Sequential chemotherapy with combination irinotecan and cisplatin followed by docetaxel for treatment-naïve patients with advanced non-small cell lung cancer.

BACKGROUND: Sequential administration of platinum-based doublet therapy and then a taxane may reduce the risk of drug resistance and, therefore, improve treatment outcome. This study was designed to evaluate the efficacy and tolerability of sequential administration of irinotecan and cisplatin and then docetaxel in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Eligible patients received irinotecan in 60-mg/m2 infusions for 30 to 60 minutes on days 1, 8, and 15, and cisplatin in 75-mg/m2 infusions for 60 minutes on day 1 every 28 days for four cycles (IC). Regardless of the response, patients received up to four cycles of sequential docetaxel in 75-mg/m2 infusions for 60 minutes. RESULTS: Forty-six patients with histologically confirmed chemotherapy-naïve stage IIIB or IV NSCLC were enrolled, of whom 42 were evaluable. The response rate at completion of chemotherapy with IC was 45.2% (95% confidence interval [CI]: 30.2%-60.3%). Five patients had improvement of disease status during sequential docetaxel, and seven patients had disease progression. Progression-free survival was 8.0 months (95% CI: 5.4-9.9 months), and the overall median survival was 14.6 months (95% CI: 9.8-17.9 months). The 1-, 2-, and 3-year survival rates were 54.3%, 22.6%, and 12.1%, respectively. The incidence of severe (> or =CTC V2 grade 3) neutropenia during IC was 23.9% compared with 95.7% for sequential docetaxel (p < 0.0001). CONCLUSION: Sequential administration of IC and then docetaxel is feasible and is associated with a prolonged progression-free survival, but the current data do not confirm an improvement in treatment outcome by the sequential approach.

Phase II randomized study comparing the toxicity profile of gemcitabine plus cisplatin with gemcitabine plus oral etoposide in the treatment of advanced non-small cell lung cancer.

OBJECTIVE: This is a randomized phase II study designed to compare the toxicity profile of a non-platinum-based with a platinum-based regimen in the treatment of advanced non-small cell lung cancer. METHODS: Eighty-nine chemotherapy-naïve patients were randomized either to gemcitabine (1,000 mg/m2, 30-min infusion on days 1, 8 and 15) and oral etoposide (50 mg, days 1-14; GE group) or gemcitabine at the same schedule and cisplatin (75 mg/m2 on day 15; GP group). The primary endpoint is toxicity, and secondary endpoints include response rate, survival outcome and quality of life (QOL). RESULTS: The incidence of WHO grade 3 or 4 anemia, neutropenia and thrombocytopenia was 29, 44 and 22% (GE group), and 28, 49 and 23% (GP group), respectively (p = 0.75, 0.95 and 0.87, respectively). The rate of grade 2 or above nausea was numerically higher in the GP arm, but the difference was not statistically significant (GE 15.5%, GP 27.7%, p = 0.20). The rate of vomiting in the GE and GP arms was 20.0 and 20.5%, respectively (p = 0.96). However, subjective changes in QOL scores on nausea and vomiting were significantly higher in the GP arm (p = 0.001). Other symptoms including sore mouth and hair loss were significantly higher in the GE arm (p = 0.003 and 0.007, respectively). There were also significant differences observed in emotional (p = 0.014), cognitive (p = 0.028) and social functioning (p = 0.034) in favor of GP. The differences in tumor response (35.5 and 46.5% for GE and GP, respectively) were not significantly different. Median time to disease progression (33.8 and 40.7 weeks, respectively) and overall survival (41.4 and 57.3 weeks, respectively) were of borderline significance in favor of the GP arm (p = 0.055). CONCLUSION: This toxicity profile of GE is similar to GP, but the apparent inferior efficacy may discourage further investigation.

A phase I safety and pharmacokinetic study of OGT 719 in patients with liver cancer.

OGT 719 (Oxford GlycoSciences, Abingdon, UK) is a novel nucleoside analogue with a galactose molecule attached to a fluorinated pyrimidine. OGT 719 has the capacity selectively to bind to asialoglycoprotein receptors that are found exclusively on hepatocytes and hepatocellular carcinoma (HCC) cells. The aim of this study was to establish the safety and to examine the pharmacokinetics of this novel compound in patients with liver cancer. Fourteen patients received a total of 37 cycles of OGT 719 at four dose levels ([500 mg/m2 first cycle, 1 000 mg/m2 subsequent cycles], 1000 mg/m2, 3 300 mg/m2 and 7500 mg/m2). OGT 719 was administered as a 3-h intravenous infusion in a 250 ml saline solution, daily for 5 days every 4 weeks. Pharmacokinetic parameters were studied during the first cycle of dose levels 1 and 2 (500 mg/m2. and 1 000 mg/m2, respectively). The maximum plasma concentration was attained within 5 min of completing the infusion and almost doubled, dose dependently, with a doubling of the infused dose. The plasma level declined rapidly in a monophasic manner with an elimination half-life of 2.1 and 2.5 h for dose level 1 and 2, respectively The mean area under the curve (AUC(o - infinity) area under the curve to 24 h; AUC(o - infinity), area under the curve to infinity) doubled at the higher dose level. None of the patients had a significant tumor response. Elimination half-life of OGT 719 by 3-h intravenous infusion is short and monophasic. Toxicity was minimal at the highest dose level.

A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma.

BACKGROUND: Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. METHODS: Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m(2) per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m(2) per day and 1.0 mg/m(2) per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences. RESULTS: Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan --> etoposide, 88 courses; etoposide --> topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m(2) per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3-4 neutropenia and the incidence of Grade 3-4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6-36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6-57.7 weeks). CONCLUSIONS: Combination therapy with topoisomerase I and II inhibitors is a safe and effective regimen for patients with SCLC. Future research on this combination should focus on an oral regimen for patients with extensive disease and poor tolerance to cisplatin. The authors recommend an oral dosage of topotecan at 1.2 mg/m(2) per day (equivalent to intravenous topotecan at 0.75 mg/m(2) per day) for 5 days followed by etoposide 50 mg twice daily for 7 days.