With 220,900 estimated new diagnoses and 40,000 deaths in the year 2003 in the USA alone, prostate cancer represents a major health problem. According to the American Cancer Society, prostate cancer will be diagnosed in one out of every six men during their lifetime, and it is the most common noncutaneous cancer and the second leading cause of cancer-related mortality in American males. The statistical data will be further aggravated with an aging population. Clinically, prostate cancer patients of various stages are frequently treated with external beam radiotherapy. As revealed by several clinical studies, prostate malignancy is a dose-responsive neoplasm and there is a strong correlation between high radiation dose and improved local control. For example, in a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer with a pretreatment PSA of more than 10 ng/mL (A. Pollack et al, Journal of Clinical Oncology 18, 3904-11, 2000), it was found that the difference in 5-year FFF (freedom from biochemical and/or disease failure) rates were 48% for the 70 Gy and 75% for the 78 Gy groups, respectively. In reality, the attempt of dose escalation using the current intensity modulated radiation therapy (IMRT) techniques have been hampered by the significantly increased radiation toxicity and risk of developing later gastrointestinal and genitourinary complications. Our clinical endeavor of providing the best possible care to prostate patients is thus being compromised because of the lack of an effective means to deliver higher radiation dose to the prostate tumor.

Preliminary studies carried out by the investigator's group have indicated that the inverse planning algorithm employed for optimizing patients' IMRT treatment are deficient and the current prostate IMRT dose distributions can be substantially improved by more effective formulation and modeling of the inverse planning problem. Indeed, we found that with the use of a new inverse planning scheme (the main feature of the new scheme is the use of nonuniform importance factors for the structures involved with inverse planning), the dose to the prostate target could be escalated, remarkably, by ~10%, while maintaining the sensitive structure doses at their current levels. An immediate implication of the finding is that the 5-year FFF rates can be increased from the current 48% (most prostate patients are treated to 70-72 Gy) to 75% without increase in radiation toxicity for locally advanced prostate cancer patients. The objective of this project is to investigate a few important issues critical to the new paradigm and to develop technical tools required to establish the novel inverse planning scheme for prostate irradiation. The specific aims are: (1) to establish an effective inverse planning algorithm with spatially nonuniform importance factors for prostate IMRT and (2) to demonstrate the impact of the novel inverse planning formalism for prostate irradiation by using 20 previously treated prostate cases. The execution of the first specific aim will put the new inverse planning formalism on a solid scientific ground and allows us to generate truly optimal radiation dose distributions for prostate cancer treatment. The accomplishment of the second specific aim will determine the level of improvement of the new treatment scheme and ensure that the new IMRT is not only feasible on a computer screen, but also actually achievable in a clinical environment.

Successful completion of the project will lay the technical foundation for the next generation IMRT treatment of prostate cancer and provide radiation oncologists with substantially improved means of delivering conformal doses of ionizing radiation to the prostate tumor while maintaining or reducing the dose to the adjacent bladder and rectum. This will significantly reduce the radiation toxicity and/or allow us to escalate tumor dose to the levels set by the physical limit of IMRT other than by the suboptimal performance of the optimization algorithms. When fully implemented, the system will allow us to destroy prostate tumor cells more effectively without unnecessarily compromising the tolerance of the adjacent normal structures. The new IMRT planning system should result in measurable improvement in treatment outcome and have widespread impact on prostate cancer management.