Clinical Evidence for Second- and Third-Line Treatment

Options in Advanced Non-Small Cell Lung Cancer

Filippo de Marinis,a Francesco Grossib

a
Thoracic Oncology Unit I, Department of Lung Diseases, San Camillo and Forlanini Hospitals, Rome, Italy;
b
Medical Oncology A, Disease Management Team – Lung Cancer,
National Institute for Cancer Research, Genova, Italy

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Key Words. NSCLC • Second-line chemotherapy • Pemetrexed • Docetaxel • Erlotinib

Disclosure: F.d.M. has acted as a consultant to Eli Lilly and Company, Roche, and Sanofi-Aventis, and has received honoraria
from Pierre Fabre, Amgen, and GlaxoSmithKline. F.G. has acted as a consultant to Eli Lilly and Company, GlaxoSmithKline, and
Roche, and has received honoraria from Sanofi-Aventis.

Abstract
In the U.S. and Europe, the current options for the sec-
ond- and third-line treatment of advanced non-small
cell lung cancer (NSCLC) are cytotoxic drugs and tar-
geted agents. Docetaxel was the first drug approved for
second-line treatment after two phase III trials demon-
strated its superiority over best supportive care (BSC)
alone and single-agent chemotherapy. Pemetrexed was
also registered for use as second-line therapy after it
was demonstrated to have activity comparable with,
and a more favorable toxicity profile than, docetaxel.
Erlotinib, an epidermal growth factor receptor inhibi-
tor, is the only biological agent to have been approved in
the U.S. and Europe for lung cancer treatment after a
study showed its superiority over BSC in recurrent (sec-
ond-/third-line) NSCLC patients. This review focuses
on these drugs, dealing with the results supporting the
choice among docetaxel, pemetrexed, and erlotinib in
second- and/or third-line treatment. The Oncologist
2008;13(suppl 1):14–20

Introduction supportive care (BSC) alone [2] and single-agent chemo-

Platinum-based chemotherapy with a third-generation therapy [3] (Table 1). In 2000, the results of these studies
agent (gemcitabine, paclitaxel, docetaxel, or vinorel- allowed the registration in the U.S. and Europe of docetaxel
bine) improves survival and quality of life in patients with (75 mg/m2 every 3 weeks) as the first cytotoxic agent for the
advanced non-small cell lung cancer (NSCLC) [1]. Despite second-line treatment of NSCLC. In these trials, docetaxel-
these favorable results, most patients receiving front-line related toxicity was relevant, despite the significantly better
chemotherapy experience disease progression. The avail- quality of life scores concerning pain control, weight loss,
ability of several new active drugs and trial results in second- and PS obtained with docetaxel in comparison with the con-
line treatment suggests that this strategy can now be consid- trol groups [4]. A phase II randomized trial [5] confirmed
ered a standard of care for patients with a good performance that docetaxel at a dose of 75 mg/m 2 has a more favorable
status (PS) who are resistant to first-line treatment [1]. toxicity profile than, and a similar efficacy to, docetaxel at
100 mg/m2. The current problem of this treatment remains
Single-Agent Docetaxel Every 3 Weeks hematologic toxicity, which, in the registration trials [2,
Two phase III trials demonstrated that docetaxel can pro- 3], represented the dose-limiting toxicity: neutropenia
duce longer survival and better quality of life than with best occurred in 54%–67% of patients and febrile neutropenia
Correspondence: Filippo de Marinis, M.D., Thoracic Oncology Unit I, Chief Carlo Forlanini Hospital, Pza Forlanini 1, 00151, Rome, Italy.
Telephone: 39-06-5555-2565; Fax: 39-06-5555-2565; e-mail: demarinis.filippo@virgilio.it Received September 10, 2007; accepted for
publication October 25, 2007. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.13-S1-14

The Oncologist 2008;13(suppl 1):14–20 www.TheOncologist.com

de Marinis, Grossi 15

Table 1. Registration trials for the treatment of recurrent NSCLC: Survival and toxicity
Median 1-Year Grade 3–4 Febrile Most frequent grade
n of Response survival time survival neutropenia neutropenia 3–4 nonhematologic
Study Arm patients rate (%) (months) rate (%) (%) (%) toxicity
TAX 317 D100 49 6.3 5.9 37 85.7 22.4 Pulmonary events
[2] (37%)
D75 55 5.5 7.5 37 67.3 1.8 Pulmonary events
(20%)
BSC 100 – 4.6 19 – – Pulmonary events
(30%)
TAX 320 D100 125 10.8 5.5 21 77 12 Fatigue (17%)
[3]
D75 125 6.7 5.7 32 54 8 Fatigue (12%)
V/I 123 0.8 5.6 19 31 1 Fatigue (11%)
JMEI [8] Pem 283 9.1 8.3 29.7 5.3 1.9 Fatigue (5.3%)
D75 288 8.8 7.9 29.7 40.2 12.7 Fatigue (5.4%)

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ISEL [21] G250 1,129 8 5.6 27 0 0 Diarrhea (3%)
BSC 563 1 5.1 21 – – Asthenia (3%)
BR.21 [22] E150 488 8.9 6.7 31 0 0 Fatigue (19%)
BSC 243 0.9 4.7 22 – – Fatigue (23%)
Abbreviations: BSC, best supportive care; D100, docetaxel 100 mg/m every 3 weeks; D75, docetaxel 75 mg/m2 every 3 weeks;
2

E150, erlotinib 150 mg daily; G250, gefitinib 250 mg daily; ISEL, Iressa Survival Evaluation in Lung cancer; NSCLC, non-small
cell lung cancer; Pem, pemetrexed 500 mg/m2 every 3 weeks; TAX, Taxotere®; V/I, vinorelbine or ifosfamide.

occurred in 1.8%–8.0%. Moreover, in these studies [2, 3],
docetaxel yielded significant nonhematologic toxicities,
mainly grade 3–4 asthenia (12%–18%). Nausea and vomit-
ing were also frequent but can generally be well controlled
with modern antiemetics.
Single-Agent Pemetrexed
Pemetrexed, a multitargeted antifolate, was shown to be
active in recurrent and progressive NSCLC in a large phase
II trial [6], and in malignant pleural mesothelioma in a
phase III trial [7].
The phase III JMEI trial demonstrated that pemetrexed
and standard 3-weekly docetaxel (75 mg/m2) have similar
efficacies when used as second-line treatments [8]. Over
1 year, 571 patients resistant to first-line chemotherapy
were randomized into this study. Pemetrexed (500 mg/m 2
i.v.) plus vitamin supplementation was administered every
3 weeks for a median of four cycles, and was shown to be
comparable with docetaxel in terms of efficacy: in both
arms, the median survival time, response rate, and 1-year
survival rate were approximately 8 months, 9%, and 30%,
respectively (Table 1).
The most interesting data from that trial are the toxic-
ity results: the safety profile of pemetrexed was signifi-
cantly better than that of docetaxel. As shown in Table 1,
patients treated with docetaxel were more likely to expe-
rience grade 3–4 neutropenia (p < .001), febrile neutro-
penia (p < .001), and infections associated with neutrope-
nia (3.3% versus 0%; p = .004) than patients treated with
pemetrexed. Consequently, fewer patients in the peme-
trexed arm required one or more hospitalizations result-
ing from neutropenic fever (1.5% versus 13.4%; p < .001),
and a more limited use of white blood cell growth factors
was observed than in patients who received docetaxel
(2.6% versus 19.2%; p < .001). The superiority of peme-
trexed over docetaxel (75 mg/m 2 every 3 weeks) was also
confirmed by noting that all of the other randomized stud-
ies using this treatment arm found more neutropenia and
febrile neutropenia with docetaxel treatment than with
pemetrexed (Fig. 1).
Following these results, at the end of 2004, pemetrexed
was registered in the U.S. and Europe for this indication, and
was included in the most recent guidelines on the treatment
of NSCLC published by the European Society of Medical
Oncology, the American Society of Clinical Oncology, and
the National Comprehensive Cancer Network [9, 10]. As a
result, pemetrexed is recommended for second-line treat-
ment, particularly for patients with a good PS (because, in
the phase III registration study, only 11% of patients had a
PS score of 2) but also for patients previously treated with
platinum-containing first-line chemotherapy who showed
neutropenia or some other toxicity, because pemetrexed
demonstrated efficacy with low incidences of hematologic
and nonhematologic toxicities.

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16 Clinical Evidence for Second-/Third-Line Advanced NSCLC Therapy
Figure 1. Main grade 3–4 World Health Organization tox-
icities measured in randomized trials evaluating docetaxel at
a dose of 75 mg/m 2 given every 3 weeks in second-line non-
small cell lung cancer, compared with those obtained with the
pemetrexed arm in its registration trial [3].
a
The main nonhematologic toxicity was nausea and vomiting.
b
First-line treatment only for elderly patients and/or patients
with a performance status score of 2.
Abbreviations: FN, febrile neutropenia; N, neutropenia; N-H,
nonhematologic toxicity (asthenia).
Pemetrexed can also be recommended for elderly
patients needing second-line chemotherapy. A recent ret-
rospective analysis [11] of the JMEI trial found that 15%
of patients ≥70 years old (n = 86) on pemetrexed had a lon-
ger time to progression and a longer median survival time
(4.6 and 9.5 months, respectively) than their counterparts
treated with docetaxel (2.9 and 7.7 months, respectively;
p > .05). Febrile neutropenia was less frequent in the
pemetrexed arm (2.5%) than in the docetaxel arm (19%;
p = .025). This analysis [11] shows that elderly patients can
have as much benefit from second-line cytotoxic chemo-
therapy with pemetrexed as younger patients, and that this
can be achieved with acceptable toxicity rates.
Single-Agent Weekly Docetaxel
In order to reduce the hematologic toxicity of docetaxel
from that seen with 75 mg/m 2 given every 3 weeks, several
clinical trials have explored weekly administration of the
drug.
In a phase II trial, Lilenbaum et al. [12] randomized
elderly chemotherapy-naïve patients and/or patients with
a PS score of 2 with advanced NSCLC to either 3-weekly
docetaxel or a weekly schedule. The primary endpoint
was toxicity, and secondary endpoints were response
rate, time to progression, and overall survival. Approxi-
mately 100 patients were enrolled, with a median age of
75 years; 75% were elderly and 50% had a PS score of 2.
Regarding the overall toxicity, the weekly docetaxel regi-
men demonstrated less neutropenia (0% versus 30%),
less febrile neutropenia (0% versus 2%), and less asthe-
nia (23% versus 37%). The median survival times in the
weekly docetaxel and 3-weekly docetaxel arms were 6.5
and 2.5 months, respectively. The authors concluded that,
in elderly patients and borderline PS patients, weekly
docetaxel is preferable to 3-weekly docetaxel in first-line
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chemotherapy.
In terms of second-line treatment, following a random-
ized phase II study [13] with safety as a primary endpoint,
a weekly docetaxel schedule was compared with the stan-
dard schedule in three phase III trials. In a Spanish study
[14], more than 250 patients were randomized between 3-
weekly and weekly docetaxel (36 mg/m 2 for 6 weeks every
2 months). The results did not demonstrate significant dif-
ferences between 3-weekly and weekly docetaxel in either
the 1-year survival rate or median survival time (27% versus
22% and 6.6 versus 5.4 months, respectively; p = .076), but
an advantage was seen with the weekly schedule in terms of
febrile neutropenia (7.8% versus 0.8%; p = .01), although it
was associated with significantly higher incidences of ane-
mia (p = .011), diarrhea (p < .05), and grade 3–4 mucositis
(p = .032).
In a German study [15], 208 patients were randomized
to receive 3-weekly or weekly docetaxel (35 mg/m 2 for 3
weeks every 28 days), and the primary endpoint was overall
survival. A significantly lower rate of hematologic toxic-
ity was recorded for the weekly arm (20.6% versus 4.8%
patients suffered from neutropenia), with a significant dif-
ference observed in the median survival time and 1-year
survival rate for the two schedules (6.3 versus 9.2 months
and 26.9% versus 39.5% in the 3-weekly and weekly treat-
ment groups, respectively; p = .07).
Finally, an Italian study [16] investigated a possible
advantage in terms of quality of life using weekly docetaxel
(33.3 mg/m 2 for 6 weeks every 2 months) versus 3-weekly
docetaxel in patients with recurrent NSCLC. No difference
was found in the global quality-of-life score at 3 weeks. The
incidences of pain, cough, and alopecia were significantly
lower under the weekly schedule, while the incidence
of diarrhea was higher. The response rates and survival
times were similar, with median survival times of 29 and
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de Marinis, Grossi
25 weeks in the 3-weekly docetaxel and weekly docetaxel
arms, respectively. Because of the sample size in each trial,
there was insufficient statistical power to detect clinically
relevant differences in overall survival.
Two meta-analyses [17, 18] were recently performed
that included these previous randomized trials in order
to evaluate whether weekly docetaxel can result in longer
survival than with the standard 3-weekly schedule in previ-
ously treated advanced NSCLC patients.
In the first meta-analysis [17], a significantly lower inci-
dence of grade 3–4 neutropenia for weekly docetaxel was
found (relative risk [RR], 0.22; 95% confidence interval
[CI], 0.19–0.42; p < .0001). This advantage translates into
an absolute benefit of 15%–19%, with nine patients need-
ing to be treated for one to receive a benefit. When consid-
ering only the phase III randomized trials (682 patients),
overall survival did not differ significantly between the two
regimens (RR, 1.01; 95% CI, 0.76–1.42; p = .785).
The second meta-analysis, recently published [18], is
based on updated individual patient data from 865 patients
enrolled in three phase III and two phase II randomized tri-
als. The results show no significant difference in efficacy
between weekly docetaxel and 3-weekly docetaxel as sec-
ond-line treatment in advanced NSCLC patients (median
survival time, 26.1 versus 27.4 weeks, respectively; hazard
ratio [HR], 1.09; 95% CI, 0.94–1.26; p = .245). The risk for
febrile neutropenia was significantly lower with the weekly
schedule. The authors concluded that weekly docetaxel rep-
resents a valid alternative for all patients with NSCLC suit-
able for second-line chemotherapy, based on a better toxic-
ity profile and no relevant differences in survival.
In conclusion, the results of four randomized trials
[13–16] and two meta-analyses [17, 18] demonstrate no
difference in survival, although there are some critical
issues because of the limited number of patients (about
700) and the different endpoints considered (safety, over-
all survival, quality of life) that mean that no clear, con-
clusive definition of the role of a weekly docetaxel sched-
ule can be determined. The use of a weekly docetaxel
schedule for relapsed NSCLC patients is not supported by
a direct comparison with pemetrexed. If the results of ran-
domized trials using both 3-weekly and weekly docetaxel
regimens are compared with the JMEI trial [8], it is pos-
sible to conclude that the primary difference in toxicity
(neutropenia and febrile neutropenia) would not be sig-
nificant (Fig. 2). However, nonhematologic toxicities and
dose scheduling are more favorable with pemetrexed,
and patients may not want to make weekly hospital visits.
Moreover, it is important to note that the weekly docetaxel
dose and schedule have not been approved by regulatory
authorities in the U.S. or Europe.
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17
Erlotinib in Second-/Third-Line Treatment
Erlotinib is the only epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitor (TKI) (Table 1) approved
in Europe and the U.S. for the treatment of recurrent NSCLC.
Gefitinib, another EGFR TKI, was granted accelerated
approval in the U.S. on the basis of response rates obtained
in two phase II randomized trials [19, 20], but one of the fol-
lowing confirmatory trials (Iressa Survival Evaluation in
Lung cancer trial 709), designed with survival as a primary
endpoint, failed to meet its primary objective [21]. As a con-
sequence, the marketing application for gefitinib was with-
drawn in Europe, and the U.S. indication was subsequently
changed in 2005 so that it could be used only in patients who
were already receiving and benefiting from it, or in ongoing
clinical trials. However, in a similar trial, oral erlotinib at
a dose of 150 mg daily demonstrated a survival advantage
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over BSC alone (median survival times and 1-year survival
rates of 6.7 versus 4.7 months and 31% versus 22% for the
erlotinib and placebo groups, respectively) [22, 23].
Selecting a Second-/Third-Line Treatment
Some issues must be examined before a decision can be made
on whether to use pemetrexed, docetaxel, or erlotinib as sec-
ond-line treatment. First, the lack of data from comparison
trials makes the choice difficult, as does the nonhomogene-
Figure 2. Main grade 3–4 World Health Organization toxici-
ties measured in randomized trials evaluating docetaxel at a
dose of 30–40 mg/m 2 given weekly in second-line non-small
cell lung cancer, compared with those obtained with the peme-
trexed arm in its registration trial [3].
a
The main nonhematologic toxicity was nausea and vomiting.
b
First-line treatment only for elderly patients and/or patients
with a performance status score of 2.
Abbreviations: FN, febrile neutropenia; N, neutropenia; N-H,
nonhematologic toxicity (asthenia).
18 Clinical Evidence for Second-/Third-Line Advanced NSCLC Therapy

Table 2. Second-line registered drugs: Clinical prognostic factors and results

ECOG ≥2 Previous
Adeno- perfor- chemo- Median
Median Male/ carci- mance sta- therapy PFS/ survival 1-Year Never-
n of age female noma tus score regimens Response TTP time survival smokers
Study Arm patients (years) (%) (%) 2/3 (%) (%) rate (%) (weeks) (months) rate (%) (%)
TAX D75 55 61 66/34 NA 25 20 5.5 12.3 7.5 37 NA
317 [2]
BSC 100 61 65/35 NA 25 24 – 6.7 4.6 19 NA
TAX D75 125 59 66/34 56 18 26 6.7 8.5 5.7 32 NA
320 [3]
V/I 123 60 65/35 52 15 29 0.8 7.9 5.6 19 NA
JMEI Pem 283 59 69/31 54 11 0 9.1 12.6 8.3 30 NA
[8]
D75 288 57 75/25 49 12 0 8.8 12.6 7.9 30 NA
a a
BR.21 E150 488 62 65/35 50 26/9 50 8.9 9.7 6.7 (6.3) 31 (32) 21.3
[22] (243) a

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BSC 243 59 66/34 49 23/9 50 0.9 8.0 4.7 (5.5) a 22.5 17.3
(121) a (23) a
a
In the second-line setting only.
Abbreviations: BSC, best supportive care; D75, docetaxel 75 mg/m2 every 3 weeks; E150, erlotinib 150 mg daily; NA, not avail-
able; Pem, pemetrexed 500 mg/m2 every 3 weeks; PFS, progression-free survival; TAX, Taxotere®; TTP, time to progression;
V/I, vinorelbine or ifosfamide.

ity of prognostic characteristics between patients enrolled in
the JMEI [8] and BR.21 [22] studies and the lack of impor-
tant data such as patients’ smoking history in the JMEI study
(Table 2), even if the predictive role of a nonsmoking atti-
tude in patients treated with chemotherapy is still unclear.
A retrospective study from Singapore [24] observed no
differences in response rates between current and former
smokers, finding respective median survival times of 18.5
and 13.6 months (p = .14). In another study, Nordquist et al.
[25] reported a 5-year survival rate of 23% for patients with
adenocarcinoma of the lung who had never smoked (never-
smokers), compared with 16% for smokers (p = .004).
With the use of EGFR TKIs, dramatic differences in
response to therapy have been reported between never-
smokers and smokers. A multivariate analysis of the BR.21
trial [26] showed that a nonsmoking history was a signifi-
cant independent predictor of survival, with a median sur-
vival time of 12.3 months for never-smokers (n = 104) ver-
sus 5.5 months for former/current smokers (n = 358; HR,
0.54; 95% CI, 0.41–0.71). The same efficacy in never-smok-
ers was found in the Tarceva® Responses in Conjunction
with Paclitaxel and Carboplatin (TRIBUTE) study [27], in
which, in the subset analysis of never-smokers, the group
treated with erlotinib had a median survival time of 22.5
months, compared with only 10.1 months for smokers. All
of these results confirm the need to better define the pre-
dictive role of a nonsmoking attitude in prospective trials
comparing cytotoxic agents with EGFR TKIs.
It is worthwhile emphasizing that the marketing
approval for the two chemotherapy agents recommends use
“after failure of a previous chemotherapy treatment” in the
case of docetaxel and “after previous chemotherapy” for
pemetrexed, while the use of erlotinib is advised “after fail-
ure of at least one previous chemotherapy regimen.” Strictly
conforming to these therapeutic recommendations would
mean that the two chemotherapy agents should be used only
in second-line treatment, while erlotinib could be used in
second- and also subsequent-line therapy.
A retrospective analysis has shown that improvement
in survival beyond second-line treatment using chemother-
apy is only modest [28]. In the case of erlotinib, benefits in
response and survival are similar for those undergoing sec-
ond- or subsequent-line treatment (median survival times
of 6.3 months and 6.8 months for second- and third-line
treatments, respectively) [22], so it seems rational to con-
sider second-line treatment with docetaxel or pemetrexed
and third-line treatment with erlotinib.
In support of this idea, data derived from a direct com-
parison of second-line erlotinib treatment with the standard
chemotherapy agents pemetrexed and docetaxel in a phase
III trial are still not available, and the population treated
in the erlotinib registration trial [22, 23] was considered
unsuitable for chemotherapy treatment [29]. The option of
third-line erlotinib use is also supported by the fact that 50%
of patients enrolled in the BR.21 study had already received
two lines of chemotherapy, and that this drug, while having

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a good tolerability profile without hematologic toxicity, had
also shown positive results for both patients with a PS score
of 0–1 and those with a PS score of 2–3 (the response rate
was 8% for patients with a PS score of 0–1 and 11% for those
with a PS score of 2–3; the median survival times were 8.3,
4.3, and 1.9 months in the PS score 0–1, PS score 2, and PS
score 3 groups, respectively) [22, 23].
In view of these results, it is reasonable to suggest the use
of erlotinib in third-line therapy, where the PS of patients is
usually diminished. However, certain factors, either clini-
cal (never-smoker, adenocarcinoma or bronchioloalveolar
subtype, female sex, Asian ethnicity) [30, 31] or molecular
(immunohistochemical EGFR expression [26], amplifica-
tion of EGFR measured by fluorescence in situ hybridiza-
tion [32], or EGFR mutations [33, 34]), have been shown
to be predictive of benefits in response and, in some cases,
survival when using EGFR inhibitors as second-line treat-
ments. Thus, even though the presence of EGFR mutations
did not correlate with longer survival in the BR.21 study
[26], the use of EGFR inhibitors could be recommended for
second-line therapy instead of chemotherapy.
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Conclusions
There are some issues that should be considered when
choosing between chemotherapy and targeted therapy in
the second-line treatment of NSCLC [35]. Pemetrexed is
the only drug that has been directly compared in the second-
line setting with an active cytotoxic agent, docetaxel, rather
than with BSC [8], as is the case for gefitinib [21] and erlo-
tinib [22]. Moreover, the demonstrated superiority of tar-
geted agents over BSC for third-line treatment opens up the
debate, in our opinion, about whether second- and third-line
treatment options should be evaluated separately. While we
are waiting for the results of phase III trials randomizing
patients to receive either docetaxel, pemetrexed, or EGFR
inhibitors, the comparable activity of pemetrexed, together
with its favorable toxicity profile (versus docetaxel), sug-
gests that pemetrexed may be the best option at present
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for second-line treatment. Erlotinib, therefore, represents
the best third-line option in recurrent NSCLC, and could
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unsuitable for chemotherapy, or in those with a favorable
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OTncologist
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 Clinical Evidence for Second- and Third-Line Treatment Options in Advanced
Non-Small Cell Lung Cancer
Filippo de Marinis and Francesco Grossi
Oncologist 2008;13;14-20
DOI: 10.1634/theoncologist.13-S1-14
This information is current as of March 14, 2011

Updated Information including high-resolution figures, can be found at:

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