Paclitaxel in the Treatment of Small-Cell Lung Cancer

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(Drug information on 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(Drug information on 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.