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Paclitaxel in the Treatment of Small-Cell Lung Cancer

Paclitaxel in the Treatment of Small-Cell Lung Cancer

ABSTRACT: New treatment strategies for small-cell lung cancer patients are required, as there have been few developments in the past 20 years. Paclitaxel (Taxol) has been shown to be effective in non–small-cell lung cancer when given in combination with a platinum agent or as single-agent chemotherapy. Early studies of paclitaxel in patients with small-cell lung cancer have also been encouraging. The activity of the paclitaxel/cisplatin (Platinol) combination is at least comparable to standard protocols, and when given in a regimen of paclitaxel at 175 mg/m² plus cisplatin at 75 mg/m²/day, clinical and hematologic toxicity is mild to moderate. Another study undertaken in Marburg, Germany, suggests that paclitaxel plus cisplatin produced significantly superior survival vs a historical control group. The addition of etoposide to the paclitaxel/cisplatin combination has also been tested, but no clear benefit has been shown. Encouraging data from existing small studies form the basis for large trials being planned to establish the optimal regimen incorporating paclitaxel in small-cell lung cancer patients. [ONCOLOGY 13(4):65-71, 1999]

Introduction

Little progress has been made in the treatment of small-cell lung
cancer during the past 2 decades. Patients without distant metastases
currently have a 10% to 15% chance of survival at 5 years, and with
the optimization of chemotherapy protocols and the introduction of
multimodality treatments, prognosis in this subgroup of patients has
been improved in recent years. Nevertheless, the prognosis of
patients with distant metastases remains poor, with a 3-year survival
rate of less than 5% and nearly no chance of cure.

Furthermore, in patients with extensive disease, no improvement of
treatment results has been observed in the past 25 years. Recently,
the Copenhagen Group[1] published an analysis of the prognosis of
patients with extensive disease treated from 1973 to 1981 compared to
the prognosis of patients treated from 1982 to 1992. The median
survival of 508 patients treated in the former studies was 208 days.
These results were not significantly inferior to the median survival
of 215 days for 423 patients treated in the more recent trials. Our
study group at University Hospital in Marburg, Germany has obtained
similar results. From 1981 to 1993, we performed five randomized
trials including 738 patients with metastatic disease. The median
survival of the whole group was 234 days, and the survival curves of
these five consecutive trials were nearly identical.

From the results of these trials, it appears that so-called standard
chemotherapy regimens show a comparable activity—at least in the
subgroup of patients with extensive small-cell lung cancer—and
no particular drug combination seems to be superior to others. To
overcome this stagnation of treatment results in small-cell lung
cancer, the introduction of new drugs with a higher activity into
treatment protocols is necessary.

Paclitaxel (Taxol) is a relatively new cytostatic drug with a unique
mechanism of action. The drug is highly active in various
malignancies such as ovarian cancer, breast cancer, and
non–small-cell lung cancer. This well-documented activity, even
in tumors resistant to standard chemotherapy regimens, makes the drug
especially interesting for testing in small-cell lung cancer.

Single-Agent Paclitaxel

Two trials in patients with metastatic small-cell lung cancer have
tested the activity of paclitaxel as single-agent treatment. In the
Eastern Cooperative Oncology Group (ECOG) study from Ettinger et
al,[2] 32 patients received a dose of 250 mg/m² as a 24-hour
infusion every 3 weeks. The remission rate was 34%, and median
survival was 43 weeks. In the second trial from the North Central
Cancer Treatment Group (NCCTG),[3] 37 patients were treated with a
similar protocol; 41% of them achieved a partial remission. These
small phase II trials demonstrated the activity of paclitaxel for the
treatment of small-cell lung cancer and provided the basis for the
subsequent incorporation of this drug into polychemotherapy regimens.

To date, experience with paclitaxel in combination chemotherapy for
small-cell lung cancer is still limited. Table
1
gives an overview of the currently available data, including
the number of evaluable patients with limited or extensive disease in
each study.

Cisplatin/Paclitaxel in Extensive Disease

The combination of cisplatin (Platinol) and paclitaxel has been
tested in two phase II trials—one from the NCCTG and one from
Marburg University.

The NCCTG Trial

In the study from the NCCTG,[4] 71 chemotherapy-naive patients with
extensive disease were treated with cisplatin and paclitaxel. At dose
level 1, 23 patients received a dose of cisplatin (75 mg/m²on
day 1) and paclitaxel (135 mg/m² on day 1). Due to the very low
toxicity with no World Health Organization (WHO) grade 3 or 4
hematologic toxicity, 48 patients received an increased paclitaxel
dose of 175 mg/m² on day 1. A total of six cycles were given in
3-week intervals. The treatment schedule is given in Table
2
.

At the higher dose level, leukopenia WHO grade 3 was seen in 24% and
WHO grade 4 leukopenia in 2% of the patients. No severe
thrombocytopenia occurred. Other severe clinical side effects were
nausea in 18%, vomiting in 13%, myalgia in 4%, and neurotoxicity in 2%.

The response to treatment was 71% at the low dose and 89% at the high
dose. Progression-free survival (4.8 vs 5.5 months) as well as median
survival (7.9 vs 8.7 months) were slightly higher in patients
receiving the higher paclitaxel dose.

German Multicenter Trials

In the multicenter German study conducted at Marburg University, the
combination of cisplatin (75 mg/m² on day 1) and paclitaxel (175
mg/m²on day 1) was administered to 62 patients with metastatic
small-cell lung cancer. Six cycles were given in 3-week intervals to
49 male patients and 13 female patients. Median performance status
was WHO grade 1, and the median age was 62 years. An elevated lactate
dehydrogenase (LDH) level was documented in 36 patients (56%). (The
main patient characteristics are summarized in Table
3
.) All of the patients had metastatic organ involvement, 25
patients (40%) had one involved site, 22 patients (35%) had two
metatstatic sites, and 15 patients (24%) had three or more metastatic sites.

At least five cycles of chemotherapy were given to 33 patients (53%).
Fifteen patients received only one or two cycles, and another 15
patients only three or four cycles. Treatment was stopped prematurely
because of progressive disease in 21 patients and death during the
induction therapy in three patients. In four additional cases,
patients refused further treatment, and in two patients, renal
impairment was responsible for the discontinuation of the
chemotherapy. Additional severe clinical side effects were the
occurrence of WHO grade 3 myalgia in two patients.

Despite these side effects, treatment was well tolerated overall.
Regarding hematologic toxicity, thrombocytopenia was observed in only
two cycles (WHO grade 3) and leukopenia in only one cycle (WHO grade 3).

The treatment results of the Marburg and NCCTG trials are summarized in Table
4
. Eight patients (13%) achieved a complete remission and 35
patients (56%) a partial remission, for an overall response rate of
69%. No change was seen in 11 cases, and eight patients had
progressive disease despite therapy. The median progression-free
survival of all patients was 156 days, and the median survival 356
days. Figure 1 shows the
survival curve for all patients.

Both trials indicate that the combination of cisplatin (75 mg/m²
on day 1) and paclitaxel (175 mg/m² on day 1) as a 3-hour
infusion is a well-tolerated regimen in patients with small-cell lung
cancer, with mild hematologic side effects. Therefore, the addition
of the third drug seems to be feasible in order to achieve a further
intensification of the treatment.

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