Non-small-cell lung cancer
(NSCLC) accounts for approximately
80% of all cases
of lung cancer and is the leading cause
of cancer death in the world.[1] NSCLC
was long considered a poorly
chemosensitive disease, and the role of
systemic therapy was unclear. Since
the publication of a meta-analysis in
1995, it has been accepted that platinum-
based chemotherapy modestly but
significantly prolongs survival and improves
quality of life over best supportive
care in patients with NSCLC.[2]
Incorporation of newer active drugs
(taxanes, gemcitabine(Drug information on gemcitabine) [Gemzar], vinorelbine)
has led to regimens that
achieve higher response rates than older
regimens, although not necessarily a
survival advantage.[3] Randomized
studies also showed that cisplatin(Drug information on cisplatin)-based
chemotherapy and new chemotherapeutic
agents result in improved quality
of life compared with best supportive
care.[4] More recently, phase III trials
showed that two-drug regimens including
a platinum and one of the new
cytotoxic agents offer an improved response
and survival rate compared with
a single agent,[5,6] whereas three-drug
regimens do not improve survival in
advanced disease.[7]
Despite the survival benefit associated
with first-line chemotherapy, the
majority of patients will experience relapse
or disease progression. Because
of improved therapeutic results with
newer agents and supportive therapies,
an increasing number of patients maintain
a good performance status after
first-line treatment and are eligible for
further treatment. In this review, we
summarize the published results of second-
line treatment in NSCLC and discuss
future strategies.
Second-Line Therapy in
NSCLC: Standard Options
Recent studies have demonstrated
that several new chemotherapy agents
may be useful for the treatment of
refractory or recurrent NSCLC after
initial platinum-based chemotherapy.
Results obtained with docetaxel (Taxotere),[
8,9] pemetrexed(Drug information on pemetrexed) (Alimta),[10] gefitinib(Drug information on gefitinib) (Iressa),[11] and erlotinib
(Tarceva) are particularly consistent.[
12] Table 1 summarizes the results
obtained with these agents in
previously treated patients.
Docetaxel
Four phase II trials showed that docetaxel(Drug information on docetaxel) was active in pretreated
NSCLC patients. When used as a single
agent, docetaxel (100 mg/m2 every
3 weeks) provided response rates
ranging from 16% to 22%, with grade
3/4 neutropenia (National Cancer Institute
Common Toxicity Criteria,
NCI-CTC) being the primary doselimiting
event.[13-16] In a phase II
study conducted by Fossella et al in
platinum-refractory NSCLC, the response
rate was 21% and median survival
was 42 weeks.[14]
These promising results led to two
large phase III trials that established
docetaxel as the first chemotherapeutic
agent with proven benefit for patients
with recurrent or refractory disease following
platinum-based first-line chemotherapy.[
8,9] In the TAX 320 trial,
373 NSCLC patients showing disease
progression after platinum-based chemotherapy
were randomly assigned to
docetaxel or to a control arm of vinorelbine
or ifosfamide(Drug information on ifosfamide).[8] The response rate
was significantly higher in the group of
patients treated with docetaxel (11%
for those treated with 100 mg/m2, and
7% for those treated with 75 mg/m2)
than in the group treated with navelbine
or ifosfamide (1%). Importantly,
overall survival was initially similar
between the two arms, but the survival
analysis was censored when additional
poststudy chemotherapy was administered,
and the 1-year survival rate
proved significantly higher in the docetaxel
arm (32% vs 10%, P < .01).
Quality-of-life analysis measured using
the Lung Cancer Symptom Scale
demonstrated a significant improvement
in quality of life for patients treated
with docetaxel.[17]
In another phase III trial, Shepherd
et al randomly allocated 104 NSCLC
patients pretreated with platinumbased
chemotherapy to docetaxel,
100 mg/m2, or best supportive care.[9]
Because of the excess toxicity observed
in the docetaxel arm, the drug
dose was reduced to 75 mg/m2 in the
second half of the trial. Time to progression
was longer for docetaxel patients
than for best supportive care
patients (10.6 vs 6.7 weeks, respectively,
P < .001), as was median survival
(7.0 vs 4.6 months, P = .047).
The difference was more significant
for patients receiving docetaxel,
75 mg/m2, compared with corresponding
best supportive care patients (7.5
vs 4.6 months, P = .01). Importantly,
the fraction of patients alive at 1 year
was significantly higher in the docetaxel
group (37% vs 11%, P = .003).
This study demonstrated that treatment
with docetaxel was associated
with significant prolongation of survival,
and at a dose of 75 mg/m2, the
benefits of docetaxel therapy outweigh
the risks. It is also interesting to note
that the response rate obtained with
docetaxel was only 7%. Although the
expected response rate is low, the benefit
in 1-year survival and the qualityof-
life improvement justify docetaxel
use in pretreated patients. At the
present time, docetaxel (75 mg/m2
every 3 weeks) is considered the standard
regimen to which other experimental
schedules should be compared.
In order to identify a less toxic schedule,
French investigators conducted a
randomized phase II study comparing
docetaxel at the standard every-3-week
schedule with docetaxel at a weekly
dose of 40 mg/m2, in patients who had
failed after first-line platinum-based
chemotherapy.[18] This study, conducted
in 125 advanced NSCLC patients,
showed a significantly lower rate of
severe neutropenia in the weekly arm,
with comparable efficacy in terms of
survival (5 months for both arms).
These results suggested that the weekly
regimen could be considered as a
good alternative for patients at risk for
severe neutropenia.
Recent phase III trials suggested that
non-platinum-based doublets may be
equivalent to platinum doublets in terms
of efficacy.[19] These data suggest that
non-platinum-based combinations, including
docetaxel-based regimens,
should be explored in the second-line
setting. Two recent randomized phase II
trials compared docetaxel, 75 mg/m2
every 3 weeks, to docetaxel/irinotecan
(Camptosar).[20,21] Both trials showed
that the addition of irinotecan(Drug information on irinotecan) to docetaxel
failed to improve response rate or
survival, while increasing gastrointestinal
toxicity. Therefore, docetaxelbased
two-drug combinations are not
recommended as second-line therapy
outside of the clinical trial setting.
Pemetrexed
Pemetrexed is a novel antimetabolite
that inhibits at least three enzymes-
thymidilate synthase, dihydrofolate
reductase, and glycinamide ribonucleotide
formyltransferase-involved in
the folate pathway.[22,23] As a single
agent, pemetrexed has been evaluated
in both first- and second-line therapy in
patients with advanced NSCLC. In the
two trials that evaluated the drug as
first-line therapy, response rates ranged
from 16% to 23%, and median survival
was 9.6 and 8.4 months.[24,25] These
results were comparable to those obtained
for single-agent studies of agents
with established activity in NSCLC,
supporting further evaluation of pemetrexed
as first-line therapy in association
with a platinum drug.
In a phase II trial, Smit et al evaluated
activity and tolerability of pemetrexed
in 81 NSCLC patients progressing
during or within 3 months after
first-line chemotherapy.[26] The response
rate was 4.5% in platinumpretreated
patients and 14.1% in non-
platinum-pretreated patients, with an
overall median survival of 5.7 months.
On the basis of the activity seen in
this second-line study, a randomized
phase III trial comparing single-agent
pemetrexed with single-agent docetaxel
as second-line chemotherapy
was undertaken. In this study, patients
received folate and vitamin B12 supplementation,
in light of evidence that
pemetrexed therapy without supplementation
results in a significantly
higher incidence of hematologic and
nonhematologic toxicity.[27]
A total of 571 NSCLC patients who
had relapsed or progressed after firstline
chemotherapy were randomly assigned
to pemetrexed, 500 mg/m2 every
21 days, or docetaxel, 75 mg/m2 every
21 days.[10] No difference was observed
in response rate (9.1% vs 8.8%,
P = .10) or in survival (median survival
= 8.3 vs 7.9 months; 1-year survival
= 29.7% in both groups; hazard ratio
[HR] = 0.99) between pemetrexed and
docetaxel recipients, respectively. Patients
receiving docetaxel were more
likely to have grade 3/4 neutropenia
(40.2% vs 5.3%, P < .001), febrile neutropenia
(12.7% vs 1.9%, P < .001),
neutropenia with infections (3.3% vs
0%, P = .004), hospitalizations for
neutropenic fever (13.4% vs 1.5%,
P < .001), hospitalizations due to other
drug-related adverse events (10.5%
vs 6.4%, P = .092), use of granulocyte
colony-stimulating factor
(G-CSF, Neupogen) support (19.2%
vs 2.6%, P < .001), and all-grade
alopecia (37.7% vs 6.4%, P < .001),
compared with patients receiving
pemetrexed. Based on these findings,
in August 2004, the US Food and
Drug Administration (FDA) approved
pemetrexed for the second-line treatment
of advanced NSCLC.
Tyrosine Kinase Inhibitors
Epidermal growth factor receptor
(EGFR) is the target for cancer therapies
such as gefitinib or erlotinib,
which inhibit the tyrosine kinase activity
of EGFR by reversibly competing
with adenosine(Drug information on adenosine) triphosphate (ATP)
at the ATP-binding site within the
EGFR protein. Both drugs are orally
active, selective EGFR tyrosine kinase
inhibitors (TKIs) that have
demonstrated antitumor activity
against a variety of human cancer cell
lines expressing EGFR, including
NSCLC.[28,29] Phase I studies, evaluating
the safety and tolerability of
gefitinib, identified rash and diarrhea
as unique, dose-related toxicities. Of
note, an 11% response rate has been
observed among the 100 NSCLC patients
enrolled in these trials.[30]
- Gefitinib-To confirm the objective response data and symptomatic benefit seen in phase I trials, investigators conducted two large phase II studies in pretreated NSCLC patients. In the first trial (Iressa Dose Evaluation in Advanced Lung Cancer, or IDEAL 1), 210 pretreated NSCLC patients were randomized to gefitinib at a 250- or 500-mg daily dose.[31] This trial showed an 18% response rate, with symptomatic improvement in 40% of patients, and no significant difference between the two dose levels. In the subsequently published US trial (IDEAL 2), 216 NSCLC patients who had failed two or more prior chemotherapy regimens containing platinum and docetaxel were randomly assigned to gefitinib at 250 or 500 mg daily. This trial confirmed that gefitinib is active in heavily pretreated NSCLC patients, with a response rate of 11.8% and symptom improvement in 43% of patients in the 250-mg arm.[11] On May 5, 2003, based on the results of the IDEAL 2 trial,[11] the FDA approved single-agent gefitinib, at the daily dose of 250 mg, for the treatment of patients with advanced or metastatic NSCLC after failure of both platinumand docetaxel-based chemotherapies. The approval of this drug was dependent on the assurance by the drug's manufacturer (AstraZeneca) that randomized trials would be conducted to demonstrate an improvement in survival or symptoms for patients receiving the drug. Two large phase III studies compared standard chemotherapy vs the same chemotherapy regimen plus gefitinib as first-line therapy.[32,33] Both trials failed to demonstrate any survival advantage for patients receiving gefitinib. On December 17, 2004, AstraZeneca announced the results of the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, a large phase III study comparing gefitinib with placebo as second- or third-line therapy in NSCLC. This study failed to demonstrate any survival advantage for patients receiving gefitinib.
- Erlotinib-Paralleling the experience with gefitinib, erlotinib demonstrated activity in the second-line setting, but first-line trials showed no advantage to erlotinib in conjunction with standard chemotherapy.[38,39] On November 20, 2004, the FDA approved erlotinib for the treatment of patients with advanced NSCLC pretreated with standard chemotherapy. The FDA based this decision on results from a randomized double-blind, placebo-controlled pivotal phase III trial of patients with second- or thirdline advanced NSCLC.[12] In this study, patients receiving erlotinib had a median survival of 6.7 months, compared to 4.7 months in patients who received placebo-a 42.5% improvement. A hazard ratio of 0.73 and a P value less than .001 were determined for comparisons of overall survival. In addition, 31.2% of patients receiving erlotinib in the study were alive at 1 year vs 21.5% in the placebo arm. Although the difference in the results obtained with gefitinib and erlotinib could be related to differences between these two drugs, it is possible that these conflicting results are due to the fact that the trial populations were not selected for any clinical or biologic characteristics. In the era of targeted therapies, it is not possible to treat all patients similarly, and the identification of individuals more likely to benefit from a particular treatment is of crucial importance.
The negative results of the ISEL
trial clearly indicate that it is not reasonable
to propose TKI therapy for all
patients with NSCLC, and targeted therapies
should be offered only to patients
presenting the biologic characteristics
that predict sensitivity (Table 2). All
trials conducted with TKIs to date have
shown that some clinical characteristics
are significantly associated with
response to the treatment (eg, female
gender, adenocarcinoma histology, and
never-smoking history). These features
are related to TKI sensitivity because
they are significantly associated with
biologic predictors of response. It is
now clear that patients carrying specific
EGFR gene mutations[34,35] or amplifications[
36]-producing activation
of antiapoptotic EGFR-dependent pathways[
37]-are more sensitive to the
drug. Further prospective trials should
be conducted in patients selected for
these biologic characteristics.
Results reported with gemcitabine are conflicting. Nine phase II trials, evaluating activity and tolerability of gemcitabine in single-agent therapy, demonstrated response rates ranging from 0% to 21%.[40-48] Rosvold evaluated the activity of gemcitabine as second-line chemotherapy in 28 patients with advanced NSCLC progressing after prior carboplatin(Drug information on carboplatin) plus paclitaxel. This small phase II trial showed that gemcitabine is an active, well tolerated salvage regimen inpatients failing carboplatin-plus-paclitaxel first-line chemotherapy, producing a 21% objective response rate.[48] An Italian phase II trial tested gemcitabine as a single agent in 83 pretreated patients with advanced NSCLC. In this study, patients received gemcitabine at 1,000 mg/m2 once a week for 3 weeks every 28 days. Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks. Treatment was well tolerated. In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy.[41] Several trials evaluated the activity of gemcitabine in combination with other drugs in pretreated NSCLC patients. When combined with etoposide(Drug information on etoposide) or topotecan(Drug information on topotecan) (Hycamtin), gemcitabine obtained response rates of 21%[49] and 15%,[50] respectively. Five trials studied the combination of gemcitabine plus vinorelbine and showed response rates of 6% to 21%.[51-55] More recently, the combination of gemcitabine and docetaxel has been evaluated in a phase II trial conducted in 43 NSCLC patients relapsing after paclitaxel plus platinum-based chemotherapy.[ 56] In this trial, gemcitabine was administered at a dose of 1,000 mg/m2 on days 1 to 8 followed by docetaxel, 100 mg/m2 on day 1, recycled every 21 days. The combination proved to be active in terms of response rate (33%), median time to progression (6 months), and median survival (8 months), with an encouraging 28% 1-year-survival. Because of these conflicting results, no phase III trial has been conducted to compare gemcitabine to best supportive care or docetaxel in pretreated NSCLC. At the present time, the use of gemcitabine alone or in combination with other drugs is not recommended in previously treated patients. Paclitaxel
Paclitaxel has also been studied in the second-line setting. Sculier et al[57] conducted a phase II trial in patients who had failed first-line chemotherapy with platinum derivatives and/or ifosfamide, by administering paclitaxel at a dose of 225 mg/m2 given IV over 3 hours every 3 weeks. Although tolerance was acceptable, only two partial responses (3%) were observed, median survival was 4.5 months, and 1-year survival was 19%. In another multicenter trial, Socinski et al[58] sought to determine the activity of second-line, low-dose, weekly paclitaxel (80 mg/m2) in 62 patients with advanced NSCLC who failed first-line chemotherapy with carboplatin plus paclitaxel. The response rate was 8% and median survival, 5.2 months. The toxicity profile was extremely favorable, with the exception of mild-to-moderate neuropathy in 10% of the patients. In another phase II trial, 24 advanced NSCLC patients previously treated with platinum containing regimens[59] received 60 or 90 mg/m2 of paclitaxel (1- hour infusion for 6 consecutive weeks followed by 2 weeks without treatment for an 8-week cycle). Seven patients (29%) achieved a partial response and five (21%) had stable disease. Spanish investigators[60] administered weekly paclitaxel, 80 mg/m2 as a 1-hour infusion, to 40 NSCLC patients who had been previously treated with platinumbased chemotherapy. The overall response rate was 37.5%, with 2 complete and 13 partial responses; the median survival was 9.7 months and the median time to progression, 5.4 months. Although these results seem to be comparable to those obtained with docetaxel, no direct comparison has been made, and the use of paclitaxel in the second-line setting is not recommended in clinical practice. Novel Agents
Several new agents have proven active against NSCLC (Table 3). Cetuximab(Drug information on cetuximab) (Erbitux) is a monoclonal antibody that inhibits EGFR ligand binding, resulting in cell-cycle arrest and increased expression of proapoptotic proteins. Additive or synergistic growth inhibition was observed when cetuximab was combined with radiotherapy or chemotherapy in several preclinical models.[61-65] Recently, Rosell et al conducted a randomized phase II study comparing cetuximab/ cisplatin/vinorelbine vs cisplatin/vinorelbine as first-line treatment in 86 NSCLC patients who were immunihistochemically positive for EGFR expression.[66] This study suggested that cetuximab can be safely combined with chemotherapy to enhance activity. A large phase III trial comparing the cisplatin/vinorelbine/cetuximab combination vs chemotherapy alone as first-line therapy is ongoing. Bevacizumab(Drug information on bevacizumab) (Avastin) is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). The drug has been evaluated in a threearm multicenter trial,[67] in which 99 patients with advanced NSCLC were randomized to standard chemotherapy with carboplatin plus paclitaxel or the same chemotherapy combination plus two different bevacizumab doses (7.5 and 15 mg/kg). The response rate increased by about 10% with bevacizumab, and time to progression was prolonged by about 3 months (from 4.5 to 7.5 months). However, six patients developed severe hemoptysis, and four toxic deaths occurred. A subset analysis of non-squamous cell NSCLC patients evaluated the impact of bevacizumab on overall response rate, time to progression, and median survival. This analysis showed that bevacizumab may prolong survival in non-squamous cell NSCLC patients without engendering unacceptable toxicity or an excess of toxic deaths. Objective response rate (32% vs 12%) and time to progression (30 vs 17 weeks) favored patients on bevacizumab. The Eastern Cooperative Oncology Group carried out a confirmatory phase III trial, in which patients with non-squamous cell NSCLC were randomized to carboplatin plus paclitaxel alone or combined with bevacizumab at 15 mg/kg. [Editor's note: ECOG 4599 was reported at ASCO 2005; see page 1000 for discussion.] Xenograft experiments performed in various tumor types suggest that growth inhibition using bevacizumab in combination with the TKI erlotinib is greater than with either agent alone. Sandler et al recently presented results of a phase I/II trial evaluating the combination of bevacizumab and erlotinib in 40 NSCLC pretreated with at least one prior chemotherapy regimen.[68] In this study, the response rate was 17.5%, and median survival was 9.3 months. This encouraging antitumor activity and favorable toxicity profile support further development of this combination for advanced NSCLC. Although results obtained with cetuximab and bevacizumab are encouraging, at the present time, their use is not recommended outside clinical trials.
Conclusions
Although several drugs are now
available for the treatment of relapsed
NSCLC, results are disappointing and
any survival gain remains modest.
Targeted therapies, such as EGFRTKIs,
have been shown to be active
in a small group of patients with advanced
NSCLC. The recent comprehension
of the mechanisms underlying
TKI activity allow us to select patients
for such therapy, based on biologic
predictors of sensitivity. Looking
ahead, studies that correlate outcome
to biologic end points will have the
greatest ability to improve our understanding
of lung cancer biology and
the treatment of patients.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
