Circulating tumor cell counts is a better predictor of overall survival than dynamic tumor size changes – a quantitative modeling framework

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Netterberg, Ida,1988-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Uppsala University,Pharmacometrics (author)

Circulating tumor cell counts is a better predictor of overall survival than dynamic tumor size changes – a quantitative modeling framework

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LIBRIS-ID:oai:DiVA.org:uu-390191
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-390191URI

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Language:English
Summary in:English

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Purpose: Quantitative relationships between treatment-induced changes in tumor size and circulating tumor cell (CTC) counts, and their links to overall survival (OS), are lacking. We here present a population modeling framework identifying and quantifying such relationships, based on longitudinal data collected in patients with metastatic colorectal cancer (mCRC) to evaluate the value of tumor size and CTC counts as predictors of OS.Experimental design: A pharmacometric approach (i.e., population pharmacodynamic modeling) was used to characterize the changes in tumor size and CTC count and evaluate them as predictors of OS in 451 patients with mCRC treated with chemotherapy and targeted therapy in a prospectively randomized phase 3 study (CAIRO2).Results: A tumor size model of tumor quiescence and drug-resistance, was used to characterize the tumor size time-course, and was, in addition to the total normalized dose (i.e., of all administered drugs) in a given cycle, related to the CTC counts through a negative binomial model (CTC model). A CTC count≥3/7.5 mL (hazard ratio=3.51, 95% confidence interval: 2.85-4.32), as described by the CTC model, was a better predictor of OS than tumor size changes. The modeling framework was applied to explore if dose-modifications (increased and reduced) would result in a CTC count below 3/7.5 mL after 1-2 weeks of treatment.Conclusions: Time-varying CTC counts can be useful for early predicting OS in patients with mCRC, and may therefore have potential for model-based treatment individualization. Although tumor size had a strong connection to CTC, its link to OS was weaker.

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MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
Farmakokinetik och läkemedelsterapi
Pharmacokinetics and Drug Therapy

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Karlsson, Mats OUppsala universitet,Institutionen för farmaceutisk biovetenskap,Pharmacometrics (author)
Terstappen, Leon WMMDepartment of Medical Cell BioPhysics, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands (author)
Koopman, MiriamDepartment of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands (author)
Punt, Cornelis JADepartment of Medical Oncology, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands (author)
Friberg, Lena EUppsala universitet,Institutionen för farmaceutisk biovetenskap,Pharmacometrics (author)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

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In:Clinical Cancer Research1078-04321557-3265

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By the author/editor: Netterberg, Ida, ...; Karlsson, Mats O; Terstappen, Leon ...; Koopman, Miriam; Punt, Cornelis J ...; Friberg, Lena E

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