The Low Hepatic Toxicity per Gray of ⁹⁰Y Glass Microspheres Is Linked to Their Transport in the Arterial Tree Favoring a Nonuniform Trapping as Observed in Posttherapy PET Imaging

Abstract

90 Y resin and glass microsphere liver radioembolizations delivering lobar doses of 70 and 120 Gy, respectively, display hepatic toxicity similar to 40-Gy fractionated external-beam radiotherapy. We investigated how the lower number of glass microspheres could induce a sufficiently nonuniform dose distribution explaining this paradox. Methods: Microscale dosimetry was assessed in the realistic liver model developed by Gulec et al. but using the Russell's dose deposition kernel. A lattice of hexagonal prisms represented the hepatic lobules. Two hepatic arterial tree models-that is, a fixed-length and a variable-branches length-were used for the microsphere transport. Equal or asymmetric microsphere relative-spreading probability between 2 daughter vessels was assumed. Several 120-Gy liver simulations were performed: periodic simulations, where 1 or 6 glass microspheres were trapped in all and in only 1 of 6 portal tracts, respectively, and random simulations, where glass microsphere trapping assumed an equal probability for all the portal tracts or a variable probability depending on the successions of artery connections leading to the portal tract, both for the 2 arterial tree models. Results: For the 2 uniform simulations, all hepatic structures received at least 100 Gy. The fast decrease of the 90 Y kernel as the inverse of the square of the distance r is counterbalanced by the number of contributing lobules containing microspheres that increases as r 2 . The random simulation with equal-spreading probability gave for the less irradiated tissue a lobule dose distribution centered around 103 Gy (full width at half maximum, 20 Gy). The distribution became significantly asymmetric with the 60%-40% relative-spreading probability, with a shift of the maximum from 103 down to 50 Gy, and about 17% of the lobules got a dose lower than 40 Gy to their different structures. Conclusion: The large nonuniform trapping produced by the microsphere transport in the arterial tree jointly with the low number of injected glass microspheres begins to explain their lower hepatic toxicity per Gray. In addition, the nonuniform trapping supports the fact that the granular aspect of 90 Y PET imaging observed in patients could represent some reality and not only statistical noise.

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

“…Similar levels of clustering were also shown in simulations of GMS in different arterial tree models when the difference in number of spheres is taken into account [41].…”

“…A similar MC study showed that the non-uniform trapping produced by GMS transport in a simulated arterial tree may explain their lower toxicity per Gy [41]. They showed a highly asymmetric spread of dose distribution, with 17% of lobules receiving < 40 Gy.…”

“…Recent studies have shown a relatively large difference in mircoscopic radiobiology between GMS and RMS behaviour, and that the lower number of GMS used for treatment provides a less uniform irradiation, thus allowing a mean whole liver absorbed dose (D WL ) of 120 Gy with no toxicity to the radiosensitive portal triads [41,42], or 150 Gy for single treatment (268 Gy for repeat administrations) [43]. Their results provide reasoning to the D NL threshold noted in other clinical studies of 70 Gy using GMS [44] and approximately 40-50 Gy using RMS [13,45].…”

Radioembolization with 90Y-loaded microspheres: high clinical impact of treatment simulation with MAA-based dosimetry

“…Lam et al [8] also rightly underlined the fact that dosimetric results and threshold should be interpreted with caution, given the numerous confounding factors that can be encountered, such as the different radiobiological properties of available 90 Y-loaded microspheres [14], histological tumour types with different radiosensitivity profiles, underlying hepatic disease, the different dosimetric tools used, as mentioned above, and so on. These points must be kept in mind when analysing study results.…”

A Hepatic Dose-Toxicity Model Opening the Way Toward Individualized Radioembolization Planning

“…In a recent study (8), we showed by Monte Carlo simulations that the random and asymmetric spreading of microspheres between the daughter vessels at the nodes of the hepatic arterial tree induces a large nonuniformity of microscale dose distribution as observed on PET (9,10) (Fig. 1).…”