Introduction
Taxanes are among the most widely used chemotherapy agents in the treatment of early-stage and metastatic breast cancer (MBC) [
1‐
4]. Taxanes stabilize microtubules, leading to cell cycle arrest and, ultimately, cell death [
5‐
7]. Guidelines by the National Comprehensive Cancer Network currently list the taxanes solvent-based paclitaxel (sb-paclitaxel, Taxol; Bristol-Myers Squibb Co., Princeton, NJ, USA), docetaxel (Taxotere; sanofi-aventis US LLC, Bridgewater, NJ, USA), and
nab-paclitaxel (Abraxane; Celgene Corporation, Summit, NJ, USA) as agents recommended for the treatment of recurrent and MBC [
1].
sb-Paclitaxel and docetaxel have demonstrated clinical benefit in the treatment of breast cancer (BC); however, their chemical formulations have presented several limitations. Both sb-paclitaxel and docetaxel require the use of solvents to enhance their solubility (sb-paclitaxel is formulated in the castor oil derivative Cremophor EL (recently renamed Kolliphor EL; BASF Corporation, Florham Park, NJ, USA) and dehydrated ethanol, while docetaxel is formulated using the solvent polysorbate 80), and these solvents have been associated with hypersensitivity and other toxicities, including prolonged peripheral neuropathy [
8‐
10]. To ameliorate the risk of hypersensitivity reactions from solvents, patients are routinely pretreated with corticosteroids before receiving either drug [
3,
4]. These solvent vehicles also impair drug delivery to the tumor, limiting their clinical effectiveness [
10]. Further, sb-paclitaxel displays more-than-dose-proportional increases in systemic drug exposure over a narrow dose range [
11‐
14]. This nonlinear dose-responsiveness pattern is most likely explained by the entrapment of paclitaxel in solvent micelles [
14,
15]. In patients with MBC, no significant dose–response relationship was observed with increasing doses of sb-paclitaxel administered every 3 weeks (q3w; response rates of 23 %, 26 %, and 21 % for 175, 210, or 250 mg/m
2 doses, respectively) [
16]. Although time to progression did significantly increase with increasing dose (
P = 0.045), this effect was not apparent in a multivariate analysis that included dose and covariates such as estrogen receptor status, line of therapy, number of metastatic sites, performance status, and prior treatment. There were no significant differences in overall survival (OS) among the doses, and the increasing dose of sb-paclitaxel resulted in a higher incidence of toxicities, including neutropenia, neuropathy, and alopecia.
nab-Paclitaxel, an albumin-bound form of paclitaxel, is solvent free and was designed to improve the therapeutic index of paclitaxel (that is, to increase antitumor activity and reduce toxicities such as hypersensitivity reactions) [
2,
17]. Compared with sb-paclitaxel,
nab-paclitaxel has demonstrated enhanced transport across endothelial cell monolayers and greater tumor delivery of paclitaxel in preclinical models [
17]. A phase I dose escalation study of patients with solid tumors determined that the maximum tolerated dose of
nab-paclitaxel administered q3w was 300 mg/m
2, and treatment at this dose resulted in two partial responses in patients with BC and prior exposure to sb-paclitaxel [
18]. Dose-limiting toxicities included sensory neuropathy, stomatitis, and superficial keratopathy. In a phase II trial of patients with MBC,
nab-paclitaxel at the maximum tolerated dose q3w resulted in a 48 % overall response rate (ORR) for all patients and a 64 % ORR for chemotherapy-naïve patients [
19]. In a pivotal phase III trial of patients with MBC,
nab-paclitaxel at a slightly lower dose of 260 mg/m
2 demonstrated superior antitumor activity compared with sb-paclitaxel 175 mg/m
2 (both administered q3w) [
20]. In 2005,
nab-paclitaxel was approved for the treatment of MBC after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy [
2]. Prior therapy should have included an anthracycline unless clinically contraindicated. The recommended starting dose of
nab-paclitaxel for the treatment of MBC is 260 mg/m
2 administered intravenously over 30 min q3w.
Despite a higher drug cost than other taxanes,
nab-paclitaxel appeared to be cost-effective in health economic studies. In fact, a meta-analysis of clinical and safety data from randomized trials in MBC found that both the number of grade 3/4 toxicities and resulting management costs were lower for
nab-paclitaxel relative to docetaxel and sb-paclitaxel [
21]. The cost-effectiveness of
nab-paclitaxel in MBC has also been demonstrated in model-based and retrospective analyses [
22,
23].
Weekly sb-paclitaxel administration appears to be the optimal schedule for treatment of MBC. Weekly sb-paclitaxel resulted in superior efficacy compared with treatment q3w in patients with MBC (ORR: 42 % vs 29 %,
P = 0.0004; time to progression: 9 vs 5 months,
P < 0.0001; and OS: 24 vs 12 months,
P = 0.0092 for weekly vs q3w, respectively) [
24]. This schedule was also superior to treatment q3w in the adjuvant setting after standard administration of doxorubicin plus cyclophosphamide (AC) [
25].
Initial evidence suggested that a weekly
nab-paclitaxel regimen could also be feasible for patients with MBC. A phase I trial of
nab-paclitaxel administered weekly for 3 consecutive weeks followed by 1 week of rest (that is, during the first 3 of 4 weeks (qw 3/4)) demonstrated the feasibility of this schedule in patients with advanced solid tumors, and established the maximum tolerated doses for this
nab-paclitaxel regimen to be 100 mg/m
2 for heavily pretreated patients and 150 mg/m
2 for lightly pretreated patients (
n = 39, nine patients with BC) [
26]. Dose-limiting toxicities included grade 4 neutropenia and grade 3 peripheral neuropathy, and a partial response was noted in one patient with BC. The positive results observed with weekly sb-paclitaxel and promising results from the phase I trial of
nab-paclitaxel administered qw 3/4 has led many to question whether weekly dosing might be preferable to a schedule q3w for
nab-paclitaxel.
Here we review the experience to date with nab-paclitaxel-based therapy for the treatment of BC, with the goal of understanding the optimal dose/schedule of nab-paclitaxel in both the metastatic and early-stage settings.
Conclusions
nab-Paclitaxel is approved for MBC at a dose of 260 mg/m
2 q3w [
2]. However, numerous studies have suggested that a schedule qw 3/4 could also be a reasonable option. In fact, a phase II trial demonstrated better ORRs for qw 3/4 regimens (100 mg/m
2 and 150 mg/m
2) versus a q3w regimen as monotherapy [
29,
30]. The 100 mg/m
2 dose demonstrated a more manageable tolerability profile compared with either of the other regimens, with lower rates of grade 3/4 neutropenia, sensory neuropathy, and fatigue, whereas the 150 mg/m
2 dose demonstrated the longest OS, albeit with considerably more toxicity [
30].
Some data in this review call into question whether intense regimens of
nab-paclitaxel are the most appropriate approach for MBC, particularly in combination with bevacizumab, since delaying disease progression is the main aim of therapy. High rates of dose modification and discontinuation were observed with
nab-paclitaxel 150 mg/m
2 monotherapy qw 3/4 in a phase II trial and with
nab-paclitaxel 150 mg/m
2 qw 3/4 plus bevacizumab in a phase III trial [
29,
30,
33]. Toxicity also limited delivery of
nab-paclitaxel at 260 mg/m
2 q2w and 130 mg/m
2 weekly uninterrupted, both in combination with bevacizumab, in a phase II trial [
31].
In contrast to treatment for MBC,
nab-paclitaxel at 260 mg/m
2 q2w plus bevacizumab for early-stage disease was feasible [
31,
44,
45]. The question of whether a drug-drug interaction exists between
nab-paclitaxel and bevacizumab has not been examined. However, it is unlikely that future MBC trials will test the combination since the US Food and Drug Administration approval of bevacizumab for MBC has been withdrawn [
46].
Patients who were treated with neoadjuvant
nab-paclitaxel 150 mg/m
2 qw 3/4 in the GEICAM 2011–2012 trial experienced less toxicity compared with the patients treated with the same regimen in the metastatic setting described above. The only grade 3/4 toxicity reported by >5 % of patients in the neoadjuvant trial was neutropenia (16 %), and the median relative dose intensity was 98.5 % [
39]. Grade 3 sensory neuropathy occurred in two patients (2.5 %), and there were no cases of grade 4 neuropathy [
39]. Furthermore, the regimen was effective, eliciting a clinical response rate of 77 % and a 25 % rate of residual cancer burden 0 or 1 [
38]. In the GeparSepto trial, the weekly
nab-paclitaxel dose had to be reduced from 150 mg/m
2 to 125 mg/m
2, resulting in a 38 % pCR rate and grade 3/4 sensory neuropathy in 10 % of patients [
36]. Thus, although the 150 mg/m
2 qw 3/4 dose may be questionable in MBC, results were mixed for this regimen as a neoadjuvant treatment option.
Numerous studies have revealed substantial clinical activity for
nab-paclitaxel in the metastatic setting, and a growing number of reports suggest similar activity in early-stage disease. Optimizing regimens in BC treatment depends on a number of patient-specific and disease-specific factors. Although multiple schedules and doses have demonstrated feasibility and activity, single-agent
nab-paclitaxel may be preferable to combination therapy for unselected patient populations. Ongoing and future trials will reveal whether combination therapies are advantageous for patients with aggressive disease subtypes [
47].
Competing interests
MM has participated in Celgene advisory boards and received honoraria for his involvement.