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Current Paradigms in First-Line Treatment of Non–Small-Cell Lung Cancer

Current Paradigms in First-Line Treatment of Non–Small-Cell Lung Cancer

ABSTRACT: Standard first-line chemotherapy for the majority of patients with advanced non–small-cell lung cancer (NSCLC) consists of platinumbased combination regimens including one of the newer-generation agents, such as gemcitabine (Gemzar), a taxane, vinorelbine (Navelbine), or irinotecan (Camptosar). Several effective regimens are available, the choice of which will depend on treatment goals, individual patient or disease factors, as well as physician preferences. This paper surveys randomized trials of many of the newer-generation chemotherapy combinations in patients with advanced NSCLC to examine several issues, such as which new-generation regimen to use, whether a platinum agent is needed, the optimal number of drugs in the combination, and treatment duration.

The majority of patients with
non-small-cell lung cancer
(NSCLC) who are of good performance
status will receive chemotherapy
at some time in the
management of their disease. A metaanalysis
of 52 randomized trials, published
in 1995, supported the use of
cisplatin-based chemotherapy in
NSCLC, based on a 1.5-month improvement
in median survival and a
10% absolute 1-year survival benefit
with chemotherapy vs best supportive
care (NSCLC Collaborative
Group).[1] Chemotherapy was also
associated with improved symptom
control and quality of life. More recently,
platinum-based doublets containing
newer agents including
gemcitabine (Gemzar), the taxanes,
vinorelbine (Navelbine), irinotecan
(Camptosar) and others have demonstrated
improved activity in the firstline
treatment of NSCLC, with
response rates ≥ 40% in several randomized
trials.[2-5]

With several potential regimens
available, it is worth examining key
trials that helped establish current
treatment approaches in NSCLC. This
paper will focus on first-line chemotherapy
for NSCLC, using mainly phase III randomized trials to examine
issues such as which new-generation
regimen to use, whether a
platinum agent should be included,
and if so, cisplatin or carboplatin
(Paraplatin), how many drugs to combine,
and the optimal treatment duration.
Trials that will be discussed,
primarily in terms of response and
survival results, are summarized in
Table 1.

Which Third-Generation
Regimen to Use?
Vinorelbine/Platinum Trials
Vinorelbine was the first of the
third-generation chemotherapy drugs
established for use in lung cancer, and has now accrued more than a
decade of experience in this disease.
Le Chevalier et al conducted a pivotal
trial comparing vinorelbine/cisplatin,
vindesine/cisplatin, and vinorelbine
alone in 612 patients with stage IIIA/B
and IV NSCLC.[2] Response rate improved
significantly with vinorelbine/
cisplatin compared with the other
treatments, (30%, 19% [P = .02], 14%
[P < .001], respectively). Notably,
this was the first trial demonstrating
a 40% 1-year survival rate in advanced
NSCLC (in the vinorelbine/
cisplatin patients), whereas 1-year
survival rates with previous-generation
regimens had ranged around 20%
to 25%.

In the TAX 326 trial, first-line vi-norelbine/cisplatin was compared with
docetaxel/cisplatin and docetaxel/carboplatin
in more than 1,200 advanced
NSCLC patients, with no significant
benefit shown for vinorelbine.[3] Depierre
et al also compared vinorelbine/
cisplatin with single-agent
vinorelbine. Response rate was significantly
higher (43% vs 16%, P =
.0001) when cisplatin was added to
single-agent vinorelbine, although
there were no differences in either
median survival (~ 8 mo) or 1-year
survival rates (~ 35%) between treatment
groups in this study.[6]

Paclitaxel/Platinum Trials
An important study conducted by
the Eastern Cooperative Oncology
Group (ECOG 5592) helped establish
the role of paclitaxel in NSCLC.[7]
Patients (N = 599) received first-line
etoposide/cisplatin or paclitaxel/cisplatin,
with paclitaxel administered at
two doses (135 mg/m2 or 250 mg/m2)
infused over 24 hours. The two paclitaxel
groups combined had superior
1-year survival rates and median survival
times (39% and 9.9 months vs
32% and 7.6 months, P = .048) and
significantly improved response rates
(~26% vs 12%, P < .001) compared
with those achieved with etoposide/
cisplatin, respectively.

A European Organization for Research
and Treatment of Cancer
(EORTC) trial with more than 300
advanced NSCLC patients compared
teniposide (Vumon)/cisplatin and paclitaxel/
cisplatin using a more standard
3-hour paclitaxel infusion time.
A significant response benefit was
seen in the paclitaxel arm (41% vs
28%, P = .018), although 1-year survival
rates were similar (~42%) in the
two groups.[4] In a study of first-line
paclitaxel/cisplatin vs cisplatin alone
in 414 patients, Gatzemeier et al reported
a significant response improvement
(26% vs 17%, P = .028) but no
survival benefit with the paclitaxel
doublet.[8]

Standard initial chemotherapy for
advanced NSCLC in the United States
is paclitaxel plus carboplatin. Belani
et al[9] compared paclitaxel and carboplatin
with the second-generation
regimen of etoposide and cisplatin,
and showed only nonsignificant trends
in favor of the paclitaxel regimen.

The Southwest Oncology Group
(SWOG) compared paclitaxel/carboplatin
and vinorelbine/cisplatin
(SWOG 9509) and found response
rates of 25% in the paclitaxel/carboplatin
arm and 28% in the vinorelbine/
cisplatin arm, with similar
survival rates (median: 8 months).[10]
Patients on the vinorelbine arm had
significantly more nausea and vomiting,
whereas patients on the paclitaxel
arm had significantly more
neurotoxicity. More patients receiving
vinorelbine/cisplatin discontinued
treatment because of toxicity, but quality-
of-life analyses identified no differences
between the two arms.

In a multinational study reported by
Rosell et al, 618 chemotherapy-naive
advanced NSCLC patients received
paclitaxel infused over 3 hours combined
with carboplatin or cisplatin, with
no differences in response rates (~25%)
shown.[11] However, with 22 months
of follow-up, updated analysis showed
median survivals of 8.2 and 9.8
months, respectively (P = .019), suggesting
that cisplatin may be a slightly
more active agent than carboplatin
when combined with paclitaxel.

To compare the most important
third-generation regimens in advanced
NSCLC (stage IIIB, IV, or recurrent
disease), Schiller and colleagues at
ECOG undertook a large 1,200-patient
trial (ECOG 1594) that compared
the best arm of their previous trial
(paclitaxel at 135 mg/m2 infused over
24 hours and cisplatin at 75 mg/m2) to
three other third-generation regimens,
including gemcitabine/cisplatin, docetaxel/
cisplatin, and paclitaxel at 225
mg/m2 infused over 3 hours with carboplatin
(Paraplatin). The results of
the paclitaxel/carboplatin arm were
somewhat disappointing, with a response
rate of only 17% and median
and 1-year survival rates of 8.5 months
and 34%, respectively.[12] However,
these results were similar to those seen
in the other three arms, and none of the three study arms was significantly
better than the reference arm of paclitaxel
and cisplatin.

Gemcitabine/Platinum Studies
Gemcitabine has been studied combined
with platinum as first-line therapy
for NSCLC in several phase III
randomized studies. Sandler et al from
the Hoosier Oncology Group (HOG)
conducted a randomized phase III
study (n = 522) comparing cisplatin
at 100 mg/m2 on day 1 plus gemcitabine
at 1,000 mg/m2 on days 1, 8, and
15 every 4 weeks to cisplatin at 100
mg/m2 on day 1, every 4 weeks.[13]

Patients receiving cisplatin/gemcitabine
had significantly improved response
(30.4% vs 11.1%; P < .0001),
median time to progression (5.6 vs
3.7 months; P = .0013), and overall
survival (9.1 vs 7.6 months; P = .004).
Toxicity was mostly hematologic
(more pronounced in the combination
arm) with grade 4 neutropenia in
35.3% of patients vs 1.2%; neutropenic
fever was < 5% in both arms.
Grade 4 thrombocytopenia occurred
in 25.4% of patients on the combination
arm vs 0.8% of those on the
monotherapy arm.

In a study conducted by Cardenal
et al comparing gemcitabine/cisplatin
and the second- generation regimen
etoposide/cisplatin in 133 advanced
NSCLC patients, the gemcitabine regimen
produced a significantly higher
overall response rate (41% vs 22%,
P = .02) and a significant delay in
time to disease progression (6.9 vs
4.3 months, P = .01).[14] Survival
was similar in the two arms.

The ECOG 1594 study mentioned
previously, which compared four
third-generation regimens, included
gemcitabine/cisplatin as one treatment
arm. Response and 1-year survival
rates with the gemcitabine combination
(22%, 36%) were similar to those
achieved with paclitaxel/cisplatin
(21%, 31%), and higher than those of
docetaxel/cisplatin (17%, 31%) and
paclitaxel/carboplatin (17%, 34%) although
these differences were not
significant.[12] The only significant
study finding was that of time to disease
progression, favoring the gemcitabine/
cisplatin doublet (4.2 vs 3.4, 3.7,
and 3.1 months, respectively, P < .05).

The gemcitabine/cisplatin doublet
and paclitaxel/cisplatin doublets comprised
two out the three arms of an
EORTC trial (EORTC 08975) [15] vs
MIC (mitomycin [Mutamycin], ifosfamide
[Ifex], cisplatin). No significant
differences were seen for either
response or survival rates.

Notwithstanding the excellent response
rates achieved when gemcitabine
is combined with cisplatin, many
physicians prefer to use carboplatin
based on tolerability issues. When
administered with carboplatin, gemcitabine
is generally given on a day 1,
day 8 schedule and the carboplatin
dose must be reduced to an area under
the concentration curve (AUC) of
5 to lessen risk of severe thrombocytopenia.
Gemcitabine/carboplatin has
only been compared in randomized
trials to second-generation regimens.

In one study of gemcitabine/carboplatin
vs MIC or MVP (mitomycin,
vinblastine, cisplatin), no
significant differences in response and
survival outcomes were noted.[16]
However, a significant survival advantage
favoring gemcitabine/carboplatin
over MIP (mitomycin,
ifosfamide, cisplatin) was demonstrated
in another randomized trial (n =
422) for median survival, 10.0 vs 6.5
mo; 1-year survival rates, 38% vs
28%; P = .0043.[17] Gemcitabine/carboplatin
also provided significantly
better response (27% vs 15%, P < .05) and mean (11.5 vs 7.9 mo, P =
.0001) and 1-year (36% vs 12%, P < .05) survival results than the secondgeneration
vinblastine/cisplatin regimen.[
18] These results thus
demonstrate the utility of carboplatin
as an alternate to cisplatin in gemcitabine-
containing regimens.

Docetaxel/Platinum Regimens
The four-arm ECOG 1594 study
included the docetaxel/cisplatin regimen,
wherein the response rate (17%)
and median survival (7.4 months)
were lower than those achieved with
the paclitaxel/cisplatin or gemcitabine/
cisplatin doublets (P = not significant).[
12] On the other hand, in the
large TAX 326 study, docetaxel/cisplatin
had improved response rates
(32%, 24%, 25%, P = .029) relative
to docetaxel/carboplatin and vinorelbine/cisplatin, respectively.[3] Furthermore,
while 2-year survival rates
are often not reported, docetaxel/cisplatin
treatment resulted in a 7% absolute
2-year survival improvement
over that achieved with vinorelbine/
cisplatin (21% vs. 14%). Quality-oflife
assessments also favored the docetaxel
arms in this trial.

In a smaller study from Japan involving
more than 300 chemotherapy-
naive stage IV NSCLC patients,
docetaxel/cisplatin significantly improved
response rate (37% vs 21%,
P < .01) and median survival (11.3 vs
9.6 mo, P = .014) over that achieved
with vindesine/cisplatin, and there was
a trend toward improved 1-year survival
(48% vs 41%).[19]

Irinotecan/Platinum Regimens
Randomized trials of first-line
irinotecan in advanced NSCLC have
also been carried out. Negoro et al
compared irinotecan/cisplatin, vindesine/
cisplatin, and irinotecan alone
in approximately 400 patients.[20]
Significant improvements in response
rates (44%, 32%, 21%, respectively,
PP = .004, for irinotecan/cisplatin
vs vindesine/cisplatin; and 42.1
vs 36.4 weeks for irinotecan alone vs
vindesine/cisplatin, P = .018). In contrast,
preliminary data from a randomized
trial comparing irinotecan/
cisplatin with vindesine/cisplatin, paclitaxel/
carboplatin, and gemcitabine/
cisplatin showed similar response rates
(~30%) for the four treatment groups,
with no survival data yet available.[21]

Pemetrexed
Pemetrexed (Alimta) is a multitargeted
antifolate with response rates of
≥ 20% as a single agent and approximately
40% when combined with cisplatin,
even in patients with advanced
NSCLC.[22,23] This agent has demonstrated
its activity in second-line
NSCLC, and randomized trials in the
first-line setting are awaited to determine further the role of pemetrexed.
Possible combination partners under
investigation include gemcitabine, vinorelbine,
carboplatin, and oxaliplatin
(Eloxatin).

Is Platinum Necessary?

Data from several randomized trials
of first-line treatment in advanced
NSCLC can be used to address whether
a platinum agent is necessary. For
example, EORTC 08975 included
combinations of cisplatin with
gemcitabine or paclitaxel and the nonplatinum
paclitaxel/gemcitabine doublet.[
15] No significant differences
were noted, although the lowest response
rate of 27% and median survival
time of 6.9 months occurred in
the nonplatinum arm-results lower
than one would expect with a thirdgeneration
platinum-based regimen.

A trial by Gridelli et al undertaken
by the National Cancer Institute (NCI)
of Italy Naples group and the NCI
Canada also found inferior results for
the non-platinum regimen (vinorelbine/
gemcitabine) compared with
gemcitabine or vinorelbine combined
with cisplatin.[24] Time to disease
progression was significantly poorer
in the nonplatinum arm (P = .004),
while response and 1-year survival
differences were not statistically significant,
although trended in favor of
cisplatin use. Toxicity was greater in
this study in the cisplatin arm, but
patients treated with the cisplatinbased
regimens had more improvement
in their symptoms. It is also of
interest that, despite greater toxicity
in the platinum arm, quality of life
was similar in both arms.

Two other studies involving approximately
900 chemotherapy-naive
advanced NSCLC patients demonstrated
virtual equivalence of nonplatinum
and platinum regimens, in
comparisons of docetaxel/cisplatin vs
docetaxel/gemcitabine[25], and paclitaxel/
carboplatin vs paclitaxel/gemcitabine.[
26] Response rates ranged from
28% to 35% with the four regimens,
with ~10-month median survival times
and ~40% 1-year survival rates.

While these study results are somewhat
mixed regarding the need for
platinum therapy, a recent meta-analysis by D'Addario et al provides support
for platinum-containing chemotherapy.[
27] This meta-analysis compared
effects of platinum and nonplatinum
regimens administered to
more than 7,500 patients with NSCLC
participating in 37 trials. Response
rates significantly improved with platinum-
based chemotherapy (P < .0001)
when all trials were considered, and
also when only the 1,563 patients
treated with third-generation regimens
were assessed (P = .0032). Survival
also favored cisplatin-based treatment,
although the difference was not statistically
significant for the third-generation
regimens.

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