TY - JOUR
T1 - Comparing Circulating Tumor Cell Counts with Dynamic Tumor Size Changes as Predictor of Overall Survival
T2 - A Quantitative Modeling Framework
AU - Netterberg, Ida
AU - Karlsson, Mats O.
AU - Terstappen, Leon W.M.M.
AU - Koopman, Miriam
AU - Punt, Cornelis J.A.
AU - Friberg, Lena E.
PY - 2020/9
Y1 - 2020/9
N2 - 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 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 III 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). Tumor size changes did not contribute additional predictive value when the mean CTC count was a predictor of OS. Treatment reduced the typical mean count from 1.43 to 0.477 (HR = 3.94). The modeling framework was applied to explore whether dose modifications (increased and reduced) would result in a CTC count below 1/7.5 mL after 1 to 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 was connected to CTC, its link to OS was weaker.
AB - 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 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 III 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). Tumor size changes did not contribute additional predictive value when the mean CTC count was a predictor of OS. Treatment reduced the typical mean count from 1.43 to 0.477 (HR = 3.94). The modeling framework was applied to explore whether dose modifications (increased and reduced) would result in a CTC count below 1/7.5 mL after 1 to 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 was connected to CTC, its link to OS was weaker.
KW - 22/2 OA procedure
UR - https://doi.org/10.1158/1078-0432.22475192
UR - https://doi.org/10.1158/1078-0432.22475189
UR - https://doi.org/10.1158/1078-0432.22475186
UR - https://doi.org/10.1158/1078-0432.22475183
UR - https://doi.org/10.1158/1078-0432.22475180
UR - https://doi.org/10.1158/1078-0432.22475177.v1
UR - https://doi.org/10.1158/1078-0432.22475174
UR - https://doi.org/10.1158/1078-0432.22475171
UR - https://doi.org/10.1158/1078-0432.22475168
U2 - 10.1158/1078-0432.CCR-19-2570
DO - 10.1158/1078-0432.CCR-19-2570
M3 - Article
SN - 1078-0432
VL - 26
SP - 4892
EP - 4900
JO - Clinical cancer research
JF - Clinical cancer research
IS - 18
ER -