Gemcitabine and Carboplatin: A Well-Tolerated Active Combination for Advanced N
Gemcitabine and Carboplatin: A Well-Tolerated Active Combination for Advanced Non-Small-Cell Lung Cancer
abstract & commentary
Synopsis: Chemotherapy has been shown in a number of studies to enhance survival and quality of life in non-small-cell lung cancer, but the effects are small. The current trial investigates the use of escalating doses of gemcitabine in combination with a standard dose of carboplatin in previously untreated patients with advanced lung cancer. Median duration of response was 13 months and overall survival was 16 months.
Source: Iaffaioli RV, et al. J Clin Oncol 1999;17: 921-926.
Developing new chemotherapy regimens for the treatment of advanced lung cancer has been the subject of research for many investigative teams in clinical oncology. This work is predicated upon the demonstration of enhanced quality-of-life and survival with certain regimens, particularly those that include cisplatin.1,2 The thrust to develop new regimens derives from the only modest enhancement of survival by the currently used standard regimens. The purpose of the current study was to examine gemcitabine and carboplatin in a combination phase I-II study in patients with stage IIIB and IV non-small-cell lung cancer. The selection of these drugs was based on earlier work that indicated gemcitabine to have significant single-agent effects in lung cancer and the absence of nausea from carboplatin when compared to cisplatin.3 Gemcitabine is relatively less myelotoxic than some other active agents and might even synergize with carboplatin.
Chemotherapy-naive patients with advanced lung cancer received carboplatin at a single dose (AUC 5 mg/mL/min) and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of a 28-day cycle.
Neutropenia was the dose-limiting toxicity, and it occurred in three of five patients receiving gemcitabine at 1200 mg/m2. Nonhematologic toxicities were mild. Thus, the recommendation for future phase II trials includes a dose of gemcitabine at 1100 mg/m2 with carboplatin AUC 5.
Although it was not the goal of the current study to establish efficacy, it was noted that 13 of 26 patients had either a partial (35%) or complete (15%) response. The median duration of response was 13 months (range, 3-223 months) and the median overall survival was 16 months (range, 3-226 months). These figures compare favorably with other, perhaps more toxic regimens and thus, there is anticipation that this new combination may be a step forward in the treatment of advanced lung cancer.
COMMENTARY
This clinical investigation by Iaffaioli and colleagues sets the stage for future trials of an interesting regimen. The primary end point of the current trial was simply to define for future investigations the recommended dose of gemcitabine when used in combination with carboplatin. Nonetheless, the impressive response rate, particularly with regard to duration of response and median overall survival, is hard to ignore. Of course, one has to use caution when making phase II conclusions from phase I data, but at least it can be said that the combination looks encouraging.
With regard to toxicity, it appears that the combination of gemcitabine and carboplatin is acceptable. Gemcitabine, with only modest hematologic toxicity, is apparently combined safely with carboplatin, particularly on the schedule used. In this regard, it is encouraging to note that no dose reductions were required and no patients were withdrawn from study due to failure to achieve hematologic recovery. Approximately 25% of the treatment courses were delayed by one week due to neutropenia or thrombocytopenia, but the protocol was not abandoned by any patient who reached the gemcitabine dose of 1100 mg/m2 because of marrow toxicity.
Furthermore, the nonhematologic side effects were encouragingly mild. Only two of the 26 patients reached a grade 3 level of nausea and vomiting. Alopecia was common but all nonhematologic toxic effects were of short duration after treatment interruption. Thus, it is difficult to find fault with the conclusions of Iaffaioli et al that this combination of gemcitabine and carboplatin is worthy of further study. If the phase II trials that are currently underway substantiate these early indicators of efficacy, it will be a regimen that will soon be investigated for front-line treatment of advanced lung cancer.
References
1. Souquet PJ, et al. Lancet 1993;342:19-21.
2. Grilli R, et al. J Clin Oncol 1993;11:1866-1872.
3. Gatzemeier U, et al. Eur J Cancer 1996;32A:243-248.
Which one of the following statements about the use of gem citabine with carboplatin for advanced lung cancer is true?
a. It is now established as front-line therapy for previously untreated patients.
b. The combination has an acceptable toxicity profile, and has been established by phase II trials to be highly effective.
c. The combination has an acceptable toxicity profile, but phase II trials need to be completed before it should be widely used in this setting.
d. The combination has an unacceptable toxicity profile, and future studies of its efficacy are not warranted.
e. The combination has an acceptable toxicity profile, but does not appear to be sufficiently active to warrant additional study.
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