Metastatic breast cancer survival rates are improving with advances in methods of staging, screening and treatment
BPharm MSc MRPharmS
The Rivers Hospital
High Wych Road
Metastatic breast cancer survival rates are improving with advances in methods of staging, screening and of course treatment.
Important advances means clinicians now have more options for managing stage IV breast cancer. This article examines improvements in response and survival rates with the use of Abraxane, a solvent-free chemotherapy treatment that uses a novel technology to deliver the drug paclitaxel.
Metastatic breast cancer, or stage IV disease, is the most advanced type of breast cancer. Metastasis is the process by which cancer cells spread from the original tumour site-that is, the breast area-to different regions of the body. These cells migrate through the lymphatic system and blood vessels to form deposits in almost any part of the body. Regional metastases spread to the areas surrounding the breast, whereas in advanced disease metastases may reach distant organs-most commonly the lymph nodes, bones, lungs and liver.
Metastatic breast cancer survival rates are improving with advances in methods of staging, screening and treatment.
During the mid-1990s several trials showed paclitaxel and docetaxel to be among the most important agents, compared to the reference drug doxorubicin, in the treatment of metastatic disease. However, despite widespread use, both the taxanes were associated with significant toxicities such as alopecia, fatigue, myalgia, nail changes, myelosuppression, neuropathy and hypersensitivity reactions caused by the solvents used to solubilise the active ingredient. These toxicities had an impact on duration of therapy and combination with other agents with overlapping toxicity.
This article illustrates improvements in response and survival rates with the use of Abraxane (ABI-007) – a 130-nm nanoparticle albumin-bound (nab)-form of paclitaxel – in metastatic disease. Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in patients who have failed first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated. Abraxane is supplied as a white to yellow, sterile, lyophilised powder for reconstitution with 20ml 0.9% sodium chloride prior to intravenous infusion. Each single-dose vial contains 100mg, yielding a suspension of 5mg/ml nab-paclitaxel and approximately 425mg sodium.
Gradishar et al reported a phase III trial which compared Abraxane with conventional polyethoxylated castor oil-based paclitaxel. This study compared antitumour activity as well as safety/tolerability in metastatic disease. Abraxane 260mg/m2 IV over 30 minutes with no standard premedication was compared with paclitaxel 175mg/m2 IV over three hours with standard dexamethasone and antihistamine premedication. In all treated patients, the response rates-complete, CR and partial, PR-were 33% and 19%, respectively p=0.001. Abraxane also significantly prolonged time to disease progression, median 23 weeks (19.4-26.1) compared to 16.9 weeks (15.1-20.9). Abraxane significantly prolonged overall survival, OS median 56.4 weeks (45.1-76.9) compared to 46.7 weeks (39.0-55.3). Abraxane was well tolerated, with improved haematological toxicities but worse sensory neuropathy – 20% grade 2 compared to 10% in the conventional paclitaxel group.
This aspect of Abraxane toxicity was shown to improve rapidly. Of 24 patients (10%) with grade 3 neuropathy, 14 had rapid improvement with a median time of 22 days vs 79 days with conventional paclitaxel. Only 3% (6/233) discontinued Abraxane due to sensory neuropathy-there was no motor neuropathy. This trial clearly demonstrated that even without conventional premedication there were no serious hypersensitivity reactions.
Paclitaxel was compared with docetaxel in a randomised trial reported in 2005. Jones et al demonstrated superior time to progression (TTP, 5.7 vs 3.7 months) p<0.0001 and OS (15.4 vs 12.7 months) p=0.03 with a trend (p= 0.1) towards superior response rates. Higher rates of neutropenia and febrile neutropenia were, however, associated with the docetaxel group.
This trial was probably fundamental in the development of docetaxel as the agent of choice, toxicities accepted, when using a taxane in the first-line metastatic setting. Gradishar reported the activity of Abraxane to be broadly equivalent to docetaxel, though less myelosuppressive and easier to administer.
The poor water solubility of taxanes, which require a solvent to achieve an aqueous solution for administration, is key to the challenges faced in administering them. Paclitaxel was formulated with polyethoxylated castor oil (Cremophor EL), while docetaxel required polysorbate 80 (Tween 80) and ethanol. These solvents are responsible for some of the taxane toxicities-particularly hypersensitivity and neurotoxicity. The leaching of plasticisers from infusion bags and giving sets by Cremophor EL may contribute to neurotoxicity, and also results in the need for corticosteroid and antihistamine premedication. It is also known that this solubiliser may entrap paclitaxel with the formation of micelles. This has the effect of reducing the penetration of the active agent into tumour sites and may explain the lack of dose response seen with paclitaxel. Increasing the dose does not lead to increased response, only increased toxicity.
Thus the formulation of a solvent-free paclitaxel using nano-sized particles coated with albumin has facilitated delivery of the active agent to the tumour. These particles bind to gp60 receptors on the vascular endothelium in exactly the same way as normal albumin. An activated receptor leads to the formation of caveolae, which transport the cytotoxic agent inside the cell. A protein SPARC (secreted protein acidic and rich in cysteine) effectively concentrates the albumin-coated particles at the tumour cell. Hence, the natural biology of the tumour cell is harnessed to deliver the active agent to the cell and the site of action. SPARC may well be an important biomarker as it is overexpressed in many tumour types, and in breast cancer can be associated with poorer outcomes. It is this mode of action that effectively delivers about 35% more active agent compared to conventional paclitaxel.
In the Cancer and Leukaemia Group B (CALGB) 9342 study, no difference in efficacy was seen with increased doses of solvent-based paclitaxel-although toxicity was greater with higher dose. Seidman et al demonstrated that paclitaxel activity is influenced by dosing schedule, with a weekly schedule showing a higher response rate than a three-weekly one. There was no difference in TTP or OS.
Rivera et al reported the results of a trial comparing conventional three-weekly to weekly docetaxel, which, contrary to the results seen with paclitaxel, showed improved response with the conventional three-weekly regimen.
In a phase II study, Blum et al6 demonstrated in a taxane refractory population the prospect of administration of Abraxane weekly and at doses exceeding those used for solvent-based paclitaxel with excellent antitumour activity.
Gradishar et al then explored weekly Abraxane at 100mg/m2 and 150mg/m2 with Abraxane 300mg/m2 every three weeks and docetaxel 100mg/m2 every three weeks. Three hundred patients were randomised. The results were assessed by independent review and demonstrated statistically and clinically superior efficacy in terms of progression-free survival (PFS) for either weekly dose of Abraxane compared to the conventional three-weekly dose of docetaxel. The results also indicated a trend towards an improved overall response rate (ORR) for weekly Abraxane compared to three-weekly docetaxel (45-49% compared to 35%). Independent review and investigator-assessed disease control rate (DCR) showed evidence that DCR was significantly higher in patients receiving weekly Abraxane compared to docetaxel. Although not significantly different, the DCR for three-weekly Abraxane at 300mg/m2 response was reported as 10% higher than that for three-weekly docetaxel (68% vs 58%).
Abraxane 150mg/m2 demonstrated significantly prolonged PFS (>5 months) compared with docetaxel 100mg/m2 every three weeks in both independent (p=0.0065) and investigator (p=0.012) assessment. Median PFS was longer (>3 months) in the Abraxane 300mg/m2 group compared with the docetaxel group in both independent and investigator assessment, although this did not reach statistical significance.
Collectively, the efficacy data from this study suggest the superiority of Abraxane compared with conventional paclitaxel and docetaxel as well as the superiority of weekly over three-weekly administration regimens.
Overall, the Abraxane doses demonstrated a favourable safety profile. The rates of treatment-associated adverse events were higher in the docetaxel group for neutropenia, febrile neutropenia and fatigue compared with any dose of Abraxane. Alopecia and grade 3 or 4 sensory neuropathy were comparable between the Abraxane arms and docetaxel, although recovery occurred more rapidly after treatment with any Abraxane dose compared with docetaxel.
The enhanced efficacy and reduced toxicity of Abraxane may, in part, be explained by higher intracellular delivery of the active cytotoxic agent through the albumin-based nanoparticle technology.
These results suggest that weekly Abraxane may be an appropriate alternative to docetaxel in the treatment of metastatic breast cancer, although this is currently outside the licence. The technology offers the prospect of overcoming the limitations arising from the use of toxic solvents and the potential for increased efficacy without increased toxicity. Higher doses of the active agent can be administered using shorter infusion times and without the need for special infusion sets and corticosteroid and antihistamine premedication.
These positive data have initiated a range of studies to investigate combination therapy with other chemotherapy and biological agents known to have significant activity in metastatic breast cancer.
The expression of caveolin-1, a structural component on caveolae in breast cancer, is associated with triple-negative disease. In addition, the overexpression of SPARC may correlate with response to Abraxane. It is postulated therefore that patients with triple-negative disease may respond particularly well to this novel substance.
A number of questions have been answered. But I believe that many remain to be answered by future development of our knowledge of this novel approach to drug delivery.
1. Gradishar WJ, et al. J Clin Oncol 2005;23:7794-803.
2. Jones SE, et al. J Clin Oncol 2005; 23:5542-51.
3. Cancer and Leukaemia Group B (CALGB) 9342 study. J Clin Oncol 2004;22:2061-8.
4. Anglo Celtic IV trial. J Clin Oncol 26:1642-1649.
5. Rivera E, et al. Cancer 2008;112:1455-61.
6. Blum JL, et al. Clin Breast Cancer 2007;7:850-6.
7. Gradishar WJ, et al. J Clin Oncol 2009;27:3611-9.