Multiscale dosimetric and radiobiological modeling for radiopharmaceutical therapy (RPT), Part 3: Considerations at different temporal scales

Introduction: Part 2 of this series of exhibits discussed the critical role of spatial scale in understanding and optimizing radiopharmaceutical therapy (RPT). However, RPT is also strongly influenced by a multitude of dynamic processes, including both the pharmacokinetics of the administered radiopharmaceuticals and the pharmacodynamics of the radiobiological response. The aim of this exhibit is to present and discuss different temporal scales that must be considered for RPT in view of therapeutic response.

Methods: We have identified the following important aspects for which a deeper understanding of the temporal effects are needed to correctly model and optimize RPTs: 1) the time it takes to infuse the radiopharmaceutical, 2) the residence time of the radiopharmaceutical in tumors and healthy organs, 3) the duration and fractionation schedule of the treatment, which is one of the main differences between RPT and external beam radiation therapy (EBRT), 4) single-cell repair and cell cycle intervals, for both cancerous and healthy cells, and 5) overall long-time treatment responses and clinical outcomes, including the remission or recurrence of disease, or the appearance of acute and late radiation sequelae based on absorbed and biological effective doses. These distinct aspects span a broad spectrum of temporal scales, including seconds, minutes, days, months, and years. We present an overview of the hypothetical relationships between temporal scales and the outcomes of a complete RPT therapy (i.e. accounting for all cycles) and contrast them with the corresponding temporal scales in EBRT, from which dose-toxicity limits are currently adopted.

Results: 1) The rate at which radiopharmaceuticals are infused (e.g., bolus, slow infusion, or multiple small bolus infusions) can lead to higher or lower uptake in both tumors and healthy organs given the levels of saturation of the receptors. 2) This will affect individual residence times and consequently the absorbed dose in tissue. 3) Irradiation from one RPT cycle lasts weeks due to the slow radioactive decay and the fact that the radiopharmaceutical is inside the body, while a single EBRT fraction delivers radiation only over minutes. Moreover, RPTs are performed with fewer cycles that are spaced by months, while EBRT fractions usually occur every one or two days and are completed within one or two months. 4) Given the lower dose rates and longer fractionation schedules in RPT vs. EBRT, the effects on DNA repair, cell death, and cell cycle phase are likely different and merit further study before adopting dose limits from EBRT for RPTs. This knowledge could guide the frequency at which RPT cycles should be administered, which is currently in the order of 6 to 8 weeks and could provide guidance as to whether the number of cycles can be reduced. 5) Disease remission or recurrence, along with toxicity in various OARs (e.g., bone marrow, kidneys, and salivary glands) can occur soon after the therapy administration (days) or at later times (years) at different levels. Determining these levels and temporal scales more precisely will ultimately guide treatment personalization based on overall and progression free survival and quality of life.

Conclusions: The previous part of this exhibit highlighted the importance of spatial multiscale modeling for personalized RPT dosimetry and treatment planning. In this exhibit, we expand the discussion to the temporal considerations of RPTs, including dose rates, possible differences in radiopharmaceutical administration, tissue uptake and residence, and radiobiological response. We highlight differences with EBRT, and discuss the validity of EBRT-extrapolated absorbed dose limits for RPT. These considerations are expected to provide critical insights into the eventual optimization of RPT delivery, including infusion, number and timing of cycles, and overall administered activity, in a way that consider expected survival, progression and quality of life.