IngentaConnect Gemcitabine: A Review of its Use in the Management of Pancreatic ...

Abstract:

Gemcitabine (Gemzar^®), an intravenously administered deoxycitidine analog, is approved in the US and several European countries for the treatment of locally advanced (unresectable) or metastatic adenocarcinoma of the pancreas, including fluorouracil-refractory disease.

Although gemcitabine demonstrates only modest activity against pancreatic tumors (like most other cytotoxic agents), and rarely prolongs median survival beyond 7 months, it has a relatively mild toxicity profile, which is particularly important in the context of palliative treatment. Gemcitabine was superior to fluorouracil in alleviating tumor-related symptoms and extending survival in a randomized, multicenter trial; it was at least as effective as other single agents (e.g. exatecan and marimastat), but less effective than a four-drug combination (fluorouracil, leucovorin, epirubicin plus carboplatin [FLEC]) in prolonging survival in similar studies. There is the suggestion that survival outcomes with the drug may be enhanced using an extended, slow infusion rate, as opposed to a short, standard infusion rate. Adding another anticancer agent to gemcitabine, however, has to date yielded mostly disappointing results relative to gemcitabine alone in phase III trials. Of the doublet combinations tested, only gemcitabine plus capecitabine and gemcitabine plus erlotinib significantly increased survival (preliminary data), while only gemcitabine plus oxaliplatin significantly improved symptom alleviation, relative to gemcitabine alone; however, a four-drug regimen of cisplatin plus epirubicin, fluorouracil, and gemcitabine (PEFG) significantly improved both outcomes. Administering gemcitabine concurrently with radiotherapy is being evaluated in the setting of locally advanced, unresectable disease. Additionally, gemcitabine and/or gemcitabine-based chemoradiotherapy are being investigated as (neo)adjuvant treatments in patients with resectable disease; disease-free survival was improved relative to observation in the first randomized trial of adjuvant gemcitabine (preliminary data).

In conclusion, systemic gemcitabine monotherapy has been widely investigated in the treatment of patients with advanced, inoperable pancreatic cancer, and is well tolerated and moderately effective in these individuals. Research is ongoing into ways of maximising treatment outcomes with gemcitabine; these approaches include combining the drug with novel chemotherapeutic agents, integrating it into chemoradiotherapy regimens, using it in patients with resectable disease, and administering it by intra-arterial infusion. Pending confirmation of promising preliminary results with certain gemcitabine-based combination chemotherapies, gemcitabine monotherapy remains the widely accepted standard of care for advanced, nonresectable pancreatic cancer.

Gemcitabine: A Review of its Use in the Management of Pancreatic Cancer