The champagne corks were popping in Switzerland on 9 June, when the National Institute for Health and Clinical Excellence (NICE), the official British drug appraisal agency, announced that Herceptin (trastuzumab) would soon be approved for use in early-stage breast cancer. For Swiss pharmaceutical giant Roche, the incorporation of Herceptin into the British NHS system will be the final crowning glory of one of the most successful marketing campaigns in medical history.

In 1998, Roche bought the international marketing rights to Herceptin from the drug's US manufacturer, Genentech. Over the last eight years, the orchestration of their joint public relations has been masterful-with newspaper headlines of a "wonder drug","a breakthrough treatment" and even a "cure", and stories of people so desperate to get hold of Herceptin that they'll sell the roof over their head to pay for it, and High Court battles to get the drug prescribed on the NHS.

How does it work?
So what's so special about Herceptin; what's all the fuss about? The headlines have got it right in one respect. Herceptin is indeed a breakthrough in chemotherapy, but it could be argued that it's about time we had one. The vast majority of chemo drugs are simply poisons, whose mode of action is to try and kill cancer cells before killing the rest of the healthy cells in the patient. Hardly 21st-century medicine.

Herceptin is different from a poison in that it's claimed to specifically target breast cancer cells, by blocking some of the chemical signals they need in order to grow. There's good evidence that some cancers, breast cancer in particular, are related to a gene called HER2. The term HER has nothing to do with the female gender; it stands for Human Epidermal growth factor Receptor, with the 2 meaning it's the second one to be discovered.

Some breast cancers have been found to be correlated with an abnormally high level of HER2 genes in the body. When that happens, the gene "orders" an excess production of receptors on the surface of cancer cells. The receptors are the "ears" of the cell, picking up chemical signals from the rest of the body, and adjusting the cell's growth accordingly. However, if there are too many receptors, as is the case in some breast cancers, the cells pick up too many growth signals, and start to multiply uncontrollably.

Herceptin works by attaching itself to the receptor "ears", thus effectively blocking them up, and preventing the chemical "grow" signals from getting through. Roche's marketing has stressed that, because Herceptin only attaches itself to HER2 breast cancer cells, it can't theoretically affect other cells in the body. Thus it's a true "breakthrough" in chemotherapy.

Targets other cells
So far so good. The problem, though, is that in practice Herceptin is not that specific. It turns out that other receptors besides breast cancer cells can get blocked by the drug. So far, the receptors that have been found to be damaged are those in the heart and lungs. Researchers at the prestigious Salk Institute have shown that Herceptin damages a gene called erbB2, which is intimately connected with heart and lung function. Interference with this gene can cause breathing problems, and damage heart muscle to the extent of actually compromising the pumping action, leading to heart failure (Recent Prog Horm Res, 2004; 59: 1-12).

Heart damage occurs in about 1 in 25 patients, a figure described as "unacceptably high" (Clin Breast Cancer, 2002; Suppl 2: S75-9).

Herceptin can also cause a litany of nasty side effects, which can occur in up to 40 per cent of cases (see box, page 6). So the claim that Herceptin is a nice, clean "targeted" cancer drug doesn't really stack up.

"Wonder-drug" endorsement
But does it work? Well, if the drug's spokesmen are anything to go by, Herceptin is nothing short of miraculous. In May last year, researchers announced at a cancer conference that the drug could reduce the risk of breast cancer recurrence by over 50 per cent within one year. One of the lead researchers in the UK, Professor Ian Smith, commented: "This is the biggest treatment development in breast cancer, in terms of the magnitude of its effect, for at least the last 25 years, perhaps as big as anything we've seen."

Prof Smith is head of the Breast Unit at the Royal Marsden Hospital, Britain's premier cancer hospital. Herceptin couldn't hope for a better endorsement-hence the media snowstorm of "wonder-drug" stories, desperate women selling their houses, and the PR blitzkrieg to coerce NHS hospitals to prescribe the drug for early-stage breast cancer.

Herceptin is relatively new to Britain, but it's been around for about eight years in the USA. The American experience is instructive; they've found that the drug is much less effective on its own than when combined with conventional chemotherapy drugs. With that approach, Herceptin's claimed "targeted" advantages are wiped out, condemning cancer patients to the myriad toxic side effects of standard chemotherapy.

Initially, the results appeared to be worth it. In October 2005, two Herceptin research papers were published in the New England Journal of Medicine, authored by about 50 doctors, reporting on how their patients responded to Herceptin plus chemotherapy. It was impressive-looking research, comparing about 4500 treated patients against different control groups (NEJM, 2005; 353: 1673-84; NEJM, 2005; 353: 1659-72).

An accompanying editorial described the results as "simply stunning", and "maybe even a cure" for breast cancer. The results showed that Herceptin plus conventional chemotherapy reduces the death rate by 33 per cent, and the cancer recurrence rate by more than 50 per cent. Those were the figures given to the press. So good were the results that the US authorities decided to stop some of the trials early, as the case for Herceptin appeared to be proven.

However, let's look at the figures more closely. The three-year, disease-free survival rate was found to be 75.4 per cent for those on conventional treatment, and 87.1 per cent for those on Herceptin. If you subtract these numbers from 100, you get 24.6 per cent versus 12.9 per cent-which is where the 50 per cent improvement in recurrence figure comes from. But another way of looking at it is that only 12 per cent of Herceptin users may be helped by the drug to remain disease-free after three years.

Hardly dramatic, hardly wonder drug, hardly cure.
What about life expectancy, the most meaningful statistic of all? Here the small print is even less impressive. In the trial that compared Herceptin to no treatment, death rates after one year "were not significantly different", with just over 2 per cent deaths in the untreated group, and just under 2 per cent in the Herceptin group. A significant number of women in that group were reported to have experienced "severe cardiotoxicity".

In other trials, Herceptin improved survival rates after three years, from 91.7 per cent to 94.3 per cent. So the reduction in the death rate is indeed the headline 33 per cent (from 8.3 per cent to 5.7 per cent). But it can also be expressed like this: Herceptin keeps about three people out of every 100 alive after three years-i.e., just 3 per cent.

Of course, that 3 per cent only applies to patients who have HER2 breast cancer. However, we know that only roughly a quarter of all breast cancer cases are HER2-positive. In other words, Herceptin is completely useless for 75 per cent of women with breast cancer.

On a more global analysis, therefore, the drug will help one quarter of 3 per cent of sufferers-i.e., less than one in a hundred women. As broadcaster, writer and breast cancer sufferer, Lisa Jardine, recently observed: "For women like myself, the new drug seems to promise a smallish reduction of an already lowish chance" of the disease recurring.

Earlier this year, Professor Peter Littlejohns, Clinical Director of NICE, analyzed the trial data, and calculated that 18 patients would have to be treated in order to prolong one life. "For every 100 suitable patients prescribed Herceptin," he wrote, "94 will have been exposed to the side effects without any benefit, at a cost of £400,000 per recurrence pre-vented" (Lancet Onc, 2006, 7: 22-3).

But, for other experts, even that puts too favourable gloss on Herceptin. In November 2005, Canadian biostatisticians delivered a bombshell. They too re-analyzed the Herceptin figures, and came to the conclusion they were phony. In a paper entitled "Randomized trials stopped early for benefit", their major criticism was that the original trials were just "interim analyses", and thus likely to show "implausibly large treatment effects". They heavily criticized the decision to stop the trials early, and recommended "clinicians should view the results of such trials with scepticism" (JAMA, 2005: 294: 2203-9).

Even The Lancet, a normally conservative medical journal, has been driven to condemn the whole Herceptin hype. "The best that can be said about Herceptin's efficacy and safety for the treatment of early breast cancer is that the available evidence is insufficient to make reliable judgments. It is profoundly misleading to suggest, even rhetorically, that the published data may be indicative of a cure for breast cancer", said a stinging editorial (Lancet 2005; 366: 1673).

Hype, hoopla and licensing
But surely Herceptin must be good for something, otherwise how would it have been licensed in the first place?

Let's look back at how it got onto the market. The drug was originally developed in the late 1990s for advanced breast cancer, when initial tests were begun with a few hundred patients-organized by the US manufacturers Genentech. It claimed significant "response rates" to Herceptin when the drug was combined with standard chemotherapy.

Two small-scale studies followed, in the first of which nine out of 37 patients with advanced breast cancer experienced "responses", although only for an average of about 8 months (Semin Oncol, 1999; 26S: 89-95). The second study used Herceptin alone, and found that five out of 43 patients "responded", although again the benefit was short-lived-about 5 months (Semin Oncol, 1999; 26S: 78-83).

Despite such modest results, press releases quoted the studies' authors as describing Herceptin as "a significant medical break-through".

The lead author of the second study, Dr Larry Norton of Memorial Sloan-Kettering Cancer Center in New York, declared, "This is the biggest difference I have ever seen in advanced breast cancer-unlike anything we have ever seen before."

Such was the media hype that few observers noticed that these studies were not only weak, but in fact not proper clinical trials at all. After all, they were neither "blinded" nor had any control groups.

But the press hoopla "created near pandemonium among breast cancer patients, who were desperate to get the latest 'cure'", says cancer industry watcher, Ralph Moss. "It made official approval a certainty." Herceptin duly became licensed for use in advanced breast cancer, and, to date, thousands of patients have already been treated. What effect has it had? Doctors are claiming huge "response rates" to the drug, meaning that tumours have been found to shrink. But the important question for any woman with advanced breast cancer is not "response" but survival. Will Herceptin really prolong my life?

Sadly, the answer appears to be no. The only published graph comparing Herceptin to standard chemotherapy shows at best a marginal and temporary effect on longevity (see box, below right).

As an example of what a truly effective chemotherapy drug can do, compare Herceptin with mistletoe (box, right).

Herceptin is just the latest in a very long line of cancer drugs that were first hailed as breakthroughs and miracles, but failed to live up to their promise. In the past, these drugs came and went with the public hardly noticing.

But today, the marketing of modern cancer drugs deliberately uses the public as a key sales tool. It starts by whipping up enthusiasm for the drug-sometimes, as we have seen, with phony statistics. Desperate patients then clamour to be given the drug.

This puts such pressure on the authorities that they cave in-even against their better judgment. NICE Clinical Director Professor Littlejohns is a case in point. In January 2006 he was seriously opposed to Herceptin, but within six months his organization had given the drug official approval.

So where can the public go for reliable objective information? Not to the press, who have consistently shown themselves to be suckers for drug industry hype; nor to cancer doctors, some of whom are in the pay of the drug companies; and not even to patient support groups, because most are propped up by "donations" or "educational grants" from drug companies.

Take the UK charity Cancer BACUP ("informing understanding supporting"). It has told patients that the results for Herceptin in early breast cancer are "impressive" and a "breakthrough", with no critique either of the data or the potential dangers of the drug. They have also consistently pressurized for patients to be given Herceptin, without declaring that one of their funders is Roche itself. In fact, almost 10 per cent of BACUP's income comes from drug companies.

The patient information group Breastcancer.org ("your lifeline to the best medical information about breast cancer") describes Her-ceptin as "a very effective treatment". Last year Genentech, Herceptin's manufacturers, gave over $50,000 to the organization. This 'generosity' helps to give Genentech and Roche a great deal of influence, if not control, of the information flow about Herceptin.

The annual payout for Herceptin in the UK alone has been put at £100m, i.e., about a quarter of the total cancer drug bill for the whole NHS.

In June, drug industry experts estimated global sales of Herceptin "will nearly triple" within the decade to $3.3 billion (21 June 2006 Decision Resources, Inc press release).

Tony Edwards