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 survivalis 81% among a group of 42 women with resected breast cancer and four ormore positive nodes who received dose-dense sequential chemotherapy usingdoxorubicin, 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 85patients with 10 or more positive nodes, reported by Peters et al (J ClinOncol11:1132-1143, 1993).

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

Treatment began within eight weeks of definitive surgery; the three90 mg/m²doses of doxorubicin were given first, followedby the three 250 mg/m² doses of paclitaxel, then the three 3 g/m²doses of cyclophosphamide. "This design was based on preclinical andclinical data suggesting that this approach might be advantageous for womenwith 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 nonrandomizeddisease-free survival is excellent, and the regimen warrants additionalstudy."

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

Use by Community Physicians

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

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

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

Dr. Burtness noted that one constant to the study was the availabilityof a research nurse who was always in touch with the nurses at the communityoffices. "She was there to back up the community nurses if unexpectedtoxicities 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 duringtreatment. "This made us suspect that she had undiagnosed metastaticdisease 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 wereinvolved, chest wall radiotherapy. "We've been using chest wall radiotherapyto prevent local recurrence a bit more liberally than the Sloan-Ketteringgroup," she said, "and that may explain why they haven't seena leukemia and we have."