Modern advances in computers have fueled parallel advances in imaging technologies. The improvements in imaging have in turn allowed a higher level of complexity to be incorporated into radiotherapy treatment planning systems. As a result of these changes, the delivery of radiotherapy evolved from therapy designed based primarily on plain (two dimensional) x-ray images and hand calculations to three-dimensional x-ray based images incorporating increasingly complex computer algorithms. More recently, biologic variables based on differences between tumor metabolism, tumor antigens, and normal tissues have been incorporated into the treatment process. In addition, greater awareness of the challenges to the accuracy of the treatment planning process, such as problems with set-error and organ movement, have begun to be systematically addressed, ushering in an era of so-called FourDimensional Radiotherapy. This review article discusses how these advances have changed the way the most common neoplasms are treated now and will be treated in the near future. (CA Cancer J Clin 2005;55:117-134.)

The specificity of the yeast proproteinprocessing Kex2 protease was examined in vivo by using a sensitive, quantitative assay. A truncated prepro-␣-factor gene encoding an ␣-factor precursor with a single ␣-factor repeat was constructed with restriction sites for cassette mutagenesis f lanking the single Kex2 cleavage site (-SLDKR2EAEA-). All of the 19 substitutions for the Lys (P 2 ) residue in the cleavage site were made. The wild-type and mutant precursors were expressed in a yeast strain lacking the chromosomal genes encoding Kex2 and prepro-␣-factor. Cleavage of the 20 sites by Kex2, expressed at the wild-type level, was assessed by using a quantitative-mating assay with an effective range greater than six orders of magnitude. All substitutions for Lys at P 2 decreased mating, from 2-fold for Arg to >10 6 -fold for Trp. Eviction of the Kex2-encoding plasmid indicated that cleavage of mutant sites by other cellular proteases was not a complicating factor. Mating efficiencies of strains expressing the mutant precursors correlated well with the specificity (k cat ͞K M ) of purified Kex2 for comparable model peptide substrates, validating the in vivo approach as a quantitative method. The results support the conclusion that K M , which is heavily inf luenced by the nature of the P 2 residue, is a major determinant of cleavage efficiency in vivo. P 2 preference followed the rank order: Lys > Arg >

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