A Conceptual Framework For Cautious Escalation Of Anticancer Treatment: How To Optimize Overall Benefit And Obviate The Need For De-Escalation Trials

Abstract

Background: The research designs used for current anticancer drug clinical development are often not suitable to determine an optimal efficacy threshold. This may lead to overtreatment, with potentially avoidable physical, emotional and financial toxicities. Also, it undermines the success rate of promising therapies, when dose is not optimized and dose-dependent toxicities are detrimental. Post-approval de-escalation trials that are then needed for dose-optimization and treatment de-intensification can require much more resources and time.

Design: Physicians and patient advocates were united in a special session on “De-escalation of treatment in Medical Oncology” at the European Society for Medical Oncology congress in 2022 to review issues of current trial designs as well as potential solutions. The supporting theoretical basis and practical examples from the literature were then compiled and summarized to propose a new framework for clinical trials in oncology.

Result: We provide the theoretical basis of a Framework for Cautious Escalation (FCE) of anticancer treatments, that aims to minimize overtreatment for a given level of benefit, but which may also increase the success rate of clinical trials. We use historical examples of cancer clinical trials to demonstrate how the application of FCE may have prevented potential overtreatments, optimized use of resources and obviated the need for subsequent de-escalation trials.

Conclusion: We propose the FCE as a new model of clinical development in oncology to prevent overtreatment and associated issues, to ultimately increase the success rate of clinical trials and deliver improved patient-centric outcomes.

Note:
Funding Information: None declared.

Conflict of Interests: The authors have declared no conflicts of interest.

Keywords: clinical trials, methodology, overtreatment, de-escalation