Herceptin

This weekend there are two interesting articles about trastuzumab (Herceptin), one in the BMJ and one in the Lancet.

The first of these is the experience of a consultant hematologist who developed HER2+ breast cancer at a time when it was difficult to get adjuvant Herceptin on the NHS. She was contacted by the Sun newspaper which was running a campaign championing Herceptin. As it was early in her chemotherapy she elected not to get involved in the campaign. Instead she decided to do some research for herself. Her concusion was that the "50% benefit" widely quoted in both medical and lay press actually translated into a 4.5% benefit for her which was equally balanced by the cardiac risk. Although the drug was not yet approved by NICE the (female) Health Minister had sent a pretty heavy signal to NICE that they had better approve it. Nothing sways government more than a campaign by the tabloids. The doctor was a clear steer that if she pushed for it she would get it. Nevertheless, she decided not to have Herceptin.

The second paper reviews the evidence. "The latest results show that the addition of trastuzumab reduced the absolute risk of death by 1·8% over 2 years and, at that stage, one extra woman will be alive for every 55 treated. However, an eighth of women randomised to trastuzumab died or relapsed over an average of 2 years." However, "trastuzumab will raise the absolute risk of symptomatic congestive heart failure by 2% at 2 years (up 0·4% from 1 year), and by 5% if subclinical harm is included." On cardiac damage they say, "the cardiologists we contacted were uncertain whether damage caused by trastuzumab is, as has been claimed, essentially short-term and reversible. Side-effects of the drug are additional to those caused by anthracyclines, drugs that by themselves can have serious outcomes 20 years after treatment. With anthracyclines, a statistically significant increase in harm is not enough to reduce the survival benefit at 15 years, but trastuzumab is from a different therapeutic class, with unknown long-term effects."

But on present evidence they conclude, "While there is cause for concern, perspective is needed: over 2 years, the risk of cardiac damage seems trivial compared with that of breast cancer recurrence. Unless catastrophic long-term side-effects emerge for trastuzumab, adjuvant Herceptin is good news for women with HER-2-positive early breast cancer and adequate cardiac function."

The group writing the review investigated the evidence for NICE to make a decision. They say, "Our work for NICE, with the 1-year median follow-up data, suggested that the adjuvant Herceptin schedule also represented value for money. We estimated that the regimen had an incremental cost-effectiveness ratio of around £18 500 per quality-adjusted life-year (QALY) gained, with two assumptions. First, survival benefits accrue over 5 years and are sustained thereafter (as with anthracyclines); second, that no cardiac events result in death (unlike with anthracyclines). If society were willing to pay £20 000 for an additional life-year with full quality of life, trastuzumab could be judged cost effective. With finite resources, the UK's National Health Service (NHS) would have to stop funding other treatments to provide trastuzumab (the opportunity cost), but the NHS could consider these cuts justified."

There is the rub. In real life money for health care is limited. Even the vast American economy is finding it so. Major corporations are facing financial meltdown because of health insrance costs. In the UK "Health trusts have been told that they have to invest in trastuzumab, and, to pay for the drug, they have to cancel services for populations who might be less vocal and well-organised than the breast cancer lobby."

"The cancellation of treatments by health trusts was not underpinned by the same kind of analysis as that which informed NICE's decision to fund trastuzumab, something that NICE's new disinvestment initiative (which helps the NHS identify and stop ineffective treatments), has to change if resource allocation is to be underpinned by procedural justice."

The point is that patient lobby groups are extremely influential, and none more so than the breast cancer lobbyists. But who will speak up for the Cinderella diseases? CLL suffers by comparison with breast cancer, but it is far better off than chronic granulomatous disease which hardly anyone has heard of, while unfashionable diseases like schizophrenia or manic depression, or diseases where the sufferer is thought blameworthy, like obesity, alcoholism or lung cancer, get a much less sympathetic press.

Another related issue in today's Lancet concerns direct-to-patient advertizing of drugs. This has been a feature of the American market since 1997, and there is an EU proposal to introduce it to Europe. A US government report
suggests that the practise is not working well in America. It found that FDA oversight was lax, "but their report also raises questions about the value of direct-to-consumer advertising and shows just how hard it is to regulate once this genie is out of the bottle. The investigators showed that from 1997 to 2005, industry spending on direct-to-consumer advertising grew on average nearly 20% per year, twice as fast as spending on drug promotion to doctors, reaching US$4·2 billion in 2005. By comparison, industry spent $31·4 billion on research and development. More than 50% of the direct-to-consumer spending went to advertisements for just 20 drugs, most for chronic conditions such as hyperlipidaemia, asthma, and allergies. Not surprisingly, these are the same drugs that drug companies are promoting directly to doctors with advertising in medical journals, drug-representative visits, and free samples. It's a smart dual-pronged strategy, because a doctor is more likely to provide a particular drug when a patient asks for it and when the doctor has free samples on hand. This is not to say that direct-to-consumer advertising does not help some patients. In many cases, patients may have been well served by advertisements that led them to discuss their concerns with their physicians. But the primary purpose of direct-to-consumer advertising remains clear: to sell lucrative, on-patent, brand-name drugs. Claims to the contrary just do not pass the straight-face test".

The paper concludes, "It would be better to fund independent information sources, free of industry influence, to provide the public with unbiased evidence-based information. If industry truly wants to inform the public, it should supply no-strings-attached funds to support such efforts. Even a small portion of the $4·2 billion being spent each year in the USA on direct-to-consumer advertising would do nicely."

I would like to put it on record that this blog receives no funding from the pharmaceuical industry and everything I say about the use of drugs is my honest opinion at the time based on my reading of the evidence without fear or favor.

But to get back to Herceptin. A recent paper in the New England Journal of Medicine reports on a Finnish trial of Herceptin as adjuvant therapy. Importantly, this trial used much smaller amounts of the antibody (20 mg/kg over 9 weeks rather than 110 mg/kg over a year). Naturally, this trial was not funded by the pharmaceutical company, but paid for by the Finnish government. The finding was as follows: "Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure."

This has particular resonance for CLL patients, particularly those who have been following Ron Taylor's work on antigen shaving. Is it possible to get an equal effect with less rituximab? You can hardly expect pharmaceutical companies to conduct trials that would result in their selling less of their product. But it is the interest of third party funders to pay for such trials. Funds for health care are limited. Lobbying for one treatment will inevitably mean that someone, somewhere will not get the treatment he needs. The market is not free, it is being manipulated.