Gemcitabine

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...
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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. Pharmacologic Properties Gemcitabine is a deoxycitidine analog prodrug that inhibits DNA synthesis through the self-potentiating actions of its active diphosphate and triphosphate derivatives, which are formed after the uptake and intracellular phosphorylation of the parent drug by nucleoside kinases. Gemcitabine demonstrates linear pharmacokinetics over the dose range 53–1000 mg/$ m^{2} $; the recommended dosage is 1000 mg/$ m^{2} $once weekly, administered by a 30-minute intravenous infusion. The maximum concentration of gemcitabine triphosphate in peripheral blood mononuclear cells (PBMCs) was attained within 30 minutes of the end of the infusion and increased in proportion to the gemcitabine dose (up to 350 mg/$ m^{2} $). Gemcitabine triphosphate formation within PBMCs was saturable at higher gemcitabine doses, although this phenomenon can be overcome using an extended, slow infusion rate (i.e. 10 mg/$ m^{2} $/min). Gemcitabine systemic exposure was significantly reduced with intra-arterial as opposed to intravenous administration of the drug. Plasma protein binding of gemcitabine is minimal, and the drug is not extensively distributed into tissues after short infusions (<70 minutes). Gemcitabine is rapidly deaminated intracellularly; up to 98% of the administered dose is excreted in the urine within 1 week. Unchanged parent drug (<10%) and the inactive 2′-deox-y-2′,2′-difluorouridine metabolite account for 99% of the excreted dose. The terminal elimination half-life of gemcitabine after short infusions ranges from 42–94 minutes depending on age and sex; however, dosage adjustments are not necessary on the basis of these characteristics. Therapeutic Efficacy In a pivotal, randomized, multicenter trial, the recommended dosage regimen of gemcitabine was superior to the previous standard of care fluorouracil (given as an intravenous bolus) in the first-line treatment of patients with advanced, inoperable pancreatic cancer. Gemcitabine was more effective than fluorouracil in alleviating three common debilitating, tumor-related signs and symptoms (pain, functional impairment, weight loss), and conferred a small survival advantage. Relative to other single agents (exatecan, marimastat, BAY 12-9566), gemcitabine had a similar or superior effect on overall survival in randomized, multicenter, phase III studies in patients with locally advanced (unresectable) or metastatic pancreatic cancer. Systemic gemcitabine was, however, inferior to combination chemotherapy with FLEC, administered intra-arterially, in this regard. As a second-line treatment, gemcitabine demonstrated useful palliative efficacy in patients with fluorouracil-refractory pancreatic cancer in a pivotal noncomparative, multicenter trial. The strategy of adding other cytotoxic or targeted anticancer agents (e.g. fluorouracil [with or without folinic acid], pemetrexed, cisplatin, oxaliplatin, irinotecan, exatecan, marimastat, tipifarnib, G17DT, virulizin, or LY293111) to gemcitabine has largely produced disappointing results in terms of improving overall survival relative to gemcitabine monotherapy in randomized, multicenter, phase II or III studies in patients with locally advanced (unresectable) or metastatic pancreatic cancer (n = 92–688). However, preliminary reports indicate that, when used as the second drug in a gemcitabine-containing doublet, capecitabine (in the larger of two studies) and erlotinib confer a survival advantage over gemcitabine alone. Similarly, combination chemotherapy with PEFG significantly improved survival relative to gemcitabine monotherapy (and was superior for the primary endpoint of progression-free survival at 4 months). Gemcitabine monotherapy did not prolong median survival beyond 7.3 months in pivotal and phase III clinical trials. However, survival may be enhanced using an extended, slow infusion of the drug as opposed to the standard (30-minute) infusion. In the only prospective, randomized studies reported to date, gemcitabine-based chemoradiotherapy was superior to fluorouracil-based chemoradiotherapy, and gemcitabine plus doxifluridine-based chemoradiotherapy was similar to paclitaxel plus doxifluridine-based chemoradiotherapy, in the treatment of patients with locally advanced, unresectable pancreatic cancer. According to preliminary results of a randomized, multicenter, phase III study, adjuvant chemotherapy with gemcitabine significantly increased the median duration of disease-free survival (relative to observation) in previously untreated patients with resected pancreatic cancer, regardless of whether the resection margin was positive or negative, or whether lymph nodes were involved. Tolerability Gemcitabine, either as monotherapy or in combination with other anticancer agents, was generally well tolerated when administered as a first-line treatment for locally advanced (unresectable) or metastatic pancreatic cancer. Fewer than 5% of patients receiving the recommended gemcitabine dosage regimen discontinued treatment because of adverse events (e.g. fever, pain, asthenia, nausea/vomiting) in a large-scale investigational new drug (compassionate use) treatment program (n = 3023). Myelosuppression was the primary dose-limiting toxicity in clinical trials, with grade 3 or 4 neutropenia occurring in up to 41% of patients, and grade 3 or 4 leukopenia, thrombocytopenia and anemia each occurring in up to 16% of patients with advanced pancreatic cancer who typically received the recommended gemcitabine dosage regimen in phase III studies (n = 107–668). Myelosuppression was increased with an extended, slow infusion of gemcitabine relative to a standard 30-minute infusion of the drug in a randomized, multicenter, phase II trial, although the number of consequent dose reductions and omissions were similar for both protocols. Compared with gemcitabine monotherapy, the incidence of some grade 3 or 4 adverse events (e.g. hematological toxicities) was significantly increased with four-drug regimens containing (PEFG) or not containing (FLEC) gemcitabine, and with pemetrexed, exatecan, or oxaliplatin as the second drug in a gemcitabine-containing doublet. ... 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Autor*in:	Frampton, James E. [verfasserIn] Wagstaff, Antona J.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2005

Schlagwörter:	Pancreatic Cancer Gemcitabine Capecitabine Pemetrexed Advanced Pancreatic Cancer

Anmerkung:	© Adis Data Information BV 2005

Übergeordnetes Werk:	Enthalten in: American Journal of Cancer - Springer International Publishing, 2002, 4(2005), 6 vom: Nov., Seite 395-416
Übergeordnetes Werk:	volume:4 ; year:2005 ; number:6 ; month:11 ; pages:395-416

Links:	Volltext

DOI / URN:	10.2165/00024669-200504060-00006

Katalog-ID:	SPR035646047