B17 Cancer

>> tom treasure,md, md, frcs, frcp: now before it getsunderway, and before i forget, i'm going to acknowledgecertain groups who are fundamentalto this work. and first of all, onthis slide, the institute of cancer research, which is thescientific clinical trial end and research end of theroyal marsden hospital, and the clinical trials unitat the royal brompton hospital, who have managed two trialswhich i'm going to talk about,

both of them fundedby cancer research uk. and also i'm going touse data which comes from the thames cancer registry,which is based within kcl and is one of the, is the largest cancerregistry in europe. now this is a ratherironic slide. you can see what it is. it's the two, two towers, andit's an advert for asbestos from 1981, by which time thedangers of asbestos in terms

of lung disease and in particular cancerwere already well known, and in a way, this is asort of rear guard action, and they're pointing out thatasbestos is throughout the building, throughout [inaudible]in insulation and pipe lagging and central heatingand everything else. and already it wasbecoming known, although probablynot widely known, that asbestos is the cause

of a particularly nastycancer called mesothelioma. now this picture here is acombination of a ct scan, an x-ray cut vertically,and a pet scan. now the, is there apointer, or shall i con? yeah. sorry. i thought i was going to beable to use this [inaudible]. on this side, you can seethe rib cage, the vertebrae. these are the shoulders, theneck, the liver, and so on. so this is a lung, and this isthe lung on the healthy side.

on this side, this brightlight is a pet scan, which shows up an area of highmetabolism, which is the cancer, and you can see it's veryextensive, surrounding and encasing the lung,and that's mesothelioma. now this is a complicated slidethat i'll take you through, but it shows the relationship between asbestosand mesothelioma. along the bottom hereyou can see from 1900 up to predictions goinginto 2040, 45 and so on.

this line, this yellow lineis the amount of asbestos that people were exposed to inthis period through the 1940's and up to about 1980, andthe bars show the imports. so that is asbestos peakingas a very valuable material in building declining andbeing effectively banned and highly regulated. then following, and thelag time is over 40 years, these green spots aredeaths from, male deaths, and that's the majorityfrom mesothelioma,

and the purple lineis the prediction of how that's likelyto be followed. so we found ourselves 15 yearsago seeing that rise and knowing that we had ahead of usa lot of patients coming to us with mesothelioma. now i was working at guy'shospital at the time, and that serves communities withthe highest mesothelioma rates in great britain, and youcan see the dark blue areas around the [inaudible],

which was shipbuildingareas and industrial areas. the plymouth and portsmouthnaval dock yards and that area of london where guy's hospitalis is the site of the old docks, commercial docks, butalso the naval dock yards down the midway, andthose patients came to us in increasing numbers. the question for us as surgeonsis what could we do about it. can we cure mesothelioma? well, attempts have been madeby very radical operations

to do this in the 70's, andif you look at this area here, you can see that this is avery extensive massive disease, and to clear it, you haveto, or the way it was done is to remove the whole ofthe lung on this side, but also the membrane around theheart, which is the pericardium, the diaphragm, strip off thepleura from the chest wall, and even then wouldyou really clear it. well, initial operationswere hazardous. there were high death rates.

the cancer came back veryquickly, but it seemed later on that if it wascombined with chemotherapy, there were better results, andthen adding in radiotherapy, people began to claim that theywere able to get longer survival and maybe even cure it. and this was the sort thing wewere exposed to at the time. i would have to tell youthere were reservations about this in britain. british surgeons didn't takeit up with great enthusiasm,

but elsewhere, it was adopted,and we reached a situation where there were publicationsclaiming good results. our patients wanted to knowwhy we couldn't offer it and were raising the money togo abroad persuaded by this sort of highly personalizedinformation. well, faced with that dilemma, we wanted to knowwhat we should do. and the first task was to seekthe evidence, which we did by formal systematic review,

and that was publishedin "lancet" 2004. it seemed to us that thesewere all retrospective studies, relatively small groupsof patients selected, reported by enthusiasts,and in all cases, the patients had completedtheir various multi modality treatments, very often twoor three treatments on top of each other, and we did notbelieve we could see evidence that the surgery was effectiveamongst that selected group of patients, havingnotable treatments.

so we argued thecase for a trial, which we published in the pmj. now to cut a very longand arduous story short, we'll cut to the report of thatstudy, which came out in the "lancet" 2011 last year. now this is a standard wayof displaying survival data if you're not familiar with it. there's the passage of timealong the bottom, six months, 12 months, 18 months, and thenin percentage the proportion

of patients surviving, andthis was a quite small study. there was only 50 patients in total depictedhere in two groups. so each downward notch is thedeath of a patient as they go from all the patients enteringdown here to 18 months. now to go back, whathappened prior to this was that we saw patients whowere potential candidates, not only for the surgery but theradiotherapy and chemotherapy that had to go with this packageto try and match the results

that were being presented to us. so all the patients hadchemotherapy and re-evaluation and further scans, and at thispoint, if they were regarded as candidates forsurgery [inaudible], we then randomly allocatedto one of two groups. so you have two groupsthere of patients. one group get the surgery,and the other don't. now the important thing is thatthis red line are the patients who have the surgeryand radiotherapy,

and they do considerablyworse and the difference, which is significant, by havingthe treatment rather than not. also important is that thisred line actually when you look at it is not dissimilar. in fact, is quite similarto the published results. the results were not that good, and within the trial we weregetting the same sort of results as were being promulgated. the important point was that wehad control group of patients

who were randomly allocatedto not have that operation, who actually didbetter by not having it. so that study was publishedlast year, and at this point, it's very important to thankcolleagues, particularly at guy's but otherhospitals around the country. the trial team at the marsden and also the britishthoracic oncology group, which brings together all thecancer specialists who deal with cancer of the chest, mainlylung cancer, but also this sort

of cancer, who awarded us thelifetime achievement award only last week, which for usis hugely appreciative from our own colleaguesbecause this was an extremely difficult study. published in the same year wasthis book by lionel shriver. now lionel shriver wrote "weneed to talk about kevin", and if you've not readthat, heard about it, or seen the film, you should. it's fascinating, but she'salso written this book,

which is about mesothelioma. and it's based ontruth in that a friend of hers had mesothelioma, notin the lung but in the abdomen, but the principles arereally very much the same. and in the same week or so, herhusband decides to, and you, this is no secret, this isall on the [inaudible] blurb so i won't be spoilingthe story for you. to cash in his lifetimesaving from his business of a million dollarsto use it in a more

or less altruisticform of retirement, and they get the newsthat she has mesothelioma. so they spend the next year with the bank balance beingeaten away, and towards the end, the last consultation withthe doctor goes like this, and her husband says, "sowhat exactly did we buy? how much time?" the doctor says, "oh, i bet weprobably extended her life a good three months," andi'm sorry, dr. goldman,

they were not a goodthree months. and the point being madeis that the quality of life for this patient in thatlast year of her life was not at all good, and noris it for many patients who have complex multimodality treatment. now, of course, if they areyoung and in their teens or their 20's withlymphoma or leukemia, and they have a terrible yearbut live for another 50 years, it's not a bad deal, butthese are older patients,

and we're very concernedabout it, and you might wonder how can anovelist put her finger on it when the doctorscount, well, of course, novelists make things up,and she happens, i think, to be right about this one,but they're not always right, but she did happen to getthis one well identified. so why don't the doctors know? well, maybe they'rejust too close up to it. they're seeing agroup of patients

who they've looked after,and they report the ones where they completedtreatment, things went well, they send in a reportto the literature. what they don't tell us aboutand, indeed, probably can't because the recordsaren't kept in that way to be accessed retrospectively, patients who they thoughtthey might make a start on this treatment butfell by the wayside for one reason or another.

the cancer progressedon chemotherapy, or the patient didn'twant it and so on. so we don't know whathappens to those patients. they certainly nevertell us in cohort studies about all the otherpatients being considered by the cancer committees,the tumor boards who were potentiallycandidates for this surgery, and none of them know what theoverall burden of the disease is in the population and howthis group of patients fit in

and to what extentthe representative. by now, you'll recognize thatthis is [inaudible] work field, and each of these figuresis a little clay figure. they're all the same inthat they're made like clay and molded in the hands of histeam and have eyes that look at you and so on, but they'reall different, and that's one of the problems that[inaudible]. well, now, moving on frommesothelioma to cancer of the colon, whichis much more common.

mesothelioma causes a coupleof thousand deaths a year; cancer of the colon40,000 patients in a year, and many of you willknow patients that have these common cancers. the three common ones arelung, breast, and colon. so the colon, the largebowel, large intestine. a cancer which developsthere is a serious matter. miserable time perhaps withconstipation and diarrhea and eventually maybeobstruction.

the cancer may block offthe bowel completely. it may erode into otherorgans and nasty leakages and fistulas occur andterrible peritonitis. so you would want a surgeonto deal with that for you and overcome thatimmediate problem. and highly successful, veryspecialized surgeons deal with that, and about halfthe patients with cancer of the colon are cured,but in the other half, the disease comes back, orthere are secondary deposits,

particularly in theliver and the lung which cause further trouble. now the question here in thismuch commoner cancer is does further, again, the matter ofadvanced aggressive surgery to remove the secondary cancerin the lung give any benefit. now, so that you can keep upin places completely new word to you - metastasis is the name for a secondary depositof cancer. and, hence, metastasectomy isthe operation to remove it.

you will see that coming up. again, we needed toseek the evidence, and here i shouldgive acknowledgement to the electronic library here, which when you'redoing this sort of searching work is justfantastic in being able to look up the world's literatureanywhere i happen to be in the world pretty well. don't have to be at my deskhere, but also the roles

in society of medicine becausesome of the things we need to look at have beenpublished long time ago and are in rarely read journalsdown in the basement. so acknowledgement to those. now, this picture, thistangled web is a citation network analysis. and, in fact, [inaudible],[laughs] who's here in the audience, helped us withthis and made this picture. all around the edge, allthose circles with numbers

in them are published papers, and there's a totalof 72 of them. they are all examples offollow-up studies of removal of lung metastasis in, with intent to completecure of a colon cancer. the lines betweenthem are citations. so in any scientific or medicalpaper, as many of you will know, that at the end of the paperwill be a list of 10, 15, 20, 30 articles, other articlesto which the authors refer.

so what you can see here isthese are all reporting the same thing over this period of 1971to 2007, very similar reports, and they're all [inaudible]each other. sort of a frenzyof mutual citation. and this is really quitetypical of what happens because there is freedom for theauthors to quote what they want to quote, and they will,of course, quote things that support their view,but that's on the edge here. there are these four whichare papers who don't agree

with them, but they don'tget much of a look in. now here's one, for example, andthis was written by this man, torkel aberg, in 1980, and heasks is this a fact or fiction. because he says it's beenassumed in all these papers, assumed, implied, orclaimed that were it not for the operation,survival would be nil, and he says, well, is that true. would some of thesepatients have survived? is it as extreme as that?

that the ones whosurvive are cured by it. now he's a mainstreamsurgeon, thoracic, cardiothoracic surgeon himself. worked in [inaudible] andwas the secretary for years of our european association,and he was the president for me. so i know him very well, andhe wrote this a long time ago. so we took that question, we hada look at it, and this is where, done by carl, andparticularly by martin upley. now here, again, you'vegot one of these graphs,

and purple line is ofpatients with colorectal cancer who at the time ofpresentation have metastases, and that is theirsurvival and data from the thames cancer registry. and there at 60 months orfive years is the typical time when people reportsurvival data - five years' survival data is apretty typical number to give for cancers, andit's 40 percent. well, first of all, it isn't 0.

it happens to be ten percentat five years going down to about five percent later, but,still, this would be a good game if it were all attributableto the surgery, but there are a couple ofproblems with that comparison. in that network analysisthat we did, we did a formal systematicreview of 51 reports from which we could get data, three and a half thousandpatients, and, overall, fairly consistent message,but 40 percent survival

at five years, but the patientsdidn't have their operation at the same time asthe colon cancer. on average, it wasthree years later. so, in fact, that steepdeclining path of the curve is to some extent irrelevantin this comparison because to enter thisgroup of patients of the 40 percent survival, they have on averagealready been free from dying for three years.

so the bit of the curvethat's more relevant is that flatter bit, but there'sa bit more to it than that. those purple line patients areones who had metastases right at the outset, but most patientswho have this surgery looked as though they werecured at the beginning, and the metastasescome back later. now the stages, theblue line that patients with the least severe invasivecancer at the time of operation and on down ones that gothrough the wall of bowel,

ones that are tending tospread out into the tissues, and only the ones in the purpleline already have spread. so if you now make a comparison,taking a group of patients which are similar inthat respect to the ones in the series, itlooks rather different. so now you reset to 0, andthat's the shape of the curve. now they're similarin only two respects. that there has been an intervalbefore the metastasectomy was performed, and they have thesame sort of mixture of severity

of the primary cancer. they may be differentin many other ways, but it certainly gives youa very different picture of the comparison which isimplicit in those 72 papers which i showed you andgoes largely unquestioned. martin and the, his coworkersdoing that with us looked at two papers for this in thebig population of patients, but at 150, they both have this40 percent five-year survival. one from america and the otherone from japan and published

in the time when there wasthis great flurry of activity in this form of surgerythen through the 1990's. and for both of them, if youlooked at a group of patients from the thames cancer registrywho resembled them at least in those two respects,quite a lot more are alive than the nil, which is assumed. so we have a problem. how to find out whatmight have happened to these selected patientswithin these studies who appear

to do well if theyhad not been operated. very much as i showedyou for mesothelioma where we've actuallydone that study. now the question isis this survival rate, are they attributableto surgery? did the surgery cause them tobe alive, or were there features of those selected forsurgery and selection for surgery which is the effect? now there are two favorablefeatures which we'll able

to get out of those papers. the number of metastases and usually the paper will saywhether there was just one, three, eight, many. usually one, two, and three,that's the typical sort of thing, and they will alsoknow the interval, and in study after study favorablefeatures or fewer metastases and a longer interval. now this is a way ofthinking about that,

a formal thought experiment. and here there are 300 littlepeople of whom 25 are green, and that would, that'sfive percent, and they are saying naturalsurvivors who would come out of the thames cancerregistry and be alive, and they're scatteredin amongst them. but now we've done abit of sorting out. those down on the bottomhave many metastases and then upwards,single metastases,

and along the other direction, they go from very shortintervals to longer intervals. this is just made up. just a way of talking about it,but that's exactly what you do because these are the featureson which patients are selected for this form of surgery. well, if you then operate onthe ones in the top corner, which is about eightpercent, in reality the number of patients selectedare less than that.

they're down aroundfive, four percent. so this is sort of beinggenerous, but just supposing 10 of those 15 naturalsurvivors are amongst the 25 that you have selectedfor surgery, you would get your 40 percent. so our view of this is that without doing arandomized trial, we won't know. that's the cover of a rathernice book, which is for those who are not, are interested butnot experts in medical research,

spells out the issues todo with testing treatment, and they're a group ofdoctors that [inaudible] and so on who've producedthis nice book. on the other side, yousee the problems of these. that the cancersare highly variable. cancers don't behavein a consistent way. some are extremely [inaudible],and some are very aggressive. also the treatmentsare not consistent. the treatment sort of respondsto the patient or the point

of view of the doctor, and veryoften in multiple treatments. and out of all thatvariation, it's difficult for an individual doctor tosee the signal from the noise, and that's the argument forhaving a randomized trial. and we're, we're[inaudible] started. it's called the [inaudible]trial, and that's for pulmonarymetastasis [inaudible] and colorectal cancer,and you can see why we go for these nifty littlealgorithms [laughs]

like [inaudible]. but my title had thelimit set by nature, and this is where thephrase comes from. this is a lovely book given tome some time ago as a present, and from arthur holman, who's acardiologist in this hospital. we, maybe somebodyeven knows him. eighteen ninety-sixhe wrote this. "surgery of the heart hasprobably reached the limit set by nature to all surgery.

no new method and no newdiscovery can overcome the natural difficultiesof which it presents." and it's a favoritequotation, which heart surgeons and [inaudible] thoracicsurgeons put up at the beginning of their lectures andsay [inaudible] see. see how good we are. that's what they thought. i put it up as a littlememento [inaudible]. he was wrong.

very good man, but he was wrong. i could be just as wrong. so when i tell you that ithink there are limits set by nature, it may not be true. maybe surgeons of thefuture will be able to do things like [inaudible]. i don't think so, otherwisei wouldn't be giving you this lecture, but one always has tohave this element of uncertainly about whether we reallyknow it or presenting this

in the department wherethere are physicists around, they fished out this. didn't know about this. albert abraham michelson in1903, much the same time, said, "the most importantfundamental laws and facts of physical science haveall been discovered, and these are now so firmlyestablished that the possibility of their ever being supplemented[inaudible] new discoveries is exceedingly remote."

i wonder if they know aboutthat in [inaudible], but anyway. that, so it's not just doctors. it's other people aswell have this impression that where we are now isthe right place to be. we've got it all sorted out. what more do we need to know? so my conclusions foryou are that the history of medicine includes manyretreats, and it isn't just because people finda better treatment.

it's quite often becausethey realize eventually, maybe after hundreds of years that the things they aren'tdoing are not only not helpful but actually harmful,and i think the surgery for mesothelioma,which i've shown you, fits into that category. also, doing more,wanting to be seen to be active may not bebetter than doing less. there are times to justback off and do less.

very, very hard, and that's hardfor patients and for doctors to face, but withsecured knowledge, you can at leastgive a firm view that less is better than more. and also the questions becomemore and more complicated. there are things in medicinewhich aren't very clear cut. if you have a cataract, and a skilled eye surgeonoperates on you, you can see. if you have an extremelyarthritic hip,

and a good orthopedic surgeonlooks after you, you can walk. but when you've got diseasesof vary, varying progression and with multiple treatments,it's more difficult to see that. and just because questions arecomplicated doesn't mean you should give that form or sortof make it up as we go along. we need plain answers,and that's why some of these trials areactually very simple, the pragmatic trials. we'll do this, andwe'll do that,

and the decision willbe made at random. so, finally, thanks to manycolleagues who've contributed to these studies, andto many colleagues who haven't necessarilyagreed with me as i've gone alongdebating these things, because the processof arguing to and fro helps clarifywhat the real issues are. so i'm grateful to them, too. but also to many past, present,and future patients willing

to be treated within trials,and we're grateful to them, but also i thinkit's worth noting that there should be somesense of duty in that because the good treatmentsthat we give now rely on patients previously who werewilling to go into studies. to have studies for the futurerelies on people to willingly go into studies now, and, ofcourse, they should be protected by good regulationand good science and not recklessexperimentation,

but without people beingin the studies now, we will not know for the future. so thank you, very much. [ applause ] >> thank you very much,professor treasure. i think we have time fora couple of questions if there are anyin the audience. [ pause ] [ inaudible audience response ]

>> there's a microphonecoming your way. there's a microphonecoming, yes. i can hear you, but it's so thatthe, that it's recorded and - >> have you ever done anyresearch as to whether surgery without chemotherapy andradiotherapy are successful? >> tom treasure, md, md,frcs, frcp: oh, oh, yes. not personally, but surgery for cancer was practiced a longtime before it was ever combined with chemotherapyand radiotherapy.

and if you have a cancerwhich is located in one place, in my case it's lung cancer,and it's well within the lung, hasn't yet spread throughthe blood or the lymphatics, and you take out thatportion of the lung, you can cure the cancercompletely, and that, certainly, well, for many casesof colon cancer. now chemotherapy goes in the blood streamand goes everywhere. so it's a means of tacklingcancer which is disseminated,

which is quite beyondthe reach of a surgeon, this microscopingand it's everywhere. increasingly, the two areput together in combinations, and those combinations have tobe studied in randomized trials, or you can't see thewood for the trees. so yes. isolatedsurgery has been studied and known to be effective. the combinations must be. not as often as someof us would like to see

of those combinationsbeing tested properly, but the straight answeris yes, they have been. [ background noise ] >> do you think thatmeat and the consumption of meat contributes tothe acquisition of cancer because i've noticed thatvegetarians when they sort of get older, they don't seem toget any or as many incidences. and eating fruit and vegetablesisn't just a sort of merry line, but is, contributes togood health and exercise?

i can't give you aclear answer to that. the best understanding of cancers are justas i showed you. asbestos and mesothelioma arelinked, but so is smoking. if you could extract thedata, you could show the same. so smoking is clearlypro-cancer. now there's a great dealof interest in nourishment, which foods are favorable. there seem to be verycompelling reasons

to make sure we have adequatevegetables, adequate roughage, and so on, but i don'tthink there's a simple cause and effect, but i don't know. it's not my area, but it'scertainly not a clear one. >> certainly, do you thinkthere's, exercise, for instance. daily exercise like, certainly,sort of daily exercise and swimming and all of thatsort of thing on a daily basis, that must help keep the bodyexempt from such things - >> tom treasure, md,md, frcs, frcp: well,

i think it keeps the body fit,but there's no real reason to think it's [inaudible]in cancer. i think it's quite importantto not be, one of the things that goes, that idon't like to see with cancer patients is a sort of you brought it onyourself attitude. if you'd only done this,or you'd only done that, this wouldn't have happened. i don't think that's very fair.

[laughs] i think you, becausei don't think it's even, it's fair even if they, even if you don't think they'velived very healthily, you still look after them. so it's not an areawhere i think it's useful in the care of patients. >> [inaudible] iwas thinking more of people conductingtheir lives to - >> tom treasure, md, md,frcs, frcp: oh, i agree.

yes, yes. absolutely. absolutely. we should all leadbetter lives and stay fit. no, it's not, i don't disagreewith the sentiment at all, but the scientific pointis there a proven link, not that i'm really awareof, and i think i'd know. >> i think these are probablyvery wise words to end on, [laughter] if you agree with me. thank you very much, all, forbeing here today, and joining me

in thanking professor treasureagain for a great talk.