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New Investigative Regimens and Cytotoxic Agents in Thoracic Cancers: Gemcitabine and Pemetrexed

New Investigative Regimens and Cytotoxic Agents in Thoracic Cancers: Gemcitabine and Pemetrexed

ABSTRACT: Several new antimetabolites, administered alone or in combination, are changing the therapeutic landscape for thoracic cancer. Two-drug combinations involving these newer drugs are becoming the standard of care for non–small-cell lung cancer (NSCLC), largely due to improvements in survival rates, time to disease progression, and response rates as well as an improved safety profile. Gemcitabine (Gemzar) has elicited considerable interest in this disease, as a combination partner in chemotherapeutic regimens. Another promising agent is pemetrexed (Alimta), a folate-based inhibitor of thymidylate synthase. In preclinical development, pemetrexed both alone and in combination with other cytotoxic agents has exhibited activity across a broad range of tumor models, including NSCLC and mesothelioma. In clinical trials of patients with NSCLC, pemetrexed has been an effective, well-tolerated agent that can be used as monotherapy or in combination with other agents at full dose. In clinical trials of patients with mesothelioma, the combination of pemetrexed and cisplatin demonstrated a significant improvement in survival, response, and patient quality-of-life parameters. The principle toxicities of pemetrexed can be minimized by folate and vitamin B12 supplements.

In recent years, development of
more effective and less toxic drugs
has changed the therapeutic landscape
for lung cancer. The urgent need
for such improved treatment options
is evidenced by the current US mortality
trends. Among men, lung cancer
has been the leading cause of
cancer death for more than 50 years.
In 2004, an estimated 93,110 men will
be diagnosed with lung cancer and
91,930 will die of the disease. Among
women, the mortality rate from lung
cancer is lower, but is continuing to
increase, even as breast cancer mortality
is declining. An estimated
80,660 women will be diagnosed with
lung cancer in 2004, of whom 68,510
will die.[1]

If current trends continue, men and
women will be equally at risk of developing
and dying from the disease,
and twice as many persons of each
sex will die of the disease than from
any other type of cancer. The current
5-year survival rate is approximately
16%. While that rate is higher than
the 5-year survival rate of 5% reported
in 1964, there is obviously considerable
room for improvement, both in
terms of earlier diagnosis and more effective, less toxic therapy of advanced
disease.

In this supplement, noted investigators
in the field of lung cancer
present articles with particular focus
on gemcitabine (Gemzar) and pemetrexed
(Alimta). First-line regimens
in non-small-cell lung cancer
(NSCLC), and the carboplatin (Paraplatin)/
gemcitabine and cisplatin/gemcitabine
combinations in advanced NSCLC are discussed, as is the potential
role of induction therapy in
early-stage NSCLC. Other multimodality
approaches such as chemoradiation
are presented. The use of the
promising antifolate pemetrexed is
discussed in studies of pemetrexed
administered as a single agent to patients
with previously treated/untreated
NSCLC. Another arena that is
covered in this supplement is the role of pemetrexed either alone or in combination
with cisplatin or carboplatin
in the management of malignant mesothelioma.
It is hoped that these data
will benefit investigators in both basic
and clinical research, as well as
those involved in the design of future
clinical trials.

Gemcitabine Monotherapy

When used as monotherapy, some
of the newer agents offer at least
equivalent survival and an improved
safety profile over combinations of
older chemotherapies used for treating
NSCLC. For example, singleagent
gemcitabine is as effective as
many doublets, such as cisplatin plus
either etoposide or vindesine (Eldesine),
yet with much lower toxicity
rates.

In one randomized multinational
multicenter study, a partial response
was reported in 12 of 66 (18.2%)
chemotherapy-naive patients treated
with gemcitabine monotherapy,
1,000 mg/m2 IV on days 1, 8, and 15
of a 28-day cycle. In comparison, partial
response was achieved in 11 of 71
(15.5%) patients receiving combination
cisplatin (100 mg/m2 IV on day 1
of each 28-day cycle) plus etoposide
(100 mg/m2 on days 1, 2, and 3 after
cisplatin).[2] There was no significant
difference between the two treatment
groups with respect to time to
disease progression or survival.

The combination therapy was
markedly more toxic than gemcitabine
monotherapy, with pronounced
respective differences in neutropenic
fever (11% vs 0 %), nausea and vomiting
(29% vs 11%), and alopecia
(62% vs 11%). A second randomized
study involved 169 NSCLC patients
who were treated with either gemcitabine
(1,000 mg/m2on days 1, 8, and
15) or cisplatin (100 mg/m2 on day 1,
plus vindesine at 3 mg/m2on days 1
and 15), both every 4 weeks.[3,4] Response rates were similar in both the
gemcitabine (20.2%) and combination
therapy (20%) groups, with no
important differences in objective response
rate, time to progression, or
median survival reported. Grade 3/4
toxicity was significantly higher in
the cisplatin/vindesine group for leukopenia
(P = .0003), neutropenia (P
< .0001), nausea/vomiting (P= .0006),
alopecia (P < .0001), and neurotoxicity
(P = .04). Some severe pulmonary
toxicity to gemcitabine was noted.

These studies illustrate the current
trend toward developing agents that
can produce survival rates that are at
least equivalent to those seen with
combination therapy with less toxicity.
The reduction in toxicity is particularly
important among patients with
NSCLC, who often have many comorbid
diseases. Thus, newer drugs
such as gemcitabine may provide a
useful alternative strategy for patients
for whom the main purpose of treatment
is palliation.[5]

Newer Two-Drug Combinations
vs Single Agents

Two-drug combinations involving
the newer drugs (gemcitabine, docetaxel
[Taxotere], paclitaxel, vinorelbine
[Navelbine]) are replacing
single-agent therapy as standard of
care, largely due to improvements in
survival rates, time to disease progression,
and response rates, as supported
by results of two recent
randomized comparative studies.

The first phase III study, which
involved 522 chemotherapy-naive
NSCLC patients, compared efficacy
and safety of combination therapy
with gemcitabine (1,000 mg/m2 on
days 1, 8, and 15) plus cisplatin (100
mg/m2 on day 1 of a 28-day cycle) vs
cisplatin alone (100 mg/m2 IV on day
1 of 28-day cycle).[6] Combination
therapy demonstrated a significant
improvement over cisplatin monotherapy
with regard to response rate
(30.4% vs 11.1%, P < .0001), median
time to progressive disease (5.6 vs
3.7 months, P = .0013), and overall
survival (9.1 vs 7.6 months, P = .004).
At 1 year, the estimated probability of
survival was 39% for the gemcitabine/
cisplatin arm compared with 28% for the cisplatin monotherapy arm.
The 2-year survival rates were 15%
and 8%, respectively.

Toxicity was more pronounced in
the combination arm than the monotherapy
arm, including grade 4 neutropenia
(35.3% vs 1.2%) and grade 4
thrombocytopenia (25.4% vs 0.8%).

Similar benefits from combination
therapy were observed in a second
study, in which 415 patients were randomized
to treatment with cisplatin at
100 mg/m2 every 4 weeks, administered
either as monotherapy or in
combination with vinorelbine at
25 mg/m2 weekly.[7] One-year survival
was 20% for cisplatin alone and
36% for the combination arm. Twoyear
survival was 12% in the combination
therapy group compared with
7% for cisplatin alone. There was a
partial response rate of 12% vs a 26%
response rate (2% complete response
plus 24% partial response, P = .0002)
in the combination arm. Significant
advantages in progression-free survival
(median 2 vs 4 months; P = .0001)
and overall survival (median 6 vs 8
months; P = .0018). Grades 3 and 4
granulocytopenia was reported in 81%
of the combination arm and 5% of the
monotherapy arm.

Other evidence supports use of the
newer two-drug combinations rather
than monotherapy with one of the new
agents. In three recent clinical trials,
addition of a second agent such as
carboplatin or cisplatin to a monotherapy
regimen of one of the new
agents such as gemcitabine, docetaxel,
or paclitaxel increased median survival
by at least 2 months and
increased 1-year survival by 4% to
12%.[8,9]

Lilenbaum and the Cancer and
Leukemia Group B (CALGB) reported
a study (n = 99) comparing a regimen
of paclitaxel alone vs paclitaxel
plus carboplatin. Median survival was
6.7 months vs 8.8 months, respectively;
1-year survival rates were 33% vs
37%, respectively.[10] In a second
comparative study (n = 307), Georgoulias
and coworkers administered a
regimen of docetaxel (100 mg/m2 on
day 1) plus cisplatin (80 mg/m2 on
day 2) was associated with longer
median survival (10.1 vs 8.0 months)
and higher 1-year survival rate (48% vs 42%) than cisplatin alone.[8]

The most striking evidence in favor
of combination therapy comes
from a Swedish Lung Cancer Group
study involving 322 patients with advanced
NSCLC who were treated with
either gemcitabine monotherapy at
1,250 mg/m2 on days 1 and 8 every
21 days, or the same regimen of
gemcitabine plus carboplatin, area under
the concentration-time curve (AUC)
5 on day 1 every 21 days.[9] The objective
response rate was 12% for the
monotherapy group compared with
30% for the combination therapy group.
Respective time to progression was 9.0
vs 11.0 months, and 1-year survival
rates were 32% and 44%.

Doublet vs Doublet

Results of a recent large (n = 1,155)
study conducted by Schiller et al and
the Eastern Cooperative Oncology
Group (ECOG 1594) suggest that
none of the newer two-drug combinations
is clearly superior. Patients with
advanced NSCLC were randomly assigned
to a reference regimen of cisplatin
and paclitaxel or to one of three
experimental regimens: cisplatin and
gemcitabine, cisplatin and docetaxel,
or carboplatin and paclitaxel.[11]

The overall response rate was 19%,
with a median survival of 7.9 months.
Survival rate was 33% at 1 year and
11% at 2 years. The response rate did
not differ significantly between patients
assigned to receive cisplatin and
paclitaxel (17%) and those assigned
to receive any of the three experimental
regimens (cisplatin and gemcitabine,
22%; cisplatin and docetaxel,
17%; and carboplatin and paclitaxel,
17%). Likewise, 1-year survival rates
did not vary significantly between cisplatin
and paclitaxel (31%) and the
experimental regimens (cisplatin and
gemcitabine, 36%; cisplatin and docetaxel,
31%; and carboplatin and paclitaxel,
34%).

Kelly et al reported another randomized
phase III trial (n = 408) that
demonstrated equal efficacy between
paclitaxel (225 mg/m2, day 1 every
28 days) and carboplatin (AUC 6, day
1 every 21 days) compared with vinorelbine
(25 mg/m2/wk) and cisplatin
(100 mg/m2/d, day 1 every 28 days).[12] The response rate was 25%
in the paclitaxel and carboplatin arm
and 28% in the vinorelbine and cisplatin
arm. Median survival was
8 months in both treatment arms,
while 1-year survival rates were 38%
and 36%, respectively. Significantly
(P = .001) more patients in the vinorelbine
and cisplatin arm discontinued
therapy because of toxicity, particularly
grade 3 and 4 leukopenia, neutropenia,
and nausea and vomiting.

Carboplatin vs Cisplatin

Several studies suggest that carboplatin
compared with gemcitabine or
with paclitaxel is as effective as cisplatin
in combination with these
agents. For example, two recent randomized
trials suggest that gemcitabine
plus carboplatin may be as
effective as gemcitabine plus cisplatin
for patients with advanced
NSCLC. The first was a phase II study
of 120 patients treated with either gemcitabine
(1,200 mg/m2 days 1 and 8)
plus carboplatin (AUC 5 at day 2) or
gemcitabine (1,200 mg/m2 days 1 and
8) plus cisplatin (80 mg/m2day 2),
with cycles repeated every 3 weeks.[13]

The objective response rate was
41.9% for gemcitabine plus cisplatin
and 31.0% for gemcitabine plus carboplatin
(P = .29). Median survival
was 10.4 months for gemcitabine plus
cisplatin and 10.8 months for gemcitabine
plus carboplatin. Overall toxicity
was significantly more common in
the gemcitabine plus cisplatin arm
(P < .005).

The second trial was a multicenter
phase III trial by Zatloukal et al involving
176 patients.[14] Patients in
both treatment arms were given gemcitabine
(1,200 mg/m2 on days 1 and
8) plus either cisplatin (80 mg/m2) or
carboplatin (AUC 5). The overall response
rates were 41% for the gemcitabine
plus cisplatin arm and 29%
for the gemcitabine plus carboplatin
arm. Median survival was 8.8 and 8.0
months, respectively. Patients with at
least one grade 3/4 toxicity, excluding
nausea, vomiting or alopecia, were
44% in gemcitabine plus cisplatin arm
and 54% in gemcitabine plus carboplatin
group. The only significantly
different toxicities were nausea and vomiting in the gemcitabine plus cisplatin
group and thrombocytopenia
in the gemcitabine plus carboplatin
group.

These studies suggest that the combination
of gemcitabine plus carboplatin
may be an acceptable alternative
for patients with advanced NSCLC,
especially when they are unable to
receive cisplatin. The ECOG trial cited
previously[11] is a good example
of a trial showing equivalent efficacy
for paclitaxel combined with either
cisplatin or carboplatin.

Chemotherapy for
Elderly Patients

Age does not appear to be a significant
independent prognostic factor
for outcome in NSCLC, and elderly
patients with good performance status
can tolerate the same treatment as
younger patients. In the Elderly Vinorelbine
Study (ELVIS) of Gridelli
et al involving 191 patients over 70,
median survival was 28 weeks among
those receiving vinorelbine (on days
1 and 8, every 21 days) compared
with 21 weeks in those receiving best
supportive care.[15] Respective 1-year
survival rates were 32% and 14%.
Moreover, patients who received vinorelbine
fared better than controls
on measures of lung cancer symptoms
and pain and on social, cognitive,
and physical functioning.
Hematologic toxicity included grade
3/4 neutropenia in 10% of patients
and grade 2/3 anemia in 16% of patients.
The principal nonhematologic
toxicities were constipation and fatigue.

The question of whether elderly
patients should receive one- or twodrug
chemotherapy regimens has not
been fully answered, although some
recent trials suggest that two-drug
combinations improve outcome.
Frasci and colleagues conducted a randomized
study of 240 patients with
NSCLC between the ages of 71 and
85 years who received gemcitabine at
1,200 mg/m2, plus vinorelbine at 30
mg/m2 on days 1 and 8 every 3 weeks,
or vinorelbine monotherapy.[16] Median
survival was 28 weeks in the
combination therapy group and 18
weeks in the vinorelbine monotherapy group. Respective projected 1-year
survival was 30% and 13%. The rates
of hematologic and nonhematologic
toxicities were not significantly different
in the two arms.

In the CALGB trial[10] comparing
paclitaxel to the combination of
paclitaxel/carboplatin, the combination
was superior in all subsets including
the elderly.

In contrast, results of a phase II
randomized study of suggest that
monotherapy may be as active and
tolerable as combination therapy in
NSCLC patients over 70 years old.
The 147 patients were randomly assigned to one of three regimens: single-
agent gemcitabine at 1,200 mg/m2
given on days 1 and 8; a combination
of gemcitabine at 1,000 mg/m2 and
vinorelbine at 25 mg/m2, both given
on days 1 and 8 every 3 weeks; or
vinorelbine monotherapy.[17] Median
survival was 6.5 months for gemcitabine
alone, 8.5 months for
vinorelbine alone, and 7.4 months
for combination therapy. Respective
1-year survival rates were 28%, 42%,
and 34%.

With gemcitabine monotherapy,
the principle toxicities were grade 4
thrombocytopenia and grade 2 hepatic
toxicity in one patient each and
grade 2 pulmonary toxicity in two
patients. The combination regimen
was associated with grade 5 neutropenia
and thrombocytopenia in one
patient each, grade 3 anemia necessitating
transfusion in two patients, and
grade 4 fever in two patients. In addition,
four patients with severe cardiac
comorbidities experienced grade 3
heart toxicity.

Performance Status and
Choice of Regimen

Performance status (PS) has been
established as an independent prognostic
variable, as patients with PS 2
have a significantly lower rate of survival
than those with a PS of 0 or
1.[11] Some evidence suggests that
cisplatin-containing combinations, including
those with paclitaxel, gemcitabine,
or docetaxel, are too toxic for
PS 2 patients.

In ECOG 1594, for example, which
involved 64 PS 2 patients with advanced
NSCLC, Sweeney et al reported
that the proportion of patients
who developed grades 3, 4, or 5 toxicity
ranged from 55% to 88% during
therapy with four different regimens:
paclitaxel (135 mg/m2) over 24 hours
with cisplatin (75 mg/m2) on a 21-day
cycle; cisplatin (100 mg/m2) with gemcitabine
(1,000 mg/m2) on days 1, 8,
and 15 on a 28-day cycle; cisplatin
(75 mg/m2) with docetaxel (75 mg/
m2) on a 21-day cycle; and paclitaxel
(225 mg/m2) over 3 hours with carboplatin
(AUC 6).[18]

Nonhematologic grade 3/4 toxicities
occurred significantly less often in the paclitaxel and carboplatin arm
(P = .0032). (Note that the cisplatin
dose of 100 mg/m2 in the cisplatingemcitabine
arm was higher than what
is normally used in actual practice, because
cisplatin doses above 80 mg/m2
only add incrementally more toxicity
without efficacy.) The overall response
rate was 14%, and the overall
median survival was 4.1 months. None
of the four regimens tested demonstrated
any survival advantage.

A subsequent study by Langer et
al compared 98 PS 2 patients who
were randomized to receive paclitaxel
(200 mg/m2) plus carboplatin (AUC
6 every 3 weeks) or gemcitabine
(1,000 mg/m2 on days 1 and 8) plus
cisplatin (50 mg/m2 day 1 every 3
weeks). For the gemcitabine/cisplatin
arm, the overall response rate was 21%
and median survival was 6.8 months.
Respective findings for the paclitaxel/
carboplatin arm were 10% and 6.1
months.[19]

In the CALGB trial,[10] the combination
of paclitaxel/carboplatin was
superior to paclitaxel alone in the
PS 2 subset.

Second-Line Chemotherapeutic
Regimens

For second-line therapy, some new
agents such as docetaxel have been
shown to provide clinically meaningful
survival benefit to patients with
advanced NSCLC whose disease has
relapsed or progressed after platinumbased
chemotherapy. Fossella et al
conducted a randomized study of 373
patients with advanced NSCLC who
had previously failed platinum-containing
chemotherapy,[20] survival
was determined for regimens of docetaxel,
in dosages of either 75 or 100
mg/m2, compared with a control regimen
of vinorelbine or ifosfamide
(Ifex). Overall response rates for the
docetaxel 75 and 100 mg/m2 groups
and the control group were 6.7%,
10.8%, and 0.8%, respectively (P =
.036 and P = .001). Median survival
was 7.0, 6.5, and 6.0 months. Oneyear
survival was 37%, 30%, and
19%.[20]

A second study compared outcome
in 103 NSCLC patients who received
either docetaxel at 75 mg/m2, or best standard care after failing platinumbased
chemotherapy.[21] Overall response
rates were 6% and 0%, and
median survival was 7.5 and 4.6
months (P = .01), respectively. At 1
year, the survival rates were 37% and
12% (P = .003). Results of these studies
support standard use of docetaxel,
75 mg/m2 IV every 3 weeks, for standard
second-line therapy.

Pemetrexed

Pemetrexed is a novel cytotoxic
agent that was designed as a thymidylate
synthase inhibitor similar to methotrexate,
raltitrexed, and lometrexol
(Figure 1).[22] It inhibits multiple enzymes
in the DNA synthesis pathway,
including thymidylate synthase,
glycinamide ribonucleotide formyltransferase,
and dihydrofolate reductase
(Figure 2).[23] Hence, the original
name was multitargeted antifolate. Most
lung cancers overexpress thymidylate
synthase and a variety of genes involved
in cell cycle regulation.[24]

Preclinical Studies
In preclinical development, pemetrexed
both alone and in combination
with other antitumor agents has exhibited
antitumor activity across a
broad range of tumor models, including
some that are generally considered
chemoresistant. In vitro, pemetrexed has been shown to inhibit
growth of a large panel of human cancer
cell lines, including lung cancer
and mesothelioma, as well as colorectal
cancer, renal cell carcinoma, hepatocellular
carcinoma, and pancreatic
cancer.[25,26] In vivo studies of human
NSCLC xenografts in athymic
nude mice demonstrated that pemetrexed
appears to be especially effective
in combination therapies.
Addition of pemetrexed to fluorouracil,
gemcitabine, cisplatin, vinorelbine,
carboplatin, oxaliplatin
(Eloxatin), doxorubicin, and paclitaxel
produced additive or synergistic
growth inhibition. Pemetrexed appeared
to be especially effective in
combination with fluorouracil or an
antitumor platinum complex.

Phase I Trials
The phase I trials of single-agent
pemetrexed have used a daily * 5
schedule every 3 weeks, weekly for 4
weeks every 6 weeks, and once every
3 weeks. in patients with a variety of
solid tumors (Table 1).[27-29] The
best tolerability profile occurred in
the study of 37 patients by Rinaldi
and coworkers who administered dosages
ranging from 50 to 700 mg/m2
every 3 weeks, and reported that four
patients achieved a partial response
and six a minor response. The maximum
tolerated dose was 600 mg/m2; this was the dose selected for further
study, although subsequent evidence
of hematologic and cutaneous toxicity
prompted a starting dose reduction
to 500 mg/m2.[29] In all phase I trials,
neutropenia was the major dose-limiting
effect, regardless of regimen.
Nonhematologic toxicities included
anorexia, mild nausea, diarrhea, mucositis,
rash, and reversible elevations
of hepatic enzymes.

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