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

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2014 82: 57Med Leg JJustin Stebbing

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

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Papers Presented to the Society

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

Justin StebbingFaculty 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. Itis a pleasure to welcome Professor Justin Stebbing, whois the Professor of Oncology and Clinical Oncologist atthe – well, I still call it the Hammersmith Hospital, butit is probably Imperial, and it was the RoyalPostgraduate Medical School. He is going to talk tous tonight about Cancer: where we were, where we areand (hopefully) where we are going. I am not going tosay very much about Justin’s academic achievements,except to make one observation, which is that he hasmore than twice my number of publications and he isprobably half as old as I am. (Laughter) So that isperhaps some sort of yardstick as to how you canjudge 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 therest need data’’, and every day in clinic patients see meand they say what do I think about such-and-such andhow do I feel about X, Y and Z, and to the intelligentones my reply is fairly consistent, that I don’t havefeelings, I don’t think about it, the data are the dataand what we feel and think is different to what the

reality is. If what we felt and thought was right wewouldn’t need to do all this clever research all thetime. So if you have got a study in 35,000 adultAmericans, as published in the Journal of theAmerican Medical Association two months ago, show-ing that taking Vitamin E for 10 years doubles your riskof cancer, that is good enough for me, despite the factthat people then think antioxidants will cure every-thing. If you have got a study in the New EnglandJournal of Medicine three weeks ago showing that in400,000 Americans over 10 years the more coffee theydrank the lower their mortality, and even in those whodrink more than six to ten cups a day it is inverselyproportional, then you might say ‘‘Well, you know,coffee is a wealthy person’s drink, you’re comparingwealthy versus non-wealthy people. People drinkcoffee at work; you’re comparing workers versus non-workers’’, but there is probably something in it.

Now, when I think of oncology I think of this oldJapanese painting. When I think of legal reports I alsothink 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 ratherbeautiful, and when it comes to cancer I am afraid weare a big disappointment, because if you look at therelative risk, at the decline in the incidence of deathfrom heart disease, strokes, infections, it is well over

A meeting of the Society was held at the Medical Society of London,11 Chandos Street, Cavendish Square, London, W1G 9EB, onThursday, 11th April, 2013. The President, Dr Martin Mansell, wasin the Chair.

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50%, but for cancer in the last 60 years there has beenan only 8% decline in death rate, albeit with the provisothat cancer is a disease of age and we are living longer,so we have a simple failure. So I am not here to extolany of our virtues and say how great we are, I am heresimply to say that we have failed.

Now, why have we failed? Well, cancers mix, cells aremixed. At different sites in the body, cancer can behavedifferently. Within a different cancer organ (and that isthe way I think of it) the cells are different. It invades theimmune system. It is designed, when we are above acertain age, dare I say it, to kill us. We are no longerprotected by our genome, so cancer comes along andquite simply our treatments are just not good enough;I think about cancer as a lottery model, and by that Imean every day each cell in your body can buy a lotteryticket to get cancer. And what is the probability of win-ning the lottery? Well, it is pretty close to zero.Obviously, when they advertise the lottery they say ‘‘Itcould be you’’ to make you think it could be you, but it ispretty close to zero. So each day you might buy a lotteryticket, so over a lifetime one in three of us get cancer andone in four of us die from cancer, because over a lifetime,when you get so many lottery tickets, you might one daywin or, in this case lose, if you see the analogy, the lot-tery, and if you smoke youmust buy two lottery tickets aday. So all that means is ‘‘So my grandfather lived to be130 and smoked 80 cigarettes a day’’.Well, that’s fine. Hejust didn’t win the lottery. And then I think of it like youneed 100 points to get a cancer, so smoking will give you60, for example. So, if you don’t get the other 40, that’swhy my uncle lived to be 120 and smoked 100 cigarettesa day. So he did very well.

Now, when I do a medico-legal report (and I doabout one a week) it is never about the actual manage-ment of the cancer. The medico-legal reports I do arecharacterised by the fact that someone has been diag-nosed with cancer. . . if you are diagnosed with a pan-creatic cancer your median survival, even if it isoperable, will be about a year. Oncologists like med-ians. . . The median of a point of data is the middlenumber, so the median of 2, 2, 2, 2, 2, a million, is 2,because it is the middle number, and the reason whyboring, nerdy academics like me like medians is becauseit is not offset by changes in range. So the million won’tcolour the median, but it will colour the average. So theaverage of that sequence of numbers is about 150,000,but the median is still 2.

So we love medians and we are statistically veryboring, and we have an obsession as oncologists withreductionism and understanding, as opposed to con-trolling cancer, but we know in 80% of cases thecauses of cancer. So in that patient the pancreaticcancer will be caused by mutations in KRAS, p53, orc-MYC or LMTK3, which is a gene my lab discovered.

We know 90% of pancreatic, breast, or colorectal orlung cancers are caused by mutation of one of thosegenes, but we can’t yet drug them, and the reason whywe can’t drug them is. . . There is no good reason whywe shouldn’t but people say we can’t. It is like sayingthe internet is unsurfable, or the moon is unwalkable,but let me be clear: causation in medicine and causationin law are very, very different things. So first of all inmedicine you have an association. So hepatitis C isassociated with liver cancers, HIV was associated withAIDS. They then become causative, but for causationin medicine A happens then B happens. If A doesn’thappen, then B doesn’t happen. For B to happen youhave to have A, and in the absence of A, B does nothappen. In law if A happens then B happens, then Acauses B. So if you are an obese diabetic smoker whotakes one of Merck’s Vioxx tablets and then sues thecompany, obviously you won’t be a platinum plaintiffin that situation, like a healthy young female. Youmight be what they would class as a bronze plaintiff.But causation in medicine and law are two totally dif-ferent things. So in medicine we have very, very rigor-ous criteria for saying something causes something. Inlaw it is totally different. You are nodding negatively.You disagree. I understand. Maybe I am simplifying itgrossly, but the fact that in America, in particular, youhave these huge law suits when people have so manycomorbid conditions, which you don’t tend to have inEurope, I think proves that. The truth is probablysomewhere between.

So our measure of success in oncology is a decreasein the size of the tumour. This is cross-sectional ima-ging of that patient with pancreatic cancer when theyrelapsed. So our measure of success is going throughthese scans, A, B, C, D, and the liver is that thing in thetop left, and you can see that the liver is really cleaningup of metastases, but if they go D, C, B, A, the otherway round, we are all very down and we blame our-selves, even though we’re never as good as we think weare and we’re never as bad as we think we are, and wedon’t know what would have happened without thedrugs. So without the drugs they could have progressedinstantaneously or within days and with the drugsmaybe they progressed within months, but we accuseourselves of failure. So our measure of success is very,very different.

My personal journey, when I went from Oxford toJohn Hopkins, following in the footsteps of WilliamOsler, is really important, because it is really hard tomake an assessment of a situation without seeing apatient, and of course 90% of the medico-legal reportsI deal with deal with the situation after death. I can tellyou that when you are in clinic with an individualpatient everything is so easy in retrospect and I knowit’s a cliche and you know that things are often very,

58 Medico-Legal Journal 82(2)



very different. I remember this week the advice I gavesomeone. A patient’s husband came to see me and Isaid ‘‘We can do this, this, this and this’’, and hedescribed his wife to me beautifully and when I methis wife the advice was totally different, and it is very,very difficult when you are in the legal profession some-times to look at things from outside without seeing theindividual, and I remember, you know, in the words ofWilliam Osler, ‘‘It is much more important to know whatsort of patient has a disease than what sort of disease apatient has’’. So that was really what John Hopkins waslike, on the right.

So let’s talk about how we treated cancer in the pastand present. In 1917, at the third battle of Ypres, theGermans used mustard gas on the first day, and peopleconveniently forget that the British used it the next day,and the survivors, for those lucky or sort of unluckyenough to survive, they had terrible mouth sores, theirhair fell out, they had breathing difficulties, sometimeslike the side-effects we see from chemotherapy, andmustard gas is a very, very simple compound.

Now, in the Second World War you will rememberthat the Germans didn’t use mustard gas, but near BariHarbour, in Italy, the American Fleet was stationed,and this ghastly picture, which is actually in theNational Art Gallery, shows that the USS JohnHarvey 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 20bombs, each containing 100 tons of mustard gas, onboard the USS John Harvey, and they were calledMother, or Ma actually, because that’s, you know,the way Americans call mother. They were called Ma1 to 20. So Ma 17 had 100 tons of mustard gas in it. Sothe Luftwaffe drop a bomb on board the USS JohnHarvey and the bomb sort of blows up the mustardgas bomb, if you see what I mean, and all the sailorsare doused in mustard gas. Now, there was a very cleverUS Surgeon General on board the boat called ColonelStewart Alexander, and he measured their blood countsand he realised that on Day 5 the blood counts stoppeddividing, so he thought maybe there is something inmustard gas that stops cells dividing, and he was abso-lutely right, and mustard gas was then taken back toHarvard, to the Sidney Farber, which is now the Dana-Farber, at Harvard, and it was the very first chemother-apy. So 80% of the chemotherapies I have described areseventh generation grandchildren of mustard gas. Thatwas the first chemotherapy because of the Germanattack on the USS John Harvey.

The second way chemotherapy was made was in1971, when President Nixon signed the Cancer Act,when every compound known to mankind was testedfor 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 weresort of my heroes. So when I was in the States in theearly 90s as a junior doctor we saw this huge actionagainst HIV. We had no treatment for it whatsoever,none whatsoever, and the ribbons that often you seesort of attached to oncology were often used in HIV.Now, HIV was discovered as a virus in 1983, and whathappened to HIV cancers? I used to see HIV cancers allthe time in the early 90s, and then they absolutely dis-appeared. So we know the immune system is importantin cancer, and the cancers absolutely disappeared, andthe reason they disappeared was because the HIV wassuccessfully treated and the immune system was recon-stituted and the virus was eradicated. And we alsounderstood we respond differently.

So that is Bella, on the left, who is a chimp inLondon Zoo, and that is a Sooty Mangabey inLondon Zoo, and Bella is now 32 years old, and chim-panzees often develop HIV, but they never developAIDS, and Sooty Mangabeys often develop HIV andthey always develop AIDS, even though they’re incred-ibly closely related, and we’re incredibly closely relatedto chimpanzees. So a few years ago I wanted to find outthe factor present in chimpanzees responsible for whythey didn’t respond. I remember going to London Zooto get some blood from Bella, and they put a tranqui-liser, benzodiazepine, in her Coca Cola that she liked todrink as a treat about once a month; she took one littlesip of it and spat it out all over the floor. So WayneBoardman, who was the chief vet at London Zoo, said‘‘I know what we’ll do’’ and he put the tranquiliser in atub of Ben & Jerry’s that she had as a treat only onceevery four months, because it rots your teeth, and shetook one little taste of it, spat it out and then picked upher excreta off the floor, packed it in the tub andhanded it back to Wayne Boardman, who was thechief vet. (Laughter)

So the reality now, if you look at the 3D structure ofproteins from HIV in humans and if you look at che-motherapies – and these two are chemotherapies andthese two are anti-HIV medicines – they are very, verysimilar, but HIV as a virus has been around since 1983.If I were diagnosed as being HIV positive tomorrowI would be bothered in the sense that I am not reallya pill taker, but I would be also comforted by the factthat I would have every confidence that I would have acompletely normal life expectancy. You tell people theyhave got heart failure and they’re sort of like ‘‘No. Ohwell. . .’’, but their 10-year survival is 10%. HIV:normal life expectancy. It’s the issue of drug accessand distribution, not the disease. Prostate cancer, a dis-ease you die with, whereas most other cancers, whenthey spread, they are a disease you die from.

Now, in oncology, we have divided cancer by its het-erogeneous nature into all these different sub-types, and

Stebbing 59



we treat them all differently, but the problem withoncology right now and the problem with cancer treat-ment is we can tell when something won’t work but wecan’t tell if something will work, so we can predictresistance but we cannot predict response. So we aregetting there. In the old days we used this blanketapproach derived from mustard gas and chemotherapyand Nixon’s rules and ‘‘war on cancer’’; you know, iftwo wrongs don’t make a right, try three. Nowadays weare genetically testing it, but we can never tell if some-thing will work, we can only tell if something won’twork. But in some cancers we’re definitely curingthem. So in chronic myeloid leukaemia we have adrug called Imatinib; in some breast cancers we havea drug called Herceptin; in some lung cancers wehave Tarceva and all these other drugs, and they allhave really difficult and unpronounceable names, soyou always call them by their trade name, you nevercall them by their real name. Drug companies are veryclever in that way.

But the reality is, when I look at clinical trials we usestatistics called Kaplan–Meier curves, and I know howyou are all really interested in statistics, especiallybefore dinner; it sort of makes you want to put yourhead in the oven and your feet in icy water and say ‘‘Onthe whole I feel just fine’’; but that’s the average, andremember we like to use medians. So on the x-axis (onthe horizontal axis) we have the survival in years, on they-axis (on the vertical axis) we have the probabilityyou’re alive, and if you open any cancer journal thisis what you see on every single page, and the thick redline is the merged trial cohort, and the top dotted line,that is with the really good treatment, and the bottomdotted line is without the really good treatment, but thepeople you are saving are only the people in betweenthe two dotted lines. The people above the top dottedline were going to live anyway and the people below thebottom dotted line were going to die anyway, so theonly people you save are the people in between.

So advances in knowledge are made in very, verysmall steps, not giant leaps. In my career, spanning20 years as an oncologist, I have only known one ortwo giant leaps. Advances in knowledge, contrary towhat one would believe from the Daily Mail, aremade in very, very small steps.

So we know there are many different types of can-cers. Some are curable. Why are some cancers curable,such as testicular cancer, placental cancer? When Iwork at Hammer House of Horrors, like WormwoodScrubs and the Hammersmith, we are the largestcentre in the UK for placentas that turn into cancers,which sounds shocking. Obviously people are prettyupset when you tell them during pregnancy that theplacenta has turned into cancer, but if you thinkabout it, a placenta is a growing thing, develops its

own blood supply and invades surrounding tissue, soit is not really surprising that some of them can turninto cancers. But they are completely and easily cur-able. And why is that? That is because you can killrapidly dividing cells, because all the mutations inthose cells turn the cancer genes on, and we call them‘‘oncogenes’’, and you can kill cells that divide. Imaginea cancer cell is like a car. An oncogene is like the accel-erator pressed down, so the car won’t stop. The prob-lem with some cancers is that the mutations are in thetumour suppressor genes, and what that means is notthat they grow, it is that they won’t die, so the brake inthe car isn’t working, and they hang around, they’reinsidious, and chemotherapy doesn’t make much differ-ence. But for lymphoma and testicular cancer they’reeasily, easily curable.

When I started my career I cured about maybe 40%of people I saw; 10 years ago it was 50%; now it isabout 60%; and we cured the tumours that are called‘‘wild type tumours’’, which are the unmutatedtumours, which are the tumours which have most simi-larity to your original tissues.

Now, this is a PET scan before treatment, and this isa PET scan during treatment on a recent patient ofmine with a metastatic lung cancer, and things havechanged in oncology, to the extent that the median sur-vival now of most tumours is bone-only metastases. Sothat is the median. So that is the point at which 50% ofpeople die. So many people live a lot longer. It is now9 years. That is metastatic cancer; 9 years with bonemetastases. So if your diagnosed when you are 70,considering that the life expectancy in this country is80 – actually in America it is 78, because of all thehamburgers, and in Japan it is 82 – consideringthe life expectancy is 80, one would expect to die withthe illness, not from it.

Now, when I see patients in clinic everyone isobsessed with earlier diagnosis. That is a complete mis-nomer, because most cancers obey what is called ‘‘leadtime bias’’. So imagine your lifespan, and you are bornat point A, which is this microphone, and you die atpoint B, which is that speaker. If you diagnose cancerthere, you die at the speaker. If you diagnose it there,you still die at the speaker, but it looks like you havelived longer. It is a statistical aberration, but the DailyMail would have you believe otherwise. The proof ofthe pudding is, for example, mammography. So ima-gine all of you were breast cancers. If you were sitting ina woman’s breast would you say ‘‘Hmm, I’m going towait 3 years for the next mammogram to be diag-nosed’’? What I am trying to say is that screening pro-grammes, which are hugely political, (and alloncologists know that and a lot of other people dotoo), tend to detect slow-growing tumours which werenever going to cause harm anyway. You know, there is




an advantage to mammography, but you have to screenabout 400 women to save one life. It is the same asstatin treatment for heart failure. So everyone hastheir own risks and benefits, and that is a separate dis-cussion. So tumours that are aggressive and are goingto kill you don’t wait to be detected three years later bya screening programme, they come along and kill youanyway.

So the key factor in determining how a patientresponds is the biologic characteristics of the tumourand the sensitivity to that treatment. Now, with certaincancers when one diagnoses them earlier in the primarysetting it is better, but if the cancer returns, any cancerthat returns always obeys the phenomena of lead timebias. People think it matters enormously if you diag-nose a recurrent cancer in the liver if it is 3 cm or 1 cm.It doesn’t matter to that patient’s outcome. It matterswith the initial diagnosis sometimes provided it hasn’tspread.

People think when I see them that the immuneresponse is everything and chemotherapy is going todamage the immune response. A guy called PramodSrivastava, who I worked with in America, won theNobel Prize for ‘‘Median Variation on the ImmuneEscape Theory of Cancer’’, in which he said‘‘Everyone develops cancer, but the immune systemclears them’’, and all of his studies of immunotherapyin cancer, many of which I was involved with, failed. SoI have this picture up in my lab at the Hammersmith,‘‘FAILURE – We can’t spell failure without U’’, just toremind me.

These days with new treatments we do double-blindtests, but there is only any point giving it to the wealthypatients, because NICE won’t have others afford itanyway, and there are ways to spin statistics.

So let me give you an example with a mammographyanalogy that I have just presented. If you do mammo-grams yearly on women aged 40 to 50, you double therate of detection of breast cancer, which sounds very,very impressive. I could also say if you do yearly mam-mograms on people aged 40 to 50 you take the rate ofdetection of breast cancer to 1 in 1000 to 2 in 1000,which sounds a little less impressive. I could then sayyou need to screen 1000 women yearly and do 40 biop-sies, 38 of which will be false, to diagnose 1 extra breastcancer, and you can go on and on, and I can go on andon with statistics like that. But what people feel andthink about cancer and what the reality is are oftencompletely removed from one another, and that iswhy I love trials and I love research, because whatyou feel and what the reality is are totally differentthings.

The biggest risk, I think, in oncology is not takingrisks. So I love these quotes from Einstein ‘‘If you can’texplain it simply, you don’t understand it well enough’’.

He used to say you need to be able to explain thingsusing the objects on a table. ‘‘Knowledge is limited;imagination encircles the world’’. These days we knowthat there are these molecules called kinases insidecancer cells which add a phosphate group and, if youremember from chemistry, if you put phosphorous inwater it fizzes and makes a bang and causes a chemicalreaction. So if you add phosphate to things it’s a mas-sive on signal, which is really quite dramatic. There are700 proteins which make this nice flowery thing calledthe human kinome inside human cells which adds phos-phate and there is an on signal, and the way cancertreatments 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 treatingthe right person with the right tumour at the righttime with the right cancer, and we know that becauseof cell signalling. We know that the kinases when theyare active turn on this cascade of events and 1 kinaseturns on 2 proteins which turns on 4, and it is incrediblyrare that I read a medico-legal report and the actualmanagement, once diagnosis has been made, is errone-ous in any way.

Now, because I am really interested in this topic, acouple of years ago, I went through the autopsy speci-mens of 2000 chimpanzees – I know you would all loveto do that yourselves! Chimpanzees are our closestliving relative, and it was quite incredible that not asingle one of them died from cancer. So it led us todescribe this gene LMTK3, which is new to humans,from chimpanzees and might explain why humans arethe only animals that frequently get cancers. Now, youcould argue that humans live a lot longer (80 years old)than chimpanzees, but there is something in it; there isprobably something in the genes.

People I see in the clinic will say ‘‘Doesn’t red meatcause colon cancer?’’ and again I have to rely on thefact that in South America they have higher red meatconsumption than anywhere else in the world and havezero colon cancer. So you then might argue ‘‘Well, themeat in South America is fresher, it lacks insecticides’’.The arguments, I hear them all the time, every singleday, and you have to understand that people have very,very strong views about cancer. Patients sit down withme every day and they have very fixed views aboutwhere their cancer came from, where it is going, howbest to treat it, based on an accumulation of knowledgegenerally derived from the Daily Mail. But lawyers canbe the same as well. Oncologists generally don’t havefeelings and views. It is generally very, very, very boringand data driven. The stringency criteria that I think wehave in medicine is the highest in any sort of group, andone reason I love medicine is that I could take any ofyou and put you in the lab and within 3 months youcould be researching a project and be at the edge of

Stebbing 61



knowledge, because we understand it so little at thecurrent time.

So what we found, for example, with this geneLMTK3 is that it is prognostic. So what does prognos-tic mean, which is a term used a lot? Prognostic meanshow long someone is going to live for. It is also pre-dictive, and what that means is it tells you how to treatpeople, because you can inhibit it and drug it.

So the way I think about cancer and the way I thinkabout a cancer cell is like this tube map. The good thingabout mustard gas and the good thing about chemo-therapy is that with chemotherapy you can inhibit everysingle tube station. With targeted agents, like the anti-kinase drugs, you can only take out one tube station,but everyone wants a targeted agent. The problem withthat is that if I get to work by going through SwissCottage to Green Park, then to Barons Court, I canremove Green Park with a drug but I could still walkto Chalk Farm and go to King’s Cross and get thePiccadilly Line, if you like; I could go a differentroute; and the cancer cell would take longer to getthere but it would still get there, which is why with acombination of chemotherapy and targeted agents thetargeted agents take out the major tube stations and thechemotherapies inhibit them all, and that is why a com-bination is where we are at the moment and where wegoing. Ultimately, we want enough targeted agents sothat we can take out Green Park, Waterloo, Victoriaand King’s Cross, and so on and so forth, so that thewhole tube network crumbles. But we are not there yet,and we are also not there working out if the signallingpathways happen in series or parallel or they’re com-pletely jumbled up together. So we have got a very, verylong way to go.

So, for example, Glaxo recently came to me and theysaid to me ‘‘Justin, we would like to give you �50 mil-lion to image all your cancer patients’ tumours’’. So Isaid to them ‘‘I am really pleased you want to give meall this money to image all these tumours; I am reallypleased you are interested in it’’, and they said ‘‘No, no,no, no, we’re not interested in it at all. We think in anycancer mass there are about 1000 signalling pathways,and in the brain we think there are about 10,000, so ifwe can totally image and understand all the traffic jamsand all the signalling pathways in a cancer mass we cantreat it like a little brain and understand neurocognitionand consciousness, because we have got a lot ofgreat cancer drugs but we have very little to treat thebrain’’. So they’re sort of thinking about cancer as alittle brain.

So going forwards, as I said, we are going to have10,000 treatments for 10,000 different tumours. We aregoing to be walking in to see our oncologists with asequence at diagnosis. But some cancers will alwaysbe easy to cure and treat. Examples of that will be

testicular cancer, lymphoma, placental cancers, earlyskin cancers, kidney cancers or bladder cancers. Somecancers, like myeloma or melanoma or chronic leukae-mias, will always be difficult to treat, and that is anintrinsic feature not of our capabilities but of the bio-logic characteristics of the tumour cells themselves.Everyone wants to have a cause or a reason. If youhave an autistic kid, it is the MMR vaccine. Everyonewants a cause for things, but the reality is that these arehugely polyfactorial. We know that it is a combinationof the genes, the environment and the history. If youthink, I will see maybe five patients a day, of which acouple will have breast cancer, and they’ll say ‘‘I knowit is genetic’’, but, if you think about it, a woman hastwo breasts and, even though they have got exactly thesame history, exactly the same genes, exactly the sameenvironmental exposure, only one bit of one breast willdevelop a cancer, which blows that right out of thewater. It implies there is a random stochastic element,or at least a massive element that we don’t fullyunderstand.

I would be happy to answer questions. (Applause)

Discussion

The President: Well, Justin, thank you very much. Youhave covered a lot of ground, a lot of very interestingissues. It occurs to me – we both do expert witness work– in nephrology condition and prognosis is really fairlystraightforward because the database in terms of sur-vival for renal patients is so crude and non-specific, sothat I can start with a figure, a 5- or a 10-year survivalfigure, and then I can modify it, as it were, on whim,and nobody can say ‘‘No, that’s incorrect’’. The statis-tics that you have are very much more precise. Let’stalk about the lawyers. How well do they handlethese sort of statistical issues?

Professor Stebbing: Not well, and that is why I haveto emphasise the difference. The use of averages is a badthing, because it’s offset by patients doing really amaz-ingly and patients doing really badly. You have to usemedians and tight boundaries around the medians, thepoint at which 50% of people die. So I am always asked‘‘What is the life expectancy here?’’ and I say ‘‘Oh, themedian life expectancy’’. ‘‘What does that mean?’’I think it is really important to have some groundingin 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 lifeexpectancy parameter is the point at which 50% ofpeople die and the crucial thing is answering in a timeX, time Y and time Z, and those times will differ in thepatient’s lineage. So if Mrs Smith’s cancer had beendiagnosed two years earlier, what would her life expect-ancy have been? That has to be a median. When I read




these reports people mix up these terms all the time andit really, really muddies the water.

The President: Thank you. That is the answer Iwanted to hear. So let’s throw it open to the floor.Will you please identify yourself and use themicrophone.

Mrs Brahams: Diana Brahams, barrister, retired;Editor of the Medico-Legal Journal. I used to do a lotof this kind of work. You said lawyers have a differentview of causation. Well, yes and no. I mean, the thing islawyers like things to be kind of sewn up. They don’tlike ‘‘possibly’’, they only like ‘‘probably’’, and I amsure you are fed up with hearing that, but, to provesomething you have to demonstrate it is on the balanceof probabilities so; anything over 50% will do. Doctorsare not very comfortable with it and I do understandthat, but lawyers also do understand that post hoc isn’tnecessarily propter hoc; it doesn’t follow necessarily thatbecause somebody has had a cup of tea and they are illafterwards it was the tea that did it, and there are mul-tiple causes very often and sometimes it is enough toshow that there is one factor which pushed them overthe edge, and again doctors aren’t very comfortablewith this concept. It is a different way of looking atthings. Doctors like to feel that they can be sure,rather than on the balance of probabilities, and thatis a problem, I think, for you, as well as for the lawyers.

Professor Stebbing: Do you think we are becominglike 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 termsof statistics, the average person is pretty hopeless atunderstanding . . .

Professor Stebbing: I am not presenting complexstatistics here.

Mrs Brahams: No, but, I mean, even simple ones -the average lay person will have great difficulty withthem, I think lawyers probably are a bit more sophis-ticated. Anyway . . .

Professor Stebbing: You know, when people go onMBA courses one of the first statistics they’re told isthat if there are 23 or more people in the room theprobability that two have the same birthday is greaterthan 50%, and people say ‘‘No, that’s rubbish; that’srubbish. How can that be?’’ People think that can’t beright, but it’s an absolutely true statement that if thereare 23 or more people in the room the probability thattwo have the same birthday is greater than 50%, butthat is not the same as the probability that someone inthis room has your birthday, okay? I want to be clearabout that. That is a totally different probability, andagain it is what people feel and what the reality is thatare very, very different. But, you know, when I talk tomy American lawyer friends they’re categorising plain-tiffs into platinum blonds, gold, silver – I am sorry, but

they do, you know – and the drug companies settle enmasse with these things. I don’t think drug companiesare the big bad people, you know, that people makethem out to be actually. You know, Roche, for exam-ple, spend $10 billion a year on R&D. They’re theones who are going to find the cure for cancer, notme, I am afraid.

Mrs Brahams: Yes, but they don’t like publishingtrials which are negative.

Professor Stebbing: No. I think that is an absolutelytrue statement, and that is a problem, but it is a minorproblem. Journals don’t like it as well; it’s hard toget it in.

Ms Lee: Linda Lee, solicitor. I’m afraid you’re goingto 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 likeAmerica. I think, first of all, America isn’t quite likeAmerica seems to be, because a lot of the initial deci-sions that are made by juries are overturned later whenit goes on appeal to lawyers only. In this country fromApril 1 the Government has said ‘‘We are determinedthat people will not bring claims’’ and they have made awhole series of changes to prevent people bringingclaims for personal injury. I think that is disgracefulwhere people have justifiable claims and cannot bringthem. They are creating an industry of third party fun-ders who will make a lot of money by taking damagesfrom people simply so that they can bring a claim at all.So I would like to make that statement. The secondstatement is this. I confess I started off doing physicsbefore I did law, so I do have a bit of understanding ofstatistics, and I challenge your assertion that all medicsare good at statistics. One of my great frustrations withoncology cases is there is a possibility of a ‘‘lost years’’claim. So if you can say at the point of diagnosis on thebalance of probabilities how many years would theyhave lived for the case in question but what shouldthey have lived for, so you are comparing those two,the difference in years of when you should have sur-vived to you can claim, and the number of oncologistswho could present data in that way was very small.

Professor Stebbing: I have to apologise. I shouldhave corrected myself after I said it. I didn’t mean itto sound the way it did. I think you are absolutelycorrect.

Ms Lee: It would be helpful if you could give ahandy guide to other experts, perhaps in the Journal,as to how to present data in that way, because they dostruggle.

Professor Stebbing: I would be happy to. You know,the other point is – I wish I had a blackboard – when itcomes to differences in absolute and relative risk. Wehave done averages and medians; that is sort of class 1.

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Class 2 would be relative versus absolute risk. So, forexample, if I have 100 women and I treat 100 womenwith chemotherapy for breast cancer and I don’t treat100 women with chemotherapy for breast cancer. Sothere is treat and not treat. In group A 94 will bealive at 5 years, and in group B 92 will be alive, some-thing like that. So the absolute benefit of Group Atreatment is 2%. But the relative benefit is thenumber you have saved, which is 2, over the numberwho would have died, which is 8, so it becomes 25%.Now, if you read that a statin saves 50% of all heartattacks, that is not 50 out of 100 people, that is 50% ofthe 10 out of 100 who would have had heart attacks.That is statistic session number 2, if you like. I won’t do3, unless you are desperate for me to. So statistics levelnumber 2 is the difference between absolute risk andrelative risk. I mean, I am guilty of it, grossly guiltyin clinic, where you kind of think ‘‘Do you want togive this woman chemotherapy? How shall I presentthe statistics? Do you want to do a mammogram?’’You can present the data in all sorts of ways. Thereis no way the patient is going to on the whole under-stand it. You can spin it in all sorts of ways. You cansay ‘‘Oh, there’s a 25% benefit from chemotherapy’’.That is a 25% relative benefit. That is 25% of the oneswho would have died, but the number who would havedied is tiny, because it shows we cured 92% anyway, soyou are only taking cure rate from 92% to 94%. That ishardly 25%, but that is what oncologists like me say inclinic, which we are guilty of, and that is not good. Thatis just another statistic. Don’t worry, we are not thatbad.

Mr Gardiner: My name is Bill Gardiner. I am achemist/barrister, but I was a British Petroleumemployee really, until I became a lawyer, so my ques-tion is detached and cynical, if you don’t mind, and thatis that in industry, whether it is the pharmaceuticalindustry or my industry, we tended to go for what arecalled ‘‘easy wins’’, and when I think about the actualhuman conditions of breast, testicle, prostate and thethings we fret about, those are certain things which acustomer would like to discover was an ‘‘easy win’’, andI just wonder, having spent a lot of time making deci-sions about how much to give scientists to try to dis-cover something which would make money for BPChemicals, if you could tell us, from your viewpointas a recipient of money, how decent the business is onwhat would do the public good and what are the ‘‘easywins’’?

Professor Stebbing: I am not sure I fully understandthe question. Could you phrase it in a different way?Are you asking about drug companies?

Mr Gardiner: Well, I am speaking actually in generalabout intellectual endeavour, and any inventive personwould like to have some fame as having won the ‘‘easy

win’’, and how that is set alongside the reality of whatthe public wishes to happen, and I mentioned thethree . . .

Professor Stebbing: I mean, a lot of low-hangingfruit obviously in oncology has gone. I will answeryour question in this way – 13 years ago they success-fully sequenced the whole human genome; that is 3 bil-lion base pairs, 3 billion letters of DNA; and from thatthere are 30,000 genes and, because of splicing of thosegenes, it makes 100,000 proteins, and it was thought, ofthose 100,000 proteins, about 5000 would be cancertargets; that means there would be on cancer cellsand, if you blocked them, like removing King’s Cross,the cancer cells would die. The number of cancer tar-gets is about 20 to 30, so it is actually much harder andmuch more polyfactorial and much more driven by lotsof different things than we could ever have imaged ordreaded or realised, which is why HIV is pretty curable(for want of a better word), and cancer is somethingthat is still going to be around in 100 years’ time. Idon’t know if that answers your question. Maybe inpart. Any other questions?

The President: Justin, we were talking before we gotunderway about cancer of the prostate, the commonestmale cancer. . .

Professor Stebbing: It’s not. Lung cancer is. Itdepends how you define ‘‘common’’. With some can-cers the incidence exceeds the prevalence. So the inci-dence is the number of new cases per year and theprevalence is the total number of cases in the popula-tion. So with most cancers the prevalence massivelyexceeds the incidence. With breast cancer there are550,000 women living having had or with breastcancer in the UK and there are 40,000 new cases peryear, so the incidence is 40,000 and the prevalence isnearly 600,000. With prostate cancer the incidencematches the same sort of numbers. But with, say,lung cancer or pancreatic cancer the incidence ishigher than the prevalence because people die of it soquickly. So when you say it is the commonest, againeven a simple word like that creates pandemoniumamongst statisticians, because does it mean incidence,does it mean prevalence? Certainly it is the commonestmale one when it comes to prevalence, but it’s notcommon when it comes to incidence.

The President: A very simple question. (Laughter) Iam proud to say that I have now reached the big ‘‘6’’with an ‘‘0’’ on it. Should I be measuring my PSA everyyear, every month? What is your advice?

Professor Stebbing: As I kind of insinuated before,for a screening test to work, detecting the disease earlierhas to be associated with a better outcome, althoughthe only thing that will do is it will make it look like youhave lived with the cancer for longer. The reality is,Martin, we don’t really understand how to treat early




prostate cancer. Our understanding of early prostatecancer is primitive, and I am being kind there to primi-tive. I mean, it is poor. We have no idea how to treatearly prostate cancer, in my opinion, but, you know,you kind of might want to know, because there are afew aggressive variants that can present very young, asyou are well aware as a nephrologist, these kind ofanaplastic tumours, typically in African Americans,or whatever. But on the whole we don’t understandhow to treat early prostate cancer. On the otherhand, I had a colonoscopy a short while ago, andbecause I’m a real man I had it under general anaes-thetic, because I know that colon cancer exists as polypfor 5 years before it becomes a cancer, and so that tome is a good screening test, but it’s not nationally indi-cated because it’s a real fuss, whereas PSA is quite easy.So the problem with screening programmes is that theinterplay between politics, data and the programme istoo complex for us to derive the maximum good fromit. In France, for example, they do have a screeningprogramme for prostate cancer that is very advancedand people with a family history go into special imagingand special things. We are just not developed enoughhere to have it in the NHS at the moment. That is myanswer.

The President: Thank you.Dr Josse: Eddie Josse. I am a medic and though

most of my work is in forensic medicine, I suppose asmall amount is in a condition that was untreatable 60years ago, and that was tuberculosis, and now, ofcourse, the position has totally changed and it hasbecome quite treatable, and yet it had an incidence asgreat, if not greater, than cancer and a death rate of30% to 35% of all those who developed tuberculosis, sothere is hope yet. The point I wanted to make thoughwas that in 1956 I became Prof. Windeyer’s pre-reg.houseman. In those days you could do oncology andradiology at pre-reg. level, and I remember giving intra-venous nitrogen mustard and I remember the superbresults in some patients. Particularly I remember onewith epidermolysis bullosa with malignant changes, andthe thing just melted, and cutaneous lymphoma; thingsjust melted away with this drug. But God forbid if yougave it subcutaneously in error; then, you know, all hellbroke loose. (Laughter)

Professor Stebbing: But for TB you need to treat itfor 6 months, as you know, and for typical pneumoniayou treat it for five days, and the reason why is becausethe TB bug multiplies very, very slowly. So that is whywith some cancers you can’t really treat them becausethey multiply too slowly. It is the same analogy. Andsome cancers divide very rapidly, so you can easily curethem. So people get very worried, ‘‘Oh, my gosh, thecancer is dividing rapidly’’. To an oncologist that isoften great.

The President: Are there any more questions orcomments. The lawyers are strangely non-combatant 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 peoplewho are complaining that a chance was missed to makethe early diagnosis, and that is the lost years that werebeing mentioned just now. Is that the sort of thing thatyou are having to deal with, because effectively, as adoctor, you are more of a judge in the case than thejudge?

Professor Stebbing: Yes, and I just find it really,really difficult, because, you know, to me a lot of can-cers present after the horse has bolted. The outcomewould have been same for them if they had presentedlater. You know, if you specialise in this area, howdifficult it can be. Even if it had been diagnosed2 years earlier oncologists will often not admit thatthe patient could have done much better. A good exam-ple of that would be if the disease had been metastaticall along, then anywhere along the treatment line Idon’t think anyone would say that it could have beenbetter. 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 ofthem there is this sort of muddy water in between and itis really, really hard. I find it difficult. And then thesestudies of tumour doubling time are the most primitive,awful, terrible, disgracefully quoted studies I have everknown; they’re in the most rubbish journals, because agood journal would never take them, because theywouldn’t stand a peer review, but yet people quotethem all the time. I am sure you have heard them ump-teen times. They’re awful studies. I am sorry, but it iswhat 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 thatsome cancers are low-lying fruit and are easy and othersare intrinsically difficult. I can understand how you cansay that in retrospect, but you seemed to be saying thatin prospect, as though you know that pancreatic canceris always going to be difficult, or multiple myeloma isalways going to be difficult. Is this to do with thenumber of gene target cells that there are and, if so,does that not mean that somebody may get a luckyhit whereupon they will change?

Professor Stebbing: No, because there are too manygenes in total. It is the tube map analogy. The differencebetween a squamous cell lung cancer and an adenocar-cinoma is that in a squamous cell lung cancer you haveabout 100 tube stations malfunctioning, and it is verydifficult to treat them all, and in an adenocarcinoma itmay be 5 to 10, which is much easier. But the way you

Stebbing 65



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 ofthem you gave were about life expectancy, as to whatyour life expectancy would be in your timeline. I didthat, but I did it with children, and I felt that theevidence was not straightforward; that is that theincidence of death rate from cancer, probably overthree-quarters of the last century, went up very consid-erably, very much related to the fall in death rate fromother factors - that was quite well documented – butthat the survival rate for treating cancers like leukae-mia, there is no question about it, with proper detec-tion, led to a dramatic . . .

Professor Stebbing: I want to be clear: in the 1960sand 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 thatyou have people outside Leeds Children’s Hospital col-lecting for Great Ormond Street, which winds uppaediatricians there no end, these are vanishingly rareillnesses compared to cancers in adults. If I tell you thenumbers: there are fewer under 18-year olds diagnosed

with cancer than the twentieth commonest adult. I haveto be frank with you, 350 children die a year of cancerin the UK, and that is terrible, terrible for the parentsand families and children, though those numbers areminuscule, obviously, compared to any adult tumour.I am sorry to be blunt.

Professor Zeitlin: I am not clear whether it is negli-gent not to pick them up or whether they’re so few thatthe 350 doesn’t matter.

Professor Stebbing: Okay. What I would say is thatfor every 1000 CT scans you do you will probablycause, in 30 to 40 years’ time, an extra cancer. So ifsomeone is 60 or 70 it doesn’t matter, but if someoneis a kid it matters hugely. So these diagnostic tests arenot benign, as you know.

The President: Okay. So I am going to wind thingsup now. We can carry on, I hope, over the drinks andcanapes. Justin, I want to think you for a superblecture.

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 thetalk, so I hope that we will see you. (Applause)




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