Protracted metronomic therapies for grade II gliomas: Theoretical proof of concept of a novel therapeutic strategy.
VM Pérez-García: Laboratory of Mathematical Oncology (MôLAB), Universidad de Castilla-La Mancha.
A Martínez-González: Laboratory of Mathematical Oncology (MôLAB), Universidad de Castilla-La Mancha.
A Henares: Facultad de Matemáticas, Universidad de Granada, Spain.
J Belmonte-Beitia: Laboratory of Mathematical Oncology (MôLAB), Universidad de Castilla-La Mancha.
M Bogdanska: Faculty of Mathematics, Informatics and Mechanics, University of Varsaw, Poland.
T Galochkina: Claude Bernard University, Lyon, France.
A Bratus: Lomosonov State University, Faculty of Computational Mathematics and Cybernetics, Moscow, Russian Federation.
M Murek: Universitätsklinik für Neurochirurgie, Bern University Hospital, Switzerland.
LA Pérez-Romasanta: Servicio de Oncología Radioterápica, Hospital Universitario de Salamanca, Spain.
Grade II gliomas are slowly growing primary brain tumors that mostly affect young patients and become fatal after few years. Current clinical management includes surgery as first line treatment. Cytotoxic therapies such as radiotherapy or chemotherapy are used initially only for patients with bad prognosis.
Therapies such as radiotherapy are administrated following the maximum dose in minimum time principle. This is basically the same schedule used for high grade brain tumors in spite of their growth being much faster.
We have developed a mathematical model describing the basic facts of grade II glioma progression and response to radiotherapy. The model includes the dynamics in time of two cellular compartments (active tumor cells and lethally damaged tumor cells). The fraction of tumor cells damaged by a radiation dose is estimated by the linear-quadratic model.
In a series of studies we have first developed the model  and then tested it against several well known clinical facts of grade II glioma response to radiotherapy . Then we have proven that if the toxicity is to be preserved as the one of the standard treatment the most effective fractionation is that of the standard scheme . However, the model predicts there is a much more effective (protracted) fractionation in which the doses of 1.8 Gy are spaced by a distance that can be estimated to be a fraction of the tumor potential doubling time and radiosensitivity, typically of the order of 1-2 months, the potential survival gain being of the order of years .
Finally, it is found that the optimal strategy when both the dose per fraction and the time spacing between fractions are left free, with the restriction of same toxicity (biological effect on the healthy tissue) as the standard fractionation is a combination of protraction with metronomic therapies, lowering the dose per fractions to levels below 1 Gy .
The next step is finding a good animal model to test the ideas. We are open to collaborations on that.
 Pérez-García VM, Bogdanska M, Martinez-González A, Belmonte-Beitia J, Shucht P, Pérez-Romasanta LA, Delay effects in the response of low grade gliomas to radiotherapy: A mathematical model and its therapeutical implications, Mathematical Medicine and Biology (2015),
 Pallud J et al. Dynamics imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas. (2012) 14:1-10.
 Galochkina T, Bratus A, Pérez-García VM (2015) Optimal radiation fractionation for low-grade gliomas: Insights from a mathematical model, Mathematical Biosciences 267:1-9
 Pérez-García VM, Pérez-Romasanta LA, Extreme protraction for low grade gliomas: Theoretical proof of concept of a novel therapeutical strategy, Mathematical Medicine and Biology (2015) (http://dx.doi.org/10.1093/imammb/dqv017).
 Pérez-García VM, Martínez-González A, Henares A, Galochkina T, Pérez-Romasanta LA, Protracted metronomic therapies for grade II gliomas: Theoretical proof of concept of a novel therapeutic strategy (in preparation)Format: Poster