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Originally published as JCO Early Release 10.1200/JCO.2003.05.079 on July 1 2003 © 2003 American Society for Clinical Oncology
Quality Trials and Quality of Life in Non–Small-Cell Lung Cancer
1 Department of Medical Oncology, Guy’s and St Thomas’ Hospital, London, UK IN THIS issue of the Journal of Clinical Oncology, Fossella et al1 report the results of a phase III clinical study in which 1,218 patients with advanced non–small-cell lung cancer (NSCLC) were randomly assigned to one of three treatments. The control arm of the trial was a combination of cisplatin and vinorelbine (cisplatin 100 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1, 8, 15, and 22 every 4 weeks), which was compared with either cisplatin and docetaxel (cisplatin 75 mg/m2 and docetaxel 75 mg/m2 every 21 days) or carboplatin and docetaxel (carboplatin area under the time-concentration curve 6, and docetaxel 75 mg/m2 every 21 days). The trial was well balanced in terms of tumor type, extent of disease, weight loss, sex, and age. There were no statistically significant differences in time to disease progression among the three different regimens. Although the survival estimates favored docetaxel and cisplatin over vinorelbine and cisplatin, with a longer median survival (11.3 v 10.1 months) and 2-year survival rate (21% v 14%), these differences did not reach statistical significance. The overall response rate (by intention-to-treat analysis) was higher for docetaxel and cisplatin compared with vinorelbine and cisplatin (31.6% v 24.5%; P = .029). Hematologic toxicity was similar in all three arms. However, importantly, the authors also report in some detail the quality of life (QoL) analysis. In evaluating a cancer treatment, two types of effects should be considered: cancer outcomes, such as response assessment and response duration, which are markers of drug activity; and patient outcome measures, such as survival and QoL, which are markers of drug efficacy.2 Clearly, a new treatment that significantly increases survival compared with previously available therapy should become the new standard. Equally, consideration should be given to changing to a newer regimen if there are consistent benefits in tolerability and QoL. QoL assessment is, therefore, an important part of many of the newer trial protocols, but is often given less weight when a decision is made about which treatment is better, compared with changes in survival. The disease-specific Lung Cancer Symptoms Scale (LCSS)3 and the global QoL scale, EuroQol,4 were used in the study by Fossella et al.1 Patients treated with either of the docetaxel-containing regimens reported improved QoL, whereas the QoL for those treated with cisplatin and vinorelbine generally decreased. In longitudinal analysis, the differences compared with cisplatin and vinorelbine were significantly better for both scales in patients treated with docetaxel and carboplatin (LCSS, P = .016; EuroQol, P < .001), and were significantly better for EuroQol in those treated with cisplatin and docetaxel (P = .016). In any assessment of QoL, patient compliance and data collection are the most serious problems in the subsequent analysis. Missing data can result from administrative difficulties. These losses will reduce the statistical power of the analysis, but can be reduced by following published guidelines.5 Missing data that result from the patient’s own QoL are necessarily more difficult to prevent. It has been demonstrated that patients with a deteriorating QoL are less likely to be compliant at future evaluations.6 In addition, it has been demonstrated that the baseline QoL estimates are worse for those patients who subsequently complete a few questionnaires as compared with those who complete all questionnaires until the end of treatment.7 In these circumstances, the drop-out process can itself be informative. However, most statistical analyses of QoL date assume that the missing data occur at random, and therefore, bias can be introduced into subsequent comparisons. In the study of Fossella et al,1 although approximately two thirds of patients completed the questionnaires at baseline, the numbers of patients at the subsequent time points are not reported. In addition, the duration of each treatment cycle varied among the three regimens, making the data, as presented graphically in the article, difficult to interpret. For example, at week 6, patients receiving the docetaxel-containing regimens would have completed two cycles of therapy, whereas patients receiving cisplatin and vinorelbine would have been at the midpoint of their second cycle of therapy. These time points for QoL assessment are therefore not necessarily comparable when related to timing of therapy. Additional detail and clarification in these matters would strengthen the article. However, the reported QoL differences are supported by the finding that patients receiving docetaxel-based regimens experienced significantly less weight loss and significantly less decline in their performance status compared with those receiving cisplatin and vinorelbine. Cytotoxic chemotherapy can have various effects on patient QoL. By reducing tumor burden, treatment may reduce tumor-related symptoms and thereby improve QoL. One should bear in mind that patients receiving the docetaxel-containing regimens were given 48 mg of dexamethasone every 3 weeks, and this may have contributed to relief of cancer-related symptoms. In contrast, treatment-related toxicity can have a negative influence on patient QoL. Although the dose-intensity of cisplatin was the same in the cisplatin plus vinorelbine combination and the cisplatin plus docetaxel combination, because the former was a 4-week cycle, patients received cisplatin at a dose of 100 mg/m2. In addition, patients were required to attend for weekly vinorelbine injections. In the study of Fossella et al,1 the cisplatin and vinorelbine combination was associated with more treatment-related toxicity than the docetaxel-containing regimens, with significantly more grade 3 to 4 nausea, vomiting, and anemia. These excess toxicities have been observed in several other clinical trials comparing cisplatin and vinorelbine with different platinum-based combinations.8,9 In these studies, no QoL differences were observed between cisplatin and vinorelbine compared with carboplatin and paclitaxel,8 or compared with gemcitabine and cisplatin or carboplatin and paclitaxel.8 Nevertheless, the toxicities of cisplatin and vinorelbine led one group to suggest that the "potential limitations may undermine the usefulness of vinorelbine and cisplatin as a reference arm for future trials."9 The findings from the current study support this view. So, where has all this information taken us? This study confirms the efficacy of docetaxel-containing regimens and demonstrates QoL benefits as compared with cisplatin and vinorelbine, a widely used regimen in the treatment of patients with advanced NSCLC.10 Other novel combinations of cytotoxic agents have also been reported to have significant QoL benefits compared with previous standard regimens. In a recent London Lung Group trial reported in an abstract at the American Society of Clinical Oncology meeting in 2002 (Orlando, FL, May 18–21), carboplatin plus gemcitabine was compared with the previous standard treatment of mitomycin, ifosfamide, and cisplatin.11 In this trial, both survival and QoL were improved with the newer regimen. The reduced toxicities but increased QoL benefits from the newer combination therapies containing docetaxel or gemcitabine certainly offer advantages to patients with NSCLC, many of whom are not robust at the time treatment begins. These benefits, as well as improvements in survival and differences in cost, should be considered when a new gold-standard treatment is chosen. Therefore, these data indicate that cisplatin and vinorelbine should no longer be considered a standard first-line therapy in the management of advanced NSCLC. REFERENCES
1. Fosella F, Pereira JR, von Pawel J: Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non–small-cell lung cancer. J Clin Oncol 21: 3016–3024, 2003
2. American Society of Clinical Oncology: Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. J Clin Oncol 14:671–679, 1996 3. Hollen PJ, Gralla RJ, Kris MG, et al: Quality of life assessment in individuals with lung cancer: Testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer 29A:S51–S58, 1993 4. Brooks R: EuroQol: The current state of play. Health Policy 37:53–72, 1996[CrossRef][Medline] 5. Aaronson NK: Assessing the quality of life of patients in cancer clinical trials: Common problems and common sense solutions. Eur J Cancer 28A:1304–1307, 1992[Medline] 6. Herndon JE II, Fleishman S, Kosty MP, et al: A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials 18:286–300, 1997[CrossRef][Medline]
7. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer: The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91:66–72, 1999
8. Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19:3210–3218, 2001
9. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non–small-cell lung cancer. J Clin Oncol 20:4285–4291, 2002
10. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98, 2002 11. Rudd RM, Gower NH, James LH, et al: Phase III randomized comparison of gemcitabine and carboplatin (GC) with mitomycin, ifosfamide and cisplatin (MIP) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1164)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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