Gemcitabine-Containing Regimens vs Others in First-Line Treatment of NSCLC

Results of randomized clinical
trials have established carboplatin
(Paraplatin)/paclitaxel,
cisplatin/gemcitabine (Gemzar), cisplatin/
docetaxel (Taxotere), and cisplatin/
vinorelbine (Navelbine) as
standard first-line treatments for advanced/
metastatic non-small-cell lung
cancer (NSCLC). To address the relative
merits of these regimens, an informal
meta-analysis of efficacy and
toxicity findings in randomized trials
evaluating these regimens was performed.

Similarly, an informal meta-analysis
was performed to compare carboplatin-
containing regimens with
cisplatin-containing regimens to assess
the potential merits of replacing
cisplatin with carboplatin in combination
with gemcitabine or docetaxel.
In addition, a formal meta-analysis of
trials comparing gemcitabine/platinum
regimens with other platinumbased
regimens in NSCLC has been
performed with regard to progressionfree
survival and overall survival.

Informal Meta-analysis of
Standard First-Line Regimens

Our informal meta-analysis included
13 major randomized trials of
carboplatin/paclitaxel, cisplatin/gemcitabine,
cisplatin/docetaxel, or cisplatin/
vinorelbine as first-line
regimens in advanced NSCLC; 12 of
the trials had enrollment greater than
150 patients. Select results from these
trials-consisting of objective response
rate, median and 1-year survival,
and major toxicities-were
weighted for patient accrual, mathematically
averaged, and compared.
The 18 treatment arms included in the
analysis are shown in Table 1.[1-12]

The comparison of efficacy outcomes
is shown in Table 2. Objective
response rates were similar for the
four regimens, ranging from 24% to
30%. Survival outcomes also showed
little difference among regimens, with
median duration of survival ranging
from 8.6 to 9.1 months and 1-year
survival ranging from 37% to 39%.
These findings are consistent with
those reported by Schiller et al in the
Eastern Cooperative Oncology Group
(ECOG) 1594 trial, which showed no
significant differences in overall survival
(and nearly superimposed survival
curves) with cisplatin/paclitaxel,
cisplatin/gemcitabine, cisplatin/docetaxel,
and carboplatin/paclitaxel[3]
and with the Southwest Oncology
Group comparing carboplatin/paclitaxel
to cisplatin/vinorelbine.[2]

The comparison of toxicities is
shown in Table 3. The lowest rate of
grade 4 granulocytopenia is seen with
carboplatin/paclitaxel (15%) and the
highest with cisplatin/docetaxel
(35%). Rates of febrile neutropenia
ranged from 1% to 2% with carboplatin/
paclitaxel and cisplatin/gemcitabine
and from 4% to 5% with
cisplatin/ docetaxel and cisplatin/vinorelbine.
The highest rate of grade 4
thrombocytopenia is observed with
cisplatin/gemcitabine. It is important
to note, however, both that this thrombocytopenia
is characteristically transient
and does not result in serious
bleeding complications and that the
six cisplatin/gemcitabine arms included
in the analysis reflect use of gemcitabine
on a schedule of days 1, 8,
and 15 every 28 days. (Note that the
cisplatin dose of 100 mg/m² in some
of trials was higher than what is normally
used in actual practice; cisplatin
doses > 80 mg/m² only add incrementally
more toxicity without efficacy.)

With regard to the latter, hematologic
toxicity is markedly reduced
with no loss of efficacy when gemcitabine
is given in the now-standard
schedule of day 1 and 8 every 21
days. For example, a comparison of
gemcitabine at 1,000 mg/m² on days
1, 8, and 15 every 28 days or 1,000
mg/m² on days 1 and 18 every 21
days plus cisplatin at 70 mg/m² on
day 2 with both gemcitabine regimens
showed that treatment with the 21-
day schedule was associated with an
increase in dose intensity of both drugs
(due to improved delivery), a reduction
in neutropenia (25% vs 35%), a
reduction in thrombocytopenia (7%
vs 40%), an increase in anemia (10%
vs 0%, due to more frequent dosing
of cisplatin), reduced nonhematologic
toxicity (25% vs 33%), and a numeric
but nonsignificant improvement
in response rate (55% vs 40%).[13]

With regard to nonhematologic
toxicities, grade 3/4 neurologic toxicity
is most common with carboplatin/
paclitaxel, likely reflecting the increased
risk with paclitaxel given on
a 21-day schedule, with rates for the
cisplatin-containing combinations reflecting
the usual 6% to 10% rate of
grade 3 neurologic toxicity seen with
cisplatin. The rate of grade 3/4 arthralgias/
myalgias is also highest with
carboplatin/paclitaxel, likely reflecting
the generally self-limiting and
manageable toxicity that occurs on
days 3 to 5 after paclitaxel administration,
and lowest with cisplatin/gemcitabine.
Alopecia of any grade is far
more common with taxane-containing
regimens than with cisplatin/gemcitabine
or cisplatin/vinorelbine.
Cisplatin-induced nephrotoxicity and
gastrointestinal toxicity have also been
reported in clinical trials.

Informal Meta-analysis: Can
Carboplatin Replace Cisplatin
in Combination With
Gemcitabine or Docetaxel?

It is unclear whether cisplatin-containing
combinations with docetaxel
or gemcitabine are superior to carboplatin-
containing combinations. The
findings of the TAX 326 trial, which
showed a survival advantage of cisplatin/
docetaxel over cisplatin/vinorelbine
and no difference in this regard
between cisplatin/vinorelbine and carboplatin/
docetaxel regimens, are
sometimes interpreted to indicate an
advantage of cisplatin/docetaxel over
carboplatin/docetaxel.[9] However, a
number of trials have shown no difference
between cisplatin- and carboplatin-
containing regimens, including
a trial comparing cisplatin/gemcitabine
and carboplatin/gemcitabine,[14]
with many data indicating that carboplatin-
containing regimens are better
tolerated.

We performed a meta-analysis of
13 trials involving 17 arms of firstline
treatment with carboplatin/
paclitaxel, cisplatin/gemcitabine, carboplatin/
gemcitabine, cisplatin/docetaxel,
and carboplatin/docetaxel
(Table 4).[1-10,14-16] Therapeutic
outcome comparisons show no
marked difference between cisplatin/
gemcitabine and carboplatin/gemcitabine
treatments, with perhaps some
indication of trends favoring the latter
(Table 5). There appears to be
little difference between cisplatin/
docetaxel and carboplatin/docetaxel
in terms of patient survival. Comparison
of toxicities for carboplatin in
combination with paclitaxel, gemcitabine,
or docetaxel-the three most
widely used carboplatin-containing
regimens in the United States-shows
advantages of the carboplatin/gemcitabine
regimen over one or both
other regimens in terms of granulocytopenia,
neurologic toxicity, arthralgias/
myalgias, and alopecia
(Table 6).

Conclusions

The use of two-drug platinumbased
regimens have improved survival
in advanced NSCLC. Our
informal meta-analysis of trials evaluating
carboplatin/paclitaxel, cisplatin/
gemcitabine, cisplatin/docetaxel,
and cisplatin/vinorelbine indicates
comparable efficacy of the regimens
in terms of response rate, time to disease
progression, and survival, with
some advantages in terms of toxicity
accruing to the regimens not containing
taxanes. It also appears that carboplatin
could be substituted for
cisplatin in combination with gemcitabine
or docetaxel without loss of effectiveness
and with advantages in
terms of toxicity and ease of drug
administration. In this regard, the data
may be particularly strong in favor of
the carboplatin/gemcitabine combination,
which appears to have the best
therapeutic index of the platinumbased
combinations.

A recent formal meta-analysis indeed
suggests that there are efficacy
advantages to gemcitabine/platinum
combinations compared with other
platinum-based regimens in the treatment
of NSCLC. Le Chevalier et al
performed a meta-analysis of overall
survival and time to disease progression
in randomized trials comparing
combinations of gemcitabine with carboplatin
or cisplatin against a platinum-
based regimen.[17] Thirteen
trials were identified for the analysis,
representing a total population of
4,556 patients.

A total of 17 comparators were
identified, including 12 platinumbased
doublets (6 cisplatin/vinorelbine,
2 cisplatin/paclitaxel, 2
carboplatin/paclitaxel, 1 cisplatin/docetaxel,
and 1 cisplatin/etoposide), 4
platinum-based triplets (mitomycin/
vinorelbine/cisplatin or mitomycin/
ifosfamide/cisplatin), and 1 singleagent
cisplatin regimen. Hazard ra-
tios were calculated using a fixedeffects
model, with statistical heterogeneity
being addressed using a
random-effects model when appropriate,
and absolute treatment benefit at
1 year was estimated.

For overall survival, there was a
significant reduction in mortality in
favor of the gemcitabine-platinum
arms versus platinum-based comparator
arms; the hazard ratio for gemcitabine-
based treatment was 0.90 (95%
confidence interval [CI] = 0.84-0.96,
P < .001), and the absolute survival
advantage at 1-year was 3.9%. There
was also a significant improvement in
time to disease progression in favor
of gemcitabine regimens; the hazard
ratio was 0.87 (95% CI = 0.82-0.93,
P < .001), and the absolute improvement
in progression-free survival at
1-year was 4.2%.

Although the superiority of any one
of the currently accepted regimens for
first-line treatment of advanced
NSCLC has not been clearly defined
by individual clinical trials, analysis
of available data in aggregate suggests
that there may indeed be differences
in effectiveness, tolerability, and
toxicity among these regimens. On
the basis of informal meta-analyses
and the formal meta-analysis conducted
by Le Chevalier et al,[17] it would
appear that gemcitabine/platinum regimens
pose an advantage in terms of
therapeutic response and that gemcitabine/
carboplatin may be considered
the preferred regimen on the basis of its
overall efficacy and toxicity profiles.