The proposed project has the overall goal of developing methods and tools, founded on clinical and experimental data, to optimize three- dimensional conformal radiation therapy - with specific reference to understanding and taking advantage of dose-volume effects. The dose-volume response of normal tissues and tumors will be determined, to the extent possible, through the analysis of clinical and experimental data. The data for selected sites will be accumulated from published results and through collaborations with other investigators. The attempt will be made to fit the available data with existing and new models of ours and others. A comprehensive methodology for fitting clinical data which will include an analysis of goodness-of-fit and confidence limits on model parameters will be developed based on the methods of maximum likelihood and resampling statistics. Censored character of the clinical data will be accounted for through modeling the latency periods and dose- survival relationships. This time adjustment is necessary when one fits the model to clinical data with the follow-up times not long enough to reach the plateau level of the recurrence-free or complication-free survival curve. Techniques to pick a set of optimal beam directions and their intensity profiles will be developed. Several biological and physical score functions will be investigated to determine their utility for optimizing dose distributions with intensity modulated beams. The issue of how many (or how few) beam directions are needed for optimal plans will be studied for various sites and score functions. Models of tissue response to radiation will be used to determine the optimal margins for both open and intensity modulated beams. A user-friendly "point-and-click" interface, including spreadsheets and protocols, to allow a clinician to inspect and fine-tune biological models used in optimizing and/or quantitative assessing treatment plans and to inspect the concordance of the models with clinical judgment will be developed. The optimization package will be implemented on our three- dimensional treatment planning system. New models of the dose-volume response of normal tissues and tumors will be developed if and as dictated by data analysis. The new models will take into account the spatial distribution of function of an organ as determined by various functional studies (e.g. SPECT studies for lung), and correlation of the survival of clonogens or functional subunits and the vitality of the neighboring clonogens/functional subunits. The results of this research will be applied to clinical cases to budge their efficacy. It is expected that the outcome of the proposed research will make the optimization of three-dimensional conformal radiotherapy a compelling part of modem routine treatment planning.