn Taylor is also an oncologist and a researcher at the University of Oxford.
Taylor
As I was talking to women in the clinic about radiotherapy I realised that we knew a lot about the benefits but we didn’t know that much about the long term risks. And so we did this study to assess what are the risks of breast cancer radiotherapy and we concentrated on the serious risks rather than the short term temporary risks.
Porter
And so short term temporary risks might be things like damage to the skin that makes the woman feel uncomfortable but you were looking for more sinister things that were going on. What sort of things were on your mind?
Taylor
Well we knew from other cancer types that radiotherapy can cause second cancers. So another cancer appearing many years later that was itself caused by the radiotherapy. And we give dose to the local area, usually the breast and the surrounding lymph nodes, when we do that some of the radiation dose is also received by the surrounding tissues, so tissues such as the heart, the lungs and the soft tissues and some of that radiation dose can cause side effects many years down the line. And so that’s why breast cancer radiotherapy increases the risk of lung cancer and heart disease.
Porter
So looking at a simple explanation you’re using focused x-rays on the breast tissue to kill, you hope, any cancer cells but as a result of collateral damage, spread if you like, there’s a sub-lethal dose of radiation to other tissues that may induce cancerous change?
Taylor
Yes and that’s why the lung is particularly affected in breast cancer because the lung is close to the breast but usually the benefits of radiotherapy far outweighs any risks of second cancers. But what we didn’t know was how to quantify the risk for one of my patients today, how do we translate that into a risk that is useful to me as an oncologist.
Porter
So what did you find?
Taylor
We found that for non-smokers the chance of getting a lung cancer because of the radiotherapy is tiny. So for non-smokers there’s no need to worry. But for smokers the risk is much bigger. And for some smokers the risk from radiotherapy may actually be bigger than the benefit. But interestingly we also showed that if a woman gives up smoking at the time of her radiotherapy then she can avoid much of that risk. So that’s a very practical helpful message for us in the clinic.
Porter
So you did find a significant risk in women who smoked, one that actually may negate the benefits of having radiotherapy for their breast cancer.
Taylor
Yes.
Porter
Can you give me some idea of the scale of the risk? If a woman was smoking during her radiotherapy and had been a smoker previously what were the odds of her getting a lung cancer as a result of her treatment?
Taylor
We need to think in terms of long term risks here because the risk of lung cancer caused by radiotherapy doesn’t start until at least 10 years later. So we looked at 30 year risks. So for a 50 year old woman having radiotherapy today we looked at her risk of getting a radiation induced lung cancer before she reached age 80. And for a long term smoker who doesn’t give up smoking, keeps smoking on into her old age, the risk of getting a lung cancer as a result of the radiotherapy was a few percent and that can actually be similar to the benefits. So for smokers who are being considered for breast cancer radiotherapy we recommend stopping smoking and we recommend that quite strongly now and we support women through that because it’s very difficult to give up smoking when you’ve just been diagnosed with breast cancer, it’s a difficult time anywhere and I think women need support. The good news from our study is I think for the majority of women being considered for breast cancer radiotherapy they’re non-smokers and the benefits are much, much bigger than the risks.
Porter
Oncologist Carolyn Taylor. More details of her research on our website.
Just time to tell you about next week’s programme in which I meet someone who very nearly died from a broken heart and, it turns out, he is far from alone.