The Rise and Fall of Modern Medicine

by James Le Fanu

  But unknown to Zuelzer the protocol of treatment devised by Pinkel in 1967 would indeed produce the ‘cures’ that many had begun to think might elude them for ever, as the cure rate soared from 0.07 per cent to over 50 per cent. ‘We conclude from the results of this study that complete remission of childhood ALL is significantly prolonged by intensive combination chemotherapy. The toxicity and infection encountered are significant but certainly not prohibitive in view of the results obtained,’ Pinkel observed in 1971, and everyone agreed. The following year, when he gave the annual guest lecture at the Leukaemia Research Fund in London, he outlined to an ‘entranced audience’ of doctors from all parts of Britain the clinical studies co-ordinated at St Jude’s over many years.6 ‘There is now no place for the palliative treatment of leukaemia,’ The Lancet commented in an editorial. ‘Dr Pinkel’s results are impressive, not least for the methodical manner in which seemingly intractable problems have been solved at every stage.’7

  To properly appreciate Pinkel’s achievement it is necessary to clarify the fundamental problems of treating cancer. When a malignant tumour is limited to one part of the body – say, the breast or the gut – it can be removed and, with luck, cured, either by surgery or radiotherapy. But when the cancer is dispersed – as with acute leukaemia (and the same applies to any cancer that has spread or ‘metastasised’) – the only hope lies in drug treatment, which can selectively kill the cancer cells wherever they might be. This would be relatively straightforward were the cancer cells different in some special way that could be interfered with, thus making it possible to kill them while leaving the healthy cells untouched. But though cancer cells are indeed different from normal ones, it has never been possible to turn those differences to therapeutic advantage. The problem was aptly summarised by Professor W. H. Woglom, a distinguished cancer researcher, back in 1945: ‘Those who have not been trained in chemistry or medicine may not realise how difficult the problem really is. It is almost, not quite, but almost as hard as finding some agent that will dissolve away the left ear but leave the right ear untouched.’ In the thirty years following Woglom’s disheartening analogy, hundreds of thousands of chemicals were investigated for their anti-cancer activity, of which a handful, thirty or so, were found to be of any value. Virtually all owe their origins to chance observation or luck.

  The first was nitrogen mustard. At the outbreak of the Second World War, it was anticipated that the Axis powers, Germany and Japan, would resort to chemical warfare – and the use of mustard gas in particular – on a massive scale. Alarmed at the prospect, the US military authorities set up the Chemical Warfare Service to find an antidote. The immediate incapacitating effect of mustard gas is to cause a severe watery inflammation of the eyes (conjunctivitis) and painful blistering of the skin. Its lethality, however, results from its effect on the bone marrow, where it destroys developing blood cells, leaving its victims vulnerable to haemorrhage and overwhelming infections. These effects had first been documented at the close of the First World War and were to be confirmed in 1943 when a German raid on the US fleet in Bari harbour on the Italian peninsula sank a ship – the Harvey – with 100 tonnes of mustard gas on board.8 In a medical report compiled on those exposed to the gas, Colonel Stewart Alexander of the US Medical Corps observed ‘the effects upon the white blood cells was most severe – on the third or fourth day the count began to drop in a steep downward trend’.9

  But if nitrogen mustard kills off the white cells in the bone marrow, might it not also reduce the malignant proliferation of white cells that occurs in patients with leukaemia or lymphoma? As part of the US military research programme, two young scientists, Alfred Gilman and Louis Goodman of Yale University (later to become famous for their classic textbook The Pharmacological Basis of Therapeutics), decided to give nitrogen mustard to ‘one lone mouse’ with an advanced lymphoma (cancer of the lymph glands) and ‘after just two administrations of the compound the tumour began to soften and regress to such an extent it could no longer be palpated’.

  ‘The results of this experiment,’ Gilman recalled twenty years later, ‘were sufficiently encouraging to consider a therapeutic trial in man.’ And so the first cancer patient to be treated with chemotherapy was Mr J.D., a 48-year-old silversmith with a lymphosarcoma. He had massive swelling of the lymph nodes around his face, making chewing and swallowing impossible; in his armpits, such that he was unable to bring his arms down to his side; and within his chest, blocking the return of the blood to the heart and causing his head and neck to swell.

  The research programme with nitrogen mustard was classified as ‘Top Secret’, so neither Mr J.D. nor his doctor was allowed to know the nature of the chemical with which he was to be treated. The entry on his chart simply read ‘0.1mg per kg compound X given intravenously’. The treatment lasted ten days in all, by which time the massive swellings had evaporated and ‘all signs and symptoms due to the disease disappeared’. A month later the tumour recurred, requiring a further course of therapy. He lived on for another two months, ‘his death hastened by the untoward effect of the drug on his bone marrow’, i.e. the nitrogen mustard, besides killing off the lymphoma cells, had also destroyed the platelets and white cells in the bone marrow. The next patient did not do so well, as the treatment failed to shrink the tumour while simultaneously wiping out his bone marrow or, in Gilman’s words, ‘the tumour was resistant and the tension during the period his blood count was falling was not tempered by the satisfaction of a clinical response’. The experience of these two patients accurately anticipated the results of cancer chemotherapy over the next twenty years, producing at first a short-lived remission but culminating in death, either from recurrence of the disease or the toxicity of the drug.10

  Nonetheless, this was a more auspicious beginning than might at first appear. First the spectacle of dying patients – such as Mr J.D. – being rescued from their imminent demise by a drug that appeared to ‘melt away’ the tumour is emotionally very resonant, comparable to watching a miracle take place before one’s eyes – albeit a temporary one.11

  Next, nitrogen mustard turned out to be ‘far too toxic’ even for the treatment of cancer, but modification of its chemical structure led to a whole group of anti-cancer drugs appearing in the next decade, including thiotepa (1950), chlorambucil (1953), melphalan (1953) and cyclophosphamide (1957). But the third and most significant consequence of Mr J.D.’s three-month remission was that his experimental treatment had been carried out under the auspices of the director of the Chemical Warfare Service, Cornelius ‘Dusty’ Rhoads. At the end of the war, when the Service was closed down, Dr Rhoads realised the experience gained by the scientists and doctors he had employed could be put to best use within an organisation specifically created to conduct research into the treatment of cancer.12 He persuaded the philanthropists Alfred Sloan and Charles Kettering to put up the money, and in 1948 the Sloan-Kettering Institute was founded, lavishly equipped with more than 100 laboratories. Here, under Dr Rhoads’s leadership, the ex-employees of the Chemical Warfare Service came together and over the following twenty years the pursuit of a ‘cure’ for cancer became serious science. That cure, in the form of Pinkel’s results of his treatment of ALL at St Jude’s Hospital in 1971, was still twenty-six years away. The intervening years can be divided into three phases. During Phase I, several more anti-cancer drugs were discovered. Phase II started in the mid-1950s, by when it had become clear how difficult it was to assess the relative value (if any) of these new drugs without their systematic evaluation on a major scale through the means of the ‘clinical trial’. In Phase III, starting around 1962, the new drugs and the methods of evaluating them were combined for the ‘final push’.

  Phase I: The Discovery of Anti-Cancer Drugs

  Aminopterin: Following nitrogen mustard, the next important anti-cancer drug would be aminopterin. In 1933 a British physician working in Bombay, Dr Lucy Wills, identified a particular type of anaemia in textile workers which she attributed
to their grinding poverty and grossly deficient diet. The anaemia, she found, could be reversed by the consumption of Marmite, which is made from purest yeast which, she inferred, must contain some as yet unidentified vital nutritional factor or vitamin, subsequently identified as the vitamin folic acid.13 Twelve years later, in 1945, when virtually every newly discovered compound was being tested for its potential as an anti-cancer drug, Sidney Farber, Professor of Pathology at Harvard Medical School and the ‘godfather of cancer treatments’, gave this newly discovered vitamin to patients with a variety of advanced cancers. It had no effect, except in seven patients with leukaemia in whom regrettably it had the reverse effect of that intended, accelerating their demise. ‘Post-mortem studies of the bone marrow showed acceleration of the leukaemic process to a degree not encountered in 200 autopsies of children who had not been given folic acid,’ he wrote.14 Farber, rather than being downhearted, made an inspired, imaginative guess that may seem obvious now but certainly was not at the time: if folic acid made leukaemia worse, then a chemical that antagonised it might have the originally desired effect of treating the disease. He turned to Dr Y. Subba Row of the pharmaceutical company Lederle, who had worked out the chemical structure of folic acid, and asked if it were possible, invoking the concept of ‘competitive inhibition’ already encountered, to find a compound slightly different from folic acid that could act as a ‘false’ building brick, blocking the vitamin’s action on the leukaemic cells. Subba Row produced a series of such compounds, one of which, aminopterin, was used to treat sixteen children with acute leukaemia: ten showed ‘clinical evidence of improvement’.15 Three years later in 1949 aminopterin was superseded by a more effective variant known as methotrexate (MTX).

  Steroids: In 1949, Philip Hench of the Mayo Clinic, as already described, reported the apparently miraculous effect of cortisone in patients crippled with rheumatoid arthritis – subsequently found to be effective in so many other illnesses. It was thus only natural for Farber to try it in children with leukaemia. In 1950 he reported the first case of a five-year-old boy who, having failed to improve with aminopterin, went into remission with an injection that increased the amount of naturally occurring steroids in the body.16

  Antibiotics (actinomycin): If steroids could induce remission in leukaemia, then there was every reason to try the second main pillar of the therapeutic revolution – antibiotics – especially those that had been put aside as being too toxic. In the early 1950s Selman Waksman (the discoverer of streptomycin) provided Farber with a related compound, dactinomycin, which he used to treat a boy dying from Wilms’ tumour of the kidney with metastases in both lungs. He died within three weeks but ‘post-mortem examination revealed what was at the time unique in our experience – the metastasis had disappeared and in many areas of the lung had been replaced by a fibrous material’.17 Actinomycin C, as the drug became known, was subsequently shown not only to cure Wilms’ tumour but also to be effective against the cancer of the placenta, choriocarcinoma, cancer of the testes and Ewing’s sarcoma, a childhood tumour of the bone. Nor was this the end of the antibiotic contribution to anti-cancer therapy, for ten years later two others – daunomycin and bleomycin – were found to be effective against other cancers.18

  6-mercaptopurine: Over four decades, George Hitchings and Gertrude Elion, as already described, synthesised drugs that interfered in one way or another with the genetic material DNA by acting as ‘false building blocks’ for one of its main constituents, one of which, 6-mp, would play a vital role in the treatment of leukaemia.19

  The rest: Virtually all the other anti-cancer drugs emerged either from screening programmes of chemicals for their anti-cancer activity or were stumbled on by accident. In the West Indies a tea made from the leaves of the white-flowered periwinkle, Vinca rosa, was reputed to help patients with diabetes. Doctors at the University of Western Ontario, hoping this might lead to an alternative to insulin, were disappointed to find that it had no measurable effect on reducing blood sugar, but the more they increased the dose, the more their experimental animals died from multiple abscesses caused, they discovered, by a precipitous fall in the white blood count. The same thought occurred to them as had struck the early investigators of nitrogen mustard, that anything that destroys white blood cells might antagonise their malignant proliferation and thus might be a useful treatment for leukaemia. The result was vincristine, which, as will be seen, played a particularly important role in the final cure of leukaemia.20 The most circumstantial and fortuitous discovery of all was platinum. When investigating whether electricity might influence the growth of bacteria, Barnett Rosenberg of Michigan State University placed samples of the bacterium E. coli in a bath of water and electrocuted them with a current passing between two platinum electrodes. When the bugs were examined after a couple of hours it was obvious they had ceased to divide (there was no ‘pinching of the waist’) but their growth was unimpaired and they had formed into long filaments up to 300 times their normal length. This was such an extraordinary phenomenon that it was only natural to find out what might be responsible. Rosenberg eliminated the obvious possibilities – the electric current itself, the temperature and acidity of the bath – concluding finally that the platinum on the electrodes must be responsible.21 Cisplatin – a chemical derivative of platinum – was subsequently shown to interfere with DNA prior to the division of the cell, and thus to be a potent anti-cancer agent, especially against tumours of the testes and ovaries.

  Phase II: Evaluating Anti-Cancer Drugs

  The common theme running through the discovery of these cancer drugs was that there was no common theme. Their origins were so varied and bizarre that it was only natural to wonder how many more there might be waiting ‘out there’ – including perhaps the ‘magic bullet’ that would miraculously cure cancer, just as antibiotics had miraculously cured infectious diseases. It seemed only sensible to rationalise the process. Accordingly, in 1954, the United States Congress made the funds available to the National Cancer Institute for the creation of a Cancer Chemotherapy National Service Center, which over the next decade was to screen 82,700 synthetic chemicals, 115,000 fermentation products and 17,200 plant products –214,900 in total – for their anti-cancer potential. Further, the need to test these anti-cancer drugs led to the formation of ‘an extraordinary clinical trials network’: the establishment of a unique co-operative venture where standard protocols for the treatment of leukaemia and lymphoma were drawn up comparing one combination of drugs with another.22

  Phase III: The Final Steps

  By the late 1950s the situation appeared, at least in retrospect, quite hopeful. There were now several drugs, each of which individually could induce a remission in leukaemia, albeit only a short-lived one. Next, thanks to the largesse of Congress, the NCI was now flush with funds. All that was needed for the answer to fall out was the setting up of clinical trials using appropriate combinations of drugs. There were in addition some straws in the wind of cancers – albeit quite unusual ones – that could be cured by a single anti-cancer drug, including the cancer of the placenta, choriocarcinoma, and a childhood cancer common in East Africa, Burkitt’s lymphoma.23

  Needless to say, this was not the prevailing view at the time. Chemotherapy seemed to have achieved very little other than prolonging the miserable lives of children for a few more months. For all anybody knew, the chemotherapy approach might be a complete red herring and the ‘answer’ might lie elsewhere. Leukaemia in mice had been shown to be caused by a virus, so perhaps the thrust of medical research should be towards identifying a similar infectious cause among humans. Indeed, the future direction of chemotherapy was not at all clear; the greater its even very limited success, the more intractable the problem seemed to be. First there was the issue of drug resistance, where a drug that ‘first time round’ induced a remission turned out to be completely ineffective when given on the second or subsequent occasions. Somehow the leukaemic cells must acquire the means of counteracting its ant
icancer effects – but how? The only possible solution – which had proved necessary in the antibiotic treatment of tuberculosis – was to use several drugs at once, but this would lead to unacceptable levels of toxicity. Next, and even more seriously, some children were now living just long enough to die from a complication that had never been seen before – the leukaemic cells infiltrated the brain and surrounding tissues, with predictably dire results, rapidly leading to coma and death. The brain, it emerged, was a ‘sanctuary’ within which the leukaemic cells could hide protected from the anti-cancer drugs, which were unable to cross from the blood into the brain.24 Thus, the anti-cancer drugs would also have to be injected directly into the spinal fluid and the brain would have to be irradiated if these ‘protected’ leukaemic cells were to be eliminated.25 Even were a child to be subjected to all this there was no guarantee, not even an odds-on chance, that he or she would survive for long enough to make it worthwhile. In such circumstances it is scarcely surprising that the pioneers perceived themselves to be professionally isolated, with many paediatricians openly critical of their experimental therapies: ‘We were viewed as being either malicious, or having a screw loose,’ recalls Dr Alexander Spiers of London’s Hammersmith Hospital.26