A Radiant Visitor

In an historic first, Cancer For All welcomes a guest, Stacey McGowan, who is a physicist just starting a Ph.D. on something called Proton Therapy. She is a member of the Department of Oncology in Cambridge and you can find out more about her in her blog www.planningforprotons.com but today she is going to take us into her world with a simple guide to radiotherapy in the treatment of cancer.

As undergraduate there was a lot of pressure to know what you wanted to do after graduation. I knew I wanted to stay in physics as it was what I loved; I also knew I wanted a job that meant something to me. I did not want to work in finance or for a defence company. At the time I also didn’t think I wanted to go into research! This seemed to have left me with two options, to work in the energy industry, or in medicine.

A lot of people, including my undergrad self, are unaware of medical physicists and their role in the hospital and in treating patients. After an inspiring talk at a careers event from a medical physicist working in the NHS I knew that this was what I wanted to do after graduation: I wanted to be a medical physicist.

There are three main methods for treating cancer; surgery, chemotherapy and radiotherapy. A patient will usually receive one or more of these methods as part of their treatment. Of the cures achieved about 49% of them involve surgery, 11% involve chemotherapy and 40% involve radiotherapy. However of the NHS’s cancer budget surgery costs around 22%, chemotherapy 18% and radiotherapy just 5%. This makes radiotherapy both a successful treatment option, sometimes on its own but usually in combination with surgery or chemotherapy, and it is extremely cost effective. Despite this many people don’t really know what radiotherapy is and the prospect of it as a treatment often makes patients apprehensive. As much as radiation sounds scary, we are exposed to it all the time in nature from the sun and soil and nowadays in our homes from electrical devices including Wi-Fi and mobile phones. In addition, we use it in many diagnostic applications including X-rays, CT scanners and nuclear medicine.

The difference between the radiation used for cancer treatment and that received from other sources is in the amount of radiation, or dose, delivered. When I talk about dose, think of it in the same way you would any other type of medicine. An oncology doctor will prescribe a course of radiotherapy with a specific dose to be delivered to the patient every weekday for between 4 and 6 weeks. The radiation is delivered in the form of X-rays – highly energetic particles of light – delivered at higher energies and doses than those used to image a broken bone (Editor’s enlightenment: physicists tend to use the word ‘light’ to mean electromagnetic radiation of any wavelength – not just what the eye sees). To create such highly energetic light we need a powerful machine that can also precisely deliver the X-rays to the part of the patient where the cancer lies. This machine is known to the medical community as a linac, and to the scientific community as a linear accelerator!

The linacs used in the hospital differ from those used in physics research as medical linacs have a very different role and it is the medical physicists’ job to ensure they work as intended. The X-rays delivered to the patient will harm cells in their body, both cancerous and healthy, by damaging their DNA. It is extremely important that the cancer cells receive the dose necessary to kill them so that they cannot continue to grow, resulting in a cure. It is also a priority that healthy tissue receives the smallest possible radiation dose to ensure a low chance of long term side effects. To accomplish these goals linacs are designed to rotate about the patient so that the tumour can be targeted from more than one direction. Treatment is usually delivered in daily doses (known as fractions) over a period of a few weeks because healthy cells are better at repairing damage to their DNA than cancer cells, so they can recover from each dose, whereas damage will accumulate in the tumour cells. Cumulative DNA damage leads to cell death, stopping the cancer in its tracks.

Linacs can also shape the beam so that it will match the shape of the tumour, shielding the adjacent healthy tissue from the highest radiation doses. To produce such patient-specific and intricate treatments powerful computer programs are used to design the treatment based on images of the patient (usually CT scans). Oncologists and physicists will work together, distinguishing cancer tissue from healthy, choosing beam directions and designing beam shapes to ensure that the patient receives the optimal treatment.

Many types of cancers respond to radiotherapy including those of the lung, breast, prostate, brain and spine and the method can be used to treat both adults and children. The short term side effects from radiotherapy vary depending on the region being treated. For example, radiation of the abdominal area may cause digestive and bowel discomfort or if the head and neck is the target, the patient may experience difficulty swallowing and develop a dry mouth. Generally radiotherapy can lead to tiredness, nausea and skin irritation in the targeted areas. Long term side effects can include secondary cancer, more probably in young patients, and growth problems in children.

The future of radiotherapy in the NHS is to use of protons and not X-rays to deliver radiation for specific types of cancer. The nature of protons makes the aim of cure without complication more achievable and is the topic of my PhD research.

Unlike X-rays, protons have a finite range (we can choose where they stop) which reduces the amount of radiation exposure to the patient, making this form of therapy especially beneficial for spine and brain tumours in adults and for most cancers in children. Proton therapy is particularly attractive for treating childhood cancers because it is less likely than conventional radiotherapy to cause growth defects and other health complications, including the development of cancers in later life.

Despite the UK lacking the facilities necessary to treat cancer using proton radiotherapy, a limited number of NHS patients are currently offered this option abroad as part of the NHS Proton Overseas Programme. The Government also announced in April 2012 that two proton centres will be established in England, in Manchester and in London. It is hoped that these will start to treat patients by early 2017.

Stacey McGowan

Department of Oncology, University of Cambridge

http://www.planningforprotons.com

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Whose side are you on?

Writing this blog – intended to be on current cancer-related topics – has been very good for me, if no one else, because it makes me read things I wouldn’t otherwise bother with. So I’m wiser than I would have been – but here’s a shocking admission: I’m becoming increasingly sympathetic to those who wish that scientists would just go away – or at least shut up sometimes. Of course I’m being jolly unfair: it’s not so much fellow boffins I’m miffed with as the ‘media’ – the BBC and the leading newspapers. They’re the ones who bring ‘stuff’ to my attention. Do you think I spend my time reading a journal called Alcohol and Alcoholism?!

Thanks to the medja, in just the last couple of weeks I’ve read that women’s height is linked to ovarian cancer  (BBC), breast cancer screening results in ‘unnecessary treatment’ (Telegraph), and a glass of wine carries a breast cancer warning (The Independent), – oh, and I should take an take an aspirin a day to cut cancer risk (Guardian). Just a month or two ago there was a similar stampede of ‘beef is bad’. This week the University of Gothenburg weighed in by discovering that some people are so ‘addicted’ to Facebook that they open it the moment they switch on their computers! And getting hooked (to Facebook, that is) makes women unhappy. Thank heavens they didn’t get round to emails or prostate cancer in Gothenburg or I might be needing something stronger than aspirin for my depression.

If you’d looked at all these important scientific surveys you’d have spotted that they have one thing in common: they never mention fun. Not one of them. Ever. Not a smile, nary a joyous feeling – and as for anything orgasmic …

Salvation is at hand

The good news is that some relieving guidance has popped up in the midst of all this ‘thou shalt not’, ‘it’s too late’ and ‘now look what you’ve done’. The absolutely astonishing thing is its source – ‘provenance’ as the antiques freaks like to put it. You aren’t going to believe this but it’s to the good old Church of England that we turn in the shape of a vicar from Hove (go on then …). This blessed man has revealed that not only is it a ‘good thing’ but it’s almost a moral duty, perhaps even a religious obligation, to spend Easter Sunday in bed, eating chocolate and having sex – and, by implication, doing anything else that feels as though it should be in the ‘naughty but nice’ statistical bracket. Well – who would have thought you’d read it here – praise be for the C of E!            Photograph by Hemera/Thinkstock

Here comes another of them scientists

Having let the grumpies have their say, shall we do as we preach and have a balanced, non-inflammatory comment on behalf of beleaguered boffins? Oh alright. Should the studies I listed have been done? Yes (apart from the Scandi one, obviously). They’re by excellent groups and they add another brick to the wall, even if it’s only reaffirming what we knew. The ovarian/height link paper makes a good case by pointing out that the evidence so far published on whether height, weight and body mass index (BMI) have any link with the risk of getting ovarian cancer has not given a very clear picture. They were thus prompted to put together 47 of these studies (a meta analysis) – and what emerged was that the risk increases with height and, for women who have never used hormone therapy, with BMI. However, the important point is that although the increases are statistically significant, they are very small. My colleague Paul Pharoah has helpfully estimated that they show that being 5ft 6in rather than 5ft tall raises the lifetime risk of ovarian cancer from about 16 in 1000 to 20 in 1000.

So these reports are good, though not seismic, stuff. And yes, it’s great that the media pick up on what science produces and bring it to the attention of the wider world. It would just be nice if they were less keen on eye-catching, doomy, headlines. How about taking a lead from The Sun, an organ not previously mentioned in this column, that headlined the C of E story with Easter Sinday. What might they do? Aspirin v. Expirin? I came up with a cracker for the ovarian study but a problem with talking and writing about cancer is the ease with which jokes (mine anyway!) teeter into what some would consider to be the realms of bad taste. So a green light for The Sun then!

Final thought for the day: am I now (1) religiously taking aspirin OR (2) opting for Nick the Vic’s life support strategy? I think you know the answer to that one.

References

Collaborative Group on Epidemiological Studies of Ovarian Cancer (2012) Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies. PLoS Med 9(4): e1001200. doi:10.1371/journal.pmed.1001200

Kalager, M., Adami, H.O., Bretthauer, M. and Tamimi, R.M. (2012). Overdiagnosis of Invasive Breast Cancer Due to 491 Mammography Screening: Results From the Norwegian Screening Program. Annals of Internal Medicine 156, 491-499.

Rothwell, P.M., Wilson, M., Price. J.F., Belch, J.F.F., Meade, T.W. and Mehta, Z. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. The Lancet, Early Online Publication, 21 March 2012 doi:10.1016/S0140-6736(12)60209-8Cite or Link Using DOI

Obesity and Cancer

Science, you could say, comes in two sorts. There’s the stuff we more or less understand – and there’s the rest. We’re pretty secure with the earth being round and orbiting the sun, the heart being a pump connected to a network of tubes that keeps us alive, DNA carrying the genetic code – and a few other things. But human beings are curious souls and we tend to be fascinated by what we don’t know and can’t see – why the Dance of the Seven Veils caught on, I guess.

Scientists are, of course, the extreme example – they spend their lives pursuing the unknown (and, as Fred Hoyle gloomily remarked, they’re always wrong and yet they always go on). But in this media era they pay a public price for their doggedness because they get asked the pressing questions of the moment. Is global warning going to finish us off soon, why is British sport generally so poor and – today’s teaser – does being fat make you more likely to get cancer?

A few facts go a long way

The major cancers have become familiar because the numbers afflicted are so staggering – but the one good thing is that the epidemiology can tell us something about the disease. Thus for cancers of the bowel, endometrium, kidney, oesophagus and pancreas and also for postmenopausal breast cancer there is clear evidence that being overweight or obese makes you more susceptible. In other words, if you compare large groups with those cancers to equally large numbers without, the disease groups contain significantly more people who are fat. We should add that the above list is conservative. A number of other cancers are almost certainly more common in those who are overweight (brain, thyroid, liver, ovary, prostate and stomach tumours as well as multiple myeloma, leukaemia, non-Hodgkin lymphoma and malignant melanoma in men).

Sizing up the problem

The usual measure is Body Mass Index (BMI) – your weight (in kilograms) divided by the square of your height (in metres). A BMI of 25 to 29.9 and you’re overweight; over 30 is obese. In England in 2009 just over 61% of adults and 28% of children (aged 2-10) were overweight or obese and of these, 23% of adults and 14% of children were obese. And every year these figures get bigger.

How big is the risk?

Impossible to say exactly – for one thing we don’t know how long you need to be exposed to the risk (i.e. being overweight) for cancer to develop but in 2010 just over 5% of the total of new cancer cases in the UK was due to excess weight. That’s another conservative estimate, but it means at least 17,000 out of 309,000 cases, with bowel and breast cancers being the major sites.

What’s going on?

Showing an association is a good start but the important thing is to find out which molecules make that link. For obesity and cancer detail remains obscure but broad outlines are emerging, summarised in the sketch. In obesity fat (adipose) cells increase in both number and size (so it’s a double problem: more cells – and the fat cells themselves are fatter). As this happens other cells are recruited to adipose tissue and, from this cellular cooperative, signalling proteins are released that have the potential to drive tumours. This picture is similar to that of the microenvironment of tumours themselves, where many types of cell infiltrate the new growth. Initially this inflammatory and immune response aims to kill the tumour but if it fails the balance of signalling shifts so that it actually helps the tumour grow. In addition to signals from fat cells themselves, obesity is usually associated with increased levels of circulating growth hormones (e.g., insulin) and of lipids, both of which may also promote tumour development.

Thus many signals with cancerous potential arise in obese individuals. In principle these could initiate tumour growth or they could accelerate it in cancers that have started to develop independently of obesity. So it is complicated – but at least as new signalling strands emerge they offer new targets for drug therapy.

In obesity abnormal signals from fatty tissue can combine with others arising from perturbed metabolism to help cancers develop

Reference

World Cancer Research Fund (WCRF) Panel on Food, Nutrition, Physical Activity, and the Prevention of Cancer (WCRF, 2007).

Three cancers for the price of one?

Damaging the DNA Double-helix

A colleague of mine works on double-stranded DNA repair, as it’s called in the trade. This is something that goes on in all of us as our cells patch up DNA that’s being continuously assaulted by things that cause mutations. One source of damage is radiation that can snip the double helix, leaving separate bits of chromosomes floating around in the nucleus. Anything involving ‘snipping’ suggests a pretty potent type of mutation and it does indeed present a real problem because the cell has to find ways of tagging the floating ends, bringing them together and stitching them up. Amazingly, Nature has come up with not one but several ways of doing this and, by and large, they work pretty well. In ferreting around to define the proteins involved, my friend and his team also tried out drugs that might block repair. Having found a very effective one they set up a company to develop it – duly taken over by AstraZeneca, with the result that I now know one person in science who is very rich. The hope is that the drug might work against ovarian, prostate and breast cancers – which would be very good news for AstraZeneca!

But, you may already be asking, what’s the use of a repair blocker? Surely that’s the last thing you want in staving off cancer? Well, yes – and no. All things being equal, you do want to keep repair systems working but, if one of them becomes defective as part of cancer development, knocking out another may push the cell over the brink so that it can’t deal with the DNA chaos and commits suicide.

Bear in mind that our picture of cancer is one of widespread damage to DNA. But the genetic anarchy of cancer has parallels with the political variety in that both have limits. If the Molotov cocktail fraternity so disrupt society that the binmen stop collecting rubbish, everyone dies of cholera – not exactly a great social reform. Cancer too walks a tightrope between the disruption needed to overcome normal cell control and an extreme level of chaos that would simply kill the cell.

Two of the most familiar ‘cancer genes’ are BRCA1 and BRCA2, mutated forms of which can be inherited to give rise to several types of cancer. It turns out that both BRCAs play roles in DNA repair. The drug that has improved my friend’s bank balance is olaparib and it targets another DNA repair pathway – involving an enzyme called PARP (for poly (ADP-ribose) polymerase). So that’s why it’s useful: if the BRCA route is already blocked by mutation, inhibiting a second repair pathway (PARP) may scupper the cancer cell.

BRCA mutations cause about 5% of breast cancers and 10% of ovarian cancers and they can also give rise to prostate cancer. Small-scale clinical trials of olaparib and several related PARP inhibitors have shown anti-tumour effects against all three of these cancers. However, the most recent trial showed no significant effect on survival of breast cancer patients. Whilst this is a set-back for the PARP inhibitor field, another trial has shown significant effects on ovarian cancer.

As so often in the history of cancer treatment, great expectations have taken a bit of a knock but the PARP story is far from over and it still holds the promise than one class of drugs may be effective against several different types of cancer. If it were to turn out that way it would be great news for some cancer patients – and not bad for one or two bank balances.

Surviving cancer in the UK and other places

Over the years a number of surveys have concluded that, despite progressive improvements, the UK five-year survival rates for common cancers are worse than the European average by 5 to 15%. The most recent of these has just emerged, comparing survival from four of the most important cancers – breast, bowel, lung and ovarian – at one and five years following diagnosis between 1995 and 2007 in the UK, Denmark, Norway, Sweden, Australia and Canada. Their conclusion was that, despite improvements in survival rates, the disparities remain and that the life expectancy of cancer patients in the UK is shorter than in other countries.

Before we get too downcast by these facts we should note that the UK five-year survival rate for breast cancer, for example, has now reached 82% whereas 40 years ago it was 40%. However, the UK clearly has a problem for which there might be three broad causes: (1) later diagnosis, (2) more aggressive forms of the disease, (3) variable standard of treatment.  It seems probable that all three play a part.

Where you live in the UK bears significantly on your cancer risk.  The National Cancer Intelligence Centre has produced a Cancer Atlas that compares incidence and death rate from the 21 most common cancers in different counties of the UK.  The differences reflect levels of smoking, drinking, poor diet and social deprivation and show that regions of northern England and Scotland are cancer ‘hot spots’.  Their estimate is that if the worst areas could be converted to the best there would be 25,000 fewer new cases and 17,000 fewer deaths a year: with about 156,000 cancer deaths per year that would represent an 11% decrease.

One sensible plan might be to concentrate cancer care into a smaller number of centres of expertise, along the lines of what has been proposed for heart disease.

World, USA and UK cancer deaths 2008.

Reference

Coleman, M.P., Forman, D., Bryant, H., Butler, J., Rachet, B., Maringe, C., Nur, U., Tracey, E., Coory, M., Hatcher, J., McGahan, C.E., Turner, D., Marrett, L., Gjerstorff, M.L., Johannesen, T.B., Adolfsson, J., Lambe, M., Lawrence, G., Meechan, D., Morris, E.J., Middleton, R., Steward, J., Richards, M.A. and the ICBP Module 1 Working Group. (2011). Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995—2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. The Lancet, 377, 127–138.