Table 1: Combination cytotoxic therapy for patients with MBC pretreated with, or resistant to, taxanes or anthracyclines.

Therapeutic combinationApproval statusMechanism of additive/synergistic actionClinical dataMost common grade 3-4 adverse events

Docetaxel plus capecitabine (DX) [66, 67]Phase III
Approved
Taxane increases thymidine phosphorylase at tumor site, required for conversion of capecitabine to active 5-FUDX 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%

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-FUPX [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%

Paclitaxel plus gemcitabine (PG) [70]Phase III
Approved
Taxane arrests cell cycle for gemcitabine to induce cytotoxicity and stimulates apoptotic pathwayPG 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%

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-FUDG 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%

Capecitabine plus ixabepilone (XI) [72]Phase III
Approved
Synergism demonstrated preclinically, but a mechanism has not been definedXI 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%

Vinorelbine plus gemcitabine (VG) [73]Phase III
Not approved
Synergism demonstrated preclinically, but a mechanism has not been definedVG 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%

ALT: alanine aminotransferase; AST: aspartate aminotransferase; CI: confidence interval; FU: fluorouracil; HR: hazard ratio; NSD: not significantly different; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; RR: response rate; TTP: time to progression.