转移性和晚期NSCLC的化学治疗

Seminars in Surgical Oncology 2003; 21:98–110
Chemotherapy in Metastatic and Locally
Advanced Non-small Cell Lung Cancer
DAVID R. SPIGEL, MD* AND F. ANTHONY GRECO, MD
The Sarah Cannon Cancer Center, Nashville, Tennessee
The majority of patients with non-small cell lung cancer have locally advanced and metastatic
disease at diagnosis. Combination platinum-based chemotherapy is the standard treatment
for patients with advanced disease who have a performance status of 0–1. Chemotherapy is
superior to supportive care alone in terms of survival, palliation of symptoms, and in many
studies, improving quality of life. Newer third generation therapies such as paclitaxel, docetaxel,
vinorelbine, and gemcitabine have been proven effective as single agents with minimal
toxicity, compared with supportive care alone. In combination with platinum, these agents
produce higher response rates than older platinum-based regimens, are associated with additional
survival benefits, and are generally more convenient and less toxic for patients. Newer
nonplatinum doublets appear equivalent to newer platinum-regimens and have expanded the
options available for patients. Targeted agents are promising and may soon offer patients
more effective and less toxic therapies. Progress in treatment in the advanced setting has led
to advances in the care of locally advanced disease. Combination chemoradiotherapy is a
standard treatment for locally advanced disease, and studies with newer agents are in
progress. Semin. Surg. Oncol. 21:98–110, 2003.
2003 Wiley-Liss, Inc.
KEY WORDS: non-small cell lung cancer; NSCLC; advanced; unresectable;
metastatic; locally advanced; chemotherapy; supportive care;
platinum; third generation; radiotherapy
INTRODUCTION
Worldwide, over 1,000,000 people are diagnosed with
lung cancer each year. Non-small cell lung cancer
(NSCLC) accounts for 80% of newcases, and the majority
of these are already locally advanced or metastatic at
diagnosis. Among those eligible for potential curative
resection, over half will ultimately develop metastatic
disease. Among all patients with NSCLC, fewer than 15%
will be long-term survivors.
Advanced NSCLC includes unresectable locally advanced,
metastatic, and recurrent disease. Unresectable
locally advanced disease primarily includes patients
with stage III disease. Patients with untreated advanced
NSCLC have a median survival of approximately
4–6 months. With the rare exception of oligometastatic
disease (patients with solitary brain, adrenal, or cervical
nodal metastases, 1% of all stage IV patients), treatment is
not intended to cure. Rather, the goals in caring for patients
with advanced NSCLC are primarily palliative—to improve
the symptoms of progressive disease, improve the
quality of life (QOL), and extend survival.
Multiple randomized studies in advanced NSCLC have
unequivocally shown that combination platinum-based
chemotherapy is superior to standard supportive care (SC)
in achieving these goals [1,2]. Chemotherapy extends survival,
palliates symptoms, and improves QOL in patients
with advanced disease [3,4]. Accordingly, in 1997, the
American Society of Clinical Oncology published clinical
practice guidelines for the care of patients with unresectable
locally advanced and metastatic NSCLC, recommending
chemotherapy in patients with good performance
status (Eastern Cooperative Oncology Group [ECOG]
PS of 0–1, and possibly 2) [5]. Currently, platinum-based
systemic chemotherapy is regarded as standard care in the
treatment of advanced disease.
In the last decade, and since these guidelines were
published, several new nonplatinum ‘‘third’’ generation
agents have been studied in combination regimens for
*Correspondence to: David R. Spigel, 250 25th Ave. N., Suite 110,
Nashville, TN 37203. E-mail: dspigel@tnonc.com
DOI 10.1002/ssu.10027
Published online inWiley InterScience (www.interscience.wiley.com).

2003 Wiley-Liss, Inc.
patients with advanced NSCLC. These agents have proven
effective and safe, and have increased the array of available
treatment options for patients. Although gains have
been modest overall, improvements in dosing, scheduling,
and toxicity represent real incremental achievements in
care. More recent progress has been seen with new oral
agents designed to target intracellular signaling and cellular
proliferation. In select patients, these innovative
therapies have resulted in remarkable responses with
minimal toxicity. These ‘‘fourth’’ generation agents mark
a fundamental shift in drug design and may further impact
the treatment of advanced lung cancer, allowing more
patients to live better and longer. This paper reviews the
newer agents used in the treatment of metastatic and
locally advanced NSCLC as well as achievements from
selected pivotal trials to date.
ADVANCED NSCLC
Platinum Combination
Chemotherapy Vs. Standard Supportive Care
Chemotherapy has been used in the treatment of advanced
NSCLC for over 30 years. So called first generation
agents (e.g., cyclophosphamide, methotrexate, or
doxorubicin) were commonly used in the treatment of
other malignancies, but had little if any activity in the
treatment of NSCLC, proving no better than standard SC
alone (also referred to as Best Supportive Care, or more
recently, Standard Palliative Care [6]). The second generation
drugs included cisplatin or carboplatin, mitomycin,
ifosfamide, etoposide, and the vinca alkaloids. As a group,
these newer agents were more effective and their use
became more widespread during the 1980s.
A 1983 multicenter trial sponsored by the National
Cancer Institute of Canada (NCIC) was the first pivotal
trial demonstrating the superiority of combination chemotherapy,
albeit modest, over SCalone [7]. Prior to this trial,
multiple platinum regimens had failed to consistently result
in any improvement in survival over SC, in part
because many of the earlier platinum-based trials had been
criticized for poor study design, inadequate staging, and
inconsistent treatment. The NCIC study was a prospective
randomized trial that compared two regimens—cyclophosphamide/
doxorubicin/cisplatin (CAP) and cisplatin/
vindesine (CV)—to SC alone. The median overall survival
was statistically improved with chemotherapy compared
to SC (CAP 8.2 months, CV 6.2 months, SC 4.3 months,
chemotherapy vs. SC, P¼0.02, Table I). Similar findings
were seen in a large randomized trial that compared
mitomycin, ifosfamide, and cisplatin (MIC) to SC alone
[8].MICresulted in improvements in both median survival
and in QOL. This was again demonstrated in an Italian
study, which randomized 102 patients to cisplatin/
cyclophosphamide/mitomycin (CCM) or SC [4]. CCM
extended median survival by approximately 4–5 months.
An improvement in QOL seen in treated patients suggested
that palliation outweighed any short-term toxicity
from chemotherapy. Most recently, a British group presented
preliminary findings from a large multicenter trial
which randomized patients with advanced NSCLC to
chemotherapy using CV, MIC, mitomycin/vinblastine/
cisplatin (MVP) or vinorelbine/cisplatin (CN) to SC
alone [9]. Investigators found an improvement in the
chemotherapy-treated groups (hazards ratio [HR]¼0.77,
95% confidence interval¼0.66–0.91, P¼0.0015). Importantly,
there were no differences in QOL or in any
TABLE I. Pivotal Randomized Trials of Platinum Chemotherapy Vs. Standard Supportive Care
Overall Median survival
Reference N response rate (%) (months)/1-yr survival (%) QOL
Rapp et al. [7] 233 CAP 15 8.2
CV 25 6.2
SC 4.3
Cullen et al. [8] 351 MIC 32 6.7/25
SC 4.8/17
Cartei et al. [4] 102 CCM NR 8.5 QOL improved
SC NR 4
Stephens et al. [9] 725 CV NR Do difference in
MIC NR QOL/more toxicity
MVP NR in general with
CN NR 7.8/28 chemotherapy
SC 5.7/19
Thongprasert et al. [3] 287 IEP 40 5.9/30 QOL improved
MVP 42 8.1/39
SC 4.1/13
BOLD, P<.05; NR, not reported; CAP, cyclophosphamide/doxorubicin/cisplatin; CV, cisplatin/vindesine;
MIC, mitomycin/ifosfamide/cisplatin; CCM, cisplatin/cyclophosphamide/mitomycin; MVP, mitomycin/
vinblastine/cisplatin; CN, cisplatin/vinorelbine; IEP, ifosfamide/epirubicin/cisplatin; SPC, standard
palliative care.
Chemotherapy in Advanced NSCLC 99
other secondary endpoints, including physical or emotional
functioning, fatigue, pain, or dyspnea.
Collectively, these trials represent what is now a substantial
body of evidence that supports a modest beneficial
effect of platinum-based chemotherapy on survival in
advanced NSCLC. This is perhaps best shown in a metaanalysis
of randomized trials published by the NSCLC
Collaborative Group in 1995 [2]. One part of this analysis
examined eight trials (including two studies mentioned
above [4,7]) in the advanced setting, which randomized
patients to platinum-based chemotherapy or SC. The
overall HR for chemotherapy was 0.73 (P<0.0001). This
translated into a 10% absolute improvement in survival at
1 year, and an increased median survival of approximately
1–2 months. Although no study has consistently shown
superiority for any single platinum-based regimen, combination
therapy with cisplatin and a vinca alkaloid, and
later with etoposide, became standard regimens for
advanced NSCLC.
Third Generation Agents
In the last decade, a number of new nonplatinum agents
have been tested in advanced NSCLC. These include:
vinorelbine, gemcitabine, irinotecan, and the taxanes—
paclitaxel and docetaxel. Response rates for each of these
agents alone range from 10% to 30%. Compared as single
agents to SC alone, these too produce unequivocal improvements
in median survival and QOL [10]. Compared
as single agents to older platinum combination regimens
such as CVor CE, they generally produce equivalent responses
(15% to 30%) and median survival (7–11 months),
but often with less toxicity [11,12].
New vs. old: platinum combination regimens. Several
randomized studies have compared these third generation
agents in combination with platinum to older more
standard, platinum-based regimens (Table II). As a group,
these newer combination regimens have achieved higher
response rates, are more convenient and less toxic, and in
some studies result in small, but real, improvements in
both QOL and median survival.
The taxanes—paclitaxel and docetaxel, are two of the
most commonly used agents in oncology and are now
standard agents in the first- and second-line treatment of
advanced NSCLC, respectively. In 1993, a pivotal phase II
trial examining carboplatin/paclitaxel (CaP) in 53 patients
with advanced NSCLC in part helped establish what is
now a standard regimen in the United States [13]. The
overall response rate (ORR) was 62%, with a median
survival of 1 year. Although this was a phase II study, these
early results were obviously very promising. An important
multicenter trial performed byECOGrandomized patients
with advanced disease to cisplatin/paclitaxel (CP) at two
different paclitaxel doses or to the older, more standard CE
[14]. As shown in Table II, compared with etoposide,
ORRs were superior for both paclitaxel regimens. Survival
was also improved, although these differences were only
seen when the paclitaxel cohorts were combined. Of note,
in a subgroup analysis, these results held true for IIIB
patients, however there was no statistical difference between
arms in patients with advanced disease. Toxicity
was similar across all three arms and there were no differences
in QOL among the regimens. A similar trial conducted
by the European Organization for the Research and
Treatment of Cancer (EORTC) compared CP to CT with
teniposide instead of etoposide. CP resulted in an improvement
in QOL, convenience, toxicity, and response
rate, although improvements in survival were not seen
[15]. Similarly, in the Kunitoh et al. [16] trial, cisplatin/
docetaxel (CD) resulted in higher response rates and
tended toward an improvement in survival compared to the
older CV regimen.
Vinorelbine was studied in a large trial by LeChevalier
et al. [12]. This was a three-arm trial that randomized
patients to vinorelbine alone, to CN, or to the olderCV.CN
led to both a higher ORR and median survival than CV.
Gemcitabine has been combined with cisplatin
(CG) and compared to CE in a randomized trial by
Cardenal et al. [17]. Higher response rates were seen in
the gemcitabine arm, but differences in median survival
were not statistically significant. However, this trial of
133 patients has been criticized for being underpowered.
An Italian study randomized patients to CG or the
control regimen MIC. While response rates were higher
with gemcitabine, again there were no differences in
survival or QOL [18]. However, investigators in two
additional unpublished gemcitabine trials found opposite
results. In one, CG was compared to CV and MVC
[19], and in the second, to MIC [20]. In both trials,
response rates were comparable to the control arms, but
improvements in median survival were seen (unlike in the
previous trials.) In the latter trial, CG was better tolerated
as well.
Irinotecan has been compared to CV in two trials, with
equivocal results. In a prospective multicenter randomized
study by Masuda et al. [21], no significant differences were
seen in terms of ORR or median survival. However, a
subset analysis found an increase in survival for patients
with metastatic disease. Niho et al. [22] also found no
significant differences in terms of response rate or survival
in a smaller randomized trial.
In summary, the newer platinum-based combination
regimens generally result in higher response rates than the
older standard platinum regimens. Differences in survival
have been modest at best and not consistently demonstrated.
However, no newregimen was found to be inferior
in terms of either endpoint. Additionally, many of these
newer regimens were easier for patients both in terms of
toxicity and scheduling. For all of these reasons, many of
100 Spigel and Greco
these new platinum combinations are now standard
regimens in the treatment of advanced NSCLC.
New vs. new: platinum combination regimens. A
next logical question is whether any one of these newer
platinum/third generation regimens is better than any
other. More recent (and ongoing) trials have examined
this issue (Table III). The largest trial to date was an
ECOG study that randomized over 1,100 patients with
advanced disease to one of four arms: CP, CG, CD, or
CaP [23]. Most of these patients had a PS of 1 and recurrent
or metastatic disease, as well as other similar
baseline characteristics. The authors found no statistical
differences in ORR or survival among any of the treatment
arms. The arm receiving CG had a one-month
longer progression-free survival than the more standard
CP arm, however greater renal toxicity was seen. No data
were collected on the use of second line therapies (i.e.,
potential crossover effects) and QOL was not assessed.
Also, CaP had less toxicity than the other regimens. This
important study confirmed what many had interpreted
from prior studies and clinically—that no newer regimen
was better than another as a first-line treatment.
A Southwest Oncology Group (SWOG) study similarly
compared CN and CaP in over 400 patients. Again, no
differences were evident in terms of ORR, median survival,
or QOL. However, the CaP arm had less nausea,
renal toxicity, and marrow suppression, and was more
convenient for patients [24]. An EORTC study also
recently failed to demonstrate any meaningful response
or survival differences in a three-arm trial that randomized
patients to CP, CG, or GP. Interestingly, the GP arm tended
toward a lower response rate and decreased survival.
Other recent studies have also addressed whether superiority
can be achieved with the addition of a newer agent
to a new platinum regimen or in nonplatinum regimens
using two or three newer agents. Thompson et al. [25]
TABLE II. Pivotal Randomized Trials With Newer Platinum Regimens in Advanced NSCLC
Overall Median survival
Reference N response rate (%) (months)/1-yr survival (%) QOL Toxicity
New vs. Old
Paclitaxel trials
Bonomi et al. [14] 599 CP 10/37 No differences Similar
135 mg/m2 25 11/40
250 mg/m2 28 8/32
CE 12
Giaccone et al. [15] 317 CP 41 9.7/41 Early improvements CT: " leukopenia,
CT 28 9.9/43 with CP neutropenia, and
thrombocytopenia
Docetaxel trials
Kunitoh et al. [16] 302 CD 37 12.3/48
CV 21 11/43
Vinorelbine trials
LeChavalier et al. [12] 612 N 14 31/30
CN 30 40/35
CV 19 32/27
Gemcitabine trials
Cardenal et al. [17] 133 CG 41 8.7 No differences CG: " nausea and
CE 22 7.2 vomiting
Crino et al. [18] 307 CG 38 8.6 No differences CG: " thrombocytopenia
Mic 26 9.6
Melo et al. [19] 248 MVC 27 6.4 CG: " thrombocytopenia
CV 37 9
CG (two schedules) 9.4/9.6
48 (for each)
Rudd et al. [20] 422 CG 37 10/38 CG: # nausea, vomiting,
MIC 41 6.5/28 alopecia and
constipation
Irinotecan trials
Masuda et al. [21] 378 I 21 46/41
CI 44 50/46
CV 32 46/38
Niho et al. [22] 203 CI 29 11
CV 22 12
BOLD, P<.05; CaP, carboplatin/paclitaxel; CE, cisplatin/etoposide; CP, cisplatin/paclitaxel; CT, cisplatin/teniposide; N, vinorelbine; CN,
cisplatin/vinorelbine; CV, cisplatin/vindesine; CG, cisplatin/gemcitabine; MIC, mitomycin/ifosfamide/cisplatin; MVC, mitomycin/vinblastine/
cisplatin; I, irinotecan; CI, cisplatin/irinotecan; CD, cisplatin/docetaxel.
Chemotherapy in Advanced NSCLC 101
randomized over 200 patients to PG, PCaG, PCaN, or GN
and found no statistical advantage for one regimen.
Likewise, Comella et al. [26] could not find any survival
differences among patients randomized to PG, GPN, or
CGP. In both studies, toxicity was increased in the threeagent
arms. A more recent trial by Kosmidis et al. [27]
comparing PG to CaP, again found no differences in
response rates, survival, or toxicity.
In summary, new chemotherapy combinations (þ/
platinum) are all likely to be similar in activity. The
ECOG and SWOG studies continue to find convenience
and toxicity advantages for CaP, and each have chosen
this regimen as a standard control arm in ongoing trials.
CaP is considered a standard community regimen in the
United States, however several other regimens appear
to share similar efficacy and some are also associated
with a low toxicity profile (vinorelbine, gemcitabine/
carboplatin, gemcitabine/weekly docetaxol, and gemcitabine/
paclitaxel.)
Special Issues in Chemotherapy
Second-line therapy. Advanced NSCLC is a progressive
disease. The median time to progression with current
therapy is 3–4 months. Docetaxel is the only Food and
Drug Administration (FDA)–approved second-line treatment
for advanced NSCLC, with response rates ranging
from 5% to 25% in this setting. M.D. Anderson (The
University of Texas M. D. Anderson Cancer Center,
Houston, TX) conducted a phase II study in 44 patients
who had progressed on platinum-based therapy and who
were treated with single-agent docetaxel [30]. The ORR
was 21% and median survival was 10 months. The
NSCLC Study Group [31] subsequently conducted a
larger confirmatory study that randomized similar
patients (n¼373) to docetaxel, ifosfamide, or vinorelbine.
Docetaxel achieved superior response rates of 11%
with 100 mg/m2, and 7% with 75 mg/m2, compared to 1%
with either ifosfamide or vinorelbine (P¼0.001 and
P¼0.036, respectively). The 1-year survival was also
greater. Similar results were confirmed in a second phase
III trial comparing docetaxel to SC [32]. No other phase
III trials to date have consistently confirmed similar
results for any other third generation agents.
Patient selection. The American Society of Clinical
Oncology (ASCO) guidelines on the use of chemotherapy
in advanced NSCLC recommend chemotherapy only for
patients with a PS of 0–1, and possibly 2 [5]. This was
based on evidence from multiple trials, which show that
patients with a better PS are more likely to benefit from
treatment than patients with a poor PS. Despite the guidelines,
treatment of patients with a PS of 2 is generally not
recommended. These patients are at greater risk for toxicity
and complications of treatment, and are unlikely to
realize survival benefits. In the recent large ECOG trial
that randomized patients to one of four new platinum
TABLE III. Pivotal Trials With Newer Platinum Regimens in Advanced NSCLC
Overall Median survival
Reference N response rate (%) (months)/1-yr survival (%) QOL Toxicity
Schiller et al. [23] 1155 CP 21 7.8/31 CG: " renal toxicity
CG 22 8.1/36
CD 17 7.4/31
CaP 17 8.1/34
van Meerbeeck et al. [28] 480 CP 31 8.1/35
CG 36 8.8/33
PG 27 6.9/26
Kelly et al. [24] 408 CaP 29 8/36 No differences CN: " marrow suppression/
CN 25 8/38 nausea
Thompson et al. [25] 205 PG 29 7.8/40
PCaG 34 10.3/38
PCaN 42 5/32
GN 29 11.3/49
Comella et al. [26] 247 PG 28 8.8/39
GPN 44 11.8/47
CGP 48 11.8/46
Rodriguez et al. [29] 1218 CD 32 /46 QOL improved Decetaxel more convenient
CaD /38 with docetaxel than vinorelbine
CN 25 /41 arms
Kosmidis et al. [27] 508 PG 28 10.4/35
CaP 35 9.8/41
Bold, P<.05; CP, cisplatin/paclitaxel; CG, cisplatin/gemcitabine; CD, cisplatin/docetaxel; CaP, carboplatin/paclitaxel; CN, cisplatin/vinorelbine;
PG, paclitaxel/gemcitabine; PCaG, paclitaxel/carboplatin/gemcitabine; PCaN, paclitaxel/carboplatin/vinorelbine; GN, gemcitabine/vinorelbine;
GPN, gemcitabine/paclitaxel/vinorelbine; CGP, cisplatin/gemcitabine/paclitaxel; CaD, carboplatin/docetaxel.
102 Spigel and Greco
regimens, patients with a PS of 2 were initially enrolled.
However, the trial was amended to exclude their enrollment
after a high rate of serious adverse events was seen
in these patients [33]. The median survival among these
patients was 3.9 months compared with 10.8 months
and 7.1 months in those patients with a PS of 0 or 1,
respectively (P<0.001 by the log-rank test for both
comparisons). Subgroup analyses in other trials have also
failed to show a survival benefit in patients with a PS of
2 [34]. However, it is important to consider that these
patients comprise a minority of those enrolled in past
(and current) clinical trials. As well, results from the large
Cullen et al. [8] randomized study of MIC and SC suggest
that these patients may receive early palliative benefits, if
not improvements in tumor response or survival. Nonetheless,
the potential benefits of chemotherapy in patients
with a PS of 2 are minimal in most, and the risks of toxicity
are high. The routine use of combination platinum
therapy in these patients should be discouraged.
Treatment in the elderly. More than half of patients
diagnosed with NSCLC are over the age of 65. Yet, many
patients are not offered systemic chemotherapy because
they are elderly. With advancing age comes an increased
risk of comorbid health conditions, organ dysfunction,
and polypharmacy, and hence a greater risk for complications
from a treatment that is intended to be palliative.
In general, single-agent chemotherapy is less toxic than
combination therapy. Several third generation agents
have been shown as single agents to be equivalent to older
platinum-combinations, and they are often less toxic
[1,12]. A multicenter randomized study compared singleagent
vinorelbine with SC alone in 161 patients 70 years
of age or older with a PS of 0–2 [34]. The trial was closed
early due to poor accrual, however treatment improved
symptoms and QOL scores, despite being associated with
some toxicity. Median survival was also modestly increased
(5.2 months vs. 5.0 months, P¼0.03, HR¼0.65,
95% CI¼0.45–0.93). Gemcitabine has been compared
as a single agent to SC alone in an elderly cohort [35].
Patients treated with gemcitabine reported improvements
in QOL and symptoms compared with those receiving SC
alone; however no differences in survival were seen.
More recently, Hainsworth et al. [36] conducted a phase
II study in previously untreated elderly patients (31%
with a PS of 2) using weekly docetaxel/gemcitabine. The
ORR was 29% and minimal toxicity was seen.
The Multicenter Italian Lung Cancer in the Elderly
Study (MILES) recently published a randomized prospective
three-arm trial comparing gemcitabine (G), vinorelbine
(N), and the combination (GN) in 698 elderly
patients with advanced disease (median age 74 years) [37].
ORR and median survival were not significantly improved
with the combination over either agent alone (ORR¼16%
for G, 18% for N, and 21% for GN; P¼0.18 for G vs. GN
and 0.47 for N vs. GN; median survival (months)¼7 for
G, 9 for N, and 8 for GN, P¼0.69 and 0.93). QOL was
similar across arms, however GN was associated with
more thrombocytopenia, neutropenia, cardiac and hepatic
toxicity, vomiting, and fatigue.
In general, age should not be used as a determinant in
decisions regarding the use of chemotherapy. In this population,
PS remains the best guide.
Dosing/scheduling/duration. Table IV lists doses and
toxicities for common agents used in the treatment of
advanced NSCLC. In general, 21-day and 28-day regimens
are more convenient for patients, as are carboplatinbased
regimens that require less hydration and are
generally less toxic than cisplatin. No schedule (weekly,
21-day, or 28-day) has been found to be superior to
another in terms of palliating symptoms or extending
survival. However, toxicity profiles can vary depending
on the schedule, as shown.
There are limited data on the appropriate duration of
chemotherapy and timing of response assessment. Recently,
Smith et al. [38] from the Royal Marsden (London,
England) addressed this question in a multicenter randomized
trial of 308 patients that compared three vs. six
cycles of mitomycin/vinblastine/cisplatin chemotherapy
for advanced disease. In the six-course arm, only 31% of
patients completed therapy. At ASCO in 2001, Depierre
et al. [39] presented results from a French Cooperative
Oncology Group trial where patients were randomized
to a ‘‘maintenance’’ regimen of vinorelbine or SC alone
(n¼179) after responding to primary treatment with MIC.
Maintenance therapy consisted of weekly vinorelbine for
6 months and did not result in improvements in survival.
Nor were any differences seen in symptom control, though
fatigue and nausea were better in the SC arm. Most
recently, Socinski et al. [40] published a trial looking at
duration, randomizing 230 patients with advanced disease
to four cycles of CaP or to continuous CaP until progression
or toxicity. At progression, all patients received
second-line weekly paclitaxel. The median number of
cycles delivered in the continuous arm was four. There
were no differences in ORR, survival, or QOL.
In light of these trials, first-line treatment should be for
two cycles before assessing for response. If there is no
evidence of disease progression, and patients are tolerating
treatment, two to six more cycles may be administered,
with the understanding that any survival and palliative
benefits are likely to be achieved by four cycles.
Novel Agents
EGFR targeted agents. In the last few years, several
novel agents have entered into clinical trials in advanced
NSCLC. Elucidation of the epidermal growth factor
receptor (EGFR) family, coupled with the success of
traztuzumab in breast cancer and the oral therapy
Chemotherapy in Advanced NSCLC 103
imatinib in chronic myelogenous leukemia and gastrointestinal
stromal tumors, have led to much enthusiasm
for similar approaches to targeted therapy in NSCLC.
In theory, blocking the EGFR (which is usually overexpressed
in NSCLC) could inhibit tyrosine kinase
function and affect cellular activation and proliferation.
Much of the early focus has been on the development of
oral tyrosine kinase inhibitors and monoclonal antibodies
to EGFR.
Gefitinib/Erlotinib. Gefitinib (ZD1839, IressaTM) and
Erlotinib (OSI-774, TarcevaTM) are oral small molecule
inhibitors of the receptor-bound tyrosine kinase. Responses
to both agents were seen in phase I trials. Gefitinib
recently received FDA approval for third-line treatment
in advanced NSCLC based on the following phase II/III
experience. IDEAL1 was a phase II trial of approximately
200 patients with advanced disease who had received
at least one prior platinum regimen [41]. Patients were
randomized to one of two doses of gefitinib. Response
rates for both arms were 18% to 19%, with median survivals
of 78 months. Significantly, 40% of patients reported
symptom improvement. IDEAL2 was a similar
trial in design and size, in which patients were eligible
if they had received two prior therapies (where at least
one contained platinum, and the second, docetaxel). Response
rates and median survival were slightly lower in
this trial (9% to 12% and 5–6 months, respectively) [42].
The most common toxicity in both trials was a reversible
rash, which some have speculated may correlate with
response. Importantly, recent data from two phase III
trials (INTACT 1 and 2) with CaPþ/
gefitinib and
CGþ/
gefitinib as first-line therapy in advanced disease
found no survival advantage for the triplet combination
[43,44]. This was obviously very disappointing, given the
remarkable responses and stable disease seen in some
heavily-pretreated patients in early trials. However, this
also underscores the fact that lung cancer is heterogeneous,
and that appropriately selecting patients for
targeted therapies will be an important challenge in the
future.
A phase II trial of erlotinib in 56 previously-treated
patients demonstrated responses in 11%, with similar skin
toxicity. Erlotinib achieved stable disease in 34%, with a
median survival of 9 months [45]. Four phase III trials
are in progress with erlotinib. Two are frontline trials
combining erlotinib with CG or CaP, and two are in the
second line setting in combination with docetaxel or as
monotherapy.
Cetuximab. Cetuximab (IMC-C225, ErbitruxTM) is an
infusional monoclonal antibody that binds to the external
domain of the EGFR. It is being tested in combination
with docetaxel in the refractory setting [46]. Recently
presented results in abstract form report a response rate
of 20% with minimal toxicity. As with the oral EGFR
inhibitors, cetuximab will likely be best used in selected
patients.
Trastuzumab. Trastuzumab is a monoclonal antibody
to HER2, a member of the EGFR family. HER2 is overexpressed
in 25% of NSCLCs. Overexpression has been a
predictive marker in breast cancer for treatment with
trastuzumab. Phase II studies in NSCLC, in combination
with third generation regimens, are in progress. An early
TABLE IV. Common Agents Used in the Treatment of Advanced NSCLC
Agent Dose/schedule Toxicities
Second generation agents
Cisplatin 75 mg/m2 d1 q 3–4 weeks Nephrotoxicity, neurotoxicity, ototoxicity, nausea/vomiting
Carboplatin AUC 5–6/q 3–4 weeks Myelosuppression, nausea/vomiting
Third generation agents
Paclitaxel 3 week: 175–200 mg/m2 as a 1–3 hr Myelosuppression, nausea, alopecia, hypersensitivity
infusion q 3 weeks reactions, neuropathy, myalgias/arthralgias
Weekly: 50–100 mg/m2 as a Weekly: Neutropenia is less common, as are arthralgias/
1 hr weekly infusion myalgias and stomatitis. However, peripheral neuropathy
is increased (especially at doses >100 mg/m2/week.)
Docetaxel Myelosuppression, nausea/vomiting, alopecia, fluid retention,
3-week: 75 mg/m2 q 3 weeks stomatitis, dysesthesias, asthenia, skin and nail toxicity.
Weekly: 30–35 mg/m2 Weekly: results in less neutropenia and stomatitis; however,
weekly3 then 1 week break fatigue and fluid-retention become dose-limiting
Vinorelbine Weekly: 20–30 mg/m2 Myelosuppression, pain at injection site, constipation,
neuropathy.
Gemcitabine 800–1250 mg/m2 weekly Myelosuppression, nausea/vomiting, diarrhea, elevated liver
2,3 then 1 week break function tests, fever
Irinotecan 100 mg/m2 weekly2–4 then Myelosuppression, anemia, nausea/vomiting, diarrhea, fever
1–2 week break
104 Spigel and Greco
trial of 56 patients reported response rates of 21% with
a median survival of 10 months, however only 6% of
patients were HER2 3þ by immunohistochemistry, and
17% were HER2 2þ [47].
Antiangiogenic agents. A shift in treatment strategy
has been the targeting of new blood vessel formation in
tumors. Angiogenesis is an integral component of tumor
growth and metastasis. Cancer cells promote vessel development
via the release of multiple growth factors and
attraction of inflammatory mediators. VEGF is an integral
growth factor in this process. Bevacizumab is a
monoclonal antibody to VEGF. Several other antiangiogenic
agents in development are: thalidomide, celocoxib,
CI-1040, BMS-275291, and AE-941. Each of these has
entered into phase II or III study.
Bevacizumab. DeVore et al. [48] recently presented
results from a phase II trial comparing bevacizumab and
CaP or CaP alone in 99 patients with advanced NSCLC.
The combined arm had a 10% improvement in response
rate, and time-to-progression was extended by three
months. Hemoptysis occurred in six of the patients
receiving bevacizumab and was fatal in four. Four of the
cases of hemoptysis were in patients with squamous
tumors—suggesting that a central location of the tumor
predisposed patients to bleeding. Results are eagerly
awaited from a phase III study of CaPþ/
bevacizumab
in patients with nonsquamous histology.
In summary, there are a number of agents in development
that represent a shift in the traditional approach to
drug design and treatment in NSCLC. Many of these are
oral and appear to be safe alone and in combination regimens.
For some patients these agents can be clearly
effective. Efforts to better select patients for these
therapies are ongoing and will be important in clinical
trial design.
LOCALLY ADVANCED NSCLC: IIIA/IIIB
Locally advanced NSCLC includes stage IIIA and IIIB
disease. Stage IIIB is generally considered unresectable
NSCLC. Historically, a minority of IIIA patients have
been considered resectable. However, resectability can
vary by institutional and surgical experience, patient
selection, and adequacy of staging. Moreover, in 1997 the
International Staging System reclassified T3N0 disease as
IIB (from IIIA), making this distinction even less clear.
Finally, downstaging with neoadjuvant therapy has allowed
some patients with previously unresectable IIIA
and IIIB disease to undergo surgery.
The role of chemotherapy in locally-advanced disease is
becoming increasingly better defined, largely from the
experience in the advanced setting. Currently, chemotherapy
in combination with radiation therapy represents a
standard treatment for unresectable stage III disease and
improves the cure rate compared to radiotherapy alone.
Yet several issues remain unresolved in terms of the
optimal choice of agents, dosing, and scheduling.
Resectable IIIA or IIIB
Although selected patients with IIIB disease are eligible
for up front surgery, the vast majority of resectable locally
advanced disease is so-called, nonbulky IIIA, and represents
a minority of all stage III patients. Adjuvant
radiation therapy is considered standard treatment in
reducing the risk of intrathoracic progression, however it
has not been shown to affect survival. Therefore, several
trials have looked at the role of adjuvant systemic
chemotherapyþ/
radiation therapy in an effort to reduce
distant failure. Overall, adjuvant systemic chemotherapy
has not been shown to impact survival. The Lung Cancer
Study Group trial randomized patients to CAPþradiation
or to radiation alone after resection. There were no statistically
significant differences in overall survival (20% in
both groups) [49]. Similarly, a United States intergroup
trial found no advantage to CE added to radiation compared
to radiation alone [50] (Table V).
We await results from the Adjuvant Lung Project in
Italy—a trial that randomized over 1,500 patients with
resected I–IIIA NSCLC to MVP or no treatment. Several
other adjuvant trials in Europe and the U.S. are in progress
as well.
Chemotherapy has also been examined in the neoadjuvant
setting. The French Thoracic Cooperative Group
recently published the results from a large neoadjuvant
trial in patients with stage I (except T1N0), II, and IIIA
disease [52].Atotal of 355 patients were randomized to up
front MIC for two cycles followed by surgery or to surgery
alone. Both cohorts received adjuvant radiation. Patients
on the chemotherapy arm who had a partial clinical or
complete pathologic response received two additional
cycles of adjuvant chemotherapy. Improvements in
median survival were seen with chemotherapy, although
statistical significance was not achieved (37 months vs. 26
months, P¼0.15). However, the trial showed a delayed
benefit for neoadjuvant chemotherapy, with survival
differences that became more apparent at four years
(44% vs. 35%). After adjusting for stage, the relative risk
(RR) of death with chemotherapy was estimated at 0.80
(95% CI¼0.61–1.04; P¼0.089), with most benefit
confined to patients with N0-N1 disease (RR¼0.68;
95% CI¼0.49–0.96; P¼0.027). Of note, neoadjuvant
therapy appeared to be associated with more toxicity
including fistula formation and empyema.
Two other small randomized studies by Rossell and
Roth showed improvements in median survival with neoadjuvant
chemotherapy vs. radiation alone, with each
reaching statistical significance [53,54].
In selected patients with favorable prognostic factors,
neoadjuvant chemotherapy cures 20% to 30% of patients
Chemotherapy in Advanced NSCLC 105
TABLE V. Chemotherapy in Locally Advanced NSCLC: Pivotal Adjuvant and Neoadjuvant Trials
Reference N Treatment arms Results Conclusions
Adjuvant trials
Lung Cancer Study 172 Med surv (mos): Median time to treatment failure was
Group [49] CAPþXRT 20 14 ms (CAP) vs. 8 mos ( P< .05)
vs. However, 3-yr survival 20% in both arms
XRT 13
Keller et al. [50] 488 Med surv (mos): No differences in survival or recurrence
CEþXRT 38 vs. 38
vs. Local failure:
XRT 12% vs. 13%
Ohta et al. [51] 209 3-yr DFS: No differences in survival or recurrence
CV 37% vs. 42%
vs. Med surv (mos):
No Tx 31 vs. 37
NeoAdjuvant trials
Depierre et al. [52] 355 Med surv (mos): Survival differences between both arms
MIC!surgery! 37 increased from 3.8% at 1-yr to 8.6%
XRT at 4 yr
vs.
Surgery!XRT 26
Rosell et al. [53] 60 Med surv: Small size-? confounding
MIC!surgery! 26 mos
XRT
vs.
surgery!XRT 8 mos
Roth et al. [54] 60 Med surv: Small size-? confounding
CCyE!surgery 64 mos
!XRT
vs.
surgery!XRT 11 mos
Unresectable
Cullen et al. [8] 446 Trend towards improvement in survival
MIC!XRT with MIC arm
vs.
XRT
Jeremic et al. [55] 131 Med surv (mos)/4-yr surv (%): Distant metastasis-free survival rate did
not significantly differ between arms
Hyperfractionated 22/23
XRTþCaE
vs.
Hyperfractionated 14/9
XRT
LeChevalier et al. [56] 353 Med surv (mos)/2-yr surv (%): Distant recurrences decreased with
CcyVL 12/21 chemotherapy
vs.
XRT 10/14
Dillman et al. [57] 155 Med surv (mos)/2-yr surv (%):
CVi!XRT 13.8/26
vs.
XRT 9.7/13
Sause et al. [58] 452 Med surv (mos)/1-yr surv (%): Chemotherapy arm statistically superior
XRT 11.4/46 to the other arms
vs.
CVi!XRT 13.8/60
vs.
XRT (twice daily) 12.3/51
BOLD, P<.05; CAP, cyclophosphamide/doxorubicin/cisplatin; CE, cisplatin/etoposide; CV, cisplatin/vindesine; MIC, mitomycin/ifosfamide/
cisplatin; CCyE, cisplatin/cyclophosphamide/etoposide; CCyVL, cisplatin/cyclophosphamide/vindesine/lomustine; CVi, Cisplatin/vinblastine;
CaE, carbolatin/etoposide.
106 Spigel and Greco
with resectable locally advanced disease—even clinical
N2 disease. Whether induction therapy should be chemotherapy
alone or concurrent chemoradiotherapy, remains
unanswered. Randomized phase III studies have not been
published.
Two recent randomized phase II studies using newer
third-generation agents in the neoadjuvant setting in combination
with radiation have produced impressive response
rates of 50% to 60% and median survivals of 14–17
months [59,60]. Randomized phase III studies with newer
agents are in progress.
Unresectable IIIA or IIIB
Surgery and radiation are effective in reducing local
progression, however they have not consistently improved
survival. Trimodality therapy with the addition of preoperative
chemotherapy has been more promising in terms
of improving disease-free and overall survival in some
studies. However, surgery is not a good option in most
patients with locally-advanced disease, and there has been
persuasive evidence from trials that surgery may not be
necessary—where concurrent chemoradiotherapy in IIIB
disease produced results similar to IIIA. This is the subject
of an ongoing intergroup trial in the United States.
Five important studies have addressed chemotherapy
in the treatment of unresectable locally advanced disease.
Dillman et al.’s [57] Cancer and Leukemia Group B
(CALGB) trial was the first to prove that induction therapy
with chemotherapy followed by radiation was superior to
radiation alone. Median 2-year and 3-year survival was
significantly improved in the chemotherapy arm. These
results were subsequently confirmed in an ECOG trial that
randomized patients to standard radiation or to chemotherapy
with cisplatin/vinblastine (CVi), for two months,
followed by either twice-daily or standard radiation
therapy. Median and 1-year survivals were statistically
superior in the CVi arm [58]. LeChavalier et al. [56]
also conducted a large randomized study comparing
radiotherapy alone (the control arm) with a combination
of radiotherapy and chemotherapy. Chemotherapy included
vindesine/cyclophosphamide/cisplatin/lomustine. The
2-year survival rate was 14% with radiotherapy alone
and 21% in the combination arm, largely a function of
a decrease in distant recurrences (P¼0.08). A large
randomized trial by Cullen et al. [8] that compared MIC
followed by radiation to radiation alone found a trend
towards an improved survival with MIC. Additionally,
Jeremic et al. [55] randomized patients to hyperfractionated
radiation concurrent with carboplatin/etoposide or
to radiation alone. Median and, importantly, 4-year
survival was statistically increased in the chemotherapy
arm.
For patients with unresectable locally advanced disease,
an emerging standard of care is concurrent chemoradiotherapy.
To date, a preferred regimen has not been defined
and on-going studies are employing many of the newer
agents from the metastatic setting.
SUMMARY
Combination chemotherapy should be the standard
treatment for advanced NSCLC in patients with a PS of
0–1. Multiple studies have convincingly shown that
chemotherapy, both combination platinum and singleagent
third-generation regimens, is superior to supportive
care alone in extending survival, reducing the symptoms
of progressive disease, and improving QOL. For now,
newer platinum-based combination regimens should be
used in the frontline setting. However, accumulating
evidence suggests nonplatinum doublet combinations
may be as effective, more convenient, and less toxic for
patients. In addition, emerging data are showing that these
agents will play increasingly important roles in the locally
advanced setting for both resectable and unresectable
disease.
The use of chemotherapy, however, should be selective.
Physicians must carefully balance the potential palliative
and survival benefits against potential serious toxicities.
Interestingly, many patients are more willing to accept the
risks of this trade-off for palliation than their physicians
might expect. In a recent, often-cited study, Silvestri et al.
[61] performed scripted interviews in 81 patients with
advanced NSCLC who had previously been treated with
cisplatin-based therapy. Patients were asked to quantify
what they would consider to be a minimal survival advantage
to justify the use of potentially toxic chemotherapy.
The minimum survival threshold for accepting toxicity
varied widely, with a median of 4–5 months for mild
toxicity and 9 months for severe toxicity. Over threefourths
of patients would not choose chemotherapy for a
survival benefit of only 3 months when given the choice
between supportive care and chemotherapy. However,
over two-thirds would choose therapy if it substantially
reduced symptoms without prolonging life. Obviously this
is a small study, perhaps influenced by selection bias.
Nonetheless, it addresses the importance of using chemotherapy
judiciously as well as other supportive measures
such as antiemetics, radiotherapy, pain medication, antibiotics,
and anticoagulation—which all have improved
significantly over the last decade.
Chemotherapy continues to improve as well.With each
generation of new agents, progress can be seen (Table VI).
Though gains in response rates and survival have been
modest at best, recent data are now including survival
beyond 2 years—something rarely seen with older studies
[62]. As well, newer agents and combinations are better
tolerated and easier for patients to receive in the outpatient
setting. We expect that chemotherapy is effective enough
Chemotherapy in Advanced NSCLC 107
at this time to improve the cure rate of patients with early
stage NSCLC (IA, IB, and II), however no definite data
have yet been reported. Novel agents, many oral, are in
clinical trials, and may soon add to the gains of the last
three decades. Our challenge is to continue to be rigorous
in study design and evaluation, and to carefully use new
agents to improve the lives of our patients.
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