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Options in Advanced Non-Small Cell Lung Cancer: A Review and Report on a Phase II Study of Vinorelbine Plus Gemcitabine

University of Miami School of Medicine and The Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida, USA

Correspondence: Rogerio Lilenbaum, M.D., University of Miami School of Medicine and The Mount Sinai Comprehensive Cancer Center, 4306 Alton Road, Miami Beach, FL 33140-2840, USA. Telephone: 305-535-3310; Fax: 305-35-3324; e-mail: rlilenbaum{at}salick.com

	ABSTRACT

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Although platinum-containing regimens prolong survival in advanced non-small cell lung cancer (NSCLC), toxicity remains substantial. There is a clear need for a nonplatinum-based regimen which is active, well tolerated, and suitable for outpatient administration. Vinorelbine and gemcitabine have different mechanisms of action and are both active in NSCLC. A phase II trial was undertaken to evaluate activity and tolerability when the two drugs were administered as a first-line combination regimen in 32 patients with stage IIIB/IV disease. Gemcitabine was administered at a dose of 1,000-1,250 mg/m² together with vinorelbine 25 mg/m² on days 1 and 8 of a 21-day cycle. The overall response rate was 25%, median survival 8.3 months and one-year survival rate 38% (48% in patients of performance status 0-1). Grade 3/4 neutropenia was observed in 38% of 148 treatment cycles, however, thrombocytopenia was infrequent and there was no grade 3/4 anemia. Nonhematological toxicity was minimal. The response and survival rates experienced were comparable with standard platinum-based combinations. Ongoing randomized trials will further define the role of the vinorelbine/gemcitabine combination in advanced NSCLC.

Key Words. Vinorelbine • Gemcitabine • Lung Cancer

	INTRODUCTION

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There are now many chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC). Among possible regimens are those that combine a platinum agent with one of the two taxanes, vinorelbine or gemcitabine.

The Southwest Oncology Group phase III trial found that carboplatin plus paclitaxel and cisplatin plus vinorelbine produced similar rates of response (25% versus 28%) and one-year survival (38% versus 36%) [1]. Hematologic toxicity was greater with cisplatin plus vinorelbine while neuropathy was more severe with the carboplatin/paclitaxel combination. Quality of life was similar in the two arms of the study. The use of carboplatin plus paclitaxel was more expensive.

The Eastern Cooperative Oncology Group 1594 study compared four possible doublets in a total of more than a thousand patients with stage IIIB/IV disease [2]. The time to progression among patients receiving gemcitabine plus cisplatin (median 4.5 months) was statistically significantly longer than that among patients treated with paclitaxel plus cisplatin (3.5 months), docetaxel plus cisplatin (3.6 months), or paclitaxel plus carboplatin (3.3 months). However, the proportion of patients alive at one year (which ranged from 31% to 36% across the four arms of the trial) showed no significant differences according to treatment.

Therefore, it appears that these platinum-based regimens have comparable efficacy in advanced NSCLC. Toxicity varied according to the combination, but no regimen is without appreciable problems in this regard, especially when used in patients with less than optimal performance status (PS).

Hence there is considerable need to develop regimens that will deliver equivalent survival to that achieved with platinum regimens, but with less toxicity. In this context, taxane-based doublets have been investigated. In a randomized phase III trial, Kosmidis et al. compared paclitaxel plus carboplatin with paclitaxel plus gemcitabine [3]. According to the preliminary analysis, the response rates were 29% with paclitaxel plus carboplatin and 37% with paclitaxel plus gemcitabine. The one-year survival rates were 41% and 51%, respectively. Neither of these endpoints were statistically significant. A randomized phase II study combining docetaxel with cisplatin, or with gemcitabine, produced similar results between the study groups [4]. Among patients treated with docetaxel plus cisplatin, the response rate was 32% and the one-year survival rate was 42%. With docetaxel plus gemcitabine, the corresponding figures were response rate 34% and survival 38%. Importantly, the toxicity profile did not appear to be more favorable with the taxane-based doublets.

Of the nontaxane, nonplatinum-based doublets, three have been studied in advanced NSCLC: vinorelbine plus gemcitabine, vinorelbine plus ifosfamide, and gemcitabine plus irinotecan. The pilot data for vinorelbine/gemcitabine were promising and the remainder of this paper describes our phase II experience with this combination [5].

Both vinorelbine and gemcitabine are active as single agents in NSCLC [6-9]. The dose-limiting toxicity for both drugs is myelosuppression, with thrombocytopenia more common in the case of gemcitabine and neutropenia with vinorelbine. However, the nonhematological toxicities of the two agents do not overlap. The two drugs have different mechanisms of antitumor activity, gemcitabine being a nucleoside analogue (which inhibits DNA replication and cell growth, and masks DNA chain termination), while vinorelbine binds to the tubulin (and has an inhibitory effect on the polymerization of mitotic microtubules), offering the possibility of additive or even synergistic effects [10, 11]. Importantly from the practical point of view, both gemcitabine and vinorelbine can be given in the outpatient setting using a convenient weekly schedule.

	PHASE II STUDY OF A VINORELBINE/GEMCITABINE COMBINATION: DESIGN

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Patients
Patients eligible for this trial had documented stage IIIB or stage IV NSCLC, no prior history of chemotherapy, and a PS of 0-2 [6].

Treatment
An initial six patients in this study received gemcitabine 1,000 mg/m2 given over 30 min plus vinorelbine 25 mg/m2 over 6 min, both administered i.v. on days 1 and 8, with cycles repeated every 21 days. After the first six patients were enrolled, the dose of gemcitabine increased to 1,250 mg/m2. Growth factors were not routinely used.

	RESULTS

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Patients
The 32 patients recruited were evenly divided between the sexes. Their median age was 67 years (range 45-83; 14 patients were older than 70 and four patients were aged over 80). Seventy-eight percent of patients had a PS of 0 or 1 and 22% had a PS of 2. Disease stage was IV in 69% and IIIB in 16% (all of whom had malignant pleural effusion). Five patients had brain metastases that had previously been irradiated and were neurologically stable at the start of chemotherapy.

Efficacy
Activity was evaluated by intention-to-treat analysis. No complete responses were observed. However, eight patients (25%; 95% confidence interval 12%-43%) had a partial response and 17 (53%) had stable disease. Over the first two cycles, there were only three cases of progressive disease. There were two early deaths, one from disease and one from toxicity. One patient was lost to follow-up after two cycles and one patient chose to discontinue protocol treatment in favor of alternative therapy (not evaluable for response, but included in the survival analysis).

At a median follow-up of 13 months (range 12-22 months), the median survival time was 8.3 months and the median failure-free survival was 4.4 months. At one year, 38% of patients were alive. Among the 78% of patients with a PS of 0-1, the median survival was 11.7 months and the one-year survival rate was 48% (Figure 1).

View larger version (9K): [in this window] [in a new window]   Figure 1. Survival curves stratified by PS in a phase II study, combining vinorelbine with gemcitabine, in advanced NSCLC [6].

No cases of grade 4 nonhematologic toxicity were seen. Of grade 3 toxicities, two patients (6%) had nausea and vomiting, one patient (3%) had constipation and three patients (9%) had fatigue. Grade 2 peripheral neuropathy was seen in two patients (6%), phlebitis in two, skin rash in two, and alopecia in six (19%).

	DISCUSSION

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The population of patients included in this phase II study was relatively elderly, yet the regimen used was well tolerated and proved practical to administer on a convenient outpatient weekly schedule. The severity of toxicities experienced was substantially less than would be expected with platinum-based combinations in a comparable group of patients [12, 13].

The combination of vinorelbine with gemcitabine was active and the survival experience encouraging. The one-year survival rate of 38% is comfortably within the range of that previously reported with platinum or paclitaxel-based regimens [1, 3]. The 48% one-year survival seen in patients with PS of 0 or 1 must be regarded as an exciting result.

Our conclusions are supported by another phase II trial conducted in Italy in which 52 patients (28 stage IIIB, 24 stage IV) were treated with gemcitabine 1,200 mg/m² plus vinorelbine 30 mg/m² on days 1 and 8, q 21 days [14]. The response rate was 36% by intent-to-treat analysis, and the median duration of survival was nine months. In this study, the design of which closely matched our own, the 37% rate of grade 3/4 neutropenia was almost identical to that which we observed.

In addition to the phase II experience presented here, the vinorelbine/gemcitabine combination is being assessed in several phase III randomized trials. In the Southern Italy Cooperative Oncology Group study, which accrued 152 elderly or poor PS patients, the overall response rates reported are 22% with vinorelbine plus gemcitabine and 15% with vinorelbine alone [15]. Another ongoing Italian trial is comparing vinorelbine alone versus gemcitabine alone versus the combination, also in elderly patients. A joint Canadian-Italian study is comparing gemcitabine plus vinorelbine versus cisplatin/vinorelbine or cisplatin/gemcitabine. The results of this study, which compares directly platinum and nonplatinum combinations, are eagerly awaited. A U.S. multicenter phase II trial of vinorelbine/gemcitabine versus carboplatin/paclitaxel, which has quality of life as a major endpoint, has also begun.

The combination of vinorelbine with gemcitabine appears to be at least as active as platinum-based combinations and is undoubtedly less toxic. However, until the results of the randomized trials become available, vinorelbine plus gemcitabine is probably most appropriate for use in patients who are elderly or of less than optimal PS.

	REFERENCES

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lilenbaum, R. Search for Related Content PubMed PubMed Citation Articles by Lilenbaum, R.