An application of genetic algorithms to chemotherapy treatment.
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The present work investigates methods for optimising cancer chemotherapy within the bounds of clinical acceptability and making this optimisation easily accessible to oncologists. Clinical oncologists wish to be able to improve existing treatment regimens in a systematic, effective and reliable way. In order to satisfy these requirements a novel approach to chemotherapy optimisation has been developed, which utilises Genetic Algorithms in an intelligent search process for good chemotherapy treatments. The following chapters consequently address various issues related to this approach. Chapter 1 gives some biomedical background to the problem of cancer and its treatment. The complexity of the cancer phenomenon, as well as the multi-variable and multi-constrained nature of chemotherapy treatment, strongly support the use of mathematical modelling for predicting and controlling the development of cancer. Some existing mathematical models, which describe the proliferation process of cancerous cells and the effect of anti-cancer drugs on this process, are presented in Chapter 2. Having mentioned the control of cancer development, the relevance of optimisation and optimal control theory becomes evident for achieving the optimal treatment outcome subject to the constraints of cancer chemotherapy. A survey of traditional optimisation methods applicable to the problem under investigation is given in Chapter 3 with the conclusion that the constraints imposed on cancer chemotherapy and general non-linearity of the optimisation functionals associated with the objectives of cancer treatment often make these methods of optimisation ineffective. Contrariwise, Genetic Algorithms (GAs), featuring the methods of evolutionary search and optimisation, have recently demonstrated in many practical situations an ability to quickly discover useful solutions to highly-constrained, irregular and discontinuous problems that have been difficult to solve by traditional optimisation methods. Chapter 4 presents the essence of Genetic Algorithms, as well as their salient features and properties, and prepares the ground for the utilisation of Genetic Algorithms for optimising cancer chemotherapy treatment. The particulars of chemotherapy optimisation using Genetic Algorithms are given in Chapter 5 and Chapter 6, which present the original work of this thesis. In Chapter 5 the optimisation problem of single-drug chemotherapy is formulated as a search task and solved by several numerical methods. The results obtained from different optimisation methods are used to assess the quality of the GA solution and the effectiveness of Genetic Algorithms as a whole. Also, in Chapter 5 a new approach to tuning GA factors is developed, whereby the optimisation performance of Genetic Algorithms can be significantly improved. This approach is based on statistical inference about the significance of GA factors and on regression analysis of the GA performance. Being less computationally intensive compared to the existing methods of GA factor adjusting, the newly developed approach often gives better tuning results. Chapter 6 deals with the optimisation of multi-drug chemotherapy, which is a more practical and challenging problem. Its practicality can be explained by oncologists' preferences to administer anti-cancer drugs in various combinations in order to better cope with the occurrence of drug resistant cells. However, the imposition of strict toxicity constraints on combining various anticancer drugs together, makes the optimisation problem of multi-drug chemotherapy very difficult to solve, especially when complex treatment objectives are considered. Nevertheless, the experimental results of Chapter 6 demonstrate that this problem is tractable to Genetic Algorithms, which are capable of finding good chemotherapeutic regimens in different treatment situations. On the basis of these results a decision has been made to encapsulate Genetic Algorithms into an independent optimisation module and to embed this module into a more general and user-oriented environment - the Oncology Workbench. The particulars of this encapsulation and embedding are also given in Chapter 6. Finally, Chapter 7 concludes the present work by summarising the contributions made to the knowledge of the subject treated and by outlining the directions for further investigations. The main contributions are: (1) a novel application of the Genetic Algorithm technique in the field of cancer chemotherapy optimisation, (2) the development of a statistical method for tuning the values of GA factors, and (3) the development of a robust and versatile optimisation utility for a clinically usable decision support system. The latter contribution of this thesis creates an opportunity to widen the application domain of Genetic Algorithms within the field of drug treatments and to allow more clinicians to benefit from utilising the GA optimisation.