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State-of-the-Art Treatment for Advanced NonSMQ-8211-SMQSmall-Cell Lung Cancer

State-of-the-Art Treatment for Advanced NonSMQ-8211-SMQSmall-Cell Lung Cancer

ABSTRACT: Patients with locally advanced or metastatic nonSMQ-8211-SMQsmall-cell lung cancer (stage III and IV) who are not candidates for surgery and exhibit good performance status are typically treated with concurrent radiation and platinum-based chemotherapy for disease palliation. Platinum- based chemotherapies, used alone or with radiation therapy, offer a small but significant survival benefit compared with supportive care. The incorporation of first-line agents such as gemcitabine (Gemzar), vinorelbine (Navelbine), and paclitaxel, as well as secondline agents such as docetaxel (Taxotere), in doublet and triplet combinations has had a further significant therapeutic impact. Randomized trials have shown that cisplatin-based therapy in combination with new agents results in improved 1- and 2-year survival rates in patients with adequate performance status. The 1-year survival benefit has significantly improved, with greater symptom relief and improved quality of life in these patients. Thus, delaying disease progression with combination chemotherapy appears both beneficial and cost-effective in patients with advanced nonSMQ-8211-SMQsmall-cell lung cancer. Newer approachesSMQ-8212-SMQ including targeting critical signaling pathways, such as tyrosine kinase receptors, angiogenesis, and downstream signal transduction mechanismsSMQ-8212-SMQmay provide novel agents with an improved toxicity profile and the potential for better disease management.

Lung cancer is the second most
common cancer and the leading
cause of cancer death in
both men and women in the United
States.[1] It is responsible for more
deaths than prostate, colon, and breast
cancer combined, with an estimated
157,200 deaths from lung cancer in
2003.[1] The 5-year survival rate for
patients diagnosed with lung cancer
in 2003 is projected to be 15%, reflecting
only a 2% increase over the
last 4 years.[1,2] Of the estimated
172,000 cases of lung cancer in 2003,
non-small-cell lung cancer will account
for 80% to 85%.[3] Unfortunately,
due to the inherent resistance
of non-small-cell lung cancer to chemotherapy
and radiation therapy, coupled
with a limited understanding of
the molecular events involved in the
development and progression of lung
cancer, it appears that this disease will
be one of the most challenging to overcome
in the 21st century.

Non-small-cell lung cancer is one
of the most aggressive types of cancers,
with 30% to 40% of patients presenting
with distant metastases. Left
untreated, the median survival time for
a patient with metastatic disease is
approximately 4 to 5 months. In general,
when surgery is not considered,
patients with locally advanced or
metastatic non-smal--cell lung cancer
(stage III and IV) and good performance
status are treated with concurrent
radiation and platinum-based chemotherapy
for palliation of symptoms
from the primary tumor.[4,5] The time
between diagnosis and treatment appears
to be a critical prognostic factor
for median survival. The American
Society of Clinical Oncology Guidelines
support treatment as soon as a
diagnosis is made.[5] Findings suggest
that appropriate and early delivery of
chemotherapy improves patient
survival.

Studies that support these findings
will be discussed in the following sections,
including those that support the
use of combination chemotherapy to
provide symptom relief and enhance
survival time. In addition, selected
novel agents are reviewed, especially
those targeted to pathways critical to
oncogenesis.

Platinum-Based Chemotherapy

With the entry of cisplatin in the
1970s, the median survival time for
patients with advanced non-small-cell
lung cancer increased, especially when
cisplatin was combined with chest irradiation.[
6,7] Early clinical studies
with cisplatin in patients with advanced-
stage non-small-cell lung cancer
demonstrated that this agent improved
median survival (by approximately
3 months), relieved symptoms,
and improved patient quality of life
compared with best supportive
care.[8] A meta-analysis of patient
data from 54 randomized clinical trials
(1965 through 1991) showed that
cisplatin-based chemotherapy combined
with radiation therapy was associated
with short-term palliation of
symptoms and an absolute survival
benefit of 4% at 2 years.[4]

Third-Generation
Chemotherapeutics

First-and second-generation platinum
therapies (ie, cisplatin-and
carboplatin [Paraplatin]-based regi-
mens) appear to be equally effective
when used for advanced non-smallcell
lung cancer, although carboplatin
has a more favorable therapeutic index
than cisplatin, particularly with
regard to nonhematologic toxicities.[
9,10] These regimens, however,
have resulted in a limited short-term
survival benefit in patients with stage
IIIB/IV non-small-cell lung cancer.[
8,11] Since the 1990s, third-generation
non-platinum-based agents,
such as paclitaxel, gemcitabine
(Gemzar), vinorelbine (Navelbine),
docetaxel (Taxotere), and irinotecan
(CPT-11, Camptosar), have been used
as first- and second-line therapies for
non-small-cell lung cancer and have
shown efficacy and good tolerability.[
12-16]

How Effective Are Current
Combination Chemotherapies?

To evaluate whether a selected
combination regimen might be superior
to other regimens, the Eastern
Cooperative Oncology Group
(ECOG) conducted a randomized
study to compare four different regimens
in 1,207 patients (1,155 eligible)
with advanced non-small-cell lung
cancer (stage IIIB/IV) and good performance
status (ECOG score of 0-1
vs 2).[17] Treatment arms included (1)
gemcitabine at 1,000 mg/m2 on days 1,
8, and 15 plus cisplatin at 100 mg/m2
on day 1 of a 4-week cycle; (2)
docetaxel at 75 mg/m2 plus cisplatin
at 75 mg/m2 on day 1 of a 3-week
cycle; (3) paclitaxel at 225 mg/m2
given over a 3-hour period on day 1,
plus carboplatin on the same day at a
dose calculated to produce an area
under the concentration-time curve
(AUC) of 6.0 mg/mL/min in a 3-week
cycle; and (4) paclitaxel at 135 mg/m2
delivered over a 24-hour period on day
1, plus cisplatin at 75 mg/m2 given on
day 2 for a 3-week cycle (as the reference
regimen).

While no significant difference in
response rates and survival were observed
between treatment groups,
gemcitabine/cisplatin was associated
with a significantly longer time to
disease progression than cisplatin/
paclitaxel (4.2 vs 3.4 months,
P = .001) (Table 1). Survival at 2 years
was also longest for patients receiving
gemcitabine/cisplatin (13%), although
this difference was not statistically
significant.

The gemcitabine/cisplatin arm was
associated with an increased likelihood
of grade 3, 4, or 5 renal toxicity
compared with paclitaxel/cisplatin
(9% vs 3%) and a higher rate of grade
3/4 thrombocytopenia (50% vs 6%).
Overall grade 4 and 5 toxicities were
similar for all treatment groups with
the exception of paclitaxel/carboplatin,
which showed a significantly
decreased incidence in grade 4 and 5
toxicities compared with paclitaxel/
cisplatin (P < .05). It was concluded
that, while all treatments are effective
as palliative therapy and moderately
improve survival at 1 and 2 years, none
of the four combination regimens were
superior for treatment of advanced
non-small-cell lung cancer.

A recent multicenter phase III
study, TAX 326, was designed to compare
the safety and efficacy of platinum
combinations in advanced non-
small-cell lung cancer using identical
doses of a third-generation chemotherapeutic
agent (docetaxel) in
combination with comparable doses
of either cisplatin or carboplatin
(Table 2).[10,18] TAX 326 was an
international, multicenter, randomized
trial that included 1,220 patients
with advanced non-small-cell lung
cancer. Patients were randomized to
receive one of three regimens: (1)
docetaxel at 75 mg/m2 plus cisplatin
at 75 mg/m2 every 3 weeks; (2)
docetaxel at 75 mg/m2 plus carboplatin
at AUC 6 every 3 weeks; or (3)
vinorelbine at 25 mg/m2 days 1, 8, 15,
and 22 plus cisplatin at 100 mg/m2 day
1 every 4 weeks (control arm).

Median survival was 11.3 months
in arm 1, 9.4 months in arm 2, and 10.1
months in the control arm. The 1-year
survival rates were 46% in arm 1, 38%
in arm 2, and 41% in the control arm.
Arm 1 was equivalent to and nearly
superior to arm 2 with respect to survival.
The efficacy of arm 2 was not
inferior to the control arm. Hematologic
toxicity was similar across treatment
arms. Patients treated with
vinorelbine/cisplatin had the highest
incidence of nausea and vomiting.
Over 900 patients completed qualityof-
life evaluations. Improvements in
quality of life and clinical benefit, as
measured by reduction in pain, improvement
in performance status, and
lack of major weight loss, were seen
on both docetaxel arms. TAX 326, the
largest trial yet conducted in advanced
non-small-cell lung cancer, has demonstrated
that the combination of
docetaxel/cisplatin is at least equivalent
to the combination of vinorelbine
and cisplatin, and in this study was
shown to be superior in terms of
survival.

In a phase III study by the Swedish
Lung Cancer Study Group,[19]
gemcitabine in combination with
carboplatin for the treatment of advanced
disease was found to significantly
increase objective response rate
(30% vs 12%) and median time to
progression (6 vs 4 months, P = .001)
compared to treatment with gem-
gemcitabine
alone. Median survival for
both groups was 9 months. In a study
conducted by the Cancer and Leukemia
Group B, paclitaxel in combination
with carboplatin was associated
with an improvement in response rate
compared with paclitaxel alone (30%
vs 16%, P < .001), with a median survival
of 8.5 months for the combination
vs 6.5 months for paclitaxel alone
(P = .023).

Another study by Georgoulias and
colleagues[20] compared the combination
of docetaxel/cisplatin to
docetaxel alone. The regimen resulted
in a significantly higher objective response
rate, but this did not translate
into improved overall survival. Thus,
it is logical to determine which doublet
combinations are best tolerated
and offer the greatest benefit for patients
with advanced non-small-cell
lung cancer. This was difficult, however,
as no single comparative study
had been statistically powered to address
such an issue.

In addition to the aforementioned
studies, numerous other randomized
trials have shown that there are several
third-generation platinum-based
combinations that may be considered
in patients with metastatic non-smallcell
lung cancer.

Triple Combination
Chemotherapy Regimens

Triple combination chemotherapy
has recently been evaluated to determine
if this would further improve
patient outcomes relative to doublet
regimens. The Spanish Lung Cancer
Group conducted a phase III trial comparing
a cisplatin-based triple combination
regimen, a nonplatinum sequential
doublet regimen, and a
cisplatin-based regimen (as the reference
arm) in 562 patients with advanced
non-small-cell lung cancer.[21] Treatment
regimens consisted of arm A:
cisplatin at 100 mg/m2 on day 1 plus
gemcitabine at 1,250 mg/m2 on days 1
and 8; arm B: cisplatin at 100 mg/m2
on day 1, gemcitabine at 1,000 mg/m2
on days 1 and 8, and vinorelbine at
25 mg/m2 on days 1 and 8, repeated
every 3 weeks; and arm C: gemcitabine
at 1,000 mg/m2 plus vinorelbine
at 30 mg/m2 on days 1 and 8 for
three cycles, followed by ifosfamide
(Ifex) at 3 g/m2 on day 1 plus
vinorelbine at 30 mg/m2 on days 1 and
8. Eligibility criteria included measurable
stage IV (brain metastases eligible
if asymptomatic) or stage IIIB (malignant
pleural effusion) non-small-cell
lung cancer and a performance status
of 0 to 2.

Overall response rates among 410
eligible patients were best in arm A
(41%) and arm B (40%) compared
with arm C (24%). Median survival
was similar for the three treatment
groups. Toxicities observed in arms A,
B, and C included grades 3/4 neutropenia
in 26.3%, 30.1%, and 18.5%;
neutropenic fever in 6.3%, 22.4%, and
7.4%; and grades 3/4 thrombocytopenia
in 18.2%, 23.1%, and 7.4%, respectively.
The overall incidence of
neuropathy, nausea and vomiting, and
renal toxicity was similar in all three
arms. Thus, triple combination chemotherapy
was associated with an increase
in overall toxicity and did not
have an efficacy advantage over twodrug
combinations. Furthermore, alternating
two-drug combinations
failed to improve response or survival
compared with a standard two-drug
regimen.

The mitomycin, ifosfamide, and
cisplatin (MIP) regimen, which is
commonly used in Europe, was not
found to be superior for survival in
patients with advanced non-small-cell
lung cancer compared with the doublet
of gemcitabine/carboplatin.[22] In
this study, 422 patients were randomized
to receive gemcitabine
(1,200 mg/m2 on days 1 and 8) plus
carboplatin at AUC 5, or mitomycin
(6 mg/m2 on day 1) plus ifosfamide
(3 mg/m2 on day 1) and
cisplatin (50 mg/m2 on day 1). The
gemcita-bine/carboplatin combination
was better tolerated than the triple
combination but was associated with
greater grade 3/4 thrombocytopenia
(8% vs 3%). While overall response
rates were similar, median survival and
1-year survival were improved with
gemcitabine/carboplatin compared
with the triple combination (10.0 vs
6.5 months and 38% vs 40%, respectively;
P = .0043). In summary, data
do not suggest that three-drug combinations
or alternating two-drug combinations
are superior to two-drug
combinations in the treatment of
non-mall-ell lung cancer.

Chemotherapy in the Elderly

The incidence of lung cancer is
highest in patients between the ages
of 70 and 80. Due to a reluctance to
administer chemotherapy to elderly
patients because of lack of a perceived
benefit and/or possible increased toxicity,
presence of comorbidities,
and/or poor performance status, elderly
patients have often not received
chemotherapy. However, a retrospective
analysis of a randomized phase III
trial of platinum-based chemotherapy
regimens (ECOG 5592) was recently
reported that compared outcomes of
patients 70 years of age or older with
those of younger patients.[23] Elderly
patients who were physically fit were
able to tolerate platinum-based chemotherapy
as well as younger patients.
In the study, all patients were randomized
to one of a variety of platinumbased
therapies and evaluated for response
and drug tolerance.

Clinical response (partial or complete)
to therapy was 21.5% in
younger patients and 23.3% in patients
≥70 years of age. Median time to progression
was 4.37 months in younger
patients compared with 4.30 months
in elderly patients, with 1-ear survival
of 38% and 29%, respectively, and
2-ear survival of 14% and 12%, respectively.
Both patient populations
showed similar functional declines,
with the elderly exhibiting a higher
incidence of cardiovascular and respiratory
comorbidities and experiencing
more leukopenia and neuropsychiatric
toxicity. The authors concluded
that advanced age alone should not
preclude the use of chemotherapy for
elderly non-mall-cell lung cancer
patients with good performance status.[
23]

It is unclear whether two-drug combinations
are preferred over singleagent
therapy in the elderly. Several
third-generation chemotherapeutic
agents appear to be effective in improving
survival of patients with advanced
non-small-cell lung cancer
over the age of 70. The trial by the
Elderly Lung Cancer Vinorelbine
Study Group (ELVIS) demonstrated
that single-agent vinorelbine was superior
to best supportive care with significantly
superior survival and quality
of life for elderly patients.[24] In a
phase III trial conducted by the Southern
Italy Cooperative Oncology Group
(SICOG), the combination of
vinorelbine and gemcitabine was superior
to vinorelbine alone in elderly
patients older than 70. Median survival
with the combination was 21 weeks,
compared with 18 weeks for singleagent
vinorelbine.[25] The 1-year survival
rate was also superior in the two drug
arm.

These results conflicted with those
from the Multicenter Italian Lung
Cancer in the Elderly Study (MILES),
in which patients with advanced non-
small-cell lung cancer were randomized
to receive one of three treatments:
single-agent gemcitabine, single-agent
vinorelbine, or the combination.[26]
Early results indicated that both
gemcitabine and gemcitabine plus
vinorelbine produced the best response
rates (18.4%), and the trial was
continued to a final enrollment of 700
patients. However, further evaluation
of all patients has shown that the combination
regimen provided no statistically
significant benefit with respect
to median survival or 1-year survival
compared with single-agent vinorelbine
and was associated with more
toxicity. Hence, this study demonstrated
that the vinorelbine/gemcitabine
combination does not offer a significant
advantage over single-agent
vinorelbine or gemcitabine.

These and other similar results have
led investigators to believe that chemotherapy
should be considered for
elderly patients with good performance
status (0 or 1). Platinum-based
combinations should be considered for
those elderly patients with a good performance
status, but single agents may
be preferable for those patients with
comorbid diseases or who have performance
status of 2.

Novel Therapies for Advanced-
Stage Non-Small-Cell Lung
Cancer

With the increased use of platinumas
well as non-platinum-based firstline
regimens, the number of patients
who still have a good performance status
after first-line therapy seeking additional
therapy after relapse has increased,[
27] while the number of second-
line therapies is limited. Thus,
identifying novel therapies for the
treatment of non-small-cell lung cancer
is critical to improve outcomes for
these patients. Given that some investigators
believe a plateau has been
reached with cytotoxic chemotherapy
in the treatment of advanced non-
small-cell lung cancer, novel biologicbased
therapies may provide further
advances by virtue of their unique
mechanisms of action (Table 3).

While some of the molecular
mechanisms underlying the pathologic
processes of lung cancer remain unknown,
several cellular and biologic
advances have identified a number of
molecules and cellular pathways in
volved in the regulation of tumor
growth and proliferation. In non-
small-cell lung cancer, novel therapies
directed against certain molecular targets
may improve survival and quality
of life beyond that achieved with
chemotherapeutic agents. Selected
biological agents under investigation
for treatment of non-small-cell lung
cancer are presented in Table 3. Some
of the more actively researched molecular-
based inhibitors include anti-
epidermal growth factor receptor (anti-
EGFR) inhibitors, antiangiogenesis
agents, and antisense therapies, which
are discussed below.

Epidermal Growth Factor
Receptor Inhibitors

The epidermal growth factor receptor
(EGFR, also known as ErbB1 or
HER1) appears to play a critical role
in tumorigenesis because of its abundant
expression on cancer cells and its
ability to stimulate cellular pathways
that increase cell proliferation, decrease
cell death (apoptosis), and increase
angiogenesis.[28] Treatment
with EGFR inhibitors is associated
with a decrease in tumor cell proliferation
and/or viability in vitro and
in vivo.

  • Gefitinib-Gefitinib (Iressa), one
    of the first members in this new class
    of selective EGFR tyrosine kinase inhibitors,
    blocks EGFR activity
    (autophosphorylation) and subsequent
    signal transduction mechanisms that
    regulate proliferation, metastasis, and
    angiogenesis.[29] Gefitinib is orally
    active, and has been associated with a
    low side effect profile-primarily acneiform
    rash and diarrhea. Two
    multicenter, randomized, dosecomparative
    phase II trials of gefitinib
    as monotherapy in patients with
    locally advanced or metastatic non-
    small-cell lung cancer have been conducted.
    The Iressa Dose Evaluation
    in Advanced Lung Cancer Trial-1
    (IDEAL-1) was conducted in Japan,
    Europe, South Africa, and Australia.
    Eligible patients had received one or
    two previous chemotherapy regimens,
    one of which was to have been platinum-
    based.[30] The IDEAL-2 trial,
    conducted in the United States, required
    patients to have received at
    least two prior chemotherapy regimens
    containing a platinum agent and
    docetaxel given separately or concurrently.[
    31]

    In the IDEAL-1 trial, 210 patients
    were randomized to receive gefitinib
    at a daily oral dose of 250 mg
    (n = 103) or 500 mg (n = 106) (one
    patient did not receive treatment at the
    250-mg dose).[30] Overall response
    rates of 18.4% and 19.0% were observed
    for patients receiving the 250-
    and 500-mg doses, respectively. For
    patients who responded, median duration
    of response was more than 3
    months, and median survival times
    were 7.6 and 8.0 months for the 250-
    and 500-mg dose groups, respectively.

    In IDEAL-2, of the 216 patients
    randomized, 102 patients were treated
    with a daily oral dose of 250 mg of
    gefitinib and 114 patients received a
    dose of 500 mg of gefitinib.[31] Responses
    were observed in 11.8% of
    patients treated with 250 mg of
    gefitinib and 8.8% of patients treated
    with 500 mg. Median survival was 6.1
    and 6.0 months for patients in the 250-
    and 500-mg groups, respectively.

    Symptom improvement on the
    IDEAL trials occurred rapidly; the
    median time to improvement for both
    treatment groups was 8 days in
    IDEAL-1, and 10 days and 9 days in
    the 250- and 500-mg groups, respectively,
    in IDEAL-2. Symptom improvement
    occurred in 40.3% and
    43.1% of patients who received 250-
    mg gefitinib in the IDEAL-1 and
    IDEAL-2 studies, respectively.[32]
    For the patients receiving 500 mg/d,
    37% of the IDEAL-1 participants and
    35.1% of the IDEAL-2 participants
    had symptom improvement.[32] In
    both studies a substantially greater
    proportion of patients with an objective
    tumor response or stable disease
    showed improvements in symptoms
    compared with patients who had progressive
    disease. There was also a
    positive association between symptom
    response and survival; patients with
    improvements in symptoms had
    greater survival. Based on the results
    of these clinical trials, particularly
    IDEAL-2, gefitinib was approved for
    use in the United States in the treatment
    of patients with non-small-cell
    lung cancer in the third-line setting.

    Improvements in quality of life
    were also seen in these trials. Overall,
    the quality-of-life improvement rate
    was 23.9% and 21.9% for the 250- and
    500-mg/d dose groups, respectively,
    on IDEAL-1, and 34% and 23% for
    the 250- and 500-mg/d dose groups,
    respectively, on IDEAL-2.[32] As with
    symptom improvement, quality-of-life
    improvement was recorded in a greater
    percentage of patients who achieved
    an objective response followed by
    those with stable disease. These results
    indicate that treatment with singleagent
    gefitinib had a positive impact
    on symptoms and quality of life in
    patients with advanced non-small-cell
    lung cancer.

    Combination therapy with gefitinib
    has also been evaluated in the Iressa
    NSCLC Trials Assessing Combination
    Treatment (INTACT-1 and INTACT-
    2). These two randomized, multicenter
    phase III trials were conducted in chemotherapy-
    naive patients to determine
    if the combination of gefitinib and
    chemotherapy would show additive or

    synergistic antitumor effects. In INTACT-
    1, patients with stage III/IV
    non-small-cell lung cancer were randomized
    to treatment with
    gemcitabine at 1,250 mg/m2 administered
    on days 1 and 8 and cisplatin at
    80 mg/m2 on day 1, or to the same
    chemotherapy regimen combined with
    250 or 500 mg/d of gefitinib. Patients
    in INTACT-2 were randomized to receive
    carboplatin at AUC 6 plus
    paclitaxel at 225 mg/m2 administered
    every 3 weeks with or without the same
    doses of gefitinib. Although the combination
    of gefitinib and platinum chemotherapy
    doublets was well tolerated in
    both studies, no statistically significant
    increase in response rate, survival, or
    time to worsening of symptoms was
    demonstrated with the addition of this
    EGFR inhibitor.[33,34]

  • Erlotinib-Erlotinib-Erlotinib (Tarceva) is
    a quinazoline small-molecule tyrosine
    kinase inhibitor that exhibits its effect
    at nanomolar concentrations. In a
    phase I study, patients with advanced
    solid malignancies refractory to conventional
    chemotherapy were treated
    with erlotinib.[35] Forty patients were
    enrolled, four of whom had non-
    small-ell lung cancer. Diarrhea and
    skin rash were the primary toxicities
    that precluded treatment with doses
    greater than 150 mg/d. Among patients
    with advanced, platinum-refractory
    non-small-cell lung cancer,
    14.3% had an objective response and
    28.6% had stable disease.[35]

    A phase II trial evaluating erlotinib
    at 150 mg/d enrolled 56 patients with
    progressive, recurrent non-small-cell
    lung cancer previously treated with a
    platinum-based chemotherapy regimen.[
    36] Eight patients (14.3%)
    achieved response (one complete, seven
    partial; six confirmed at week 12 and
    beyond), 16 patients (28.6%) had stable
    disease lasting ≥ 12 weeks, and 28 patients
    (57.1%) had documented progression
    of their underlying malignancy.
    Toxicities included rash and diarrhea,
    and were generally mild. Only a single
    patient required transient dose reductions
    due to skin toxicity.

  • Cetuximab-Cetuximab (Erbitux)
    is a mouse-human chimerized monoclonal
    antibody that specifically binds
    to the EGFR, thereby inhibiting downstream
    signal transduction pathways.[
    37] In preclinical in vivo and
    in vitro studies, cetuximab has been
    shown to enhance radiosensitivity,
    promote radiation-induced apoptosis,
    decrease cell proliferation, inhibit radiation-
    induced damage repair, and
    inhibit tumor angiogenesis. Furthermore,
    cetuximab has been shown to
    enhance cytotoxicity when combined
    with various chemotherapeutic
    agents.[37]

    In the clinical setting, phase I studies
    of cetuximab alone and in combination
    with cisplatin have been reported.[
    38] Baselga et al presented a
    summary of three initial studies, which
    included a single-dose trial of
    cetuximab (CP02-9401), a weekly
    multiple-dose trial (once weekly for 4
    weeks) (CP02-9502), or weekly in
    combination with cisplatin (CP02-
    9503). In CP02-9503, patients were
    restricted to those who had head and
    neck cancers (n = 16) and non-smallcell
    lung cancer (n = 6). A total of 52
    patients were treated in these three
    studies. In the CP02-9401 and CP02-
    9502 studies, cetuximab was administered
    intravenously at doses ranging
    from 5 to 100 mg/m2. In CP02-9503,
    cetuximab doses ranged from 5 to
    400 mg/m2 given weekly with addition
    of cisplatin, every 4 weeks, at 60
    mg/m2 1 hour following cetuximab administration.
    Initially, three patients
    were treated with 100 mg/m2 of
    cisplatin, but two experienced grade 3
    or higher toxicities; the dose was therefore
    reduced to 60 mg/m2.

    Overall, cetuximab was well tolerated,
    with five episodes of grade 3 or
    higher toxicity occurring with 317
    doses of cetuximab. The most frequent
    adverse reactions included fever and
    chills, asthenia, transaminase elevations,
    nausea, and skin toxicities
    (flushing [4 cases], seborrheic dermatitis
    [1 case], and acneiform rash [6
    cases]).

    A phase II study of cetuximab in
    combination with docetaxel in chemotherapy-
    refractory patients with advanced
    non-small-cell lung cancer
    was reported.[39] Cetuximab was administered
    at 400 mg/m2 IV during the
    first week followed by 250 mg/m2
    IV weekly. Docetaxel was adminis
    tered at 75 mg/m2 IV every 3 weeks.
    Twenty-five patients had been enrolled
    at the time of the report, and 20 patients
    were evaluable for response. Preliminary
    results showed that after two cycles
    of therapy, four patients had a partial
    response and six had stable disease.
    Toxicities included acneiform rash
    (grade 2/3) in five patients and febrile
    neutropenia (grade 2/3) in two patients.

    A phase II open-label, multicenter,
    nonrandomized study has been designed
    to evaluate the safety and toxicity
    of chemotherapy with cetuximab
    in patients with stage IIIA/B non-
    small-cell lung cancer. Other objectives
    are to determine the survival rate
    with this regimen in comparison to established
    regimens, and to determine
    the potential correlation of EGFR expression
    with survival rate. In this
    study, patients will initially receive
    cetuximab at 400 mg/m2 IV on day 1.
    Beginning on day 8, cetuximab at
    250 mg/m2 plus paclitaxel at 45 mg/
    m2 and carboplatin at AUC 2 will be
    delivered weekly for 7 weeks during
    concurrent radiation therapy (63.0 Gy
    in 34 daily fractions over 7 weeks).
    Concurrent cetuximab plus chemotherapy/
    radiation therapy will be followed
    by 3 weeks of single-agent
    cetuximab at 250 mg/m2/wk. Patients
    then receive two cycles of paclitaxel at
    200 mg/m2 and carboplatin at AUC 6
    every 3 weeks, plus cetuximab at
    250 mg/m2/wk for 6 weeks. This study
    plans to accrue a minimum of 70 patients.

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