title: In Silico Oncology: Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model.
abstract: The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs' cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with the molecular profile of patients could serve as a basis for reliable personalized predictions.
authors.affiliation: In Silico Oncology and In Silico Medicine Group, Institute of Communication and Computer Systems, National Technical University of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Kolokotroni
authors.affiliation: In Silico Oncology and In Silico Medicine Group, Institute of Communication and Computer Systems, National Technical University of Athens, Athens, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dionysiou
authors.affiliation: Institute of Pathology, University of Saarland, Homburg (Saar), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Veith
authors.affiliation: Institute of Pathology, University of Saarland, Homburg (Saar), Germany.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Philips Research, Hamburg, Germany.
authors.forename: Jörg
authors.identifier: http://orcid.org/0000-0002-4500-6137
authors.initials: J
authors.lastname: Sabczynski
authors.affiliation: Philips Research, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Franz
authors.affiliation: Department of Nuclear Medicine, University of Saarland, Homburg (Saar), Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Grgic
authors.affiliation: Department of Radiotherapy and Radiation Oncology, University of Saarland, Homburg (Saar), Germany.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0003-1122-1557
authors.initials: J
authors.lastname: Palm
authors.affiliation: Institute of Pathology, University of Saarland, Homburg (Saar), Germany.
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.affiliation: In Silico Oncology and In Silico Medicine Group, Institute of Communication and Computer Systems, National Technical University of Athens, Athens, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Stamatakos