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Metronomic Schedule of Paclitaxel Is Effective in Hormone Receptor–Positive and Hormone Receptor–Negative Breast Cancer

Rita S. Mehta, Donna Jackson, Toni Schubbert Department of Medicine, Division of Hematology and Oncology, University of California Irvine, Irvine, CA
To the Editor:
Hugh et al¹ are to be lauded for their comprehensive analysis of the benefit estimation of a docetaxel-based regimen compared with the standard fluorouracil-based regimen in various breast cancer subsets. After comparing trials in which paclitaxel rather than docetaxel was used, they suggest that the benefit seen with docetaxel in hormone receptor–positive subsets may have resulted from either docetaxel being a more efficacious taxane, or a docetaxel-specific schedule that was better than the schedule of paclitaxel once every 3 weeks. However, they do not expand on paclitaxel scheduling; we believe this is a crucial omission in their discussion. In fact, missing from their discussion is a major phase III randomized trial that clearly established the superiority of paclitaxel once per week over paclitaxel once every 3 weeks,² whereas the overall survival benefit of docetaxel once every 3 weeks over paclitaxel once every 3 weeks has yet to be demonstrated. In fact, the superiority of paclitaxel once per week over paclitaxel once every 3 weeks was first predicted by Green et al,³ who showed paclitaxel once per week compared with paclitaxel once every 3 weeks increased pathologic complete response—a surrogate of disease-free and overall survival—in the neoadjuvant setting in operable breast cancer, in both hormone receptor–positive and hormone receptor–negative subsets. In the confirmatory trial by Sparano et al,² which evaluated the 5-year disease-free and overall survival end points and compared the two taxanes and the two taxane schedules in a 2 x 2 factorial design, paclitaxel once per week compared with paclitaxel once every 3 weeks significantly improved 5-year progression-free survival in hormone receptor–negative breast cancer, including triple-negative and human epidermal growth factor receptor 2 (HER2) –positive subsets of breast cancer, and hormone receptor–positive breast cancer, which combines luminal-A and luminal-B subtypes of breast cancer. This was seen despite the fact that patients with HER2-positive breast cancer (including luminal-B breast cancer, an HER2-positive subtype) were preferentially enrolled onto the alternate trastuzumab trials; these patients were more likely to have chemotherapy-sensitive disease and therefore more likely to benefit from weekly paclitaxel. It is likely that the small subgroup of patients with hormone receptor–positive breast cancer with low Ki-67 proliferation index that did not benefit from a docetaxel-based regimen in the study by Hugh et al¹ may not have benefited from paclitaxel once per week either. This subgroup may be akin to the group identified by multigene assay that did not benefit from first-generation chemotherapy regimens. Until this subset of patients who will not benefit from paclitaxel once per week is identified, weekly paclitaxel after anthracyclines should be standard in all subsets of breast cancer, including triple-negative, hormone receptor–positive (estrogen receptor–positive and/or progesterone receptor–positive and either HER2-positive and/or Ki67^high breast cancer), HER2–positive, and luminal-A (estrogen receptor–positive and/or progesterone receptor–positive but not HER2-positive or Ki67^high breast cancer)^2–7 breast cancer. Moreover, drug-specific optimal schedules of chemotherapy must always be compared when comparing across trials and/or assessing outcome in different subsets of breast cancer, because optimal schedules of various chemotherapies are an important advancement in the treatment of various malignancies, demonstrated convincingly in Ewing's sarcoma and ovarian cancer,^8,9 in addition to breast cancer.


http://clincancerres.aacrjournals.or...2/14/4331.full
Influence of Formulation Vehicle on Metronomic Taxane Chemotherapy: Albumin-Bound versus Cremophor EL–Based Paclitaxel

1. Sylvia S.W. Ng1,
2. Alex Sparreboom2,
3. Yuval Shaked1,
4. Christina Lee1,
5. Shan Man1,
6. Neil Desai3,
7. Patrick Soon-Shiong3,
8. William D. Figg2 and
9. Robert S. Kerbel1

+ Author Affiliations

1. Authors' Affiliations:¹Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; ²Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, NIH, Bethesda, Maryland; and ³Abraxis BioScience, Santa Monica, California

1. Requests for reprints:
   Robert S. Kerbel, Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Room S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada, M4N 3M5. Phone: 416-480-5711; Fax: 416-480-5884; E-mail: Robert.Kerbel@sri.utoronto.ca.

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Abstract

Purpose: Low-dose metronomic chemotherapy treatments, especially when combined with ‘dedicated’ antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL–free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem.

Experimental Design: The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts.
Results: ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol.
Conclusions: Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.



An alternative dosing regimen to pulsatile maximum tolerated dose (MTD) or “dose dense” and dose-intensive chemotherapy is “metronomic chemotherapy”: the frequent administration of such drugs at close regular intervals with no prolonged breaks over long periods of time (1). The reduced toxicity and comparable or even increased efficacy of metronomic regimens compared with some MTD counterparts have been shown in a number of preclinical models (2, 3). In addition, metronomic chemotherapy regimens are particularly well suited for long-term combination with relatively non–toxic-targeted biological therapeutics especially antiangiogenic drugs (4, 5), sometimes being used after an initial short course of MTD chemotherapy (i.e., “chemo-switching” protocols; refs. 4, 6). Some phase II clinical trials have been reported with encouraging results, both in terms of antitumor efficacy and reduced toxicity, although such results need to be validated in larger randomized phase II or III trials (7–9). These trials have involved combinations of two metronomically given drugs [e.g., cyclophosphamide and methotrexate (7) or cyclophosphamide and etoposide (8)] given orally on a daily basis, or similar protocols in combination with a drug such as bevacizumab (Avastin), the anti-vascular endothelial growth factor antibody (9).
Virtually every class of chemotherapeutic drug has been reported to have antiangiogenic properties (10), which in many cases can be amplified by metronomic dosing schedules (1). However, the selection of chemotherapeutic drugs for metronomic regimens remains somewhat arbitrary. It is not clear whether some agents or classes of agents are better suited for metronomic chemotherapy than others. Taxanes, such as paclitaxel, would seem to be excellent candidates based on the finding that ultra low (e.g., picomolar) concentrations of paclitaxel can selectively inhibit endothelial functions relevant to angiogenesis, or even kill such cells (11–15). In addition, long-term metronomic chemotherapy using microtubule-inhibiting taxanes as opposed to mutagenic and hence potentially carcinogenic DNA damaging drugs, such as alkylating agents, could also be an advantage, especially in patients receiving adjuvant metronomic therapy regimens over long periods of time for early-stage disease (16). Furthermore, taxane metronomic chemotherapy may be useful to combine with metronomic chemotherapy using another class of drug, such as anti-metabolites (e.g., UFT, the oral 5-fluorouracil prodrug; ref. 16). For example, we have recently reported that a concurrent combination of daily oral low-dose UFT and cyclophosphamide can successfully control highly advanced visceral metastases of human breast cancer in immunodeficient mice, whereas UFT or cyclophosphamide used alone could not (17). However, clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol were previously reported to nullify the antiangiogenic activity of paclitaxel, suggesting that this agent or other anticancer drugs formulated in cremophor EL and other commonly used solubilization vehicles, such as polysorbate 80 (Tween 80), may need to be used at much higher doses than anticipated to achieve effective metronomic chemotherapy (18). As such, the advantage of reduced acute serious side effects associated with low-dose paclitaxel regimens versus conventional MTD paclitaxel may be compromised. Clearly, the presence of cremophor EL in Taxol hampers the use of paclitaxel in metronomic chemotherapy. This may explain, for example, the results of Klement et al. (19), in which metronomic Taxol on its own had little obvious effects on transplanted primary human breast tumors in several models.
ABI-007 (Abraxane), a novel cremophor EL–free, albumin-bound, 130-nm form of paclitaxel, was developed to retain the therapeutic benefits of paclitaxel but eliminate cremophor EL–associated toxicities in the Taxol formulation. Several clinical trials have shown the improved pharmacokinetic and toxicity profiles as well as therapeutic efficacy of ABI-007 over Taxol in MTD regimens (20–24). We hypothesized that the cremophor EL–free nature of ABI-007 may render paclitaxel-based metronomic chemotherapy feasible. With this in mind, the primary objective of this study was to evaluate the therapeutic potential of paclitaxel-based metronomic regimens using ABI-007.



Discussion

Our results show that metronomic chemotherapy using albumin-bound nanoparticle paclitaxel (ABI-007), but not paclitaxel formulated in cremophor EL (Taxol), exhibits potent in vivo antitumor activity. It was previously reported that clinically relevant concentrations of formulation vehicles, such as cremophor EL, nullify the in vitro antiangiogenic effect of taxanes (18). Paclitaxel at 4 nmol/L dissolved in DMSO but not in cremophor EL suppressed rat aortic angiogenesis and HUVEC proliferation (18). In the present study, ABI-007 at 5 nmol/L induced responses similar to those elicited by paclitaxel at 4 nmol/L dissolved in DMSO, indicating that the antiangiogenic property of paclitaxel was effectively delivered by cremophor EL–free ABI-007. Desai et al. (32) recently showed that paclitaxel in ABI-007 is actively transported into and across endothelial cells by gp60 (a specific albumin receptor)–mediated caveolar transcytosis, a process that is inhibited by cremophor EL in Taxol.
One cycle of either MTD ABI-007 or MTD Taxol was shown herein to cause marked tumor growth inhibition and transient regression in two different xenograft models (MDA-MB-231 and PC3). However, MTD Taxol–treated tumors rapidly resumed growth 3 weeks after the last dose of drug (day 42), whereas the growth of MTD ABI-007–treated tumors continued to be suppressed. The ability of MTD ABI-007 but not MTD Taxol to significantly reduce viable CEPs in MDA-MB-231 tumor-bearing mice might contribute, at least in part, to the enduring antitumor effect of the former. A higher paclitaxel plasma clearance and a larger volume of distribution for ABI-007 than for Taxol was recently reported in humans (33) as well as more rapid cellular uptake and binding (32), suggesting that paclitaxel in the ABI-007 formulation might be more effective against CEPs than Taxol. Higher intratumoral paclitaxel concentration achieved by the ABI-007 formulation could be another contributing factor (32, 33). We cannot explain why there was a lack of a significant decrease in viable CEPs by MTD ABI-007 in PC3 tumor-bearing mice. The possibility that the s.c. PC3 tumors might be less dependent on recruitment of CEPs for angiogenesis compared with the orthotopic MDA-MB-231 tumors cannot be excluded.
The significant weight loss and transient paralysis associated with MTD ABI-007 treatment and the absence of cremophor EL in the formulation prompted us to explore the feasibility of using ABI-007 in metronomic regimens as a less toxic but still highly effective antitumor alternative, one that would be well suited for long-term combination with other drugs, such as vascular endothelial growth factor–targeted antiangiogenic drugs (4, 6).
....
metronomic ABI-007 at 3 to 10 mg/kg given i.p. daily for 4 weeks effectively inhibited MDA-MB-231 and PC3 tumor growth. The observed decrease in tumor volume was accompanied by a dose-dependent reduction in viable CEP levels in both xenograft models. It should also be noted that the total dose of ABI-007 given over 4 weeks in the metronomic regimen, especially in the 10 mg/kg/d treatment group, was substantially higher than that given over 5 days in the MTD regimen (280 versus 150 mg), and yet no significant weight loss was evident in the former. In marked contrast, metronomic Taxol failed to suppress tumor growth or significantly alter viable CEP levels.

...A trend of decreasing angiogenesis with increasing metronomic ABI-007 doses was evident, whereas MTD Taxol and MTD ABI-007 did not seem to block angiogenesis, although statistical significance was not reached with any treatment. Viable CEP levels may be a more sensitive marker than intratumoral microvessel density or Matrigel plug angiogenesis in the evaluation of response to treatment modalities with an antiangiogenic/antivasculogenic component. Although the mechanistic basis of metronomic chemotherapy is thought to be primarily antiangiogenic (2–4, 30), recent evidence showed that long-term metronomic chemotherapy in mice using cyclophosphamide can also stimulate immune responses by augmenting memory T cells and depleting both regulatory and suppressor T cells (35). We cannot exclude the possibility that metronomic chemotherapy using paclitaxel may also induce similar immunomodulatory responses. It is becoming increasingly clear that metronomic chemotherapy regimens exert multiple effects in addition to angiogenesis inhibition. In summary, we have shown that paclitaxel in the absence of cremophor EL is a viable and effective drug for metronomic chemotherapy. The therapeutic potential of metronomic ABI-007 given alone or in combination with other anticancer and/or antiangiogenic agents warrants investigation in the clinical setting. Our findings especially underscore the importance of selecting an optimal formulation strategy for cytotoxic drugs (and other investigational agents) to be used in metronomic chemotherapy regimens. Clearly, the potential of the nanoparticle albumin-bound technology extends beyond paclitaxel. For instance, Nab-028, the novel taxane ABI-028 formulated as albumin-bound nanoparticles, showed improved efficacy and lower toxicity than ABI-028 formulated in Tween 80 (36). 17-(Allylamino)-17-demethoxygeldanamycin, a hydrophobic drug that inhibits HSP90 and shows poor tolerability when solubilized in a DMSO-egg lecithin vehicle, was successfully prepared as an albumin-bound nanoparticle formulation suitable for i.v. administration (37). Finally, with respect to the use of taxanes in metronomic chemotherapy regimens, a comparison of nanoparticle-based formulations, such as ABI-007, with orally bioavailable taxanes (e.g., BMS-275183) would seem timely because our results suggest that metronomic chemotherapy with low-dose, cremophor EL–free taxanes should be feasible and effective.


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