Reply to the letter to the editor ‘Toxicity adjustment in the ESMO-MCBS: a Gestalt approach?’ by Del Paggio

Reply to the letter to the editor ‘Toxicity adjustment in the ESMO-MCBS: a Gestalt approach?’... Toxicity adjustment in the ESMO-MCBS: a diligent process of data interpretation with peer review that is far from ‘Gestalt’ We appreciated Dr Del Paggio’s continuing interest in the ESMO-MCBS [1]. 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] 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]. 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] 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] 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. Funding None declared. Disclosure The authors have declared the following: JB: Director of EORTC. EORTC conducts many studies sponsored by, or otherwise supported by, a large number of companies. EORTC is an independent research organisation. MJP: Board member: Radius. Consultant (honoraria): AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Crescendo Biologics, Periphagen, Huya, Debiopharm, and PharmaMar. Research grants to Institute: AstraZeneca, Lilly, MDS, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, and Servier. Speakers bureau/stock ownership: none. GP: Consulting and advisory services, research support: Amgen, Merck, Astra Zeneca, Roche, BMS, MSD and Lilly. J-YD: Compensated participation to Advisory boards, lecture; Symposia: Amgen, Merck Serono, Bayer, Roche/Genentech, Sanofi, AstraZeneca, Boehringer-Ingelheim, and Sirtex until April 2016. No further compensated participation in industry events from May 2016 onwards. JT: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. CZ: Honoraria: AstraZeneca, Celgene, Roche, Novartis, Bristol Myers Squibb, MSD, Ariad and Newgen. EGEV: Currently conducting research sponsored by the following companies: Amgen, Roche/Genentech, Chugai Pharma, Synthon, AstraZeneca, Radius Health, CytomX Therapeutics and Nordic Nanovector (all payments to the institution). Consulting or advisory role for the following companies: Synthon, Medication and Merck (all payments to the institution). Not a member of any speakers’ bureau. All remaining authors have declared no conflicts of interest. References 1 Del Paggio JC. Toxicity adjustment in the ESMO-MCBS: a gestalt approach? Ann Oncol  2018; 29( 2): 520– 521. 2 Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med  2010; 362( 10): 865– 869. Google Scholar CrossRef Search ADS PubMed  3 Ioannidis JP, Evans SJ, Gøtzsche PC et al.   Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med  2004; 141( 10): 781– 788. Google Scholar CrossRef Search ADS PubMed  4 Herbst RS, Baas P, Kim DW 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( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  5 Cherny NI, Dafni U, Bogaerts J et al.   ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol  2017; 28( 10): 2340– 2366. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Reply to the letter to the editor ‘Toxicity adjustment in the ESMO-MCBS: a Gestalt approach?’ by Del Paggio

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Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
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1569-8041
D.O.I.
10.1093/annonc/mdx649
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Abstract

Toxicity adjustment in the ESMO-MCBS: a diligent process of data interpretation with peer review that is far from ‘Gestalt’ We appreciated Dr Del Paggio’s continuing interest in the ESMO-MCBS [1]. 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] 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]. 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] 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] 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. Funding None declared. Disclosure The authors have declared the following: JB: Director of EORTC. EORTC conducts many studies sponsored by, or otherwise supported by, a large number of companies. EORTC is an independent research organisation. MJP: Board member: Radius. Consultant (honoraria): AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Crescendo Biologics, Periphagen, Huya, Debiopharm, and PharmaMar. Research grants to Institute: AstraZeneca, Lilly, MDS, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, and Servier. Speakers bureau/stock ownership: none. GP: Consulting and advisory services, research support: Amgen, Merck, Astra Zeneca, Roche, BMS, MSD and Lilly. J-YD: Compensated participation to Advisory boards, lecture; Symposia: Amgen, Merck Serono, Bayer, Roche/Genentech, Sanofi, AstraZeneca, Boehringer-Ingelheim, and Sirtex until April 2016. No further compensated participation in industry events from May 2016 onwards. JT: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. CZ: Honoraria: AstraZeneca, Celgene, Roche, Novartis, Bristol Myers Squibb, MSD, Ariad and Newgen. EGEV: Currently conducting research sponsored by the following companies: Amgen, Roche/Genentech, Chugai Pharma, Synthon, AstraZeneca, Radius Health, CytomX Therapeutics and Nordic Nanovector (all payments to the institution). Consulting or advisory role for the following companies: Synthon, Medication and Merck (all payments to the institution). Not a member of any speakers’ bureau. All remaining authors have declared no conflicts of interest. References 1 Del Paggio JC. Toxicity adjustment in the ESMO-MCBS: a gestalt approach? Ann Oncol  2018; 29( 2): 520– 521. 2 Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med  2010; 362( 10): 865– 869. Google Scholar CrossRef Search ADS PubMed  3 Ioannidis JP, Evans SJ, Gøtzsche PC et al.   Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med  2004; 141( 10): 781– 788. Google Scholar CrossRef Search ADS PubMed  4 Herbst RS, Baas P, Kim DW 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( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  5 Cherny NI, Dafni U, Bogaerts J et al.   ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol  2017; 28( 10): 2340– 2366. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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