Reply to the letter to the editor ‘Toxicity adjustment in the ESMO-MCBS: a Gestalt approach?’ by Del Paggio
Authors: N.I. Cherny, U. Dafni, J. Bogaerts, N.J. Latino, G. Pentheroudakis, J.-Y. Douillard, J. Tabernero, C. Zielinski, M.J. Piccart, E.G.E. de Vries
Journal: Annals of Oncology (2017)

We appreciated Dr Del Paggio’s continuing interest in the ESMO-MCBS [1.Del Paggio J.C. Toxicity adjustment in the ESMO-MCBS: a gestalt approach?.Ann Oncol. 2018; 29: 520-521Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. In Form 2a of the ESMO-MCBS, which scales studies with evidence of benefit in overall survival, the ESMO-MCBS provides a 1 point bonus if the newer treatment is associated with fewer adverse events that undermine daily well-being. We acknowledge the inconsistency in the language used in Form 2a whereby statistical significance is referred to in the trigger question regarding toxicity (‘Are there statistically significantly less grade 3–4 toxicities impacting on daily well-being?’) but not in the adjustment criteria (‘Upgrade 1 level if improved quality of life and/or less grade 3–4 toxicities impacting daily well-being are shown’). It is understandable that this may contribute to confusion in applying the form. We agree with Dr Del Paggio that the reporting of toxicity data in oncology studies is often suboptimal [2.Basch E. The missing voice of patients in drug-safety reporting.N Engl J Med. 2010; 362: 865-869Crossref PubMed Scopus (426) Google Scholar] and, when presented, it is most commonly described using simple descriptive statistics without confidence intervals or evaluation of statistical significance. Indeed, these latter details are not required by the CONSORT extension relating to standards for the reporting on harms in RCTs [3.Ioannidis J.P. Evans S.J. Gøtzsche P.C. et al.Better reporting of harms in randomized trials: an extension of the CONSORT statement.Ann Intern Med. 2004; 141: 781-788Crossref PubMed Scopus (1099) Google Scholar]. These limitations in reporting do not diminish the imperative to evaluate the relative burden of adverse events, as best as is reasonably possible, based on the available data. The example presented by Dr Del Paggio illustrates this well. The Keynote 10 study of pembrolizumab 2 mg/kg or 10 mg/kg body weight versus docetaxel as second-line therapy for patients with non-small-cell lung cancer [4.Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4543) Google Scholar] reported that the incidence of grade 3–5 adverse advents for these three groups were 13%, 16% and 35%, respectively. Additionally, the rates of permanent discontinuation of study drug because of toxicity were 4%–5% for the two dosing schedules of pembrolizumab versus 10% for docetaxel. Neither confidence intervals are presented nor are there any data regarding statistical significance. Nevertheless, it is worth noting that if one were to conduct significance testing, the incidence of grade 3–5 adverse events is in fact statistically significantly different between the pembrolizumab 2 mg/kg or 10 mg/kg arms and the docetaxel arm (Fisher’s exact test P < 0.001 for both). Even when subtracting, in the docetaxel arm, the 13% caused by neutropenia and alopecia, the remaining difference in favour of the study agent pembrolizumab (9% or 6%) is again statistically significant (P = 0.013 and 0.046, respectively). All ESMO published ESMO-MCBS scores are generated by either the ESMO-MCBS Working Group or the ESMO Guidelines Committee and are peer reviewed by both and also by the relevant faculty according to a standard operating procedure. The peer review process focuses both on accuracy of data extraction and reasonableness of the conclusions. In this example, all reviewers concurred that there was adequate evidence to invoke this bonus. This decision is derived from a diligent process of data interpretation with a review process, and it is inaccurate to characterise it as a process of ‘Gestalt’ or superficial impression. Feedback, such as that provided by Dr Del Paggio, and peer review for reasonableness help provide the substrate to identify potential shortcomings for future revisions. The current paper [5.Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-Magnitude of Clinical Benefit Scale Version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar] already acknowledges the need for refinement in our approach to toxicity scoring and states that this will be addressed in the next revision of the scale. None declared.