Topotecan versus paclitaxel in second-line therapy: a lost opportunity for quality-of-life evaluation?
Authors: G. Apolone, A. Buda
Journal: Annals of Oncology (2004)

ten Bokkel Huinink et al., on behalf of the International Topotecan Group, have recently published a paper on the long-term outcomes of 226 patients with advanced epithelial ovarian cancer who failed one prior platinum-based regimen and were enrolled in a multicentre randomised phase III study comparing topotecan versus paclitaxel as second-line therapy [1.ten Bokkel Huinink W. Lane S.R. Ross G.A. Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovrian cancer.Ann Oncol. 2004; 15: 100-103Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. This study is an update of a study whose main results were previously published in 1997 and 2001 [2.ten Bokkel Huinink W. Gore M. Carmichael J. et al.Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.J Clin Oncol. 1997; 15: 2183-2193Crossref PubMed Scopus (654) Google Scholar, 3.Gore M. ten Bokkel Huinink W. Carmichael J. et al.Clinical evidence for topotecan-paclitaxel non-cross-resistance in ovarian cancer.J Clin Oncol. 2001; 19: 1893-1900Crossref PubMed Scopus (90) Google Scholar]. In the first paper, activity (response rate, duration of response, time to progression), safety (quantitative and qualitative data by common toxicity criteria) and efficacy (survival) appeared to be statistically equivalent (i.e. no significant statistical differences were observed at the usual 0.05 P value level) [2.ten Bokkel Huinink W. Gore M. Carmichael J. et al.Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.J Clin Oncol. 1997; 15: 2183-2193Crossref PubMed Scopus (654) Google Scholar]. The second paper reported, together with an analysis of the non-cross resistance of the two drugs, an update of (progression-free and overall) survival that confirmed the substantial comparability of topotecan when compared with paclitaxel [3.Gore M. ten Bokkel Huinink W. Carmichael J. et al.Clinical evidence for topotecan-paclitaxel non-cross-resistance in ovarian cancer.J Clin Oncol. 2001; 19: 1893-1900Crossref PubMed Scopus (90) Google Scholar]. In the present paper, a further update of survival is presented using follow-up data that have now been collected for more than 4 years [1.ten Bokkel Huinink W. Lane S.R. Ross G.A. Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovrian cancer.Ann Oncol. 2004; 15: 100-103Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. In addition, quality-of-life data are also reported. Overall, topotecan and paclitaxel continue to show comparable efficacy as the differences observed in terms of median survival between the two arms (63 versus 53 weeks) did not reach statistical significance (P=0.44). As to the quality of life, ten Bokkel Huinink and colleagues reported that the findings from the EORTC QOL-C30 questionnaire were ‘similar’ for the two groups, although no quantitative data were shown. These findings, together with supportive data regarding haematological and non-haematological toxicity, are the basis of their conclusions on the topotecan value: ‘...the gain in survival was not achieved at the expense of quality of life, as measured by the EORTC QOL-C30 questionnaire, which showed quality of life to be consistent throughout therapy’ [1.ten Bokkel Huinink W. Lane S.R. Ross G.A. Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovrian cancer.Ann Oncol. 2004; 15: 100-103Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. We believe that this statement is an over-interpretation of the evidence shown in the paper and, according to our understanding, it is not actually based on solid findings. As a matter of fact, what ten Bokkel Huinink et al. have presented here is not a formal quality-of-life assessment but an evaluation of patient-reported outcomes based on simple, although standardised, cancer-generic symptom scores, the less reliable section of the EORTC QOL-C30 questionnaire [4.Aaronson N. Ahmedzay S. Bergman B. et al.The European Organisation for Research and Treatment of cancer QLQ-30. A quality of life instrument for use in international clinical trials in oncology.J Natl Cancer Inst. 1993; 85: 365-376Crossref PubMed Scopus (10334) Google Scholar]. The fact that changes in symptom scores from baseline to the end of best response in the evaluable patients (75 and 85% of patients in the two arms) were not statistically different does not mean that a difference in quality of life does not exist, but simply means that with this approach and with these measures, a statistically significant difference was not observed. The interpretation of ten Bokkel Huinink et al. (i.e. no statistically significant differences in self-reported symptoms = no differences in quality of life = gain in survival for topotecan not hampered by quality-of-life worsening) is just an opinion that is not supported by data, as alternative explanations are possible. To support our point, we would like to raise three issues. The probability that a difference will be found when there is one relies on several factors that usually are prospectively taken into account with the study design, including the size of the sample (that is estimated a priori), and the measurement precision: in general, with larger differences (effect size) and better measures (reliability), differences will be detected more easily. In the present paper, with a sample size estimated to detect a difference between groups in terms of response rate or survival, it is not clear (because it is not explicitly reported or discussed) what was the power of the study to detect differences in self-reported symptoms using measures that have a relatively poor reliability [4.Aaronson N. Ahmedzay S. Bergman B. et al.The European Organisation for Research and Treatment of cancer QLQ-30. A quality of life instrument for use in international clinical trials in oncology.J Natl Cancer Inst. 1993; 85: 365-376Crossref PubMed Scopus (10334) Google Scholar]. In addition, information about how quality-of-life assessment has been carried out has not been given either in the previous reports or in the present paper, e.g. hypothesis testing, rationale to use given measures, the mode and timing of the questionnaire administration, handling of missing data, etc. Finally, it is quite unusual that the measures actually used were those from the EORTC QOL-C30 questionnaire pertaining to the symptoms and not the more valid and reliable multi-item scales exploring more sensitive and relevant domains that have, a priori, a higher probability to detect a difference in quality of life, if present. Quality-of-life assessment is a complex task, either from the conceptual or pragmatic point of view and, although there are recommendations and standards published to assure quality in this field [5.Chassany O. Sagnier P. Marquis P. et al.Patient-reported outcomes: the examples of health-quality of life—a European guidance document for the improved integration of health related quality of life assessment in the drug regulatory process.Drug Inf J. 2002; 36: 209-238Crossref Scopus (306) Google Scholar], previous reviews on randomised controlled trials including quality-of-life evaluation in different cancer sites have shown, overall, a number of methodological shortcomings [6.Efficace F. Bottomley A. Osoba D. et al.Beyond the development of health-related quality-of-life (HRQOL) measures: a checklist for evaluating HRQOL outcomes in cancer clinical trials—does HRQOL evaluation in prostate cancer research inform clinical decision making?.J Clin Oncol. 2003; 21: 3502-3511Crossref PubMed Scopus (201) Google Scholar] that hamper the validity and interpretation of results. This setting was indeed a very good opportunity to check whether, in the presence of equivalence of activity and efficacy and with a different pattern in toxicity, quality-of-life evaluation would give additional and valuable information for clinical decision making. The paper by ten Bokkel Huinink et al. is another example of a lost opportunity to corroborate good quality-of-life data with opinions not fully supported by traditional clinical outcomes.