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Small, Node-Negative, HER2-Negative

DR HUDIS: In examining these responses in Figure 16, regarding which chemotherapy clinical investigators and practicing oncologists use for patients with smaller, node-negative tumors, I think it’s important to start with the fact that AC has never beaten CMF in a randomized trial. In addition, the data increasingly point to HER2 status as the selector of anthracycline benefit, including the pooled analysis presented by Gennari at the San Antonio meeting in 2006.

I know the overview says that there’s an overall benefit for an anthracycline-based regimen, and I don’t dispute that, but it’s conceivable that much of that benefit is being driven by the HER2 subset, with real neutrality outside of the HER2 subset.

For those reasons, as well as the increased recognition of the long-term risks of cardiac toxicity, acute leukemia and MDS associated with anthracyclines, there is motivation to look beyond AC — that is, we want more effective regimens than CMF but also regimens with less acute and chronic toxicities. I believe that’s the background for the drift away from AC in whatever direction we go.

Currently, if I’m going to use something other than dose-dense AC/paclitaxel, I generally use CMF. The patients for whom we use CMF have low-risk breast cancer that is often ER-positive, almost always node-negative and almost always small in size.

In our practice, we use some TC. I found Steve Jones’s updated presentation last year, showing TC to be superior to AC in disease-free survival, to be convincing that TC is not worse than AC, and probably better, and that because it eliminates the anthracycline-associated cardiac toxicity, it might be the preferred regimen. All else being equal, I would be in that camp myself. However, there are a couple of nuances to consider.

First, it remains conceivable that in HER2-positive breast cancer you would want the anthracycline, and that’s not easily addressed in the trial. Second, clinicians who use TC pretty consistently point out that, although it is less toxic long term, acutely it’s a fairly rigorous regimen for patients and may be more rigorous even than AC. Apart from the cardiac and leukemia risks, the toxicity profiles aren’t so different, and the rate of neutropenic fever is actually higher for TC than for AC.

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The third issue is the uncertainty about the optimal schedule and dose density. We have to admit that we don’t have direct evidence that AC every two weeks is better than every three weeks. However, some people suspect that’s the case and it gives you a nice, short regimen.

So the choice of using dose-dense AC without a taxane is rational, but it is not evidence based, at least not directly. The reason why I say it’s rational is that I dispute any argument that says administering four doses of full-dose AC at two-week intervals could be inferior to administering it at three-week intervals. I simply don’t have an example of any drug in oncology that has ever played out that way, but that’s an argument people sometimes make about duration of therapy, as if the time from the first treatment to the last treatment is important.

I don’t buy that, because it’s more convenient to complete therapy in eight weeks rather than 12. And because dose-dense therapy with GCSF support reduces the risk of hospitalization from neutropenic fever, I don’t have any trouble with administering this regimen off study.

However, we have good evidence that for the patients in whom an anthracycline makes a difference, a taxane also makes a difference, so by the time I’m administering AC, I’m also administering the taxane, so administering AC alone is rare for me.

Breast Cancer Update Think Tank 2006 (2)

DR JOYCE O’SHAUGHNESSY: In my practice, I don’t use AC any more as a four-cycle regimen. I’ve switched over to TC. When I’m going to use four cycles for patients with lower-risk, ER-positive, node-negative disease, I use TC.

DR DEBU TRIPATHY: TC is a reasonable non-anthracycline regimen. The US Oncology trial was a smaller study, so our level of confidence is lower, but at least everything pointed in the right direction.

Despite the limitations of being a small study, being spread out over a long period of time and having broad eligibility criteria, it did show that TC is as good or even better than AC. For patients with cardiac risk factors, it’s a reasonable regimen to use.

For patients who don’t have cardiac risk factors, I believe TC should be brought up as an option. When I consider the overall toxicity profile, it’s hard for me to figure out which was better tolerated because the spectrum of toxicities was different. The TC regimen had more hematologic toxicities and edema, whereas the AC regimen had more GI and cardiac toxicities.

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