Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. [Intensive chemotherapy and autograft of hematopoietic stem cells in the treatment of metastatic cancer: results of the national protocol Pegase 04].
The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer.
                Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates.
                A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity.
                This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects. We report hereby the results of the french multicentric randomized PEGASE 04 protocol established to evaluate the impact on survival of high-dose chemotherapy over conventional chemotherapy for MBC patients.
                Inclusion criteria were: age < or = 60 year, PS < 2, adenocarcinoma initially metastatic or in first relapse, chemosensitive disease. Randomization was done after 4-6 courses of conventionnal chemotherapy between high-dose (Mitoxantrone, 45 mg/m2, Cyclophosphamide: 120 mg/kg, Melphalan: 140 mg/m2), and the pursuit of the same conventionnal chemotherapy. Between 09/92 and 12/96, 61 chemosensitive patients were enrolled: 29 were referred to standard chemotherapy, 32 to intensive therapy. At randomization, 13 pts (21.3%) were in complete response and 48 in partial response.
                The median progression-free survivals were 20 and 35.3 months in the standard and intensive groups (p=0.06). The relapse rates were respectively 79.3% vs 50.8% at 3 years and 90.8% vs 90.7% at 5 years. The median overall survivals were 20 and 43.4 months, with an overall survival rate of 18.5% vs 29.8% at 5 years (p=0.12).
                The CMA regimen could prolong the progression-free survival of MBC patients, however without any significant impact on overall survival.
Although there is evidence that high dose chemotherapy and autograft significantly improves event-free survival compared to conventional chemotherapy in women with metastatic breast cancer there is no significant evidence of benefit in overall survival. High dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic breast cancer outside of clinical trials.