Taxanes The taxanes, docetaxel and paclitaxel, have at least equivalent activity to doxorubicin as single agents. Taxanes stabilize polymerized microtubules thereby disrupting mitoses and have signifcant activity in second- or third-line therapy in patients resistant to anthracyclines with response rates of 16–21% for paclitaxel (Seidman et al., 1995; Paridaens et al., 2000) and 42–51% for docetaxel (Ravdin et al., 1995; Valero et al., 1995; Trudeau et al., 1996; Sjostrom et al., 1999). For docetaxel the main side-efects included Xuid retention syndrome with peripheral oedema, skin and nail changes and febrile neutropenia in 10–20% of patients. Fluid retention may be abrogated by pre and posttreatment with corticosteroids and the subsequent use of diuretics. A compassionate use programme in 825 heavily pretreated patients (i.e. an unselected population), conWrmed the activity seen in trials even as third-line treatment with a response rate of 22.9% (95% CI: 20.2%–26.2%) (Alexandre et al., 2000). This study also highlighted the need for dose reduction to 75 mg/m2 or less in patients with liver dysfunction or heavy pretreatment in whom toxicities such as leucopenia, oedema and Xuid retention are more frequent and severe, probably because hepatobiliary excretion is the major elimination routine for docetaxel. These results in Phase II studies and a compassionate programme are encouraging as the options for women with anthracycline-resistant disease have been limited. Mitomycin C and vinblastine is a commonly used palliative regimen with a response rate of 16% in anthracycline-resistant breast cancer compared with30% for docetaxel in a comparative study in 392 patients (Nabholtz et al., 1999). In this study, time to treatment progression was superior (19 vs. 11 weeks) for docetaxel as was survival (11.4 vs. 8.7 months). In comparison with 5-FU and methotrexate, docetaxel was again superior with a response rate of 42% compared with 21% (Sjostrom et al., 1999). Paclitaxel is commonly given at doses of 175–200 mg/m2 every three weeks. Higher doses (_250 mg/m2 are not associated with improved response rates, but do incur a sensory neuropathy (Winer et al., 1998). The response rates in anthracycline-refractory patients between 16% and 21% appear lower than with docetaxel and similarly as a Wrst-line agent the response rates with paclitaxel, 25–32%, are lower than with docetaxel (41–61%), although there are no direct comparative studies (Seidman, 1995; Vermoken & Ten Bokkel Huinick, 1996; Paridaens et al., 2000). Initial concerns about cardiotoxicity with paclitaxel have not resulted in clinical problems in single-agent studies, although asymptomatic arrythmias are seen. In Wrst-line therapy doxorubicin was superior to paclitaxel with a response rate of 41% versus 25% and median progression-free survival (7.5 vs. 3.9 month) (Paridaens et al., 2000). In this study the crossover response to doxorubicin was 30% and to paclitaxel 16%, indicating non-cross resistance. There is renewed interest in scheduling with both taxanes. For paclitaxel increased duration of infusion (24 h vs. 3 h) may have a slightly improved response rate, but is inconvenient and associated with more haematological and neurotoxicity. Weekly schedules have been used for both taxanes. Paclitaxel can be given at 80–90 mg/m2 per week with response rates of around 30%, but a much lower incidence of neutropenia, neuropathy and alopecia than with the threeweekly scheduling possibly making this a useful schedule for patients requiring a taxane, but at risk of neutropenia (Seidman et al., 1998). Another potential use of weekly schedules may be with biological agents such as trastuzumab or cytotoxic drugs which are given weekly, e.g. vinorelbine, gemcitabine. Both taxanes have been used in combination with anthracyclines (Gianni et al., 1995, 1997; Esposito et al., 1999; Sparano et al., 1999). There is no pharmacokinetic interaction between anthracyclines and paclitaxel, however docetaxel increases plasma concentration of doxorubicin (Gianni et al., 1997) leading to a need for dose reduction of docetaxel to 75 mg/m2 in combination regimens. Despite high response rates in Phase II studies of up to 94% (Gianni et al., 1995) comparative studies have not demonstrated any superiority for anthracycline/ taxane combinations over standard anthracycline/cyclophosphamide regimens to date. The lack of cross resistance demonstrated between paclitaxel and doxorubicin (Paridaens et al., 2000) makes sequential rather than combination studies attractive. Vinorelbine Vinorelbine is a semisynthetic vinca alkaloid which inhibits formation of the mitotic spindle (in contrast to taxanes which promote and stabilize assembly of microtubules after spindle formation). The response rate in phase II studies was 20–30% in previously treated patients, including those refractory to anthracyclines (Bertsch & Donaldson, 1995; Vermoken & Ten Bokkel Huinick, 1996). In a comparative study against melphalan the response rate was superior to melphalan at 46.5% compared with 28.2% with time to tumour progression of 12 weeks compared with 8 weeks (Jones et al., 1995). Haematological toxicity is doselimiting with Grade 3 or 4 neutropenia in 75% of patients. Although this is not cumulative it may limit planned weekly administration. Vinorelbine also causes mild peripheral neuropathy and autonomic neuropathy but no alopecia. Vinorelbine is well tolerated with a symptomatic toxicity proWle better than conventional regimens such as FEC or FAC in randomized trials, despite a higher incidence of neutropenia (Namer et al., 1997). Preclinical data indicate synergism between vinca alkaloids and taxanes and this has been conWrmed in a trial of 49 patients (Romero Acna et al., 1999). There have been no comparative trials as yet on the relative merits between vinorelbine and taxanes in terms of quality of life and health economics. One cost–utility analysis has demonstrated economic advantages for vinorelbine compared with taxanes with at least equivalent quality-adjusted progression-free survival despite lower absolute response rates and time to progression. Fluoropyrimidines Capecitabine is a rationally designed selectively tumour-activated Xuoropyrimidine carbamate which is eVectively an oral 5-Xuorouracil prodrug with intramoural activity. Interest in this arose because of the recognition that infusional 5-Xuorouracil via central venous access, gave response rates of 20–30% in patients with end stage breast cancer even if they had received prior bolus 5-FU. However, continuous infusional treatment is inconvenient. Oral capecitabine has shown a response rate of 20% in 135 heavily pretreated paclitaxel-resistant patients, including patients who had received anthracyclines (Blum et al., 1999). This activity was conWrmed in a randomized phase II trial against paclitaxel in anthracycline-resistant patients with response rates of 36% versus 21% and median time to disease progression of 92 versus 95 days (Moiseyenko et al., 1998). Toxicities are those expected with Xuoropyramidines, with neutropenia, gastrointestinal problems (diarrhoea) and hand–foot syndrome. A guiding principle in chemotherapy for breast cancer is to maximize response by using the best standard regimen Wrst. This approach means that most newagents are evaluated in very advanced disease, the response rate is low in these resistant patients hence valuable drugs may be discarded. This approach can be challenged by a prospective randomized phase III trial in which the safety and eYcacy of using a phase II drug before standard chemotherapy was evaluated (Constanza et al., 1999). This study in 365 women showed that the use of single-agent or phase II drugs (trimetrexate, melphalan, amoniWde, carboplatin, elsamitrucin) for up to four cycles did not compromise response to a standard regimen (CAF) irrespective of the response to the experimental drug. Dose intensification Retrospective literature review had indicated that higher doses or dose intensity were associated with improved survival (Hryniuk & Bush, 1984). Certainly a moderate increase in dose of around twofold has been associated with increased response rate, but no improvement in time to progression or overall survival (Bastholt et al., 1996; Hortobagyi et al., 1987). These studies also conWrmed that chemotherapy given at suboptimal doses resulted in an inferior outcome, emphasizing the need for standard doses when a decision to treat is made. These data led to renewed interest in dose intensiWcation, with high-dose chemotherapy supported by growth factors and/or bone marrow transplantation or peripheral blood stem cell support. Phase II trials in the 1980s were promising and by 1995 breast cancer was the most common indication for high-dose chemotherapy and bone marrow transplant in the United States. Few patients were in clinical trials and any apparently superior results may have been due to selection bias in favour of younger age and good performance status (Antman et al., 1997). A retrospective analysis by Rahman et al. (1997) emphasized this issue. This group evaluated the results of 1581 patients with metastatic breast cancer who were treated with doxorubucin containing regimens with standard doses within clinical trials. Those who would have met the criteria for high-dose treatment, i.e. transplant candidates, had a better response rate, progression-free survival and overall survival although they only received standard chemotherapy. In a randomized trial comparing high-dose consolidation with maintenance chemotherapy in conventional doses after remission induction, there was no improvement in survival with the high-dose approach (Stadtmauer et al., 2000).
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