Dosimetry and Radiobiology of Alpha-Particle Emitters

In almost every case, administered activity (AA)-based dosing has been used to define the maximum tolerated dose in phase I radiopharmaceutical therapy (RPT) trials. This dose-level is then used (with some exceptions) in all subsequent patients. Such an approach is inherently sub-optimal because the absorbed dose to normal organs and to tumour can vary, in some cases, substantially for a given AA across different patients. Accordingly, AA-based RPT leads to conservative treatment that, typically, prevents normal organ toxicity but at the expense of tumour control. Aside from a compromised ability to efficiently identify the tolerable treatment level, selection of AA as the escalation variable in phase 1 trials also fails to make the most of a unique opportunity in the development and commercialization of an RPT. That is, to collect critical dose-response data that could much more efficiently guide implementations of the treatment beyond the patient population under study. Empiric escalation also precludes the collection of data relevant to developing and testing radiobiological models of tumour control and normal organ tolerance that are specific to RPT and that may be compared and contrasted with models developed in radiotherapy. A more rational approach to phase I escalation involves an escalation scheme in which the absorbed dose to the dose-limiting organ is the escalation variable. Key to implementing absorbed dose escalation in RPT is the ability to image the activity distribution of the therapeutic radiopharmaceutical longitudinally. If quantitative imaging of the RPT is possible, and treatment may be divided into two or more fractions then the first fraction may be used to perform dosimetry. The activity administered for subsequent fractions can then be adjusted based upon the results of the dosimetry calculation. This is a potential alternative to collecting a pre-therapy tracer study. When the therapeutic radiopharmaceutical does not emit photons adequate for imaging or when the administered activity for therapy is below the imaging sensitivity of current imaging technologies, validated imaging surrogates of the therapeutic radiopharmaceutical may be used. Examples of both approaches may be found in the literature