Dose-Dense Adjuvant Chemo for Node+ Breast Cancer

ATLANTA—With dose-escalation studies of adjuvant chemotherapy in node-positive breast cancer producing mixed results, many researchers are moving to the dose-density approach, Clifford A. Hudis, MD, said at the Third Annual Perspectives in Breast Cancer meeting.

“We’ve operated on the assumption that by increasing the dose of specific drugs, we’re going to increase cell kill. The fact that dose escalation may not work in all situations comes as a challenge to those of us who have pursued higher dose therapy,” said Dr. Hudis, of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York.

Dose density, he said, is the use of multiple cycles of optimally dosed chemotherapy administered as often as possible. The underlying theory is this: If there is a smaller dose of chemotherapy that, because of a flat dose-response relationship, gives about the same cell kill as a larger dose, the smaller one may be preferable because the larger dose is more toxic and thus is limited in terms of repeatability.

“In between intervals of the larger dose, you have regrowth of cells that are sensitive but were not eliminated by that one dose,” he said.

This hypothesis is supported by Bonadonna’s study showing better 10-year disease-free survival for sequential (more dose-dense) versus alternating (less dose-dense) therapy using doxorubicin and CMF, he said.

With the discovery of the antitumor activity of paclitaxel (Taxol) in breast cancer and its non-cross resistance with doxorubicin, researchers were quickly motivated to incorporate the taxane into their dose-density studies.

In a pilot study at Sloan-Kettering, 42 breast cancer patients with at least four involved nodes (median, eight) were given, in sequence, three cycles of three different drugs at 2-week intervals: first, doxorubicin (90 mg/m²) with G-CSF (Neupogen) support; then, paclitaxel (250 mg/m² every 24 hours); then cyclophosphamide (3 g/m²).

“That’s nine cycles of chemotherapy over 18 weeks, with no autologous stem cells required. However, it certainly is very dose intensive and does require G-CSF,” Dr. Hudis said.

The updated results with a median of 36 months of follow-up show an 81% relapse-free survival curve. “This is very promising, although with all the caveats that one needs to bring to a nonrandom-ized, single-center phase II study,” he said.

Dr. Hudis pointed to several ongoing randomized studies that should provide definitive answers about the value of sequential dose-dense regimens. A prospective randomized SWOG-led intergroup trial for breast cancer patients with four to nine involved nodes has, to date, enrolled more than 200 patients.

Patients receive either the sequential dose-dense regimen used by Dr. Hudis in his pilot study or a dose-escalated approach—doxorubicin and cyclophosphamide given at 3-week intervals for four cycles followed by one of two high-dose chemotherapy stem-cell transplant regimens (STAMP I or V).

Another important intergroup study that may most clearly define the value of dose-dense therapy in women with node-positive breast cancer is CALBG 9741. In this four-arm trial, patients will receive chemotherapy either concurrently or sequentially, administered at either 2- or 3-week intervals.

The sequential regimen consists of four cycles of doxorubicin (60 mg/m²), followed by four cycles of paclitaxel (175 mg/m²), followed by four cycles of cyclophosphamide (600 mg/m²). The concurrent regimen, using the same doses, calls for four cycles of doxorubicin plus cyclophosphamide, followed by four cycles of paclitaxel.

Patients will get all their chemotherapy either every 3 weeks or every 2 weeks with G-CSF support. This means that the sequential regimen will last either 24 or 36 weeks, while the concurrent regimen will run either 16 or 24 weeks.

“I’m optimistic that this trial will enroll patients relatively easily because the only variables are the duration of therapy, the intertreatment interval, and the use of G-CSF,” he said. “Everyone is going to get four doses of what we think are the most effective agents.”