Gemcitabine has been studied extensively (83 studies) in women with advanced breast cancer, mainly in the phase II setting. While gemcitabine has demonstrated some activity and has generally been well tolerated, there appears to be no particular advantage of gemcitabine over existing chemotherapeutic agents in the third-line or greater setting. Four randomized phase III trials of gemcitabine-based chemotherapy in women with advanced breast cancer have been reported in the literature. The results of those randomized trials, while difficult to compare directly, suggest that gemcitabine as a single agent is inferior to standard anthracycline-based chemotherapy in patients who are anthracycline naïve. The data suggest that the greatest benefit to be derived from gemcitabine in women with metastatic breast cancer is achieved when it is administered in the first- or second-line setting with a taxane. In particular, the phase III study by Chan et al demonstrated that gemcitabine plus docetaxel was as efficacious as the standard arm of capecitabine and docetaxel in the first- or second-line setting, with significantly reduced toxicity. The trial by O'Shaughnessy et al, combining capecitabine and docetaxel, is one of the few phase III trials to have reported an overall survival advantage in women with advanced breast cancer. The utility of that regimen, however, was hampered by the significant toxicities seen clinically, especially hand-foot syndrome and mucositis Thus, one can hypothesize that the combination of gemcitabine and docetaxel might be a better-tolerated alternative to the capecitabine–docetaxel regimen. Although at this time the results of the Chan study have yet to be fully published, the Breast Cancer Disease Site Group (DSG) believes it very unlikely that those results will change with the final publication, given the strength of the evidence presented in the abstract and the maturity of the data, and barring any major error on the part of the researchers.
The results of the gemcitabine plus paclitaxel trial, showing the superiority of gemcitabine–paclitaxel over paclitaxel alone, led to the approval by the US Food and Drug Administration, and the recent approval by Health Canada, of that combination for women with metastatic breast cancer after failure of prior anthracycline-containing adjuvant therapy. Based on those approvals, the Breast Cancer DSG believes the results to be sufficient to warrant a recommendation at this time, while awaiting the peer-reviewed publication. Single-agent paclitaxel has generally not been considered as efficacious as single-agent docetaxel in the treatment of women with metastatic breast cancer, and one might expect a paclitaxel doublet to be superior to paclitaxel alone. Docetaxel, given as a single agent or in combination has generally been accepted as the standard taxane in the treatment of women with metastatic breast cancer. However the randomized phase II trial by Khoo et al suggests that the choice of taxane, paclitaxel or docetaxel, may not make any meaningful difference in the efficacy of gemcitabine plus taxane combinations.
While gemcitabine appears to be generally well tolerated when administered with a taxane doublet, one phase III study by Zielinkski et al demonstrated equal efficacy with significantly higher hematological toxicity in patients treated with a gemcitabine/taxane triplet (GET) over those treated with 5-fluorouracil plus epirubicin plus cyclophosphamide (FEC) chemotherapy. Patients receiving gemcitabine/taxane triplet also experienced significantly more grade 3/4 polyneuropathy and mucositis. This trial suggests that there is no additional benefit, and more toxicity, to the addition of a third chemotherapeutic agent to a gemcitabine/taxane doublet.
The large number of non-randomized phase II trials identified indicates that gemcitabine, alone or in combination, is generally effective with acceptable toxicity but not more so than other currently accepted regimens. The results of the phase II trials do not support the acceptance of gemcitabine as a standard therapeutic option in women with metastatic breast cancer in the third-line or greater setting. Gemcitabine should not be considered as first-line therapy in women with metastatic breast cancer who are anthracycline naïve. Gemcitabine is most effective when administered with a taxane (docetaxel/paclitaxel) in the first- or second-line setting. Gemcitabine/taxane combinations represent a viable alternative to currently accepted taxane combinations such as capecitabine–docetaxel. There is no evidence at the present time to support the use of gemcitabine triplets, given the equal efficacy to anthracycline triplets and the added toxicity.
