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Therapeutic combination | Approval status | Mechanism of additive/synergistic action | Clinical data | Most common grade 3-4 adverse events |
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Docetaxel plus capecitabine (DX) [66, 67] | Phase III Approved | Taxane increases thymidine phosphorylase at tumor site, required for conversion of capecitabine to active 5-FU | DX versus single-agent D ORR: 42% versus 30% (P = 0.006) TTP: median 6.1 versus 4.2 months, HR = 0.652 (95% CI: 0.545–0.780; P = 0.0001) OS: median 14.5 versus 11.5 months, HR = 0.777 (95% CI: 0.645–0.942; P < 0.01) | DX versus single-agent D Neutropenic fever: 16% versus 21% Neutropenia: 16% versus 15% Stomatitis: 17% versus 5% Diarrhea: 14% versus 5% Nausea: 6% versus 2% Hand-foot syndrome: 24% versus 1% Alopecia: 6% versus 7% Fatigue/asthenia: 8% versus 11% |
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Paclitaxel plus capecitabine (PX) [68, 69] | Phase II Not approved | Taxane increases thymidine phosphorylase at tumor site, required for conversion of capecitabine to active 5-FU | PX [68, 69] ORR: 52%/81% TTP: median 8.1/8.4 months OS: median 16.5/21.6 months | PX [69] Hand-foot syndrome: 20% Neutropenia: 13% Fatigue: 7% |
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Paclitaxel plus gemcitabine (PG) [70] | Phase III Approved | Taxane arrests cell cycle for gemcitabine to induce cytotoxicity and stimulates apoptotic pathway | PG versus single-agent P RR: 41.4% versus 26.2% (P = 0.002) TTP: median 6.14 versus 3.98 months, HR = 0.70 (95% CI: 0.59–0.85; P = 0.002) OS: median 18.6 versus 15.8 months, HR = 0.82 (95% CI: 0.67–1.00; P = 0.019) | PG versus single-agent P Neutropenia: 47.5% versus 11.5% Anemia: 5.8% versus 1.5% Thrombocytopenia: 6.1% versus 0% Febrile neutropenia: 5.0% versus 1.2% Alopecia: 17.2% versus 22.0% Fatigue: 6.9% versus 1.2% ALT: 5.0% versus 0.4% Sensory neuropathy: 5.7% versus 3.9% |
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Docetaxel plus gemcitabine (DG) versus docetaxel plus capecitabine (DX) [71] | DG: phase III Not approved | Taxane arrests cell cycle for gemcitabine to induce cytotoxicity; taxane increases thymidine phosphorylase at tumor site, required for conversion of capecitabine to active 5-FU | DG versus DX RR: NSD PFS: NSD OS: NSD | DG versus DX Anemia: 6% versus 2% Neutropenia: 84% versus 79% Febrile neutropenia/neutropenic sepsis: 8% versus 4% Thrombocytopenia: 9% versus 4% Leukopenia: 77% versus 66% ALT/AST: 9% versus 5% Diarrhea: 8% versus 18% Nausea/vomiting: 10% versus 4% Mucositis: 4% versus 15% Asthenia: 7% versus 11% Hand-foot syndrome: 0% versus 26% |
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Capecitabine plus ixabepilone (XI) [72] | Phase III Approved | Synergism demonstrated preclinically, but a mechanism has not been defined | XI versus single-agent X ORR: 35% versus 14% (P < 0.0001) PFS: median 5.8 versus 4.2 months, HR = 0.75 (95% CI: 0.64–0.88; P = 0.0003) OS: median 12.9 versus 11.1 months, HR = 0.90 (95% CI: 0.70–1.05; NSD) | XI versus single-agent X Peripheral sensory neuropathy: 20.8% versus 0% Hand-foot syndrome: 18% versus 17% Diarrhea: 6% versus 8.5% Fatigue: 9% versus 3.3% Myalgia: 8% versus 0.3% Asthenia: 7.8% versus 0.8% Leukopenia: 57% versus 6% Anemia: 10% versus 4.5% Neutropenia: 68% versus 11% Thrombocytopenia: 8% versus 4% |
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Vinorelbine plus gemcitabine (VG) [73] | Phase III Not approved | Synergism demonstrated preclinically, but a mechanism has not been defined | VG versus single-agent V ORR: 36% versus 26% (NSD) PFS: HR = 0.66 (95% CI: 0.50–0.88) OS: HR = 1.04 (95% CI: 0.78–1.39; NSD) | VG versus single-agent V Neutropenia: 61% versus 44% Febrile neutropenia: 11% versus 6% Anemia: 6% versus 5% Thrombocytopenia: 8% versus 2% Alopecia (grade 2): 17% versus 17% Fatigue: 24% versus 17% ALT: 8% versus 3% AST: 5% versus 6% Prothrombin time or part prothrombin time alterations, or both: 7% versus 8% Constipation: 5% versus 2% Other infection: 9% versus 6% Dyspnea: 5% versus 6% |
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