  Citation: Androulakis, I.; Mestrom, R.M.C.; Christianen, M.E.M.C.; Kolkman-Deurloo, I.-K.K.; van Rhoon, G.C. A Novel Framework for the Optimization of Simultaneous ThermoBrachyTherapy. Cancers 2022, 14, 1425. https://doi.org/10.3390/ cancers14061425 Academic Editor: David Wong Received: 30 January 2022 Accepted: 10 March 2022 Published: 10 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article A Novel Framework for the Optimization of Simultaneous ThermoBrachyTherapy Ioannis Androulakis 1, * , Rob M. C. Mestrom 2 , Miranda E. M. C. Christianen 1 , Inger-Karine K. Kolkman-Deurloo 1 and Gerard C. van Rhoon 1,3, * 1 Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 Rotterdam, The Netherlands; m.christianen@erasmusmc.nl (M.E.M.C.C.); i.kolkman-deurloo@erasmusmc.nl (I.-K.K.K.-D.) 2 Department of Electrical Engineering, Eindhoven University of Technology, 5600 Eindhoven, The Netherlands; r.m.c.mestrom@tue.nl 3 Departmentof Radiation Science and Technology, Delft University of Technology, 2629 Delft, The Netherlands * Correspondence: i.androulakis@erasmusmc.nl (I.A.); g.c.vanrhoon@erasmusmc.nl (G.C.v.R.) Simple Summary: ThermoBrachyTherapy, a combination therapy where radiation and heat are simultaneously applied using needle-shaped applicators from within the target, is a potentially very effective treatment for prostate cancer. When radiation and thermal therapies are applied, the dose coverage of each treatment is preplanned without considering the combined effect of the two dose distributions. In this study, we propose a method to automatically plan the thermal dose in such a treatment, based on the combined effect with the radiation. Furthermore, we apply the method on 10 patients and compare the treatment to a brachytherapy-only treatment plan. In this way, we show that, with properly optimized ThermoBrachyTherapy, we can provide equivalent combined dose coverages to the prostate, while reducing the dose delivered to critical organs surrounding the prostate, which might translate to reduced toxicity of the treatment. Abstract: In high-dose-rate brachytherapy (HDR-BT) for prostate cancer treatment, interstitial hy- perthermia (IHT) is applied to sensitize the tumor to the radiation (RT) dose, aiming at a more efficient treatment. Simultaneous application of HDR-BT and IHT is anticipated to provide maximum radiosensitization of the tumor. With this rationale, the ThermoBrachyTherapy applicators have been designed and developed, enabling simultaneous irradiation and heating. In this research, we present a method to optimize the three-dimensional temperature distribution for simultaneous HDR-BT and IHT based on the resulting equivalent physical dose (EQD phys ) of the combined treatment. First, the temperature resulting from each electrode is precomputed. Then, for a given set of electrode settings and a precomputed radiation dose, the EQD phys is calculated based on the temperature-dependent linear-quadratic model. Finally, the optimum set of electrode settings is found through an optimiza- tion algorithm. The method is applied on implant geometries and anatomical data of 10 previously irradiated patients, using reported thermoradiobiological parameters and physical doses. We found that an equal equivalent dose coverage of the target can be achieved with a physical RT dose reduction of 20% together with a significantly lower EQD phys to the organs at risk (p-value < 0.001), even in the least favorable scenarios. As a result, simultaneous ThermoBrachyTherapy could lead to a relevant therapeutic benefit for patients with prostate cancer. Keywords: hyperthermia; induced; brachytherapy; prostatic neoplasms; interstitial hyperthermia; treatment plan optimization; prostate; thermoradiotherapy; linear quadratic model; biological modeling 1. Introduction High-dose-rate brachytherapy (HDR-BT) is a well-established treatment option in lo- calized prostate cancer treatment [1]. Radiobiological clinical data have shown that prostate Cancers 2022, 14, 1425. https://doi.org/10.3390/cancers14061425 https://www.mdpi.com/journal/cancers