Addressing the quality of the ESMO-MCBS
Authors: J.C. Del Paggio
Journal: Annals of Oncology (2017)

The utility of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)—one of a variety of value frameworks that seeks to quantify the clinical benefit of anticancer therapies [1.Cherny N.I. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar]—is currently under evaluation by the oncology community. Having worked with the ESMO-MCBS as a means of understanding the modern landscape of clinical benefit in contemporary oncological randomized-controlled trials (RCTs) [2.Del Paggio J.C. et al.Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit?.Ann Oncol. 2017; 28: 157-162Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar], one of the unique and important aspects of the scale is its emphasis on quality of life (QOL) data, presented in the context of each clinical trial it seeks to evaluate. For decades now, QOL endpoints have been considered a ‘fundamental task’ of all oncological RCTs [3.Roila F. Cortesi E. Quality of life as a primary end point in oncology.Ann Oncol. 2001; 12: S3-S6Abstract Full Text PDF PubMed Google Scholar], given that the sine qua non of anticancer therapies is to allow patients to live longer and/or live better. In this vein, ESMO-MCBS makes an effort to address the ‘living better’ portion of clinical benefit by explicitly adjusting grades up or down, which may translate into a therapy meeting arbitrary benefit thresholds, or possibly failing to do so. QOL adjustments, however, are of focus in ESMO-MCBS in studies evaluating progression-free survival (PFS) [1.Cherny N.I. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar]. Adjustments include upgrading one level if patients on the experimental therapy have improved QOL (although the framework is not explicit as to how this data should be presented); grades are downgraded one level if there is a statistically significant improvement in PFS by the experimental therapy, but QOL analysis shows no improvement over the control therapy. This significant shifting in the level of benefit is commendable, as it differs from the relatively insubstantial QOL adjustments among other value frameworks. The main issue with this approach becomes apparent when QOL data are not presented directly in the RCT being evaluated. As a result, these RCTs receive a ‘free pass’ with respect to QOL adjustment, which would have otherwise been to their detriment. To illustrate with an example, when lapatinib was added to letrozole for first-line hormone receptor-positive metastatic breast cancer, PFS improvement was shown to be 5.2 months [HR 0.71; 95% CI, 0.53–0.96] [4.Johnston S. et al.Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.J Clin Oncol. 2009; 27: 5538-5546Crossref PubMed Scopus (883) Google Scholar]; the ESMO-MCBS grade for this RCT is 3. This particular trial did not disclose any QOL data, despite no difference in QOL between experimental and control groups subsequently being shown [5.Sherrill B. et al.Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib.Oncologist. 2010; 15: 944-953Crossref PubMed Scopus (22) Google Scholar]. Had this been noted in the original RCT, the grade would have been reduced to 2. Although both grades would fail to meet arbitrary benefit thresholds by ESMO-MCBS criteria [1.Cherny N.I. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar], one can appreciate how grades may be misconstrued if the grader does not actively seek additional data to ‘complete’ the grade. Of course, grades can change as data matures [1.Cherny N.I. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar]; nevertheless, the surrogate endpoints evaluated using ESMO-MCBS are often the endpoints used as the basis for drug approval, despite a lack of firm establishment for such surrogacy [6.Saad E.D. et al.Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.Ann Oncol. 2010; 21: 7-12Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Thus, a failure to present QOL data paradoxically results in a higher ESMO-MCBS grade for some trials. Future iterations of the ESMO-MCBS should, therefore, consider addressing this issue explicitly by incorporating adjustments to trials that fail to address the effect of the experimental therapy on patient QOL. None declared.