Radiopharmaceutical Dose-Response and Relative Biological Effectiveness Assessment Using an Integrated Metric for in vivo Tumor Growth
Abstract
Purpose
Translation of tissue and tumor dose-response thresholds from external-beam radiation therapy (EBRT) to radiopharmaceutical therapies (RPTs) for dose optimization requires accurate values of relative biological effectiveness (RBE), which are still not known precisely. RBE is often measured in preclinical xenograft tumor experiments using the timing of post-therapy regrowth through metrics such as growth delay time (GDT). These regrowth-based metrics are ill posed for therapeutic studies aiming for tumor suppression. We defined a straightforward integration metric that accommodates both tumor growth and regression and explored its utility for RPT RBE measurements in mice.
Methods
Mean tumor burden (MTB) for an in vivo tumor volume function was defined as the integrated area under the curve, normalized to initial volume and averaged in time. MTB correlation with absorbed dose was compared to GDT for in vivo radiobiology studies of prostate cancer xenograft models in mice using daily fractionated EBRT, alpha-particle RPT (225Ac-DOTA-YS5), or positron/Auger RPT (134Ce-PSMA-617). Ex vivo 225Ac-progeny gamma counting (Hidex AMG, Python) and in vivo 134Ce/134La-PET imaging (nanoScan, OLINDA/EXM) were used for tumor dosimetry. Linear (GDT) and exponential (MTB) dose-response curves for each modality provided the basis for a dose-independent RBE calculation.
Results
GDT could not be calculated in cases of tumor regression (N=11/41) and required extrapolation for partial regrowth (N=10/41). MTB yielded similar or lower variance than GDT in all treatment cohorts. The in vivo RBE value for 225Ac-DOTA-YS5 compared to EBRT (10—40 Gy at 2 Gy/fx) was 5.4±0.3 (MTB) or 1.8±0.9 (GDT). For 134Ce-PSMA-617, the in vivo RBE was 0.5±0.3 (MTB) or 0.1±0.1 (GDT).
Conclusion
MTB-calculated RBE was consistent with literature alpha- and positron-RBE values, while GDT was undefined for 27% of treated subjects. This straightforward metric facilitates assessment of biological effects in therapy studies that induce in vivo tumor suppression.