Anthracycline antibiotics (doxorubicin and epirubicin) are among the most active drugs in MBC and cause anti-tumour effects by a variety of mechanisms including generation of oxygen free radicals and impairing DNA replication.
Recent studies have conferred that overexpression of topoisomerase II alpha (TOP2A) gene may provide as a rational predictive marker for response to anthracycline therapy. It is often co-amplified in 35% of tumours with HER-2 amplification. But its level of overexpression in HER2 negative cancer is not well defined.
They have been shown to retain significant activity in women who develop metastases more than 12 months after receiving adjuvant anthracyclines, but their efficacy in women who have an anthracycline-free interval of less than 12 months is uncertain (19-22).
Fossati et al. in 1998 demonstrated that first-line treatment with anthracycline-containing combination regimens had superior efficacy compared with mono-chemotherapy (15).
The most commonly used combinations are AC/EC (doxorubicin/ epirubicin plus cyclophosphamide) or CAF/CEF (cyclophosphamide/ 5-fluorouracil plus doxorubicin or epirubicin), which have yielded response rates in 40-70% of the patients (23).
Systematic Reviews 2006 showed a statistically significant advantage of anthracycline containing regimens over non-anthracycline regimens for tumour response and TTP but no improvement in OS and was also associated with greater toxicity (24).
Their use is limited by cumulative dose-dependent cardio toxicity, above 450 mg/m2 of doxorubicin or 1,000 mg/m2 of epirubicin. They are also associated with significant acute toxicity (nausea and vomiting, myelotoxicity, alopecia).
Myocet (liposome- encapsulated doxorubicin) (75mg/m2 every 3 weeks) and Caelyx (PLD 50 mg/m every 4 weeks doxorubicin 60 mg/m2 every 3 weeks) have shown within randomised trials to be equally effective and significantly less cardiotoxic than conventional doxocubicin in metastatic breast cancer.
Paclitaxel and docetaxel, are microtubule inhibitors, and also inhibit tumour angiogenesis.
In patients whose disease has progressed during or following anthracycline therapy or who are ineligible for further anthracycline therapy, taxanes have been considered the agent of choice. Paclitaxel and docetaxel have shown a 30-50% response rate in patients with anthracycline-resistant breast carcinoma. Taxanes are also increasingly being used, either as single agents or together with other agents as firstline treatment for MBC.
A systematic review of 21 randomised MBC trials by Ghersi et al. in 2005, comparing taxane with non-taxane regimens showed evidence in favour of taxane-based regimens in terms of OS and RR. But if the analysis is limited to the trials in women receiving first-line chemotherapy for metastatic breast cancer the difference is no longer statistically significant (25).
Combinations of taxanes and targeted biologic agents, such as trastuzumab, present clinical synergism with significant improvements in overall survival in patients with MBC.
The efficacy of docetaxel and paclitaxel can be increased while decreasing drug-related toxicity, by adapting dose-dense schedules of drug administration.
Docetaxel is now generally considered as the standard treatment for antracycline pretreated MBC. As a single agent, it produces objective responses in up to 60% of chemotherapy naive patients with MBC.
In a trial including first- and second-line therapy, docetaxel and capecitabine combination showed a better RR and OS compared to docetaxel alone.
In a mono-therapy trial in anthracycline-naive MBC patients, docetaxel (100 mg/m2 every 3 weeks) produced a superior response rate (48% vs 33%; p = 0.008) but similar survival when compared with doxorubicin (75 mg/m2 3 weekly) (20). Comparisons of single-agent docetaxel to combinations such as mitomycin/vinblastine or methotrexate/ fluorouracil have favoured the taxane in treating MBC after anthracycline resistance (26-29).
Docetaxel although generally well tolerated as a single agent, long-term use is often limited by haematological toxicities, peripheral neuropathy, fatigue, nail toxicity, and fluid retention. There is randomised evidence that the weekly docetaxel regimen is at least as effective as the every-3-weeks regimen and causes less toxicity, but requires weekly outpatient visits.
Paclitaxel has been shown to produce equivalent RR, TTP, and survival to CMFP (cyclophosphamide, methotrexate, fluorouracil, and prednisolone) chemotherapy as front-line treatment for patients with MBC (30).
But, with the 3-weekly schedule, at the dose of 175 mg/m2, paclitaxel has been unable to demonstrate superiority over either doxorubicin or docetaxel in the first-line metastatic setting.
Weekly paclitaxel regimen at doses ranging between 80 and 90 mg/m2/week has demonstrated higher activity and less toxicity for MBC in both nonrandomised and in randomised clinical trials (55,56). It is also effective and well tolerated in heavily pretreated refractory disease and in elderly patients or those with poor performance status. There is evidence for better outcomes when used in combination with gemcitabine as a first-line treatment in MBC.
The side effects of paclitaxel include hypersensitivity reactions (such as shortness of breath or skin rash), myelosupression, peripheral neuropathy, cardiac rhythm disturbances, joint or muscle pain, diarrhoea, nausea and vomiting, or hair loss. Patients often receive premedication before receiving paclitaxel to prevent possible allergic reactions.
A newer albumin-bound formulation of paclitaxel (ABI-007) showed the safety of a high dose of 300 mg/m2 infused over 30 minutes without pre-medication. A significantly higher RR, TTP, and lower incidence of grade 4 neutropenia and no hypersensitivity reactions were seen when compared to paclitaxel (31).
The oral capecitabine is designed to generate 5FU preferentially in tumour tissue and to mimic continuous infusion 5FU through activation pathway involving thymidine phosphorylase.
Capecitabine monotherapy at 1,250 mg/m2 twice daily for 14 days every 21 days has been well tolerated. When used following failure of anthracycline and taxane therapy, it has achieved response rates of 15% - 26% and a median survival in excess of 1 year (33-36). The common adverse events are hand-foot syndrome, diarrhoea, and nausea but Myelo-suppression and alopecia are rare.
Capecitabine a dose of 1,000 mg/m2 twice daily has been shown to be safe and effective in the 70 years and older patients who are candidates for cytotoxic therapy and do not have severely impaired renal function (37).
Capecitabine plus docetaxel significantly increased survival compared with docetaxel alone (14.5 vs 11.5 months) in patients with metastatic disease recurring after anthracycline therapy.
Capecitabine/trastuzumab combination therapy has produced promising efficacy and safety results for first- or second-line therapy in patients with HER2 overexpressing metastatic breast cancer (38, 39).
Gemcitabine, a nucleotide analogue that inhibits DNA synthesis has produced an ORR of 20-30% in those with previous exposure to chemotherapy, and 40% as first-line treatment in MBC (40-42). It is well tolerated in general including in the elderly patients. It is associated with a low incidence of nausea, vomiting, and alopecia. The most common dose-limiting toxicities are usually neutropenia and thrombocytopenia. The combination of gemcitabine plus paclitaxel has shown a 68% overall response rate as first-line chemotherapy and a 48% as second-line therapy (17).
Gemcitabine has also been shown to be active in combination with docetaxel (ORR: 36-79%) and a phase III trial has shown that gemcitabine plus docetaxel (1,000 mg/m2 on days 1 and 8 plus docetaxel 75 mg/m2) is as effective as capecitabine (1,250 mg/m2 bd day 1 through 14) plus same dose docetaxel, but with significantly less drug-related hand-foot syndrome, mucositis, and diarrhoea (43).
The efficacy of vinorelbine, a third generation vinca alkaloid, alone or in combination with other agents has been extensively investigated in MBC. Response rates, varying from 35-50%, have been demonstrated as a first-line single agent. Myelosuppression, gastrointestinal toxicities, and peripheral neuropathy are the primary toxicities (44).
Addition of Vinorelbine to epiribicin has been shown to confer higher RR and PFS but no OS benefit. An oral formulation of vinorelbine, an effective and well-tolerated agent, was evaluated as first-line chemotherapy for MBC offering an alternative to the intravenous route.
Platinum compounds or alkylating agents have shown significant activity in previously untreated patients with MBC. Single-agent carboplatin produces ORR of 20-35% (45-47). Retrospective review of clinical trials by Perez revealed that carboplatin combined with paclitaxel or docetaxel was more effective than carboplatin or taxanes alone, with ORR of 53-62% in the first-line treatment of MBC.
Recent phase III data suggest that adding carboplatin to a paclitaxel/ trastuzumab regimen produces superior efficacy than paclitaxel/ trastuzumab alone for patients with HER2-positive metastatic disease. Myelosuppression is more common with this three-drug regimen.
However, preliminary results from the NCCTG 98-32-52 trial suggest that a weekly schedule of carboplatin/paclitaxel plus trastuzumab produces at least as effective results as the 3-weekly schedule but with much less toxicity.
It has been suggested that "triple negative" (TN) breast cancers, (ERve, PR-ve, HER2 -ve) may be particularly sensitive target for platinum compound. This is based on preclinical evidence which suggests the possibility of TN breast cancers sharing BRCAl-associated DNA repair defects, which may be targeted with DNA cross-linking agents like platinum compounds. Currently there is an ongoing clinical trial by CRUK using carboplatin for patients with metastatic genetic breast cancer with BRCA1 or 2 mutations.
Trastuzumab is a humanised monoclonal antibody directed against HER2 glycoprotein, overexpressed in 20-25% of human breast cancers. As a single agent it has a response rate around 35% in selected MBC patients (48). The addition of trastuzumab to chemotherapy results in significant improvements in clinical outcomes, including overall survival.
Slamon et al. demonstrated the addition of trastuzumab to paclitaxel significantly increased TTP (p < 0.001; median 6.9 months versus 3.0 months) and RR (p < 0.001; 49% versus 17%), and resulted in improved OS (median 25 months vs 18 months) in anthracycline-pretreated patients with HER2 positive MBC (49). Marty et al. observed similar results, in a study comparing trastuzumab plus with docetaxel alone as first-line therapy for HER2 positive MBC (50).
Combinations of trastuzumab and other cytotoxic agents, including, gemcitabine, carboplatin, and vinorelbine, are also highly active first- or second-line therapies in patients with HER2 overexpressing MBC.
Despite impressive tumour response rates, most of the metastatic patients develop disease progression during treatment. Although a few retrospective analyses supporting the practice of continuing trastuzumab alone or combined with other drugs beyond disease progression, in the absence of data from randomised trials is at least debatable.
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