Patients with metastatic breast cancer who receive combination chemotherapy have improved relapse-free and overall survival rates,[1-5] and some have long-term remissions. Currently, patients with early breast cancer commonly receive adjuvant therapy, which includes anthracyclines in cases of high risk of relapse. Although anthracycline-related cumulative toxicities can often be avoided, strong biologic and clinical[9-11] data show that patients with metastatic disease previously treated with anthracyclines in earlier disease stages have a worse prognosis and lower chance of benefit from anthracycline-containing regimens than do chemotherapynaive patients. Therefore, alternative chemotherapies are needed for advanced breast cancer, among which are combinations of taxanes with newer agents such as gemcitabine (Gemzar). The taxanes, either as single agents or combined with other drugs, have become the standard front-line therapy for patients whose disease progresses after anthracycline chemotherapy. The combination of paclitaxel and doxorubicin has been shown to be less active in patients who have previously received adjuvant anthracycline treatment. There is a clear need for active combinations that do not include anthracyclines in this population. Appeal of Combination Therapy Gemcitabine is a cytosine arabinoside prodrug analog with activity in a wide range of tumors. Cytotoxicity of this agent is related to the cellular accumulation of gemcitabine triphosphate (dFdCTP), inducing a G0/G1 and S phase arrest in human solid tumor cells. Single-agent gemcitabine induced response rates ranging from 15% to 46% in breast cancer patients, with minimal toxicity, even in heavily pretreated patients.[ 14] Paclitaxel acts by stabilizing microtubules, blocking eukaryotic cells in the G2/M mitotic phase. When administered on a weekly or every-3- week schedule, paclitaxel has been shown to be among the most active therapies for breast cancer.[16,17] In randomized clinical trials, paclitaxel was equal in efficacy to CMFP (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil [5-FU], prednisone) in patients with advanced breast cancer. In randomized trials involving anthracycline-naive patients, results with paclitaxel combined with anthracyclines were equivalent[ 19] or superior to those achieved with standard cyclophosphamide, doxorubicin, and 5-FU. Use of gemcitabine combined with paclitaxel is particularly appealing because the drugs have different mechanisms of action and nonoverlapping toxicities. In vivo, paclitaxel increases the accumulation of dFdCTP. In non-small-cell lung cancer cell lines, paclitaxel administered immediately before gemcitabine significantly increased the accumulation of dFdCTP, the incorporation of gemcitabine into RNA, and the apoptotic index. In the mouse model, the greatest delay in tumor growth was obtained when paclitaxel was administered on days 1 and 15, with gemcitabine given every 3 days. In addition to the well-established days 1 and 8 schedules, the paclitaxel/ gemcitabine combination was also evaluated in a phase I study using an every-2-week schedule. Paclitaxel was infused over 3 hours, followed by gemcitabine as a 30- to 60-minute infusion. Dose-limiting toxicities were neutropenia and alanine transaminase (SGPT) elevations. Doses recommended for biweekly phase II studies were 150 mg/m2 for paclitaxel plus 3,000 mg/m2 for gemcitabine. Phase II Trials of Gemcitabine With Paclitaxel Six phase II trials have explored the combination of gemcitabine with paclitaxel. Doses, schedules, and response rates are summarized in Table 1. Three trials were performed in patients receiving first-line treatment for metastatic breast cancer, and three trials involved second- or third-line therapy. Administration schedules were every 3 weeks and every 2 weeks (biweekly) in three trials each. Overall response rates ranged from 40% to 71%, with the highest rates observed in studies of chemotherapy-naive patients (responses are summarized in Table 2). The combination was generally well tolerated, particularly in the firstline setting. In the study by Sanchez- Rovira et al assessing second- or third-line gemcitabine/paclitaxel, 15% of patients had grade 3 or 4 hematologic toxicity, and 34% required granulocyte colony-stimulating factor (G-CSF [Neupogen]) support. Murad et al observed grade 3 or 4 neutropenia in 35% of patients, neutropenic fever in 7%, and neuropathy in 7%. Colomer et al observed grade 4 neutropenia in 17% of patients. Nonhematologic toxicities occurred in less than 5% of cases, except for elevated liver enzyme levels (8%). Preliminary reports by Delfino et al, Vici et al, and Genot et al, presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2002, showed manageable toxicities.[27-30] Colomer at al also observed that patients with elevated levels of circulating HER2 extracellular domain (ECD) had poorer response to therapy (83% vs 42%, P = .02). This finding confirmed results of an earlier study[26,31] and is the basis for a subsequent phase II clinical trial of gemcitabine and paclitaxel plus trastuzumab (Herceptin) in HER2 ECDpositive patients. In addition, interesting pharmacogenomics studies are being performed in patients with primary breast cancer who are receiving neoadjuvant treatment with the gemcitabine/paclitaxel combination.[ 32] Phase III Trial of Gemcitabine and Paclitaxel Early results of a randomized comparison of gemcitabine/paclitaxel vs paclitaxel alone have been published in abstract form.[33,34] This study compared the combination with paclitaxel in 529 metastatic breast cancer patients previously treated with an anthracycline but no previous chemotherapy for advanced disease. Study objectives were overall survival, progression-free survival, overall response rate, quality of life, pain palliation, toxicity, and time to progressive disease (primary interim analysis objective). The study design is shown in Figure 1. Results for the multicenter JHQG trial presented by O'Shaughnessy at the ASCO annual meeting in 2003 favored the gemcitabine/paclitaxel combination (n = 267) over paclitaxel (n = 262). The median time to progression was 5.4 months (95% CI = 4.6-6.1 mo) for gemcitabine/ paclitaxel and 3.5 months (95% CI = 2.9-4.0 mo) for paclitaxel (P = .0013). The hazard ratio of being progression-free at 6 months was 0.734 (95% CI = 0.607-0.889; P = .0015), with an increased probability of ~50% for the combination. The disease progression-free survival was significantly better with gemcitabine/ paclitaxel (P = .0021). The overall response rate was 39.3% (95% CI = 33.5%-45.2%) for gemcitabine/ paclitaxel and 25.6% (95% CI = 20.3%- 30.9%) for paclitaxel (P = .0007). Furthermore, the combination was associated with a trend toward numerical improvements in analgesic level, pain relief, and global quality of life (P = NS). Grade 4 hematologic toxicity (by Common Toxicity Criteria) was more pronounced with gemcitabine/ paclitaxel than with paclitaxel (17.2% vs 6.6% neutropenia, 1.1% vs 0.4% anemia, 0.4% vs 0% thrombocytopenia, 0.4% vs 0% febrile neutropenia). Nonhematologic toxicity was manageable in both arms. There was one toxic death per arm. Conclusions from this study were that gemcitabine plus paclitaxel demonstrated significant efficacy advantages over paclitaxel alone in patients with metastatic breast cancer, and toxicity was as expected and manageable. During the 2004 ASCO annual meeting, Albain et al presented the initial report of overall survival for this study. The overall survival hazard ratio (HR) was 0.775, significantly in favor of gemcitabine plus paclitaxel (P = .018). A statistically significant advantage of gemcitabine plus paclitaxel over paclitaxel was also reported (18.5 months vs 15.8 months, HR = .775, P = .018). One-year survival was significantly increased for the gemcitabine/paclitaxel arm (70.7% vs 60.9%; P = .019), and the HR favoring the combination persisted (Cox regresion) even after adjusting for baseline covariates: 0.740 (P = .006). Thirty-eight percent of patients receiving gemcitabine plus paclitaxel ceased therapy due to disease progression, vs 55% in the paclitaxel arm, and therapy ended due to adverse events in 6.7% of patients receiving gemcitabine plus paclitaxel, vs 5.0% of those in the paclitaxel arm. Thus, the survival advantage reported in this study has definitively established a role for gemcitabine in the treatment of metastatic breast cancer. Triplet Combinations of Gemcitabine and Paclitaxel Plus an Anthracycline The addition of an anthracycline to the gemcitabine/paclitaxel combination in patients with metastatic breast cancer has been explored in phase II trials, with excellent response rates of 90.2% in the neoadjuvant study reported at the European Breast Cancer Conference in 2004 by Gennari et al and 80% achieved by Sanchez-Rovira and colleagues in the metastatic setting and somewhat greater toxicity than observed with gemcitabine/paclitaxel. In the multicenter Italian study by Gennari et al, of the 41 patients who completed the gemcitabine/epirubicin [Ellence]/paclitaxel regimen and underwent surgery, 6 (14.6%) had a pathologic complete response; three were down- graded to negative axillary nodes. Although results of a randomized comparison of GET (gemcitabine/epirubicin/ paclitaxel) vs FEC (5-FU/epirubicin/ cyclophosphamide), presented at the ASCO annual meeting in 2002, did not show a therapeutic advantage for GET in advanced breast cancer,[ 37] these triplet combinations are being explored in the neoadjuvant setting, with impressive response rates reported.  Further research from other investigators, expected in the near future, will provide additional information on the use of gemcitabine and taxanes with and without other chemotherapy agents in patients with metastatic breast cancer. Conclusion Gemcitabine and paclitaxel possess activity against metastatic breast cancer, with low toxicity with gemcitabine/ paclitaxel regimens. Phase III data show a clear advantage for gemcitabine plus paclitaxel over paclitaxel alone in parameters such as time to disease progression, overall survival, and objective response. Moreoever, triplet combinations, with an anthracycline being added to gemcitabine/ paclitaxel, are being explored in the metastatic and neoadjuvant settings.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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