DR TERRY MAMOUNAS SUPPLEMENT

DR NEIL LOVE: One of the most interesting developments in breast cancer clinical research has been the evolution of trials on the use of taxanes in the adjuvant setting. Dr Henderson discussed possible explanations for why both his Intergroup study and the NSABP trial that was presented at the 2000 NIH Consensus Conference seemed to show a benefit for taxanes only in receptor-negative patients. I met with Dr Terry Mamounas to obtain an update on the current clinical trials of the NSABP, and newer studies that are in the planning stages. Dr Mamounas began our conversation by commenting on the current NSABP strategy to address the issue of taxanes in the adjuvant setting.

DR TERRY MAMOUNAS: The NSABP B-30 is a trial for patients with positive nodes irrespective of HER2/neu overexpression that actually addresses the issue of sequential taxane administration versus combination of both anthracyclines and taxanes. This is a three-arm trial comparing the AC followed by docetaxel regimen as used in the preoperative B-27 trial, the combination regimen of AT, Adriamycin-Taxotere at 50 and 75 milligrams per meter squared, and the triple combination of Adriamycin, Taxotere and cyclophosphamide at 50, 75 and 500. I think that’s an important question, as we will be hearing data from combination trials, comparing, for example, TAC versus FAC in the BCRG study, and the AT versus AC that the Intergroup has done. I think the question of whether sequential versus combination therapy is better, will become paramount in the next few months. So, I think the B-30 trial is actually a very important trial.

DR LOVE: What was involved in selecting Taxotere versus Taxol?

DR MAMOUNAS: For the combination regimen, as you know, the initial data with Adriamycin and Taxol were very promising. From phase II studies from Europe, we saw response rates in the high 90s, so we became very impressed with the combination, although those studies also showed a significant increase in cardiac toxicity when you gave Taxol in combination with AC.

Now, although this cardiac toxicity can be attenuated if you move Taxol a little bit further out and give it several hours later or the next day, or if you change the duration of the infusion. The fact is that, perhaps, the efficacy may be attenuated, as well. The phase II studies of Adriamycin and Taxotere did not show this increase in cardiac toxicity. Whether this is because of the different taxane or because, perhaps, of the vehicle the taxanes are dissolved — as you know, Taxol is dissolved in cremophor and studies have shown that cremophor increases the AUC of Adriamycin. So, it may not be the Taxol that’s doing it; it may be the cremophor. Taxotere is dissolved in polysorbate, and polysorbate did not seem to increase the AUC of Adriamycin. So, for whatever reason, it appears that the combination of docetaxel and Adriamycin does not increase, substantially, cardiac toxicity. That was the main reason that we selected this combination for the adjuvant setting.

DR LOVE: Any interest in the capecitabine-Taxotere combination in terms of adjuvant therapy?

DR MAMOUNAS: Yes. In fact, we are actually designing a trial, which we’ve now submitted to the NCI and got protocol-concept approval. That will be a neoadjuvant study following the B-27 protocol. And it will compare the AC followed by docetaxel regimen as used in the B-27, to the AC followed by docetaxel plus capecitabine regimen based on the data from the O’Shaughnessy trial, showing that this regimen actually improved survival in patients with metastatic breast cancer. So, we’d certainly like to move it into the adjuvant setting.

DR LOVE: Can you talk a little bit about the B-27 results, which were just presented in San Antonio?

DR MAMOUNAS: Sure. The B-27 study was a three-arm trial. It was a neoadjuvant study comparing the AC regimen followed by surgery to AC followed by docetaxel and then surgery, or to the so-called “sandwich” approach, where AC was given first, surgery in the middle, and then docetaxel postoperatively.

Of course, the main goal of this study was to see whether adding docetaxel would improve disease-free or overall survival similar to the B-28 study or the CLGB 9344. But, in addition, since this was a neoadjuvant study, we wanted to see whether adding docetaxel preoperatively would improve on clinical and pathologic response rates, and also whether we can downstage the axillary nodes further. By adding docetaxel postoperatively, we wanted to see if, indeed, there is a benefit, and whether this benefit will come from a subset of patients, particularly those that still have residual positive nodes following AC. Would these patients benefit, or will all patients benefit?

DR LOVE: Now, again, what was the rationale for using Taxotere?

DR MAMOUNAS: Early on, when we became involved with the development of taxanes as adjuvant therapy, certainly Taxol was the first taxane that hit the market, so to speak, in the metastatic setting. And we used that in our B-28 study. We early on became aware of the data of phase II studies of docetaxel in anthracycline-resistant breast cancer, where, as you know average response rate was about 47 percent in the three phase II studies. In this particular population of patients, before taxanes, the best we could do was about a 20-percent rate with any other agent we had. So, we were fairly impressed at the time, with this data. That was the main reason that we selected docetaxel for this particular study, because we wanted to see what kind of response we would get following anthracyclines, or for those patients that, let’s say, are resistant to AC for four cycles, would they respond to Taxotere. And we can do that.

Of course, subsequently, there’s several other pieces of data that became available, particularly from phase III trials, that show that docetaxel is actually more active than Adriamycin and, perhaps, is one of the most active agents we have in breast cancer. So, I think our decision was the right one.

DR LOVE: What did you see in the trial?

DR MAMOUNAS: Well, at the last San Antonio meeting, we reported the results from the Assessment of Response, comparing the second group of patients — the AC followed by docetaxel preoperatively — to the response with AC alone either from the first group or the third group. It turns out that docetaxel increased both clinical and pathologic response. Clinical response went from 85 percent to 91 percent, but more importantly, the clinical complete response went from 40 percent to 65 percent. Even more importantly, pathologic response was essentially doubled from about 13.5 percent in the AC alone group to 25.6 in the AC followed by docetaxel.

Now, there is one interesting piece of information that probably wasn’t brought out at the meeting. When you look at the B-18 study — the first neoadjuvant study we did — the tumors in that study were much smaller than in the B-27 trial. The median tumor size in B-18 was about 2.2 centimeters and in B-27 it was 4.5-4.7 centimeters. It was very large. There were very large tumors in that trial, but despite that, the pathologic response rate with AC was the same. It was about 13 percent both in B-18 and B-27, which, to me, indicates that biologically if a tumor is to respond to neoadjuvant chemotherapy it will respond no matter how big it is. It’s just a matter of some inherent biology of the tumor, oncogene expression or whatever. So, the fact that tumor size did not affect the rate of pathologic response with the AC regimen is actually a very interesting observation.

DR LOVE: That’s fascinating. It’s interesting, too, that the NSABP members chose to put women with larger tumors in. Do you think that’s because when B-18 came out, people were thinking that this is going to affect disease-free and overall survival? Once they saw that it didn’t, then they started leaning towards larger tumors? Or did they know that during the trial accrual?

DR MAMOUNAS: No. I think they did know that when B-27 was running, but the main reason, I think, that we put the larger tumors in was that because we gave more therapy. We gave eight cycles of therapy with the taxane, which certainly has significant toxicity, as well. There was a natural selection to put the higher-risk patients in that protocol, and not the patients with the 1.5-centimeter tumors.

DR LOVE: One of the things that came out in the adjuvant trial — I want to ask you about that with the AC followed by Taxol, as well as the Intergroup trial — was whether there’s a difference in terms of ER receptors. Did you look at the B-27 trial in terms of response rate based on receptors?

DR MAMOUNAS: Yes, we did. The reason that we didn’t present that data is, in that category because patients were undergoing pathological complete response, a good number of patients were unknown receptors. We never had the chance to measure receptors, because they had their diagnosis by F&A, and then they went into pathologic response.

DR LOVE: So, they didn’t have to have cores?

DR MAMOUNAS: They did not have to have cores, but we did a sub-study, which we will eventually report, where core biopsies were performed in about 700 patients. So, we know their status. But it turns out, for those patients that we knew their receptor status, from before based on a core biopsy, the pathologic response was doubled, equally, in the ER-positive as well as the ER-negative patients. The problem was in terms of absolute numbers the pathologic response was less for ER-positive patients than for ER-negative patients. And that’s something we know from the overview analysis. ER-negative patients are more chemosensitive than ER-positive patients are. But in both categories, there was a doubling of response when we added docetaxel.

DR LOVE: That’s interesting. You’re saying that ER-positive cancers do not respond as well to AC.

DR MAMOUNAS: Mm-hmm.

DR LOVE: Have we known that before?

DR MAMOUNAS: Well, we know this from the overview analysis. We know that patients that are ER-positive have less relative reduction in recurrence and mortality from chemotherapy alone, than patients that are ER-negative.

DR LOVE: But is that in the face of having tamoxifen or they’re not getting tamoxifen. Because in the overview, I’d assume most of those women are getting tamoxifen.

DR MAMOUNAS: Right. It’s in the face of getting tamoxifen, and the fact is that, in our study, as well, patients got tamoxifen from the beginning.

DR LOVE: So, they were actually on tamoxifen at the time.

DR MAMOUNAS: Right.

DR LOVE: So, maybe that was complicating the difference.

DR MAMOUNAS: It’s possible that because they responded to tamoxifen they are less chemosensitive. For whatever reason, it appears, though, that if you are ER-positive, you have less of a chance of responding to chemotherapy than if you are ER-negative.

DR LOVE: Fascinating. How long do you think it’s going to be before you see disease-free or overall survival? B-18 was a little disappointing in that regard, do you have any hopes that maybe we’ll see something in B-27.

DR MAMOUNAS: Certainly it will be quite some time. I think it will be probably another couple of years. These analyses are based on event rate, and when the events are there, then we’ll do the final analysis. You’re right, B-18 did not show a difference in terms of disease-free or overall survival, preoperatively or postoperatively. B-27 may or may not support this finding.

It will be very interesting, actually, to see whether the second arm and the third arm have the same outcome and, of course, if it’s different than the first arm. In other words, if the preoperative docetaxel and preoperative AC patients do as well as those who get AC preoperatively, but docetaxel postoperatively. If both arms are the same and superior to the AC arm, I think the deduction will be whether you give chemotherapy before or after, it doesn’t make a difference. So, I think everybody will select to do it according to his or her own bias or preferences.

But if, for some reason, the second arm is better than the third arm, then it may be a boost to neoadjuvant chemotherapy. But it also may be the fact that when you give it sequentially without the interruption to do surgery in the middle, if, for some reason, the third arm is better than the second arm, then it may be important to do surgery at some point and not delay surgery anymore to give the other four cycles of neoadjuvant chemotherapy. So, there are all kinds of possible permutations of the results.

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