Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer.

PURPOSE: The use of granulocyte colony-stimulating factor (G-CSF) to increase cytotoxic dose-intensity was assessed in a randomized trial in better-prognosis small-cell lung cancer (SCLC). Both control and G-CSF arms were subject to the same dose-intensification strategy. PATIENTS AND METHODS: Patients with newly diagnosed SCLC and either no or one adverse prognostic factor were randomized to receive vincristine, ifosfamide, carboplatin, and etoposide (VICE) alone or with recombinant human (rHu)G-CSF (lenograstim) 5 micrograms/kg/d between cycles. Six chemotherapy cycles were given, with prophylactic cranial irradiation after cycle 1 and thoracic irradiation after cycle 3. There was no fixed dose interval. In both arms, patients were eligible for re-treatment when the WBC count was > or = 3 x 10(9)/L and platelet count was > or = 100 x 10(9)/L. No dose reductions were permitted. Dose-intensity was expressed relative to standard every-4-weeks VICE. RESULTS: Sixty-five consecutive patients in one institution were randomized to control (n = 31) or G-CSF (n = 34). WBC and neutrophil counts were consistently higher in G-CSF patients than in the control group, but there were no significant differences in the incidence of febrile neutropenia, antibiotic or transfusion requirements, or days in hospital. In both treatment arms, the median dose-intensity was greater than one for each cycle (control group, P = .0009; G-CSF group, P = .0001). The G-CSF group received a significantly higher dose-intensity than the control group, with the greatest difference in the first three cycles (1.34 v 1.17, P = .001). There were more chemotherapy-related deaths in the G-CSF group than in the control group (six v one), but this group had a better 2-year survival rate (32% with G-CSF, 95% confidence interval [CI], 16 to 48; 15% with controls, 95% CI, 2 to 27). CONCLUSION: The dose-intensity of VICE chemotherapy was increased in both groups. Patients randomized to receive G-CSF achieved a significantly higher dose-intensity than controls. Despite early toxicity, they had a better 2-year survival rate.

Pharmacoeconomic evaluation of lenograstim. Conclusions and future directions.

To evaluate the safety and efficacy of lenograstim, a new recombinant human granulocyte colony-stimulating factor (rHuG-CSF), as an adjunct to cancer chemotherapy, 3 phase III randomised clinical trials were recently conducted in Europe in patients with inflammatory breast cancer, non-Hodgkin's lymphoma, and small cell lung cancer. To explore the economic implications of lenograstim therapy, a multinational pharmacoeconomics programme was undertaken using data collected during these clinical trials. This programme consisted of concurrent prospective economic evaluations undertaken by study teams in France (non-Hodgkin's lymphoma), Germany and Italy (a combined evaluation in inflammatory breast cancer) and the UK (small cell lung cancer). In these studies, attention was focused on the direct costs of medical care-principally the costs of cancer chemotherapy as well as its associated morbidity. In 2 of the pharmacoeconomic evaluations (i.e. the French, German/Italian), lenograstim was found to generate cost savings as a result of reductions in morbidity associated with chemotherapy. However, the cost of lenograstim therapy would be likely to exceed these savings, leading to an overall increase in the costs of cancer treatment. Whether the use of lenograstim is cost-effective will therefore largely depend on its impact on patient survival and quality of life, and current practical use. These issues are the focus of additional clinical studies currently underway. In addition, new research is focusing on the clinical benefits of lenograstim in other areas of oncology and haematology. Further pharmacoeconomic studies in these areas are also warranted.

Overview of the lenograstim pharmacoeconomics programme.

Lenograstim is a recombinant colony-stimulating factor that has been shown to be a useful adjunctive agent in cancer chemotherapy. Clinical trials have demonstrated the efficacy of lenograstim in correcting chemotherapy-induced neutropenia and associated complications in inflammatory breast cancer and non-Hodgkin's lymphoma, and in facilitating dose intensification of chemotherapy in small cell lung cancer. To meet increasing demands for economic data on new drug entities, a lenograstim pharmacoeconomics programme was established. This programme involved prospective economic evaluations of lenograstim that were undertaken as part of phase III randomised clinical trials by a combined German/Italian health-economics team (inflammatory breast cancer), a French team (non-Hodgkin's lymphoma), and a team from the UK (small cell lung cancer).

Phase I-II trial of intensification of the MAID regimen with support of lenograstim (rHuG-CSF) in patients with advanced soft-tissue sarcoma (STS).

This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.

Mobilization of CD34+ cells by glycosylated and nonglycosylated G-CSF in healthy volunteers--a comparative study.

In vitro studies indicate that lenograstim (glycosylated G-CSF) is more potent than filgrastim (nonglycosylated G-CSF) on a weight for weight basis. However, such a difference has not yet been shown in vivo. The primary objective of this trial was to compare the efficacy of equivalent doses (microgram) of lenograstim and filgrastim in mobilizing CD34+ cells. Thirty-two healthy male volunteers, median age 27 yr (19-44 yr), were randomized to receive either lenograstim 10 micrograms/kg followed by filgrastim 10 micrograms/kg or vice versa with a washout period of a minimum 4 wk. Both drugs were administered as s.c. injections once daily for 5 d (d 1-5). CD34+ cells were mobilized with a similar kinetics, peaking at median d 6 (5-6) for both drugs. A significant difference in favour of lenograstim was shown for peak number of CD34+ cells/microliter blood (104 +/- 38 vs. 82 +/- 35, mean +/- 1 SD, p < 0.0001, paired t-test, n = 30) and number of CFU-GM/microliter blood at d 6 (14.6 +/- 8.4 vs. 10.2 +/- 4.6, p < 0.0001), respectively. There was no difference in the d 6 number of CD3+ cells. Both drugs were generally well tolerated and did not differ with respect to number of adverse events. In conclusion, lenograstim 10 micrograms/kg/d mobilizes PBPC more efficiently than the identical dose of filgrastim, indicating a difference in in vivo potency between the two G-CSFs.