Phase II Randomized Trial of Vinorelbine and Gemcitabine vs Carboplatin and Paclitaxel in Advanced Non-Small-Cell Lung Cancer

Abstract & Commentary

Synopsis: This study was designed to compare overall toxicity and quality of life between the 2 regimens: vinorelbine and gemcitabine (VG) vs carboplatin and paclitaxel (CP).

Source: Lilenbaum RC, et al. Ann Oncol. 2005;16:97-101.

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 VG or CP. Patients with advanced non-small-cell lung cancer are frequently treated with a platinum-based regimen. Platinum-based doublets have comparable efficacy but slightly different toxicity profiles. Compared to single-agent therapy, platinum-based combinations tend to improve survival without a detriment in quality of life. 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. Among the non-platinum, non-taxane combinations, VG is the most extensively tested. In phase II trials in advanced NSCLC, VG showed efficacy comparable to platinum combinations and a seemingly more favorable toxicity profile. In recent phase III studies, the combination of VG was compared with cisplatin-based doublets. Overall, there was no significant difference in survival, but toxicity was indeed less pronounced.

Comment by Stuart M. Lichtman, MD

The eligibility of the trial included 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. 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, 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. The primary end point of the trial was quality of life (QoL) assessed by the Lung Cancer Symptom Scale (LCSS).1 The LCSS instrument is composed of 2 components: a 9-item patient self-administered questionnaire and a 6-item component completed by health care professionals. Within the 9-item patient questionnaire, 6 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 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 6 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.

A total of 165 patients (82 for VG and 83 for CP) were enrolled from 25 participating centers. 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 of 0-1. The 2 arms were well balanced with regard to demographics and baseline parameters. The median number of cycles was 4 in both arms, with 40% and 41% completing all 6 cycles in arms VG and CP, respectively. The primary reason for discontinuation of treatment was disease progression in both arms. 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% vs 1.2%) (P = 0.017). Two patients in the VG arm had febrile neutropenia. No treatment-related deaths occurred. 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). Slight increases were seen for the mean change from baseline for the VG group for the first 3 cycles, whereas slight decreases were seen in the mean changes from base line for the CP group for the first 4 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. Efficacy parameters were comparable between the 2 treatments. 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 for VG and 4.8 months for CP. Median survival was 7.8 months for VG and 8.6 months for CP. One-year survival rates were 38.4% for the VG arm and 31.9% for the CP arm. None of the efficacy parameters were significantly different between the 2 treatment arms.

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.2 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. The VG combination seemed to produce lower hematologic toxicity, lower neuropathy, and lower alopecia, when indirectly compared to more standard combinations. Therefore, it was chosen to compare this regimen to CP, the most widely used platinum-based doublet. Treatment was well tolerated in both arms. However, there were notable differences in hematologic and non-hematologic toxicity. VG 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 VG. Although some of these toxic effects are likely to impact on the quality of life of individual patients, the LCSS QoL analysis showed no significant difference between the 2 treatments. These results were similar to those reported by Gridelli and colleagues.3 In the accompanying editorial, Dr. Joan Schiller concluded that VG represents a viable option for patients concerned about certain treatment-related toxic effects.4 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.5 This regimen may also be appropriate for the elderly and possibly poor performance status patient.4,7-9

Stuart M. Lichtman, MD, FACP, Associate Professor of Medicine, NYU School of Medicine Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, is on the Editorial Board for Clinical Oncology Alert.

References

1. Hollen PJ, et al. Support Care Cancer. 1994;2: 213-222.

2. Smit EF, et al. J Clin Oncol. 2003;21:3909-3917.

3. Gridelli C, et al. J Clin Oncol. 2003;21:3025-3034.

4. Schiller JH. J Clin Oncol. 2003;21:3009-3010.

5. Pfister DG, et al. J Clin Oncol. 2004;22:330-353.

6. Gridelli C, et al. Ann Oncol. 2004;15:419-426.

7. Gridelli C, et al. J Natl Cancer Inst. 2003;95:362-372.

8. Gridelli C, et al. Eur J Cancer. 1997;33:392-397.