Drugs of hope or drugs of delusion?

In the UK recently hardly a day goes past without newspaper or TV headlines about another dying cancer patient denied a chemotherapy drug in the PCT lottery postcode. Whether its avastin, sutent, erbitux…breast cancer, colorectal cancer, lung cancer, or Hampshire, West Sussex, mid Essex things are not right in the world of cancer drug allocation. The impression is that cancer patients are dying in their thousands for want of the right drug at the right moment.

The Observer (26.10.08) carries news of a report by Macmillan Cancer Support which condemns the slowness of the system used by PCTs to consider appeals for exceptional treatment. Apparently only 49% of exceptional funding requests are dealt with within a month. Earlier in the summer oncologist Professor Karol Sikora, in his report Paying for Patient Care, identified 136,000 UK patients who could benefit from 10 cancer treatments, allegedly available in other west European countries but not in the UK. In the same report Ian Beaumont of the charity Bowel Cancer UK claimed that access to these drugs can make the difference between ‘dying in agony or having some kind of quality of life in your last months with your loved ones’. This is emotive stuff.

Then last week (4.11.08) the government announced an immediate change in the regulations relating to ‘co payments’ and NHS treatment. Now people who want the ‘right’ to buy drugs (often cancer drugs) not available on the NHS will not be penalised by having the rest of their NHS treatment denied. Alan Johnson’s announcements draw on the recommendations of Mike Richards’ review: Improving Access to medicines for NHS patients. Thankfully Richards’ report is not narrowly focused only on the co payments issue but also explores ways of minimising the number of patients who may want to purchase additional drugs. The fourteen recommendations, accepted by Johnson, would if implemented, improve the current system of application for exceptional treatment and the speed of NICE approval systems.

In this emotional debate the general public could be forgiven for thinking that the expensive drugs which desperate cancer patients are queuing up to buy offer significant life saving benefits. Sadly in most cases they don’t. The use of avastin for advanced breast cancer is a case in point. Avastin (bevacizumab), a drug manufactured by Genentech in the US and Roche in Europe, is designed to cut off the blood supply to cancerous tumours. Initially hailed as a ‘wonder drug’ for lung and colorectal cancer, the reality is quite different. Trials of avastin for advanced breast cancer have been disappointing. In the US in December 2007 a committee of the FDA (Federal Drug Administration) recommended not approving avastin for breast cancer on the basis of trial results which showed that though the addition of avastin to the chemotherapy drug taxol improved progression free survival on average by 5.5 months that there was no statistically significant benefits in overall survival. Despite the committee’s recommendation, lobbying by the manufacturers and some patients’ groups (not all) led the FDA to subsequently approve the drug. (March 2008.) Trial results in the UK have been similarly unexciting and NICE recently decided to suspend its consideration of avastin for advanced breast cancer in the light of Roche’s refusal to provide sufficient evidence of efficacy.

The distinction between progression free survival (PFS) and overall survival (OS) is an important one. Traditionally the ‘gold standard’ for outcomes in cancer trials has been the endpoint of overall survival. How much longer may a patient live because of this drug rather than that drug? Progression free survival used to be a lesser goal, but now appears to have become an endpoint in itself. PFS simply refers to the time before a tumour grows larger again. Additional progression free time does not measure symptom free time: it’s more a case of measuring the difference in tumour size on a scan.

Despite these findings and despite the fact that in trials those on avastin suffered more serious side effects than those only receiving the chemotherapy drug (hypertension and thrombosis, and a few deaths) avastin continues to be a popular drug. I know many patients with advanced breast cancer, convinced, despite the objective evidence, that avastin may significantly improve their life expectancy. Other controversial drugs do sometimes show incremental improvements in overall survival, but they are usually of the order of say 3-6 months additional life.

I know that personal perspectives on the meaning of additional survival time change significantly once someone has cancer. If you don’t have cancer then any drug regime which promises a few months of extra life seems paltry. However, if you have cancer the hope of a few extra months or even weeks can feel really valuable. If you are a young mother with terminal breast cancer then three additional months can mean the difference between taking your 5 year old on their first day of school, and not doing so. Many people with cancer will also argue that the ‘median is not the message’… that median survival statistics will always hide the good news results at the far end of the bell curve where people survive much longer. Terminal cancer patients are also not swayed by cold accountants’ arguments about cost effectiveness.

UK survival rates for most kinds of cancer lag behind both those in the USA (though here there are serious questions about the data being flawed in favour of those lucky few who have the most generous kind of medical insurance) and in the rest of western Europe. It may be the case that some of the new drugs are more readily available elsewhere and that their use contributes to superior survival rates, or it may be that other factors to do with earlier diagnosis and better screening play a more significant part.

Such public focus on the rights and wrongs of ‘denying’ dying patients access to costly drugs obscures other important issues. Something is terribly wrong in the world of cancer research and in treatment development if we can get so angry about expensive drugs which make little difference to survival yet fail to ask questions about why something better isn’t on offer. In a brilliantly argued piece in Fortune Magazine in March 2004 Clifton Leaf explores the systemic problems which have prevented much real progress being made in improving survival from most kinds of cancer. While some leading cancer experts in both the UK and USA (Sikora for example) argue that cancer will soon be a ‘chronic’ manageable disease, the reality is that improvements in survival for many cancers…ovarian, pancreatic, lung for example are measurable in months not years. As far as metastatic breast cancer is concerned yes some targeted treatments, notably herceptin and some of the aromatase inhibitors, are prolonging life, but the death rate for breast cancer in the UK still stands at around 12,300 a year, decreasing by perhaps 200 annually. Clifton Leaf says that ‘the models of cancer stink’; he criticises the widespread use of mouse models and the FDA’s standards for judging drugs, making the point that research is often focused on tumour shrinkage, rather than where it should be on the process of metastesis which is in the end what kills most people with cancer.

Mike Richards’ review draws attention to the difficulties that clinicians have in communicating effectively to patients nearing the end of the lives about the actual costs and benefits of further treatments. In this he draws upon a piece of qualitative research published in a BMJ paper in July 2008 which found that most patients are not given clear information about the survival gains of palliative chemotherapy. It seems to me that the silence and misinformation which used to accompany a cancer diagnosis has now become commonplace in the avoidance of realistic discussion about final treatments. Perhaps doctors and patients collude with each other in pretending that expensive wonder drugs offer more ‘hope’ of prolonging life than is ever really the case. Surely hope has to be reframed in a more honest way and right now the hope offered by so many ‘wonder drugs’ seems an empty one, a delusion. Anger is a legitimate response to terminal cancer but would that anger not be more usefully directed at the collective failure of the scientific, medical and pharmaceutical communities to find real breakthroughs and a cure for cancer?

Audrey, Abel, Blazeby, Falk and Campbell (July 2008) What oncologists tell patients about survival benefits of palliative chemotherapy and implications for informed consent. BMJ 31

Stephen Jay Gould. The Median is not the Message.

Clifton Leaf (2004) Why We’re Losing the War on Cancer. Fortune Magazine. March 22nd 2004.

Mike Richards. (2008) Improving access to medicines for NHS patients.