Can Medicine Be Cured Page 12
Drugs and chemotherapy generally do little for patients with advanced cancer. They come with a high cost, both in terms of their price and their side effects, and because the clamour for them from patients and oncologists elbows aside other, better ways of improving cancer survival, such as prevention and earlier diagnosis. A 2004 meta-analysis examined whether chemotherapy drugs improved survival in patients with ‘solid’ cancers (as opposed to blood cancers, such as leukaemia). Chemotherapy prolonged survival in some, such as testicular cancer, Hodgkin’s disease, cancer of the cervix, lymphoma and ovarian cancer. These cancers, however, added up to only 10 per cent of all cases. In the other 90 per cent of cancers (breast, lung, colon, prostate), chemotherapy improved survival by only 3 months. In 2005, a paper in the British Journal of Cancer looked at 14 consecutive new cancer drugs approved by the European Medicines Agency, and found the average extra life gained was a miserly 1.2 months. More recently, 48 new drugs approved by the US Food and Drug Administration between 2002 and 2014 gave a median 2.1 month survival benefit.
Many expert commentators have expressed concern about trials of cancer drugs. Peter Wise, a physician and researcher at Charing Cross Hospital in London, waited until after retirement to write a damning analysis of cancer drug trials for the British Medical Journal entitled ‘Cancer drugs, survival, and ethics’:
Many drugs approved on the basis of better progression-free survival have been subsequently found not to produce better overall survival than the comparator drug. Some of these drugs are logically withdrawn but others remain inexplicably on the market.
Surrogate endpoints [meaningless outcomes such as progression-free survival] are also used by the FDA [the US Food and Drug Administration] and EMA [European Medicine Agency] for accelerated and conditional approval, respectively, of what are judged to be urgently needed new drugs. A 2010 FDA review revealed that 45 per cent of cancer drugs given accelerated approvals were not granted full approval, either because subsequent trials failed to confirm effectiveness or because the results of trials were not submitted. One reason may be the industry’s reluctance to communicate negative results…
The FDA’s decision to introduce a ‘breakthrough’ category in 2012 compounds the risks of premature approval on limited evidence. The pressure for early approval is enhanced by lobbying from patient advocacy groups, prompted by industry and with often premature media announcements of drugs that are ‘game changing’, ‘groundbreaking’, ‘revolutionary’, ‘miracle’, or other unjustifiable superlatives. The risky practice of approval before proof gains even more momentum.
In the US, the 2016 21st Century Cures Act modified the FDA drug approval process, and lowered even further the evidentiary standards for new drugs; the bill had bipartisan support, pushed by more than 1,400 lobbyists.
The journalist A. A. Gill was diagnosed with metastatic lung cancer in 2016, aged sixty-two. He announced his illness in the Sunday Times, where he was a regular contributor as a restaurant critic and TV reviewer: ‘In truth, I’ve got an embarrassment of cancer, the full English. There is barely a morsel of offal not included. I have a trucker’s gut-buster, gimpy, malevolent, meaty malignancy.’ He wrote about his treatment in his last-ever piece for the Sunday Times. At his first meeting with an oncologist at Charing Cross Hospital in London, he asked about chemotherapy:
Well, there’s a new treatment, immunotherapy. It’s the biggest breakthrough in cancer treatment for decades… It’s new and it’s still being trialled, but we’re a long way along the line and it is the way cancer treatment is bound to go. It’s better for some growths than others, but it’s particularly successful with yours. If you were in Germany or Scandinavia or Japan or America, or with the right insurance here, this is what you would be treated with.
Gill’s partner Nicola Formby asked the oncologist if he would get better treatment as a private (rather than NHS) patient: ‘If he had insurance, I’d put him on immunotherapy – specifically nivolumab. As would every oncologist in the First World. But I can’t do it on the National Health.’ Gill researched the wonder drug: ‘The National Institute for Health and Care Excellence (NICE), the quango that acts as the quartermaster for the health service, won’t pay. Nivolumab is too expensive – £60,000 to £100,000 a year for a lung-cancer patient; about four times the cost of chemo.’ Gill’s article appeared in the Sunday Times Magazine on 11 December 2016. The end of the piece states: ‘Since A. A. Gill wrote this article he has started nivolumab.’ The Sunday Times didn’t mention the other thing Gill did since he had written the article: he died the day before the piece came out, too late, it would appear, for the news to get to the printing presses. I was troubled when I read this article. Gill clearly spent much of the few months between diagnosis and death fretting about the failure of the NHS to treat him with nivolumab. I was even more troubled by the fact that his oncologist dangled before this dying man a drug that he knew he couldn’t prescribe.
Drugs like nivolumab, which give very modest survival gains in most, work spectacularly well in the occasional patient. They are like lottery tickets, but are presented to the patient as a sure thing. Six months after A. A. Gill’s death, the New England Journal of Medicine published a randomized trial comparing nivolumab with the standard platinum-based chemotherapy for stage IV lung cancer. Median survival in the nivolumab group was 14.4 months versus 13.2 months in the chemotherapy group: not exactly a paradigm shift or game changer, or ‘the biggest breakthrough in cancer treatment for decades’. In 2015, 46,388 people were diagnosed with lung cancer in Britain. Even if only a quarter of this number qualified for nivolumab, and were treated for a year, the cost would be somewhere between £0.7 billion and £1 billion, roughly what is spent every year on hospice care in Britain. And this is the problem with these debates: the sad story of A. A. Gill is told without context. We assume that all these decisions about paying for new cancer drugs occur in isolation, that there are no consequences for the rest of the health service or society in general. This is sentimentality in its true and pernicious form. The medical–industrial complex relies on this childishness. We claim to respect science and the scientific method, but we don’t really understand it, so our decisions on the applications of science are irrational. I have used the example of the under-funding of hospice care, but the real danger of this alleged ‘progress’ is not to other aspects of health care, but to our society at large. We must have higher, and better, priorities than feeble, incremental and attritional extension of survival in patients with incurable cancer. Some medical–industrial bully (or tabloid journalist) will retort: ‘Surely extending A. A Gill’s life by even a few months is worth £100,000?’ This is always followed by the trump card: ‘How can you put a price on a life?’ Predictably, NICE recommended, in November 2017, that the Cancer Drugs Fund pay for nivolumab in patients with a particular type of lung cancer (squamous cell) who have already been treated with chemotherapy.
‘Precision’ medicine refers to the matching of cancer patients with drugs that target the genes driving their disease. Currently, patients with lung and breast cancer are routinely screened for particular genetic mutations, but new-generation genetic sequencing can screen for hundreds of mutations, either in a sample taken from the tumour, or even in a blood test (a ‘liquid biopsy’). Many new cancer drugs target a specific gene mutation, rather than a type (lung, breast, colon) of cancer. According to advocates of precision medicine, the genetics of a tumour are more important than its location. This new molecular profiling is currently very expensive, and produces a great deal of data that doctors often don’t know how to interpret. Another limitation of this approach is that cancers are very effective at developing resistance to drugs, and developing new mutations. New genomics companies, such as Foundation Medicine, offer a ‘portfolio of genomic tests’, interrogating more than 300 genes and matching the patient’s tumour to the best available current therapies. This company has built up a cancer genomics database called FoundationCore™ from 180,000
patient records, and works ‘with more than 30 biopharma partners’. Their mission statement contains the ominous phrase ‘We never give up’.
Although genomics and precision medicine have so far not led to any dramatic improvement in cancer survival, we can be sure that this genetics-driven paradigm will drive up the already inflated cost of cancer treatment. Many precision drugs are biological agents – drugs that are produced from natural sources of biological material – as opposed to traditional drugs that are chemically synthesized and are much more expensive to develop and produce. Pharma relies on the fact that doctors (if permitted) will eagerly prescribe such drugs, regardless of cost or evidence of benefit: the medical profession has become the front-of-house sales team for the industry. Doctors’ professional culture obliges them to do something – anything – rather than nothing. It is now regarded as unacceptable for a doctor to tell a patient that they can’t treat their disease, particularly when that disease is cancer. Oncologists, in particular, find it almost impossible to admit to such therapeutic impotence. Some brave non-conformists do indeed come clean and have the Difficult Conversation – the admission that nothing more can be done – but for many, the siren call of the new breakthrough, the paradigm shift, the game changer, is too powerful to resist.
Robert Weinberg is one the great figures of American cancer research. He is professor at the Massachusetts Institute of Technology Center for Molecular Oncology, and has worked for decades on the genetics of cancer. In 2014, he wrote a candid, almost confessional essay for the journal Cell, entitled ‘Coming full circle: from endless complexity to simplicity and back again’. Weinberg charted the evolution of cancer research since the 1970s. He wrote that Nixon’s War on Cancer was fuelled by the mistaken conviction that cancer was caused by infectious DNA tumour retroviruses – a common phenomenon in other animals but not, as it turned out, in humans:
Those working on DNA tumour viruses… jumped on the bandwagon, since the war cry had expanded… In retrospect, few seemed deterred by the well-established observation that most types of human cancer did not represent communicable diseases… By the mid-1970s, with rare exception, tumour virologists had come up empty-handed in their search for human retroviruses.
In the late 1970s, a new paradigm emerged, which held that cancer was a disease caused by a small number of easily identifiable genetic mutations. Weinberg was one of this new generation of molecular biologists, who dominated cancer research in the 1980s and 1990s. Their discovery of mutations (oncogenes), such as K-ras, APC and p53, did not lead, however, to the therapeutic revolution they had imagined. In the twenty-first century, cancer research entered the era of Big Data, gathered from all the ‘omes’ – genomes, transcriptomes, proteomes, epigenomes, kinomes, methylomes, glycomes and matrisomes. ‘Omics’ now finishes the science words which once ended in ‘ology’. The ‘omics’ era has forced researchers to accept that cancer was quite a bit more complicated than they had thought:
Then there is the nettlesome problem of multistep tumour progression: cancer is a moving target, and whatever interactions operate at one stage of tumour progression are likely to change during the next one, so that multiple solutions will need to be worked out for individual tumours. Even within an individual tumour… analyses of tumour DNAs now indicate multiple, genetically distinct subpopulations whose representation seems to vary dramatically from one stage of tumour progression to another.
The data that we now generate overwhelm our abilities of interpretation, and the attempts of the new discipline of ‘systems biology’ to address this shortfall have to date produced few insights into cancer biology… The coupling between observational data and biological insight is frayed if not broken.
We lack the conceptual paradigms and computational strategies for dealing with this complexity. And equally painful, we don’t know how to integrate individual data sets, such as those deriving from cancer genome analyses, with other, equally important data sets, such as proteomics [the large-scale study of proteins].
Weinberg concluded: ‘We can’t really assimilate and interpret most of the data that we accumulate. How will all this play out? I wouldn’t pretend to know.’
Cancer medicine (oncology) has become, in the words of its own leaders, a culture of medical excess. The Lancet Oncology commission on ‘Delivering affordable cancer care in high-income countries’ was written by a group of eminent cancer researchers from around the world, and was published in 2011. The commission estimated the global economic impact of cancer at nearly $900 billion. Spending on cancer care is rising rapidly for many reasons, including ‘overutilization, disincentivization driven by reimbursement rules and defensive medical practice, consumer-driven over-demand, high-cost innovation, and futile disease-directed care’. The authors concluded that the current model of cancer treatment is unsustainable:
We are increasingly faced with the question of whether the sometimes minor benefits of proven interventions are worth the cost to individuals and society. Novel, more effective, and less toxic interventions are needed, but the price of innovation contributes further to the costs of care. We are thus at a crossroads where our choices, or refusal to make choices, have clear implications for our ability to provide care in the future.
The War on Cancer is unwinnable, but looks as if it will intensify. So far, the new genetics and molecular medicine have given us treatments of marginal benefit at huge cost. As a society, we have unquestioningly accepted this cost, believing that any advance – no matter how small – in this war of attrition is worth achieving. The cost, however, is too high, and the war is unsustainable.
9
Consumerism, the NHS and the ‘Mature Civilization’
The NHS Cancer Drugs Fund was created by consumerist demand; this consumerism is slowly destroying Britain’s most beloved institution. As I write, the NHS is marking – not really celebrating – its seventieth birthday, and the British acknowledge that it is in trouble. The onward march of the culture of medical excess, combined with a larger, older and frailer population, has led many to conclude that the service, and its foundation model, are no longer sustainable. Enoch Powell predicted this in 1966 in his book A New Look at Medicine and Politics. Powell is generally unknown to people under the age of fifty, proof of his own dictum that all political careers end in failure. With his precise antique diction, delivered in an incantatory Black Country-accented voice, he sounded like a relic of the Victorian Age. For most of those familiar with his name, the only thing they can recall about him is the ‘rivers of blood’ speech from April 1968, his denunciation of black immigration and the Race Relations Bill. An intellectual at a time when politician-intellectuals were still a feature of British public life, Powell was too idiosyncratic and too much his own man to make it to the very top. He did, however, hold ministerial office, as financial secretary to the Treasury (1957–8) and health minister (1960–3). His short book, written in the elegant style of the classicist, was on his experience as health minister. The book is regarded by many as one of the best ever written on the NHS. It is as relevant now as it was in 1966.
Although Powell’s successors as health secretary have been uninspiring, I have sympathy for them because, as he so eloquently explained, demand is infinite: ‘The vulgar assumption is that there is a definable amount of medical care “needed”, and if that “need” was met, no more would be demanded. This is absurd. Every advance in medical science creates new needs that did not exist until the means of meeting them came into existence.’ There will never be a time when the public and the health professions will agree that spending on health has reached an adequate level. The founders of the NHS naively believed that free health care would lead to a healthier populace, which would eventually lead to ever-decreasing demand for its services. Powell pointed out the error of this belief, and anticipated Ivan Illich, who later coined the phrase ‘Sisyphus syndrome’ to mean that the more health care given to a population, the greater their demand for care. The combinatio
n of technological change and rising expectation has driven ever-increasing spending on health care.
The word ‘rationing’ has traditionally been banned by British health secretaries, but Powell argued that rationing was inevitable:
In brutal simplicity, it has to be rationed… The task is not made easier by the political convention that the existence of any rationing at all must be strenuously denied. The public are encouraged to believe that rationing in medical care was banished by the National Health Service, and that the very idea of rationing being applied to medical care is immoral and repugnant… The worst kind of rationing is that which is unacknowledged; for it is the essence of a good rationing system to be intelligible and consciously accepted.
How do we divide this limited sum equitably? Enoch Powell respected the British electorate, and did not attempt to delude or patronize them, but many of his political successors did. Beginning in the late 1980s with the Thatcher administration, successive Conservative and Labour governments have persuaded the users of the NHS that there is no rationing of health care, and that the service can be both free and run on consumerist principles of choice and service user satisfaction. From Kenneth Clarke, all health secretaries have advocated for greater patient choice. The moral philosopher Robin Downie has argued that consumerism in health care is incompatible with a publicly funded service. He pointed out that in a traditional consumer–seller interaction, the purchaser, having been given adequate information, bears the responsibility for the choice. But ‘this situation does not apply in medicine. In law it is the doctor who carries the responsibility. In other words, the locus of responsibility in the two contexts of consumerism and medical professionalism are incompatible.’