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Comparison of Four Chemotherapy Regimens for
Advanced Non–Small-Cell Lung Cancer
Joan H. Schiller, M.D., David Harrington, Ph.D., Chandra P.
Belani, M.D., Corey Langer, M.D., Alan Sandler, M.D., James Krook, M.D.,
Junming Zhu, Ph.D., David H. Johnson, M.D., for the Eastern Cooperative
Oncology Group
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ABSTRACT
Background We conducted
a randomized study to determine whether any of three chemotherapy
regimens was superior to cisplatin and paclitaxel in patients with
advanced non–small-cell lung cancer.
Methods A total of
1207 patients with advanced non–small-cell lung cancer were randomly
assigned to a reference regimen of cisplatin and paclitaxel or to
one of three experimental regimens: cisplatin and gemcitabine,
cisplatin and docetaxel, or carboplatin and paclitaxel.
Results The response
rate for all 1155 eligible patients was 19 percent, with a median
survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5),
a 1-year survival rate of 33 percent (95 percent confidence
interval, 30 to 36 percent), and a 2-year survival rate of 11
percent (95 percent confidence interval, 8 to 12 percent). The
response rate and survival did not differ significantly between
patients assigned to receive cisplatin and paclitaxel and those
assigned to receive any of the three experimental regimens.
Treatment with cisplatin and gemcitabine was associated with a
significantly longer time to the progression of disease than was
treatment with cisplatin and paclitaxel but was more likely to cause
grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3
percent of those treated with cisplatin plus paclitaxel). Patients
with a performance status of 2 had a significantly lower rate of
survival than did those with a performance status of 0 or 1.
Conclusions None of four
chemotherapy regimens offered a significant advantage over the
others in the treatment of advanced non–small-cell lung cancer.
Approximately one third of all
cancer-related deaths are due to lung cancer, which accounts for
more deaths each year than breast, prostate, and colon cancer
combined. The median survival of patients with untreated metastatic
non–small-cell lung cancer is only four to five months, with a
survival rate at one year of only 10 percent.1
Chemotherapy for advanced non–small-cell lung cancer is often
considered ineffective or excessively toxic. However, meta-analyses
have demonstrated that, as compared with supportive care,
chemotherapy results in a small improvement in survival in patients
with advanced non–small-cell lung cancer.2,3,4
In addition, randomized studies comparing chemotherapy with the
"best supportive care" have shown that chemotherapy reduces symptoms
and improves the quality of life.5
Over the past decade, a number of new agents have become available
for the treatment of metastatic non–small-cell lung cancer, including
the taxanes, gemcitabine, and vinorelbine. The combination of one or
more of these agents with a platinum compound has resulted in high
response rates and prolonged survival at one year in phase 2
studies.6,7,8,9,10
However, there have been few comparisons of these newer chemotherapy
regimens, which are now used frequently, with each other.
The Eastern Cooperative Oncology Group (ECOG) conducted a
randomized clinical trial to compare the efficacy of three commonly
used regimens with that of a reference regimen of cisplatin and
paclitaxel.11
The primary objective of this study was to compare overall survival in
patients treated with cisplatin and gemcitabine, cisplatin and
docetaxel, carboplatin and paclitaxel, or cisplatin and paclitaxel.
Methods
Patients with non–small-cell lung cancer that was classified as
stage IIIB (with malignant pleural or pericardial effusion), stage
IV, or recurrent disease were randomly assigned to one of four
treatment groups (Figure
1). The first group received the reference treatment: 135 mg of
paclitaxel per square meter of body-surface area, administered over
a 24-hour period on day 1, followed by 75 mg of cisplatin per square
meter on day 2. The cycle was repeated every three weeks. In the
second group, gemcitabine, at a dose of 1000 mg per square meter,
was administered on days 1, 8, and 15, and cisplatin, at a dose of
100 mg per square meter, was administered on day 1 of a four-week
cycle. Patients in the third group received 75 mg of docetaxel per
square meter and 75 mg of cisplatin per square meter on day 1
of a three-week cycle. Those in the fourth group were treated with
225 mg of paclitaxel per square meter, given over a three-hour period
on day 1, followed on the same day by carboplatin at a dose
calculated to produce an area under the concentration–time curve of
6.0 mg per milliliter per minute, in a three-week cycle. Patients
were stratified according to ECOG performance status (0 or 1 vs. 2,
with higher scores indicating greater impairment), weight loss in
the previous six months (<5 percent vs. 
5 percent),
the stage of disease (IIIB vs. IV or recurrent disease), and the
presence or absence of brain metastases.
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Eligibility Criteria
Patients who had received prior chemotherapy were ineligible for
the study. The criteria for eligibility included confirmed disease, measurable
or nonmeasurable; an age of at least 18 years; and adequate
hematologic function (as indicated by a white-cell count of at least
4000 per cubic millimeter and a platelet count of at least 100,000
per cubic millimeter), hepatic function (as indicated by a bilirubin
level that did not exceed 1.5 mg per deciliter [25.6 µmol per
liter]), and renal function (as indicated by a creatinine level that
did not exceed 1.5 mg per deciliter [132.6 µmol per liter]). Prior
radiation therapy at symptomatic sites was permitted provided that
the indicator sites (the sites that were followed to determine
whether there was a response) had not been irradiated and that the
radiation therapy had been completed before chemotherapy was
initiated. Patients with stable brain metastases were eligible. All
patients gave informed consent.
Standard ECOG response criteria were used. Briefly, a complete
response was defined as the absence of disease at all known sites
for at least four weeks. A partial response was defined as a 50
percent reduction in the sum of the perpendicular diameters of all
measurable lesions, lasting at least four weeks. Progressive disease
was defined as either a 25 percent increase in the area of any one
lesion over the prior measurement or the development of one or more
new lesions. Survival was calculated from the date of enrollment to
the date of death or the date when the patient was last known to be
alive. The time to the progression of disease was calculated from
the date of enrollment to the date of progression or death; data for
patients who were alive and relapse-free were censored as of the
date of the last known follow-up visit.
The protocol was approved by the institutional review board at
each participating center. All patients gave written informed consent.
Statistical Analysis
Survival from the date of enrollment was the main end point. The
primary analysis specified by the protocol was a comparison of each
of the survival distributions for the three experimental-treatment groups
with that for the control reference-treatment group, with the use of
a two-sided log-rank test.12 To
control for type I error (i.e., to control for multiple comparisons),
a nominal two-sided P value of 0.016 was used for each comparison.
The study was designed to have 80 percent power to detect a 33
percent increase in median survival in the experimental-treatment groups
— that is, a median survival of 12 months, since the reference
regimen had resulted in a median survival of 9 months in a previous
study.11
Full power to detect a 33 percent improvement in survival would have
required a total of approximately 1070 deaths in the four groups, or
535 per pairwise comparison. On the basis of accrual and eligibility
rates in previous ECOG trials, we estimated that we would need to
enroll 300 patients per treatment group over a 30-month period.
Interim analyses for the study were monitored by the ECOG Data
Monitoring Committee. The design specified two interim analyses and
one final analysis of the survival data, with the use of an
O'Brien–Fleming boundary,13
when 33 percent, 67 percent, and 100 percent of the anticipated
number of deaths had occurred.
All reported P values are two-sided and were adjusted for interim
analyses according to the O'Brien–Fleming method. All time-to-event
distributions were estimated by the Kaplan–Meier method.14
All reported time-to-event comparisons were made with the use of the
log-rank test. Categorical data, such as data on treatment,
responses, and toxic effects, were compared among treatment groups
with the use of Fisher's exact test.15
Results
A total of 1207 patients were enrolled in the study between October
1996 and May 1999. The median follow-up period was 8.0 months. As of
May 1, 2001, 1074 patients had died. Of the 1207 patients who were
enrolled, 52 (4.3 percent) were subsequently found to be ineligible
(Table 1).
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The clinical characteristics of the patients in the four groups were
similar (Table 1).
The median age was 63 years. Almost two thirds of the patients were
men. Sixty-four percent of patients had a performance-status score
of 1, and 13 percent had brain metastases. About two thirds of the
patients had a weight loss of less than 5 percent in the previous
six months. Most (87 percent) had stage IV or recurrent disease.
The median survival for all 1207 patients was 8.0 months; the
survival rate at 1 year was 34 percent, and the rate at 2 years was
12 percent (Table
2). Analyses that compared the total group of 1207 patients with
the group of 1155 eligible patients showed no significant
differences in response rates, survival, or the time to the
progression of disease.
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The overall response rate for the 1155 eligible patients was 19
percent (Table 3).
In the group of patients who received cisplatin and paclitaxel, the
median survival was 7.8 months, and the 1-year and 2-year survival
rates were 31 percent and 10 percent, respectively (Table 3 and Figure 2A). There
were no significant differences in the response rate or survival
among the three experimental-treatment groups. The median survival was
8.1 months among the patients who received cisplatin and gemcitabine,
7.4 months among those who received cisplatin and docetaxel, and 8.1
months among those who received carboplatin and paclitaxel (Table 3). The
survival rate for those three groups was 36 percent, 31 percent, and
34 percent, respectively, at one year and 13 percent, 11 percent,
and 11 percent, respectively, at two years.
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The median time to the progression of disease was 3.4 months in the
cisplatin-plus-paclitaxel group, as compared with 4.2 months in the
cisplatin-plus-gemcitabine group (P=0.001 by the two-sided log-rank
test) (Table 3).
The median time to progression in the other two
experimental-treatment groups did not differ significantly from that
in the cisplatin-plus-paclitaxel group (Figure 2B). Since
the protocol specified that patients should be assessed for disease
progression after every two cycles of treatment, patients who
received cisplatin and docetaxel or carboplatin and paclitaxel,
regimens that were administered in 21-day cycles, might have been
found to have radiographic evidence of progression earlier than
patients who received cisplatin and gemcitabine, which was
administered in a 28-day cycle. However, that was not the case (data
not shown).
According to the original trial design, patients with an ECOG
performance status of 2, as well as those with a performance status
of 0 or 1, were eligible for enrollment. However, in October 1997,
after 66 patients with a performance status of 2 had been enrolled,
the study design was amended to include only patients with a
performance status of 0 or 1 because of the high rate of serious
adverse events in the patients with a performance status of 2.16
The median survival among patients with a performance status of 0
was 10.8 months, as compared with 7.1 months for patients with a
performance status of 1 and 3.9 months for those with a performance
status of 2 (P<0.001 by the log-rank test for both comparisons) (Table 2).
Table
4 shows toxic complications in the four groups. These complications
were the types usually associated with combination chemotherapy.
They were similar in the four groups, with several exceptions, as
noted in the table.
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Fifty-three percent of the patients who received carboplatin and
paclitaxel were withdrawn from the study because of progressive disease,
as compared with 44 percent of the patients who received cisplatin
and paclitaxel (P<0.001). Twenty-seven percent of the patients
who received cisplatin and gemcitabine were withdrawn because of
complications of therapy, as compared with 15 percent of the
patients who received cisplatin and paclitaxel (P<0.001 by
Fisher's exact test).
Discussion
Cisplatin-based chemotherapy for metastatic non–small-cell lung
cancer results in a small but statistically significant improvement
in survival, as compared with supportive care alone.2,3,4
Whereas older chemotherapy regimens (e.g., mitomycin, ifosfamide, and
cisplatin) resulted in survival rates of 10 to 15 percent at one
year, second-generation regimens (e.g., cisplatin and etoposide)
have typically resulted in survival rates of 20 to 25 percent at one
year.1,5,17,18,19,20
Our trial showed that third-generation regimens result in survival
rates of 33 percent at one year and 11 percent at two years among
patients with good performance status.
We sought to determine whether any of three newer third-generation
chemotherapy regimens was superior to the first of these third-generation
regimens, cisplatin plus paclitaxel, with respect to survival. There
were no significant differences in survival between patients who
received one of the three experimental regimens and those who
received cisplatin and paclitaxel. Although the time to the
progression of disease was longer in the group of patients who
received cisplatin plus gemcitabine than in the other groups, this
result was at the expense of greater renal toxicity. Given the lack
of a survival benefit with this regimen and its greater toxicity,
the clinical relevance of the increase in the time to disease
progression is questionable.
Toxicity is particularly problematic in patients with a poor performance
status. Patients with a performance status of 2 were excluded from
our study after the early results suggested that such patients were
likely to be more susceptible to adverse events, including death
within 30 days from any cause, than were patients with a performance
status of 0 or 1. Since the role of chemotherapy in the treatment of
advanced non–small-cell lung cancer is supportive and palliative at
best, the routine use of platinum-based combination chemotherapy in
patients with a poor performance status cannot be recommended.
Although we did not obtain data on second-line chemotherapy in
this study, it is possible that some of our patients crossed over to
another therapy when the disease progressed. The effect of such a
crossover on the results of this trial is unknown. We also did not
compare the cost effectiveness of the four regimens, which is of
potential importance, given the differences in the costs of the
various drugs and in the costs associated with their administration.21
Finally, the quality of life was not assessed in this study.
Although reductions in toxicity are often assumed to improve the
quality of life, in a recent Southwest Oncology Group study
comparing cisplatin and vinorelbine with carboplatin and paclitaxel,
there were no differences in the quality of life between the two
treatment groups, despite significantly lower rates of toxic effects
in the group of patients who received carboplatin and paclitaxel.21
We conclude that third-generation chemotherapy regimens in
patients with non–small-cell lung cancer who have a good performance
status can moderately improve survival at one and two years. No
significant difference in survival was observed among four commonly
used regimens, although the regimen of carboplatin and paclitaxel
had a lower rate of toxic effects than the other regimens. On the
basis of these results, ECOG has chosen carboplatin and paclitaxel as
its reference regimen for future studies.
Supported by
a grant (CA-23318) from the National Institutes of Health. Dr.
Schiller also received support from the William S. Middleton
Veterans Affairs Hospital. Drs. Schiller, Belani, Langer, Sandler,
and Johnson have received research support from Eli Lilly,
Bristol-Myers, and Aventis and have served as consultants to Eli
Lilly and Bristol-Myers. Drs. Schiller, Belani, Langer, and Sandler
have served as consultants to Aventis. Dr. Langer is a member of
speakers' bureaus for Eli Lilly, Bristol-Myers, and Aventis.
Source Information
From the University of Wisconsin Hospital and Clinics, Madison
(J.H.S.); the Dana–Farber Cancer Institute, Boston (D.H., J.Z.); the University
of Pittsburgh Cancer Institute, Pittsburgh (C.P.B.); the Fox Chase Cancer
Center, Philadelphia (C.L.); Indiana University, Indianapolis (A.S.); the
Duluth Clinic, Duluth, Minn. (J.K.); and Vanderbilt University, Nashville
(D.H.J.).
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[Full Text]
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.