Poor success rates
Despite the enormous resources devoted to the development of drugs to treat cancer, the results are less than impressive. In a recent article in the BMJ, Dr Peter Wise former consultant of Charing Cross Hospital and Imperial College Medical School in London reflects on some of the ethical issues which have a bearing on the research, regulation and practice of drugs used as chemotherapeutic agents (1). Although there have been some successes, the fact remains that for 90% of patients, including those with tumours of the lung, prostate, colorectum, and breast, the effect of drug therapy was to increase five-year survival by less than 2.5%. This means that these patients had their lives extended by about three months. Those drugs approved by the US Food and Drugs Administration between 2002 and 2014 increased the survival time by just over two months. Fourteen recent drug regimes approved by the European Medicines Agency were even worse with an increased average survival time of just over one month.
In an interview, here is how Dr Wise described what this actually means in practice (2):
“I discovered that as many as 75% of patients with cancer assumed that drugs were more or less likely to ‘cure’ their cancer – which is in fact a dangerous illusion. In most instances even ‘control’ is very unlikely due to the development of adaptive resistance – the escape phenomenon that complicates almost every patient treated with almost every cancer drug – even the newest ones. As such, and with few exceptions (such as leukaemia, lymphoma, cancers of the thyroid, cervix, ovary and testicle) cancer drugs delayed death by no more than 4 or 5 months – and at the enormous expense of between $100,000 and $200,000 annually. The health ‘expense’ was there too: an 80% incidence of side effects, of which 20-40% were severe and could cause life-threatening infection and affect liver, lungs, heart and brain. Nor did it seem that we (or even more importantly, the patients) were really aware of those benefit:risk ratios. And I discover that almost all results came from the well-equipped clinical trial centres. And I had then to ask: does cancer treatment in the ‘community’ with its often stretched resources even match the trial centres’ results – because properly and safely treating the side-effects is even more important than treating the cancer itself? And then, what about Asia, Africa and South America? With which I discover that no-one can really answer my queries – and that’s bad, too.”
Weaknesses in the current system
The case for approving and using these drugs is crucially dependent on trials which supposedly provide the information on effectiveness and safety. There are a number of issues of concern.
It cannot be assumed that the results obtained in a trial will be the same when the drug is being used generally. Those who participate in the trials are carefully selected and are not necessarily representative of the population as a whole. In any case the staffing, procedures and facilities are inevitably different and may therefore have an influence on the response to the drug. Although overall survival, which measures the increase in survival time, is readily understood, it does require trials to continue for a long time to obtain meaningful results. In order to reduce costs, drug companies often focus on surrogate end-points because that allows them to shorten the trials and lower the number of participants. This also has the advantage that it reduces the time to get the drugs onto the market. The surrogate end-points used include response rate, early tumour shrinkage and progression free survival, which means the time from assignment to progressive disease or death from any cause.
The big problem is that these surrogate end-points may not be very reliable indicators of genuine improvement. In fact, may drugs approved on the basis of the results of progression-free survival have been no better in terms of overall survival than those used as comparator drugs. Although some of these have been withdrawn, others remain on the market.
Dr Wise commented on the approval process as follows:
“The whole approval system is suspect. Who would believe that over the last 12 years, the US FDA approved 71 cancer drugs that were known to prolong life on average by only 2.1 months – of which seven by one month or less – and with similar results from Europe’s FDA equivalent, the EMA. Do government regulatory approval bodies indeed want more than the welfare of the community they are supposed to serve? The data suggest that they do! The corporate tax they receive from copious global cancer pharma sales of around $120bn annually might also be an incentive to approve. The USA alone gets a corporate tax ‘reward’ that I estimated at $3.8bn annually. Industry-government conspiracy has been described in other ways, too. So, is that low threshold of approval really ethical – for drugs with so little benefit and costs that often require patients to dig deep into their own pockets for so little reward?” (2).
What emerges very clearly from this is the very little progress that has actually been achieved with respect to the use of drugs for the treatment of most types of cancer. Despite the huge expenditure, the fact remains that much of what we hear about all the so-called “breakthroughs” is just a load of rubbish. The pharmaceutical industry combines with the medical profession to hype up the benefits, which is usually just a few extra months of life. For the vast majority of cancer patients, the chances of a complete cure in which the disease is totally eliminated are practically non-existent. On the other hand most of these drug treatments are likely to involve regular visits to hospital, tests and scans not to mention some very nasty side effects. If the hard facts are presented to individuals, I suspect most would refuse the treatment. Perhaps a more attractive alternative would be best supportive care (BSC) without the use of drugs. As Dr Wise has discovered this may well prolong life in a way that is worth living because the quality is much superior that normally experienced with chemotherapy. As a consequence the patient can then spend his/her life with friends and family ….well away from hospitals and doctors. Of course, this approach is very much less costly. Surely a “no-brainer”?