The current American Society of
Clinical Oncology (ASCO) treatment guideline for selected patients with metastatic non-small-cell lung
cancer is up to eight cycles of platinum-based chemotherapy. This
recommendation is based on several lines of evidence. Cisplatin (Platinol) is
one of the most active drugs in non-small-cell lung cancer (NSCLC), with a
single-agent response rate of approximately 20%. In many different preclinical
models, platinum is synergistic with other chemotherapy drugs and with
radiation. The superiority of platinum-containing chemotherapy was suggested by
a retrospective analysis of the Southwest Oncology Group (SWOG) database, which
showed that patients who are treated with platinum-containing regimens lived
longer than similar patients treated with non-platinum regimens.
This impression was confirmed by a 1995 meta-analysis of 52
randomized clinical trials conducted between 1965 and 1991 that included more
than 9,000 patients. This meta-analysis demonstrated that compared with best
supportive care, cisplatin-based chemotherapy improved median survival by 6
weeks and survival at 1 year from 5% to 15%. Whether this modest increase in
survival was offset by the toxicity of chemotherapy was not evaluated in these
Most of the clinical trials included in the meta-analysis
evaluated regimens in which cisplatin was paired with either etoposide or
vindesine. Other regimens popular during that time paired cisplatin with
vinblastine, mitomycin (Mutamycin), doxorubicin, cyclophosphamide (Cytoxan,
Neosar), or ifosfamide (Ifex). Studies that compared the most active regimens
composed of these agents reported a median survival of 6 to 9 months.[4-6]
Another meta-analysis that included clinical studies published between 1976 and
1995 suggested that combination chemotherapy provided no significant survival
advantage compared with single-agent cisplatin. Because etoposide, doxorubicin, mitomycin, and vinca alkaloids other than vinorelbine (Navelbine) have
relatively modest single- agent activity in NSCLC, it is not surprising that
regimens that combined these drugs with cisplatin were only marginally (if at
all) better than cisplatin alone.
During the past decade, however, several drugs have been
introduced that are at least as active as cisplatin. In addition to vinorelbine,
these drugs include paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine
(Gemzar), and irinotecan (CPT-11, Camptosar).
As a single agent, paclitaxel produces a response rate of
approximately 20%. Two recent European studies evaluated the combination of
cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.
In one study, cisplatin/paclitaxel was compared with cisplatin alone, and in
the other study, cisplatin/paclitaxel was compared to the combination
cisplatin/teniposide (Vumon). Although neither study demonstrated a
difference in median survival time, both reported improved quality of life among
patients who received cisplatin and paclitaxel (Table
Preliminary results of a study comparing the combination of
carboplatin (Paraplatin)/paclitaxel to cisplatin/etoposide reported comparable
survival with both combinations. Febrile neutropenia occurred less
frequently in patients receiving carboplatin and paclitaxel, but myalgias and
neuropathy were more common. The SWOG reported preliminary results of a study
that compared carboplatin/paclitaxel to cisplatin/vinorelbine. No difference
in survival was noted. However, fewer patients dropped out of the
carboplatin/paclitaxel arm, suggesting that this regimen is better tolerated.
The Eastern Cooperative Oncology Group (ECOG) performed a
randomized study comparing cisplatin/etoposide to cisplatin/paclitaxel.
Patients were randomly assigned to one of three treatment arms: control
(cisplatin and etoposide), paclitaxel 135 (cisplatin and paclitaxel as a 24-hour
infusion at 135 mg/m2 per cycle), and paclitaxel 250 (cisplatin and paclitaxel
as a 24-hour infusion at 250 mg/m2 per cycle with granulocyte colony-stimulating
factor [G-CSF (Neupogen)] support). Survival was better in both
paclitaxel-containing arms than in the control arm, but the difference reached
standard levels of statistical significance only if results of the two
paclitaxel-containing groups were combined (1-year survival of 39% vs 32%, P =
.048). Patient tolerability and preservation of quality of life were fairly
comparable with the different regimens.
Vinorelbine is a vinca alkaloid that produces a response rate of
30% in patients with non-small-cell lung cancer. A three-arm European study
reported by Le Chevalier et al compared cisplatin/vinorelbine to vinorelbine
alone or to cisplatin/vindesine. A total of 612 patients were evaluated.
Survival was better for patients treated with cisplatin/vinorelbine, and was
similar in the other two treatment arms (Table
2). A subsequent subset analysis
showed that the survival benefit was limited to patients with good functional
status. Patients with a performance status of 2 had similar survival regardless
of the treatment they received.
A SWOG study compared cisplatin/vinorelbine to cisplatin
alone. Survival at 1 year was significantly better with the combination (36%
vs 20%). Although neither of these studies attempted to evaluate quality of
life, vinorelbine was well tolerated at active doses. A Japanese study compared
the combination regimen MVP (mitomycin/vindesine/cisplatin [Platinol]) to MNP
(mitomycin/vinorelbine[Navelbine]/cisplatin [Platinol]). Median survival was
significantly better in the group treated with MNP. An Italian trial comparing
cisplatin/vinorelbine to MVP reported a similar time to survival and disease
progression, but less toxicity, in the group treated with cisplatin and
vinorelbine. These studies indicate that treatment with the combination of
vinorelbine/cisplatin produces a clinically meaningful benefit for patients with
advanced non-small-cell lung cancer compared to cisplatin alone or
combinations that include cisplatin and vindesine.
Two Italian studies have demonstrated that vinorelbine can be
safely given to elderly patients, alone or in combination, and significantly
improves survival.[18,19] In the first of these studies, vinorelbine, compared
with best supportive care, improved survival at 1 year from 14% to 32% and
provided a better quality of life. The second study compared the
vinorelbine/gemcitabine combination with vinorelbine alone and showed that the
combination improved survival at 1 year from 13% to 30%. Palliation of
symptoms and quality of life were improved in patients who received the
combination. The difference between these two studies in the survival of
patients treated with single-agent vinorelbine was presumed to be related to
patient selection and underscores the necessity of randomized comparisons of
different treatment regimens.
Docetaxel in Non-Small-Cell
As a single agent, docetaxel appears to be as active as
paclitaxel. In a European study, previously untreated non-small-cell lung
cancer patients were randomly assigned to receive docetaxel at 100 mg/m2 every 3
weeks or best supportive care. Survival and quality of life were improved in the
chemotherapy arm (Table 3). Docetaxel is also one of the few drugs that has
confirmed activity in patients who have previously received platinum-containing
Shepherd et al randomly assigned previously treated patients to
receive docetaxel or best supportive care. The docetaxel dose was initially
100 mg/m2; because of excessive toxicity it was decreased to 75 mg/m2 after
enrollment of half of the patients. Overall, both survival and quality of life
were better in patients who received docetaxel treatment. This improvement
was particularly marked for patients receiving the 75 mg/m2 dose, in whom 1-year
survival was 40% compared with 16% in control patients.
In a study by Fossella et al, previously treated patients were
randomized to receive docetaxel 100 (docetaxel at 100 mg/m2 per cycle),
docetaxel 75 (docetaxel at 75 mg/m2 per cycle), or to a control arm of
vinorelbine or ifosfamide treatment. About one-third of the 373 enrolled
patients were primarily resistant to initial chemotherapy, and a similar
percentage had received at least two previous chemotherapy regimens. Previous
treatment with paclitaxel was permitted, and 37% of patients had received this
drug as part of their previous therapy. Based on an intent-to-treat analysis,
survival at 1 year was superior in the docetaxel 75 group (32%) than in the
other two treatment arms (21% and 19% in the docetaxel 100 and control groups,
respectively). Progression-free survival and quality of life were improved in
both docetaxel arms. At the time of disease progression, more than one-third
of the patients received additional chemotherapy.
In an attempt to adjust for the effect this poststudy treatment
may have had on survival, an analysis was performed in which patients were
censored at the time of administration of poststudy chemotherapy. This analysis
suggested a survival advantage for both docetaxel arms. Serious toxicities were
more common in the docetaxel 100 arm, but this difference was not statistically
Gemcitabine is also active in non-small-cell lung cancer, and
early reports suggest that it has activity in previously treated patients. A
study which included 522 evaluable patients compared the combination of
cisplatin/gemcitabine with cisplatin alone. One-year survival was
substantially better in patients treated with the combination (39% vs 28%) (Table
4). Hematologic toxicity was more pronounced with the combination, but
nonhematologic toxicity and quality-of-life assessments were similar in the two
treatment groups. Randomized phase II studies that compared gemcitabine with
cisplatin/etoposide, and gemcitabine/docetaxel with cisplatin/docetaxel reported
comparable response rates.[26-28]
A randomized trial comparing cisplatin/gemcitabine with
cisplatin/etoposide demonstrated a superior response rate (41% vs 22%) and
progression-free survival (6.9 months vs 4.3 months), with comparable toxicities
for the two treatments. A preliminary report of another study, which
compared gemcitabine/paclitaxel with carboplatin/paclitaxel, reported a higher
response rate in the gemcitabine/paclitaxel arm.
Irinotecan in Non-Small-Cell
The reported activity of irinotecan in advanced non-small-cell
lung cancer has ranged from 15% to 32%. Two randomized studies from Japan
compared the combination of cisplatin/irinotecan with a standard regimen in
patients with previously untreated non-small-cell lung cancer (Table
the study by Masuda et al, 378 patients were randomly assigned to receive
cisplatin/irinotecan, irinotecan alone, or cisplatin/vindesine. In a second
randomized study, 203 patients received cisplatin/irinotecan or
cisplatin/vindesine. Although no survival differences were detected
individually in these studies, an analysis that combined the data showed that
patients treated with cisplatin/irinotecan had significantly better 1-year
survival than those receiving the control regimen of cisplatin/vindesine.
The results of these clinical studies support the following
Treatment with cisplatin-based chemotherapy produces
survival superior to that achieved with best supportive care.
Several newer drugs (the US Food and Drug Administration-approved
taxanes, vinorelbine, gemcitabine, and irinotecan) are better tolerated than
cisplatin and have at least comparable single-agent activity.
Docetaxel and perhaps some of the other newer drugs improve
survival in patients previously treated with a platinum-containing regimen.
The combination of cisplatin and one of these newer drugs
produces survival superior to cisplatin alone.
The combination of cisplatin and one of these newer drugs
produces superior survival, fewer side effects, or both, compared with earlier
standard combinations such as cisplatin/vindesine or cisplatin/etoposide.
A question that remains unanswered is whether there is a
"best choice" among the possible combinations of a platinum drug and
one of the newer agents. Based on the SWOG study, the combination of
carboplatin/paclitaxel appears to be as active as cisplatin/vinorelbine.
Preliminary results of an ECOG study, in which patients were randomly assigned
to one of four treatment arms (cisplatin/paclitaxel, cisplatin/gemcitabine,
cisplatin/docetaxel, or carboplatin/paclitaxel), were reported last year and
1-year survival rates (ranging from 31% to 36%). If survival is comparable
between these regimens, then other factors will help to define the best choice
for patients. Other considerations include patient tolerability, cost, ease of
administration, and rationale for and ability to include noncytotoxic agents
(such as inhibitors of signal transduction pathways or angiogenesis) into the
Another unanswered question is whether a nonplatinum regimen
will prove superior to the best combinations of a platinum agent and one of the
newer drugs. Virtually every two-drug combination of the newer agents has been
developed, most of which are being tested or will be tested in patients with non-small-cell
lung cancer (Table 6). During the next few years, clinical researchers face the
challenge to determine efficiently the answers to these questions.
This work was supported in part by grants from the Public Health
Service, National Cancer Institute (CA 16359 and CA 75588).
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