Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 4 de noviembre del 2005
ABI-007 (brand name Abraxane™) is a protein-bound form of the popular chemotherapy drug paclitaxel (brand name Taxol®)). Standard paclitaxel is formulated with ethanol and a substance called Cremophor EL (polyoxyethylated castor oil) in order to improve drug delivery. However, these additives are felt to contribute to the side effects associated with paclitaxel, thereby increasing the potential need for dose reduction and reducing patients' quality of life. Furthermore, Cremophor EL may cause some of the hypersensitivity reactions that occur in 25-50% of patients during infusion and that require preventive steroid premedication. To make matters worse, ethanol and Cremophor EL leach plasticizers from PVC bags and infusion sets, requiring preparation and administration of paclitaxel in glass bottles or non-PVC infusion systems.
The protein that is complexed with paclitaxel to make Abraxane is albumin, a naturally occurring, blood-soluble protein. Abraxane is Cremophor-free, and was developed to help alleviate the side effects of paclitaxel. Also, ABI-007 achieves a higher concentration of paclitaxel in solution, resulting in decreased infusion volume and time, and no need for non-standard infusion sets. Albumin is an ideal protein to deliver the taxane to tumor cells, as it is well-tolerated and large in size. The 100- and 200- nm paclitaxel-albumin particles preferentially deliver drug to tumor cells; the particles are too large for many normal cells. In addition, many solid tumors secrete SPARC, (secreted protein acidic rich in cysteine), which has an affinity for binding albumin and thus may help accumulate ABI-007 inside tumors. Interestingly, SPARC has been identified as an independent negative prognostic factor for overall and disease-free survival in patients with head and neck cancer (Chin et al. Int Jour Can 2001).
Preclinical studies of ABI-007 have found higher intratumoral levels, lower blood levels, and higher tissue levels with slower metabolism than paclitaxel. Phase II studies have found significant response rates in various tumor types.
A phase III clinical trial directly compared ABI-007 to paclitaxel in 454 patients with metastatic breast cancer (O'Shaughnessy J, et al). Patients were randomized to either 260 mg/m2 ABI-007 over 30 minutes once every 3 weeks without premedication, or 175 mg/m2 paclitaxel administered over 3 hours once every 3 weeks with premedication, including dexamethasone and antihistamines. ABI-007 had a higher overall response rate (ORR) and time to tumor progression (TTP) than paclitaxel, including patients who had received extensive prior chemotherapy. Grade 4 neutropenia was significantly reduced in patients treated with ABI-007, and grades 3 or 4 hypersensitivity reactions did not occur in the group of patients treated with ABI-007. Sensory neuropathy was worse in the ABI-007 arm; however, this was an acceptable and manageable toxicity. Based on these findings, ABI-007 was recently FDA-approved for marketing in metastatic breast cancer.
In an effort to expand the role of ABI-007, researchers are investigating its use in head and neck cancers. In a phase II study of patients with head and neck cancer presented at ASCO 2003, an impressive 89/91 patients had complete response, partial response, or stable disease. Response to ABI-007 appears to be directly related to SPARC positivity, with 10/12 SPARC+, poor prognosis tumors demonstrating objective response to ABI-007 in one small study. Further study is needed to establish a clinical role for ABI-007 in head and neck tumors, as well as other types of cancers. Thus far, the future of ABI-007 appears very promising.English