The Role of Capecitabine in First-Line Treatment for Patients with Metastatic Breast Cancer

Gelmon, Karen A.; Chan, Arlene; Harbeck, Nadia

doi:10.1634/theoncologist.11-90001-42

Cited by 36 publications

(22 citation statements)

References 50 publications

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“…Metronomic dosing results in low plasma concentrations of capecitabine and its intermediates and simulates a low-dose infusion of 5-FU (18). When administered daily, capecitabine efficacy is superior to intravenous 5-FU infusion in the treatment of anthracycline-resistant metastatic breast cancer (19) and is approved for colorectal cancer treatment (20). Recent studies of metronomically dosed capecitabine with gemcitabine show comparable or modestly improved survival times and good tolerability (21,22).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

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LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

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Section: Introductionmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

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“…Chemotherapeutic regimens containing taxanes and anthracyclines are the current standard of care for hormone-refractory MBC, and are being used earlier in the course of the disease with increasing frequency [2][3][4]. Sequential single-agent therapies including capecitabine, gemcitabine, and vinorelbine are preferred to combination regimens for MBC progressing after anthracyclines and taxanes, with capecitabine being the only approved monotherapy [5][6][7][8][9]. While these agents exhibit antitumor activity in this patient population, none showed a survival benefit either alone or in combination with other drugs [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Sequential single-agent therapies including capecitabine, gemcitabine, and vinorelbine are preferred to combination regimens for MBC progressing after anthracyclines and taxanes, with capecitabine being the only approved monotherapy [5][6][7][8][9]. While these agents exhibit antitumor activity in this patient population, none showed a survival benefit either alone or in combination with other drugs [8,9]. The prognosis is particularly unfavorable for patients with a reduced performance status who are typically more symptomatic and less responsive to treatment than those with a good performance status [10][11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies

Roché

Conte

Perez

et al. 2010

Breast Cancer Res Treat

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Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky's performance status (KPS) 70-80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70-80 subset (n = 606) or KPS 90-100 subset (n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70-80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90-100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70-80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433).

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“…The phase II studies of gastric and NSCLC have also shown promising results using the above combinations [19][20][21][22]. The maximum concentration of vorinostat tolerable by human body was determined using two phase I pharmacokinetic and pharmacodynamics studies in combination with FOLFOX or 5-FU/LV chemotherapy regimens [23,24] in CRC.…”

Section: Discussionmentioning

confidence: 99%

Combined Effect of Vorinostat and Grape Seed Proanthocyanidins on Modulation of Thymidine Phosphorylase in Non-Small Cell Lung Cancer

Wu¹,

Cao²,

Liu³

2015

Trop. J. Pharm Res

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The Role of Capecitabine in First-Line Treatment for Patients with Metastatic Breast Cancer

Cited by 36 publications

References 50 publications

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies

Combined Effect of Vorinostat and Grape Seed Proanthocyanidins on Modulation of Thymidine Phosphorylase in Non-Small Cell Lung Cancer

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