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Longitudinal analysis of organ-specific tumor lesion sizes in metastatic colorectal cancer patients receiving first line standard chemotherapy in combination with anti-angiogenic treatment

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Abstract

The purpose of this work is to assess the heterogeneity across organs of response to treatment in metastatic colorectal patient based on longitudinal individual target lesion diameters (ILD) in comparison to sum of tumor lesion diameters (SLD). Data were from the McCAVE trial, in which 189 previously untreated patients with metastatic colorectal carcinoma (mCRC) received either bevacizumab (control, C) or vanucizumab (experimental, E), on top of standard chemotherapy. Bayesian hierarchical longitudinal non-linear mixed effect models were fitted to the data using Hamilton Monte Carlo algorithm to characterize the time dynamics of the tumor burden, and to obtain estimates of the tumor shrinkage and regrowth rates. The ILD model brought more nuanced results than to the SLD model. Besides substantial differences in tumor size at baseline (with lesions located in liver more than twice as large as the ones in lungs), it revealed a more durable response in lesions located in lymph nodes and ‘other organs’ compared to liver and lungs. Specifically, in lymph nodes and ‘other organs’, the projected time to nadir was doubled in group E (2.12 and 2.44 years respectively) compared to group C (1.07 and 1.20 years respectively). This long period of tumor shrinkage associated with a slightly larger change from baseline at nadir (− 51.4% in lymph nodes and − 62.6% in ‘other organs’ in the group E, compared to − 46.2% and − 46.9% in group C) resulted in a clinically meaningful difference in the tumor dynamics of patients in group E compared to the group C. The proportion of variance explained by the inter-lesion variability for each model parameter was large (ranging between 10 and 56%), reflecting the heterogeneity in tumor dynamics across organs. These findings suggest that there is value in understanding both within- and between-patient variability in tumor size’s time dynamics using an appropriate modeling framework, as this information may help in pairing the right treatment with individual patient profile.

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Acknowledgements

The authors would like to thank all the patients and personal of the investigator sites who participated in the McCAVE study, as well as the vanucizumab project team for their direct or indirect contribution to this research.

Funding

Funding was provided by F. Hoffmann-La Roche.

Author information

Authors and Affiliations

  1. Biostatistics, F. Hoffmann-La Roche AG, Basel, Switzerland

    Francois Mercier

  2. Clinical Pharmacology, Genentech/Roche, Paris, France

    Marion Kerioui

  3. Université de Tours, Université de Nantes, INSERM SPHERE, UMR 1246, Tours, France

    Solène Desmée

  4. INSERM, UMR 1135, Paris, France

    Jeremie Guedj

  5. Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Munich, Germany

    Oliver Krieter

  6. Clinical Pharmacology, Genentech/Roche, Marseille, France

    Rene Bruno

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  1. Francois Mercier
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  4. Jeremie Guedj
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Contributions

FM: study supervision, development of methodology, analysis and interpretation of data, writing, review of the initial manuscript and revisions; MK: analysis and interpretation of data, review of the initial manuscript; SD: study supervision, analysis and interpretation of data, writing, development of methodology, review of the initial manuscript; JG: study supervision, analysis and interpretation of data, writing, development of methodology, review of the initial manuscript; RB: study supervision, analysis and interpretation of data, writing, review of the initial manuscript; OK: analysis and interpretation of data, writing, review of the initial manuscript.

Corresponding author

Correspondence to Francois Mercier.

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Conflict of interest

Francois Mercier, Marion Kerioui, Rene Bruno, and Oliver Krieter are Roche/Genentech employees. Francois Mercier, Rene Bruno and Oliver Krieter are Roche shareholders. Francois Mercier declares that he has no conflict of interest. Marion Kerioui declares that she has no conflict of interest. Solene Desmee declares that she has no conflict of interest. Jeremie Guedj declares that he has no conflict of interest. Rene Bruno declares that he has no conflict of interest. Oliver Krieter declares that he has no conflict of interest.

Code availability

The core program used to fit the data is provided in Supplementary material as Supplementary Text 1.

Ethical approval

The McCAVE study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent as approved by local institutional review boards.

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Mercier, F., Kerioui, M., Desmée, S. et al. Longitudinal analysis of organ-specific tumor lesion sizes in metastatic colorectal cancer patients receiving first line standard chemotherapy in combination with anti-angiogenic treatment. J Pharmacokinet Pharmacodyn 47, 613–625 (2020). https://doi.org/10.1007/s10928-020-09714-z

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  • DOI: https://doi.org/10.1007/s10928-020-09714-z

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