Lung cancer is the most common malignant
disease in the western world. Although the incidence is stabilizing
or even decreasing in men in this area, the number of women affected
is increasing. In eastern Europe, China, and the developing countries
the incidence in both genders is rapidly increasing.
Treatment of small-cell lung cancer has developed during the past 25
years from local therapy, surgery, and radiotherapy, to systemic
treatment, combination chemotherapy, and recently the addition of
radiotherapy for disease limited to the thorax. For
nonsmall-cell lung cancer the treatment has been surgery for
the earlier stages (I and II) and radiotherapy for stage III. For
patients with disseminated disease the development of treatment has
not followed the same route as for small-cell lung cancer due to the
lack of clearly active chemotherapeutic agents. However, for stage IV
disease, discussion of the role of systemic therapy has recently changed.
In a meta-analysis of a large number of studies comparing one
treatment modality with that same treatment plus chemotherapy, it was
demonstrated that the addition of combination chemotherapy to best
supportive care resulted in a survival improvement at 1 year of 10%
to 25% and an improvement of the median survival from 4 to 6
months. Still this benefit is regarded as very small and serious
doubts remain whether this was sufficient to consider combination
chemotherapy as standard treatment for disseminated
nonsmall-cell lung cancer. One of the main reasons for these
doubts was the important role of cisplatin (Platinol) demonstrated in
this meta-analysis. It remained questionable whether the survival
benefit was offset by the toxicity of the chemotherapy, especially of cisplatin.
At the beginning of the 1990s new classes of drugs became available
for clinical evaluation: taxanes, topo-I-isomerases, and a new
antimetabolite. In a number of phase II studies activity was
demonstrated against nonsmall-cell lung cancer. The activity of
paclitaxel (Taxol) was especially impressive, with a response rate
> 20% and a 1-year survival rate of > 40%.[3,4]
Combining paclitaxel with cisplatin was a logical step in the
development of chemotherapy for nonsmall-cell lung cancer;
hence a number of studies were started in Europe.
In a phase I study Rowinsky et al reported that administration of
cisplatin followed by a 24-hour infusion of paclitaxel was more
myelotoxic than the reverse (paclitaxel then cisplatin). The
recommended doses were 75 mg/m² for cisplatin and 130 to 170
mg/m² for paclitaxel. The same group investigated the maximum
tolerated doses of both drugs when administered with granulocyte
colony-stimulating factor. Dose-limiting toxicity was peripheral
neuropathy at a 300-mg/m² dose of paclitaxel with 75 mg/m²
In a study by Klastersky et al the dose-limiting toxicity was
defined in a study starting with cisplatin at a dose of 100 mg/m²
and a 3-hour paclitaxel infusion at 135 mg/m² every 3 weeks. It
was possible to increase the doses to 120 mg/m² of cisplatin and
200 mg/m² of paclitaxel without dose-limiting acute toxicity.
After 3 to 4 courses neurotoxicity appeared to be dose-limiting; it
became clear that prolonged treatment with this combination was
impossible. In 8 of 17 patients a response was seen, with an overall
response rate of 47%.
The results of this study were more or less confirmed by others (Table
1): in all the phase II studies in Europe combining cisplatin
and paclitaxel, the response rate was around 40%.[8-10] Based on
these results it was necessary to evaluate the combination of
cisplatin and paclitaxel in a randomized study, comparing it with one
of the old standard regimens.
The Lung Cancer Cooperative Group of the European Organization for
Research and Treatment of Cancer (EORTC-LCCG) started relatively late
with the evaluation of combination chemotherapy in nonsmall-cell
lung cancer. In a randomized phase II study the role of teniposide
(Vumon) was evaluated and the difference in activity between a 1-day
schedule and a 3-day schedule was proven. This is comparable to
the activity of etoposide in small-cell lung cancer in which
prolonged treatment gave a much higher response rate than a 1-day
infusion with etoposide. In the EORTC study the combination of
teniposide with cisplatin demonstrated a higher activity than
teniposide alone. The best survival was achieved in the group treated
with cisplatin and teniposide using a 3-day schedule as opposed to
the 1-day schedule.
Based on these results the EORTC-LCCG considered cisplatin and
teniposide their standard treatment. For any phase III study the
group recommended that the standard arm should be teniposide and
cisplatin and the experimental arm should include the most active old
single agentcisplatin. At that time the possibility of
combining cisplatin with a new drug had not been extensively tested.
Data on the combination of cisplatin and paclitaxel were among the
earliest of the possible new combinations; therefore the group
decided to compare this promising new combination with their standard
regimen of cisplatin and teniposide. The doses of both drugs in this
study were based on the study by Klastersky et al. In a randomized
phase II study both combinations were tested. At that time toxicity
of evaluated patients in both regimens was considered acceptable and
activity was confirmed. As initially planned the study went on as
a phase III study.
Inclusion criteria were standard, excluding previous malignancies,
prior chemotherapy, brain metastases, poor performance status, organ
failure, and age > 75 years. All patients had measurable or
evaluable disease. Response was assessed every two cycles by the
optimal method to define it, and toxicity was scored during and after
In 2.5 years 332 patients were included and 15 patients were not
eligible. The sample size was based on an increase of the median
survival from 7 months in the standard arm to 10 months in the
experimental arm. Treatment consisted of 80 mg/m²of cisplatin on
day 1 in both arms, and 175 mg/m² of paclitaxel prior to
cisplatin on day 1 in the experimental arm and 100 mg/m² of
teniposide on days 1, 3, and 5 in the standard arm. In both arms six
cycles were planned every 3 weeks.
Reasons for delaying chemotherapy or dose-adjustment were standard.
The median age of the patients in both arms was 58.5 years;
prognostic factors such as weight loss, prior therapy, performance
status, and stage were balanced between the two arms. Performance
status was in general good; 11% had a performance status of 2, 55% a
performance status of 1, and around 34% a performance status of 0.
Weight loss > 5% occurred in 27% of the patients. Stage IV was
noted in 61.5% of the patients. Adenocarcinoma was the most common
histologic type, in slightly more than half of the patients.
The response rate was significantly higher in the cisplatin and
paclitaxel arm (41%) vs the teniposide and cisplatin arm (28%).
Despite this, median survival was not different between the two arms
at 9.7 and 9.9 months, respectively. The survival rate after 1 and 2
years was also comparable (Table 2).
However, toxicity, especially myelotoxicity, was more severe in the
teniposide and cisplatin arm; in the cisplatin and paclitaxel
patients neurotoxicity was far more common, although it did not often
lead to dose-reduction or discontinuation of the administration of
paclitaxel (Table 3). Overall
the number of courses was higher in the cisplatin-paclitaxel group
and toxicity was less.
In a subgroup of the patients a quality-of-life measurement was
performed, reporting a better quality of life during the first period
of the treatment. Later on this difference disappeared with a rapidly
dropping number of forms available for analysis in both arms.
Since the demonstration of a survival benefit for patients with
stages IIIB and IV disease treated with combination chemotherapy, the
use of chemotherapy has attracted more interest. Even physicians who
previously had very negative attitudes toward chemotherapy for this
disease are now willing to consider this treatment for selected
patients. Relatively young patients with good prognostic factors are
especially considered good candidates.
Furthermore, one should keep in mind that the results of the
meta-analysis are based on what are nowadays called old chemotherapy
regimens. With the introduction of the new agents such as paclitaxel,
docetaxel (Taxotere), irinotecan (Camptosar), navelbine
(Vinorelbine), and gemcitabine (Gemzar), the possibilities of
chemotherapy are probably changing. The higher activity of each of
these new agents compared to the older agents has enlarged the
expectations of chemotherapy considerably. Furthermore the toxicity
was found to be acceptable and certainly not worse than with the
In a number of phase II studies in previously untreated patients the
activity of these agents has been confirmed. One of the most striking
observations in patients treated with paclitaxel as a single agent
was the high percentage of 1-year survivors. A logical step in the
further development is the use of the active new agent with the other
active agents. At this stage most trials are focusing on the
evaluation of the new agent in combination with what is considered to
be the cornerstone of chemotherapy for nonsmall-cell lung
cancercisplatin. Standard treatment regimens from the 1980s are
used for comparison, for instance, cisplatin and etoposide or
cisplatin and vindesine. A convenient schedule of cisplatin and
paclitaxel was found in a number of phase II studies and considered
suitable for evaluation in a multicenter randomized study. The
EORTC-LCCG found the combination to be active in the phase II part of
the study and decided to continue accrual for the planned phase III
study. The hope of gaining survival benefit was unfortunately not
fullfilled. Despite a significantly higher response rate, the control
arm was comparable with regard to median survival times and 1- and
2-year survival rates. The experimental regimen behaved as expected
with a response rate, median survival time, and 1- and 2-year
survival rate arm as found in the phase II studies. The reason why
the standard regimen resulted in a longer survival time than in the
study in which it was initially evaluated is unclear. It is
possible that the selection of patients was more restricted with
relatively fewer patients with a performance status of 2.
However, the toxicity and quality of life were worse in the standard
treatment arm. Despite a reduction of the dose from 120 mg/m2 to 100
mg/m2 in comparison with the previous randomized phase II study,
hematologic toxicity was still rather severe with a high incidence of
grades III/IV myelotoxicity, infections, and red blood cell
transfusions. The toxicity of the experimental arm was as expected,
with neurotoxicity and myalgia and arthralgia shortly after the
infusion as the most important toxicities.
The favorable toxicity profile and quality-of-life advantage is the
reason for the EORTC-LCCG to consider the cisplatin and paclitaxel
arm as the new standard arm. Subsequently the LCCG is planning a new
study in which the main theme is to try not to use the most toxic
chemotherapeutic agentcisplatinbut to combine two of the
new and active agents. To date, the combination of 200 mg/m² of
paclitaxel on day 1 with 1,000 mg/m² of gemcitabine on days 1
and 8 has been tested. Myelotoxicity was acceptable and activity was
found, although the response rate is probably somewhat lower than
expected. To date, an additive effect has been found.
Combining paclitaxel with other new agents is a logical step toward
reducing toxicity and developing a simple outpatient regimen without
the need for time-consuming hydration procedures to prevent
neurotoxicity. The use of these relatively expensive new agents will
become cost-effective if hospitalization for the administration of
chemotherapy is not necessary. Therefore schedules with a shorter
infusion time for paclitaxel will be more than welcome.
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