Hitting the bull’s-eye  pg. 4

Unless the drug is tested first in patients in whom it is most likely to work.

This is what happened with the targeted therapy trastuzumab (Herceptin), which is directed against the HER-2 protein (a receptor similar to the EGFR). Herceptin first proved itself in clinical trials in the sickest patients whose tumors had high expression of HER-2.

It is now used as an adjuvant therapy—a treatment given usually after the main treatment, to boost its effectiveness—in breast cancer. Herceptin may never have reached that stage if patients in the early trials had not been “selected” for high expression levels of HER-2 in their tumors.

“If those initial trials had not been limited to patients with high HER-2 levels, it would have threatened the development of a drug that we know works as long as it is used against the right cancers,” says Carlos Arteaga, M.D., Vice Chancellor’s Professor of Breast Cancer Research at Vanderbilt. “Herceptin alters the natural history of women with breast cancer overexpressing the HER-2 protein (by increasing their chances for survival).”

Are they worth it?

Targeted therapies come at a cost.

“The presumption is that targeted therapies will only cause good things to happen and not bad things. Sadly, that is not the case,” Johnson says. He cites studies showing that long term use of both Gleevec and Herceptin can cause heart failure.

And then there’s the financial cost—up to $10,000 per month for the newest drugs.

“There’s no rhyme or reason for the cost of cancer drugs in this country,” Johnson says. “And what’s interesting is that the drug gets the blame for being ‘ineffective’ because it only offers a two-week survival advantage. I’m not praising the drug for giving you two weeks of survival, but each of us knows that used in a more appropriate way, we can get these huge benefits that were seen with Herceptin.”

The trouble, Johnson says, is the hype about the promise of these new drugs, which when apparently not met, creates disappointment and cynicism.

Carbone takes issue with the idea perpetuated in the lay press that the effectiveness of targeted drugs can be fully assessed by measures of median survival.

“It’s extremely misleading to say that a drug only gives you a six-week survival difference, without any additional explanation,” Carbone says.

Survival curves report a population average. About half of the patients will get no benefit at all and half will have “some benefit that’s very real: the tumor shrinks by a measurable amount, the patients feel better, and they live longer,” he says. About a quarter of the patients will have major shrinkage of the tumor, and in about 5 percent, the tumor will virtually disappear.

“For that 5 or 25 percent of patients, that’s a heck of a lot more benefit than a six-week survival difference tells you about,” Carbone says.

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