Larry Norton: From A to B in Breast Cancer
Larry Norton: From A to B in Breast Cancer
Dr. Miller: With a little trepidation, I have to ask you about the adjuvant chemotherapy study.
Dr. Norton: They compared 2 dose-dense regimens.
Dr. Miller: You gave birth to dose-dense therapy. This study compared paclitaxel every 2 weeks to a perhaps denser weekly version.
Dr. Norton: I'm glad you asked that question because this has confused people in trying to understand this. The regimen that the mathematical modeling said was not optimal was every 3 weeks. We had a very well-done series of experiments trying to find the dose-response curve for paclitaxel, and that information was used in the modeling for planning the appropriate scheduling of the drug. If you look at the dose-response relationship, the modeling actually predicted that weekly and every-2-weeks paclitaxel at a higher dose would be equivalent. We piloted the every-2-weeks regimen at Memorial Sloan-Kettering Cancer Center with growth factor.When that was done, it was moved into a cooperative group trial and showed, with every-2-week doxorubicin/cyclophosphamide, real, significant benefit.In fact, the simple expedient of giving those drugs every 2 weeks rather than every 3 weeks is as effective for hormone-receptor-negative disease as trastuzumab is for HER2-positive disease. Everybody says, "Oh my goodness, what a great advance trastuzumab is." And it certainly is, but it is equally effective for estrogen-receptor-negative disease to give these drugs every 2 weeks. That is something that people forget in terms of the magnitude of the effect.
While that was going on, based on the modeling at Memorial Sloan-Kettering, we piloted and published, with David Finley as first author, the weekly regimen. It wasn't in breast cancer, but it was based on the same modeling.
Dr. Miller: The regimen of 1 week of paclitaxel had been compared with every-3-weeks in a previous ECOG trial.It was also better. On the basis of the hazard ratio, it was better by about the same amount as an every-2-week regimen.
Dr. Norton: Right. Basically you have a comparison of 2 dose-dense regimens: one that requires growth factors for hematopoietic support and another that doesn't. It turns out that the weekly regimen is comparable in efficacy and is better tolerated. That is the preferable dose-dense regimen. To say that this was a comparison of "dose density" vs "non-dose density" isn't correct; they are both dose-dense if you compared either of those with every-3-weeks, which was the standard for paclitaxel. I'm noticing that it is still in wide use in many parts of the world. Either one of them would be superior in terms of efficacy. Those results are not in any way surprising. I am glad that research was done.
On the other hand, as a clinician, I have patients who come from a very long distance to see me. There is a big difference between coming every 2 weeks and coming every week if they are traveling a long distance. As long as they are not running into some of the side effects of the every-2-weeks regimen and are tolerating it well, it's a perfectly acceptable regimen for them.
Dr. Miller: Some of the options are based on the practical logistics and toxicity.
Dr. Norton: One thing that I wouldn't do is every-3-weeks, because I know that it is inferior in terms of curing cancer. We have 2 dose-dense regimens to choose from at the present time. This work has shown that they are comparable, that they are good, and that there are reasons to choose one or the other.
Clearing Up Confusion About Dose-Dense Treatment
Dr. Miller: With a little trepidation, I have to ask you about the adjuvant chemotherapy study.
Dr. Norton: They compared 2 dose-dense regimens.
Dr. Miller: You gave birth to dose-dense therapy. This study compared paclitaxel every 2 weeks to a perhaps denser weekly version.
Dr. Norton: I'm glad you asked that question because this has confused people in trying to understand this. The regimen that the mathematical modeling said was not optimal was every 3 weeks. We had a very well-done series of experiments trying to find the dose-response curve for paclitaxel, and that information was used in the modeling for planning the appropriate scheduling of the drug. If you look at the dose-response relationship, the modeling actually predicted that weekly and every-2-weeks paclitaxel at a higher dose would be equivalent. We piloted the every-2-weeks regimen at Memorial Sloan-Kettering Cancer Center with growth factor.When that was done, it was moved into a cooperative group trial and showed, with every-2-week doxorubicin/cyclophosphamide, real, significant benefit.In fact, the simple expedient of giving those drugs every 2 weeks rather than every 3 weeks is as effective for hormone-receptor-negative disease as trastuzumab is for HER2-positive disease. Everybody says, "Oh my goodness, what a great advance trastuzumab is." And it certainly is, but it is equally effective for estrogen-receptor-negative disease to give these drugs every 2 weeks. That is something that people forget in terms of the magnitude of the effect.
While that was going on, based on the modeling at Memorial Sloan-Kettering, we piloted and published, with David Finley as first author, the weekly regimen. It wasn't in breast cancer, but it was based on the same modeling.
Dr. Miller: The regimen of 1 week of paclitaxel had been compared with every-3-weeks in a previous ECOG trial.It was also better. On the basis of the hazard ratio, it was better by about the same amount as an every-2-week regimen.
Dr. Norton: Right. Basically you have a comparison of 2 dose-dense regimens: one that requires growth factors for hematopoietic support and another that doesn't. It turns out that the weekly regimen is comparable in efficacy and is better tolerated. That is the preferable dose-dense regimen. To say that this was a comparison of "dose density" vs "non-dose density" isn't correct; they are both dose-dense if you compared either of those with every-3-weeks, which was the standard for paclitaxel. I'm noticing that it is still in wide use in many parts of the world. Either one of them would be superior in terms of efficacy. Those results are not in any way surprising. I am glad that research was done.
On the other hand, as a clinician, I have patients who come from a very long distance to see me. There is a big difference between coming every 2 weeks and coming every week if they are traveling a long distance. As long as they are not running into some of the side effects of the every-2-weeks regimen and are tolerating it well, it's a perfectly acceptable regimen for them.
Dr. Miller: Some of the options are based on the practical logistics and toxicity.
Dr. Norton: One thing that I wouldn't do is every-3-weeks, because I know that it is inferior in terms of curing cancer. We have 2 dose-dense regimens to choose from at the present time. This work has shown that they are comparable, that they are good, and that there are reasons to choose one or the other.