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Summary

Background: Docetaxel and paclitaxel are among the most active substances for the treatment of breast cancer. As both drugs are used today in adjuvant regimens, efficacy data from pivotal trials in the metastatic setting in taxane-naive populations cannot reliably be used as references. Patients and Methods: The Taxane Re-Challenge Cohort Study identified participants from 6 prospective (neo-)adjuvant taxane-based studies with recurrent disease and collected data on their subsequent treatment. Out of 381 recurrent patients, 106 (27.8%) were re-challenged with a taxane-based treatment as first- or later-line therapy for recurrent disease. Results: Taxanes were used as first-line therapy in 74 patients and showed a response rate of 48.6% (including complete responses in 27.0%). The response rate was dependent on the disease-free interval (<1 year: 34.8%; 1-2 years: 42.9%; >2 years: 63.3%; p = 0.04) and visceral metastasis (present: 62.5%; not present 32.4%; p = 0.01). Patients without visceral metastasis and with a disease-free interval of >2 years achieved the longest overall survival. Hormone and HER2 receptor status were not predictive; however, triple-negative tumors responded in 50.0%. The overall response rate of later-line taxane-based treatment was 28.2%. Conclusion: Re-challenging taxanes appears to be effective and therefore represents a reasonable option in this population.

Purpose

Whether combination chemotherapy offers an advantage over sequential therapy in metastatic breast cancer (MBC) is still an unsettled issue. Polychemotherapy regimens containing taxanes has been shown to increase overall survival (OS), time to tumor progression (TTP), and overall response rate (ORR) when compared with regimens that did not contain a taxanes, while taxane-based doublets have a statistically significant benefit over single-agent taxane only for progression-free survival. However, the term “taxanes” generally includes both paclitaxel and docetaxel, drugs with different clinical activity. Aim of this work is to compare OS, TTP, and ORR in patients with MBC receiving docetaxel alone or in combination with chemotherapy using a formal meta-analysis.

Methods

We performed a systematic review of all published trials comparing docetaxel alone or in combination with other chemotherapeutic agents in MBC.

Results

Three randomized clinical trials including 1,313 patients were retrieved. A significant reduction of risk ratio was found in TTP (P ≤ 0.0001) but not in OS (P = 0.48) or ORR (P = 0.10) for patients treated with a chemotherapy agent plus docetaxel compared with docetaxel alone. Treatment with docetaxel alone is associated with a lower incidence of grade 3 diarrhea and stomatitis (diarrhea, P = 0.011; stomatitis, P = 0.0004).

Conclusion

Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and ORR in MBC. This review confirms that it is unlikely that any single agent or combination chemotherapy regimen will emerge as superior in MBC, due to its heterogeneous nature.

The role of taxanes in the treatment of breast cancer is becoming increasingly important. In clinical practice, the taxanes are now standard therapy in both early-stage and metastatic breast cancer. Since the 1990s, multiple randomized clinical trials have been evaluating the efficacy of taxanes in the treatment of metastatic breast cancer. These trials have included treatment with taxanes alone or in combination with other chemotherapeutic agents. Pre-existing published guidelines for the use of taxanes in the management of metastatic breast cancer are available. The mandate of the Alberta Cancer Board Provincial Breast Tumour Group Guideline Panel was to consider and adapt the recommendations of the existing guidelines and to develop de novo guidelines to account for current evidence. For this task, the panel used the adapte process, which is a systematic process of guideline adaptation developed by the adapte Collaboration.

The recommendations formulated by the panel included the identification of taxane regimens that could be offered in anthracycline-naïve patients, anthracycline-pretreated or -resistant patients, and patients overexpressing the human epidermal growth factor receptor 2. Potential toxicities and benefits in terms of time to progression, progression-free survival, overall survival, and quality of life were also considered.

Taxanes (paclitaxel and docetaxel) are currently used to treat ovarian, breast, lung, and head and neck cancers. Despite its clinical success taxane-based treatment could be significantly improved by identifying those patients whose tumors are more likely to present a clinical response. In this mini-review we discuss the accumulating evidence indicating that the breast and ovarian cancer susceptibility gene product BRCA1 mediates cellular response to taxanes. We review data from in vitro, animal, and clinical studies, and discuss them in context of response to therapy. We argue that levels of BRCA1 in tumors may provide a predictive marker for the response to treatment with taxanes. In addition, the study of the role of BRCA1 in the mechanism of action of taxanes might reveal alternative approaches to avoid resistance.

Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clinical advances of taxanes have been limited by their highly hydrophobic molecular status. To overcome this poor water solubility, lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of standard paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane®, in association with other traditional and non-traditional drugs (new antineoplastic agents and targeted molecules), will give the oncologist many different effective treatment options for patients in this setting.

Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®, Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab-paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer.

Purpose

We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease.

Patient and Methods

Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle.

Results

Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months.

Conclusion

Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.

Resistance to taxanes, related to limited efficacy of systemic therapy in cancer patients, is multifactorial. Among mechanisms of resistance to taxanes, those related to microtubule-associated proteins (MAP), including protein Tau, are of great importance. Protein Tau (50–64 kD) binds to beta-tubulin in the same place as paclitaxel. In preclinical studies, low expression of Tau in cancer cells was associated with increased sensitivity to paclitaxel. High expression of Tau protein in ER-positive breast cancers indicates resistance to taxane-containing chemotherapy and sensitivity to hormonal treatment. This article reviews current knowledge on predictive value of protein Tau in response to taxanes. Better understanding of its role may facilitate patients selection to this sort of treatment and lead to treatment optimization.

Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician’s treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.

Breast cancer is the most frequent tumor among women worldwide and is the second cause of cancer-related mortality in the US. Metastatic breast cancer (MBC) accounts for less than 10% of newly diagnosed breast cancer patients and about 30% of early breast cancer patients will develop recurrent, advanced, or metastatic disease. It remains an incurable illness and the primary goal of its management is palliative. Several agents are active for the first-line treatment of MBC. The taxanes, paclitaxel and docetaxel, represent the standard of care for the treatment of these patients. Among the various schedules, docetaxel can be administered weekly, achieving similar efficacy results with lower toxicity compared with conventional schedules. Weekly docetaxel (25–40 mg/m2) has been widely tested in several phase I and II studies both as a single agent and in multichemotherapy regimens, reaching overall response rates ranging from 26% and 86% or 20% and 73% with docetaxel alone or in combination, respectively, depending on doses, associations, and line of treatment. Overall, published data support the administration of weekly docetaxel for the treatment of MBC patients even if data from phase III randomized trials are still lacking.

Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.

Purpose

Metastatic breast cancer patients are usually exposed to taxane and anthracycline as neoadjuvant, adjuvant and palliative chemotherapeutic agents. This study was designed to determine the efficacy and safety of the use of a gemcitabine and cisplatin (GP) combination treatment in patients with metastatic breast cancer that were pretreated with anthracycline and taxane.

Materials and Methods

We evaluated the use of a GP regimen (1,000 mg/m2 gemcitabine administered on days 1 and 8 plus 60 mg/m2 cisplatin administered on day 1 every 3 weeks) in 38 breast cancer patients who had received prior chemotherapy with anthracycline and taxane as an adjuvant or neoadjuvant therapy, or as a palliative therapy.

Results

The median patient age was 49 years (age range, 35~69 years). The overall response rate was 28.9% in 11 patients (95% confidence interval [CI], 14~44%). The median time to progression was 5.2 months (95% CI, 3.6~6.8 months). Median survival was 19.5 months (95% CI, 11.2~27.8 months). Major grade 3/4 hematological toxicity was due to leukopenia (36 of 157 cycles, 23.1%). Non-hematological toxicity was rarely severe; grade1/2 nausea and vomiting were observed in 37.8% of the patients. There were no treatment related deaths.

Conclusions

Our results suggest that the use of gemcitabine plus cisplatin appears to be effective and has an acceptable toxicity profile in patients with advanced breast cancer that have been pretreated with anthracycline and taxane.

The epothilone analog ixabepilone exhibits reduced susceptibility to several important tumor survival mechanisms that limit the efficacy of taxanes and anthracyclines. As a single agent, ixabepilone has shown promise in metastatic breast cancer when anthracyclines, taxanes, or capecitabine have failed; and in early-stage breast cancer that is taxane-naïve or has previously received taxanes in the adjuvant or metastatic setting. Compared with capecitabine alone, ixabepilone used in combination with capecitabine in patients previously treated with and resistant to anthracyclines and taxanes produced a 25% reduction in the risk of disease progression. Triple-negative tumors showed particular susceptibility to this doublet. Ixabepilone has also demonstrated efficacy as first-line therapy in combination with targeted agents such as bevacizumab and trastuzumab. Ongoing investigations should provide insight as to how this agent could be integrated into treatment of early-stage disease. In clinical studies, toxicities with ixabepilone were manageable and reversible through dose reduction or delay, even in patients with extensive or heavily-pretreated disease. Thus, ixabepilone represents a useful addition to the therapeutic options available for advanced breast cancer, and it may extend progression-free survival in patients with limited treatment options.

Taxane therapy is commonly used in the treatment of metastatic breast cancer. However, most patients will eventually become refractory to these agents. Ixabepilone is a newly approved chemotherapeutic agent for the treatment of metastatic breast cancer. Although it targets microtubules similarly to docetaxel and paclitaxel, ixabepilone has activity in patients that are refractory to taxanes. This review summarizes the pharmacology of ixapebilone and clinical trials with the drug both as a single agent and in combination. Data were obtained using searches of PubMed and abstracts of the annual meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium from 1995 to 2008. Ixapebilone is a semi-synthetic analog of epothilone B that acts to induce apoptosis of cancer cells via the stabilization of microtubules. Phase I clinical trials have employed various dosing schedules ranging from daily to weekly to 3-weekly. Dose-limiting toxicites included neuropathy and neutropenia. Responses were seen in a variety of tumor types. Phase II studies verified activity in taxane-refractory metastatic breast cancer. The FDA has approved ixabepilone for use as monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer. Ixabepilone is an efficacious option for patients with refractory metastatic breast cancer. The safety profile is similar to that of taxanes, with neuropathy and neutropenia being dose-limiting. Studies are ongoing with the use of both iv and oral formulations and in combination with other chemotherapeutic and biologic agents.

The treatment of metastatic breast cancer (MBC) has become increasingly challenging as the primary goals of therapy include prolonging life without added toxicity. While multiple agents are approved for the therapy of MBC, there is no standard approach for therapy beyond the second-line. Eribulin mesylate, an analog of the marine sponge halichondrin B, is a non-taxane microtubule dynamics inhibitor with a mechanism of action distinct from other tubulin-targeted drugs. Based on a significant extension in overall survival seen in a Phase III clinical trial, eribulin was approved for third-line therapy in MBC patients following anthracycline and taxane failure. Eribulin has a manageable toxicity profile and a low incidence of peripheral neuropathy. In this review, we discuss the natural source of eribulin, pharmacology, mode of action, preclinical and clinical data, and patient-focused perspectives.

Despite the activity of standard chemotherapies in advanced breast cancer, disease progression remains inevitable. Most patients exposed to anthracyclines and taxanes develop resistance and a significant subset shows primary resistance. The increasing use of these agents as adjuvant therapy may result in more anthracycline- and taxane-resistant patients in the metastatic setting; few treatment options are available for patients with metastatic breast cancer (MBC) resistant to multiple chemotherapies. The heterogeneity of breast cancer represents another therapeutic challenge. Breast cancers may be classified as luminal, human epidermal growth factor 2 (HER2)-positive, or estrogen receptor-, progesterone receptor-, and human epidermal growth factor 2-negative (ER/PR/HER2-negative, triple negative). HER2-positive and ER/PR/HER2-negative tumors are associated with poor prognosis owing to aggressive disease and poor long-term response to therapy. The epothilone B analog ixabepilone has low susceptibility to multiple mechanisms of resistance and has demonstrated activity in patients with MBC resistant to anthracyclines, taxanes, and/or capecitabine. Ixabepilone is the first epothilone to be approved, as monotherapy or in combination with capecitabine, for treatment of resistant/refractory MBC or locally advanced breast cancer. Treatment with ixabepilone is an option for patients with ER/PR/HER2-negative or HER2-positive disease and/or primary resistance to taxanes.

Background

Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel.

Methods

Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n=5) or recurrence within six months of treatment completion (n=42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m2 days 1,8,15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%).

Results

Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34–78) years, serous histology: 72%, and high-grade: 81%. Efficacy: One complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95%CI: 2.2–6.7); overall survival was 17.4 months (95%CI: 13.2–20.8). Seventeen patients (36%) had PFS>six months. Toxicity: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1.

Conclusions

Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.

This article provides an overview of recent advances in chemotherapy that may be used for the treatment of patients with locally advanced or metastatic breast cancer (mbc). Key phase ii and iii trial data for eribulin mesylate, ixabepilone, and nab-paclitaxel, published since 2006, are discussed on the basis of recency, depth, and quality.

Eribulin mesylate is the first monotherapy to significantly increase overall survival in patients with pretreated mbc, but nab-paclitaxel offers a novel and safer mode of delivery in comparison with standard taxanes. By contrast, the use of ixabepilone will be limited for now, until the associated neurotoxicity can be better managed. Alongside a brief overview of the other major chemotherapies currently in use, we have aimed to provide a Canadian context for how these novel agents may be integrated into clinical practice.

Background

There are few patient-reported data regarding quality of life after taxane-based adjuvant chemotherapy and none regarding mental health outcomes.

Methods

This was a naturalistic, longitudinal study that used a case–control design. Data were derived from a randomized clinical trial in patients who had stage II/III breast cancer (N = 227). Paclitaxel (Taxol) was approved for use midway during the accrual period (1994–1999). Patients who received taxanes as part of their adjuvant chemotherapy (the taxane group; n = 55) were matched with patients receiving regimens without taxanes (the no-taxane group; n = 83) on trial arm, lymph node status, surgery type, menopausal status, and partner status. Mixed-effects models tested for group differences in nurse evaluations of patients' symptoms and Karnofsky performance status and in patient-reported quality of life (the 36-item Medical Outcomes Study Short Form) and emotional distress (Profile of Mood States; Center for Epidemiological Studies Depression scale).

Results

As expected, patients in the taxane group experienced significantly higher rates of selected toxicities, including arthralgia/myalgia (45% vs 26%) and ataxia (20% vs 5%). Patients in the taxane group also had significantly worse emotional distress and mental quality of life throughout adjuvant treatment. Rates of probable clinical depression also were high. In contrast, these outcomes were improving for patients in the no-taxane group (all P <.023). Emotional recovery for patients in the taxane group required 2 years on average versus 6 to 12 months for patients in the no-taxane group. During Years 3 through 5, the groups had similar outcomes.

Conclusions

These data suggested that taxane-based chemotherapies confer risk for significant psychological symptoms. Depression, in particular, should be monitored.

Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL® (CrEL) and Tween 80® respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane®), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.

Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere, which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes.

Adjuvant chemotherapy reduces risk of relapse and cancer-related mortality in early stage breast cancer. Over the last decade, taxanes (paclitaxel and docetaxel) have been incorporated into various adjuvant trials and have demonstrated a significant benefit in the management of early stage breast cancer. Clinical trials using combinations of taxanes with targeted therapy have also shown considerable activity in breast cancer. This article reviews the pharmacology of docetaxel, a semi-synthetic taxane, and the clinical trials supporting its use in patients with node-positive breast cancer.

Background

Nab-paclitaxel is a solvent-free, taxane-based chemotherapy approved for the treatment of metastatic breast cancer (mbc). This study reports clinical benefit and toxicities experienced by women with mbc treated with nab-paclitaxel at the Ottawa Hospital Cancer Centre.

Methods

Women with mbc treated with single-agent nab-paclitaxel between June 2006 and December 2010 were included in this analysis. Retrospective data obtained included demographics, disease characteristics, prior chemotherapy, nab-paclitaxel treatment, toxicity, and survival. Clinical benefit was defined as partial or complete response or stable disease (by clinical or radiologic evaluation, or both) at 6 months or more.

Results

Of 43 women (mean age: 57.0 years; range: 34–74 years), most had disease positive for estrogen or progesterone receptor (72.1%, 58.1%), or both. Nab-paclitaxel was administered weekly (qw: 44.2%), every 3 weeks (q3w: 46.5%), q3w switched to qw (7.0%), or qw switched to q3w (2.3%). Median duration of therapy was 5.1 months (qw) and 3.0 months (q3w). Sensory neuropathy was the primary toxicity (45.4% qw, 38.1% q3w; p = 0.62). Clinical benefit was observed in most women (76.2% qw, 57.1% q3w; p = 0.20). Women receiving nab-paclitaxel had a median overall survival of 13.6 months qw (range: 8.1–28.3 months) and 10.8 months q3w (range: 5.9–17.9 months; p = 0.03). Regardless of dosing schedule, women experiencing clinical benefit lived significantly longer than those not experiencing a benefit (17.3 months vs. 7.7 months; hazard ratio: 0.14; 95% confidence interval: 0.06 to 0.33).

Conclusions

Our clinical experience demonstrates that most women treated with nab-paclitaxel experienced some clinical benefit. Patients achieving clinical benefit lived significantly longer than those who did not. Nab-paclitaxel was well tolerated, with the primary toxicity being mild sensory neuropathy. Nab-paclitaxel represents another treatment option, with a favourable toxicity profile, for women with mbc.

Purpose

We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.

Patients and Methods

A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death.

Results

There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible.

Conclusion

This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m−2 q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9–43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2–7.2), median progression-free survival was 3.7 months (95% CI: 2.8–4.2) and median overall survival was 14.3 months (95% CI: 9.2–19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.