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High-dose chemotherapy of breast cancer: still controversial
(ASCO-Meeting in Atlanta, May 1999)

High-dose chemotherapy of breast cancer remains one of the most controversial topics in oncology according to experts at the ASCO-Meeting 1999. Most of the recent clinical trials presented at the meeting do not suggest that more aggressive regimens will lead to higher success rates. Only one out of 5 studies showed convincing benefit in favour of high-dose chemotherapy.

High-dose therapy and ABMT

High-dose chemotherapy in combination with ABMT (autologous bone marrow transplant) was thought to be a very promising approach in the treatment of metastatic stage IV breast cancer. Thus, the results of the Philadelphia Intergroup study were somewhat disappointing, said Dr. E. A. Stadtmauer who presented the data at the meeting. This 7-year trial involving 199 women with metastatic disease did not show any superiority of ABMT + chemotherapy compared to a conventional treatment with CMF (cyclophosphamide, methotrexate, 5-FU). The study included patients who had shown a complete or partial response to a therapy with CMF or FAC and were subsequently randomised to either CMF or ABMT combined with the STAMP V High-dose regimen (cyclophosphamide, thiotepa, carboplatin).

Rates for complete response were somewhat higher in the ABMT group (27% versus 19%, p not significant), but this did not translate to improved overall survival, time to progression or progressionfree survival (table 1).

Subgroup analyses also did not yield any results suggesting that the ABMT approach might be of benefit to a subset of patients.

Transplant in stage II/IIIa breast cancer

The CALGB/SWOG/NCIC trial was designed to compare the efficacy of stem cell transplant and a High-dose chemotherapy supported by G-CSF in patients with stage II/IlIa disease, said Dr. W. Peters. The study included only patients with >10 involved axillary nodes and no evidence of metastatic disease. All patients received an initial therapy with standard CAF and were then randomised to a single transplant regimen (cyclophosphamide 5635 mg/m², cisplatin 165 mg/m², BCNU 600 mg/m²) or a single highdose cycle of the same drugs at 900, 90 and 90 mg/m² respectively once with G-CSF support. At a median follow-up of 37 months, 68% of the patients in the transplant group had survived without event compared to 64% in the High-dose group. This lack of difference in the EFS (event free survival; primary endpoint of the study) might be due to the rather short observation period at this time of analysis. According to the study protocol two more years of follow-up are presumed, noted Dr. Peters. Concerning the relapse rates there was a more striking and significant difference favouring the transplant regimen (21,6% versus 32,2%), but the overall survival rate was nearly the same in both groups (around 70% after 5 years).

High risk despite tailoring dose?

According to the results of a scandinavian study presented by Dr. Berger intensive chemotherapy might lead to worrisome side effects even when the dose is adapted on an individualized basis. This trial included 274 highrisk patients with a >70% chance to relapse. Patients were randomised to receive a dose-intensive FEC regimen (9 cycles of 5-FU, epirubicin, cyclophosphamide) or 3 cycles of standard dose FEC followed by a single transplant with the STAMP V regimen. Patients in the dose-intensive group were treated with a fixed dose of 5-FU (600mg/m²) and individualized doses of epirubicin (to a maximum of 120mg/m²) and cyclophosphamide (1800mg/m²) depending on the nadir blood cell counts of the preceding cycle. Both groups received local radiotherapy and tamoxien (ER+ tumors) after completion of the chemotherapy.

Data analysis at a median follow-up of 24 months showed a somewhat higher relapse rate in the transplant group (92 patients) compared to the dose-intensive group (66 patients). But no difference could be established in terms of survival rate (approx. 80%), said Dr. Berger. What sounds alarming is the pretty high incidence of MDS/AML (3% within 24 months), a condition that has been described in other High-dose trials with alkylating agents.

High-dose transplant regimen versus CAF

Promising results were presented by Dr. Bezwoda on the behalf of a South African study group who compared a standard-dose CAF therapy with a High-dose transplant regimen consisting of cyclophosphamide (4,4g/m²), mitoxantrone (45mg/m²) and etoposide (1,5g/m²). Chemotherapy in the transplant group was administered after G-CSF therapy (on the same day as the stem cell collection) and 2 days before reinfusion of the stem cells. Although the trial involved only 154 patients with high-risk breast cancer the results deserve attention when taking the long follow-up (median 5 years) into account, noted Dr. Bezwoda.

Data analysis revealed a significant difference in relapse rates favourin the transplant regimen (21 patients versus 55; fig.1). As to the estimated survival time there was also a significant difference (>400 weeks versus 320 weeks) suggesting that the transplant regimen might become the treatment of choice in these patients - although there was a considerable incidence of grade 3-4 side effects (nausea, vomiting, alopecia).

Small study suggests superiority of High-dose therapy

Another trial with promising results was performed in France (PEGASE 04 protocol) according to Dr. J-P Lotz who presented the data at the meeting. This trial involved 61 patients who were initially treated with 4 to 6 cycles of a standard chemotherapy and then randomised to a High-dose transplant regimen (mitoxantrone 45mg/m², CPM 120mg/kg, L-PAM 140mg/m² + filgrastim) or the extension of the conventional therapy. 39 patients presented with the first relapse of the disease, 22 patients were treated for the first manifestation of metastatic disease. Baseline characteristics were well balanced between the two groups with the exception of pulmonary metastases (15 in the High-dose group, 4 in the conventional group).

At the time of randomisation 13 patients were in CR and 48 presented with PR. As to efficacy (figure 2) a significant increase of progression-free survival was observed in the High-dose group (26,9 months versus 15,7 months) whereas the difference in overall survival time showed a trend in favour of the High-dose group (36 versus 15,7 months) but did not reach statistical significance. A clear cut advantage favouring the High-dose regimen could be established in terms of relapse rates (27% versus 52%).

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