INTERVIEW WITH DR. MICHAEL BAUM

DR. LOVE: The other thing, and I guess that's about to go into trial with IBIS II.

DR. BAUM: Yes, IBIS II has been hanging on there, very wisely, until we got the first results from ATAC. So, I think IBIS II kept their cool, have been very clever, and there are other chemoprevention trials that are having to consider their position very carefully.

DR. LOVE: Now IBIS II is going to be anastrozole vs. tamoxifen vs. placebo.

DR. BAUM: That's right

DR. LOVE: I guess when you talk about other trials the one that pops into mind is the STAR trial comparing two SERMs - tamoxifen and raloxifene.

DR. BAUM: I hope that trial will successfully go through to completion. I think, as I understand, there are already 13000 women on that trial, I hope it does go through to completion.

DR. LOVE: Why don't we talk about the side effects and toxicity.

DR. BAUM: Those that favor tamoxifen over anastrozole, the important one is fractures. There is a numerically modest, but highly significant excess fracture rate in the anastrozole arm. I also have sight of the details subprotocol looking at bone mineral metabolism in the trial, and I can't divulge those data, but they certainly would support the clinical finding that women on an aromatase inhibitor are more at risk of osteopenia and osteoporosis and fractures.

DR. LOVE: Of course, we don't have a comparison to a menopausal woman who's not receiving any therapy.

DR. BAUM: No, and you could argue that it is merely that tamoxifen is protecting the skeleton, but I don't buy that argument because tamoxifen is the gold standard, so if they weren't having anastrozole they would be having tamoxifen.

DR. LOVE: But I mean maybe at a biologic, scientific level, it's interesting to me because I always wondered whether or not you would see more bone loss by lowering the levels beyond menopausal levels, which we actually talked about in Miami.

DR. BAUM: I don't want to give too much away, but I think we will be seeing excess bone loss compared with a controlled population.

DR. LOVE: Can you give some idea in terms of the magnitude of the risk of fractures that was seen. It's hard to tell from the numbers, they're fairly small at this point.

DR. BAUM: Yes, it was in excess in absolute terms of about 4%, something like that, in absolute terms. There is another curious adverse event associated with anastrozole, and that comes within the category muscular skeletal disorders, but that hardly does justice to it. It's an arthralgia, a very peculiar arthralgia, which seems to be linked to aromatase inhibitors, we don't understand the mechanism, but it's there. I don't think it has contributed to withdrawing therapy, but it is a real problem, and women should be warned. Again, it is relatively uncommon, about 8%.

DR. LOVE: What is the typical clinical scenario? What do women complain of?

DR. BAUM: Well, aches and pains.

DR. LOVE: No particular location?

DR. BAUM: No the joint of the fingers and toes, the small joints often the weight bearing joints.

DR. LOVE: Any way to quantify how much it affects the quality of life or how bad it is?

DR. BAUM: We've got a subprotocol measuring quality of life in all of these woman. So far they are pretty well matched overall. I think the important issue is how many women withdrew treatment as a result of that. I can't remember the exact detail, but very few.

DR. LOVE: Is there a typical time sequence? Does it usually start right after therapy?

DR. BAUM: It comes on pretty early on. Bear in mind there is only a two and a half-year average exposure to the drug, so it can come on within the first year.

DR. LOVE: Does it stop when the drug is stopped?

DR. BAUM: I can't answer that question.

DR. LOVE: Getting back to the issue of bones, what are your thoughts in terms of how much of a problem this is going to be. You mentioned during the presentation the issue, and Trevor had just presented really neat data on bisphosphonates.

DR. BAUM: Well, it was a wonderful coincidence. No one could ever have orchestrated this. That I should be giving the ATAC paper shortly after Trevor Powles gave the paper on bisphosphonates. Providing we recognize this potential for rapid bone loss, then we can monitor these women with DEXA scans, bone mineral density scans, at say six monthly intervals. Those that are falling into the osteopenic range, we can start intervening. Now, since yesterday the number of protocols that have been suggested to me is huge, but one that we now already seriously considering is second randomization to Arimidex alone or Arimidex plus bisphosphonate.

DR. LOVE: Secondary within the trial?

DR. BAUM: Yes, don't ask me to go into any further details because we haven't even got to the "back of an envelope" stage. We're at the "back of the beer mat" stage, before you get into the "back of the envelope" stage. But some how or other we need to see if there's synergism between an aromatase inhibitor and a bisphosphonate. In the meantime though we can introduce bisphosphonates and calcium, if a woman is beginning to demonstrate osteopenia.

DR. LOVE: Just parenthetically what are your thoughts in terms of the data both from Trevor and the other two studies out there right now in terms of the potential impact of bisphosphonates both on bone and non-bone mets?

DR. BAUM: I don't understand the effects on non-bone mets, but that doesn't matter, if it's real, it's real. Certainly I'm convinced that there is an effect on bone mets. During the time the drug is being given, this is an interesting cause effect of bisphosphonates, and it might mean that if you are going to use it then you may have to use it longer than two years. Although Trevor Powles minimized it, some of the side effects are bothersome, the diarrhea and esophagitis. I'm not sure how well tolerated it would be long-term. But, it is certainly something we must consider.

DR. LOVE: What about the mortality advantage that he saw?

DR. BAUM: That was fairly surprising. He would be the first to say that this is a relatively small study, just over 1000 patients, and I hope there will be an overview of the three bisphosphonate trials as soon as possible. Then we can look at that with some statistical power.

DR. LOVE: The other side effect that you brought up in your presentation or the question of a side effect was a cognitive function, although I don't think you see anything yet.

DR. BAUM: I must emphasize this is purely theoretical, but it is something we take very seriously. There are data suggestive that long term estrogen deprivation can impair cognitive function. Also, the hormone replacement therapy can enhance cognitive function. On our steering committee and chairman of the subcommittee on quality of life is Professor Lesley Fallowfield, who is an authority on this subject. She has conducted a pilot study on this together with Professor Tony Howell on about 100 patients within the trial. But that's merely a feasibility trial to develop the instruments. We are hoping to do two things, one an exit trial of patients coming off treatment in ATAC, and secondly a prospective study linked to IBIS II.

DR. LOVE: That would be particularly good because they have a control arm.

DR. BAUM: It would be especially good because of the control arm.

DR. LOVE: I'm sure you have looked at the data on HRT. The whole issue of HRT and all kinds of things, including cardiovascular effects are getting relooked at now. How strong is that association?

DR. BAUM: It is very weak. The trouble is HRT was introduced without any clinical trials. So lots of the things we think we know about HRT are almost anecdotal. Particularly if you consider cognitive function, women on HRT are not typical of the population. They're a selected group of the population. I think we have to look upon that experience as hypothesis generating. I think the only thing we know with confidence is the effect on bone mineral density.

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