Taxanes: impact on pancreatic cancer.
Taxanes are core therapeutic components for several advanced malignancies, and have been studied extensively in pancreatic adenocarcinomas with mixed results. Although the triplet combination FOLFIRINOX improves outcomes for patients with metastatic disease, it is compounded by significant toxicity, and novel regimens, rationally designed and based on thorough mechanistic activity on the tumor targets, are clearly needed. Solvent-based taxanes, docetaxel and paclitaxel, have little activity as single agents, but combinations with fluoropyrimidines and gemcitabine show efficacy, albeit they have not undergone testing in phase III trials. Pancreatic cancer is characterized by an abundant desmoplastic, fibroinflammatory and hypoperfused stroma, which has been blamed for its overall chemoresistance. Nanoparticle bound paclitaxel (nab-paclitaxel) has been pharmacologically designed as a novel water-soluble agent, with improved therapeutic index compared with the cremophor-based formulation, capable of achieving higher systemic exposure. In preclinical systems, when combined with gemcitabine, nab-paclitaxel increased intratumoral gemcitabine delivery, possibly due to inducing stromal 'collapse' and through inhibition of the gemcitabine-catabolizing enzyme cytidine deaminase. Most recently, the combination of nab-paclitaxel and gemcitabine demonstrated significant survival benefit with good tolerability in metastatic pancreatic cancer in the phase III trial MPACT, and now represents one of the gold-standard regimens for this disease. Although taxanes are overall potent chemotherapeutics for various cancers, it is clear that for meaningful results in pancreatic adenocarcinomas, rationally designed combinations and novel technologies for drug delivery are likely to be most successful.
aDepartment of Medicine, University of Washington, Seattle, Washington bTranslational Genomics Research Institute (TGen)/Virginia Piper Cancer Center, Scottsdale, Arizona, USA.
E Gabriela
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Chiorean
Daniel D
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Von Hoff
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D006801:Humans; D020360:Neoadjuvant Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids