Dosimetry-Driven Personalization of Radiopharmaceutical Therapies: Evidence and Opportunities.

Abstract

Radiopharmaceutical therapy (RPT) is growing in clinical importance and utilization. First-generation RPTs such as ¹³¹I-tositumomab (Bexxar) radioimmunotherapy of lymphoma used simplified whole-body dosimetry in each patient to adjust administered activity levels to deal with patient-to-patient heterogeneity of radiation absorbed dose coefficients. In contrast, the commercially successful ¹⁷⁷Lu-vipivotide tetraxetan and ¹⁷⁷Lu-DOTATATE RPTs are given as one administered-activity-fits-all treatment approach not incorporating patient dosimetry. External beam radiotherapy dosimetry has been refined over nearly 100 years and is now routinely deployed in planning each therapy. This article reviews the tumor radiation dose-response data for external beam radiotherapy, showing many common cancers are more effectively treated with a precisely delivered higher rather than lower radiation dose. Data showing the heterogeneity of absorbed dose to tumors and normal organs using state-of-the-art dosimetry methods are reviewed for current RPTs, which strongly suggest a significant number of patients are underdosed, relative to organ tolerance, when assuring safety with one administered-activity-fits-all approaches. Data are presented which strongly suggest improved outcomes for patients in whom dosimetry is used to plan the RPT. Challenges in variability of measurement of radiation absorbed dose from RPT are highlighted, which are minimized by standardization. Cautions are identified when dosimetry suggests a diminished return on additional treatments after the initial cycles. A path forward is proposed in which dosimetry data are increasingly collected in clinical practice in a nascent National Oncologic Dosimetry Registry to aid in combination therapies with external beam radiotherapy, for dose escalation and optimization in individual patients and to better inform the field on the safety and longer-term tolerability of RPT. RPT is evolving rapidly but is generally not curative. We suggest dosimetry will be an important part of the path forward to move RPT from life-prolonging to curative.