Data-Driven Predictive Models of Diffuse Low-Grade Gliomas Under Chemotherapy

Diffuse low-grade gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training data set of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter.

[1]  P. Varlet,et al.  Oedema‐based model for diffuse low‐grade gliomas: application to clinical cases under radiotherapy , 2014, Cell proliferation.

[2]  L. Taillandier,et al.  Predictive models for diffuse low-grade glioma patients under chemotherapy , 2016, 2016 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[3]  R. Guillevin,et al.  Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas. , 2013, Neuro-oncology.

[4]  Laurent Capelle,et al.  Dynamic history of low‐grade gliomas before and after temozolomide treatment , 2007, Annals of neurology.

[5]  J. S. Hunter,et al.  Statistics for Experimenters: An Introduction to Design, Data Analysis, and Model Building. , 1979 .

[6]  Luc Taillandier,et al.  Computational modeling of the WHO grade II glioma dynamics: principles and applications to management paradigm , 2008, Neurosurgical Review.

[7]  S. Shapiro,et al.  An Analysis of Variance Test for Normality (Complete Samples) , 1965 .

[8]  F. Ducray,et al.  Prediction of Response to Temozolomide in Low‐Grade Glioma Patients Based on Tumor Size Dynamics and Genetic Characteristics , 2015, CPT: pharmacometrics & systems pharmacology.

[9]  Laurent Capelle,et al.  Continuous growth of mean tumor diameter in a subset of grade II gliomas , 2003, Annals of neurology.

[10]  Hugues Duffau,et al.  Surgery of low-grade gliomas: towards a ‘functional neurooncology’ , 2009, Current opinion in oncology.

[11]  M. J. van den Bent,et al.  First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response. , 2011, Neuro-oncology.

[12]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[13]  Johan Pallud,et al.  A Tumor Growth Inhibition Model for Low-Grade Glioma Treated with Chemotherapy or Radiotherapy , 2012, Clinical Cancer Research.

[14]  Olivier Delattre,et al.  Two types of chromosome 1p losses with opposite significance in gliomas , 2005, Annals of neurology.

[15]  A. Christopoulos,et al.  Fitting Models to Biological Data Using Linear and Nonlinear Regression: A Practical Guide to Curve Fitting , 2004 .

[16]  E. Shaw,et al.  A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. , 2006, Cancer research.

[17]  L. Taillandier,et al.  Gliomes de grade II , 2008 .

[18]  J. Durbin,et al.  Testing for serial correlation in least squares regression. II. , 1950, Biometrika.

[19]  J. Navarro-Pedreño Numerical Methods for Least Squares Problems , 1996 .

[20]  Elizabeth A. Peck,et al.  Introduction to Linear Regression Analysis , 2001 .

[21]  H. Maurer,et al.  Dynamics and optimal control of chemotherapy for low grade gliomas: Insights from a mathematical model , 2016 .

[22]  J. Durbin,et al.  Testing for serial correlation in least squares regression. I. , 1950, Biometrika.

[23]  Brigitta G. Baumert,et al.  Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma , 2016, The Lancet. Oncology.

[24]  Luc Taillandier,et al.  Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas , 2006, Annals of neurology.

[25]  Stephen R. Thomas,et al.  Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas. , 2013, Neuro-Oncology.

[26]  L. Taillandier Chemotherapy for Diffuse Low-Grade Gliomas , 2013 .

[27]  H Duffau,et al.  Temozolomide for low-grade gliomas , 2007, Neurology.

[28]  R. Guillevin,et al.  Natural history of incidental world health organization grade II gliomas , 2010, Annals of neurology.

[29]  K. Hoang-Xuan,et al.  Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  H. White A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test for Heteroskedasticity , 1980 .