, Volume 54, Issue 3, pp 447-472
Date: 27 Oct 2012

Gemcitabine

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Summary

Synopsis

Gemcitabine [2′- deoxy- 2′,2′- difluorocytidine monohydrochloride (β isomer); dFdC] is a novel deoxycytidine analogue which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy.

Gemcitabine monotherapy produced an objective tumour response in 18 to 26% of patients with advanced non-small cell lung cancer (NSCLC) and appears to have similar efficacy to cisplatin plus etoposide. Objective response rates ranging from 26 to 54% were recorded when gemcitabine was combined with cisplatin, and 1- year survival duration after such treatment ranged from 35 to 61 %. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clinical trials.

Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addition, direct costs associated with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options, according to retrospective cost-minimisation analyses. The combination of gemcitabine plus cisplatin was associated with a lower cost per tumour response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness analysis.

In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clinical status. It also showed modest antitumour and palliative efficacy in patients refractory to fluorouracil.

Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The available data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerabilty profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study.

Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity associated with many other chemotherapy regimens. More detailed characterisation of its risk-benefit profile compared with those of current and developing regimens for NSCLC should be possible once results from several ongoing studies are available. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and aalliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognised.

Pharmacodynamic Properties

Gemcitabine [2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β isomer); dFdC] is a novel analogue of deoxycytidine which inhibits DNA synthesis. After cellular uptake, gemcitabine is phosphorylated to gemcitabine di- and triphosphate, the active metabolites. Gemcitabine triphosphate competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death. Its effects in this respect are enhanced by a number of unique self-potentiating pharmacological activities of gemcitabine di- and triphosphate. These effects maintain high intracellular concentrations of gemcitabine metabolites and reduce levels of deoxycytidine triphosphate (with which gemcitabine triphosphate competes for incorporation into DNA).

Gemcitabine has shown cytotoxic effects against a range of cancer cell lines invitroand had antitumour activity in a broad spectrum of animal models, including xenografts from patients with non-small cell lung cancer (NSCLC) or pancreatic cancer. Its effects invivowere schedule-rather than dose-dependent. At the maximum tolerated dose in murine models, gemcitabine inhibited the growth of human NSCLC xenografts by 45 to 76% compared with untreated control animals. It also inhibited growth of 3 of 4 human pancreatic cancer xenografts in mice by 69 to 73% at the maximum tolerated dose.

Pharmacokinetic Properties

Peak plasma concentrations of gemcitabine are reached 15 to 30 minutes after the start of a 30-minute intravenous infusion and typically range from 10 to 40 mg/L. Steady-state gemcitabine concentrations showed a linear relationship to dose over the dose range 53 to 1000 mg/m in one study in patients with a range of malignancies. Intracellular concentrations of gemcitabine triphosphate in peripheral blood mononuclear cells from these patients peaked within 30 minutes of starting the infusion and increased in proportion to dose up to gemcitabine 350 mg/m2. Increasing the dose beyond this level had no significant effect on the area under the intracellular concentration-time curve for gemcitabine triphosphate, indicating intracellular saturation.

Plasma binding of gemcitabine is minimal and the drug is not extensively distributed to tissues after short infusions. Gemcitabine is rapidly metabolised intracellularly, with a median elimination half-life of 8 minutes reported in one study in patients with cancer. Less than 10% of a radiolabelled gemcitabine dose is excreted unchanged in urine (significant amounts of the inactive metabolite 2′-deoxy-2′,2′-difluorouridine are detected in urine). Urinary excretion accounted for 30 to 96% (median 77%) of the administered dose in one small study.

Clinical Potential

Monotherapy with gemcitabine produced objective responses in 18 to 26% of patients with advanced NSCLC. Median response duration ranged from 3.3 to 12.7 months and overall median survival duration was 6.2 to 12.3 months. 22% of patients had an objective response in the largest trial of gemcitabine monotherapy (n=151); overall median survival duration was 9.4 months. Objective response rates for gemcitabine monotherapy and cisplatin plus etoposide were similar in 2 comparative trials (18 vs15% and 19 vs21%), as was median survival duration (6.6 vs7.6 months and 9.3 vs12 months). Gemcitabine in combination with cisplatin produced better results than gemcitabine monotherapy in patients with NSCLC: objective response rates ranged from 26 to 54% and overall median survival duration ranged from 10.4 to 15.4 months in 3 trials. Furthermore, estimated 1-year survival after treatment with gemcitabine plus cisplatin ranged from 35 to 61% in several studies. Improvements in pain were experienced by 31 to 52% of patients with NSCLC who received gemcitabine ± cisplatin in 3 non-comparative studies. Primary disease symptoms (cough, dyspnoea, haemoptysis and pleural effusion) improved in 42 to 89% of patients in one study and in 22 to 68% of patients in another; haemoptysis improved in about two-thirds of patients in both trials.

Gemcitabine was considered highly cost effective in comparison with best supportive care for NSCLC, according to a retrospective pharmacoeconomic analysis. It provided 1 additional life-year saved at a cost of $Can3193 (1993 Canadian dollars). Sensitivity analysis indicated that gemcitabine was still cost effective when the acquisition cost was increased by 80% and the assumed survival advantage over best supportive care was reduced by half. The cost per tumour response of gemcitabine plus cisplatin was 39, 35 or 8% lower than that of etoposide plus cisplatin, vinorelbine plus cisplatin or mitomycin plus ifosfamide plus cisplatin, respectively, according to another retrospective cost-effectiveness analysis (detailed statistical analysis not provided).

Results from a number of retrospective cost-minimisation analyses (which excluded primary drug costs) suggest that direct costs associated with administration of gemcitabine are lower than those for other NSCLC chemotherapy options. This was primarily because of the reduced cost of managing adverse events during gemcitabine therapy and the ability to administer the drug on an outpatient basis.

Gemcitabine was significantly more effective than fluorouracil with respect to both survival and palliative efficacy in a single comparative study in patients with advanced pancreatic cancer. Patients receiving gemcitabine had a 1.6-, 4.8- or 9-fold higher chance of surviving to 6, 9 or 12 months, respectively, than fluorouracil recipients (median survival difference between gemcitabine and fluorouracil recipients was 1.5 months). Furthermore, 5 times as many patients were considered to have derived clinical benefit from gemcitabine as from fluorouracil, based on assessment of pain, analgesic use, performance status and body weight.

Tolerability

Myelosuppression, transient elevation of hepatic enzymes and nausea and vomiting were the most common WHO grade 3 or 4 adverse events in 979 patients who received gemcitabine monotherapy at a starting dose of 800 to 1250 mg/m during clinical trials. However, fewer than 1% of patients withdrew from treatment for each of these reasons. Myelosuppression was the primary dose-limiting toxicity, with grade 3 or 4 neutropenia occurring in 25% of patients. Nausea and vomiting was common (69% at any grade) but occurred predominantly at grade 1 or 2. Transient elevations in hepatic enzymes occurred in about two-thirds of gemcitabine recipients, but were not associated with dose or treatment duration. Overall, about 10% of gemcitabine recipients stopped receiving treatment because of adverse effects (no single effect predominated).

The combination of gemcitabine with cisplatin was considered well tolerated in several small noncomparative trials in patients with NSCLC; grade 3 or 4 neutropenia and nausea and vomiting both occurred in ≈50% of patients in the largest available study (n=55); however, toxicity was considered to be easily managed overall.

Data from 2 comparative studies in patients with NSCLC indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide, although statistical analysis was not provided for either study.

Grade 3 or 4 adverse effects were more common in patients receiving gemcitabine than in those receiving fluorouracil in a randomised study in 126 patients with pancreatic cancer. Treatment withdrawal as a result of adverse effects was about 3 times more common among gemcitabine recipients (14.3%) than among patients receiving fluorouracil (4.8%). However, gemcitabine was generally well tolerated: the most common grade 3 event was neutropenia (19% of patients) and the incidence of individual grade 4 adverse effects was ≤7%. Grade 3 or 4 neutropenia was noted in 26% of patients receiving gemcitabine, compared with 5% of those treated with fluorouracil (p<001), but there was no significant difference between groups for grade 4 neutropenia (6.9 vs3.3%).

Dosage and Administration

The recommended dose for gemcitabine is 1000 mg/m2 as a 30-minute intravenous infusion administered once weekly (dose can be escalated to 1250 or 1500 mg/m2 in the absence of significant toxicity). Patients with NSCLC should be treated using a repeated 4-week cycle (3 weeks on, 1 week off), whereas those with pancreatic cancer receive the drug on an initial 8-week cycle (7 weeks on, 1 week off) followed by the 4-week cycle thereafter. Patients receiving gemcitabine should be monitored regularly for myelosuppression and periodically for renal and hepatic dysfunction.

Various sections of the manuscript reviewed by: R.P. Abratt, Department of Radiation Oncology, University of Cape Town, Cape Town, South Africa; H.Anderson, Chest Clinic, Wythenshawe Hospital, Manchester, England; S. Bank, Division of Gastroenterology, Long Island Jewish Medical Center, New York, New York, USA; A.M. Bergman, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; J.P. Bernard, Centre Hospitalier Lyon Sud, Pierre Benite, France; L. Crinó, Divisione di Oncologia Medica, Policlinico Monteluce, Perugia, Italy; J.M. Kroep, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; G.J. Peters, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; M.L. Rothenberg, Department of Medicine, Division of Medical Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; W.P. Steward, Department of Oncology, Leicester Royal Infirmary, Leicester, England; N. Thatcher, Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester, England; C.J.A. van Moorsel, Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.