DR CRAIG HENDERSON SUPPLEMENT

DR LOVE: You said that you wouldn’t be offering chemotherapy to this 60-year-old woman who’s ER-positive. Does that, in general, mean that for postmenopausal women who are ER-positive, you’re not using chemotherapy?

DR HENDERSON: That’s correct. And that’s always sort of been my position. However, I do want to make sure that there are two footnotes to that. One is that I always go through all of the evidence. I present the evidence from the overviews as being probably the most reliable. Number two is that I always indicate to the patients that I see that I think it is reasonable to get chemotherapy, and that I think it’s reasonable to make either choice. The benefit, however, is very, very modest. Let’s just take the woman you described. She’s in a 60 to 70-year-old category. The effects on survival are going to be about one-half to one-third the effects of chemotherapy on premenopausal women.

Then, if you take the women who are receptor-positive, the effects are going to be even smaller than that. It’s very difficult to get precise numbers, because the most reliable source is the overview. Of course, as women get older and older, we have fewer and fewer observations.

DR LOVE: But the reason that there’s less of an effect is because the baseline relapse rate is being decreased by hormonal therapy. Is that your take?

DR HENDERSON: No.

DR LOVE: What’s the reason?

DR HENDERSON: I don’t think we know all of the reasons. I can speculate. And, again, it’s important to understand that this is speculation. A lot of this is stuff I’ve just been talking about this last year and not much before that, because I’ve been trying to understand what happened in what people refer to as the taxane trial. Why weren’t there more effects from taxanes in the receptor-positive women?

What we do know, first of all, with considerable certainty, is that each year that a woman gets older, there is less effect of chemotherapy. So, for example, in a young woman, the reduction in the odds of death is going to be pushing 30 percent or slightly higher. And each decade that gets smaller, so that by the time you get to a woman 60 to 70 years old, the reduction in the odds of death has fallen to about nine percent.

Interestingly, tamoxifen of course goes in exactly the opposite pattern, going from young to old. Now, the first time I saw these data – these were generated originally by Richard Peto – I said, “Well, that’s just an effect of chemotherapy on the ovaries.” We didn’t really have menopausal data that was as good as the age data. Age of human beings all over the world is accurate, by and large, and menopausal data is very inaccurate for a number of reasons, which most logisticians readily understand. But I don’t think they even understand fully how inaccurate it is. But we know that the menopause doesn’t at a moment in time, and we know that, different studies use different definitions and so on. But I finally got him to do an analysis on the relationship between both tamoxifen and chemotherapy and menopause. And it wasn’t neat in the same way that age was. Age, every time, it’s consistent. You see this pattern. And, in fact, there’s a highly significant linear effect. But you don’t see it with menopause.

So, he first presented this to me, probably, in the late ‘80s, maybe with the 1990 overview. In fact, it may have gone back to ’85, but I just rejected it out of hand as this just doesn’t make sense to me. For 15 years, I’ve been trying to figure out how to explain this. But it’s definitely a real phenomenon. And it’s not simply explained by menopausal status, for the reasons I just gave you. Then we come along to this taxane trial, and the thing that’s interesting is that in the ER-negative patients, adding Taxol is very beneficial, whether you’re premenopausal or postmenopausal. So, if you were a 60-year-old woman with five positive nodes or ER-negative, I would have no problem giving her chemotherapy. But she was ER-positive. So, why don’t we see an effect?

In fact, my first reaction – and this is not published. Nobody’s really looked at it – but my first reaction was it was because we were using five years of tamoxifen. I thought, if you use longer and better hormone therapy, then there’s less for the chemotherapy to add.

DR LOVE: It’s harder to see it.

DR HENDERSON: That’s right.

DR LOVE: Fewer events.

DR HENDERSON: What I did is I went back to the overview, and I took all of the trials where women had gotten one year of tamoxifen plus or minus chemotherapy. I then put all the trials together that had gotten two years plus or minus chemotherapy, then five years plus or minus chemotherapy. My hypothesis was that if you got only one year of tamoxifen, the chemotherapy would have a greater benefit than if you’d gotten five years of tamoxifen. That was my first hypothesis. Wrong. It didn’t work out. I couldn’t show that. And using the overview data, of course, I had large numbers. So, that wasn’t the explanation.

Then I thought we know that among women ages 50 to 59 in the overviews, 20 percent of those women are actually menstruating. They’re truly premenopausal. So, I thought, well, maybe that’s part of it. It’s kind of mucking it up. We’re seeing a premenopausal effect in women that were classified as postmenopausal.

But then, all of a sudden we have – well, not all of a sudden – we have these data that were presented by Kathy Albain last year at ASCO. I think it’s a very important study. This is the Intergroup study, and they randomized ER-positive women to tamoxifen or tamoxifen plus CAF.

Now, those women, unlike the ones in the overviews, were all postmenopausal. In other words, they had to have stopped menstruating. So, unlike the NSABP studies, there wasn’t a question. They defined it not by age, but by menopausal status. And secondly, the effect is enormous.

So, then I went back again to the overview data – and I haven’t finished this analysis. This was very preliminary – and some of it was stimulated discussions with Kathy Albain, among others, so I don’t want to take all the credit for this. But if you look at the incidence of amenorrhea and I think almost all people will agree at this point that in premenopausal women, that there is a relationship between the development of amenorrhea and the effectiveness of chemotherapy. I won’t review all that, but there’s an abundance of data.

So, then, the next thing you say, if that’s the case, then you would expect that those regimens which cause the most amenorrhea would be the regimens that would be most effective in at least premenopausal women. So, if you go back and you look, you see that the most effective regimens, the highest incidence of amenorrhea actually comes with CMF. But, also, if you look at the Canadian trial using CEF, in fact that has given some of the most dramatic and the largest actual benefits from adjuvant chemotherapy of any trial that’s been done thus far. But in that particular trial, they used cyclophosphamide in the same way we do with CMF; that is, daily oral cyclophosphamide times 14 days. And that’s exactly what Kathy Albain did in her trial. She used classic CAF.

So, then I went back to the overview — and it’s hard to sort these things out. And, as I said, I’m still working on it. But, I see that the trials that used the classic CAF, CEF and CMF, using just exactly like it was in the original Bonnadonna trial, actually seemed to be the most effective trials that we have.

Then I went back, also, and look at work that people have done – there’s a paper in JCO, where they looked at the incidence of amenorrhea with different regimens, and it’s very interesting. CA times four is one of the lowest. This leads me to the possibility that, in fact, maybe one of the reasons that we didn’t see an effect of adding four cycles of Taxol is we were giving four injections, and that this prolonged suppression somehow may be a critical factor. So, I come around to think that a prolonged cyclophosphamide may be a very important issue. Also the duration itself may be important, but we have that six-month duration with the taxane trial. Well, now, how does this relate to the question you asked?

DR LOVE: Whatever that might have been.

DR HENDERSON: Well, you were asking about a 60-year-old woman.

DR LOVE: Exactly. Right.

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