title: A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.
abstract: Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17-18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy.
authors.affiliation: Department of Economics, Monash University, Melbourne, Victoria, Australia.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Angus
authors.affiliation: Faculty of Mathematics Informatics and Mechanics, Institute of Applied Mathematics and Mechanics, University of Warsaw, Warsaw, Mazowieckie, Poland.
authors.forename: Monika Joanna
authors.initials: MJ
authors.lastname: Piotrowska
mesh_terms: D000465:Algorithms; D024221:Antineoplastic Protocols; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000532:radiotherapy*; D017711:Nonlinear Dynamics; D011878:Radiotherapy / Q000379:methods*; D011879:Radiotherapy Dosage