Preliminary clinical results with gemcitabine(Drug information on gemcitabine), an investigational difluoronucleoside, were presented during scientific sessions organized by the 7th World Conference on Lung Cancer, which was held in Colorado Springs last year. The agent produced promising response rates in patients with non-small-cell lung cancer (NSCLC), in both single-agent and combination chemotherapy trials.
The research presentations and posters at the meeting focused on data from completed phase II clinical trials in Europe, Japan, and Canada in which gemcitabine had been given to patients with inoperable NSCLC.
Two multicenter phase II studies were conducted to determine the clinical efficacy of gemcitabine for the treatment of non-small-cell lung cancer. The first study evaluated 151 patients with inoperable NSCLC. Gemcitabine, 1,250 mg/m², was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by 1 week of rest. This constituted one treatment cycle.
The results of the trial indicated an overall response rate of 22%, which included 3 complete and 30 partial responses. According to the lead investigator, Ulrich Gatzemeier, MD, Grosshansdorf Hospital, Germany, this response rate compares favorably with single-agent response rates reported in the medical literature for other existing drugs used against lung cancer. Similar response rates were reported in two independent Japanese studies enrolling a combined 136 patients with previously untreated NSCLC, of which 116 were evaluable at the time. The dosing schedule was comparable to that used in the European study, although the initial gemcitabine dose was 1,000 mg/m², with allowance made for increasing the dose to 1,250 mg/m², depending on the patients' tolerance levels during the first cycle. An overall response rate of 23% was reported.
Both studies showed gemcitabine to be generally well tolerated. Overall, the most common side effects reported were neutropenia in the first study and leukopenia, anemia, loss of appetite, and fatigue in the second study. Gemcitabine's "overall mild toxicities, in particular, modest myelotoxicity, may warrant further investigation of this drug in combination with other anticancer agents," said lead investigator Yushi Nakai, MD, of the Sendai Kousei Hospital in Japan.
Preliminary results from two phase I combination studies involving gemcitabine and cisplatin(Drug information on cisplatin) to treat NSCLC were also presented at the Colorado conference.
One study was conducted to determine the maximum tolerated doses of a 4-week cycle of gemcitabine and cisplatin when administered for 3 weeks, with a 1-week rest period. The starting dose of gemcitabine was 1,000 mg/m² for 3 weeks. At the next dose level, only cisplatin was increased to 30 mg/m² per week for 3 weeks. Thereafter, dose escalations were made only for gemcitabine (to 1,250 mg/m² and 1,500 mg/m²). At the time of the conference, 25 patients (24 eligible) had been entered in the study. The initial partial response rate for this study was 7 out of 12 patients.
Similar results were reported in a second phase I dose-escalation study of gemcitabine in combination with cisplatin, using a different dosing schedule. In 15 patients, gemcitabine 1,000 mg/m² was administered as a 30-minute IV infusion on days 1, 8, and 15 of a 28-day cycle. On day 15, cisplatin was given immediately after gemcitabine administration at the following dose levels: 60 mg/m² (3 patients), 75 mg/m² (3 patients), and 100 mg/m² (9 patients). For these patients, gemcitabine did not add to expected cisplatin toxicity. The most commonly noted side effects included neutropenia, thrombocytopenia, transient rise in liver function tests, nausea, and vomiting. The number of evaluable patients with response rates was two out of three at the 60-mg/m² cisplatin dose level, none out of three at 75 mg/m², and four out of four at 100 mg/m².
Based on the findings of these two studies, The Toronto Hospital's Frances A. Shepherd, MD, one of the lead investigators, said, "The preliminary response data suggest that the gemcitabine and cisplatin [combination] is an active regimen against NSCLC. It is well tolerated and deserves further study in comparison with other chemotherapy combinations."
Lung cancers are among the most difficult cancers to treat. An effective therapy for advanced NSCLC, which accounts for nearly 75% of all lung cancer cases, has been particularly elusive. The 5-year survival rate for those with NSCLC stands at less than 10%.
Gemcitabine is being tested by Eli Lilly and Company, which has applications pending for regulatory approval of this compound in 19 countries outside the United States for the indication of non-small-cell lung cancer. The drug is also being studied for the treatment of pancreatic cancer in an ongoing US registration trial. Data also suggest that gemcitabine may have activity against other solid tumors, including breast, ovarian, bladder, and prostate cancers. Further studies with these tumors are planned to confirm the activity of the compound.