Hamid R. Mirshahidi* Loma Linda University Cancer Center and School of Medicine, Loma Linda, CA

  ABSTRACT

A number of chemotherapy options are available in metastatic breast cancer. Many of the regimens are found to be beneficial as single agents and some are effective as combination agents. In majority of the patients, since the goal of treatment is palliation, it is important to consider the side effects, patient preference, and quality of life, in addition to efficacy, before finalizing the chemotherapy plans. In general, single-agent chemotherapy regimens are preferred over combination agents for the same reason. But in patients with rapidly progressing disease, combination regimens may be used.

Keywords: metastatic breast cancer, management, chemotherapy, ixabepilone, albumin-bound paclitaxel, vinorelbine, paclitaxel, docetaxel, capecitabine, gemcitabine, pegylated liposomal doxorubicin

  INTRODUCTION

Metastatic breast cancer (MBC) is a heterogeneous disease that has a diversity of different clinical presentation, varying from an oligometastatic disease to diffuse and multiple organ involvement. Despite advances in detection, adjuvant therapy, and the understanding of the molecular bases of breast cancer biology, approximately 30% to 50% of patients with early-stage breast cancer develop recurrent and metastatic disease (1, 2).

Overall, survival of patients with MBC is slowly but steadily improving, and the risk of death is decreasing by 1% to 2% each year (3, 4). The greatest advance is probably associated with the development and widespread availability of current systemic therapies. However, earlier diagnosis of metastatic disease may also result in a lead time bias, deceptively improving the overall survival (OS) (3). An increasing number of randomized clinical trials showed statistically significant improvements in disease control with chemotherapy in MBC, and a small but identifiable group of patients also achieved long-term remission.

Both monotherapy (Table 1) and combination chemotherapy regimens (Table 2) have been studied in patients with MBC. Combination regimens have been used for the treatment of rapidly progressing disease to achieve fast response rates (RRs) and possible improvement in progression-free survival (PFS) and OS. However, combination chemotherapy regimens may increase toxicity and related side effects (5).

TABLE 1

Ixabepilone is a member of epothilones, a novel class of antineoplastic agents that stabilize microtubule dynamics and induce cell cycle arrest at G2/M phase and apoptosis (6, 7). A unique property of ixabepi-lone is its ability to inhibit the growth of cells and tumors that overexpress drug efflux transporters and/or β-tubulin III or mutant β-tubulin III iso-types, both of which are associated with primary and acquired resistance to taxanes (8, 9). Ixabepilone at 40 mg/m² every 3 weeks has shown efficacy across all lines of treatment in a variety of patients with breast cancer. The early phase II trials showed efficacy of ixabepilone in patients with MBC who were taxane-naïve or anthracycline, taxane, and capecitabine resistant, as well as in patients with primary taxane resistance. Overall response rate (ORR) in patients who were resistant to anthracyclines, taxanes, and capecitabine was around 12%, with a median PFS, time to progression (TTP), and OS of 3.1, 2.2, and 7.9 to 8.6 months, respectively (10, 11). ORR, median TTP, and OS in patients who had received prior adjuvant anthracyclines and taxanes were 41.5%, 4.8 and 22.0 months, respectively (12).

Consequently, ixabepilone monotherapy was approved for treatment of MBC as third-line therapy in patients who are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Alternate dosing of single-agent ixabepilone has also been evaluated in MBC. In a phase II trial, 37 patients received ixabepilone 6 mg/m² intravenously (IV) over 1 hour on days 1 to 5 every 3 weeks. All patients in this study had received prior taxane-based chemotherapy. ORR, median duration of response, and TTP were 22.0%, 3.9, and 2.6 months, respectively (13). This regimen was also evaluated in 23 taxane-naive patients who had received prior anthracyclines and capecitabine. ORR, median duration of response, and TTP were 57.0%, 5.6 and 5.5 months, respectively (14). Weekly ixabepilone (15 mg/m² for 3 weeks with a 1-week break) was also active and well tolerated when paired with bevacizumab or carboplatin and trastuzumab (15, 16). The weekly regimen resulted in lower rate of grade 3 peripheral neuropathy and grade 3/4 neutropenia.

Two phase III studies compared combination of ixabepilone and capecitabine with capecitabine monotherapy. Ixabepilone in CA163–046 trial (the Anthracycline/Taxane [A/T]-resistant study) improved PFS significantly and doubled ORR. The difference in median OS was not statistically significant; however, it favored combination regimen (12.9 vs 11.1 months; hazard ratio [HR] = 0.9, and P = .19). Based on predefined subset analyses, combination arm showed a clinically meaningful increase in OS in patients with Karnofsky performance status (KPS) of 70% or 80% (HR = 0.75) (17–19). The results of the second study (the A/T pretreated study) were published recently. This study was conducted in tandem with the first trail. Patients did not require the specific chemotherapy resistance criteria used in the A/T-resistant study. The combination improved median PFS (6.2 vs 4.2 months; HR = 0.79; P = .0005) and RR (43% vs 29%; P <.0001), significantly. Unfortunately, there was no statistically significant difference in OS between the two arms. However, median OS in symptomatic patients with KPS of 70% or 80% and also adjusted OS for baseline covariates (including PS) were improved significantly (HR = 0.76 and HR = 0.85, with P = .0231, respectively) (20).

The efficacy of ixabepilone monotherapy or combination therapy with capecitabine in patients with pretreated and/or resistant triple-negative MBC was also comparable with the efficacy observed in the overall populations (21).

The most frequent grade 3 and 4 adverse events associated with ixabepilone are neutropenia (53–58%), peripheral sensory neuropathy (12–20%), and fatigue (6–27%), and febrile neutropenia (≤6%). Peripheral sensory neuropathy is generally reversible after dose reduction. The median time to resolution to baseline or grade 1 is 5.4 to 6 weeks. Ixabepilone dose reductions are recommended in patients with mild to moderate hepatic impairment (11,12,17,18,20). A dose of 40 mg/m² could be reduced to 32 mg/m² and subsequently to 25 mg/ m2 should toxicities arise.

Albumin-bound paclitaxel (ABP) is a Cremophor-free formulation of paclitaxel designed to increase drug delivery to tumors via endothelial cell transcytosis (22, 23). Activity of single-agent ABP was evaluated in phase II/III trials in patients with MBC. ABD was administered at 260 to 300 mg/m² on day 1 every 3 weeks or 100 to 125 mg/m² on days 1, 8, and 15 every 4 weeks in these studies. ORR in these studies varied between 12% and 48% (23–25). The highest RR (48%) was observed in patients treated with high-dose ABP (300 mg/m² every 3 weeks). The RR in patients who received this agent as first-line chemotherapy was 64%, with median TTP and OS of 6.7 and 15.9 months, respectively (23).

A phase III trial compared the efficacy of ABP (260 mg/m²) versus standard paclitaxel (175 mg/m²) in patients who had not received prior taxanes in the metastatic setting or relapsed within 12 months of adjuvant taxane therapy. The difference in ORR (33% vs 19%; P = .001) and median TTP (5.8 vs 4.2 months; HR = 0.75; P = .006) was statistically significant. Median OS was not significantly different (16.3 vs 13.9 months; P = .374); however, it was in favor of ABP (24).

The efficacy and safety of ABP administered at 300 mg/m² every 3 weeks, 100 mg/m² or 150 mg/m² weekly, were tested against docetaxel (100 mg/m², every 3 weeks) in patients with previously untreated MBC. Compared with docetaxel, weekly ABP (150 mg/m²) demonstrated a significantly longer PFS by independent radiologist assessment (12.9 vs 7.5 months, P = .0065). Both weekly doses of ABP demonstrated higher RR (49% in 150 mg/m² and 45% in 100 mg/m²) compared with docetaxel (35%). By contrast, no difference in PFS and ORR was observed in high-dose every-3-weeks ABP over standard dose of docetaxel (26).

ABP has not been studied in patients with hepatic or renal dysfunction, and the appropriate dose of albumin–ixabepilone in patients’ bilirubin > 1.5 mg/dL is not known. Therefore, caution should be exercised when treating patients with hepatic dysfunction.

Grade 3 and 4 toxicities associated with ABP are neutropenia (18–51%) and peripheral sensory neuropathy (8–19%). Weekly administration is associated with a higher incidence of grade 3 and 4 peripheral sensory neuropathy (19%) than the every-3-week regimens (2–11%). The increase in neuropathy is attributed to administration of a higher dose of paclitaxel in the ABP arm.

Vinorelbine

Vinorelbine is a semisynthetic vinca alkaloid with some activity in MBC after failure of anthracyclines and taxanes. Vinorelbine monotherapy (20–30 mg/ m2 weekly) was evaluated as first- and second-line therapy in patients with MBC as well as in pretreated patients with anthracycline and taxanes. ORR in these studies varied between 16% and 47% (27

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