SWOG-S0221: Comparing different schedules of adjuvant AC and paclitaxel

This Intergroup trial (Figure 1.1) will compare a regimen of oral cyclophosphamide and a weekly anthracycline to the dose-dense every two-week doxorubicin and cyclophosphamide (AC) regimen used in CALGB-9741. It will also compare dose-dense every two-week to weekly paclitaxel.

Frankly, I don't know which regimens will be better, and I have pure equipoise on this particular study. The trial is not as clean a comparison as the one in CALGB-9741, in which all the doses were kept exactly the same and only the schedule was varied.

For the dose-dense regimens, the additional expense associated with filgrastim and pegfil-grastim is a real and very important concern.

Larry Norton, MD

SWOG-S0221 is an important study, particularly with regard to the best way to administer paclitaxel. Weekly paclitaxel is a potentially interesting regimen, and it's logical to compare it to a dose-dense regimen that is probably more expensive.

On the other hand, weekly paclitaxel will require weekly visits to the hospital, which might not be easy. In the meantime, ECOG-1199 will provide a head-to-head comparison of every three-week paclitaxel, every three-week docetaxel, weekly paclitaxel and weekly docetaxel (Figure 1.2).

Martine Piccart, MD, PhD

Utilization of dose-dense taxanes

Except for cost issues, no reason exists to not use paclitaxel in a dose-dense fashion. We do not yet know how docetaxel should be administered, and it should be studied as an every two-week regimen. I've heard doctors state that they don't want to use a more aggressive dose-dense regimen unless the patients are at very high risk. Frankly, the dose-dense regimen is less toxic, more effective and faster. If CALGB-9741 had demonstrated that the regimens had equal efficacy, there would be real arguments for using a dose-dense regimen just from the toxicity point of view.

Larry Norton, MD

A few years ago we piloted a trial of every two-week docetaxel. It was too toxic, and the patients experienced very serious skin problems and mucositis. I don't believe docetaxel will be a good drug to use every two weeks. It is very effective when used every three weeks, and I don't think it will be more effective when administered weekly. I believe the comparison should be between the every three-week docetaxel and dose-dense paclitaxel.

Martine Piccart, MD, PhD

Utilization of dose-dense AC in patients with node-negative disease

As a result of CALGB-9741, the adjuvant trial CALGB-40101 in patients with node-negative disease was amended to use every two-week AC. The proof of greater efficacy with less toxicity was the major consideration in that protocol amendment. In terms of the science, I think it's reasonable to use every two-week AC without a taxane in a nonprotocol setting. I would hypothesize that patients with negative nodes or a low volume of disease may benefit even more.

From years of trials and the worldwide overview pioneered by Richard Peto, we've learned that if something works in patients with node-negative disease, it will work in patients with node-positive disease and vice versa. I don't think it's necessary to show that dose-dense therapy is going to work in patients with node-negative disease.

It is a question of the risk of relapse for the patient. A patient with a six-centimeter, poorly differentiated primary tumor and negative nodes has an enormous risk of relapse, and that patient should benefit as much as a patient with a smaller primary tumor and a few positive nodes.

Aside from any issues of efficacy, the dose-dense approach offers considerable advantages in terms of completing therapy earlier. We offer our patients a choice. We say, "Let's start dose-dense therapy and see how you do. If you really hate it and you need an extra week, we can always delay things." I've not had a single person who wanted a delay. They just want to complete therapy.

Larry Norton, MD

Those of us who have been following the developments in the mathematical model really believe that CALGB-9741 is a positive trial because it addresses this mathematical concept. Others are more skeptical and believe the difference is due to the paclitaxel schedule. We don't have a clear answer.

Ideally, we should evaluate whether the anthracycline or the taxane must be administered in a dose-dense manner. We don't have time to answer these questions, as too many other important questions need to be addressed. However, I believe it's reasonable to use dose-dense AC. In Europe it's not possible to use dose-dense chemotherapy because of financial issues.

Martine Piccart, MD, PhD

Neoadjuvant trial of dose-dense therapy

In Europe we compared preoperative every two-week epirubicin and cyclophos-phamide (EC) administered with filgrastim over three months to the Canadian CEF regimen administered over six months in patients with locally advanced tumors. The trial enrolled about 400 patients; hence, it was underpowered and we didn't observe a difference. Interestingly, every two-week EC was nice in the sense that the chemotherapy was completed in three months instead of six months. I don't believe we are harming women with this regimen, and I have no problem with the choice of this particular schedule.

Martine Piccart, MD, PhD

The mathematical model predicts that dose-dense therapy is not better in terms of response in the preoperative setting because of the large tumor volume. We learned from Gompertzian growth that faster regrowth occurs with more regression. Negative data in the preoperative setting corroborate this particular view. Hence, dose density is not going to play a role in that setting.

Larry Norton, MD

Molecular determinants of Gompertzian growth

We're close to finding the molecular determinants of Gompertzian growth (i.e., which systems are deranged in neoplasia). For many centuries, cancer was thought of as a disease of increased proliferation. In fact, when pathologists see many cells on a slide, they label it as hyperproliferative. In reality, all they can say is that it's very dense and there are many cells. The presence of many cells may mean proliferation, a reduction in cell loss, apoptosis or senescence. The cells may have accumulated over a long period of time, and they are not necessarily rapidly dividing.

Now, molecular tools are available to assess and describe which genes are associated with proliferation, apoptosis, senescence, the geometry of the tumor or the spatial arrangement of the cells. All of those factors are clearly related to the Gompertzian phenomenon. This exciting era in breast cancer clinical research will tie together molecular analyses and well-designed clinical trials so that we understand the biology and the intervention, and then link them together.

Larry Norton, MD

We have a trial that is still in the planning stages in which molecular biological factors will be evaluated prospectively in patients receiving different treatment schedules. We will repeat CALGB-9741 while building into the trial one or two biological hypotheses. The first hypothesis is that highly proliferating tumors are going to derive a huge benefit from dose-dense therapy. The second hypothesis is that a dose-dense strategy is most effective in tumors that are completely lacking all receptors (i.e., ER-negative, PR-negative), for which chemotherapy is the only treatment option. Some of those tumors are very aggressive and highly proliferating.

Martine Piccart, MD, PhD

Incidence of dose reductions and delays in adjuvant chemotherapy

Gary Lyman conducted a nationwide survey of community-based oncology practices to determine the incidence of dose reductions and delays in patients receiving adjuvant chemotherapy. It's really very scary now that we have the dose-dense data.

If changing therapy from every three weeks to every two weeks can reduce the annual odds of death by 31 percent, I shudder to think what going from three to four or five weeks will do in terms of impairing our ability to cure the cancer. Also, with the anthracyclines, the optimal dose seems to be 60 mg/m2 higher doses don't provide any benefit, but lower doses rapidly reduce efficacy. I'm worried about dose modifications and schedule changes.

Larry Norton, MD

Use of adjuvant aromatase inhibitors in postmenopausal women

We're closer to being able to make a statement about the use of up-front adjuvant aromatase inhibitors in postmenopausal women. I still believe, however, that it is a tad premature. We still don't know about the aromatase inhibitors' long-term efficacy and toxicity profiles.

Solid data indicate that patients benefit for more than a decade after two to five years of adjuvant tamoxifen, but we don't have comparable data for the aromatase inhibitors. I wouldn't fault a physician for using an adjuvant aromatase inhibitor as front-line therapy; the ATAC trial data indicate that is a reasonable alternative. But in the absence of a survival difference, which is important, it would not be wrong to start with tamoxifen.

Interesting studies are looking at the sequential use of selective estrogen-receptor modulators (SERMs) and aromatase inhibitors. Good biological reasons suggest that it may make sense to set up the tumor with a SERM first, before using an aromatase inhibitor. The data from Italy about the sequential use of a SERM and an aromatase inhibitor is provocative. In the next six to nine months, as we see more data, we'll be in a better position to make a definitive statement.

A sequential strategy would provide the opportunity to improve bone mineral density in patients with osteopenia or osteoporosis, which can be treated aggressively during the period of time the patient is receiving a SERM. I believe bone mineral density will be a big issue in this patient population because chemotherapy induces premature menopause in younger women. We're going to have a gargantuan population of cured individuals who will have problems with fractures, which in some cases can be life-threatening. We must work hard to maintain bone mineral density.

Larry Norton, MD

I agree with Larry. In the future, we may find out that we need to start with an aromatase inhibitor in some of these endocrine-responsive tumors that have other elements of aggressiveness, like HER2 overexpression. For other tumors, a sequential strategy (e.g., two to three years of tamoxifen followed by three to four years of an aromatase inhibitor) may be preferred. A differential strategy according to the tumor's molecular markers would not surprise me.

Martine Piccart, MD, PhD

Select Publications

Dr Piccart is the Head of the Chemotherapy Department at the Jules Bordet Institute and Chairwoman of the Breast International Group in Brussels, Belgium. Dr Norton is Deputy Physician-in-Chief and Director of Breast Cancer Programs and Chair in Clinical Oncology at the Memorial Sloan-Kettering Cancer Center in New York, New York.

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