Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer

BMC Cancer

Victoria Homer¹  Kristian Brock¹  Claire Potter¹  Gurjinder Soul²  Cody Chiuzan³  Shing Lee³ 

[1] Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK;Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK;Mailman School of Public Health, Columbia University, New York, NY, USA;

关键词: Dose finding;    Phase I;    Toxicity;    Efficacy;    Response;    Monotone;    Cancer;   

DOI  :  10.1186/s12885-021-08440-0

来源: Springer

【 摘 要 】

BackgroundThe overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies.MethodsWe extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions.ResultsWe found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption.ConclusionsOur conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.

【 授权许可】

CC BY