A new initiative in brachytherapy first proposed under the auspices of this grant, involves pulsed as opposed to continuous low dose irradiation using a computer controlled remote afterloader. A single Ir-192 source steps under computer control through the catheters of an implant or applicator with dwell times in each position determined to produce an optimized dose distribution. This results in several advantages: improved dose optimization, greatly improved radiation safety since no source preparation is involved, only one source to replace, and no variation in overall treatment time between patients. A commercial company has produced a machine based on this principle which is in use worldwide and hundreds of patients have already been treated successfully, using pulse lengths and frequencies that the applicants suggested. To date, the emphasis has been on demonstrating the equivalence of pulsed (PDR) to continuous low dose rate (CLDR). However, the applicants suggest that appropriate PDR regimens will allow an increase in the differential between effects on tumors relative to late-responding normal tissues. Specifically, there is strong evidence that late- responding tissues repair sublethal damage more slowly than early responding tissues, including tumors. The basic hypothesis upon which this proposal is based is that a difference in repair half-times (T1/2) between early and late responding tissues can be exploited to improve the therapeutic ratio in brachytherapy in the same way as differences in the alpha/beta ratios are exploited in external beam radiotherapy. To exploit this difference in repair times, the optimal PDR regimen would not consist of equal doses per pulse but would use larger doses in the first and last pulses and less in the intermediate pulses. The applicants refer to the process of designing these improved schemes as temporal optimization. This potentially increased differential between systems with different rates of repair can be modeled in vitro using well characterized cell lines with different rates of repair to test the hypothesis that temporal optimization of PDR spare cells with a long T1/2 more than cells with a short T1/2. Measurements of cell survival ratios will be made using an automated cellular imaging system, allowing ratios in cellular survival of factors of 2 to 5 to be identified. While cells cultured in vitro cannot mimic all the complexities of tissues in vivo, they can demonstrate a specific principle - as indeed they did for the initial concept of pulse brachytherapy. Temporal optimization of PDR has potential applications in interstitial implants in, for example, head and neck or prostate cancers, as well as in the endocavitary treatment of carcinoma of the cervix.
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