Beset by all these difficulties, two groups of doctors would play a decisive role in the ‘final push’. At the National Cancer Institute, Drs Emil Freireich and Emil Frei III provided the intellectual framework within which to proceed. They had found two or more drugs were better than one and, crucially, their toxic effects could be controlled by ‘supportive therapy’ with blood transfusions and adequate antibiotics. In addition, the cytotoxic drugs turned out to have different effects: steroids and vincristine were relatively non-toxic but the remission they induced did not last as long as that following treatment with the more toxic MTX and 6-mp. Perhaps there might be some way of exploiting this effect?27
Then there was Dr Sidney Farber and his protégé Dr Donald Pinkel at St Jude’s Hospital, the two physicians who had treated more children with leukaemia than everyone else in the world. They were sustained in their difficult task by the perspective that
the greatest mental peace is obtained by the realisation that a group of doctors and nurses are doing everything that can be done in the light of available knowledge. The needs of the family are met by a policy of complete truth and the only promise that is made is based upon the hope that the next step forward may come in time. [When] the atmosphere is one of guarded optimism based upon actual achievement, fear is more easy to dispel and to be replaced by a courageous handling of problems.28
The breakthrough, when it came, turned out to be philosophical rather than practical: the theoretical demonstration by Dr Howard Skipper of the Sloan-Kettering Institute of how childhood leukaemia should in principle be curable, which transformed the psychological perspective of all involved. For if, as Skipper predicted, ‘curing’ children of leukaemia was an attainable goal then the dreadful problem of toxicity became less significant. The ends, the cure, justified the means – any means – of getting there, even if it required the intensification of treatment to the point where some children would necessarily die from the drugs they were given rather than from their leukaemia.
Skipper had been thinking about cancer for a long time. Like so many of his colleagues his career had started in the Chemical Warfare Service, whose director, Cornelius Rhoads, in his postwar role as head of the Sloan-Kettering Institute, had recruited him to set up an outpost of the Institute in Birmingham, Alabama. Once Skipper had posed the question to himself – ‘What does it take to cure leukaemia?’ – the answer was obvious: every cancer cell had to be destroyed, as if even a single one were left behind it would double and double again and within a few months there would be more than enough to cause a relapse. The obvious way of killing off the last surviving cancer cell would be to give drugs in sufficient doses and quantities to wipe it out. Skipper, however, perceived that the problem was more subtle than this. The drugs they were using would not eliminate an absolute number of cancer cells each time they were given, but only the same percentage, with significant implications.29 Consider a combination of drugs capable of killing 99 per cent of leukaemic cells. If there were 1,000,000 leukaemic cells in the bone marrow then, following the first course of treatment, their numbers would fall by 990,000 to just 10,000. But even when the number of leukaemic cells is down to 100, exactly the same dosage of drugs would only knock out 99 cells and still leave one remaining. This turned out to be an instance of a well-known biological phenomenon – ‘first order kinetics’ – best illustrated by the following analogy:
Imagine a little boy standing outside a hen house in which a thousand eggs were scattered at random. The boy has an unlimited supply of small nails. He runs back and forth, and without aiming at anything in particular, throws the nails through the chicken wire. What would be expected to happen? Most of the nails would probably strike the wire and fall outside. Of the few that go directly through, each egg is likely to be struck many times before it is broken but sooner or later it will receive a fatal blow. Then suppose that by the time the boy has thrown a bushel of nails, nine hundred of the thousand eggs have been broken. The nails continue to come in as thick and fast as ever but each nail has a smaller chance of breaking an egg because there are only a tenth as many eggs. Each egg, however, gets hit just as often as it did before and so we may expect the second bushel of nails to break about ninety of the remaining one hundred eggs. And so on.30
If the law of first order kinetics was correct, then the prevailing method of inducing a remission with one drug or a combination of drugs, and then reducing the dosage to cut down the danger of drug toxicity, was clearly wrong. Skipper’s theoretical view argued the contrary: once remission had been induced then the dose of drugs had to be maintained at as high a level as possible because the fewer the leukaemic cells there were in the body the more difficult it was to kill them. Armed with this theoretical perspective Freireich and Frei at the NCI fashioned the vital drug protocol: relatively non-toxic vincristine and steroids (prednisone) would be used first to induce a remission, but the leukaemia cells would then be hit again and again with MTX and 6-mp, with treatment continuing for two to three years in the hope of eliminating ‘the last surviving cancer cell’.
In Memphis, at St Jude’s Hospital, Dr Pinkel went one step further by also giving radiotherapy to the ‘sanctuary’ of the brain and MTX directly into the spinal fluid in the hope of eliminating any leukaemic cells that might be residing there. He started this new regime in 1962 but the dose of radiation he chose failed to prevent relapse.31 He responded by doubling the dose and that did the trick, reducing the incidence of relapse in the brain twenty-fold. With this he was able to report, as already described, that the prevailing ‘cure rate’ of leukaemia (children surviving more than five years) of 0.07 per cent in 1962 had leaped to more than 50 per cent.32 Nor was that the end. For the next twenty years, yet further improvements emerged from the rigorous analysis of new drug protocols where various combinations of drugs were juggled around in endless combinations, eventually pushing the cure rate up to 71 per cent.33
The cure of ALL is proof of the power of science to solve the apparently insoluble. But science can certainly not claim all the credit, for many aspects of the cure of ALL remain frankly inexplicable, as Pinkel himself acknowledged in a lecture in 1979.34 Firstly, and obviously, ALL could not have been cured without the anti-cancer drugs developed between 1945 and 1960, but these, with the exception of 6-mp, were in one way or another all discovered by ‘accident’.
Secondly, there is the question of their mode of action. Here Donald Pinkel, perhaps surprisingly, comments on ‘the scant knowledge of how anti-leukaemic drugs work in humans’. Virtually all interfere with the DNA of the cell and therefore the ability of the cancer cell to divide. In the early days, when it was thought that leukaemic cells divided more rapidly than normal cells, this provided an obvious rationale for their anti-cancer activity. But, in fact, leukaemic cells divide more slowly than normal cells, which makes it difficult to understand precisely how they work. There are, of course, various other possibilities. The self-repair mechanism of cancer cells can be defective, making them less able to correct the damage to their DNA caused by the anti-cancer drugs.35 But there is also a suggestion that some of the drugs might have some ‘unknown’ anti-cancer activity quite separate from interfering with DNA. As one doctor observed: ‘I am not convinced the action of various drugs is indeed restricted to the reproductive mechanism of the cells. Anyone who has seen the rapid shrinkage of leukaemic infiltration and the explosive destruction at the microscopic level must keep an open mind on the question.’36 Finally, Dr Pinkel was frankly sceptical that medical treatment alone could explain the cure of ALL. He speculated instead that ‘leukaemic therapy in children may suppress the lymphocytic proliferation of ALL until the body’s own control mechanism becomes operative’.
Following the eventual success of the long march towards a cure of ALL, there was every reason to be optimistic about the future. ‘The next ten years will be wonderful ones for cancer therapy,’ Sidney Farber told Newsweek columnist Stewart Alsop – himself a leukaemia survivor �
�� ‘the time could come quite soon when the beast will be tamed . . . surely it is worth a major national effort to speed the coming of that time.’37 The ‘major national effort’ materialised immediately in the form of President Richard Nixon’s ‘War Against Cancer’. Nixon, keen to outflank potential presidential candidate Senator Ted Kennedy, proclaimed in his State of the Union message in 1971: ‘The time has come when the same kind of concerted effort that split the atom and took man to the Moon should be turned towards conquering this dreaded disease. Let us make a total commitment to achieve that goal.’ And so two days before Christmas 1971 he signed a Congressional bill that would over the next decade increase federal funding for the National Cancer Institute from $400 million to nearly $1 billion dollars a year.
Cancer research was now awash with funds. There was certainly much to do to improve on the results already achieved by Donald Pinkel and to apply the chemo approach to other cancers known to be sensitive to drugs: lymphomas, rare childhood cancers like osteosarcoma, leukaemia in adults, and testicular cancer.38 The results were certainly impressive, but the problem was this class of cancers were relatively rare, only representing a tiny fraction of the total – less than 1 per cent. To win the ‘War Against Cancer’, this form of treatment also had to be applied to the much commoner types of the lung, breast, gut, the so-called ‘solid’ tumours that arise from ‘solid’ organs, which had (or might) spread or metastasise throughout the body. Confronted by this challenge, bright young doctors flocked to join the newly created specialty of oncology, but there was never the slightest possibility they would achieve similar results. These solid tumours are biologically entirely different from the treatable cancers like ALL. Their causation is intimately bound up with the inevitability of ageing (the risk of getting cancer increases incrementally with each passing decade), so it was as unrealistic to suggest they might be curable on a large scale as it would be to say that ageing itself was curable.
Further, solid tumours respond poorly – if at all – to the anticancer drugs. This ‘resistance’ – which contrasts so markedly with the ‘sensitivity’ of leukaemic cells – can be attributed to their different origin. Most solid tumours arise from tissues that are exposed to the outside world, such as the larynx, lung, stomach or colon. These tissues must be robust and plentifully endowed with mechanisms to eliminate toxins to which they are exposed, which obviously include cytotoxic drugs. ‘Sensitive’ cancers by contrast – such as those arising from the blood – are contained within the body and so, not requiring mechanisms to protect themselves against toxic exposure, are unable to defend themselves against the onslaught of anti-cancer drugs.
It is a reflection of the enormous optimism generated by the ALL breakthrough that these clear limitations to the applications of chemo to the solid tumours were scarcely recognised. There was, on the contrary, more than enough money from the NCI to pay for legions of researchers to investigate the effects of treatment in clinical trials, just as they had done so successfully with ALL, and there were more than enough oncologists to test out these new treatments on the solid tumours.39 Two factors fuelled this enthusiasm for chemo. First it offered hope – or rather the appearance of hope – to patients with advanced cancer and was at least ‘something else that could be done which might make a difference’. And if it did not work, the doctors could reassure themselves with the argument that they had not quite yet got the magic formula right, the correct combination of drugs given in the correct dosage to crack this particular cancer.
The results were predictably appalling, with those receiving chemotherapy dying more rapidly and with a much worse quality of life than those receiving no therapy.40 The blindness of oncologists to what they were doing is well exemplified by a 1983 report claiming that chemo was no more toxic to the elderly than to the young, so they should receive chemo at maximum doses. Curiously the author of this report, Dr Colin Beg of Harvard University, felt it unnecessary to make any reference to the results of treatment, where only 20 per cent of elderly cancer patients have any response to treatment (i.e. 80 per cent do not) and the duration of survival with treatment was on average only six months.41 In Britain Tim McElwain of London’s Royal Marsden Hospital commented on ‘the confusion of busyness with progress . . . with nasty drugs being thrown at unfortunate patients with very little evidence of gain’. The remorseless litany of failure generated two very different responses on either side of the Atlantic. In the United States the oncologists remained bullish, making exaggerated and readily refutable claims about the benefits of chemotherapy. In Britain, by contrast, where there was no financial incentive for doctors to prescribe chemo and therefore to justify its use, there was more a mood of self-doubt and soul-searching. In 1984 Professor J. S. Malpas of St Bartholomew’s Hospital described oncology ‘as a child of much promise of which much was expected . . . which it could be said has failed to live up to expectations’.42
Indeed it was not until the mid-1990s that modest improvements of around 10 per cent in survival in patients with some types of solid tumour provided at least some justification for the widespread use of chemotherapy.43
11
1978: THE FIRST
‘TEST-TUBE’ BABY
The burgeoning prestige of medicine in the post-war years was grounded not only in its substantial achievements, but the perception that some of those achievements – such as heart transplants and ‘test-tube’ babies – verged on the miraculous. And it was extraordinary to be able to remove a man’s ailing heart and replace it with another, and to facilitate the act of procreation and thus fulfil for the infertile the deep human need to have children.
It is thus only logical to infer that those responsible must be very clever and the possibilities of what medicine could achieve – given sufficient funds – must be limitless. The reality, as seen repeatedly with the ‘definitive’ moments of post-war medicine, was rather different. The achievements did not arise from a profound understanding of the nature of medical problems but, more often than not, from chance or luck or some technological development. And the same is true for the events leading up to the birth of Louise Joy Brown, the first ‘test-tube’ baby conceived by ‘in vitro fertilisation’, usually shortened to IVF.
Fertilisation ‘in vitro’ means ‘in a glass tube’, to distinguish it from fertilisation ‘in vivo’ – in the living body. IVF might seem to be an amazing scientific breakthrough, but is little more than a sophisticated piece of plumbing for women with blocked fallopian tubes, whose eggs cannot pass from the ovary down into the uterus to be fertilised by the partner’s sperm. The solution to overcoming the blockage – at least in theory – is obvious: obtain an egg from the ovary, add the partner’s sperm, then pop the fertilised conceptus back into the uterus through the cervix with the help of a piece of plastic tube. With luck, it will stick. Nature does the rest – the difficult part – where the tiny fertilised egg grows and multiplies to form a foetus made up of billions of cells, each with its own specialised function. Thus the contribution of human agency through the procedure of IVF in initiating the process is important enough, but it cannot bear comparison with the real miracle – the ineffable mysteries of embryonic development itself.
This sanguine view of the scientific significance of IVF is not intended to belittle the work of those who did so much to make it happen. Rather the reverse: IVF merits its place in the pantheon of great events of post-war medicine on its own account but also because it illustrates better than anything else the essential attributes and multi-faceted nature of the research from which those ‘major events’ finally emerged. The first point is how difficult it can be to establish even the simplest facts – that it was indeed possible to fertilise a human egg in vitro. Next there is the crucial role of human personality, and in particular that of its pioneer Bob Edwards, who through the two phases of the development of IVF experienced first nine years and then eight years of bitter disappointment that would have convinced any lesser person to give up in despa
ir. Then there is the essential contribution of the cross-fertilisation of ideas from other disciplines. Bob Edwards did not set out to find a treatment for infertility because of blocked fallopian tubes. His primary interest in the fertilisation of human eggs was the observation of the earliest stages of human development, and this just happened to coincide with the blossoming of research into the use of fertility drugs in women where infertility resulted from a completely different reason – the failure to ovulate, or produce eggs. Thus IVF emerged from the fusion of two quite separate areas of scientific endeavour. Finally, there was, as so often happens, the singular contribution of technological development, in this case the laparoscope, which permitted eggs to be removed from the ovary without the necessity for a major operation. This made IVF a practicable proposition.
Each of these developments warrants closer scrutiny, but first, to emphasise why IVF was a definitive moment in post-war medicine, comes a description of the culminating event, the birth of Louise Joy Brown in 1978. The dramatis personae in this ‘sensational story of the world’s first test-tube baby’ are Bob Edwards, Reader in Physiology at Cambridge University; his collaborator Patrick Steptoe, Consultant Obstetrician at Oldham General Hospital; Sheena Steptoe, wife of Patrick Steptoe; and the parents, Lesley and John Brown. Just before midnight on Tuesday 25 July 1978, Patrick Steptoe performed a Caesarean on Lesley Brown and delivered Louise Joy, who weighed 5lb 12oz. Meanwhile, elsewhere in the hospital, husband John Brown was sitting in his wife’s room with Sheena Steptoe.
The Rise and Fall of Modern Medicine Page 17