Development and Validation of a Prediction Model of Overall Survival in High-Risk Neuroblastoma Using Mechanistic Modeling of Metastasis

Sébastien Benzekry (1) , Coline Sentis (2) , Carole Coze (2) , Laëtitia Tessonnier (2) , Nicolas André (3, 2)

1 COMPO - Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique
2 TIMONE - Hôpital de la Timone [CHU - APHM]
3 SMARTc - Simulation and Modeling of Adaptive Response for Therapeutics in Cancer

Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and better tailor treatments. We established a mechanistic model of metastasis in HRNB relying on two processes: growth and dissemination relying on two patient-specific parameters: the dissemination rate μ and the minimal visible lesion size S vis. This model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels, and the metaiodobenzylguanidine International Society for Paediatric Oncology European (SIOPEN) score from nuclear imaging, using data from 49 metastatic patients. It was able to describe the data of total tumor mass (lactate dehydrogenase, R 2. 0.99) and number of visible metastases (SIOPEN, R 2 = 0.96). A prediction model of overall survival (OS) was then developed using Cox regression. Clinical variables alone were not able to generate a model with sufficient OS prognosis ability (P = .507). The parameter μ was found to be independent of the clinical variables and positively associated with OS (P = .0739 in multivariable analysis). Critically, addition of this computational biomarker significantly improved prediction of OS with a concordance index increasing from 0.675 (95% CI, 0.663 to 0.688) to 0.733 (95% CI, 0.722 to 0.744, P , .0001), resulting in significant OS prognosis ability (P = .0422).

Domaines: Modélisation et simulation; Cancer; Analyse de données, Statistiques et Probabilités [physics.data-an]; Santé publique et épidémiologie; Pharmacologie; Applications [stat.AP]

Sébastien Benzekry, Coline Sentis, Carole Coze, Laëtitia Tessonnier, Nicolas André. Development and Validation of a Prediction Model of Overall Survival in High-Risk Neuroblastoma Using Mechanistic Modeling of Metastasis. JCO Clinical Cancer Informatics, 2021, 5, pp.81-90. ⟨10.1200/CCI.20.00092⟩. ⟨hal-03147049⟩