Coincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by 90Y positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. In part 1, we reviewed the recent literature supporting the use of post-radioembolization 90Y PET/CT, described our scan protocol, patient cohort, diagnostic reporting guidelines, and results of qualitative analysis . In brief, we showed that with proper diagnostic reporting technique and emphasis on continuity of care, the presence of background noise did not pose a problem and 90Y PET/CT consistently out-performed 90Y bremsstrahlung single-photon emission computed tomography with integrated CT (SPECT/CT) in all aspects of qualitative analysis .
The terms ‘predictive dosimetry’, ‘target’, ‘non-target’, ‘technical success’, and the ‘planning-therapy continuum’ were also defined in part 1 . It is important for the understanding of part 2 to reiterate that our definition of technical success, an adaptation from conventional reporting standards , refers to the qualitative assessment of a satisfactory 90Y activity biodistribution in accordance with radiation planning expectations and should not be confused with ‘clinical success’  which is quantitatively related to dose-response radiobiology.
A knowledge gap exists today between institutions which practice predictive dosimetry and others which rely on semi-empirical methods . Readers who are accustomed to semi-empirical therapy planning may struggle to understand the dosimetric concepts discussed in this paper or its relevance to clinical practice. These readers are encouraged to refer to our recent series of publications explaining concepts in modern predictive dosimetry for 90Y resin microspheres and common misconceptions [3–6].
Where prognostication is of concern, qualitative analysis alone will not suffice . The scientific language of dose-response radiobiology is the radiation absorbed dose expressed in grays (Gy), not the prescribed activity expressed in becquerels (Bq). To realize the full potential of post-radioembolization 90Y PET/CT, absorbed dose quantification should be performed in relevant clinical settings. As 90Y radioembolization is a brachytherapy delivered by β--emitting microspheres, any tissue response is expected to follow predictable dose-response radiobiology. In principle, accurate knowledge of radiation thresholds in both target and non-target tissue facilitates the optimization of predictive dosimetry and enables the prognostication of technically unsuccessful cases to guide adjuvant therapy or mitigative action to minimize non-target radiation toxicity.
However, accurate tissue radiation thresholds for 90Y resin microspheres have remained elusive despite more than two decades of clinical use. Current radiation planning limits are broad and quote mean absorbed doses which falsely assume a uniform dose distribution: tumor > 120 Gy, non-tumorous liver < 50 to 70 Gy, lungs < 20 to 30 Gy [7–9]. As a consequence of this uncertainty, dosimetric dilemmas may be encountered in patients who may benefit from radiation planning up to the limits of normal tissue radiation tolerance. Furthermore, normal tissue radiation thresholds for 90Y resin microspheres shunted to non-target viscera such as the stomach or duodenum are largely unknown, precluding informed decision making for appropriate mitigative action. Historically, research into dose-response data had been technically challenging: intraoperative beta probes or histological examinations are invasive [10, 11], quantification by 90Y bremsstrahlung scintigraphy is problematic and largely inaccurate , and predictive dosimetry simulated by 99mTc macroaggregated albumin (MAA) is subject to variable accuracy due to the physical limitations of MAA .
Dosimetric studies have shown 99mTc MAA to be feasible for simulating the post-radioembolization biodistribution of 90Y resin microspheres [13–16]. However, 99mTc MAA is an imperfect surrogate for 90Y resin microspheres. Due to biophysical and technical differences such as particle size, specific gravity, injected particle load, microembolization, and catheter placement, 99mTc MAA can never exactly replicate the post-radioembolization biodistribution of 90Y resin microspheres [12, 17]. Therefore, predictive dosimetry simulated by 99mTc MAA provides only an estimate of the tissue absorbed doses intended by the nuclear medicine physician . Traditionally based on planar scintigraphy [13, 14], modern predictive dosimetry employs SPECT/CT to tomographically assess the biodistribution of 99mTc MAA and to improve its quantitative accuracy . So far, the accuracy of 99mTc MAA SPECT/CT predictive dosimetry has only been indirectly validated by inference from follow-up response [6, 18, 19]. For technically successful cases without visually significant discordant biodistribution between 99mTc MAA and 90Y resin microspheres, a direct ‘Gy-to-Gy’ comparison of intended doses by 99mTc MAA SPECT/CT predictive dosimetry versus post-radioembolization doses by microsphere biodistribution analysis has not yet been performed to date.
Recent experimental and clinical studies have shown post-radioembolization 90Y PET quantification to be accurate and feasible [1, 20, 21]. 90Y PET/CT thus presents a new opportunity to study the radiobiology of 90Y resin microspheres in a rapid, convenient, and noninvasive manner, with the ability to tomographically evaluate the dose distribution of an entire target organ in high resolution by a single scan. Moreover, quantitative 90Y PET data can be translated into dose-volume histograms (DVHs) to dosimetrically account for the heterogeneous nature of microsphere biodistribution.
In part 2 of our two-part retrospective report, we focus on post-radioembolization 90Y PET quantification on the same patient cohort as was reported in part 1 . We analyze dose-responses in tumor and non-target tissue using 90Y PET-based voxel dosimetry or Medical Internal Radiation Dose (MIRD) macrodosimetry [7, 22]. We describe the potential of 90Y DVHs to guide predictive dosimetry and discuss how the quantification of non-target absorbed doses may impact post-radioembolization care. Finally, we evaluate the accuracy of tumor 99mTc MAA SPECT/CT predictive dosimetry in direct comparison to post-radioembolization doses by 90Y PET.