Elsevier

The Lancet Oncology

Volume 8, Issue 3, March 2007, Pages 219-225
The Lancet Oncology

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Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial

https://doi.org/10.1016/S1470-2045(07)70041-4Get rights and content

Summary

Background

We aimed to compare the additional benefit of gemcitabine when combined with vinorelbine above that of standard vinorelbine treatment in patients with metastatic breast cancer.

Methods

In this phase III, multicentre, open-label, randomised study, 252 women with locally recurrent and metastatic breast cancer who had been pretreated with anthracyclines and taxanes were randomly assigned single-agent vinorelbine (30 mg/m2, days 1 and 8) or gemcitabine plus vinorelbine (1200/30 mg/m2, days 1 and 8). Both study treatments were administered intravenously every 21 days until disease progression, unacceptable toxic effects, or stoppage at the request of investigator or patient. The primary endpoint was median progression-free survival. Secondary objectives included assessments of response rate, disease duration, overall survival, and characterisation of the toxicity profiles of both regimens. This study is registered with ClinicalTrials.gov, number NCT00128310.

Findings

Between 2001 and 2005, 252 women were recruited and randomised for treatment. One of these patients was ineligible. Prognostic factors were well balanced between treatment groups (median number of metastatic sites in combination group 2 (range 0–5) and in vinorelbine group 2 (range 1–6); visceral disease in 76% and 75% of patients, respectively). Median progression-free survival was 6·0 months (95% CI 4·8–7·1) for patients given gemcitabine plus vinorelbine and 4·0 months (2·9–5·1) for those assigned vinorelbine; there was 1·9 months of difference (hazard ratio 0·66 [0·50–0·88]; p=0·0028). Overall survival was 15·9 months (12·6–19·1) for the gemcitabine plus vinorelbine group and 16·4 months (11·6–21·0) for the vinorelbine group; there was 0·5 months of difference (hazard ratio 1·04 [0·78–1·39]; p=0·8046). Objective response rates were 36% for patients assigned gemcitabine plus vinorelbine (n=45) and 26% for those assigned vinorelbine (n=33) (p=0·093). Grade 3 or 4 neutropenia was reported in 75 (61% [52–70]) of the participants assigned gemcitabine plus vinorelbine, compared with 55 (44% [35–53]) of those assigned vinorelbine alone (p=0·0074). Febrile neutropenia occurred in 13 (11%) of those assigned gemcitabine plus vinorelbine, and in seven (6%) of those assigned vinorelbine alone (p=0·15). Incidences of grade 3 or 4 non-haematological toxic effects were similar between the two treatment groups.

Interpretation

Patients with metastatic breast cancer assigned gemcitabine and vinorelbine had better progression-free survival compared with those assigned vinorelbine alone. However, this finding did not translate into a difference in overall survival. Although toxicity was manageable, patients in the combined group had more haematological toxic effects. These factors should be taken into account when deciding which chemotherapy patients should receive.

Introduction

Anthracyclines and taxanes are the current standard treatments in the management of hormone-unresponsive metastatic breast cancer. Anthracycline combinations such as fluorouracil-doxorubicin-cyclophosphamide, fluorouracil-epirubicin-cyclophosphamide, and doxorubicin-cyclophosphamide are commonly used as first-line regimens for metastatic breast cancer. The results achieved with these treatments have been objective responses in more than 50% of patients, and complete responses in about 10% of patients.1 Taxanes (paclitaxel and docetaxel) are also very active agents in metastatic breast cancer, and are extensively used both in combination with anthracyclines or after anthracycline failure.2, 3, 4, 5 Chemotherapy regimens that include anthracyclines and taxanes are now the standard adjuvant treatment for high-risk early breast cancer.6, 7, 8 Such regimens have been used increasingly worldwide in this setting, which has led to a restricted use of these drugs in patients with disease relapse. New cytotoxic treatments for disseminated disease, such as gemcitabine, capecitabine, and vinorelbine are now available to treat patients who have been previously treated with anthracyclines and taxanes.9, 10, 11 Vinorelbine was extensively used in the 1990s in Europe and the USA in patients who were pretreated with anthracyclines and taxanes. Gemcitabine was introduced in the late 1990s and was also tested in patients with metastatic breast cancer and showed moderate antitumour activity and low toxicity. On the basis of the single-agent activities of vinorelbine and gemcitabine and the paucity of overlapping extra-haematological toxic effects, phase II trials12, 13, 14, 15, 16, 17, 18, 19 have tested the activity of different schedules of combinations of these two drugs, and have found encouraging antitumour activity. In 1998, the Spanish Breast Cancer Research Group (GEICAM) published the results of a phase II trial20 with gemcitabine plus vinorelbine with a response rate of 44% (95% CI 24–65) and a median time-to-treatment failure of 17 weeks months (14–20 weeks).

To assess the contributing effect of gemcitabine to this promising antitumour activity, we undertook a randomised, phase III, multicentre study that compared gemcitabine plus vinorelbine with vinorelbine alone in patients with metastatic breast cancer who had been previously treated with anthracyclines and taxanes. This report summarises the final results of this trial (GEICAM 2000–04).

Section snippets

Patients and procedures

Women with histologically confirmed locally recurrent and metastatic breast cancer who were not amenable to curative surgery or radiotherapy and who had undergone previous treatment with anthracyclines and taxanes were eligible to enter into the trial. Other eligibility criteria included: a maximum of two previous chemotherapy regimens for metastatic disease; age at least 18 years; WHO performance status of 2 or lower; sufficient bone marrow reserve (neutrophil count ≥2×109/L, platelets ≥100×109

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