What is the best schedule for administration of gemcitabine-taxane?

doi:10.1016/S0305-7372(05)80005-2

Cancer Treatment Reviews

Volume 31, Supplement 4, 2005, Pages S23-S28

https://doi.org/10.1016/S0305-7372(05)80005-2 Get rights and content

Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.

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Recently, new strategies on combinational use of two or more antitumor agents in cancer treatment gained more attention in order to decrease the side effects while using effective dosages (Colomer, 2005).
Osteosarcoma is the most common cancer in bone. Drug resistance is a challenge of current treatments that needs to be improved with novel treatment strategies. In this research, a new dual drug delivery system was developed with Gemcitabine (GEM) and Clofazimine (CLF) co-loaded liposome formulations. GEM is a well-known anticancer agent and CLF is a leprostatic and anti-inflammatory drug recently recognized as effective on cancer. GEM and CLF co-loaded liposomal formulation was achieved with compartmentalization as hydrophilic GEM being in core and lipophilic CLF sequestering in lipid-bilayer. Liposomes had high encapsulation efficiency (above 90%, GEM and above 80%, CLF). CLF release was enhanced while GEM release was slowed down in co-loaded liposomes compared to single cases. GEM/CLF co-loaded liposomes significantly enhanced cytotoxicity than GEM or CLF loaded liposomes on osteosarcoma cell line. CLF and GEM had synergistic effect (CI < 1). Results of flow cytometry showed higher apoptotic cell ratio, caspase-3 activity, mitochondrial membrane depolarized cells’ ratio for GEM/CLF co-loaded liposome treatments than other liposomes. Cytotoxicity of CLF on bone cancer cells and also its synergistic effect with GEM on osteosarcoma is reported for the first time with this study. CLF’s loading with GEM into liposome was also a new approach for enhancement of anticancer effect on Saos-2 cells. Therefore, GEM/CLF co-loaded liposomal delivery system is proposed as a novel approach for treatment of osteosarcoma.
Antitumor gemcitabine conjugated micelles from amphiphilic comb-like random copolymers
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Over the last decade, the design and fabrication of nano-sized drug delivery systems such as polymeric micelles, nanogels, liposomes and prodrug have been attracting more and more attentions [1⿿5].
Gemcitabine is an important pyrimidine antimetabolite that inhibits cellular DNA synthesis. However, the therapeutic efficacy and clinical benefit of gemcitabine are severely compromised due to its rapid plasma metabolism and low selectivity towards tumor tissues. To overcome these limitations, we prepared novel PEGylated gemcitabine-contained comb-like copolymers poly(monomethoxyl PEG₃₅₀ methylacrylate ⿿co- 5⿲-O-vinyladipyl- gemcitabine) (poly(mPEG₃₅₀MA-co-VAG) and (poly(mPEG₁₀₀₀MA-co-VAG), which could self-assemble into micelles and displayed enhanced antitumor activity. The copolymers and the formed micelles were well characterized for their structure, critical aggregation concentration (CAC), morphology, cellular uptake, cell cytotoxicity, and controlled drug release. Cellular uptake and in vitro cytotoxicity assays against human lung cancerous cells (A549) demonstrated that these micelles could be effectively internalized and induced cell apoptosis. These micelles efficiently inhibited tumor growth when injected intravenously into A549 cell derived xenograft tumor bearing Balb/C nude mice using a dose of 10 mg/kg in terms of reduced tumor volume compared to free gemcitabine. In conclusion, PEGylated micelles could protect gemcitabine from rapid plasma metabolism, provided a sustained release and showed enhanced antitumor activity, thus have the potential to be used as novel anticancer drug delivery vehicle.
Second generation liposomal cancer therapeutics: Transition from laboratory to clinic
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While conventional drug-bearing liposomes have only been described to be loaded with single drugs, second generation liposomes have been reported to be loaded with two or more different drugs simultaneously for enhanced cytotoxicity in cancer cells (Agrawal et al., 2005; Cosco et al., 2012). This strategy aims at association of two or more antitumoral compounds for reduced effective dosages and associated-side effects (Fig. 4) (Colomer, 2005; Theodossiou et al., 1998). The liposomal multidrug carrier (MDC) can either be loaded with both water soluble (in the aqueous core) and lipophilic (entrapped in the bilayers) (Cosco et al., 2012) drugs or multiple drugs with same affinity (hydrophilic/hydrophobic) without any interactions between the two compounds (Tardi et al., 2007).
Recent innovations and developments in nanotechnology have revolutionized cancer therapeutics. Engineered nanomaterials are the current workhorses in the emerging field of cancer nano-therapeutics. Lipid vesicles bearing anti-tumor drugs have turned out to be a clinically feasible and promising nano-therapeutic approach to treat cancer. Efficient entrapment of therapeutics, biocompatibility, biodegradability, low systemic toxicity, low immunogenicity and ability to bypass multidrug resistance mechanisms has made liposomes a versatile drug/gene delivery system in cancer chemotherapy. The present review attempts to explore the recent key advances in liposomal research and the vast arsenal of liposomal formulations currently being utilized in treatment and diagnosis of cancer.
Gemcitabine and tamoxifen-loaded liposomes as multidrug carriers for the treatment of breast cancer diseases
2012, International Journal of Pharmaceutics
Citation Excerpt :
During the last decade, experimentation on the treatment of cancer diseases has been pursuing an innovative and comforting strategy through the association of two or more antitumoral compounds in order to reduce the effective dosages and their side effects (Theodossiou et al., 1998; Colomer, 2005).
The effects of a lipid composition on the physico-chemical and technological properties of a multidrug carrier (MDC) containing both gemcitabine (GEM) and tamoxifen (TMX), as well as its in vitro antitumoral activity on different breast cancer cell lines, were investigated. In particular, the following three different liposomal formulations were prepared: DPPC/Chol/DSPE-mPEG2000 (6:3:1 molar ratio, formulation A), DPPC/Chol/DOTAP (6:3:1 molar ratio, formulation B) and DPPC/Chol/DPPG (6:3:1 molar ratio, formulation C). The colloidal systems were obtained by the TLE technique and the extrusion process allowed us to obtain vesicles having mean sizes of 150–200 nm, while the surface charges varied between 50 mV and −30 mV. Formulation A showed the best encapsulation efficiency between the two compounds and the presence of TMX influenced the release profile of GEM (hydrophilic compound) as a consequence of its effect on the fluidity of the bilayer. An MDC of formulation A was used to effectuate the in vitro cytotoxicity experiments (MTT-test) on MCF-7 and T47D cells. The liposomal MDC provided the best results with respect to the single drug tested in the free form or entrapped in the same liposomal formulation. The CLSM experiments showed a great degree of cell interaction of liposomal MDC after just 6 h.
A phase II trial of neoadjuvant gemcitabine, epirubicin, and docetaxel as primary treatment of patients with locally advanced or inflammatory breast cancer
2010, Clinical Breast Cancer
Citation Excerpt :
However, it is possible that optimization of drug scheduling might decrease myelosuppression and allow these 3 agents to be administered without dose reductions or delays. A biweekly schedule, with growth factor support, probably minimizes the myelosuppression encountered with other gemcitabine schedules.32–37 Other taxanes or alternate taxane dosing schedules could also help to decrease toxicity.
Three-drug regimens containing gemcitabine, an anthracycline, and a taxane produce response rates of 70%-90% in patients with metastatic breast cancer (MBC) although accompanied by considerable hematologic toxicity. We explored the combination of gemcitabine/epirubicin/docetaxel as neoadjuvant therapy. Docetaxel was administered weekly to decrease myelosuppression.
A total of 110 patients with locally advanced or inflammatory breast cancer received neoadjuvant gemcitabine 800 mg/m² intravenously (I.V.) days 1 and 8, epirubicin 75 mg/m² I.V. day 1, and docetaxel 30 mg/m² I.V. days 1 and 8, repeated every 21 days for 4 cycles. Then patients had either mastectomy or breast conservation surgery, and pathologic treatment responses were assessed. After surgery, 4 cycles of adjuvant gemcitabine 1000 mg/m² I.V. days 1 and 8 and docetaxel 35 mg/m² I.V. days 1 and 8 were administered at 21-day intervals. After patients completed chemotherapy, locoregional radiation therapy and/or anti-estrogen therapy was administered per standard guidelines.
Treatment with 4 cycles of neoadjuvant gemcitabine, epirubicin, and weekly docetaxel resulted in an objective response in 79 of 110 patients enrolled (72%; 95% CI, 63-80%). Twenty of 103 patients (19%) who had surgery had pathologic complete response (pCR). Moderate hematologic toxicity was evident during neoadjuvant therapy, with grade 3/4 neutropenia in 41% and febrile neutropenia in 11% of the patients. Protocol-specified dose modifications were required in 35% of the patients, and 58% of the patients used myeloid growth factors.
The pCR rate of 19% achieved with gemcitabine, epirubicin, and weekly docetaxel confirms previous reports with similar 3-drug regimens. The use of a weekly schedule of docetaxel did not appear to reduce the incidence of grade 3/4 hematologic toxicity.
How to maximize the efficacy of taxanes in breast cancer
2005, Cancer Treatment Reviews
The life-expectancy of women with metastatic breast cancer (MBC) is closely linked to response to therapy. A significant increase in progression-free survival (PFS) and overall survival (OS) has been demonstrated in women who achieve a complete response. Anthracycline combinations have been proven as highly effective in MBC, and anthracycline regimens plus cyclophosphamide with or without fluorouracil were established as first-line chemotherapy for MBC in the 1990s. Clinical trials have shown that anthracycline-taxane combinations are more effective than anthracyclines or taxanes alone in terms of overall response rates (ORR), PFS and OS in women who have not received prior anthracycline chemotherapy. The use of anthracycline-based regimens is limited, however, by the widespread use of anthracycline adjuvant therapy and the development of anthracycline-resistance. Platinum-taxane combinations have similar efficacy to anthracycline-based regimens and are well-tolerated by patients. Carboplatin combined with paclitaxel or docetaxel is more effective than carboplatin or taxanes alone, with ORR of 53–62%. Taxane combinations with gemcitabine or capecitabine are also more effective than docetaxel, paclitaxel, capecitabine or gemcitabine administered alone. The efficacy of docetaxel and paclitaxel can be increased, and drug-related toxicity decreased, by adapting dose-dense schedules of drug administration. The addition of trastuzumab to taxane-based chemotherapy increases the efficacy of taxane-based regimens in women with HER2-positive MBC.

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What is the best schedule for administration of gemcitabine-taxane?

Ann Oncol

Ann Oncol

Ann Oncol

Ann Oncol

Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results

J Clin Oncol

Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): first report of overall survival

J Clin Oncol 2004; ASCO Annual Meeting Proceedings (Post-Meeting Edition)

Dose-dense adjuvant chemotherapy for primary breast cancer

Breast Cancer Res.

Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicentre, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group

J Clin Oncol

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of intergroup trial C9741/Cancer and Leukaemia Group B Trial 9741

J Clin Oncol

Phase I study of gemcitabine using a once every 2 weeks schedule

Br J Cancer

Phase I trial of paclitaxel and gemcitabine administered every 2 weeks in patients with refractory solid tumors

Ann Oncol