Highlights
- •A Response Evaluation Criteria in Solid Tumors (RECIST) time to progression (TTP) criterion is tumour size exceeding 120% of its minimum.
- •A simple mathematical model well describes tumour response and relapse in treated patients.
- •Increasing tumour shrinkage rate in this model often leads to paradoxically shorter TTP.
- •This effect is large and frequent enough to invert population-level TTP-based outcomes.
- •We propose an alternative time to event metric that is consistent with shrinkage rate.
Abstract
Aim
We seek to characterize how faster tumour shrinkage rate (k) can lead to paradoxically
shorter Response Evaluation Criteria in Solid Tumors (RECIST) time to progression
(‘TTP20’ – tumour size exceeding its minimum by 5 mm and 20%) [1] and, therefore,
progression-free survival (PFS). Specifically, we investigate under what conditions
this paradoxical behaviour occurs, what fraction of patients satisfy these conditions,
whether this phenomenon can invert population-level PFS hazard ratio, and consistency
of an alternative time-to-event benefit metric with k.
Methods
We use a mathematical model treating tumour burden as decreasing drug-sensitive and
increasing drug-resistant cell subpopulations. We fit this model to data from several
clinical trials with different indications [2]. We simulated a more effective treatment
and recorded whether patients' TTP20 increased or decreased. We performed a study-level
analysis to compare the relationship of speed and depth of response with TTP20 for
both the administered ‘control’ and simulated ‘more effective’ drug. We propose and
test an alternative benefit metric: the model-projected time that tumour size reaches
120% of baseline (TTB120).
Results
Depending on indication, 3–27% of patients are estimated to have a paradoxically inverse
relationship between k and TTP20. Simulated head-to-head studies show that TTP20-based
PFS can favour the less effective drug. In contrast, TTB120 always favours the more
effective drug.
Conclusion
We demonstrate the paradoxical behaviour of RECIST TTP20 – as an exemplar of percent-change-from-nadir
based cancer progression criterion – both in theory and in observed patient data at
the individual and trial level. We propose an alternative tumour size–based criterion
(TTB120) that is directionally consistent with tumour shrinkage rate.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: February 07, 2019
Accepted:
November 1,
2018
Received in revised form:
October 29,
2018
Received:
September 12,
2018
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
