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Gemcitabine and Nonplatinum Combinations in Non-Small-Cell Lung Cancer

Gemcitabine and Nonplatinum Combinations in Non-Small-Cell Lung Cancer

ABSTRACT: Gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), and vinorelbine (Navelbine) are among the most active agents for the treatment of non-small-cell lung cancer and are generally more active than platinum compounds. When combined with a platinum compound, these agents have produced the best survival outcomes seen to date in non-small-cell lung cancer. More than 100 clinical trials have defined and expanded the role of gemcitabine, which has been combined with each of these agents to create novel combinations. Several new nonplatinum-based combinations compare favorably with platinum-based combinations with respect to toxicity and efficacy. Moreover, changing the schedule of gemcitabine administration from days 1, 8, and 15 every 4 weeks to days 1 and 8 every 3 weeks seems to allow greater dose intensity with less severe toxicity and slightly greater efficacy. Coadministration of docetaxel, paclitaxel, or vinorelbine with gemcitabine on days 1 and 8 every 3 weeks is a promising approach. In addition to a lower incidence of severe neutropenia, docetaxel, paclitaxel, and vinorelbine protect against gemcitabine-associated thrombocytopenia. [ONCOLOGY 15(Suppl 6):18-25, 2001]

Introduction

Gemcitabine (Gemzar), docetaxel (Taxotere), 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, 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 (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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