Taxanes, paclitaxel and docetaxel, are among the most effective agents used to treat breast cancer. Nab-paclitaxel (ABI-007, Abraxane) is paclitaxel encapsulated in albumin. This differs from the more conventional formulation which uses cremophor to increase the solubility of paclitaxel (CrEL-paclitaxel). In a randomized trial that formed the basis of its regulatory approval in the USA, 3-weekly nab-paclitaxel induced a higher response rate and longer time to progression than CrEL-paclitaxel in patients with metastatic breast cancer. Except for grade 3 sensory neuropathy, nab-paclitaxel was also safer. An interim analysis from a more recent randomized Phase II trial suggests that weekly nab-paclitaxel is more effective and safer than either 3-weekly nab-paclitaxel or 3-weekly docetaxel. The superior efficacy of nab-paclitaxel is presumably due to the improved safety profile, which allows for the administration of higher doses, a greater proportion of which actually reaches the tumor. Observations on the development of nab-paclitaxel have important implications for our understanding of dose response in the use of cytotoxic drugs to treat all forms of cancer. Although it is not yet clear whether nab-paclitaxel can be routinely substituted for CrEL-paclitaxel or docetaxel in breast cancer treatment regimens, it seems highly likely that this will occur within the next 5 years.
"Randomised trials studying whether induction regimens consisting of a taxane, cisplatin and 5-fluorouracil (Tax-PF) were superior to cisplatin and 5-fluorouracil (PF) have shown significant reductions of progression, locoregional failure and distant failure with Tax-PF       . Nab-paclitaxel is a novel, cremophor-free, protein stabilised, nanoparticle formulation of paclitaxel, composed primarily of unmodified paclitaxel and human albumin  . This unique formation was developed to reduce toxicities associated with paclitaxel (and removal of cremophor solvent) whilst maintaining or improving its chemotherapeutic effect. "
[Show abstract][Hide abstract] ABSTRACT: Background
Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally-advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab-paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel.
A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel + cisplatin + 5-fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ⩾95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT.
17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44–65 years), 14 patients were male, and 11 patients’ tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment.
The recommended phase 2 dose of APF is nab-paclitaxel 100 mg/m2 days 1 and 8, cisplatin 75 mg/mg2 day 1 and 5-fluorouracil 1000 mg/m2/day × 96 h days 1–4, every 3 weeks, for three cycles prior to CRT.
"This leads to dose-proportional pharmacokinetics, higher maximal tolerated dose (MTD), and improved efficacy  . Nab-paclitaxel treatment of metastatic BC patients demonstrated a higher response rate and longer time to progression when compared with Cremophor-based drug  . The superior efficacy of nab-paclitaxel versus conventional paclitaxel was also shown in preclinical xenograft models demonstrating increased incidence of tumor regressions, longer time to recurrence, and extended survival . "
[Show abstract][Hide abstract] ABSTRACT: Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450-600 mm(3)) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance.
Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry.
Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-κB pathway that upregulates VEGF-A and other tumor prosurvival proteins.
Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-κB pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics.
Neoplasia (New York, N.Y.) 04/2011; 13(4):327-38. DOI:10.1593/neo.101490 · 4.25 Impact Factor
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