Abstract
Purpose
To compare lesion-level and volumetric measures of tumor burden with sum of the longest dimensions (SLD) of target lesions on overall survival (OS) predictions using time-to-growth (TTG) as predictor.
Methods
Tumor burden and OS data from a phase 3 randomized study of second-line FOLFIRI ± aflibercept in metastatic colorectal cancer were available for 918 patients out of 1216 treated (75%). A TGI model that estimates TTG was fit to the longitudinal tumor size data (nonlinear mixed effect modeling) to estimate TTG with: SLD, sum of the measured lesion volumes (SV), individual lesion diameters (ILD), or individual lesion volumes (ILV). A parametric OS model was built with TTG estimates and assessed for prediction of the hazard ratio (HR) for survival.
Results
Individual lesions had consistent dynamics within individuals. Between-lesion variability in rate constants was lower (typically < 27% CV) than inter-patient variability (typically > 50% CV). Estimates of TTG were consistent (around 12 weeks) across tumor size assessments. TTG was highly significant in a log-logistic parametric model of OS (median over 12 months). When individual lesions were considered, TTG of the fastest progressing lesions best predicted OS. TTG obtained from the lesion-level analyses were slightly better predictors of OS than estimates from the sums, with ILV marginally better than ILD. All models predicted VELOUR HR equally well and all predicted study success.
Conclusion
This analysis revealed consistent TGI profiles across all tumor size assessments considered. TTG predicted VELOUR HR when based on any of the tumor size measures.
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Acknowledgements
The authors are indebted to Prof. A Iliadis, Aix-Marseille University, Marseille, France for scientific discussions during the course of this work; and to Mathilde Marchand, Certara Consulting Services, France for careful review of the analyses.
Funding
This study was supported by the NIH Grant R01CA194783.
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Laurent Claret and Rene Bruno were employees of Pharsight Consulting Services, Pharsight, a Certara™ Company, when this work was performed. They are now employees of Genentech-Roche. Binsheng Zhao owns patents on tumor segmentation algorithms used in this work and has received royalties from Varian Medical Systems and Keosys Medical Imaging companies. Lawrence H. Schwartz received consulting fees from Merck, Novartis; and Research support from Daichi Sankyo and Eli Lilly. All other authors have no conflict of interest.
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This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Claret, L., Pentafragka, C., Karovic, S. et al. Comparison of tumor size assessments in tumor growth inhibition-overall survival models with second-line colorectal cancer data from the VELOUR study. Cancer Chemother Pharmacol 82, 49–54 (2018). https://doi.org/10.1007/s00280-018-3587-7
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DOI: https://doi.org/10.1007/s00280-018-3587-7