Concern on quality-of-life analysis in the OPTIMAL study

Abstract

We read with interest the paper by Chen et al. investigating the quality of life (QoL) in a planned secondary analysis of the ‘OPTIMAL’ study, a randomized trial comparing erlotinib treatment with chemotherapy by gemcitabine/carboplatin (G/C) in patients harboring sensitizing EGFR mutations [1.Chen G. Feng J. Zhou C. et al.Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC).Ann Oncol. 2013; 24: 1615-1622Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. The authors used the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, a well-established validated instrument to measure the QoL [2.Webster K. Cella D. Yost K. The functional assessment of chronic illness therapy (FACIT) measurement system: properties, applications and interpretation.Health Qual Life Outcomes. 2003; 1: 79Crossref PubMed Scopus (953) Google Scholar]. It consists of a series of questions resulting in a score ranging from 0 to 144. In the methods section of their paper, Chen et al. stated that an improvement of six points in the FACT-L total score can be considered clinically relevant, a threshold based on the methodology used in previous studies [3.Mok T.S. Wu Y.-L. Thongprasert S. et al.Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7038) Google Scholar, 4.Cella D. Eton D.T. Fairclough D.L. et al.What is a clinically meaningful change on the functional assessment of cancer therapy-lung (FACT-L) questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592.J Clin Epidemiol. 2002; 55: 285-295Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar]. Chen et al. state that each patient who showed at least once an elevation of six points (or higher) in its FACT-L score during the study (at any cycle) was considered as clinically improved, which can introduce bias since the number of cycles is different for the two arms. Indeed, supplementary Table S1 showed that there is a great imbalance between the two arms regarding the number of patients who completed the QoL questionnaires throughout the duration of the study. Patients in G/C arm completed their questionnaires up to cycle 4 (the usual cycle number for chemotherapy), whereas >50% of the patients in the erlotinib arm provided a QoL assessment up to cycle 12 and a substantial number (30%) up to cycle 20. Indeed, even if there was no difference in QoL between the two treatment groups, patients in the erlotinib arm would have had a much higher probability to demonstrate at least once an improvement of six points or more because of their prolonged assessment period. For example, if the probability for at least one individual improvement within four cycles would be 31.5% in both the treatment arms (example data from Figure 5, total FACT-L, G/C arm), the corresponding probability for a 12-cycle assessment period would be 1 - ([1–0.315]1/4)12 = 67.9%. Thus, the corresponding odds ratio would be (0.679/1–0.679)/(0.315/1–0.315) = 4.6, suggesting that patients in the erlotinib group would appear to have a 4.6 times greater chance to fulfill the success criterion when compared with those from the G/C group, when in fact they have the same probability (31.5% in four cycles equally for both the treatment arms). Therefore—and although fewer data in G/C arm could also be attributed to more disease progression rate or more severe toxic effects compared with the erlotinib arm—the reported results of clinically relevant improvements in QoL scores and symptoms are seriously biased from this imbalance in the number of cycles. A proper data analysis would need to take into account the number of cycles. Thus, for example, the number of clinical improvements per cycle could be considered as an appropriate alternative outcome measure. As the results stand, the authors’ conclusion that erlotinib improves the quality of life compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer is questionable. For the work under consideration, SC declare having received consultancy fees from Roche; fees for educational supports from Chugai and Astra Zeneca; research grants paid to my institution from Roche, Astra Zeneca, Chugai, Pfizer, Boehringer Ingelheim and fees for attending a meeting from Roche and Astra Zeneca. TS, SS: none to declare.