Toxicity adjustment in the ESMO-MCBS: a gestalt approach?

Toxicity adjustment in the ESMO-MCBS: a gestalt approach? Version 1.1 of the ESMO Meaningful Clinical Benefit Scale (ESMO-MCBS) has recently been released [1], addressing shortcomings of the original framework with the same rigorous processes that established Version 1.0 as a seminal step forward in objectifying the clinical benefit of anticancer therapies. My research team has been particularly interested in using the framework to benchmark modern oncological treatment regimens [2], as well as to compare ESMO-MCBS outputs with those of the American Society of Clinical Oncology Value Framework: a framework with similar components, albeit differing goals [3]. In doing so, it has become clear that toxicity grade adjustments in the ESMO-MCBS can be ambiguous. This may be due to the apparent differences in toxicity penalties within each grading form (based on differing primary end points)[1]: for overall survival (OS), an upgrade occurs if there are ‘statistically significantly less grade 3–4 toxicities impacting on daily well-being’ for the experimental arm, with little guidance other than a clarification that these toxicities should not include alopecia or myelosuppressive toxicities; for progression-free survival (PFS), additional downgrading can occur, but only with pre-specified toxicities (e.g. hospitalization for toxicity >10%), again with emphasis on statistically significant differences; finally, for non-inferiority and toxicity or quality of life (QoL) studies, there is simply the phrase ‘reduced toxicity’. With the new addition of “single - arm studies” [1], there is a downgrade for ≥30% grade 3-4 toxicities, again with the aforementioned stipulations. A trial found in the new version of the framework will be used as an example to highlight potential confusion around toxicity grading: KEYNOTE-010 [3], which received an upgrade in its OS grade due to reduced toxicity in the pembrolizumab arm compared with docetaxel. First, it should be noted that there are no P-values denoting statistically significant differences in toxicities between these two groups. Second, if one ignores the alopecia/hematological toxicities and focuses only on grade 3–4 toxicities observed (i.e. one strictly follows the grading form), the difference in grade 3–4 toxicities of commonly listed side-effects is only a few percent. Is this clinically meaningful? Can the pre-specified toxicities in the PFS grading form be used as a guide to grade ‘meaningful’ OS toxicities? Should non-statistically significant differences be graded in the first place? In KEYNOTE-010, there is a clear decrease in overall toxicities as a whole in the experimental arms (13%–16% versus 35%) [4]; however, this approach fails to tease out toxicity events that may actually impact patient ‘daily well-being’ (as stated by the framework) [1]. ‘Gestalt’ is likely not the mechanism the working group had hoped for its graders to use, since it appears this would revert back to a way of interpreting benefit that was the impetus behind developing these frameworks in the first place. The importance of proper toxicity analysis is emphasized by the underreporting, and oft times poor reporting, of toxicity data [5, 6], both of which can adversely affect treatment decisions. Thus, objectifying meaningful clinical benefit—efficacy with both harm and QoL considered—remains a challenge. The oncology community awaits further revisions of the ESMO-MCBS, as Dr Cherny and his group continue to finesse their important work. Funding None declared. Disclosure The author has declared no conflicts of interest. References 1 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  2 Del Paggio JC, Azariah B, Sullivan R et al.   Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? Ann Oncol  2016; 28( 1): 157– 162. 3 Del Paggio JC, Sullivan R, Schrag D et al.   Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. Lancet Oncology  2017; 18: 887– 894. Google Scholar CrossRef Search ADS PubMed  4 Herbst RS, 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( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  5 Zhang S, Liang F, Tannock I. Use and misuse of common terminology criteria for adverse events in cancer clinical trials. BMC Cancer  2016; 16: 392. Google Scholar CrossRef Search ADS PubMed  6 Vera-Badillo FE, Napoleone M, Krzyzanowska MK et al.   Bias in reporting of randomised clinical trials in oncology. Eur J Cancer  2016; 61: 29– 35. 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

Toxicity adjustment in the ESMO-MCBS: a gestalt approach?

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Publisher
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
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx540
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Abstract

Version 1.1 of the ESMO Meaningful Clinical Benefit Scale (ESMO-MCBS) has recently been released [1], addressing shortcomings of the original framework with the same rigorous processes that established Version 1.0 as a seminal step forward in objectifying the clinical benefit of anticancer therapies. My research team has been particularly interested in using the framework to benchmark modern oncological treatment regimens [2], as well as to compare ESMO-MCBS outputs with those of the American Society of Clinical Oncology Value Framework: a framework with similar components, albeit differing goals [3]. In doing so, it has become clear that toxicity grade adjustments in the ESMO-MCBS can be ambiguous. This may be due to the apparent differences in toxicity penalties within each grading form (based on differing primary end points)[1]: for overall survival (OS), an upgrade occurs if there are ‘statistically significantly less grade 3–4 toxicities impacting on daily well-being’ for the experimental arm, with little guidance other than a clarification that these toxicities should not include alopecia or myelosuppressive toxicities; for progression-free survival (PFS), additional downgrading can occur, but only with pre-specified toxicities (e.g. hospitalization for toxicity >10%), again with emphasis on statistically significant differences; finally, for non-inferiority and toxicity or quality of life (QoL) studies, there is simply the phrase ‘reduced toxicity’. With the new addition of “single - arm studies” [1], there is a downgrade for ≥30% grade 3-4 toxicities, again with the aforementioned stipulations. A trial found in the new version of the framework will be used as an example to highlight potential confusion around toxicity grading: KEYNOTE-010 [3], which received an upgrade in its OS grade due to reduced toxicity in the pembrolizumab arm compared with docetaxel. First, it should be noted that there are no P-values denoting statistically significant differences in toxicities between these two groups. Second, if one ignores the alopecia/hematological toxicities and focuses only on grade 3–4 toxicities observed (i.e. one strictly follows the grading form), the difference in grade 3–4 toxicities of commonly listed side-effects is only a few percent. Is this clinically meaningful? Can the pre-specified toxicities in the PFS grading form be used as a guide to grade ‘meaningful’ OS toxicities? Should non-statistically significant differences be graded in the first place? In KEYNOTE-010, there is a clear decrease in overall toxicities as a whole in the experimental arms (13%–16% versus 35%) [4]; however, this approach fails to tease out toxicity events that may actually impact patient ‘daily well-being’ (as stated by the framework) [1]. ‘Gestalt’ is likely not the mechanism the working group had hoped for its graders to use, since it appears this would revert back to a way of interpreting benefit that was the impetus behind developing these frameworks in the first place. The importance of proper toxicity analysis is emphasized by the underreporting, and oft times poor reporting, of toxicity data [5, 6], both of which can adversely affect treatment decisions. Thus, objectifying meaningful clinical benefit—efficacy with both harm and QoL considered—remains a challenge. The oncology community awaits further revisions of the ESMO-MCBS, as Dr Cherny and his group continue to finesse their important work. Funding None declared. Disclosure The author has declared no conflicts of interest. References 1 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  2 Del Paggio JC, Azariah B, Sullivan R et al.   Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? Ann Oncol  2016; 28( 1): 157– 162. 3 Del Paggio JC, Sullivan R, Schrag D et al.   Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. Lancet Oncology  2017; 18: 887– 894. Google Scholar CrossRef Search ADS PubMed  4 Herbst RS, 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( 10027): 1540– 1550. Google Scholar CrossRef Search ADS PubMed  5 Zhang S, Liang F, Tannock I. Use and misuse of common terminology criteria for adverse events in cancer clinical trials. BMC Cancer  2016; 16: 392. Google Scholar CrossRef Search ADS PubMed  6 Vera-Badillo FE, Napoleone M, Krzyzanowska MK et al.   Bias in reporting of randomised clinical trials in oncology. Eur J Cancer  2016; 61: 29– 35. 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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