I HAVE nothing against miracles, but whenever there鈥檚 a big buzz about a new drug, it鈥檚 a fair bet it鈥檒l be down to the usual suspects: vested interests, early research, and uncritical journalists.
Take Herceptin (trastuzumab). In October 2005, The New England Journal of Medicine sparked a huge reaction when it published studies which showed that adding Herceptin to standard cancer therapy reduced the recurrence rate of certain breast cancers. Herceptin was an 鈥渁stonishingly effective鈥onder drug鈥�, enthused the media, while doctors talked of 鈥渞evolutionary鈥�, 鈥渟tunning鈥�, 鈥渏aw-dropping鈥� findings. In the NEJM, Jo Anne Zujewski of the US National Cancer Institute, wrote: 鈥淚n 1991, I didn鈥檛 know鈥� we would cure breast cancer鈥� in 2005, I鈥檓 convinced we have鈥�, and in an editorial, Gabriel Hortobagyi of the MD Anderson Cancer Center: 鈥淭his observation suggests a dramatic and perhaps permanent perturbation of the natural history of the disease, and may even be a cure.鈥�
And the reality? In September 1998, the US Food and Drug Administration (FDA) 鈥渇ast-tracked鈥� Herceptin for advanced (metastatic) breast cancer in women whose tumours carried the HER/2-neu marker: 25 to 30 per cent of those with advanced cancer. Herceptin on its own shrinks tumours in around 15 per cent of cases; in combination, it extends life by on average about five months against chemotherapy alone.
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Because the drug improved the survival of some patients with advanced breast cancer, it was hoped it might benefit women with earlier-stage breast cancer even more. The trials reported in NEJM tested this hypothesis. But while the findings showed an advance in the treatment of a minority of women with early-stage breast cancer, it was a modest and qualified advance, far short of the hype.
However, not all news reports made it clear that Herceptin could benefit only a small minority. Headlines screamed: 鈥淏reast Cancer Recurrence鈥� Cut in Half by a Drug鈥� (The New York Times, 26 April 2005), and 鈥淒ocs See a Huge Gain Vs. Breast Cancer鈥� (New York Daily News, 20 October 2005). Desperate patients don鈥檛 read the fine details, much less the nuanced journal articles. By emphasising that women who took Herceptin showed a 52 per cent drop in recurrence compared to women who didn鈥檛 take it, the wrong impression was promoted: that Herceptin conferred a survival advantage of more than 50 per cent across the board.
Now, appreciating the drug鈥檚 true benefit means understanding relative and absolute risk. That 52 per cent is a reduction in relative risk. Since the chance of breast cancer recurring when treated early is already small, a 52 per cent reduction in that risk is commensurately small. Even women with early breast cancer who receive no treatment after lumpectomy, see recurrence peak at 10 per cent per year after two years, then drop, levelling off at around 3 per cent at 10 years. After other standard therapies, recurrence is lower still. Importantly, as in many trials, prolonging life isn鈥檛 the main yardstick: researchers focus on how long a drug can keep patients disease-free. However, the disease may return, often with renewed vigour. So disease-free survival does not by any means translate into prolongation of life.
鈥淒esperate patients don鈥檛 read the fine details, much less the nuanced journal articles鈥�
Looking at overall survival rate at the end of one of the studies, there were 37 deaths in the control group (2.2 per cent) as opposed to 29 deaths (1.7 per cent) in the Herceptin group. The slight difference in the deaths was most likely chance alone, so adding Herceptin to chemotherapy conferred no meaningful survival advantage.
Now, Herceptin does have a small but significant positive effect on the absolute rate of recurrence in a minority of women with early stage breast cancer. But look closely at the causes of death. In one of the studies, there were 23 breast-cancer related deaths (1.4 per cent) in the Herceptin group compared with 34 (2.0 per cent) in the observation group. In terms of absolute risk, the Herceptin group achieved a very modest 0.6 per cent reduction in breast-cancer related deaths. This small gain has, however, to be weighed against the fact that Herceptin turns out to produce heart damage in 4.1 per cent of the early-stage breast cancer patients.
This is a far cry from claims for Herceptin as a potential 鈥渃ure鈥� by Hortobagyi and others. Hortobagyi, 2006 President of the American Society of Clinical Oncology (ASCO), is also a paid consultant to Genentech, Herceptin鈥檚 US distributor. According to ASCO鈥檚 Journal of Clinical Oncology, he declared consulting fees of between $10,000 and $99,999 from Genentech and equivalent in honoraria.
One of the journals to keep its head, was The Lancet: 鈥淭he best that can be said about Herceptin鈥檚 efficacy and safety for鈥� early breast cancer is that the available evidence is insufficient to make reliable judgments. It is profoundly misleading to suggest, even rhetorically, that the鈥� data may be indicative of a cure鈥︹�� Hortobagyi鈥檚 claims, were, it said, 鈥減remature鈥�: the Herceptin debate 鈥渄emands cooler heads than have so far prevailed鈥�.
Or beware journalists or doctors pulling wonder drugs out of hats!
