Nonanthracycline Containing Docetaxel-Based Combinations in Metastatic Breast Cancer

Abstract

Many active nonanthracycline-containing regimens are emerging from clinical trials and may offer the option of treating metastatic breast cancer without resorting to doxorubicin or analogues. When used first-line in metastatic breast cancer, both cisplatin and carboplatin are active agents and hence candidates for combination therapy. In a dose-finding study in patients with no prior chemotherapy for metastatic disease, docetaxel administered together with cisplatin produced a promising response rate (RR) of 60% (73% in patients without prior adjuvant chemotherapy). The combination is feasible, although adequate hydration and antiemetic medication must be given. There is also an early indication that it may be possible to dramatically cytoreduce disease in patients with locally advanced breast cancer who are treated with docetaxel plus cisplatin. Given its lower toxicity, carboplatin may also have a role in combination with the taxanes. Of the nonplatinum agents, vinorelbine appears to hold promise; its combination with docetaxel produced an RR of 59% in a group of anthracycline-pretreated patients with progressive disease. Forty-two percent of the patients studied also had prior exposure to a taxane. Weekly gemcitabine plus monthly docetaxel is feasible and active, as is the combination of docetaxel q 3 weeks with daily oral capecitabine. The Oncologist 2001;6(suppl 3):17-21The Oncologist 2001;6(suppl 3):17-21 www.TheOncologist.com Correspondence: John Crown, M.D., Elm Park, St. Vincent's Hospital, Dublin 4, Ireland. Telephone: 353-1-202-4839; Fax: 353-1-283-7719; e-mail: john.crown@icorg.ie Received February 6, 2001; accepted for publication March 5, 2001. ©AlphaMed Press 1083-7159/2001 INTRODUCTIONEvidence to date suggests that docetaxel is one of the most active single agents in metastatic breast cancer [1,2]. Docetaxel has been shown to be superior to doxorubicin in the treatment of patients with prior exposure to an alkylating agent-containing regimen, and it is also superior to mitomycin/vinblastine and methotrexate/5-fluourouracil (5-FU) in patients whose cancer had progressed following anthracycline therapy [3][4][5][6]. The latter finding is of particular relevance to designers of combination regimens in that it indicates at least a degree of non-cross-resistance between docetaxel and doxorubicin, and the use of these two drugs in combination thus seems logical. In two Breast Cancer International Research Group studies, docetaxel-doxorubicin combinations were superior to more traditional anthracycline-alkylating agentbased combinations. However, the increasing use of anthracyclines in the adjuvant setting mandates the development of nonanthracycline-containing, docetaxel-based combinations.

cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance

“…While both agents are widely used for the treatment of non-inflammatory and inflammatory breast cancer [22,23], the majority of patients develop resistance to the drugs, particularly after a previous round of chemotherapy [24]. Of the genes comprising the genetic signatures of resistance, we found that the significant majority were drug-specific and code for proteins involved in drug transport, drug metabolism, growth, survival, and cell death control.…”

Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic breast cancer

“…The widespread use of anthracycline-based chemotherapy in the adjuvant treatment of breast cancer has contributed to an increasing number of patients presenting with MBC resistant to this class of drugs. The majority of anthracycline-naïve patients with MBC are treated with anthracyclines as first-line therapy for metastatic disease [2,3]. The taxanes are also considered to be highly active agents in the treatment of breast cancer, with single-agent docetaxel showing response rates up to 49-57% in anthracycline-pretreated patients, confirming the lack of complete cross-resistance between these classes of agents [4,5].…”

Second-Line Combination Chemotherapy with Vinorelbine and Capecitabine in Patients with Advanced Breast Cancer Previously Treated with Anthracyclines and/or Taxanes

“…Moreover, the majority of anthracycline-naïve patients with ABC are treated with anthracyclines as first-line therapy for metastatic disease [2]. Thus, there is a need to develop effective non-anthracycline-containing regimens, since the use of anthracycline salvage chemotherapy is limited due to the development of drug resistance [3]. The taxanes are also considered to be highly active agents in the treatment of breast cancer, with single-agent docetaxel showing response rates (RR) up to 49–57% in anthracycline-pretreated patients, confirming the lack of complete cross-resistance between these classes of agents [4,5].…”