Phase II randomized trial of vinorelbine and gemcitabine versus carboplatin and paclitaxel in advanced non-small-cell lung cancer

R. C. Lilenbaum1,*, C.-S. Chen2, T. Chidiac3, P. O. Schwarzenberger4, M. Thant5, M. Versola6 and S. R. Lane7

1 The Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; 2 Loma Linda University Medical Center, Loma Linda, CA; 3 Mid-Ohio Oncology & Hematology Inc, Columbus, OH; 4 Stanley S. Scott Cancer Center, New Orleans, LA; 5 Maryland Hematology Oncology Associates, Baltimore MD; 6 GlaxoSmithKline, Research Triangle Park, NC; 7 GlaxoSmithKline, Upper Providence, PA, USA

* Correspondence to: Dr R. C. Lilenbaum, The Mount Sinai Comprehensive Cancer Center, 4306 Alton Road, Miami Beach, FL 33140, USA. Tel: +1-305-535-3310; Fax: +1-305-535-7128; Email: rlilenba{at}salick.com


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The purpose of this study was to compare quality of life and overall toxicity in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine–gemcitabine (VG) or carboplatin–paclitaxel (Taxol) (CP).

Patients and methods: A total of 165 previously untreated patients were randomized to the two regimens. Quality of life was assessed by the Lung Cancer Symptom Scale (LCSS). Overall toxicity and secondary efficacy end points were evaluated by standard WHO criteria.

Results: There was no significant difference in overall quality of life between the two treatments. Neutropenia, thrombocytopenia, peripheral neuropathy, and alopecia, were more common in the CP arm, whereas constipation was more frequent in the VG arm. Response rates were 14.6% in the VG arm and 16.9% in the CP arm. Median survival times were 7.8 and 8.6 months, and 1 year survival rates were 38.4% and 31.9%, respectively.

Conclusions: Patients treated with VG experienced lower toxicity, but overall quality of life was similar in both arms. Efficacy seemed comparable between VG and CP. Our study shows that VG is a viable alternative to platinum-based chemotherapy in patients with advanced NSCLC.

Key words: advanced non-small-cell lung cancer, carboplatin–paclitaxel, vinorelbine–gemcitabine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with advanced non-small-cell lung cancer (NSCLC) are frequently treated with a platinum-based regimen. Platinum-based doublets have comparable efficacy but slightly different toxicity profiles [1Go]. Compared to single-agent therapy, platinum-based combinations tend to improve survival without a detriment in quality of life [2Go, 3Go].

Non-platinum combinations were developed in an attempt to decrease toxic effects associated with the platinum compounds. Non-platinum regimens based on the taxanes, paclitaxel and docetaxel, usually in combination with gemcitabine, have been compared to standard platinum doublets in randomized trials. Overall survival was not statistically different, but toxicity did not seem to be improved with the taxane-based regimens [4Go, 5Go].

Among the non-platinum, non-taxane combinations, vinorelbine–gemcitabine is the most extensively tested. In phase II trials in advanced NSCLC, vinorelbine–gemcitabine showed efficacy comparable to platinum combinations and a seemingly more favorable toxicity profile [6Go]. In recent phase III studies, the combination of vinorelbine–gemcitabine was compared with cisplatin-based doublets [7Go, 8Go]. Overall, there was no significant difference in survival, but toxicity was indeed less pronounced.

We conducted a randomized phase II trial to compare vinorelbine–gemcitabine with carboplatin–paclitaxel. Because the data at the time our trial was designed did not support a significant survival difference, the primary objective was to compare overall toxicity and quality of life between the two regimens.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with a confirmed diagnosis of stage IIIB or IV NSCLC were eligible if they were 18 years old or older, had an ECOG performance status of 0 to 2, and received no prior chemotherapy. Radiotherapy was allowed provided measurable disease was present outside the radiation field and at least 2 weeks had elapsed between the completion of radiation and study enrollment. Patients with brain metastases were eligible if they had no neurological deficit and were off corticosteroids after definitive radiotherapy. Adequate renal, liver and bone marrow function was required. Patients with prior history of malignancy were excluded, except carcinoma in situ of the cervix or breast, and non-melanoma skin cancer. Also excluded were patients with respiratory insufficiency and oxygen dependency, severe cardiac disease, history of hypersensitivity to cremophor, pre-existing grade 3 or worse peripheral neuropathy, according to WCI criteria, and pregnant women. The protocol was approved by the participating Institutional Review Boards. All patients provided written informed consent.

Patients were randomized to receive vinorelbine 25 mg/m2 i.v. plus gemcitabine 1000 mg/m2 i.v., both given on days 1 and 8, every 21 days (VG); or paclitaxel 200 mg/m2 i.v. plus carboplatin dosed to an area under the curve (AUC) of 6 according to the Calvert formula, both administered on day 1 every 21 days (CP). Appropriate pre-medication was given to patients in the CP arm in addition to standard antiemetics in both arms. Treatment was continued until disease progression or up to six cycles. Dose modifications and delays were implemented according to anticipated toxic effects described in the protocol. Patients who received at least 1 cycle of treatment were considered assessable for toxicity.

The primary end point of the trial was quality of life (QoL) assessed by the Lung Cancer Symptom Scale (LCSS) [9Go]. The LCSS instrument is comprised of two components: a nine-item patient self-administered questionnaire and a six-item component completed by health care professionals. Within the nine-item patient questionnaire, six major symptoms are captured (loss of appetite, fatigue, cough, dyspnea, hemoptysis and pain), as well as overall symptomatic distress, functional activity and global QoL; all components were evaluated using a visual analogue scale (VAS) in which scores for lowest to highest symptom intensity or functional disability corresponded to lengths on the VAS ranging from 0 to 100 mm, respectively. The six items in the observer instrument were also scored from 0 to 100, however in increments of 25 points and with scores reversed from the patient-scored instrument (100 = none and 0 = severe). For both the patient and observer scores, a mean was taken across all component scores to provide an overall index. The LCSS was administered at week 1 of cycle 1 and at 3-week intervals regardless of modifications of the treatment schedule.

The sample size was calculated based on the mean LCSS patient score at the Course 4 measurement. It was assumed that 25% of the patient population would have died due to disease by Course 4 and another 25% of the population would have progressed in disease or have been lost to follow-up before the Course 4 measurement. In addition, it was assumed that LCSS scores would be approximately normally distributed and that the between-subject standard deviation would be no more than 17 points. Using all above assumptions and a Bernoulli random variable to generate missings at-random, a simulation was carried out to determine that 80 patients per treatment group would be sufficient to have 80% power to detect a difference of 10 points between treatment arms at the Course 4 measurement, with 5% type I error. The mean of the nine items on the LCSS patient scale and the mean of the six items of the health professional scale were computed and the change from the baseline score analyzed using longitudinal data analysis methods. Comparisons between the two groups were made using a mixed effect analysis of variance with an unstructured variance–covariance matrix.

Tumor response was assessed every two cycles by standard WHO criteria. Overall response rate was defined as complete plus partial responses. Time to progression was defined as the interval from the first day of treatment to the time disease progression was first documented. Survival was defined as the time between the first day of treatment and the date of death. Survival distributions were estimated using Kaplan–Meier methodology and comparisons between the two arms determined by the log-rank test. The Cox proportional hazards regression model was used to estimate hazard ratios. Chi-square tests were used for comparisons of proportions. All statistical comparisons were two-sided.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 165 patients (82 for VG and 83 for CP) were enrolled between July 2000 and October 2001 from 25 participating centers in the USA. Patient characteristics are summarized in Table 1. The median age was 64.4 years (range, 38–86 years). Approximately 82% of the patients had stage IV and 85% had a performance status (PS) of 0–1. The two arms were well balanced with regard to demographics and baseline parameters.


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Table 1. Patient demographics

 
The median number of cycles was four in both arms, with 40% and 41% completing all six cycles in arms VG and CP, respectively. The primary reason for discontinuation of treatment was disease progression in both arms. The most common toxic effects are summarized in Table 2. Hematologic toxicity, specifically grade 3–4 neutropenia, was more common in CP (21.7%) compared to VG (8.5%) (P=0.019). Thrombocytopenia (grades 3–4) was also more common in CP than VG (9.6% versus 1.2%) (P=0.017). Two patients in the VG arm had febrile neutropenia. No treatment-related deaths occurred.


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Table 2. Toxicity results—all patients

 
Non-hematologic toxicity was relatively mild in both arms. There were no major episodes of renal, liver, pulmonary, or cardiac toxicity. Patients on CP had a higher incidence of peripheral neuropathy (all grades): 13.3% versus 4.9% (P=0.06). As shown in Table 2, constipation was significantly more frequent with VG, whereas alopecia was significantly more common with CP. Two patients experienced a hypersensitivity reaction to paclitaxel despite adequate pre-medication.

For the patient-rated evaluations of the LCSS, baseline scores were around 32 mm for both groups (with 0 and 100 mm indicating best and worst QoL, respectively) (Table 3). Slight increases were seen for the mean change from baseline for the VG group for the first three cycles, whereas slight decreases were seen in the mean changes from baseline for the CP group for the first four cycles; none of the differences between groups achieved the 10 mm difference planned. Using the mixed effects longitudinal modeling, no statistical differences were found between the treatment groups.


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Table 3. LCSS results: change from LCSS baseline measurement

 
Efficacy parameters were comparable between the two treatments (Table 4). The overall response rate was 14.6% in VG and 16.9% in CP. In addition, 37.8% and 36.1% of patients in VG and CP, respectively, achieved stabilization of their disease. Median time to progression was 3.9 months (95% CI: 3.0–4.8) for VG and 4.8 months (95% CI: 3.3–6.5) for CP. Median survival was 7.8 months for VG (95% CI: 5.7–12.03) and 8.6 months (95% CI: 7.0–10.6) for CP. One-year survival rates were 38.4% for the VG arm and 31.9% for the CP arm (Figure 1). None of the efficacy parameters were significantly different between the two treatment arms.


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Table 4. Treatment results—all patients

 


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Figure 1. Time to disease progression and time to death for the vinorelbine–gemcitabine and carboplatin–paclitaxel treatment arms.

 
The results in elderly patients, defined as patients 70 years or older, were very similar to the overall population with respect to progression-free survival and overall survival. Elderly patients in the VG and CP arms had a median time to progression of 4.4 and 5.0 months, while median survival was 7.0 and 8.5 months, respectively. PS 2 patients have a significantly inferior outcome. For the PS 2 patients within the VG and CP arms, respectively, median time to progression was 3.1 and 1.5 months, while median survival was 3.1 and 2.9 months. Cox proportional hazard models were created to investigate the simultaneous influence of treatment, stratification factors (stage and PS) and other baseline covariates (sex and age). For overall survival, treatment was not significant, while both PS and stage were statistically significant (P< 0.001 and P=0.027, respectively).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Chemotherapy for advanced NSCLC patients has relied mainly upon platinum-based doublets, which yield predictable response, toxicity and survival outcomes. However, specific cumulative toxic effects can be substantial, including thrombocytopenia and peripheral neuropathy. Total alopecia, an inevitable consequence of the majority of platinum-based doublets, can also be troubling to patients. Therefore, the pursuit of an equally active regimen, with a more favorable toxicity profile, is quite desirable.

The development of non-platinum regimens was based on the premise of equivalent efficacy with lower overall toxicity. The non-platinum, taxane-based regimens, showed comparable survival as standard platinum-based doublets. In the study by Smit and colleagues, progression-free survival was slightly inferior with paclitaxel–gemcitabine compared to the platinum regimens, but no significant difference in overall survival was noted [5Go]. However, more importantly, overall toxicity was not reduced significantly with the non-platinum regimen. While paclitaxel or docetaxel, in combination with gemcitabine, can be considered a reasonable option for first-line therapy for advanced NSCLC patients, the available data do not support a significant advantage in toxicity over platinum-based regimens.

Based on a large body of phase II data, both American and European, the vinorelbine–gemcitabine combination seemed to produce lower hematologic toxicity, lower neuropathy, and lower alopecia, when indirectly compared to more standard combinations. Therefore, we chose to compare this regimen to paclitaxel–carboplatin, the most widely used platinum-based doublet in the USA at the time the study was conceived. Overall toxicity and quality of life were the primary objectives. The study was not powered to detect differences in efficacy.

Treatment was well tolerated in both arms. However, there were notable differences in hematologic and non-hematologic toxicity. Vinorelbine–gemcitabine resulted in a lower incidence of severe neutropenia and all grades of thrombocytopenia. In addition, peripheral neuropathy and alopecia were reduced in patients treated with vinorelbine–gemcitabine. Although some of these toxic effects are likely to impact on the quality of life of individual patients, the LCSS quality of life analysis showed no significant difference between the two treatments. There were transient changes in scores in both the patient and the health professional components, but only of minor magnitude.

Overall efficacy was comparable between the two regimens. There was a trend towards inferior progression-free and median survival in the vinorelbine–gemcitabine arm, but the differences were numerically small and the study was not adequately powered to detect survival differences. With respect to the subset analysis, our study adds to other reports that elderly patients with advanced NSCLC and a good PS benefit from chemotherapy to the same extent as younger patients. Although our numbers were small, patients with PS 2 fared significantly worse than PS 0–1 patients. No difference in efficacy or toxicity was observed between the two regimens in this particular subset.

Our results are analogous to the phase III trial recently published by Gridelli and colleagues [7Go]. The Italian investigators compared vinorelbine–gemcitabine, in the same doses and scheduled utilized as in our study, to cisplatin plus either vinorelbine or gemcitabine. Progression-free survival was inferior in the non-platinum arm, but overall survival was not significantly different. Toxicity was reduced in the vinorelbine–gemcitabine arm, but the quality of life analysis, the primary end point of the study, showed no significant differences between the two treatments when measured at 6 weeks. In the accompanying editorial, Dr Joan Schiller concluded that vinorelbine–gemcitabine represents a viable option for patients concerned about certain treatment-related toxic effects [10Go]. Indeed, the 2003 American Society of Clinical Oncology guidelines for the treatment of NSCLC consider non-platinum regimens an appropriate alternative to platinum-based chemotherapy [11Go].

In summary, our study confirms that vinorelbine and gemcitabine is an active and well-tolerated regimen for the treatment of advanced NSCLC. Treatment can be delivered rapidly in the outpatient setting and without the need for pre-medication. Efficacy was comparable to carboplatin–paclitaxel and toxicity was slightly more favorable. We reinforce the recommendation that vinorelbine–gemcitabine is an attractive alternative to platinum-based therapy.


    Acknowledgements
 
Thanks to Patricia S. Graham for her invaluable assistance in the preparation of this manuscript.

Received for publication April 1, 2004. Revision received July 29, 2004. Accepted for publication August 2, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002; 346: 92–98.[Abstract/Free Full Text]

2. Lilenbaum R, Herndon J, List M et al. Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: A randomized trial of efficacy, quality of life, and cost-effectiveness. Proc Am Soc Clin Oncol 2002; 21: A-2.

3. Sederholm S. Gemcitabine (G) compared with gemcitabine plus carboplatin (GC) in advanced non-small cell lung cancer (NSCLC): A Phase III study by the Swedish Lung Cancer Study Group (SLUSG). Proc Am Soc Clin Oncol 2002; 21: 291a (Abstr).

4. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and non-platinum based chemotherapy in advanced non-small cell lung cancer: A randomized multicenter trial. Lancet 2001; 357: 1478–1484.[CrossRef][ISI][Medline]

5. Smit EF, Van Meerbeeck JP, Lianes P et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small cell lung cancer: A Phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol 2003; 21: 3909–3917.[Abstract/Free Full Text]

6. Lilenbaum RC, Herbst RS. Vinorelbine and gemcitabine combinations in advanced non-small cell lung cancer. Clin Lung Cancer 2000; 2: 123–127.[Medline]

7. Gridelli C, Gallo C, Shepherd FA et al. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small cell lung cancer: A Phase III trial of the Italian GEMVIN investigators and the National Cancer Institute of Canada Clinical trials group. J Clin Oncol 2003; 21: 3025–3034.[Abstract/Free Full Text]

8. Alberola A, Camps C, Provencio M et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small cell lung cancer: A Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003; 3207–3213.

9. Hollen PJ, Gralla RJ, Kris MG. Quality of life during clinical trials: conceptual model for the Lung Cancer Symptom Scale (LCSS). Support Care Cancer 1994; 2: 213–222.[ISI][Medline]

10. Schiller JH. Platin or no platin? That is the question. J Clin Oncol 2003; 21: 3009–3010 [Editorial].[Free Full Text]

11. Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: Update 2003. J Clin Oncol 2004; 22: 254–261.[Abstract/Free Full Text]





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