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Long Term Analysis of Survival in the European Randomized Trial Comparing Vinorelbine/Cisplatin to Vindesine/Cisplatin and Vinorelbine Alone in Advanced Non-Small Cell Lung Cancer

Institut Gustave-Roussy, Villejuif Cedex, France

Correspondence: Thierry Le Chevalier, M.D., Institut Gustave-Roussy, Rue Camille Desmouline, Villejuif Cedex 94805 France. Telephone: 33-1-455-943-22; Fax: 33-1-421-152-19; e-mail: tle-che{at}iqr.br

	ABSTRACT

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In the period 1989-1991, 612 patients with inoperable stage IIIA/B and IV non-small cell lung cancer (NSCLC) were randomized in a phase III trial comparing three chemotherapy regimens. Survival data at five and six years of follow-up confirm the overall benefit of treatment with a combination of vinorelbine and cisplatin compared to vindesine plus cisplatin or vinorelbine alone. Of the 612 patients randomized at the start of the study, 17 have survived beyond five years. Of these patients, eight had entered the trial with metastatic disease. Multivariate analysis to detect prognostic factors suggested a possible interaction between the effect of having cisplatin in the chemotherapy received and baseline performance status. Subgroup analysis subsequently confirmed that the survival benefit of the vinorelbine plus chemotherapy regimen is evident only in patients with initial World Health Organization performance status (PS) of 0-1. Among these patients, the one-year survival rate is 38% for the vinorelbine/cisplatin arm, 29% for vindesine/cisplatin and 34% for vinorelbine alone. The corresponding figures for median survival are 43, 33 and 36 weeks. Among inoperable NSCLC patients with a PS of 2, who appear from this trial not to have benefited from the presence of cisplatin in their chemotherapy, use of single agent vinorelbine is an appropriate treatment option.

Key Words. Vinorelbine • Cisplatin • Vindesine • Randomized study • Prognostic factors

	INTRODUCTION

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Vinorelbine, one of the most active vinca alkaloids [1], has undergone extensive clinical trials in the treatment of non-small cell lung cancer (NSCLC). Promising activity was observed with vinorelbine in phase II trials, and the phase III studies have confirmed vinorelbine is active in the treatment of NSCLC [2-8].

In a phase III trial conducted between June 1989 and May 1991 in 45 European centers, a total of 612 patients with NSCLC were randomized to one of three treatments. The three arms of the study were: vinorelbine alone at a dose of 30 mg/m² weekly; vinorelbine 30 mg/m² plus cisplatin 120 mg/m² on days 1 and 29 and then q 6 weeks; and a control treatment consisting of vindesine 3 mg/m² per week for six weeks and then every other week plus cisplatin 120 mg/m² on days 1 and 29 and then q 6 weeks [8]. No G-CSF was administered in the present study.

Cisplatin and vindesine as single agents produced modest reproducible activity, and cisplatin-based regimens demonstrated survival advantages in the late 1980s in several randomized studies. They provided significant benefits to NSCLC patients compared to best supportive care (BSC) alone [9-11]. The combination of vindesine (3 mg/m²/weekly) and cisplatin (120 mg/m²) was superior to a lower dose regimen (CAP) and BSC in a study performed by the National Cancer Institute (NCI)-Canada, and was considered a reference treatment arm at the time of the design of our study [12].

The results of the trial were reported in 1994 [8]. The present paper summarizes the characteristics of the patients involved in the trial. It also presents survival data at five years of follow-up. In addition, factors predictive of survival are considered, together with evidence of an interaction between the chemotherapy regimen administered and baseline performance status (PS) [13].

	RESULTS

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Patient Characteristics
The demographic and disease characteristics of patients in the three treatment arms were well balanced and are shown in Table 1. The great majority of patients enrolled were male. There was a predominance of patients with metastastic disease. Approximately 80% of patients across the three treatment groups had a World Health Organization (WHO) PS of 0 or 1. However, the study included an appreciable minority with poorer PS, and the implications of treatment for this group are considered below. Reflecting the fact that this was a European study, the most frequent histology was squamous cell carcinoma.

At one year, the proportion of patients alive was 34% for vinorelbine plus cisplatin, 27% for vindesine plus cisplatin, and 30% with vinorelbine alone. The 40-week median survival among patients randomized to vinorelbine plus cisplatin was significantly longer than the 32-week median survival observed in patients receiving vindesine plus cisplatin, and the 31-week median survival with vinorelbine alone.

The superiority of the combination of vinorelbine and cisplatin over the other two arms was confirmed after six years of follow-up (p < 0.02 for both comparisons). The survival curves are shown in Figure 1.

View larger version (12K): [in this window] [in a new window]   Figure 1. Survival at five years by treatment group [8, 13].

Overall Prognostic Factors
To detect possible differences in the effect of treatment on different subgroups of patients, baseline characteristics were entered into a Cox analysis. Possible interactions between treatment and selected factors were tested for by adding interaction terms into the model. The final model included seven factors which were predictive of survival in this study.

On univariate analysis, the most significant factor predictive of outcome was neutrophil count. Patients with a count of >10⁴ neutrophils had a risk ratio of 2.2. The confidence intervals (CI) of this risk ratio and those associated with other prognostic factors are shown in Table 3.

This suggested that the effect of treatment with vinorelbine/cisplatin was different in patients with different PS. This is supported by the subgroup analysis shown in Table 4 which shows that the benefit of treatment with vinorelbine plus cisplatin is evident in patients of PS 0-1 but not in patients of poorer PS.

	DISCUSSION

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	REFERENCES

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1. Furuse K, Fukuoka M, Kuba M et al. Japan Vinorelbine Cancer Cooperative Study Group: randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small cell lung cancer (NSCLC). Ann Oncol 1996;7:815-820.
2. Yokoyama A, Furuse K, Niitani H et al. Multi-institutional phase II study of vinorelbine (Navelbine) in non-small cell lung cancer. Proc Am Soc Clin Oncol 1992;11:287a.
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