Herceptin: Clinical Trial by Media
Given the known side effects and limited effectiveness of Herceptin, how has it become the latest Breast Cancer miracle cure? Pat Thomas investigates.
“The history of medicine is littered with wonderful early results which over a period of time turn out to be not so wonderful – or in fact even adverse. If you look at hormone replacement therapy, or Vioxx (rofecoxib)…there are a whole string of recent examples where preliminary data led to a lot of excitement and caused changes in clinical practice and then eventually we realised they had done more harm than good. Why is it we never learn these lessons? We seem condemned to make the same mistakes each time with any new drug.”
Those words could have been written by any medical sceptic, over the years they could have, and probably have been, written in one form or another in this magazine. Yet these words were written by Richard Horton, Editor in Chief of the long established medical journal the Lancet in November 2005.
Horton was writing about the medical and media hoopla surrounding the latest miracle drug Herceptin and his words, which should have been front-page news, disappeared like a whisper in the year-long shouting match that has passed for sensible debate about this controversial drug.
In a flurry of media coverage that will have made Roche, who are responsible for the international marketing of Herceptin, wet their pants with delight, headlines screamed “How many more women must die?”, “Dying nurse sues NHS for denying her cancer drug” and “Wonder drug ‘could cure breast cancer’” while desperate punters competed for column inches with statements like “”I have no other option but to sell my home to pay for Herceptin.” and “I feel the refusal of Herceptin is as though I have been given a death sentence” and “It’s a basic human right to have the drugs you need to keep you alive”.
In a relatively short time span Herceptin has been elevated from a promising treatment for a very specific type of cancer to a wonder drug that will “cure” breast cancer and save thousands of lives each year.
From hype to reality
Herceptin is not appropriate for all breast cancers.
It is aimed at the 20 per cent of women whose cancers appear to be linked to the over-production of a protein, called HER-2, which helps regulate cell growth and development.
HER-2 was first identified in the early 1980s and nobody can say for sure what role it plays in a healthy breast cell, though in cancer cells too much of it appears to make tumours more aggressive and is associated with poor prognosis.
Herceptin is what is known as a monoclonal antibody – a genetically engineered copy of natural antibodies that target HER-2. The fine details of how it works are not entirely clear but in essence Herceptin attaches itself to HER-2 receptors on the cancer cells and blocks them from receiving growth signals. Herceptin also appears to alert the immune system to attack the cancer cells it attaches to.
Within the select population of women who are eligible and well enough to take Herceptin, only a small percentage will actually respond to it…
According to available data the majority of eligible women, around 70 per cent, fail to respond to the drug. Worse, virtually all those who do respond will eventually develop a resistance to the drug.
For women who do respond to Herceptin, the media perception is that it is a ‘life saver’. Yet the available data does not, indeed cannot, support this conclusion.
Since it was approved by the FDA in 1998 Herceptin has been the subject of a small number of published randomised clinical trials. Some of these trials are ongoing and the conclusions drawn from them are based on interim, or incomplete, data The longest of these trials has only followed women for an average of two years.
Because of this it is impossible to say whether it is actually saving lives. In cases of late stage breast cancer – that is cancer that has failed to respond to any other form of treatment and which has spread to other organs of the body – Herceptin appears to slow down or postpone its progression.
But there is no evidence to suggest that any woman taking Herceptin can go on to live out the natural span of her life cancer-free. On the contrary, the short-term studies published so far show that there is no significant difference in overall survival rates between those women who take Herceptin and those who don’t.
What is more, taking Herceptin does not cut your risk of cancer recurring by 50 per cent as alleged in the press.
In fact the data shows that the difference in recurrence between women on a conventional treatment regime versus those on a conventional treatment plus Herceptin was incremental. The Herceptin group were only 5.5 per cent less likely to suffer relapse. And because this data published in 2005 in the New England Journal of Medicine is interim it may yet be that cancer will recur in these women over a longer period of time.
In addition most Herceptin stories either gloss over or completely omit the ‘known risks’ associated with the drug.
While Herceptin may delay the spread of cancer to some parts of the body, the trade-off is that it appears to hasten its spread to others. In as many as 34 per cent of women with metastatic breast cancer who appear to be responding to Herceptin the cancer will spread to the central nervous system (brain and spine).
Around half of all women being treated for early breast cancer with Herceptin may also develop CNS tumours. The manufacturers keen to put a positive spin on a very negative effect, say this is a consequence of how ‘safe’ the drug is – suggesting that because it does not penetrate the blood brain barrier – the protective membrane around the brain that prevents drugs and other toxic substance from getting through – it is less able to protect the brain.
In addition, while Herceptin continues to be widely feted as being ‘safe’ by the media, early in 2006 the US Food and Drug Administration (FDA) was moved to warn doctors that in a reanalysis of the largest Herceptin trial to date around 4 per cent of women sustained severe heart damage while taking the drug. This was more than double the rate reported in the interim data that was published in the New England Journal of Medicine. A further, but as yet unquantified, number of women may experience mild to moderate heart symptoms and whether these are transient or progressive and permanent is largely unknown. Without long-term data it is impossible to say if these figures are an under- or over-estimate.
While no one can place a price on a human life, looked at purely in terms of cost versus benefit Herceptin is a poor investment.
According to a reanalysis of Herceptin survival data undertaken by Peter Littlejohn the clinical director of the UK’s National Institute for Clinical Excellence (NICE) and published earlier this year in the journal Lancet Oncology, 18 patients would have to be treated with Herceptin to prolong one life.
At around £20,000 per treatment this works out at £400,000 for 4 months of life. NICE is responsible for recommending drugs for use on the NHS on the basis of evidence that they actually work – it is little wonder then that it was, for so long, reluctant to recommend funding this particular treatment.
Based on what is known about Herceptin to date, the headlines shouting “Wonder drug ‘could cure breast cancer’” should be really saying “Herceptin prolongs a few lives for an average of four months at a cost of around £400,000 per life extended and for the majority of women for whom it does not work there is an increased risk of severe heart damage and the spread of their cancer to the central nervous system.”
So, how did Herceptin become the latest wonder drug on the block?
Clinical trial by medeia
It seems incredible that with so many unanswered questions, such a low response rate and such worrying adverse effects that Herceptin could ever have been hailed as a ‘miracle cure’. This accolade came not on the merits of the drug but on a tide of press release journalism, ‘creative’ PR, an urgent need for the drug’s manufacturers to recoup their research and development costs and boost their share prices, as well as politicians’ fear of ‘people power’.
There is no cure for cancer. Indeed the failure to find a cure for cancer is one of medicine’s biggest embarrassments. Instead the goal of most modern cancer treatments is to extend the lives of patients with an ongoing regimen of drugs and radiation. In theory, newer more precisely targeted biotech treatments like Herceptin should facilitate this goal and have been hailed in the medical press as holding the key to a future where cancer is a chronic condition that can be ‘managed’.
But while biotech drugs may be the future, they are also expensive to produce and tend to be so specialised that they are generally only appropriate for a small subset of patients. This means that the manufacturer will potentially have a hard time recouping its research and development costs and that it will take longer for the drug to show a profit.
To overcome this problem manufacturers are turning to sophisticated marketing and PR, which is infinitely cheaper and more effective than medical research. Increase the potential size of the market by creating a demand for a drug and the profit will be realised more quickly.
The furore over Herceptin is a textbook example of how to apply this technique and although the drug only came into public consciousness about 9 months ago, the media campaign in the UK started long before that.
While Herceptin was approved for use in 1998 it wasn’t until 2001 that the results of published human trials began to appear. In one small study of just 469 women with late stage breast cancer Herceptin added to standard treatment delayed the progression of the disease for 7.4 months compared to a 4.6-month delay for those on standard treatment alone.
In 2002 another study with similarly positive results appeared and that same year NICE approved the use of Herceptin on the NHS for women with late stage breast cancer.
Roche hoped that the NICE approval would open the floodgates for the uptake of the drug in the UK, even at £20,000 a year per treatment. But by the following year it was clear that not every potential patient was receiving the drug.
A political prescription
Poor uptake prompted Roche to compile an in-house survey comparing its own regional sales of the drug with projections of the number of potential users drawn from the office of national statistics and cancer research UK figures. it showed evidence of what the company termed “postcode prescribing”: in the Midlands 14 per cent of eligible women were receiving Herceptin. This figure rose to 28 per cent in the North and North-east, 33.5 per cent in South-east and Anglia and 61 per cent in the South-west.
The company passed the survey on to CancerBacup – whose latest financial statement show that drug companies such as Roche provide around a third of its income – and in October 2003 the charity sent out a press release headed “CancerBacup calls for action over dramatic new evidence of postcode prescribing” – a catchy phrase that implies that where a woman lives dictates whether she will be able to get hold of the latest miracle drug.
From a media point of view the concept of postcode prescribing was a gift of a story; so politically correct and appealing that nobody bothered to ask whether the apparently higher uptake of Herceptin in southern counties might have reflected, for instance, the higher population numbers there or whether middle class, better educated women in more affluent areas of the country might have been more skilled and confident in demanding the drug from their physicians, or whether the balance sheets of Trusts in these areas might have been better able to absorb the cost of the drug.
At no point did the media question the efficacy of drug itself. Instead the papers pursued the idea that the National Health Service wasn’t national or free to all regardless of means, but was instead skewed to the more affluent areas of the country. It was this lemming-like reportage that helped to turn the miracle drug into a political hot potato as well as a ‘must-have’ cure.
Finding ‘Outraged of Stoke’
During this time Roche was already funding further trials of their new drug in women with early stage HER-2 breast cancer. The results of those trials were eventually made available in May 2005 – at the annual meeting of the American Society of Clinical Oncology (ASCO).
As the media circus was gearing up, early stage cancer patient Lisa Jardine, a writer, TV presenter and professor at the University of London, received a call from an account executive at Ketchum, a PR agency working for Roche. The woman on the other end of the line had read Jardine’s story in the paper and picked up on her comment that she thought women who wanted Herceptin should have access to it.
The agency offered Jardine the chance to come and do paid talks at Roche seminars and to help find funding for her own use of Herceptin (though for safety reasons she had, by this stage, decided against the drug).
“There was no mistaking the directness of the approach” said Jardine at the time “she said she would make it worth my while.”
Roche defended the approach: “Lisa Jardine, as a public figure who had spoken openly about her own disease, was contacted in the planning stages of activity to raise awareness of the importance of accurate breast cancer diagnosis. This activity was never conducted, as it was superseded by a Department of Health initiative to encourage wide tumour type testing”
The campaign gained momentum and Roche developed close associations with other patient groups. Records show that in 2002 when cancer charities were lobbying to get Herceptin approved, the UK Breast Cancer Coalition was also receiving funding from the company. And then there is Women Fighting For Herceptin, a very vocal group of Herceptin advocates based in Staffordshire and founded by former magistrate Dorothy Griffiths.
Griffiths has done a presentation for Roche and admits to being supplied by the company with all the facts and figures she needed to make her campaign more effective. “They’re a lovely bunch of people at Roche” Griffith’s opined in the Guardian in March of this year.
When in 2005 a former employee of Roche, Rebecca Hunt (who was listed as the company’s Pharma PR Manager on CancerBacup’s ‘postcode prescribing’ press relase) offered her PR expertise for free to Women Fighting for Herceptin it must have seemed like a Godsend. But it is unlikely that Hunt, who is also UK Healthcare Director for PR giant Porter Novelli – which lists Roche as one of its clients – offered her services on a whim or a tide of public spirited good will. Even though she said at the time, “It is really inspiring to the team here to get involved in something that makes so much difference to people”, keeping major clients like Roche happy is part of Hunt’s day to day job and the work, though pro bono, will also have been undertaken with an eye on other rewards further down the line.
With a wealth of PR expertise behind them Women Fighting for Herceptin were able to garner an extraordinary amount of media interest. They had the continuing support of the local paper, the Staffordshire Sentinel and a ready supply of unhappy women who couldn’t get their hands on the drug, willing to tell their stories to TV, radio and the newspapers.
Who’s afraid of the electorate?
In October 2005 Secretary of State for Health Patricia Hewitt weighed in to the middle of the debate and announced: “From today all women diagnosed with early stage breast cancer will be tested for suitability for treatment with Herceptin. As soon as Herceptin receives a licence it will be fast-tracked for use throughout the NHS.”
Officially Hewitt took the decision not because she was bowing to media pressure but “because I believe it is the right thing to do”. But in so doing she very effectively undermined the ability of local authorities to make decisions based on the bigger picture of the needs of their local areas.
By October 2006 Primary Care Trusts (PCTs) will be obliged to offer Herceptin treatment, at an estimated cost of £20,000 per year to any qualifying woman who wants it. Around 5000 women in the UK would be suitable for the drug. To supply each of these women with Herceptin would cost an already cash-strapped NHS in the region of £100 million a year.
Although she had the power to do so, it is worth asking whether Hewitt also had the knowledge to make such an unprecedented intervention.
Patient power?
In May of this year, when Herceptin was approved for women with early stage breast cancer, Professor John Toy of Cancer Research proclaimed, “This shows that ‘patient power’ can move governments to take pro-active decisions”.
But the fast-tracking of Herceptin in the UK was not a triumph of patient power. In this country drug manufacturers cannot advertise directly to consumers like they can in the US. So they must find other ways to reach us. The stories about miracle drugs that you read in the newspapers or watch on breakfast TV are in one way or another, being bought by their manufacturers. Patient power without media power is unlikely to have the same results. In this respect Roche got lucky. Breast cancer is a ‘sexy’ story that sells newspapers. If the subject matter has not been right, it is doubtful that the campaign would have been as successful.
No doubt there are many people who, for instance, felt equally passionate about the NICE decision to restrict certain Alzheimer’s drugs. But Alzheimer’s doesn’t have the media appeal of breast cancer. Likewise, if Herceptin had been a drug for bowel cancer, which kills about 16,000 in the UK every year (making it the second most common cause of cancer death after lung cancer – breast cancer ranks third), it is unlikely that a patient campaign would have been splashed across the front page of every major newspaper in the country.
While all the parties involved bask in their media triumph, and in spite of the many subjective and anecdotal reports of Herceptin saving lives, perhaps it’s worth reviewing what we really know about Herceptin. It’s not appropriate for all breast cancers. It isn’t a cure for the cancers it is appropriate for. It doesn’t significantly prolong life or stop cancer recurring, and while you are taking it you run the risk of seriously damaging your heart and hastening the spread of cancer from your breast to your central nervous system. The majority of women who take it won’t respond to it and those who do can become resistant to it over time.
Based on what we know about breast cancer and Herceptin, what can we realistically expect from Herceptin?
- According to Cancer Research UK, 41,000 women a year are diagnosed with breast cancer in the UK. Around 20 per cent (8,200) will have HER-2 mediated cancers and will be eligible for Herceptin.
- Of this 8,200, around 20 per cent will be too ill to take the drug and around 10 per cent will be excluded due to heart problems. This leaves 5,740 women eligible to take the drug.
- At a cost of £21,800 per treatment, and assuming all 5,740 women take Herceptin, this will cost the NHS £125,132,000 per year.
- NICE suggest that only one in 18 of these women, that is 319 women, will respond to Herceptin.
- The other 5,421 will have been exposed to the risk of heart damage and central nervous system metastasis without any actual benefit.
- The actual cost of prolonging these 319 lives for an average of four months is £392,400 per woman.
Is this really what passes for a medical miracle these days?
Sidebar: HER-2 – What’s all the fuss about?
While all the media attention is focused on the role of HER-2 in breast cancer, this same protein is found in excess in many other types of cancer including lung, prostate, colo-rectal, gastric, oral, bladder, ovarian, cervical and endometrial cancer.
Already medical research is suggesting that the widespread distribution of HER-2 may mean that it is little more than a crude marker at best. At present only 35 per cent of cancer centres in the UK routinely test women diagnosed with breast cancer for HER-2 status. To remedy this Roche has pledged £1.5 million in funding to establish appropriate systems that enable more widespread and routine HER-2 testing to take place on the NHS.
Establishing HER-2 testing protocols may appear to be a good thing, allowing doctors to more quickly and accurately determine which women might benefit from the Herceptin. But it is also a money-spinner. Roche and its subsidiary Genentech (which developed the drug) own the patent on the test kits. According to a report in the journal Nature, Roche has made these HER-2 testing kits available free of charge for laboratories in major markets such as the UK and Germany while the demand for Herceptin is being established. Indeed, in some countries the availability of these kits coincided with, possibly even preceded, the launch of the drug.
Establishing this naturally occurring growth regulator as the main protagonist in this type of breast cancer has a wider, and more profitable, purpose. It is a first step in a campaign intended to broaden the use of Herceptin in other HER-2 mediated cancers. It is already being considered as a potential treatment for prostate and lung cancer.
- This article first appeared in the Ecologist July / August 2006.
