Update on High-Dose Consolidation Therapy in Breast Cancer

BETHESDA, Md—High-risk breast cancer patients receiving intermediate- or high-dose consolidation chemotherapy after CAF achieved overall survival that is "better than any other experience within the CALGB," William Peters, MD, PhD, said at the NIH Consensus Conference on Adjuvant Therapy for Breast Cancer. He gave an update of CALGB 9082/SWOG 9114/NCIC MA-13.

Dr. Peters, of the Karmanos Cancer Institute, reported 5-year follow-up, based on the occurrence of 83% of the requisite 373 events needed for final analysis. "This is a very recent update. Final data that will be important for interpretation and context are not yet available; however, the major conclusions are not likely to change," he said.

The 1999 ASCO plenary session (Atlanta) on high-dose chemotherapy, where Dr. Peters presented preliminary results based on the occurrence of 66% of the requisite events, generated much attention, and follow-up analyses of these trials have been eagerly awaited.

CALGB 9082 included 783 patients with 10 or more positive lymph nodes who received one of two doses of combination alkylating agents as consolidation after four cycles of CAF (cyclophosphamide, Adriamycin, fluorouracil). Patients were randomized to receive either high-dose cyclophosphamide, cisplatin (Plat-inol), and BCNU with bone marrow or peripheral blood progenitor cell support or intermediate doses of the same drugs with G-CSF (Neupogen) support.

Patients relapsing on the intermediate-dose regimen were eligible for subsequent autologous bone marrow transplant with the same high-dose regimen as used in the initial arm. Local-regional radiotherapy was also planned for each patient, and hormone-receptor-positive patients received tamoxifen (Nolvadex) for 5 years.

The high-dose regimen was cyclophosphamide 5,625 mg/m², cisplatin 165 mg/m², and BCNU 600 mg/m². The intermediate-dose regimen was cyclophosphamide 900 mg/m², cisplatin 90 mg/m², and BCNU 90 mg/m².

Based on 373 events (recurrences or transplant mortality), which occurred equally in the high- and intermediate-dose arms, there was no significant difference in event-free survival, which was more than 60% at 5 years for both groups, Dr. Peters reported.

At this point, the overall survival figures of CALGB 9082 appear superior to those from other trials. "The truth is, we don’t know why this difference in survival might appear, and it serves as a reason to consider other studies," Dr. Peters commented.

He added that salvage high-dose therapy and transplant may confound the interpretation of overall survival in this study, but these factors have not been sorted out yet.

While there was no significant overall survival advantage for the high-dose treatment, it did favorably affect the recurrence rate. There were 154 relapses in the intermediate-dose arm vs 115 for the high-dose recipients, for an absolute reduction of 10% and a relative reduction of 34% in number of relapses.

However, in the over-50 subgroup, high-dose therapy was actually associated with more relapses than intermediate-dose therapy. Relapses on the intermediate-dose arm peaked during the first year after randomization.

"There is an apparent earlier wave of relapse in the intermediate-dose group vs the high-dose group, which is useful for hypothesis generation. It could be consistent with a dose-response effect, and it could also be consistent with the infusion of malignant cells in the bone marrow or in peripheral blood progenitor cells," Dr. Peters suggested.

There were 32 treatment-related deaths and 7 secondary malignancies. Treatment-related mortality was higher among patients on high-dose therapy, and occurred predominantly in the first year after randomization. Transplant centers with the highest volume had the lowest rate of treatment-related mortality.

A clear increase in treatment-related mortality was noted with increasing age, with deaths occurring in 14% of women over 50 and 4% of women under 40.

"The preliminary conclusion from this study is that there is no difference in event-free survival between intermediate- and high-dose chemotherapy," Dr. Peters said. "Note that this is not a comparison with standard-dose therapy but a comparison between high-dose and intermediate-dose therapy. The high-dose outcomes are as predicted from the pilot data, but the intermediate-dose patients have done much better than expected."

He said that high-dose consolidation remains a viable treatment option, but it should not be considered outside of the context of a clinical trial. "For the high-risk patient over 50, intermediate-dose therapy would seem preferred for reasons of toxicity and efficacy," Dr. Peters maintained.

With 83% of the requisite events occurring, the overall outcomes remain better than any results previously observed in the CALGB, he reemphasized. More effective treatment, better patient selection, consolidation with combined alkylating agents, local-regional radiation therapy, and hormonal therapy may all have contributed to these outcomes, he said, "and they clearly warrant further study."