The objective of this phase III global study was to compare the efficacy of gemcitabine plus paclitaxel (GT) versus paclitaxel in patients with advanced breast cancer. It was designed as a pivotal study for the approval of G for a breast cancer treatment indication.
Patients who relapsed after adjuvant anthracyclines were randomly assigned to gemcitabine,1,250 mg/m(2) days 1 and 8 plus paclitaxel, 175 mg/m(2) on day 1; or, to paclitaxel at same dose on day 1 (both arms administered every 21 days, unblinded). The primary end point was overall survival (OS) and secondary end points were time to progression (TTP), response rate (RR), progression-free survival, response duration, and toxicity. This final OS analysis was planned at 380 deaths.
A total of 266 patients were randomly assigned to GT and 263 to paclitaxel. Median survival on GT was 18.6 months versus 15.8 months on paclitaxel (log-rank P = . 0489), with an adjusted Cox hazard ratio of 0.78 (95% CI, 0.64 to 0.96; P = .0187). The TTP was longer (6.14 v 3.98 months; log-rank P = .0002) and the RR was better (41.4% v 26.2%; P = .0002) on GT. There was more grade 3 to 4 neutropenia on GT and grade 2 to 4 fatigue and neuropathy were slightly more prevalent on GT.
This phase III study documents a role for gemcitabine in advanced breast cancer after anthracycline-based adjuvant therapy. The results establish GT as a reasonable choice for women who require cytoreduction with manageable toxicities and validate ongoing testing of GT in the adjuvant setting.
"Many phase II studies have evaluated its use as a single agent in the treatment of metastatic breast cancer (MBC), with overall response rates of 14% to 37% as first-line therapy and approximately 12% to 30% as second-line therapy after prior taxanes or anthracyclines 4. The main side effects of the drug are granulocytopenia, thrombocytopenia, and abnormal liver function tests. However, gemcitabine is most effective when administered with a taxane (docetaxel or paclitaxel) in the first- or second-line setting 5. Favorable responses and manageable toxicity profiles have also been reported when it is used in combination with other chemotherapeutic agents, such as anthracyclines and platinum compounds 6-10. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Many phase II trials investigated the combination of Gemcitabine (G) and Vinorelbine (V) in the treatment of metastatic breast cancer (MBC) with variable outcomes. This study was conducted to explore whether this combination was effective and tolerable in MBC patients who were heavily pretreated with anthracyclines and taxanes.
A phase I study was conducted first to establish the maximum tolerated dose (MTD) of the G and V combination in MBC patients. Then, a phase II study evaluated the response rates, the median time to progression (TTP), the overall survival (OS) as well as the toxicities resulting from this combination at the MTD.
Nine patients were enrolled in the phase I study. The MTD was identified as 700mg/m(2) of G on days 1 and 8 in combination with 15 mg/m(2) of V on days 2 and 9, every 21 days. Twenty-one of 25 patients involved in the phase II study were evaluable for response. No complete or partial responses were achieved; 6 patients (24.0%) had stable disease and 15 (60.0%) progressed. The median TTP was 2 months and the median OS 10 months. Grade 3/4 Neutropenia was the major hematologic toxicity, occurring in 52% of the cycles. The most common non-hematologic grade 3/4 toxicities were fatigue (18%), myalgias (17%) and arthralgias (13%).
In heavily pretreated patients with MBC, the combination of G and V at the doses stated above was ineffective as it did not induce partial or complete responses. Other chemotherapy agents or combinations should be evaluated in future studies.
Journal of Cancer 03/2014; 5(5):351-9. DOI:10.7150/jca.8304 · 3.27 Impact Factor
"In the 36 patients who received the chemotherapy as the first-line treatment, ORR was as high as 80.6%. In MBC patients receiving chemotherapy only, longer PFS and OS with this doublet were noted when compared with capecitabine/docetaxel26 or gemcitabine/paclitaxel.27 This regimen should be therefore compared with standard strategies for the treatment of MBC. "
[Show abstract][Hide abstract] ABSTRACT: Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m(2) on day 1, day 8, and day 15, followed by cisplatin 75 mg/m(2) on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.
International Journal of Nanomedicine 03/2014; 9(1):1443-52. DOI:10.2147/IJN.S58275 · 4.38 Impact Factor
"Several groups have studied combinations of the taxanes with other agents. In advanced breast cancer, combination chemotherapy regimens have demonstrated improved tumor RR, TTP, and prolonged survival when compared to single agents [25, 26]. Most trials have not tested the concurrent administration of two chemotherapy agents versus the same agents given as monotherapy in sequence. "
[Show abstract][Hide abstract] ABSTRACT: Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m(2)) was given intravenously on Day 1, vinorelbine (27.5 mg/m(2)) intravenously on Days 8 and 15, and filgrastim on Days 2-21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64-82 %) with a median OS of 22.3 months (95 % CI 18.8-31.4 months). One-year PFS was 34 % (95 % CI 24-43 %) with median of 7.2 months (95 % CI 6.4-10.3). OS at 2 and 3 years were 49 % (95 % CI 38-59 %) and 30 % (95 % CI 21-40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.
Breast Cancer Research and Treatment 12/2013; 143(2). DOI:10.1007/s10549-013-2797-2 · 3.94 Impact Factor
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