Our Shapeshifting Companion

Siddhartha Mukherjee is an oncologist, physician and laboratory scientist whose book captures the excitement of biomedical research and discovery, the wonder at the complexities of cancer and the bodies it inhabits, and the thrill of major advances in knowledge and practice. Mukherjee seldom dismisses older methods of treatment or those who promoted them, but his book is mostly about what they lacked and what future therapies promise.

Without a molecular framework for understanding cancer, he argues, doctors’ ability to intervene against this group of diseases was limited. The major methods of treatment employed before the 1990s were based on questionable premises and used the bluntest of tools: surgery, carried out on the assumption that cancer began locally before affecting other parts of the body; and radiotherapy and chemotherapy, on the assumption that cancers comprise cells that divide more rapidly than the surrounding normal ones. All of this changed with a series of exhilarating breakthroughs in the last decades of the 20th century. Scientists discovered proto-oncogenes and tumour suppressor genes, which either accelerate or inhibit tumour growth, acting as ‘jammed accelerators’ or ‘missing brakes’, as Mukherjee puts it. They learned about the dependence of cancer cells on permanently activated signalling pathways which drive them to divide and grow, and about the capacity of cancer cells to resist death signals, and to metastasise throughout the body. They also came to understand how tumours grow their own blood supplies, making use of the pathways used when blood vessels are formed to heal wounds. These discoveries opened up a new world of so-called targeted therapy.

Without such targets, Mukherjee suggests, physicians’ interventions had been crude. In the late 19th century, the Johns Hopkins surgeon William Stewart Halsted pioneered radical forms of mastectomy, shunning what he called ‘mistaken kindness’ in favour of removing not only the breast but much, much more. The key to successful treatment, he believed, was to remove the tumour while it was still localised, before it spread to other parts of the body and the chances of successful treatment disappeared. Halsted was not the first to see cancer as a local lesion that later spread. The problem was that even after surgery many cancers recurred, sometimes at the fringe of the excision. Halsted took this to mean that surgeons did not remove enough: cancer cells remained in the body, the seeds of future tumours, sometimes spread by surgeons themselves. His solution was to cut deeper and farther, removing not only the breast but also the skin, neighbouring lymph nodes, muscles and, at times, parts of the ribcage or shoulder. Mukherjee argues that Halsted’s approach was too radical for those patients in whom the disease remained local, and too conservative for those in whom it had spread. Yet radical approaches dominated cancer surgery for much of the 20th century. Halsted’s former students populated leading American hospitals and trained students in this approach, while surgeons cut ever deeper and wider.

The New York surgeon George Pack – Pack the Knife – gained a reputation for aggressive surgery in the 1930s when he upset the conventional wisdom that stomach cancer was untreatable by performing a total gastrectomy (the removal of the entire stomach), and then a total extended gastrectomy, which removed the spleen and pancreas in addition to the stomach. There followed scapulothoracic amputations (the separation of the collarbone, shoulder blade and arm, gruesomely labelled the ‘fore quarter’), hemipelvectomies (in which a leg and an adjacent bone from the pelvis were removed, labelled the ‘hind quarter’), and operations for cancers of the oesophagus, pancreas, spleen, colon and liver (he removed up to 80 per cent of the liver).

Pack was not alone in his enthusiasm for such radical operations. Bolstered by wartime improvements in anaesthesia and blood transfusion, and the development of antibiotics, other physicians joined the bandwagon in the 1950s and 1960s. Despite favourable media coverage of these interventions, there was a worry that such radical surgery generated as much fear among the public as the disease itself and led people to delay seeking medical help. American cancer campaigns in the 1950s sought to reassure the public about the effectiveness of surgery and to manage fear of the disease and its treatment. But it still remained difficult to persuade people to undergo surgery, with patients feeling they were deciding between a painful and deadly disease and a painful and mutilating operation.

Such difficulties were not helped by other doctors’ criticism of radical interventions. In the 1920s the surgeon Geoffrey Keynes (brother of Maynard) had argued that the results of radical surgery were often no better than those of more conservative procedures, and that Halsted’s centrifugal model should be reconsidered. American physicians didn’t pay much attention to Keynes’s ideas until a few surgeons revived them in the 1950s. But it turned out to be very difficult to challenge what had now become the orthodoxy of radical surgery. Critics were pilloried, and clinical trials to test radical mastectomy against rival approaches were almost impossible to set up in the US because surgeons who practised radical treatments blocked access to patients. It was years before the Keynesians began to hold sway. Those who endured radical surgery, its critics argued, did no better in terms of survival or recurrence in return for the mutilation, pain and other problems they endured.

As medical enthusiasm for radical surgery declined, other interventions gained prominence. In breast cancer, radical mastectomies gave way to lumpectomies in which the tumour was removed along with some of the normal tissue surrounding it. Mukherjee doesn’t say much about such operations, or about surgery’s other uses – to help in the diagnosis, staging and prevention of this group of diseases, for palliative or restorative purposes or in combination with radiotherapy and chemotherapy. This serves his narrative, which tells of the triumph of molecular approaches, but doesn’t capture the full range of surgical interventions against cancer.

Turning to chemotherapy, Mukherjee focuses on the use of nitrogen mustards, hormones and especially antimetabolites. The anti-cancer properties of the nitrogen mustards were identified during the Second World War while the US army was researching the pharmacological effects of the gas. Louis Goodman and Alfred Gilman noticed that injections of the gas induced remissions in mice with lymphoma, and so a patient with terminal lymphoma was also injected. The results were impressive. The tumour shrank, the patient went into remission, and a search was made for analogous compounds that might work on leukaemias and lymphomas. But the enthusiasm was short-lived. The nitrogen mustards didn’t produce lasting remission – the original patient died a few weeks later – and the nitrogen mustards and other alkylating agents never achieved the place in cancer therapy that the early results seemed to promise.

Mukherjee shows that hormones were used against cancer even before the label ‘hormone’ was coined in 1905. Nineteenth-century surgeons unknowingly manipulated the level of hormones in the body by, for instance, removing ovaries or testicles to treat cancer, and their 20th-century counterparts continued the practice. There was a burst of enthusiasm in the 194os and 1950s for surgical removal not only of the ovaries in cases of breast cancer but also the adrenal glands and pituitary gland. But surgery and other methods to change hormone levels using radiotherapy or drugs had mixed results. For example, hormone-based drugs like the androgens, oestrogens and progestins were increasingly used in cancer therapy, and in 1966 Charles Huggins won the Nobel Prize for research into the relationship between hormones and prostate cancer. But medical enthusiasm for hormone therapy faded in favour of other chemotherapeutic interventions. Hormone therapy came to be regarded as a palliative, able to cure only when used as an adjuvant to other treatments, and even then only if the cancer had not metastasised.

Hormone therapy could work not only by changing the levels of hormones in the body but also by blocking certain hormones, like oestrogen. One of the first drugs to do this was Tamoxifen, which in the 1970s and 1980s started to be used to treat breast cancer. It prevented the oestrogen that some breast cancer cells require to grow from binding to its receptor, much as a broken key in a lock prevents the insertion of another key. It’s indicative of the state of hormone research in the 1960s that the synthesis of the drug by ICI scientists wasn’t greeted with much enthusiasm within the company. ICI had developed it in the hope that it could be used as a contraceptive. But that didn’t work out, and since cancer treatments were not a corporate priority at the time, it almost ended the research programme.

Antimetabolites are drugs which are structurally similar to chemicals required for normal cellular processes, and may halt cell division or growth. In the summer of 1947 Sidney Farber, a specialist in children’s diseases, diagnosed acute lymphoblastic leukaemia (ALL) in the two-year-old son of a Boston shipyard worker. ALL almost always killed, sometimes within days of diagnosis. Conventional treatments proved useless on his small patient, and in desperation Farber injected him with an experimental drug named aminopterin, an antifolate, which impairs the function of folic acid. The results were striking: not a cure but remission – remarkable because remission was exceedingly rare in ALL cases. Farber had found a substance that seemed to target rapidly dividing cancer cells by interfering with folate metabolism. His initiative suggested that antifolates might work on certain cancers of the blood and is often seen as a key moment in the birth of chemotherapy.

But chemotherapy didn’t become the cure that many had hoped. While more and more children survived leukaemia, chemotherapy didn’t work so well in other cancers, or in all cases of childhood leukaemia. Cancer cells were highly adaptable and resistant to chemicals. So physicians tried out their own version of radical therapy. In the 1960s, they began to mix ‘cocktails’ of cytotoxins (chemicals that kill cells), to increase doses of drugs as close to the limits of human tolerance as they dared, and to continue treatment long after remission was apparent. The results often traumatised patients, and many succumbed to problems caused by the chemicals, sometimes other cancers. The poisons directed at the rapidly growing cells didn’t always distinguish between cancerous and normal growth, and normal cells that grew most rapidly (in hair, blood and the linings of the skin and gut, for example) were particularly vulnerable to damage from chemotherapy. Physicians often blurred the boundary between treatment and research, sometimes testing harsh new regimes on patients to squeeze out a few more days of life, sometimes pitting the needs of current patients against future ones.

Farber was also central to the vast growth in funding for cancer research in the US that culminated in Nixon’s 1971 ‘war on cancer’. Mukherjee argues that the problem with the ‘war’ was that it gave form to a disease that had none. Cancer, ‘a shape-shifting disease of colossal diversity,’ he writes, ‘was recast as a single, monolithic entity’ with a single cause and cure. Cancer scientists believed viruses were responsible and major research at the National Cancer Institute in the 1970s attempted to identify those that caused cancer and to develop vaccines against them. Clinical oncologists thought the cure might be multidrug cytotoxic chemotherapy, the focus of increasing attention. Both turned out to be disappointments. Despite billions of dollars spent on research in the 1970s, mortality continued to rise, survival rates after treatment barely improved, and viruses were identified as the causes of just a few rare forms of cancer. Only in the past two decades have new classes of therapy emerged. Viruses have been rehabilitated as causes of cancer, and the US Food and Drug Administration has approved drugs to prevent liver and cervical cancer. Cancer has been reframed and is now seen as a diversity of diseases with different genetic signatures.

Mukherjee says he wrote his book to explain the current state of the ‘war’. His main hope is targeted therapy, drugs aimed at specific molecules involved in tumour growth. But even here there’s reason for caution. These drugs are expensive, and the market is fragmented: the targeted groups have narrowed from those with a particular kind of cancer to those whose cancer has a particular genetic signature. So despite all the hype about targeted therapy, pharmaceutical companies are wary of the expense of trials, especially when the market for an individual drug may be very limited. Insurance companies, governments and health services worry about the high cost of the drugs that come onto the market, as do patients.

The problems go beyond questions of cost, markets and access. Even optimistic commentators accept that targeted therapy is unlikely to reduce cancer mortality significantly without major molecular testing and costly clinical trials. For everyone who benefits from a drug, many more will gain nothing. And then there’s the question of drug resistance. Cancers keep mutating so patients develop resistance to new drugs. For those facing cancer today, the situation may seem grimly reminiscent of the early years of Aids, when survival could depend on whether a patient developed resistance to a drug before or after a new one became available. Mukherjee’s cautious assessment is that cancer will remain our constant companion, but perhaps no longer a companion that kills.

His book is an ambitious intellectual, social and cultural history of this murderous, shape-shifting companion, and of efforts to understand and control it. He brings recent historical scholarship to a broader audience, interweaves it with his own experience as a physician, and adds his own research on more recent developments in cancer. It has limitations, however: it focuses on the US rather than Europe, on developments after the Second World War not before it, and on biological causes. Mukherjee has little interest in environmental or lifestyle causes of cancer; he gives only a brief mention of the struggles over tobacco that followed epidemiological evidence in the 1940s and 1950s of a link between smoking and lung cancer.

It’s worth comparing Mukherjee’s account to the historian Robert Proctor’s in Cancer Wars (1996). Where Mukherjee is interested in molecular causes of cancer, Proctor focuses on environmental causes. And where Mukherjee’s story is one of scientific discovery, Proctor tells how various industries have attempted to manufacture ignorance and confusion. As an internal memo from the tobacco industry put it in 1969, ‘Doubt is our product since it is the best means of competing with the “body of fact” that exists in the mind of the general public.’ Proctor and other historians have documented the way asbestos, nuclear and chemical companies also tried to sow doubt about their products causing cancer, and put profits before public health, even when they knew the dangers. These actions meant that attempts to tackle specific carcinogens were made later than they might have been, and it became more difficult to respond to emergent public health threats. Incurring the ire of these industries is not something to be undertaken lightly.

Mukherjee is in no danger of making them angry. He tells us much more about the politics of securing funding for biomedical research than he does about the politics of reducing exposure to occupational and environmental carcinogens. And yet the two stories are inextricable. In the late 20th century, advocates of cancer prevention complained that more resources went to treatment and basic research than to prevention, in part because it was easier for governments and cancer organisations to support such work than to implement prevention policies that affected powerful industrial interests. The consequence was a mistaken emphasis in cancer policy. As the epidemiologist Ernst Wynder put it in 1975, ‘Prevention is the only way we can make a major impact on survival … As interesting as therapy is, it … has never wiped out a disease.’ Mukherjee sidesteps these issues.

But even his account of therapeutic interventions is selective. He tells us much more about chemotherapy and surgery than about radiotherapy. Yet radiotherapy was the major alternative and supplement to surgery for almost half a century before chemotherapy. ‘The only safe weapons against cancer are surgery, X-rays [and] radium. Do not trust your life to other methods,’ an American public health poster warned in 1938. Radium was hugely expensive (a few grams cost hundreds of thousands of dollars), in extremely short supply and in high demand. The need to co-ordinate its use led to the reorganisation of cancer services in Britain after 1929, with the creation of a national network of radium therapy centres. The United States, however, shied away from this, fearful that it would mean government control of cancer. The NCI was founded in 1937 as a supplier of radium to be used to treat the poor. Critics argued that this was a harbinger of socialised medicine, and the institute abandoned its plans to expand its radium programme, and focused instead on research and training. But Mukherjee doesn’t mention these developments; nor does he tell us much about later innovations in radiotherapy such as cobalt and high-energy radiation equipment.

He also downplays the importance of efforts to get public support for anti-cancer campaigns. Improvements in therapy were possible only if public attitudes could be changed. So from the 1910s huge campaigns were launched in the US to build trust in medicine, make it easier to access specialist care, make it seem worthwhile to seek help early on, and stick with what could be a long, uncertain and painful course of treatment. The campaign succeeded, or so its advocates claimed, in sending people to their doctors: in any case physicians rarely see the advanced cancers that their forebears did. Mukherjee tells us little about this change; the new treatments he describes seem to exist in a world isolated from such efforts.