1. health and fitness
2. disease
3. cancer

PLENARY SESSION DISCUSSANTS
Chemotherapy for Advanced Non–Small-Cell Lung Cancer:
Who, What, When, Why?
By Paul A. Bunn, Jr
Abstract: Despite the poor survival of patients with
advanced (stage IIIB with pleural effusion or stage IV)
non–small-cell lung cancer, the introduction of new
chemotherapeutic agents has improved survival and
quality of life with reduced toxicity compared with
older cisplatin-based therapies. Randomized trials
support the use of two-drug combinations for patients of all ages with performance status of 0 to 1.
These two-drug combinations should contain at least
one new agent. Some of these two-drug combinations may be acceptable in selected patients with a
performance status of 2. Newer, targeted therapies
hold promise to improve outcome without adding a
great deal of additional toxicity.
J Clin Oncol 20:23s-33s. © 2002 by American
Society of Clinical Oncology.
N 1996, THE AMERICAN Society of Clinical Oncology
published its guidelines on the treatment of patients with
advanced non–small-cell lung cancer (NSCLC).1 These
guidelines indicated that patients with stage IV NSCLC who
had good performance status (PS; 0 or 1) should be offered
therapy with one of several cisplatin-based combinations
because these therapies improved survival in meta-analyses
of randomized trials,2 improved quality of life in randomized trials,3 and was reasonably cost-effective.4 Despite this
guideline, many advanced NSCLC patients were not offered
chemotherapy because of elderly age, marginal performance status (PS2), or perceived marginal survival advantage with recognized toxicities of cisplatin-based therapy.
These guidelines were also developed before the results of
randomized trials evaluating newer chemotherapeutic
agents. These randomized trials evaluating newer chemotherapeutic agents have helped clarify the optimal treatment
for patients with advanced NSCLC, and these trials form the
basis of this report. For the purposes of this report, “new”
agents are defined to include paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan. “Old” chemotherapeutic
agents include cisplatin, carboplatin, vindesine, etoposide,
mitomycin, and ifosfamide.
produced by cisplatin-based combination chemotherapy in a
meta-analysis of randomized trials.2 Paclitaxel also improved quality of life in the randomized trial comparing
paclitaxel to best supportive care.5 A randomized trial
comparing gemcitabine to best supportive care also
showed improved quality of life in patients receiving
gemcitabine, but the survival advantage of gemcitabine
was not significant in this trial, which included advanced
patients with both stage III and IV disease, PS2 patients,
and many patients who were crossed over to gemcitabine.7 It is reasonable to conclude from these trials that a
new single agent, such as a taxane, improves survival and
quality of life compared with best supportive care in
advanced NSCLC patients with a reasonable convenience, cost, and acceptable toxicity. Randomized trials
comparing a new single agent to best supportive care in
advanced NSCLC patients over the age of 70 years will
be discussed below.
I
NEWER CHEMOTHERAPEUTIC AGENTS VERSUS BEST
SUPPORTIVE CARE
Randomized trials comparing the new single agents
paclitaxel, docetaxel, and gemcitabine with best supportive
care have been reported.5-7 The survival results of the
randomized trials comparing paclitaxel5 and docetaxel6 to
best supportive care are shown in Fig 1. Both of these agents
produced a significant improvement in survival that was of
similar magnitude in the two studies. This survival improvement was a 32% reduction in the hazard rate of death in the
paclitaxel study.5 This hazard rate reduction compares quite
favorably to the 26% reduction in the hazard rate of death
NEW SINGLE AGENTS (GEMCITABINE, VINORELBINE,
OR IRINOTECAN) VERSUS OLD CISPLATIN-BASED
COMBINATIONS
Five trials that compared a new single agent to a two-drug
cisplatin-based combination are summarized in Table 1.8-12
In each study, the new single agent produced response and
survival results that were similar to those obtained with the
cisplatin-based combination but produced far less toxicity
From the University of Colorado Cancer Center, Denver, CO.
Supported in part by grant nos. P30 CA46934-14 and P50
CA58187-08 S1 from the National Cancer Institute, Bethesda, MD.
Address reprint requests to Paul A. Bunn, Jr, MD, University of
Colorado Cancer Center, 4200 E. 9th Ave, Box B 188, Denver, CO
80262; email: [email protected].
© 2002 by American Society of Clinical Oncology.
0732-183X/02/2018s-23s/$20.00
Journal of Clinical Oncology, Vol 20, No 18s (September 15 Supplement), 2002: pp 23s-33s
DOI: 10.1200/JCO.2002.07.059
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23s
24s
PAUL A. BUNN, JR
NEW SINGLE AGENT VERSUS COMBINATION OF A
NEW SINGLE AGENT PLUS CISPLATIN OR
CARBOPLATIN
Fig 1. Survival of patients with advanced NSCLC randomized to receive
best supportive care versus a single-agent taxane: (A) randomized phase III
trial comparing single-agent paclitaxel to best supportive care5; (B) randomized phase III trial comparing single-agent docetaxel to best supportive
care.6
and lower costs. For example, three randomized phase II
trials compared single-agent gemcitabine to the combination of etoposide andcisplatin8,9 or vindesine and
cisplatin.10 Response rates approximated 20% in all
groups, and there were no significant or clinically relevant survival differences among the groups. Gemcitabine
was more convenient and was associated with less hair
loss, less nausea and vomiting, less neuro-and ototoxicity, as well as less myelosuppression. Similarly, both
vinorelbine and irinotecan alone produced survival that
was nearly identical to that produced by the combination
of vindesine and cisplatin.11,12 Once again, toxicity was
much reduced in the groups receiving single-agent therapy. We can conclude that new single agents are as
effective and less toxic than older cisplatin-based combinations and can be considered for elderly and unfit
patients (see below).
Table 1.
First Author (ref)
Perng8
Manegold9
Vansteenkiste10
Le Chevalier11
Masuda12
Five randomized trials have compared a new single agent
(paclitaxel, gemcitabine, docetaxel, vinorelbine, or irinotecan) with a two-drug combination with the same new agent
combined with cisplatin or carboplatin. These studies are
summarized in Table 2.11-15 In all five trials, the combination produced a significantly higher response rate compared
with the new single agent. In four of the five trials, the
combination also produced a superior survival that was, on
average, 2 months longer at the median. The 1-year survival
rate was 4% to 12% higher with the combination in these
four trials. In one trial, the combination of irinotecan plus
cisplatin produced only a slight improvement in survival
(median, 50 weeks v 46 weeks; 1-year, 46% v 41%) that was
not statistically significant. These trials included mostly
patients with advanced stage, good PS (0 or 1), and any age.
We can conclude that while new single agents are equivalent to older two-drug combinations, they are inferior to a
new two-drug combination in advanced NSCLC patients of
any age with PS of 0 to 1. Results in PS 2 patients are
discussed below.
NEW TWO-DRUG COMBINATION VERSUS AN OLD
SINGLE AGENT
Three randomized trials have compared a new two-drug
combination (gemcitabine, vinorelbine, or paclitaxel) plus
cisplatin with cisplatin alone.16-18 The results of two of
these trials are summarized in Fig 2. A multinational study
sponsored by Eli Lilly Co. compared the two-drug combination of gemcitabine and cisplatin with cisplatin alone.16
The two-drug combination produced a significantly higher
response rate, a significantly longer time to progression, and
significantly superior survival compared with cisplatin
Randomized Trials of a Single New Agent Versus an Old Cisplatin-Based Doublet
Therapy
No. of
Patients
OR (%)
Median Survival
(weeks)
1-Year
Survival
Gemcitabine
Etoposide/cisplatin
Gemcitabine
Etoposide/cisplatin
Gemcitabine
Vindesine/cisplatin
Vinorelbine
Vindesine/cisplatin
Irinotecan
Vindesine/cisplatin
26
24
71
75
84
85
206
200
129
122
19
21
18.2
15.3
20
20
14
19
21
32
37
48
28.6
32.9
34.7
26
31
32
46
46
NR
NR
NR
NR
NR
NR
30
27
41
38
Abbreviations: OR, objective response; NR, not reported; NS, not significant.
*Statistical significance of differences in survival.
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Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
P*
NS
NS
NS
NS
NS
25s
CHEMOTHERAPY IN ADVANCED NSCLC
Table 2.
First Author (ref)
Lilenbaum
13
Sederholm14
Georgoulias15
Le Chevalier11
Masuda12
Randomized Trials of a New Agent Plus Cisplatin or Carboplatin Versus a New Agent Alone
Therapy
No. of
Patients
OR (%)
Median Survival
(weeks)
1-Year
Survival (%)
Paclitaxel
Paclitaxel/carboplatin
Gemcitabine
Gemcitabine/carboplatin
Docetaxel
Docetaxel/cisplatin
Vinorelbine
Vinorelbine/cisplatin
Vindesine/cisplatin
Irinotecan
Irinotecan/cisplatin
Vindesine/cisplatin
288
296
170
164
148
155
206
206
200
129
129
122
16
30
11.5
29.6
18
35
14
30
19
21
44
32
28.2
36.8
39
47.7
34.7
43.8
31
40
32
46
50
46
33
37
32
41
42
48
30
35
27
41
46
38
P
.04*
.016
NS
⬍ .01†
⬍ .04‡
NS
*By Wilcoxon test, NS by log-rank test.
†Comparison of vinorelbine with vinorelbine/cisplatin.
‡Comparison of vinorelbine/cisplatin with vindesine/cisplatin.
alone. The median survival was increased from 7.6 months to
9.2 months (Fig 2A). The 1-year survival rate was increased
from 28% to 39%, and the two-year survival rate was increased
from 8% to 14%. The two-drug combination arm was associated with more toxicity that was primarily hematologic in
nature and was not associated with an increase in toxic deaths
or prolonged hospitalizations. The combination of gemcitabine
and cisplatin was approved for use in the United States, largely
on the basis of the results of this trial.
Another trial conducted by the Southwest Oncology
Group (SWOG) compared the two-drug combination of
vinorelbine and cisplatin to cisplatin alone (Fig 2B).17 The
survival of patients in the vinorelbine/cisplatin arm was
significantly longer than the survival in the cisplatin-alone
arm. The two-drug combination improved the median survival from 6 months to 8 months, the 1-year survival rate
Fig 2. Survival of advanced NSCLC patients randomized to single-agent
cisplatin or a new agent plus cisplatin: single-agent cisplatin versus (A)
gemcitabine/cisplatin16 or (B) vinorelbine/cisplatin.17 Median survival differences between Figs 1B and 2B: best supportive care, 4.6 months;
single-agent docetaxel and cisplatin, 6 months; vinorelbine/cisplatin, 8
months.
from 21% to 36%, and the 2-year survival rate from 7% to
12%. Survival in the two-drug arm was superior through 48
months. The two-drug combination also produced a higher
response rate and a significantly longer time to progression.
The two-drug combination produced more toxicity, particularly myelosuppression. Despite the increase in toxicity,
there were no differences in quality of life or in toxic death
rates. This combination was also approved by the United
States Food and Drug Administration largely on the basis of
these study results.
A third randomized trial conducted in Germany compared the two-drug combination of paclitaxel and cisplatin
with cisplatin alone.18 As with the other two studies of
similar design, the two-drug combination produced a significantly higher response rate (26% v 17%) and a significantly longer time to progression (median, 4.1 months v 2.7
months). Despite these improvements, there were no differences in overall survival, as the group randomized to
cisplatin alone had a superior survival after initial progression. This was likely due to cross-over chemotherapy in this
group, but it is not possible to be certain why the longer time
to progression did not translate into a longer survival as it
did in the other two trials cited above.16,17
The results of these randomized trials taken together
indicate superiority of new two-drug combinations over
older single agents regardless of whether the single agent
was cisplatin or a new agent. It is the opinion of the author
that these improvements are clinically relevant in countries
where these therapies can be afforded.
NEW VERSUS OLD TWO-DRUG COMBINATIONS
Table 3 summarizes the results of seven randomized trials
that compared a new two-drug combination with an old
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26s
PAUL A. BUNN, JR
Table 3.
First Author (ref)
Le Chevalier
Bonomi19
Giaccone20
Cardenal21
Niho22
Matsuda12
Kunitoh23
11
Randomized Trials of Cisplatin Plus a New Agent Versus Cisplatin Plus an Old Agent
Therapy
No. of
Patients
OR (%)
Median Survival
(weeks)
1-Year
Survival (%)
Vinorelbine/cisplatin
Vinorelbine/cisplatin
Paclitaxel (low)/cisplatin*
Paclitaxel (high)/cisplatin
Etoposide/cisplatin
Paclitaxel/cisplatin
Teniposide/cisplatin
Gemcitabine/cisplatin
Etoposide/cisplatin
Irinotecan/cisplatin
Vindesine/cisplatin
Irinotecan/cisplatin
Vindesine/cisplatin
Docetaxel/cisplatin
Vindesine/cisplatin
206
200
198
201
200
166
166
68
67
100
103
129
122
151
151
44
32
25.3
27.7
12.4
28
41
41
22
29
22
44
32
37
21
50
46
41.2
43.3
32.9
42.9
42.0
37.7
30.3
45
50
50
46
49.3
41.9
40
32
37.4
40.3
32
41
43
26
32
43
48
46
38
48
43
P
.04
.048†
NS
NS
NS
NS‡
NS
*Paclitaxel (low) refers to 135 mg/m2 intravenously over 24 hours; paclitaxel (high) refers to 175 mg/m2 intravenously over 24 hours plus granulocyte
colony-stimulating factor.
†Significance comparing the two paclitaxel groups combined with the etoposide/cisplatin group; other comparisons were not significant.
‡Survival differences were significant in the stage IV subset.
cisplatin-based two-drug combination. These trials generally show an advantage for the new combination with
respect to efficacy, toxicity, quality of life, or a combination
of these end points, but the advantages were often modest
and survival differences were not consistently statistically
significant. Le Chevalier et al11 conducted a three-arm
randomized trial comparing single-agent vinorelbine with
the old two-drug combination of vindesine and cisplatin and
the new two-drug combination of vinorelbine and cisplatin.
The single-agent results are discussed above. The new
two-drug combination (vinorelbine and cisplatin) produced
a higher response rate and a significantly superior survival
compared with the older vindesine/cisplatin combination
(Table 3).
Two randomized trials compared the new paclitaxel/
cisplatin combination to the older podophyllotoxin/cisplatin
combination.19,20 The Eastern Cooperative Oncology Group
(ECOG) conducted a three-arm study that used etoposide
and cisplatin as the control arm. The two experimental arms
consisted of high-dose paclitaxel (175 mg/m2 over 24 hours
with granulocyte colony-stimulating factor support) or lowdose paclitaxel (135 mg/m2 over 24 hours without granulocyte colony-stimulating factor) plus cisplatin. As shown in
Table 3, both paclitaxel arms had significantly higher
response rates compared with the etoposide/cisplatin arm.
The survival results were also superior in these two arms,
although the differences were only significant when the two
paclitaxel arms were combined and compared with the
etoposide/cisplatin arm. The high-dose paclitaxel arm had
the highest toxicity rates. Because there was little difference
in efficacy between the two paclitaxel arms, the low-dose
paclitaxel/cisplatin arm was selected as a control for the
subsequent ECOG trial (see below).
The European Organization for the Research and Treatment of Cancer (EORTC) compared a more convenient
paclitaxel/cisplatin combination to a teniposide/cisplatin
combination.20 There were no differences in any efficacy
parameter between the two arms. The paclitaxel/cisplatin
arm had considerably less toxicity and considerably improved quality of life compared with the teniposide/cisplatin
arm. It was thus selected as a reference arm for future
EORTC trials.
Another randomized trial reported by Cardenal et al21
used an etoposide/cisplatin combination as a control and
compared it with a gemcitabine/cisplatin combination (Table 3). The gemcitabine/cisplatin arm had a higher response
rate (41% v 22%) and better survival (median, 8.7 months v
7.2 months), but the differences in survival were not
significant in this underpowered trial of 135 patients. Three
other randomized trials used a vindesine/cisplatin combination as a control.12,22,23 Two of these trials compared
irinotecan and cisplatin with vindesine and cisplatin,12,22 while
the third compared docetaxel and cisplatin with vindesine and
cisplatin (Table 3).23 There were no significant survival differences in the studies comparing irinotecan and cisplatin with
vindesine and cisplatin. A subset analysis confined to stage IV
patients in one of the trials12 showed a significant survival
advantage for the irinotecan/cisplatin therapy.
The study comparing docetaxel and cisplatin with vindesine
and cisplatin showed higher response rates and longer survival
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27s
CHEMOTHERAPY IN ADVANCED NSCLC
Table 4.
First Author (ref)
Kelly (SWOG)
24
Schiller (ECOG)25
Van Meerbeeck (EORTC)26
Georgioulias28
Kosmidis29
Satouchi30
Rodriguez31
Scagloitti32
Randomized Trials of a New Agent Combined With Another Agent
Therapy
Vinorelbine/cisplatin
Paclitaxel/carboplatin
Paclitaxel/cisplatin
Gemcitabine/cisplatin
Docetaxel/cisplatin
Paclitaxel/carboplatin
Paclitaxel/cisplatin
Gemcitabine/cisplatin
Paclitaxel/gemcitabin
Docetaxel/cisplatin
Docetaxel/gemcitabin
Paclitaxel/carboplatin
Paclitaxel/gemcitabine
Irinotecan/docetaxel
Cisplatin/docetaxel
Vinorelbine/cisplatin
Docetaxel/cisplatin
Docetaxel/carboplatin
Gemcitabine/cisplatin
Paclitaxel/carboplatin
Vinorelbine/cisplatin
No. of
Patients
OR (%)
Median Survival
(months)
1-Year
Survival (%)
2-Year
Survival (%)
202
206
292
288
293
299
159
160
161
186
167
123
130
59
53
404
408
406
205
201
201
29
25
21
21
17
15
31
36
27
31
34
29
37
35
41
NR
NR
NR
30
32
31
8
8
7.8
8.1
7.4
8.2
8.1
8.8
6.9
12
11
10.7
12.3
9.0
7.8
10
11
9
9.8
9.9
9.5
36
38
31
36
31
35
35
33
26
46
41
41
51
NR
NR
42
47
38
37
43
37
15
16
11
16
12
11
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
in the docetaxel/cisplatin group, though the differences were
not significant in this underpowered study.23
What can we conclude from these studies? In general,
there were very modest improvements with new two-drug
combinations compared with older two-drug combinations.
These benefits were sometimes modest advantages in response or survival, but more often they were advantages in
toxicity, quality of life, convenience, or a combination of
these. The developed countries have largely adopted the
new combinations for these reasons. Developing countries
where cost may be an important factor may choose the older
two-drug combinations or a single agent.
TWO-DRUG COMBINATIONS IN WHICH ONE OR
BOTH DRUGS ARE NEW DRUGS
Although the results of phase II trials and the randomized
trials discussed above suggested equivalent efficacy of
multiple two-drug combinations, a number of randomized
trials directly compared various new two-drug combinations. The results of these trials are summarized in Table 4.
The SWOG compared its standard new two-drug combination (vinorelbine and cisplatin) to another new two-drug
combination (paclitaxel and carboplatin).24 As shown in
Table 4, the two combinations produced nearly identical
response rates, median survival, and long-term survival
rates with no significant differences between the arms.
There were differences in convenience. The vinorelbine/
cisplatin arm required more visits for the vinorelbine and
P
NS
NS
NS
NS
NS
NS
NS
NS
longer visits for the cisplatin hydration. There were also
differences in toxicity. The carboplatin/paclitaxel arm produced less nausea, vomiting, renal toxicity, and myelosuppression but more neurotoxicity. There were also differences in cost, as the paclitaxel/carboplatin arm was more
expensive. However, since the paclitaxel patent has expired
in some countries, the costs for the paclitaxel/carboplatin
therapy have decreased considerably. There were no significant differences in quality of life between the two arms.
The SWOG adopted the carboplatin/paclitaxel arm as a
reference arm for future trials largely on the basis of the
convenience and toxicity data.
The ECOG conducted a phase III randomized trial that
compared four different two-drug combinations (Table 4).25
In the study’s statistical design, each of the three new
combinations was compared with their standard paclitaxel/
cisplatin combination. There were no significant differences
in response rates or in survival among the arms. The
gemcitabine/cisplatin arm was associated with a 1-month
longer time to progression compared with the paclitaxel/
cisplatin arm, and this difference was statistically significant. Most likely the difference could be attributed to the
4-week schedule of this combination compared with the
3-week schedule of the other combinations, and it is not
clinically relevant. Although there were no relevant efficacy
differences, there were differences in convenience, toxicity,
and costs. The regimens requiring weekly chemotherapy
administration and long hydration for cisplatin were less
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28s
PAUL A. BUNN, JR
convenient. The carboplatin/paclitaxel arm had significantly
fewer grade 3 and 4 toxicities, fewer episodes of nausea and
vomiting, and less febrile neutropenia but more neuropathy.
The gemcitabine/cisplatin arm had more thrombocytopenia.
The ECOG adopted the paclitaxel/carboplatin arm as a
reference for future trials on the basis of its lower rates of
severe toxicity and its convenience.
The EORTC conducted a three-arm trial comparing
their standard arm of paclitaxel and cisplatin with gemcitabine and cisplatin and with paclitaxel and gemcitabine (Table 4).26 The paclitaxel dose (175 mg/m2 over 3
hours) was lower in this study compared with other
studies with paclitaxel listed in Table 4. There were no
significant differences in response, time to progression,
or survival among the three groups, although the lowest
response rates and shortest survival were in the paclitaxel/gemcitabine arm. It is not know whether this is related
to the lower paclitaxel dose. Kosmidis et al27 did show
improved efficacy of a paclitaxel/carboplatin combination with a paclitaxel dose of 225 mg/m2 compared with
175 mg/m2 (both delivered over 3 hours). Other studies
with the paclitaxel/gemcitabine combination and a higher
paclitaxel dose showed no evidence of inferiority (Table
4).
Two Greek groups28,29 and a Japanese group30 conducted
randomized trials to determine whether two-drug combinations containing two new drugs would be superior or less
toxic compared with two-drug combinations consisting of a
new drug combined with cisplatin or carboplatin. There
were no significant differences in efficacy in any of these
three trials. There were differences in toxicity and convenience, as the cisplatin-containing arms had more nephrotoxicity, nausea, and vomiting and required long periods of
hydration. Although formal cost analyses were not part of
these studies, the combinations with two new agents were
undoubtedly more expensive.
The large randomized trials comparing three different
two-drug combinations conducted by Rodriguez et al31 and
Scagliotti et al32 also showed significant or clinically
relevant efficacy differences among the three arms (Table
4). As with the combinations tested above, the carboplatin
arms were associated with greater convenience and less
nausea, vomiting, and nephrotoxicity, while the paclitaxel
arms had more neuropathy. Once again, selection of the
reference regimen was based on nonefficacy issues.
In evaluating the totality of these randomized trials, it is
obvious that each of the multiple two-drug combinations
provided similar efficacy results. It is also apparent that each
of these combinations produces results that are strikingly
superior to both best supportive care and single-agent
cisplatin (Fig 2) and slightly superior to older cisplatin-
based two-drug combinations. Selection of the regimen of
choice should be made on the basis of experience, convenience, toxicity, and cost.
THREE DRUGS VERSUS TWO-DRUGS OR VERSUS
ALTERNATING COMBINATIONS
A number of randomized trials have compared new
two-drug combinations to three-drug combinations or to
alternating combinations. The results of these studies are
summarized in Table 5. Four trials compared two-drug
combinations with one new agent to older three-drug
combinations.33-36 In each there was little difference in
response rate, but there was superior survival associated
with the new two-drug combination in each of the four
trials, with superior median survivals ranging from 1
month33 to 2 months34 to 3 months.35,36 None of these trials
was powered to prove superiority of the newer two-drug
combinations. Toxicity was greater in the three-drug arms
of each of the three trials. It is obvious from these study
results that the use of these older three-drug combinations
should be abandoned.
Other randomized trials were designed to determine
whether new three-drug combinations containing at least
two new drugs were superior to new two-drug combinations
and/or to alternating combinations.37-39 The initial studies
of Comella et al39 suggested that the three-drug combinations could be somewhat superior in response and survival
even though they were associated with increased toxicity
and cost. This trial is somewhat difficult to interpret because
study arms changed during the course of study and because
the survival advantages were not significant using standard
statistical analysis. The studies of Alberola et al37 and
Thompson et al38 suggest that new three-drug combinations
have no true efficacy advantage over existing two-drug
combinations and are associated with greater toxicity and
cost (Table 5). In the study of Alberola et al, alternating
two-drug combinations also failed to improve response or
survival compared with a standard two-drug combination.
In summary, there is no evidence that a three-drug
combination or an alternating two-drug combination is
preferred over a two-drug combination.
TREATMENT OF ELDERLY PATIENTS (⬎ 70 YEARS)
WITH ADVANCED NSCLC
The median age of patients with advanced lung cancer is
68 years. There has been some reluctance to treat elderly
patients with chemotherapy because older combinations
produced considerable toxicity and marginal survival advantage. Nonetheless, age has failed to be established as a
major prognostic factor. To determine the optimal therapy
for elderly patients, three randomized trials were conducted
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29s
CHEMOTHERAPY IN ADVANCED NSCLC
Table 5.
First Author
(ref)
Crino
33
Tan34
Melo35
Rudd36
Alberola37
Thompson38
Comella39
Randomized Trials of Three Drugs Versus Two Drugs
Therapy
Gemcitabine/cisplatin
Mitomycin/ifosfamide/cisplatin
Vinorelbine/cisplatin
Vinorelbine/ifosfamide/cisplatin
Gemcitabine/cisplatin*
Gemcitabine/cisplatin*
Vindesine/cisplatin
Mitomycin/vinblastine/cisplatin
Gemcitabine/carboplatin
Mitomycin/ifosfamide/cisplatin
Gemcitabine/cisplatin
Gemcitabine/cisplatin/vinorelbine
Gemcitabine/vinorelbine 3
ifosfamide/vinorelbine
Paclitaxel/gemcitabine
Paclitaxel/carboplatin/gemcitabine
Paclitaxel/carboplatin/vinorelbine
Gemcitabine/vinorelbine
Gemcitabine/paclitaxel
Gemcitabine/paclitaxel/vinorelbine
Gemcitabine/paclitaxel/cisplatin
No. of
Patients
OR (%)
Median Survival
(months)
1-Year
Survival (%)
153
154
120
119
62
62
62
62
212
210
166
176
175
38
26
35
36
48.4†
48.4†
37
27
37
41
43
38
26
8.6
9.6
10.2
8.2
9.4
9.6
9.0
6.4
10.0
6.5
8.7
7.9
8.1
33
34
38
33
NR
NR
NR
NR
38
28
35
31
35
29
34
42
29
28
44
48
7.8
10.3
7.8
11.3
8.8
11.8
11.8
48
38
52
49
39
47
46
51
51
51
51
82
84
81
P
NS
NS
⬍ .05‡
.0043
NS
NS
NS
*In one arm, the cisplatin was given on day 1; cisplatin was given on day 15 in the other gemcitabine/cisplatin arm.
†The response rates were provided for the combined gemcitabine/cisplatin arms and were said to be the same in each of these arms.
‡Survival of the mitomycin/vinblastine/cisplatin arm was significantly inferior to that of the other three arms, which did not differ from one another.
in patients 70 years of age or older (Table 6). The original
study reported by Gridelli40 randomized 161 patients to
receive best supportive care or single-agent vinorelbine.
Patients receiving vinorelbine had significantly superior
survival. The median survival was increased from 4.9
months (21 weeks) in patients treated with best supportive
care to 6.5 months (28 weeks) in vinorelbine-treated patients. The 1-year survival rates were 14% for best supportive care and 32% for vinorelbine. These differences were
similar to those described in younger patients. The issue of
whether two-drug combinations are preferred over singleagent therapy in elderly patients is more problematic. As
shown in Table 6, the study by Frasci et al41 indicated that
the combination of gemcitabine and vinorelbine was supe-
Table 6.
First Author
(ref)
Gridelli40
Frasci41
Gridelli42
Therapy
Vinorelbine
Best supportive care
Gemcitabine ⫹ vinorelbine
Vinorelbine
Gemcitabine
Vinorelbine
Gemcitabine ⫹ vinorelbine
rior to vinorelbine alone. The median survival in the
two-drug combination arm was 28 weeks, compared with
21 weeks in the vinorelbine-alone arm. The 1-year
survival rate (29% v 18%) was also superior in the
two-drug arm. Although there was more toxicity in the
two-drug arm, the toxicity was thought to be acceptable
and there were no toxic deaths. Conflicting results were
reported in the study of Gridelli et al,42 who compared
single-agent vinorelbine to single-agent gemcitabine or
the combination. There was no significant difference in
survival between the arms. The best results were observed in the single-agent vinorelbine arm and the worst
results in the single-agent gemcitabine arms, though the
differences were not significant.
Chemotherapy in Elderly Patients With Advanced NSCLC
No. of
Patients
OR (%)
76
85
60
60
19.7
–
22
15
700*
18.1*
Median Survival
(weeks)
1-Year
Survival (%)
28
21
29
18
28
37
32
32
14
30
13
28
42
34
*Indicates total number, not broken down by group.
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Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
P
⬍ .05
⬍ .01
NS
30s
PAUL A. BUNN, JR
Table 7.
First Author
(ref)
Shepherd46
Fossella47
Therapy
Randomized Second-Line Trials
No. of
Patients
OR (%)
Median Time to
Progression (weeks)
Median Survival
(months)
1-Year
Survival (%)
55
100
125
125
123
6
0
7
11
1
10.6
6.7
8.5
8.4
7.9
7.5*
4.6*
5.7†
5.5
5.6†
37*
12*
32
21
19
Docetaxel 75 mg/m2
Best supportive care
Docetaxel 75 mg/m2
Docetaxel 100 mg/m2
Vinorelbine/ifosfamide
*P value of survival comparing the docetaxel 75 mg/m2 group with the best supportive care group was ⬍ .05.
†P value comparing survival of docetaxel 75 mg/m2 with vinorelbine/ifosfamide was .025; the other comparisons were not significant.
Several large randomized trials comparing different twodrug combinations or comparing a single agent with a
two-drug combination performed subset analyses in the
elderly subset of patients. The Cancer and Leukemia Group
B trial compared single-agent paclitaxel with the combination of paclitaxel and carboplatin. There were 158 patients
who were 70 years of age or older.13 The two-drug
combination was associated with a 2-month longer median
survival (8.0 months v 5.8 months) and a slightly higher
1-year survival rate (35% v 31%). The differences were not
significant in these subset analyses. The SWOG and ECOG
studies found no difference in efficacy between the various
two-drug combinations in the elderly.43,44 There were also
no significant differences in survival for those ⱖ 70 compared with those ⱕ 70 years. Toxicity rates were somewhat
higher in patients ⱖ 70, but these were thought to be
acceptable and the toxic death rate was low.
These studies have been interpreted to mean that twodrug combinations are acceptable for elderly patients with a
PS 0 or 1, while single agents may be preferred for those
with comorbid diseases or who are less fit (PS 2).
TREATMENT OF PS 2 PATIENTS
The optimal therapy for patients with PS 2 remains to be
defined, largely because they have been excluded from most
randomized trials and because they have high rates of
toxicity. PS 2 has been shown to be an independent negative
prognostic factor in almost all studies. The ECOG four-arm
randomized trial was originally designed to enroll patients
with PS of 0 to 2.25 An interim analysis indicated that PS 2
patients had unacceptable rates of serious or greater toxicity
on all three cisplatin-containing arms.45 The toxicity rates in
patients receiving carboplatin and paclitaxel were thought to
be acceptable. The interim analysis led to closure of this
trial in PS 2 patients.
The Cancer and Leukemia Group B trial that randomized
patients to paclitaxel alone or paclitaxel and carboplatin was
open to PS 2 patients, of whom 99 were enrolled. PS 2
patients randomized to receive the two-drug combination
had a significantly superior survival compared with PS 2
patients randomized to receive paclitaxel alone (median
survival, 4.7 months v 2.4 months; P ⬍ .05). Although the
toxicity rates in PS 2 patients were higher than those in PS
0 or 1 patients, the rates of severe toxicity in the PS 2
patients receiving the combination were thought to be
acceptable and there were no toxic deaths. These data
indicate that some two-drug combinations are too toxic for
PS 2 patients, whereas others are associated with acceptable
toxicity. There is some evidence, but certainly no proof, that
two-drug combinations with acceptable toxicity profiles
could be preferred over single agents or best supportive
care. Additional randomized trials restricted to PS 2 patients
are required to confirm or refute this hypothesis.
NEW SINGLE AGENTS (DOCETAXEL) VERSUS BEST
SUPPORTIVE CARE OR IFOSFAMIDE OR VINORELBINE
IN THE SECOND-LINE SETTING IN ADVANCED NSCLC
Multiple phase II trials indicated that patients with
advanced NSCLC who did not respond to platinum-based
therapies could benefit from second-line therapy with taxanes. These observations led to two randomized trials
comparing docetaxel to best supportive care or to vinorelbine or ifosfamide in the second-line setting (Table 7). A
Canadian study randomized patients to docetaxel or best
supportive care.46 The original docetaxel dose was 100
mg/m2. When this dose level was shown to be associated
with unacceptable toxicity rates, the study was amended to
a docetaxel dose of 75 mg/m2 given once every 3 weeks.
Patients randomized to docetaxel at a dose of 75 mg/m2 had
a survival outcome that was significantly superior to the
outcome of patients randomized to best supportive care.
These survival differences were even more striking at 1 year
(37% v 12% survival rates). There were no significant
survival differences in patients randomized to docetaxel 100
mg/m2 or best supportive care.
A single randomized trial in the second-line setting was
conducted in the United States and reported by Fossella et
al.47 In this three-arm trial, patients were randomized to
receive docetaxel at a high dose (100 mg/m2 intravenously
every 3 weeks), docetaxel at a more moderate dose (75
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31s
CHEMOTHERAPY IN ADVANCED NSCLC
mg/m2 intravenously every 5 weeks), or the physician’s
choice of ifosfamide or vinorelbine. As indicated in Table 7,
the response rates were higher in the two docetaxel arms.
The best survival was reported in the group randomized to
receive docetaxel at 75 mg/m2. However, the survival
differences were not statistically significant unless the two
docetaxel groups were combined and compared with the
ifosfamide/vinorelbine arm. The weight of evidence from
the two trials was thought to favor docetaxel at a dose of 75
mg/m2. This docetaxel dose schedule serves as a standard
for randomized trials in this second-line setting.
THIRD-LINE THERAPY
There are no completed randomized trials comparing a
chemotherapeutic agent with best supportive care in the
third-line setting. Because chemotherapy produces considerable and often unacceptable toxicity in this setting, some
of the newer “targeted therapies” have been studied after
failure of one or more chemotherapeutic agents. In the
initial phase I studies of the oral epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitors (TKIs), objective responses were observed in chemorefractory NSCLC
patients treated with both ZD1839 and OSI-774.48,49 These
responses were noted as early as 10 days after initiation of
therapy and lasted a median period of 5 months. These data
led to two randomized trials comparing a ZD1839 dose of
250 mg/d to 500 mg/d. In one of these trials (Ideal-1),
eligibility requirements included failure of one or more
prior chemotherapy combinations including a platinum.50 In
the other trial (Ideal-2), failure of two or more chemotherapy combinations, including a platinum and docetaxel, was
required.51 The study results are summarized in Fig 3. In the
Ideal-1 study, the overall objective response rate was 19%
and was not different between the 250-mg and the 500-mg
groups. Subjective improvement was documented in 40% of
the patients. The objective response rate did not differ
among those who had experienced failure of one, two, three,
or four prior chemotherapy combinations. The objective
response rate in the Ideal-2 study was 12%, which did not
vary by dose (250 mg/d v 500 mg/d) or by the number of
prior therapies. Symptomatic responses were noted in 43%
of patients. In both studies, there was more toxicity in the
500-mg group, so the optimal dose was defined as 250
mg/d. A reversible acneiform rash was the most frequent
toxicity. The etiology of the rash is not well defined, but it
Fig 3. Response and survival of advanced chemotherapy-refractory
NSCLC patients treated with 250 mg of ZD1839 in trials comparing 250 mg
and 500 mg daily50,51: (A) > one failed chemotherapy regimen or (B) > two
failed regimens including a platinum and docetaxel. Sx Resp, symptom
response rate.
may have been related to EGFR in the skin. It always
resolves when the therapy is held and often resolves even
with continued therapy. Similar results were obtained in a
single-arm phase II trial of OSI-774 in refractory NSCLC
patients who had experienced failure of one or more prior
chemotherapy regimens.52 In this study, the objective response rate was 14% and the median response duration was
5 months. The 1-year survival rates were encouraging in all
three trials.
These data indicate a possible benefit for EGFR TKIs in
refractory NSCLC. A phase III randomized study comparing OSI-774 to best supportive care in the third-line setting
has been started. Phase I/II trials established that ZD1839
can be safely combined with standard cytotoxic chemotherapeutic agents. Randomized trials comparing two-drug chemotherapy combinations (paclitaxel/carboplatin and gemcitabine/cisplatin) alone or combined with EGFR TKIs have
been instituted and/or completed, although the results are
not yet available.
The data presented in the randomized trials discussed
above indicate that new two-drug combinations represent
the standard approach for patients with advanced NSCLC of
any age with PS of 0 or 1. Some two-drug combinations or
single agents may be considered in PS 2 patients and/or
patients with comorbid conditions. New targeted therapies
hold promise to further improve survival and quality of life
in advanced NSCLC patients.
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