Dose Intensity Phase l/lI Trial with Carboplatin, Ifosfamide, Etoposide and Vincristine Combined with Filgrastim in Patients with Small-Cell Lung Cancer

Abstract

Background: The purpose of the study was to evaluate the feasibility of increasing dose intensity by a stepwise reduction of the time intervals between chemotherapy cycles in separate patient cohorts with small-cell lung cancer. Patients received up to 6 courses of combination chemotherapy with carboplatin, etoposide, ifosfamide and vincristine followed by support with filgrastim. Dose intensity, incidence, duration and severity of neutropenic fever and infections, objective response to chemotherapy, and safety of filgrastim were determined. Patients and Methods: 29 patients with small-cell lung cancer (limited disease: 2, extensive disease: 27) were treated with a combination of carboplatin 250 mg/m² i.v. day 1, ifosfamide 2 g/m² and etoposide 120 mg/m² i.v. days 1 and 2, etoposide 120 mg/m² orally day 3, and vincristine 1.4 mg/m² day 14. Initially, filgrastim (5 μg/kg) was administered subcutaneously from day 7 to 16. With shorter treatment intervals, filgrastim was administered on days 4-16 or 4-14. Results: An overall increase in dose intensity by a factor of 1.44 was achieved after reducing the treatment interval from 27 to 17 days. Further reduction to 14 days was not feasible due to persistent thrombocytopenia. Six patients (21%) developed a total of 9 febrile episodes, and 14 patients (48%) had to be withdrawn from the study before the completion of six cycles of chemotherapy. The median duration of infectious episodes was 6 days. Overall, a total of 22 of 27 evaluable patients had an objective response. Longer treatment intervals resulted in a lower probability for objective response (≥23 days: 10/14 patients vs. ≤17 days: 7/7 patients). Conclusion: Filgrastim allows for the reduction of treatment intervals in patients with small-cell lung cancer and increased dose intensity with acceptable hematologic and nonhematologic toxicities.

Carboplatin in the Treatment of Small Cell Lung Cancer

“…Some investigators have attempted to dose-intensify regimens by increasing the doses of the chemotherapeutic agents, but Hanauske et al evaluated dose intensification by decreasing the intervals between cycles from 27 to 17 days using a combination of carboplatin, ifosfamide, etoposide, and vincristine [35]. The specific regimen consisted of carboplatin 250 mg/m 2 i.v.…”

“…The toxicities were moderate, with 21% of patients developing febrile episodes and 48% of patients being withdrawn from the study. The shorter the cycle interval, the better the response rate, with patients receiving cycles greater than every 23 days achieving a 71% response rate and patients receiving cycles equal to or less than every 17 days having a 100% response rate [35].…”

Hematopoietic growth factors in lung cancer

“…Most clinical trials involving SCLC employed dose-dense or dose-intense regimens, and in general schedules characterized by high risk of febrile neutropenia, such as cyclophosphamidedoxorubicin-etoposide, cyclophosphamide-epirubicin-etoposide or vincristine-ifosfamide-carboplatinetoposide. Although dose-dense or dose-intense regimens did not improve the outcomes, G-CSFs consistently improved neutrophil-related outcomes and reduced the incidence of chemotherapyrelated mucositis [31][32][33][34][35][36][37][38][39][40]. Notably, an Italian study assessed the feasibility of full-dose cisplatinetoposide (the current standard for SCLC) with lenograstim compared to attenuated doses of the same drugs for elderly patients affected by SCLC; the administration of full-dose with lenograstim, while characterized by increased incidence of myelotoxicity, was feasible and associated with better outcomes [41].…”

Early Tandem High-Dose Ifosfamide, Carboplatin, Etoposide Therapy with Stem Cell Rescue for Small-Cell Lung Cancer: Brief Report on the Results of a Phase-I/II Trial

“…It remains doubtful whether small dose increments in chemotherapy over today’s standard, feasible without additional supportive therapy, lead to longer survival, although suboptimal doses in early trials have been associated with shortened survival. We as others could show that it may be feasible to administer ifosfamide, carboplatin and etoposide (ICE) chemotherapy at a higher dose intensity using 17-day intervals with granulocyte colony-stimulating factor (G-CSF; filgrastim) [5]. The potential of the approach using dose escalation with supportive hematopoietic cytokines to prolong survival in phase-III trials and the role of hematopoietic cytokines therein are still under debate [6, 7, 8, 9, 10].…”