During the past 3 decades, extensive experience has been gained
in the treatment of patients with stage III or IV lung cancer. A total of 42
phase III trials were initiated by the National Cancer Institute between 1973
and 1994 and included 9,161 patients. A meta-analysis of these North American
trials included 32 of the 42 trials, for a total of 5,820 patients, and divided
the trials into two time frames: 1973 to 1983 and 1984 to 1994. While
the percentage of women enrolled in clinical trials of lung cancer treatment was
unchanged between the two time frames (27% and 28%), there was a significant
increase in the median number of patients per treatment arm (77 vs 130; P <
.001). Five trials found a median prolongation of survival of 2 months (range:
0.7 to 2.7 months). In both time frames, median survival time was greater with
cisplatin (Platinol)-based regimens: 1973 to 1983, 5.7 vs 4.4 months (P <
.001); 1984 to 1994, 6.0 vs 4.4 months (P < .37). Many of the trials were
underpowered to show a significant improvement in median survival time. For
example, a study with 130 patients per treatment arm has 70% power to detect an
improvement in median survival time from 6 to 8 months.
Based on North American and
worldwide experience, platinum-based regimens have been the mainstay of chemotherapy regimens for non-small-cell
lung cancer for several decades. These regimens significantly reduce the risk of
death, increase median survival, and improve 1-year survival.[1,2] There is no standard platinum-based regimen, but combination regimens
with newer agents, such as gemcitabine [Gemzar], paclitaxel [Taxol], and
vinorelbine [Navelbine], are superior to platinum alone or in combination with
older agents such as etoposide and vindesine [Eldisine]. The focus of this
article is the experience with platinum-based regimens that include gemcitabine,
a deoxycitidine analog. Four phase III clinical trials of gemcitabine for the
treatment of non-small-cell lung cancer have been published in full.[4-7]
These trials and the recently reported Eastern Cooperative Oncology Group (ECOG)
E1594 trial, which demonstrated the activity of gemcitabine, are discussed.
Approval by the US Food and Drug Administration (FDA) of
gemcitabine for use in non-small-cell lung cancer was based on a study that
compared cisplatin/gemcitabine with cisplatin [Platinol] alone in approximately
260 patients per treatment arm. The study randomized 522 assessable patients
(mean age: 62 to 63 years) who had not received prior treatment for non-small-cell
lung cancer to either cisplatin/gemcitabine or cisplatin alone administered on a
28-day schedule. The treatment groups were well balanced with respect to disease
severity: 18 of 68 patients in the cisplatin/gemcitabine group and 17 of 61 in
the cisplatin group had stage IIIA/IIIB disease, respectively, and the numbers
of patients with stage IV disease were 174 vs 184 (cisplatin/gemcitabine vs
Grades 3/4 hematologic toxicities occurred more frequently in
the gemcitabine combination treatment group than in the cisplatin-alone group
(25.4% vs 0.8%). Neutropenia and thrombocytopenia were common: 57% and 50%,
respectively, in the cisplatin/gemcitabine group vs 4.5% and 3.6% in the
cisplatin group. Anemia (low hematocrit) was noted in 25% of
cisplatin/gemcitabine-treated patients and 6.5% of cisplatin-treated patients,
while the incidence of febrile neutropenia was modest (4.6% and 0.8%). The
incidence of nonhematologic toxicities reflected primarily the cisplatin
component and generally were comparable for the two treatment groups. Nausea and
vomiting were reported by 27% and 23% of patients receiving
cisplatin/gemcitabine and 21% and 19% of those receiving cisplatin, and renal
toxicity occurred in approximately 5% and 2% of these patients, respectively.
Neurotoxicity was more common with cisplatin/gemcitabine: 17.5% vs 8.6% for
Response parameters all favored the cisplatin/gemcitabine arm (Table
1). The overall response rate for cisplatin/gemcitabine was 30.4% vs
11.1% for cisplatin (P < .0001), and the median survival time was 9.1 vs 7.6
months, respectively (P = .004). One-year survival was also notably higher for
cisplatin/gemcitabine-treated patients, 39% vs 28%. The time to progressive
disease and the survival time significantly favored the cisplatin/gemcitabine
combination regimen over treatment with cisplatin alone (P = .0013 and P
respectively) (Figure 1).
A second phase III, randomized trial was conducted in a similar
patient population (no prior treatment, stage IIIB or IV non-small-cell lung
cancer). This Spanish trial of 135 patients compared gemcitabine/cisplatin
administered in a 21-day schedule with cisplatin/etoposide in an every 28-day
schedule. The primary end point was overall response rate. Approximately 50% of
patients (mean age: 58 to 59 years) in each group had stage IV disease.
Overall, toxicity was comparable for the two treatment
regimens. The incidence of neutropenia was higher in etoposide- than in
gemcitabine-treated patients (76% vs 64%), which corresponds to other studies of
etoposide-containing regimens, while the incidence of grade 3/4 thrombocytopenia
was greater with gemcitabine (56% vs 13%). Seven gemcitabine-treated patients
and 12 etoposide-treated patients developed febrile neutropenia. The incidence
of nausea and vomiting was similar in both treatment groups (39% vs 26%), while
grade 3 alopecia was far more common with etoposide (13% vs 51%).
Response to treatment was greater with gemcitabine than with
etoposide (Table 1). The overall response rates were 40.6% and 21.9%
.02), and the time to progression was 6.9 vs 4.3 months (P = .01) for
gemcitabine vs etoposide. A trend toward increased median survival time and
1-year survival of 8.7 months and 32% was seen for gemcitabine, compared with
7.2 months and 26% for etoposide. The progression-free survival curve
significantly favored gemcitabine, and the survival curve favored gemcitabine,
although not significantly. The authors concluded that compared with
etoposide/cisplatin, the gemcitabine-containing regimen provided a significantly
higher response rate and a delay in disease progression, without impairing
quality of life.
An Italian phase III trial, which included 307 patients with
stage IIIB or IV non-small-cell lung cancer who had not received previous
treatment, randomly assigned patients to either gemcitabine plus cisplatin or
mitomycin (Mutamycin) plus ifosfamide (Ifex) plus cisplatin. Both regimens were
administered on a 28-day schedule. The majority of patients (mean age: 60 to
62 years) in each treatment group had stage IV disease (123, gemcitabine; 120,
The incidence of grade 3/4 hematologic toxicities was similar in
both groups, although a higher proportion of patients in the gemcitabine group
experienced thrombocytopenia (64% vs 28%; P < .001). Neutropenia occurred
in 40% and 33% of patients receiving the gemcitabine and triplet regimen,
respectively; the occurrence of febrile neutropenia was rare (1% vs 0%). Nonhematologic toxicities occurred with similar incidence in both treatment
groups, except alopecia which had a threefold higher incidence in the triplet
regimen group (12% vs 39%; P < . 001).
The overall response rate to the gemcitabine regimen (59%) was
higher than with the triplet regimen (40%; Table
1). The time to progression
was similar in both groups (5.0 vs 4.8 mo) as was the 1-year survival (33% vs
34%). There were no differences between the two regimens in the progression-free
survival and survival curves. The results of this study are noteworthy in that,
in previous studies, the mitomycin, ifosfamide, and cisplatin regimen was shown
to be superior to supportive care and doublet regimens.
The study provides further support of the benefit of gemcitabine/cisplatin in
the treatment of non-small-cell lung cancer.
An ongoing, phase III Italian study, though underpowered, has
provided some interesting preliminary results (Table
1). The study is comparing
the triplet regimen of gemcitabine, cisplatin, and vinorelbine with
gemcitabine/cisplatin; a third treatment arm, cisplatin/vinorelbine, was
discontinued due to a markedly higher incidence of neutropenia. Sixty
patients (mean age: 60 to 62 years) with stage IIIB or IV non-small-cell lung
cancer who had not been previously treated were randomized to each treatment. A
higher proportion of patients had stage IV disease (57% to 60%), and the
majority of patients had a performance status of 1.
Occurrences of grade 3/4 hematologic toxicities were comparable
for the three treatment groups with the exception of neutropenia. Treatment
regimens containing gemcitabine were associated with a 40% to 45% incidence of
neutropenia, whereas the cisplatin/vinorelbine regimen was associated with a 75%
incidence. Thrombocytopenia did not differ markedly among groups: 30% for
gemcitabine/cisplatin, 17% for gemcitabine/cisplatin/vinorelbine, and 20% for
cisplatin/vinorelbine. Fatigue was common with all three regimens (10%, 14%,
Response to the gemcitabine-containing regimens was superior to
the cisplatin/vinorelbine regimen: 30% with gemcitabine doublet (95% confidence
interval [CI] = 19%-43%) and 47% with gemcitabine triplet regimens (95% CI =
34% to 60%) vs 25% with cisplatin/vinorelbine (95% CI = 15% to 38%) (see Table
1) as was the 1-year survival rate (40% and 45% vs 34%). Median survival time
was 42 and 51 weeks with the gemcitabine regimens compared with 35 weeks for the
cisplatin/vinorelbine regimen. In patients with stage IV non-small-cell lung
cancer, the median survival time also favored the gemcitabine regimens: 34 and
47 weeks vs 27 weeks for the cisplatin/vinorelbine regimen. Both the median
survival time and the 1-year survival rate for the gemcitabine/cisplatin regimen
observed in this study are comparable to those achieved in the ECOG E1594
clinical study discussed below.
The ECOG E1594 study evaluated four doublet regimens commonly
used for the treatment of non-small-cell lung cancer. Patients were
stratified by stage of disease (IIIB vs IV), performance status 0 to 1 vs 2,
weight loss (< 5% vs ³ 5%), and
whether they had metastases to the central nervous system. They were then
randomized to one of four treatments: cisplatin/paclitaxel (the reference
treatment arm), cisplatin/gemcitabine, cisplatin/docetaxel (Taxotere), or
carboplatin (Paraplatin)/paclitaxel (Figure 2). At an interim analysis after
approximately 100 patients with a performance status of 2 had been treated,
enrollment of performance status 2 patients, and hence stratification by
performance status, was suspended due to excessive toxicity with all four
treatment regimens in these patients.
Nearly 1,200 patients (approximately 300 per treatment arm) were
enrolled in the E1594 study, and the treatment groups were comparable with
respect to prognostic factors. The mean age of patients ranged from 61.6 to
63.9 years with a slight preponderance of males (61% to 64%), and the majority
of patients had stage IV non-small-cell lung cancer (84% to 87%). Patients
with stage IIIB disease had malignant pleural effusions. Approximately 12% to
14% of patients in each group had metastases to the central nervous system that
were controlled by radiation therapy and/or surgery. The median number of weeks
of treatment in all four arms was 12.
Overall, the response to treatment and survival were comparable
among treatment groups (Table 2). The response rate in the gemcitabine arm
(20.8%) was equivalent to that in the paclitaxel reference arm (21.2%), while
the response rates were somewhat lower, but not statistically different, in the
docetaxel (17.4%) and carboplatin (15.5%) arms. Response rates in this study are
somewhat lower than in other studies of these doublet regimens because of the
strict criterion for a confirmatory chest x-ray at 4 weeks to be considered a
treatment responder. The time to progression of disease significantly favored
gemcitabine compared with the paclitaxel reference arm (4.5 vs 3.5 mo; P =
.003). Overall survival at 1 and 2 years also tended to favor gemcitabine, but
there were no significant differences for any of the groups compared with the
reference arm (Table 2).
There was more variation among the regimens with respect to
toxicities (Table 3). Grade 3/4 anemia and thrombocytopenia occurred
significantly more often in the gemcitabine arm than in the
reference arm. The higher incidence of hematologic toxicity in the gemcitabine
arm may be due to the weekly doses of gemcitabine and more frequent monitoring
(on days 1, 8, and 15 of the 28-day schedule). Gastrointestinal toxicities were
similar among the three cisplatin-containing arms but occurred less frequently
in the carboplatin-containing arm. Grade 3 sensory neurologic toxicity tended to
occur more often in the carboplatin and gemcitabine arms.
Infections requiring hospitalization were less frequent in
comparator treatment arms, particularly the carboplatin-containing arm, than in
the reference treatment arm (cisplatin/paclitaxel), although the differences
were not significant. Use of broad-spectrum antibiotics was also lower in the
carboplatin-containing arm. An analysis of the total, aggregate worst degree of
toxicity indicated fewer severe toxicities in the carboplatin-containing
treatment arm, which was not significant when compared with the
cisplatin/paclitaxel reference arm.
In summary, the E1594 clinical trial found no differences in the
primary end point or in survival between the cisplatin/paclitaxel reference arm and each
of the comparator treatment arms. The time to progression of disease was,
however, significantly improved with the gemcitabine regimen, while the overall
response rate to carboplatin/paclitaxel was worse than with the reference
regimen, with the difference approaching statistical significance. Treatment
decisions regarding use of one of these doublet regimens in patients with non-small-cell
lung cancer, therefore, depends on other considerations, including
cost-effectiveness, side effects and toxicities, and ease of administration.
Other considerations may include the overall response rate and time to
progression of disease.
While the overall response rate in the gemcitabine arm of the
E1594 clinical trial was comparable to the reference treatment arm, the higher
incidence of hematologic toxicities may have been related to its use in
combination with cisplatin 100 mg/m2, which is also hematotoxic, to the days 1,
8, and 15 administration regimen in a 28-day schedule, or to both.
Administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 of a 21-day
schedule, gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 of a 28-day
schedule, or gemcitabine at 1,200 mg/m2 (with dose escalation) on days 1 and
8 of a 28-day schedule with carboplatin has been shown to result in a good
overall response rate and to be well tolerated.
In the United States, new regimens employing gemcitabine are
emerging for the treatment of newly diagnosed patients with stage IIIB or IV non-small-cell
lung cancer (Figure 3). For patients with a good performance status, gemcitabine
at 1,000 mg/m2 on days 1 and 8 plus carboplatin dosed at an area under the
concentration-time curve (AUC) of 6 on day 1 of a 21-day schedule is being
evaluated. In patients with a poor performance status, single-agent gemcitabine
at 1,000 to 1,250 mg/m2 on days 1 and 8 in a 21-day schedule is being studied.
Patients who relapse on either of the gemcitabine regimens would receive
docetaxel 75 mg/m2 every 3 weeks.
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