The results of clinical trials have provided insights into the potential survival benefits to be gained with vinorelbine (Navelbine) in patients with non-small-cell lung cancer. These studies have also contributed important information on the safety profile of this agent.
Phase II studies in non-small-cell lung cancer were performed in France in the mid-1980s using vinorelbine as both a single agent and in combination with cisplatin (Platinol). As a single agent, vinorelbine produced a response rate of 33% in patients with advanced non-small-cell lung cancer. When vinorelbine was used in combination with cisplatin, the response rate was 37%, with acceptable toxicity.
The response rate observed in this preliminary work provided justification for Le Chevalier et al to undertake a phase III, multicenter, European study comparing the combination of vinorelbine and cisplatin to the combination of vindesine (Eldisine) and cisplatin. The latter combination had shown a superior response rate and survival rate when compared with best supportive care in a randomized trial conducted by the National Cancer Institute of Canada. Because vinorelbine alone had shown efficacy with low toxicity in phase II trials, it was included as a third arm in the study by Le Chevalier et al.
Materials and Methods
The eligibility criteria for this trial included inoperable non-small-cell lung cancer (stage III or IV), age
£ 75 years, World Health Organization performance status
£ 2, no prior malignancy, no prior chemotherapy, no symptomatic central nervous system metastases, and at least one measurable lesion.
Eligible patients were randomized to receive: vinorelbine alone at a dose of 30 mg/m2 every week; vinorelbine at the same dosage plus cisplatin (120 mg/m2 on day 1 and day 29, then every 6 weeks); or vindesine (3 mg/m2 every week for 6 weeks, then every 2 weeks), plus cisplatin at the same dosage as in the previous group. This regimen was identical to that used in the National Cancer Institute of Canada trial.
Vinorelbine was diluted in saline and administered as a 20-minute intravenous (IV) infusion. Vindesine was administered as an IV push, with a running 5% dextrose or normal saline infusion. Cisplatin was diluted in saline and infused over 1 hour. Treatment was continued until either disease progression or toxicity necessitated its termination.
For grade 2 neutropenia, the doses of vinorelbine and vindesine were reduced by 50%. For grade 3 or 4 neutropenia, the dose of vinorelbine or vindesine was withheld. Grade 3 or 4 neurologic, hepatic, or renal toxicity resulted in discontinuation of therapy. Treatment was also discontinued in cases of severe hearing loss.
The baseline assessment included a physical examination, complete blood count and blood chemistries, chest x-ray, fiberoptic bronchoscopy, and abdominal ultrasound. Optional studies included CT of the chest, abdomen, or brain, as well as bone scans.
Patients were evaluated prior to treatment, after 10 weeks, and after 18 weeks to assess response rates. Objective responses required confirmation after an additional 4 weeks by a panel of at least three experts, who blindly reviewed all documents for the response assessments. Survival was analyzed approximately 16 months after the close of the trial.
To demonstrate a difference of 12 weeks in median survival and a difference of 15% in response rates with a type I error of 5% and a power of 80%, 190 patients were needed in each arm of the study. Randomization was stratified by center and by stage. Response rates and survival rates in the three treatment arms were compared using the chi-square test and log-rank test adjusted for prognostic factors.
Because of a concern that efficacy might be lower in the vinorelbine-alone arm than in the two cisplatin arms, an unplanned interim analysis was performed after accrual of 323 patients. At that point, the P value for a survival difference was .15, and the study was continued.
Patient Accounting and CharacteristicsBetween 1989 and 1991, 612 patients were enrolled at 45 European centers. A total of 206 patients were randomized to vinorelbine alone, 206 to vinorelbine/cisplatin, and 200 to vindesine/cisplatin. Three patients randomized to the vindesine/cisplatin arm received vinorelbine/cisplatin instead. These patients were included in the vindesine/cisplatin group in the survival analysis. Eight patients received no treatment (two in the vinorelbine-alone group, two in the vinorelbine/cisplatin group, and four in the vindesine/cisplatin group).
Of the 612 patients randomized, 24 (4%) were deemed ineligible for inclusion in the analysis. The reasons for ineligibility were brain metastases in 5 patients, prior malignancy in 2, diagnostic errors in 2, low performance status in 5, and a lack of measurable disease in 10. The numbers of ineligible patients were 4 in the vinorelbine-alone group, 9 in the vinorelbine/cisplatin group, and 11 in the vindesine/cisplatin group.
The median age of the 612 randomized patients was 60 years; 80% were men, and 80% had a performance status of 0 or 1. More than half of the patients had squamous-cell non-small-cell lung cancer, which is the most common histologic subtype in Europe. Approximately 60% of patients had distant metastatic disease.
TreatmentThe duration of treatment was similar in the three arms of the study. The median duration of treatment was 14.6 weeks for vinorelbine alone, 15.4 weeks for vinorelbine/cisplatin, and 14.4 weeks for vindesine/cisplatin.
The dose intensity was determined by dividing the given dose by the expected dose. The expected dose was the calculated full dose for the period of time that a patient was receiving treatment. For vinorelbine alone, the dose intensity was 83%. In the vinorelbine/cisplatin arm, the dose intensities for the two agents were 71% and 96%, respectively. In the vindesine/cisplatin arm, the dose intensity was 98% for both agents. The addition of cisplatin to the vinorelbine regimen had a relatively minor effect on the dose intensity of the latter agent.
Second-line treatment was allowed. A total of 362 patients received some form of second-line therapy, including surgery in 26 individuals, thoracic radiation therapy in 245, and second-line chemotherapy in 195. The analysis of survival did not take into account these second-line treatments.
Response RatesOf the 612 patients enrolled, 38 were excluded from the analysis of response. The reasons for exclusion included ineligibility in 24 patients, lack of treatment in 6, incorrect treatment in 3, and lack of documentation in 5.
Table 1 shows the objective response data by treatment group. The response rate was significantly higher with vinorelbine/cisplatin than with vindesine/cisplatin (P < .02) or vinorelbine alone (P < .001). The median duration of objective response was 9.2 months for vinorelbine/cisplatin, 9.9 months for vindesine/cisplatin, and 7.8 months for vinorelbine alone.
Survival RatesApproximately 16 months after the close of the trial, 73 patients (12%) were still alive and 4 had been lost to follow-up. The median survival duration was 31 weeks in the vinorelbine-alone arm, 40 weeks in the vinorelbine/cisplatin arm, and 32 weeks in the vindesine/cisplatin arm (Table 1). The 1-year survival rates were 30%, 35%, and 27%, respectively.
Using the log-rank test adjusted for treatment center, survival was superior with vinorelbine/cisplatin as compared with vinorelbine alone (P = .01) or vindesine/cisplatin (P = .04). For patients with stage IV disease only, the median survival time was 36 weeks with vinorelbine/cisplatin as opposed to 27 weeks with each of the other regimens (unadjusted log-rank P = .007).
ToxicityToxicity data are summarized in Table 2. Hematologic toxicity mainly consisted of neutropenia, experienced at grade 3 or 4 in 53% of patients in the vinorelbine-alone group, 79% in the vinorelbine/cisplatin group, and 48% in the vindesine/cisplatin group. This was a direct consequence of the dosage schedules in the three arms. Despite the significantly higher rate of neutropenia in the vinorelbine/cisplatin arm vs the other two arms (P < .005), only two patients died of septic complications in each of the three treatment groups. Thus, the rate of septic death was low (1%) in each group.
Thrombocytopenia was experienced by 3% of patients in each cisplatin group, but in none of those receiving vinorelbine alone.
Grade 3 or 4 neurologic toxicity was significantly more common with vindesine/cisplatin than with either vinorelbine regimen (Figure 1). Notably, cisplatin did not seem to increase the neurotoxicity of vinorelbine.
Nausea and vomiting were common in the groups receiving cisplatin, but became less frequent during the course of the study as ondansetron (Zofran) became progressively more available at the participating centers. Nausea and vomiting were reported in 12% of patients receiving vinorelbine alone, compared with 58% of those receiving vinorelbine/cisplatin and 59% of those receiving vindesine/cisplatin.
The incidence of alopecia was 14% with vinorelbine alone, 32% with vinorelbine/cisplatin, and 38% with vindesine/cisplatin.
1. Le Chevalier T, Brisgand D, Douillard J-Y, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994.
2. Rapp E, Peter JL, William A, et al: Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988.
3. Crawford J, ORourke M, Schiller J, et al: Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol 14:2774-2784, 1996.