Continuous adaptive chemotherapy dosing by using planet-formation-inspired dynamics: analytical and in silico...

Current therapeutic planning of chemotherapy is based on empirical dosimetry and intermittent dose administration, which can cause poorly defined therapeutic timepoints due to tumor heterogeneities and related highly uncertain tumor dynamics. Dynamic control strategies have been investigated to overcome these limitations, but their dependence on reliable mathematical models predicting tumor dynamics and/or their inherent intuition have hampered their use in clinical practice. This study proposes a control method for administering chemotherapeutic drugs using planet-formation-like dynamics to ensure high adaptability and versatility to uncertain tumor dynamics, taking advantage of the evolutive, deterministic, adaptive, convergent, and robust behavior of planetary systems.

The planet-formation-inspired controller was designed using accretion and gravitational attraction that occur during planet formation, such that chemotherapeutic trajectories are attracted in an analogous pattern as planetesimal bodies (masses/particles) are attracted to protoplanets. The necessary conditions to guarantee stability are provided, as well as extensive simulation results for cyclophosphamide, different tumor volumes (200 and 2,000 mm³), and different modeling characterizations (therapy with and without chemoresistance). The Sobol indices were also computed to analyze the influence of controller parameters on planet-formation-inspired administration as well as to find the influence of astrophysical-like dynamics on mechanobiological tumor dynamics.

This controller ensured either tumor remission or retention states, regardless of the initial tumor volume, tumor growth dynamics, and the potential impact of chemoresistance. Its non-linear drug administration resulted in highly robust, stable, and adaptive behaviors, with detumorization represented as an effective response metric that does not explicitly incorporate inter-individual biological variability and is associated with a uniformization of treatment times. Such planet-formation-inspired administration forces detumorization dynamics defined by geometro-pharmacokinetics that significantly outperform both non-adaptive and adaptive intermittent administrations. We also found that drag forces inside protoplanets are usually the most dominant astrophysical phenomenon influencing mechanobiological dynamics in resistance-free chemotherapy, while accretion is usually the most dominant one in cancer therapies with chemoresistance.

This study provides a computationally promising proof-of-concept highlighting that planet-formation-inspired dynamics can effectively overcome the limitations of tumor heterogeneity and uncertain tumor dynamics, presenting significant improvements compared to conventional chemotherapy administration.