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Sequential Dose-Dense Regimen Is Well Tolerated, May Improve Survival in Advanced Breast Cancer

Sequential Dose-Dense Regimen Is Well Tolerated, May Improve Survival in Advanced Breast Cancer

SAN ANTONIO—At almost three years' median follow-up, disease-free survival is 81% among a group of 42 women with resected breast cancer and four or more positive nodes who received dose-dense sequential chemotherapy using doxorubicin, paclitaxel (Taxol), and cyclophosphamide, Clifford A. Hudis, MD, said in his poster presentation.

This compares favorably with the 72% event-free survival at 30 months' follow-up achieved with cyclophosphamide, doxorubicin, and fluorouracil (CAF × 4) and stem-cell-supported high-dose consolidation in 85 patients with 10 or more positive nodes, reported by Peters et al (J Clin Oncol 11:1132-1143, 1993).

In this new pilot study, three doses of each of the three drugs were given at two-week intervals, "so there were nine doses of chemotherapy over 18 weeks, all supported by G-CSF," said Dr. Hudis, of the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center.

Treatment began within eight weeks of definitive surgery; the three 90 mg/m²doses of doxorubicin were given first, followed by the three 250 mg/m² doses of paclitaxel, then the three 3 g/m² doses of cyclophosphamide. "This design was based on preclinical and clinical data suggesting that this approach might be advantageous for women with high-risk resected breast cancer," he said.

The bottom line conclusions from the study, Dr. Hudis said, were that "the regimen is feasible with moderate toxicity, the nonrandomized disease-free survival is excellent, and the regimen warrants additional study."

An Intergroup trial of the regimen is now underway in women with four to nine involved lymph nodes. Patients are being randomized to receive the three-drug dose-dense sequential regimen or doxorubicin/cyclophosphamide for four doses conventionally and then a single cycle of high-dose chemotherapy with stem cell support.

Use by Community Physicians

In a separate paper, Barbara Ann Burtness, MD, of Yale University, described her group's experience using the same dose-dense sequential regimen in a similar patient population in the community practice setting.

"We wanted to find out if this regimen could be brought into general applicability, so we opened it up to all community doctors in Connecticut, essentially," she said. "If they wanted to administer the high-dose cyclophosphamide part of the regimen, which is in-patient, they either had to get IRB approval at their own institution or send the patients to us for treatment, but most of the patients got the initial cycles from their referring doctors."

The investigators found that they could maintain the same dose intensity as did the Memorial Sloan-Kettering group. "I think this is very interesting, especially since this regimen has now gone into a randomized Intergroup study," Dr. Burtness said. "One of the questions was, if you open this up to many centers, will it really be the same regimen? I think that we have shown that it is feasible to do this."

Dr. Burtness noted that one constant to the study was the availability of a research nurse who was always in touch with the nurses at the community offices. "She was there to back up the community nurses if unexpected toxicities developed," she said.

The 18 women in the study have been followed for 11 months with no relapses, she said, although one patient developed a number of abnormalities during treatment. "This made us suspect that she had undiagnosed metastatic disease at the start of treatment, which then responded," she said.

One patient has developed what appears to be a treatment-related leukemia. This patient had received both chemotherapy and, because eight nodes were involved, chest wall radiotherapy. "We've been using chest wall radiotherapy to prevent local recurrence a bit more liberally than the Sloan-Kettering group," she said, "and that may explain why they haven't seen a leukemia and we have."

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