Introduction
Gemcitabine (Gemzar), docetaxel(Drug information on docetaxel) (Taxotere), paclitaxel(Drug information on paclitaxel) (Taxol), and vinorelbine (Navelbine) are among the most active agents for the treatment of non-small-cell lung cancer (NSCLC). Each has been shown to produce objective responses in approximately 20% of previously untreated patients with advanced or metastatic disease and to improve survival when compared with best supportive care. When combined with a platinum compound, these agents have, to date, produced the best survival outcomes in non-small-cell lung cancer and represent the new standard of care for good performance status in patients with advanced or metastatic disease.
These new agents generally appear to be more active than platinum compounds. Gemcitabine(Drug information on gemcitabine), in particular, appears to be at the head of the class with respect to activity and patient tolerance. More than 500 patients were treated in six phase II clinical trials with gemcitabine 1.0-1.2 g/m2 on days 1, 8, and 15 every 4 weeks. Reported objective response rates are in the range of 21% to 26%.[1-6] Fewer than 7% of these patients suffered any grade 4 toxicity.
Three randomized clinical trials have shown that single-agent gemcitabine can produce response rates and survival outcomes equivalent to the combination regimens of cisplatin(Drug information on cisplatin) (Platinol)/etoposide[7,8] or cisplatin/vindesine (Eldisine)[9]. However, gemcitabine has considerably less toxicity and greater benefit with respect to improved quality of life and performance of daily activities. Therefore, investigators have hypothesized that gemcitabine could be combined with one of the other new agents to create novel nonplatinum doublet combinations with efficacy and/or toxicity profiles superior to that of standard platinum-containing combinations. This article summarizes the efforts to date that explore gemcitabine combined with docetaxel, paclitaxel, or vinorelbine.
Gemcitabine/Docetaxel Combinations
Gemcitabine with docetaxel was the first combination examined. In the initial two studies, docetaxel was added on day 1 or 15 to a standard day 1, 8, and 15 schedule of gemcitabine. Treatment was recycled every 28 days.
28-Day Schedules
Pawinski et al[10] reported the results of 30 courses of treatment in 11 patients (10 of whom had received prior chemotherapy) with a variety of tumor types. On the 28-day schedule, gemcitabine 800 mg/m2 was administered on days 1, 8, and 15 with docetaxel 85 mg/m2 on day 1. Grade 3/4 neutropenia occurred in 18 of the 30 courses (60%), including febrile neutropenia in 2 of the 11 patients. Grade 3/4 thrombocytopenia occurred in 5 of the 30 courses (17%), and grade 3 dermatitis or increased liver function tests (LFTs) occurred in one patient each. Six of the 11 patients required attenuation of the docetaxel dose. The authors concluded that it was not feasible to carry this dose and schedule forward to expanded phase II or phase III trials.
Similarly, Spiridonidis et al[11] explored escalating doses of docetaxel on day 1 or day 15 of a day 1, 8, and 15 schedule of gemcitabine 800 mg/m2 every 28 days in 40 patients (39 with prior chemotherapy) with a variety of tumor types. Dose-limiting toxicity consisted primarily of grade 4 neutropenia in 40% of patients, febrile neutropenia in 7.5%, grade 3/4 thrombocytopenia in 22.5%, grade 3 asthenia in 17.5%, grade 3 flu-like symptoms in 10%, and grade 3 fluid retention in 7.5%. The maximum tolerated dose for docetaxel was higher when it was given on day 1 compared to day 15: 100 mg/m2 vs 75 mg/m2, respectively. Furthermore, successful delivery of the planned dose of docetaxel was 98% vs 74% for the two schedules, respectively.
Objective responses were reported in four of seven patients with previously treated breast cancer and in 9 of 21 patients with previously treated NSCLC (43% response rate, 95% confidence interval [CI]: 22% to 66%), including objective regressions in brain metastases in four patients. Similar to the Pawinski study, dose-limiting myelotoxicity most often occurred on or near day 15 of this schedule, frequently requiring dose attenuations or omissions in the planned day 15 dose of gemcitabine.
21-Day Schedules
Because of the frequent need to reduce or omit day 15 treatment in these 28-day schedules, investigators began to explore 21-day schedules in which gemcitabine could be given on days 1 and 8 with docetaxel on day 1 or 8 (Table 1).
Greek Lung Cancer Cooperative Group Study
Georgoulias et al[13] reported the results of a Greek Lung Cancer Cooperative Group study that explored this new schedule in 52 patients with previously untreated NSCLC. Gemcitabine 900 mg/m2 was administered on days 1 and 8 combined with docetaxel 100 mg/m2 on day 8. Granulocyte colony-stimulating factor (G-CSF [Neupogen]) was added to the regimen at 150 µg/m2 on days 9 to 15. Data from 251 courses of treatment indicated that toxicity was relatively mild with grade 3/4 neutropenia, thrombocytopenia, or anemia in 20%, 8%, and 10% of patients, respectively, and febrile neutropenia in 8%. Grade 2 or 3 asthenia was reported in 17% and 2% of patients, respectively; fluid retention was ≤ grade 2 in 19% of patients.
Gemcitabine and docetaxel dose intensities were maintained at 600 mg/m2/wk and 33 mg/m2/wk, respectively (100% of planned dose intensity), and only 14 of 251 treatment courses were delayed secondary to toxicity. Objective responses were observed in 19 patients (36.5% response rate, 95% CI: 21.5% to 46.4%). The median response duration was 5.0 months, time to tumor progression 7.0 months, and survival 8.5 months; 1-year survival was 42%.
Similar Results From Two Studies
Two additional studies exploring this 21-day schedule soon followed. Rubio et al[14] reported the results of a study by Argentinian investigators using gemcitabine 1,000 mg/m2 on days 1 and 8 combined with docetaxel 75 mg/m2 on day 8 in 18 NSCLC patients. Hematologic toxicity was moderate with grade 3/4 neutropenia and thrombocytopenia occurring in 39% and 0% of courses, respectively. Objective responses were observed in 31% of patients.
Similar results were reported by Rebattu et al[15] with gemcitabine 1,000 mg/m2 on days 1 and 8 combined with docetaxel 85 mg/m2 on day 8 in 36 NSCLC patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 5%, respectively, of courses. Objective responses were documented in 30% of evaluable patients.
Higher Dose Intensity
The rationale of changing from a day 1, 8, and 15 every-4-week schedule to a day 1 and 8 every-3-week schedule in gemcitabine-based studies recently received support from a randomized trial by Soto Parra et al.[16] In this study, patients received cisplatin 70 mg/m2 on day 2 of either schedule with gemcitabine 1,000 mg/m2.
The relative dose intensity (calculated as mg/m2/wk) of gemcitabine was higher with the 3-week schedule than with the 4-week schedule—589 mg/m2/wk compared to 564 mg/m2/wk, respectively. The lower dose intensity of the 4-week schedule resulted from forced reductions or omissions of gemcitabine dosing on day 8 or 15 of the schedule in 17% and 80% of courses, respectively. In spite of the higher dose intensity of the 3-week schedule, grade 3/4 neutropenia, thrombocytopenia, and nonhematologic toxicity was significantly lower than with the 4-week schedule. Furthermore, the response rate was higher with the 3-week compared with the 4-week schedule (55% vs 40%, respectively), although the difference was not statistically significant.
Cisplatin/Docetaxel Comparisons
The Greek Lung Cancer Study Group[17] was the first to compare a new gemcitabine/docetaxel combination to a platinum-based combination, cisplatin/docetaxel (Table 2). A total of 347 patients with advanced or metastatic NSCLC were randomized and treated on the every-3-week schedule. The first group (180 patients) received cisplatin 80 mg/m2 on day 2 combined with docetaxel 100 mg/m2 on day 1; the second group (167 patients) received gemcitabine 1,100 mg/m2 on days 1 and 8 combined with docetaxel 100 mg/m2 on day 8. To decrease the severity of granulocytopenia expected with these moderately intensive treatments, G-CSF was administered on days 3 to 9 of the platinum-based regimen and on days 9 to 15 of the gemcitabine-based regimen.
A comparison of the toxicities of the cisplatin/docetaxel vs gemcitabine/docetaxel regimens revealed a higher rate of grade 3/4 neutropenia with the former (34% vs 20%, respectively, P = .03) but a higher incidence of febrile neutropenia with the latter (29% vs 17%, respectively, P = .004). There were no significant differences between the two regimens with respect to grade 3/4 thrombocytopenia (2% vs 4%, respectively), anemia (6% vs 4%, respectively), or fatigue (30% vs 33%, respectively).
Furthermore, analysis of therapeutic end points revealed no statistically significant differences in response rates (31% vs 34%), median time to progression (8 months each), median survival (12 months vs 11 months), or 1-year survival (46% vs 41%). Although firm conclusions cannot be reached from this randomized phase II trial, it is the first trial to demonstrate that a nonplatinum-based regimen (gemcitabine/docetaxel) may be equivalent to a platinum-based regimen with respect to efficacy.
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