Form and function: the integration of physics and biology.

Radiation oncology is a specialty that has been driven by anatomy and structure. The major advances in clinical radiation therapy for the past century have been defined by an ability to better define anatomy, improve localization of tumor masses, and use more sophisticated radiation delivery systems that have allowed a progressively improved conformation of dose around the defined anatomy. Despite the enormous gains made in understanding the biology of cancer and the interaction of radiation with matter, the impact of biology on clinical radiation therapy has been disappointing. Increased understanding of the basic biology of tumors has not had a large impact on how we deliver radiation therapy or most cancer therapy. We are a discipline that has been driven more by physics and engineering than by biology. Imaging, the link to our historic connections with our diagnostic radiology colleagues, has driven much of our practice. We now appear to be heading to a watershed where biology and imaging come together, to let us use information from both areas in clinical decision making and treatment implementation. The advances in functional imaging have begun to produce, and will continue to produce, major changes in our day-to-day practice of medicine. The article by Ling et al. in this issue of IJROBP effectively highlights the importance of functional imaging. It is deserving of attention because our specialty has only just begun to use this information effectively, but there is still a long way to go. We are all familiar with older nuclear medicine studies that allow us to detect tumors, albeit fairly poorly: gallium, carcinoembryonic antigen (CEA), or Prostascint scans. Studies such as positron emission tomography (PET) scans with F-18 fluorodeoxyglucose (FDG) as the tracer may be just the first generation of agents for enhanced tumor localization. Sensitivity is a problem, but better agents may be developed and the imaging techniques themselves will likely improve. Magnetic resonance imaging and magnetic resonance spectroscopy are other techniques which will likely be of great importance in our ability to distinguish biological parameters of the tumor to help define therapy. The ability to localize prostate cancers to defined areas of the prostate has already been demonstrated with MR spectroscopy and, with the improved dose delivery techniques already at our disposal, could markedly affect therapy. Why should the entire prostate be the target volume (at least for the boost) for a small localized lesion? We would, however, be making a mistake if we equated functional imaging with just PET and its use for determining if there are other tumor nodules present. Single photon emission computed tomography (SPECT) is also undergoing dramatic changes. SPECT is less expensive and may allow the use of more isotopes, although it has inherently less sensitivity. Either of these modalities may allow us to track changes in tumors at the molecular level in ways we could not even imagine a few years ago. Animal systems are being developed that will allow for combined PET and CT scans for small animal systems. Small animal MR systems are being developed with resolutions of 50 microns. We will be able to track gene expression in animals over time, define metabolic changes in a tumor, and perhaps track other molecular markers. The ability to detect cell surface receptors or markers of cellular radiosensitivity or resistance with PET, SPECT, or nuclear magnetic resonance (NMR) are real possibilities One of the major limitations of CT planning at present is that, although we can conform the dose quite precisely, we often do not know where the tumor is. Functional imaging gives us a potential tool to solve this problem for certain clinical situations. A major challenge will be to integrate functional imaging approaches with the techniques that we use daily with 3D treatment planning and delivery. This will take innovation, and there will be pitfalls along the way. Instead of simply identifying tumor masses on CT or other density-based imaging modalities, we will be able to translate biological differences between tumor and normal tissues, as visualized on the functional imaging studies, into treatment plans. However, we need to be certain that we can perform an accurate image registration of the planning CT with the functional imaging study, or the data will be worthless. Issues of patient immobilization and setup repro-