RADAR commentary: Evolution and current status of dosimetry in nuclear medicine.

There is a long history of absorbed dose calculations being performed to evaluate the risks involved in the application of radiopharmaceuticals to medical studies. In the 1940s, Marinelli, Quimby, and Hine (1–3) published a set of articles that presented a summary and approach to radionuclide dosimetry. In 1956 Loevinger et al. (4) summarized the field at that point, and then in 1968 the newly formed MIRD Committee of the Society of Nuclear Medicine published the original MIRD schema as MIRD Pamphlet No. 1 (5). In 2003, the RAdiation Dose Assessment Resource (RADAR) task group of the Society of Nuclear Medicine demonstrated an easily understood and unified method for calculating internal doses in nuclear medicine or radiation protection and implemented the method in easy-to-use Web and computer tools (6). Over these many years, numerous articles have been written describing new and improved dosimetry models and methods, better quantification schemes for counting, scintillation camera imaging, and radiobiologic modeling, along with recognition that baseline pretherapy dose-limiting organ radiosensitivity needed to be part of any predictive treatment plan. Internal dosimetry has always been an integral part of radionuclide drug development, being used primarily from 2 perspectives. Most often, dosimetry is performed as an a posteriori analysis after radiopharmaceutical administration (diagnostic and therapeutic) simply to provide standard dose estimates for that procedure. According to U.S. Food and Drug Administration requirements, all phase I clinical trials involving a radioactive component must include studies that will obtain sufficient data for these “characterizational” dosimetry calculations, which are done for all source and target regions in a limited number of subjects. The second type of dosimetry is used to guide therapy before treatment and is therefore performed as an a priori or predictive analysis. In external-beam or brachytherapy, dosimetry is evaluated for all patients but generally only for a single region corresponding to the treatment area. Unfortunately, unlike the universal agreement on the importance and need for characterizational dosimetry in drug development, dosimetry generally is not used to guide radionuclide therapy, despite the substantial efforts to develop and standardize internal dose methods. There is currently no consensus within the scientific community on the utility of predictive dosimetry, and regulatory agencies do not require its use for determining a treatment activity prescription, because they believe there is little evidence indicating that dosimetry is predictive (of either toxicity or response), as compared with simpler administration methods (administered activity or activity adjusted for body mass or surface area). The only exception is the case of 131I-tositumomab (Bexxar; GlaxoSmithKline) (7), for which a relatively simple yet useful (whole-body) dosimetry approach is used to provide a patient-individualized activity administration. Radiation has the unique distinction among other forms of therapy (e.g., drugs or biologics) that it can be detected external to the patient, allowing organ and body activity and clearance estimates from which individualized radiation doses can be determined. Thus, dosimetry has the potential to become an important and clinically useful scientific tool, because it offers a unique opportunity to develop an appropriate treatment activity prescription on a per-patient basis and to quantify the risk involved in the administration of a therapeutic agent to tumors and normal tissues in each patient before the treatment is given, as is always done for external-beam radiotherapy. In contrast, this is not done in chemotherapy, for which administered quantities are empirically determined. Building a consensus to support predictive dosimetry will occur only if there are data clearly showing its benefit in treatment planning and if evidence to support this position is available.