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Cancer: Where were we, where are we, where are we going Justin Stebbing Med Leg J 2014 82: 57 DOI: 10.1177/0025817214532760 The online version of this article can be found at: http://mlj.sagepub.com/content/82/2/57

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Cancer: Where were we, where are we, where are we going

Medico-Legal Journal 2014, Vol. 82(2) 57–66 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0025817214532760 mlj.sagepub.com

Justin Stebbing Faculty of Medicine, Department of Surgery & Cancer, Imperial College, London, UK

Abstract Cancer diagnosis, medicine, prevention and care is changing – all for the better. As opposed to the ‘‘old days’’ of luck, trial and error and toxicity, we are now entering a new dawn due to advances in genomics and our understanding of biology. Personalised medicine or PM (aspects of which may also be referred to as precision medicine) is a medical model that proposes the customisation of healthcare – with medical decisions, practices, and/or products being tailored to the individual patient. This talk examines how this has evolved in the field of oncology, to maximise benefits to our patients and minimise toxicity, being able to predict in advance who our therapies will work for.

Keywords Precision, predictability, evolution, genomics, proteomics, druggable, oncogene

The President: Good evening, ladies and gentlemen. It is a pleasure to welcome Professor Justin Stebbing, who is the Professor of Oncology and Clinical Oncologist at the – well, I still call it the Hammersmith Hospital, but it is probably Imperial, and it was the Royal Postgraduate Medical School. He is going to talk to us tonight about Cancer: where we were, where we are and (hopefully) where we are going. I am not going to say very much about Justin’s academic achievements, except to make one observation, which is that he has more than twice my number of publications and he is probably half as old as I am. (Laughter) So that is perhaps some sort of yardstick as to how you can judge him. So, Justin, go ahead. Professor Stebbing: Thanks a lot for having me. I just love the phrase from the Editor of the New England Journal of Medicine ‘‘In god we trust, all the rest need data’’, and every day in clinic patients see me and they say what do I think about such-and-such and how do I feel about X, Y and Z, and to the intelligent ones my reply is fairly consistent, that I don’t have feelings, I don’t think about it, the data are the data and what we feel and think is different to what the A meeting of the Society was held at the Medical Society of London, 11 Chandos Street, Cavendish Square, London, W1G 9EB, on Thursday, 11th April, 2013. The President, Dr Martin Mansell, was in the Chair.

reality is. If what we felt and thought was right we wouldn’t need to do all this clever research all the time. So if you have got a study in 35,000 adult Americans, as published in the Journal of the American Medical Association two months ago, showing that taking Vitamin E for 10 years doubles your risk of cancer, that is good enough for me, despite the fact that people then think antioxidants will cure everything. If you have got a study in the New England Journal of Medicine three weeks ago showing that in 400,000 Americans over 10 years the more coffee they drank the lower their mortality, and even in those who drink more than six to ten cups a day it is inversely proportional, then you might say ‘‘Well, you know, coffee is a wealthy person’s drink, you’re comparing wealthy versus non-wealthy people. People drink coffee at work; you’re comparing workers versus nonworkers’’, but there is probably something in it. Now, when I think of oncology I think of this old Japanese painting. When I think of legal reports I also think of it, and this painting isn’t called ‘‘The River’’, it’s not called ‘‘The House’’, it’s not called ‘‘The Trees’’, it’s called ‘‘Paired Swallows’’, which I think is rather beautiful, and when it comes to cancer I am afraid we are a big disappointment, because if you look at the relative risk, at the decline in the incidence of death from heart disease, strokes, infections, it is well over

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50%, but for cancer in the last 60 years there has been an only 8% decline in death rate, albeit with the proviso that cancer is a disease of age and we are living longer, so we have a simple failure. So I am not here to extol any of our virtues and say how great we are, I am here simply to say that we have failed. Now, why have we failed? Well, cancers mix, cells are mixed. At different sites in the body, cancer can behave differently. Within a different cancer organ (and that is the way I think of it) the cells are different. It invades the immune system. It is designed, when we are above a certain age, dare I say it, to kill us. We are no longer protected by our genome, so cancer comes along and quite simply our treatments are just not good enough; I think about cancer as a lottery model, and by that I mean every day each cell in your body can buy a lottery ticket to get cancer. And what is the probability of winning the lottery? Well, it is pretty close to zero. Obviously, when they advertise the lottery they say ‘‘It could be you’’ to make you think it could be you, but it is pretty close to zero. So each day you might buy a lottery ticket, so over a lifetime one in three of us get cancer and one in four of us die from cancer, because over a lifetime, when you get so many lottery tickets, you might one day win or, in this case lose, if you see the analogy, the lottery, and if you smoke you must buy two lottery tickets a day. So all that means is ‘‘So my grandfather lived to be 130 and smoked 80 cigarettes a day’’. Well, that’s fine. He just didn’t win the lottery. And then I think of it like you need 100 points to get a cancer, so smoking will give you 60, for example. So, if you don’t get the other 40, that’s why my uncle lived to be 120 and smoked 100 cigarettes a day. So he did very well. Now, when I do a medico-legal report (and I do about one a week) it is never about the actual management of the cancer. The medico-legal reports I do are characterised by the fact that someone has been diagnosed with cancer. . . if you are diagnosed with a pancreatic cancer your median survival, even if it is operable, will be about a year. Oncologists like medians. . . The median of a point of data is the middle number, so the median of 2, 2, 2, 2, 2, a million, is 2, because it is the middle number, and the reason why boring, nerdy academics like me like medians is because it is not offset by changes in range. So the million won’t colour the median, but it will colour the average. So the average of that sequence of numbers is about 150,000, but the median is still 2. So we love medians and we are statistically very boring, and we have an obsession as oncologists with reductionism and understanding, as opposed to controlling cancer, but we know in 80% of cases the causes of cancer. So in that patient the pancreatic cancer will be caused by mutations in KRAS, p53, or c-MYC or LMTK3, which is a gene my lab discovered.

We know 90% of pancreatic, breast, or colorectal or lung cancers are caused by mutation of one of those genes, but we can’t yet drug them, and the reason why we can’t drug them is. . . There is no good reason why we shouldn’t but people say we can’t. It is like saying the internet is unsurfable, or the moon is unwalkable, but let me be clear: causation in medicine and causation in law are very, very different things. So first of all in medicine you have an association. So hepatitis C is associated with liver cancers, HIV was associated with AIDS. They then become causative, but for causation in medicine A happens then B happens. If A doesn’t happen, then B doesn’t happen. For B to happen you have to have A, and in the absence of A, B does not happen. In law if A happens then B happens, then A causes B. So if you are an obese diabetic smoker who takes one of Merck’s Vioxx tablets and then sues the company, obviously you won’t be a platinum plaintiff in that situation, like a healthy young female. You might be what they would class as a bronze plaintiff. But causation in medicine and law are two totally different things. So in medicine we have very, very rigorous criteria for saying something causes something. In law it is totally different. You are nodding negatively. You disagree. I understand. Maybe I am simplifying it grossly, but the fact that in America, in particular, you have these huge law suits when people have so many comorbid conditions, which you don’t tend to have in Europe, I think proves that. The truth is probably somewhere between. So our measure of success in oncology is a decrease in the size of the tumour. This is cross-sectional imaging of that patient with pancreatic cancer when they relapsed. So our measure of success is going through these scans, A, B, C, D, and the liver is that thing in the top left, and you can see that the liver is really cleaning up of metastases, but if they go D, C, B, A, the other way round, we are all very down and we blame ourselves, even though we’re never as good as we think we are and we’re never as bad as we think we are, and we don’t know what would have happened without the drugs. So without the drugs they could have progressed instantaneously or within days and with the drugs maybe they progressed within months, but we accuse ourselves of failure. So our measure of success is very, very different. My personal journey, when I went from Oxford to John Hopkins, following in the footsteps of William Osler, is really important, because it is really hard to make an assessment of a situation without seeing a patient, and of course 90% of the medico-legal reports I deal with deal with the situation after death. I can tell you that when you are in clinic with an individual patient everything is so easy in retrospect and I know it’s a cliche´ and you know that things are often very,

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very different. I remember this week the advice I gave someone. A patient’s husband came to see me and I said ‘‘We can do this, this, this and this’’, and he described his wife to me beautifully and when I met his wife the advice was totally different, and it is very, very difficult when you are in the legal profession sometimes to look at things from outside without seeing the individual, and I remember, you know, in the words of William Osler, ‘‘It is much more important to know what sort of patient has a disease than what sort of disease a patient has’’. So that was really what John Hopkins was like, on the right. So let’s talk about how we treated cancer in the past and present. In 1917, at the third battle of Ypres, the Germans used mustard gas on the first day, and people conveniently forget that the British used it the next day, and the survivors, for those lucky or sort of unlucky enough to survive, they had terrible mouth sores, their hair fell out, they had breathing difficulties, sometimes like the side-effects we see from chemotherapy, and mustard gas is a very, very simple compound. Now, in the Second World War you will remember that the Germans didn’t use mustard gas, but near Bari Harbour, in Italy, the American Fleet was stationed, and this ghastly picture, which is actually in the National Art Gallery, shows that the USS John Harvey was bombed by the Luftwaffe in 1943. Now, you remember the Americans named their big bombs, like Little Man, Fat Boy, and so on. So they had 20 bombs, each containing 100 tons of mustard gas, on board the USS John Harvey, and they were called Mother, or Ma actually, because that’s, you know, the way Americans call mother. They were called Ma 1 to 20. So Ma 17 had 100 tons of mustard gas in it. So the Luftwaffe drop a bomb on board the USS John Harvey and the bomb sort of blows up the mustard gas bomb, if you see what I mean, and all the sailors are doused in mustard gas. Now, there was a very clever US Surgeon General on board the boat called Colonel Stewart Alexander, and he measured their blood counts and he realised that on Day 5 the blood counts stopped dividing, so he thought maybe there is something in mustard gas that stops cells dividing, and he was absolutely right, and mustard gas was then taken back to Harvard, to the Sidney Farber, which is now the DanaFarber, at Harvard, and it was the very first chemotherapy. So 80% of the chemotherapies I have described are seventh generation grandchildren of mustard gas. That was the first chemotherapy because of the German attack on the USS John Harvey. The second way chemotherapy was made was in 1971, when President Nixon signed the Cancer Act, when every compound known to mankind was tested for its activity against cancer. It was quite incredible. They tested over 6 to 8 million different compounds.

And then came the HIV pandemic, and these were sort of my heroes. So when I was in the States in the early 90s as a junior doctor we saw this huge action against HIV. We had no treatment for it whatsoever, none whatsoever, and the ribbons that often you see sort of attached to oncology were often used in HIV. Now, HIV was discovered as a virus in 1983, and what happened to HIV cancers? I used to see HIV cancers all the time in the early 90s, and then they absolutely disappeared. So we know the immune system is important in cancer, and the cancers absolutely disappeared, and the reason they disappeared was because the HIV was successfully treated and the immune system was reconstituted and the virus was eradicated. And we also understood we respond differently. So that is Bella, on the left, who is a chimp in London Zoo, and that is a Sooty Mangabey in London Zoo, and Bella is now 32 years old, and chimpanzees often develop HIV, but they never develop AIDS, and Sooty Mangabeys often develop HIV and they always develop AIDS, even though they’re incredibly closely related, and we’re incredibly closely related to chimpanzees. So a few years ago I wanted to find out the factor present in chimpanzees responsible for why they didn’t respond. I remember going to London Zoo to get some blood from Bella, and they put a tranquiliser, benzodiazepine, in her Coca Cola that she liked to drink as a treat about once a month; she took one little sip of it and spat it out all over the floor. So Wayne Boardman, who was the chief vet at London Zoo, said ‘‘I know what we’ll do’’ and he put the tranquiliser in a tub of Ben & Jerry’s that she had as a treat only once every four months, because it rots your teeth, and she took one little taste of it, spat it out and then picked up her excreta off the floor, packed it in the tub and handed it back to Wayne Boardman, who was the chief vet. (Laughter) So the reality now, if you look at the 3D structure of proteins from HIV in humans and if you look at chemotherapies – and these two are chemotherapies and these two are anti-HIV medicines – they are very, very similar, but HIV as a virus has been around since 1983. If I were diagnosed as being HIV positive tomorrow I would be bothered in the sense that I am not really a pill taker, but I would be also comforted by the fact that I would have every confidence that I would have a completely normal life expectancy. You tell people they have got heart failure and they’re sort of like ‘‘No. Oh well. . .’’, but their 10-year survival is 10%. HIV: normal life expectancy. It’s the issue of drug access and distribution, not the disease. Prostate cancer, a disease you die with, whereas most other cancers, when they spread, they are a disease you die from. Now, in oncology, we have divided cancer by its heterogeneous nature into all these different sub-types, and

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we treat them all differently, but the problem with oncology right now and the problem with cancer treatment is we can tell when something won’t work but we can’t tell if something will work, so we can predict resistance but we cannot predict response. So we are getting there. In the old days we used this blanket approach derived from mustard gas and chemotherapy and Nixon’s rules and ‘‘war on cancer’’; you know, if two wrongs don’t make a right, try three. Nowadays we are genetically testing it, but we can never tell if something will work, we can only tell if something won’t work. But in some cancers we’re definitely curing them. So in chronic myeloid leukaemia we have a drug called Imatinib; in some breast cancers we have a drug called Herceptin; in some lung cancers we have Tarceva and all these other drugs, and they all have really difficult and unpronounceable names, so you always call them by their trade name, you never call them by their real name. Drug companies are very clever in that way. But the reality is, when I look at clinical trials we use statistics called Kaplan–Meier curves, and I know how you are all really interested in statistics, especially before dinner; it sort of makes you want to put your head in the oven and your feet in icy water and say ‘‘On the whole I feel just fine’’; but that’s the average, and remember we like to use medians. So on the x-axis (on the horizontal axis) we have the survival in years, on the y-axis (on the vertical axis) we have the probability you’re alive, and if you open any cancer journal this is what you see on every single page, and the thick red line is the merged trial cohort, and the top dotted line, that is with the really good treatment, and the bottom dotted line is without the really good treatment, but the people you are saving are only the people in between the two dotted lines. The people above the top dotted line were going to live anyway and the people below the bottom dotted line were going to die anyway, so the only people you save are the people in between. So advances in knowledge are made in very, very small steps, not giant leaps. In my career, spanning 20 years as an oncologist, I have only known one or two giant leaps. Advances in knowledge, contrary to what one would believe from the Daily Mail, are made in very, very small steps. So we know there are many different types of cancers. Some are curable. Why are some cancers curable, such as testicular cancer, placental cancer? When I work at Hammer House of Horrors, like Wormwood Scrubs and the Hammersmith, we are the largest centre in the UK for placentas that turn into cancers, which sounds shocking. Obviously people are pretty upset when you tell them during pregnancy that the placenta has turned into cancer, but if you think about it, a placenta is a growing thing, develops its

own blood supply and invades surrounding tissue, so it is not really surprising that some of them can turn into cancers. But they are completely and easily curable. And why is that? That is because you can kill rapidly dividing cells, because all the mutations in those cells turn the cancer genes on, and we call them ‘‘oncogenes’’, and you can kill cells that divide. Imagine a cancer cell is like a car. An oncogene is like the accelerator pressed down, so the car won’t stop. The problem with some cancers is that the mutations are in the tumour suppressor genes, and what that means is not that they grow, it is that they won’t die, so the brake in the car isn’t working, and they hang around, they’re insidious, and chemotherapy doesn’t make much difference. But for lymphoma and testicular cancer they’re easily, easily curable. When I started my career I cured about maybe 40% of people I saw; 10 years ago it was 50%; now it is about 60%; and we cured the tumours that are called ‘‘wild type tumours’’, which are the unmutated tumours, which are the tumours which have most similarity to your original tissues. Now, this is a PET scan before treatment, and this is a PET scan during treatment on a recent patient of mine with a metastatic lung cancer, and things have changed in oncology, to the extent that the median survival now of most tumours is bone-only metastases. So that is the median. So that is the point at which 50% of people die. So many people live a lot longer. It is now 9 years. That is metastatic cancer; 9 years with bone metastases. So if your diagnosed when you are 70, considering that the life expectancy in this country is 80 – actually in America it is 78, because of all the hamburgers, and in Japan it is 82 – considering the life expectancy is 80, one would expect to die with the illness, not from it. Now, when I see patients in clinic everyone is obsessed with earlier diagnosis. That is a complete misnomer, because most cancers obey what is called ‘‘lead time bias’’. So imagine your lifespan, and you are born at point A, which is this microphone, and you die at point B, which is that speaker. If you diagnose cancer there, you die at the speaker. If you diagnose it there, you still die at the speaker, but it looks like you have lived longer. It is a statistical aberration, but the Daily Mail would have you believe otherwise. The proof of the pudding is, for example, mammography. So imagine all of you were breast cancers. If you were sitting in a woman’s breast would you say ‘‘Hmm, I’m going to wait 3 years for the next mammogram to be diagnosed’’? What I am trying to say is that screening programmes, which are hugely political, (and all oncologists know that and a lot of other people do too), tend to detect slow-growing tumours which were never going to cause harm anyway. You know, there is

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an advantage to mammography, but you have to screen about 400 women to save one life. It is the same as statin treatment for heart failure. So everyone has their own risks and benefits, and that is a separate discussion. So tumours that are aggressive and are going to kill you don’t wait to be detected three years later by a screening programme, they come along and kill you anyway. So the key factor in determining how a patient responds is the biologic characteristics of the tumour and the sensitivity to that treatment. Now, with certain cancers when one diagnoses them earlier in the primary setting it is better, but if the cancer returns, any cancer that returns always obeys the phenomena of lead time bias. People think it matters enormously if you diagnose a recurrent cancer in the liver if it is 3 cm or 1 cm. It doesn’t matter to that patient’s outcome. It matters with the initial diagnosis sometimes provided it hasn’t spread. People think when I see them that the immune response is everything and chemotherapy is going to damage the immune response. A guy called Pramod Srivastava, who I worked with in America, won the Nobel Prize for ‘‘Median Variation on the Immune Escape Theory of Cancer’’, in which he said ‘‘Everyone develops cancer, but the immune system clears them’’, and all of his studies of immunotherapy in cancer, many of which I was involved with, failed. So I have this picture up in my lab at the Hammersmith, ‘‘FAILURE – We can’t spell failure without U’’, just to remind me. These days with new treatments we do double-blind tests, but there is only any point giving it to the wealthy patients, because NICE won’t have others afford it anyway, and there are ways to spin statistics. So let me give you an example with a mammography analogy that I have just presented. If you do mammograms yearly on women aged 40 to 50, you double the rate of detection of breast cancer, which sounds very, very impressive. I could also say if you do yearly mammograms on people aged 40 to 50 you take the rate of detection of breast cancer to 1 in 1000 to 2 in 1000, which sounds a little less impressive. I could then say you need to screen 1000 women yearly and do 40 biopsies, 38 of which will be false, to diagnose 1 extra breast cancer, and you can go on and on, and I can go on and on with statistics like that. But what people feel and think about cancer and what the reality is are often completely removed from one another, and that is why I love trials and I love research, because what you feel and what the reality is are totally different things. The biggest risk, I think, in oncology is not taking risks. So I love these quotes from Einstein ‘‘If you can’t explain it simply, you don’t understand it well enough’’.

He used to say you need to be able to explain things using the objects on a table. ‘‘Knowledge is limited; imagination encircles the world’’. These days we know that there are these molecules called kinases inside cancer cells which add a phosphate group and, if you remember from chemistry, if you put phosphorous in water it fizzes and makes a bang and causes a chemical reaction. So if you add phosphate to things it’s a massive on signal, which is really quite dramatic. There are 700 proteins which make this nice flowery thing called the human kinome inside human cells which adds phosphate and there is an on signal, and the way cancer treatments work these days (this graph on the right) is that we can inhibit each one of them individually, to tailor-make a drug to use, so it is about treating the right person with the right tumour at the right time with the right cancer, and we know that because of cell signalling. We know that the kinases when they are active turn on this cascade of events and 1 kinase turns on 2 proteins which turns on 4, and it is incredibly rare that I read a medico-legal report and the actual management, once diagnosis has been made, is erroneous in any way. Now, because I am really interested in this topic, a couple of years ago, I went through the autopsy specimens of 2000 chimpanzees – I know you would all love to do that yourselves! Chimpanzees are our closest living relative, and it was quite incredible that not a single one of them died from cancer. So it led us to describe this gene LMTK3, which is new to humans, from chimpanzees and might explain why humans are the only animals that frequently get cancers. Now, you could argue that humans live a lot longer (80 years old) than chimpanzees, but there is something in it; there is probably something in the genes. People I see in the clinic will say ‘‘Doesn’t red meat cause colon cancer?’’ and again I have to rely on the fact that in South America they have higher red meat consumption than anywhere else in the world and have zero colon cancer. So you then might argue ‘‘Well, the meat in South America is fresher, it lacks insecticides’’. The arguments, I hear them all the time, every single day, and you have to understand that people have very, very strong views about cancer. Patients sit down with me every day and they have very fixed views about where their cancer came from, where it is going, how best to treat it, based on an accumulation of knowledge generally derived from the Daily Mail. But lawyers can be the same as well. Oncologists generally don’t have feelings and views. It is generally very, very, very boring and data driven. The stringency criteria that I think we have in medicine is the highest in any sort of group, and one reason I love medicine is that I could take any of you and put you in the lab and within 3 months you could be researching a project and be at the edge of

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knowledge, because we understand it so little at the current time. So what we found, for example, with this gene LMTK3 is that it is prognostic. So what does prognostic mean, which is a term used a lot? Prognostic means how long someone is going to live for. It is also predictive, and what that means is it tells you how to treat people, because you can inhibit it and drug it. So the way I think about cancer and the way I think about a cancer cell is like this tube map. The good thing about mustard gas and the good thing about chemotherapy is that with chemotherapy you can inhibit every single tube station. With targeted agents, like the antikinase drugs, you can only take out one tube station, but everyone wants a targeted agent. The problem with that is that if I get to work by going through Swiss Cottage to Green Park, then to Barons Court, I can remove Green Park with a drug but I could still walk to Chalk Farm and go to King’s Cross and get the Piccadilly Line, if you like; I could go a different route; and the cancer cell would take longer to get there but it would still get there, which is why with a combination of chemotherapy and targeted agents the targeted agents take out the major tube stations and the chemotherapies inhibit them all, and that is why a combination is where we are at the moment and where we going. Ultimately, we want enough targeted agents so that we can take out Green Park, Waterloo, Victoria and King’s Cross, and so on and so forth, so that the whole tube network crumbles. But we are not there yet, and we are also not there working out if the signalling pathways happen in series or parallel or they’re completely jumbled up together. So we have got a very, very long way to go. So, for example, Glaxo recently came to me and they said to me ‘‘Justin, we would like to give you 50 million to image all your cancer patients’ tumours’’. So I said to them ‘‘I am really pleased you want to give me all this money to image all these tumours; I am really pleased you are interested in it’’, and they said ‘‘No, no, no, no, we’re not interested in it at all. We think in any cancer mass there are about 1000 signalling pathways, and in the brain we think there are about 10,000, so if we can totally image and understand all the traffic jams and all the signalling pathways in a cancer mass we can treat it like a little brain and understand neurocognition and consciousness, because we have got a lot of great cancer drugs but we have very little to treat the brain’’. So they’re sort of thinking about cancer as a little brain. So going forwards, as I said, we are going to have 10,000 treatments for 10,000 different tumours. We are going to be walking in to see our oncologists with a sequence at diagnosis. But some cancers will always be easy to cure and treat. Examples of that will be

testicular cancer, lymphoma, placental cancers, early skin cancers, kidney cancers or bladder cancers. Some cancers, like myeloma or melanoma or chronic leukaemias, will always be difficult to treat, and that is an intrinsic feature not of our capabilities but of the biologic characteristics of the tumour cells themselves. Everyone wants to have a cause or a reason. If you have an autistic kid, it is the MMR vaccine. Everyone wants a cause for things, but the reality is that these are hugely polyfactorial. We know that it is a combination of the genes, the environment and the history. If you think, I will see maybe five patients a day, of which a couple will have breast cancer, and they’ll say ‘‘I know it is genetic’’, but, if you think about it, a woman has two breasts and, even though they have got exactly the same history, exactly the same genes, exactly the same environmental exposure, only one bit of one breast will develop a cancer, which blows that right out of the water. It implies there is a random stochastic element, or at least a massive element that we don’t fully understand. I would be happy to answer questions. (Applause)

Discussion The President: Well, Justin, thank you very much. You have covered a lot of ground, a lot of very interesting issues. It occurs to me – we both do expert witness work – in nephrology condition and prognosis is really fairly straightforward because the database in terms of survival for renal patients is so crude and non-specific, so that I can start with a figure, a 5- or a 10-year survival figure, and then I can modify it, as it were, on whim, and nobody can say ‘‘No, that’s incorrect’’. The statistics that you have are very much more precise. Let’s talk about the lawyers. How well do they handle these sort of statistical issues? Professor Stebbing: Not well, and that is why I have to emphasise the difference. The use of averages is a bad thing, because it’s offset by patients doing really amazingly and patients doing really badly. You have to use medians and tight boundaries around the medians, the point at which 50% of people die. So I am always asked ‘‘What is the life expectancy here?’’ and I say ‘‘Oh, the median life expectancy’’. ‘‘What does that mean?’’ I think it is really important to have some grounding in statistics in order to be able to answer that question; you know, in order to be able to give a life expectancy. Is that the average life? To me, the important life expectancy parameter is the point at which 50% of people die and the crucial thing is answering in a time X, time Y and time Z, and those times will differ in the patient’s lineage. So if Mrs Smith’s cancer had been diagnosed two years earlier, what would her life expectancy have been? That has to be a median. When I read

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these reports people mix up these terms all the time and it really, really muddies the water. The President: Thank you. That is the answer I wanted to hear. So let’s throw it open to the floor. Will you please identify yourself and use the microphone. Mrs Brahams: Diana Brahams, barrister, retired; Editor of the Medico-Legal Journal. I used to do a lot of this kind of work. You said lawyers have a different view of causation. Well, yes and no. I mean, the thing is lawyers like things to be kind of sewn up. They don’t like ‘‘possibly’’, they only like ‘‘probably’’, and I am sure you are fed up with hearing that, but, to prove something you have to demonstrate it is on the balance of probabilities so; anything over 50% will do. Doctors are not very comfortable with it and I do understand that, but lawyers also do understand that post hoc isn’t necessarily propter hoc; it doesn’t follow necessarily that because somebody has had a cup of tea and they are ill afterwards it was the tea that did it, and there are multiple causes very often and sometimes it is enough to show that there is one factor which pushed them over the edge, and again doctors aren’t very comfortable with this concept. It is a different way of looking at things. Doctors like to feel that they can be sure, rather than on the balance of probabilities, and that is a problem, I think, for you, as well as for the lawyers. Professor Stebbing: Do you think we are becoming like America, where you get on the tubes and say ‘‘1800, medical malpractice’’, or whatever? Mrs Brahams: I don’t think so, but I think, in terms of statistics, the average person is pretty hopeless at understanding . . . Professor Stebbing: I am not presenting complex statistics here. Mrs Brahams: No, but, I mean, even simple ones the average lay person will have great difficulty with them, I think lawyers probably are a bit more sophisticated. Anyway . . . Professor Stebbing: You know, when people go on MBA courses one of the first statistics they’re told is that if there are 23 or more people in the room the probability that two have the same birthday is greater than 50%, and people say ‘‘No, that’s rubbish; that’s rubbish. How can that be?’’ People think that can’t be right, but it’s an absolutely true statement that if there are 23 or more people in the room the probability that two have the same birthday is greater than 50%, but that is not the same as the probability that someone in this room has your birthday, okay? I want to be clear about that. That is a totally different probability, and again it is what people feel and what the reality is that are very, very different. But, you know, when I talk to my American lawyer friends they’re categorising plaintiffs into platinum blonds, gold, silver – I am sorry, but

they do, you know – and the drug companies settle en masse with these things. I don’t think drug companies are the big bad people, you know, that people make them out to be actually. You know, Roche, for example, spend $10 billion a year on R&D. They’re the ones who are going to find the cure for cancer, not me, I am afraid. Mrs Brahams: Yes, but they don’t like publishing trials which are negative. Professor Stebbing: No. I think that is an absolutely true statement, and that is a problem, but it is a minor problem. Journals don’t like it as well; it’s hard to get it in. Ms Lee: Linda Lee, solicitor. I’m afraid you’re going to get an onslaught from lawyers now. Professor Stebbing: That’s fine. I’m married to one. Ms Lee: There are two points I would like to make. The first point is about your question is this getting like America. I think, first of all, America isn’t quite like America seems to be, because a lot of the initial decisions that are made by juries are overturned later when it goes on appeal to lawyers only. In this country from April 1 the Government has said ‘‘We are determined that people will not bring claims’’ and they have made a whole series of changes to prevent people bringing claims for personal injury. I think that is disgraceful where people have justifiable claims and cannot bring them. They are creating an industry of third party funders who will make a lot of money by taking damages from people simply so that they can bring a claim at all. So I would like to make that statement. The second statement is this. I confess I started off doing physics before I did law, so I do have a bit of understanding of statistics, and I challenge your assertion that all medics are good at statistics. One of my great frustrations with oncology cases is there is a possibility of a ‘‘lost years’’ claim. So if you can say at the point of diagnosis on the balance of probabilities how many years would they have lived for the case in question but what should they have lived for, so you are comparing those two, the difference in years of when you should have survived to you can claim, and the number of oncologists who could present data in that way was very small. Professor Stebbing: I have to apologise. I should have corrected myself after I said it. I didn’t mean it to sound the way it did. I think you are absolutely correct. Ms Lee: It would be helpful if you could give a handy guide to other experts, perhaps in the Journal, as to how to present data in that way, because they do struggle. Professor Stebbing: I would be happy to. You know, the other point is – I wish I had a blackboard – when it comes to differences in absolute and relative risk. We have done averages and medians; that is sort of class 1.

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Class 2 would be relative versus absolute risk. So, for example, if I have 100 women and I treat 100 women with chemotherapy for breast cancer and I don’t treat 100 women with chemotherapy for breast cancer. So there is treat and not treat. In group A 94 will be alive at 5 years, and in group B 92 will be alive, something like that. So the absolute benefit of Group A treatment is 2%. But the relative benefit is the number you have saved, which is 2, over the number who would have died, which is 8, so it becomes 25%. Now, if you read that a statin saves 50% of all heart attacks, that is not 50 out of 100 people, that is 50% of the 10 out of 100 who would have had heart attacks. That is statistic session number 2, if you like. I won’t do 3, unless you are desperate for me to. So statistics level number 2 is the difference between absolute risk and relative risk. I mean, I am guilty of it, grossly guilty in clinic, where you kind of think ‘‘Do you want to give this woman chemotherapy? How shall I present the statistics? Do you want to do a mammogram?’’ You can present the data in all sorts of ways. There is no way the patient is going to on the whole understand it. You can spin it in all sorts of ways. You can say ‘‘Oh, there’s a 25% benefit from chemotherapy’’. That is a 25% relative benefit. That is 25% of the ones who would have died, but the number who would have died is tiny, because it shows we cured 92% anyway, so you are only taking cure rate from 92% to 94%. That is hardly 25%, but that is what oncologists like me say in clinic, which we are guilty of, and that is not good. That is just another statistic. Don’t worry, we are not that bad. Mr Gardiner: My name is Bill Gardiner. I am a chemist/barrister, but I was a British Petroleum employee really, until I became a lawyer, so my question is detached and cynical, if you don’t mind, and that is that in industry, whether it is the pharmaceutical industry or my industry, we tended to go for what are called ‘‘easy wins’’, and when I think about the actual human conditions of breast, testicle, prostate and the things we fret about, those are certain things which a customer would like to discover was an ‘‘easy win’’, and I just wonder, having spent a lot of time making decisions about how much to give scientists to try to discover something which would make money for BP Chemicals, if you could tell us, from your viewpoint as a recipient of money, how decent the business is on what would do the public good and what are the ‘‘easy wins’’? Professor Stebbing: I am not sure I fully understand the question. Could you phrase it in a different way? Are you asking about drug companies? Mr Gardiner: Well, I am speaking actually in general about intellectual endeavour, and any inventive person would like to have some fame as having won the ‘‘easy

win’’, and how that is set alongside the reality of what the public wishes to happen, and I mentioned the three . . . Professor Stebbing: I mean, a lot of low-hanging fruit obviously in oncology has gone. I will answer your question in this way – 13 years ago they successfully sequenced the whole human genome; that is 3 billion base pairs, 3 billion letters of DNA; and from that there are 30,000 genes and, because of splicing of those genes, it makes 100,000 proteins, and it was thought, of those 100,000 proteins, about 5000 would be cancer targets; that means there would be on cancer cells and, if you blocked them, like removing King’s Cross, the cancer cells would die. The number of cancer targets is about 20 to 30, so it is actually much harder and much more polyfactorial and much more driven by lots of different things than we could ever have imaged or dreaded or realised, which is why HIV is pretty curable (for want of a better word), and cancer is something that is still going to be around in 100 years’ time. I don’t know if that answers your question. Maybe in part. Any other questions? The President: Justin, we were talking before we got underway about cancer of the prostate, the commonest male cancer. . . Professor Stebbing: It’s not. Lung cancer is. It depends how you define ‘‘common’’. With some cancers the incidence exceeds the prevalence. So the incidence is the number of new cases per year and the prevalence is the total number of cases in the population. So with most cancers the prevalence massively exceeds the incidence. With breast cancer there are 550,000 women living having had or with breast cancer in the UK and there are 40,000 new cases per year, so the incidence is 40,000 and the prevalence is nearly 600,000. With prostate cancer the incidence matches the same sort of numbers. But with, say, lung cancer or pancreatic cancer the incidence is higher than the prevalence because people die of it so quickly. So when you say it is the commonest, again even a simple word like that creates pandemonium amongst statisticians, because does it mean incidence, does it mean prevalence? Certainly it is the commonest male one when it comes to prevalence, but it’s not common when it comes to incidence. The President: A very simple question. (Laughter) I am proud to say that I have now reached the big ‘‘6’’ with an ‘‘0’’ on it. Should I be measuring my PSA every year, every month? What is your advice? Professor Stebbing: As I kind of insinuated before, for a screening test to work, detecting the disease earlier has to be associated with a better outcome, although the only thing that will do is it will make it look like you have lived with the cancer for longer. The reality is, Martin, we don’t really understand how to treat early

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prostate cancer. Our understanding of early prostate cancer is primitive, and I am being kind there to primitive. I mean, it is poor. We have no idea how to treat early prostate cancer, in my opinion, but, you know, you kind of might want to know, because there are a few aggressive variants that can present very young, as you are well aware as a nephrologist, these kind of anaplastic tumours, typically in African Americans, or whatever. But on the whole we don’t understand how to treat early prostate cancer. On the other hand, I had a colonoscopy a short while ago, and because I’m a real man I had it under general anaesthetic, because I know that colon cancer exists as polyp for 5 years before it becomes a cancer, and so that to me is a good screening test, but it’s not nationally indicated because it’s a real fuss, whereas PSA is quite easy. So the problem with screening programmes is that the interplay between politics, data and the programme is too complex for us to derive the maximum good from it. In France, for example, they do have a screening programme for prostate cancer that is very advanced and people with a family history go into special imaging and special things. We are just not developed enough here to have it in the NHS at the moment. That is my answer. The President: Thank you. Dr Josse: Eddie Josse. I am a medic and though most of my work is in forensic medicine, I suppose a small amount is in a condition that was untreatable 60 years ago, and that was tuberculosis, and now, of course, the position has totally changed and it has become quite treatable, and yet it had an incidence as great, if not greater, than cancer and a death rate of 30% to 35% of all those who developed tuberculosis, so there is hope yet. The point I wanted to make though was that in 1956 I became Prof. Windeyer’s pre-reg. houseman. In those days you could do oncology and radiology at pre-reg. level, and I remember giving intravenous nitrogen mustard and I remember the superb results in some patients. Particularly I remember one with epidermolysis bullosa with malignant changes, and the thing just melted, and cutaneous lymphoma; things just melted away with this drug. But God forbid if you gave it subcutaneously in error; then, you know, all hell broke loose. (Laughter) Professor Stebbing: But for TB you need to treat it for 6 months, as you know, and for typical pneumonia you treat it for five days, and the reason why is because the TB bug multiplies very, very slowly. So that is why with some cancers you can’t really treat them because they multiply too slowly. It is the same analogy. And some cancers divide very rapidly, so you can easily cure them. So people get very worried, ‘‘Oh, my gosh, the cancer is dividing rapidly’’. To an oncologist that is often great.

The President: Are there any more questions or comments. The lawyers are strangely noncombatant tonight. I thought that might get a response. (Laughter) Ms Goldman: I had to rise to that. Linda Goldman, barrister. The cases that I see are all to do with people who are complaining that a chance was missed to make the early diagnosis, and that is the lost years that were being mentioned just now. Is that the sort of thing that you are having to deal with, because effectively, as a doctor, you are more of a judge in the case than the judge? Professor Stebbing: Yes, and I just find it really, really difficult, because, you know, to me a lot of cancers present after the horse has bolted. The outcome would have been same for them if they had presented later. You know, if you specialise in this area, how difficult it can be. Even if it had been diagnosed 2 years earlier oncologists will often not admit that the patient could have done much better. A good example of that would be if the disease had been metastatic all along, then anywhere along the treatment line I don’t think anyone would say that it could have been better. It is a difficult divide. You know, some cancers, if you get them really early, as opposed to really late, are curable and it is often very clear, but for most of them there is this sort of muddy water in between and it is really, really hard. I find it difficult. And then these studies of tumour doubling time are the most primitive, awful, terrible, disgracefully quoted studies I have ever known; they’re in the most rubbish journals, because a good journal would never take them, because they wouldn’t stand a peer review, but yet people quote them all the time. I am sure you have heard them umpteen times. They’re awful studies. I am sorry, but it is what it is. The President: Mr Leigh. Mr Bertie Leigh: Something has been going round in my head since you said it earlier, when you said that some cancers are low-lying fruit and are easy and others are intrinsically difficult. I can understand how you can say that in retrospect, but you seemed to be saying that in prospect, as though you know that pancreatic cancer is always going to be difficult, or multiple myeloma is always going to be difficult. Is this to do with the number of gene target cells that there are and, if so, does that not mean that somebody may get a lucky hit whereupon they will change? Professor Stebbing: No, because there are too many genes in total. It is the tube map analogy. The difference between a squamous cell lung cancer and an adenocarcinoma is that in a squamous cell lung cancer you have about 100 tube stations malfunctioning, and it is very difficult to treat them all, and in an adenocarcinoma it may be 5 to 10, which is much easier. But the way you

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are thinking, I have to tell you, is the right kind of way; it is the way an oncologist thinks, in my opinion. The President: Okay, last question. Professor Zeitlin: Harry Zeitlin. I am a little bit puzzled about some of your statistics because most of them you gave were about life expectancy, as to what your life expectancy would be in your timeline. I did that, but I did it with children, and I felt that the evidence was not straightforward; that is that the incidence of death rate from cancer, probably over three-quarters of the last century, went up very considerably, very much related to the fall in death rate from other factors - that was quite well documented – but that the survival rate for treating cancers like leukaemia, there is no question about it, with proper detection, led to a dramatic . . . Professor Stebbing: I want to be clear: in the 1960s and 1970s childhood leukaemia had a cure rate of 5%; now it is 95%. Professor Zeitlin: Yes. Professor Stebbing: But these are astonishingly rare cancers, and cancers in children, despite the fact that you have people outside Leeds Children’s Hospital collecting for Great Ormond Street, which winds up paediatricians there no end, these are vanishingly rare illnesses compared to cancers in adults. If I tell you the numbers: there are fewer under 18-year olds diagnosed

with cancer than the twentieth commonest adult. I have to be frank with you, 350 children die a year of cancer in the UK, and that is terrible, terrible for the parents and families and children, though those numbers are minuscule, obviously, compared to any adult tumour. I am sorry to be blunt. Professor Zeitlin: I am not clear whether it is negligent not to pick them up or whether they’re so few that the 350 doesn’t matter. Professor Stebbing: Okay. What I would say is that for every 1000 CT scans you do you will probably cause, in 30 to 40 years’ time, an extra cancer. So if someone is 60 or 70 it doesn’t matter, but if someone is a kid it matters hugely. So these diagnostic tests are not benign, as you know. The President: Okay. So I am going to wind things up now. We can carry on, I hope, over the drinks and canape´s. Justin, I want to think you for a superb lecture. Professor Stebbing: Thank you for having me. The President: This is a little token from the Society . . . Professor Stebbing: Thank you. The President: . . . and you are now a member of the Society for a year. That comes with having given the talk, so I hope that we will see you. (Applause)

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Cancer: Where were we, where are we, where are we going.

Cancer diagnosis, medicine, prevention and care is changing - all for the better. As opposed to the "old days" of luck, trial and error and toxicity, ...
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