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Modelling of the Electrochemical Treatment of Tumours

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Modelling of the Electrochemical Treatment of Tumours TRITA-KET R115 ISSN 1104-3466 ISRN KTH/KET/R-115-SE MMOODDEELLLLIINNGG OOFF TTHHEE EELLEECCTTRROOCCHHEEMMIICCAALL TTRREEAATTMMEENNTT OOFF TTUUMMOOUURRSS EVA NILSSON DOCTORAL THESIS Department of Chemical Engineering and Technology Applied Electrochemistry Royal Institute of Technology Stockholm 2000 AKADEMISK AVHANDLING som med tillstånd av Kungliga Tekniska Högskolan i Stockholm, framlägges till offentlig granskning för avläggande av teknisk doktorsexamen fredagen den 10 mars 2000 kl. 13.00 i Kollegiesalen, Valhallavägen 79, Kungliga Tekniska Högskolan, Stockholm. ABSTRACT The electrochemical treatment (EChT) of tumours entails that tumour tissue is treated with a continuous direct current through two or more electrodes placed in or near the tumour. Promising results have been reported from clinical trials in China, where more than ten thousand patients have been treated with EChT during the past ten years. Before clinical trials can be conducted outside of China, the underlying destruction mechanism behind EChT must be clarified and a reliable dose-planning strategy has to be developed. One approach in achieving this is through mathematical modelling. Mathematical models, describing the physicochemical reaction and transport processes of species dissolved in tissue surrounding platinum anodes and cathodes, during EChT, are developed and visualised in this thesis. The considered electrochemical reactions are oxygen and chlorine evolution, at the anode, and hydrogen evolution at the cathode. Concentration profiles of substances dissolved in tissue, and the potential profile within the tissue itself, are simulated as functions of time. In addition to the modelling work, the thesis includes an experimental EChT study on healthy mammary tissue in rats. The results from the experimental study enable an investigation of the validity of the mathematical models, as well as of their applicability for dose planning. The studies presented in this thesis have given a strong indication of the destruction mechanism involved in EChT. It is shown by the modelling work, in combination with the experiments, that the most probable cause of tissue destruction is acidification at the anode and alkalisation at the cathode. The pH profiles obtained from the theoretical models have shown good correlation with the experimentally measured destruction zones, assuming that a pH above and below certain values cause tissue destruction. This implies that the models presented in this thesis could be of use in predicting the tumour destruction produced through EChT, and thereby provide a basis for a systematic dose planning of clinical treatments. Moreover, the models can serve as valuable tools in optimising the operating conditions of EChT. Modelling work of the anode processes has explained the role of chlorine in the underlying destruction mechanism behind EChT. It is found that the reactions of chlorine with tissue play important roles as generators of hydrogen ions. The contribution of these reactions to the acidification of tissue, surrounding the anode, is strongly dependent on the applied current density and increases with decreasing current density. Key words: cancer, direct current, dose planning, electrochemical treatment (EChT), electrotherapy, mathematical modelling, tumour. THESIS CONTENTS This thesis is a summary and discussion of the following papers: I. H. von Euler, E. Nilsson, A.-S. Lagerstedt and J.M. Olsson, Development of a dose-planning method for electrochemical treatment of tumors: A study on mammary tissue in healthy female CD rats, Electro. Magnetobiol. 18 (1999) 93-104. II. E. Nilsson, J. Berendson and E. Fontes, Electrochemical treatment of tumours: a simplified mathematical model, J. Electroanal. Chem. 460 (1999) 88-99. III. E. Nilsson, J. Berendson and E. Fontes, Development of a dosage method for electrochemical treatment of tumours: a simplified mathematical model, Bioelectrochem. Bioenerg. 47 (1998) 11-18. IV. E. Nilsson, J. Berendson and E. Fontes, Impact of chlorine and acidification in the electrochemical treatment of tumours, accepted for publication, J. Appl. Electrochem. (1999). V. E. Nilsson and E. Fontes, Mathematical modelling of physico- chemical reaction and transport processes occurring around a platinum cathode during the electrochemical treatment of tumours, submitted for publication, Bioelectrochemistry (2000). VI. E. Nilsson, H. von Euler, J. Berendson, A. Thörne, P. Wersäll, I. Näslund, A.-S. Lagerstedt, K. Narfström and J.M. Olsson, Electrochemical treatment of tumours, in press, Bioelectrochemistry. ACKNOWLEDGEMENTS Many people have contributed to the contents of this thesis, and I would like to take this opportunity to thank: Jaak Berendson, my supervisor and friend, for your confidence and support in all situations. You have been the best supervisor I can imagine. Ed, my fiancé and in-house supervisor in electrochemistry, downhill skiing and driving, for the coaching, your positive thinking and for picking up the pieces during the hard times. Philip Byrne for being a friend and for your valuable opinions on the summary and papers included in this thesis. "Fikarumsgänget" at IMT, Sundsvall, for the unforgettable parties and for advising me in stock trading, driving and gambling. Torbjörn Carlberg, thank you for receiving me at Mitthögskolan. Kjersti Bergström-Boucht for everything ranging from the administrative services to the stimulating discussions about horseback riding, interior design and art. The late Daniel Simonsson, for supporting the project and for the encouragement in the beginning of my doctoral studies. The TEKTIB group, including members from Radiumhemmet, The Swedish University of Agricultural Sciences and Huddinge University Hospital, is acknowledged for their co-operation and valuable discussions. Cancerfonden, KTH, and Stiftelsen för Strategisk Forskning are acknowledged for the financial support and Permascand for supplying the electrodes. I would also like to thank the people at Applied Electrochemistry and KEP, Sundsvall, for creating a friendly and inspiring atmosphere. Finally, I would like to thank my family, Lars, Vivi-Anne and Anders for always being there for me. CONTENTS 1. INTRODUCTION 1 1.1. Experiences from the electrochemical treatment of tumours 1 1.2. Destruction mechanisms 7 1.3. Dose planning 9 1.4. Objectives of this thesis 10 2. EXPERIMENTAL 11 3. MATHEMATICAL MODELLING 13 3.1. General problem definition 13 3.2. Anode modelling 15 3.3. Cathode modelling 17 3.4. Model equations 19 3.5. Input data and numerical implementation 21 4. RESULTS AND DISCUSSION 23 4.1. Experiments in rat mammary tissue 23 4.2. Anode modelling 25 4.3. Cathode modelling 35 5. CONCLUSIONS 42 6. REFERENCES 44 APPENDIX Paper I Paper II Paper III Paper IV Paper V Paper VI 1. INTRODUCTION Electrochemical treatment (EChT) of tumours is a therapy in which tumour tissue is treated with a continuous direct current. Several factors contribute to the tumour destruction caused by EChT, although their respective roles in producing the anti-tumour effect are not yet fully understood. These uncertainties regarding the destruction mechanisms bring about the lack of a reliable dose planning methodology. In this introduction, the experimental and clinical experiences of the electrochemical treatment of tumours are reviewed. The current knowledge of the destruction mechanism underlying EChT is presented along with different attempts towards dose planning. Finally, the objective of this thesis is formulated. A short review on the application of direct current in the treatment of tumours was presented by Watson in 1991 [1]. Since then, many interesting studies have been published and for that reason a second review of the same subject was written by the present author and co-workers, see Paper VI. Sections 1.1-1.3 are based on the material presented in Paper VI, in which further details of the respective aspects can be found. 1.1. Experiences from the electrochemical treatment of tumours Reports on the anti-tumour effect of low-level direct current date back to the end of the nineteenth century [2]. However, interest in its underlying mechanisms and possible therapeutic use waned until 1959 when Humphrey and Seal reported encouraging results from its application to sarcoma tumours in mice [3]. Following this, a number of workers applied EChT in both animal tumour models and in clinical trials. Pioneering clinical studies by Nordenström Björn Nordenström, a Swedish professor in radiology, is considered to be a pioneer in the treatment of tumours with direct electric current and combination therapies in patients. In the late seventies, Nordenström started to treat primary lung cancers by applying current between two platinum wire electrodes. The anode was placed centrally in the tumour and the cathode approximately twice the tumour diameter away from the anode. The applied voltage was about 10 V. The patients were treated under local anaesthesia and were seldom uncomfortable during the treatment. A preliminary trial in five patients was published in 1978 [4], and, in his book written in 1983 [5], Nordenström reported results from the treatment of 26 lung tumours in 20 patients. Many of these patients were, for various 1 reasons, unsuitable for surgical, radiotherapeutic or chemotherapeutic treatment. The average delivered coulomb dosage (current multiplied by time) was 80 C/cm of tumour diameter. Regression was obtained in 12 out of 26 tumours and no signs of re-growth were detected after a 2-5 year follow-up
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