Pant et al this site, approximately 1.9-fold that of paclitaxel, targeting the centrosome organization and acting on the cell during S/G2/M phase. Stabilization of the microtubules disrupts the dynamic reorganization of the microtubules into spindles resulting in formation of abnormal bundles, which inhibit cell proliferation leading to cell death (Rinel and Horwitz 1991; Diaz and Andreu 1993). Compared with paclitaxel, there is a greater uptake of docetaxel into the tumor and slower efﬂux out of tumor cells, resulting in higher exposure of the tumor cells to docetaxel. This could explain the activity of docetaxel in paclitaxel-resistant tumors. Toxicity Neutropenia is the principal toxicity of docetaxel (Schrijvers et al 1993; Cortes and Pazdur 1995) and has led to dose reduc- tion and use of growth factors in patients with node-positive breast cancer. At a dose of 100 mg/m2, grade 4 neutropenia ( 500 cells/mm2) occurs in 85% of patients. The most important determinant of neutropenia is the extent of prior therapy. Despite being formulated in polysorbate 80, hyper- sensitivity reactions have been reported in approximately 31% of patients receiving docetaxel without premedications (Schrijvers et al 1993; Cortes and Pazdur 1995). The current recommendation is to give dexamethasone 8 mg twice a day for 3 days, starting a day prior to administration of docetaxel with or without H1 and H2 receptor antagonists given 30 min- utes before docetaxel (Piccart et al 1997; Markman 2003). This regimen also reduces the incidence of the unique ﬂuid retention syndrome characterized by edema, weight gain, and third-space ﬂuid collection caused by docetaxel. Evidence indicates that this is due to capillary leak and is usually not apparent until a cumulative dose of 400 mg/m2 is reached. Although ﬂuid retention is reversible, it takes several months to resolve after discontinuation of docetaxel (Piccart et al 1997). Patients developing progressive peripheral edema may be treated with diuretics for symptom relief. Skin toxicity may occur in as many as 50%–75% of patients (Schrijvers et al 1993; Markman 2003). The most common is an erythematous, pruritic, maculopapular rash that affects the forearm, hands, and feet; premedication reduces its incidence. The other less common cutaneous reactions include palmar-plantar erythrodysesthesia and ony- chodystrophy characterized by brown discoloration, ridging, onycholysis, and, in extreme cases, loss of nail plate. Mild to moderate peripheral neuropathy manifesting as paras- thesia, dysesthesia, and pain occurs in approximately 40% of patients with no prior treatment. Patients with a history of prior cisplatin therapy or alcohol abuse are particularly 420 susceptible (Zimmerman et al 1994, 1995; Piccart et al 1997; Hainsworth et al 1999). Stomatitis appears to be more frequent with docetaxel than paclitaxel. Hyperlacrimation, although initially classi- ﬁed as an unexpected side effect, is now being increasingly reported. This excessive tearing resulting from cannalicu- lar/nasolacrimal duct stenosis can lead to difﬁculty reading and driving, and it can affect quality of life (Esmaeli et al 2001). Interventions such as temporary silicone intubation and dacryocystorhinostomy with placement of silicone or pyrex tube may be needed to relieve symptoms (Esmaeli 2005). Severe gastrointestinal side effects are typically rare, although nausea, vomiting, and diarrhea may occur. Docetaxel in node-positive breast cancer The Breast Cancer International Research Group (BCIRG) 001 (Martin et al 2005) adjuvant study randomly allocated 1491 patients with node-positive breast cancer to docetaxel (75 mg/m2), doxorubicin, and cyclophosphamide (TAC) or to ﬂuorouracil, doxorubicin, and cyclophosphamide (FAC) for 6 cycles (Figure 1). At a median follow-up of 55 months, there was a 26% reduction in the risk of recurrence (hazard ratio [HR] = 0.74; 95% conﬁdence interval (CI) = 0.60–0.92; p = 0.0047) in the docetaxel arm. Longer disease-free survival (DFS) was seen in the docetaxel group regardless of the estrogen receptor/progesterone receptor status. This resulted in a beneﬁt in overall survival (OS) for TAC (87% vs 81%; p = 0.008) (46) (Table 1). Subgroup analysis showed that patients with fewer than 3 axillary nodes derived a more signiﬁcant beneﬁt from the addition of docetaxel in terms of DFS (90% vs 79%, p = 0.0002) and OS (96% vs 89%; p = 0.006). The incidence of grade 3 or 4 neutropenia (65.5% vs 49.3%, p 0.001) and febrile neutropenia (24.7% vs 2.5%, p 0.001) was higher in the TAC group. Though grade 3 or 4 infections occurred in 3.9% of patients treated with TAC and 2.2% of those treated with FAC (p = 0.05), the rates of sepsis did not differ between the two groups. The investigators concluded that TAC is superior to FAC in node-positive breast cancer patients. Voegl et al (2004) in a subanalysis of the BCIRG 001 trial investigated the role of growth factor support following neutropenic events. Granulocyte colony stimulating factor (G-CSF) was used as secondary prophylaxis for 87% (TAC) and 44% (FAC) patients. The rate of febrile neutropenia per cycle among patients receiving TAC dropped to 3.1% and FAC to 0.5% after growth factor support. This retrospective subgroup analysis demonstrated a higher rate of neutropenic Therapeutics and Clinical Risk Management 2008:4(2)