For Hepatocellular Carcinoma Treated with Yttrium-90 Microspheres, Dose Volumetrics on Post-Treatment Bremsstrahlung SPECT/CT Predict Clinical Outcomes

SIMPLE SUMMARY: Transarterial radioembolization (TARE) of the liver with Yttrium-90 (Y-90) microspheres is a prominent approach used to treat hepatocellular carcinoma (HCC), the most common primary liver cancer and the third-leading cause of cancer-related deaths worldwide. Recent studies have found that radiation dose estimates based on pretreatment simulations can predict HCC response to Y-90. We hypothesized that (1) Y-90 microspheres deposit heterogeneously due to variabilities in vascular dynamics; and (2) treatment response is better predicted by evaluating dose coverage of HCC in 3-dimensional space using actual Y-90 biodistribution derived from day-of-treatment nuclear imaging. We reviewed a cohort of 50 consecutive HCC patients with TARE Y-90 lobar treatments at a single institution looking for associations between volumetric dose coverage and clinical outcomes. Best treatment response most often occurred at 6 months post-TARE, with a migration toward better response after 3 months, complicating early imaging assessments. Islands of underdosed HCC appeared to compromise outcomes even when the mean or median dose to tumor was high. When prescribed dose increased along with the burden of disease, so did the mean dose to non-tumorous liver, limiting the safety of dose escalation. A multidisciplinary approach promises to accelerate advances in TARE dosimetry leading to improved clinical outcomes. ABSTRACT: In transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) with Yttrium-90 (Y-90) microspheres, recent studies correlate dosimetry from bremsstrahlung single photon emission tomography (SPECT/CT) with treatment outcomes; however, these studies focus on measures of central tendency rather than volumetric coverage metrics commonly used in radiation oncology. We hypothesized that three-dimensional (3D) isodose coverage of gross tumor volume (GTV) is the driving factor in HCC treatment response to TARE and is best assessed using advanced dosimetry techniques applied to nuclear imaging of actual Y-90 biodistribution. We reviewed 51 lobar TARE Y-90 treatments of 43 HCC patients. Dose prescriptions were 120 Gy for TheraSpheres and 85 Gy for SIR-Spheres. All patients underwent post-TARE Y-90 bremsstrahlung SPECT/CT imaging. Commercial software was used to contour gross tumor volume (GTV) and liver on post-TARE SPECT/CT. Y-90 dose distributions were calculated using the Local Deposition Model based on post-TARE SPECT/CT activity maps. Median gross tumor volume (GTV) dose; GTV receiving less than 100 Gy, 70 Gy and 50 Gy; minimum dose covering the hottest 70%, 95%, and 98% of the GTV (D70, D95, D98); mean dose to nontumorous liver, and disease burden (GTV/liver volume) were obtained. Clinical outcomes were collected for all patients by chart and imaging review. HCC treatment response was assessed according to the modified response criteria in solid tumors (mRECIST) guidelines. Kaplan-Meier (KM) survival estimates and multivariate regression analyses (MVA) were performed using STATA. Median survival was 22.5 months for patients achieving objective response (OR) in targeted lesions (complete response (CR) or partial response (PR) per mRECIST) vs. 7.6 months for non-responders (NR, stable disease or disease progression per mRECIST). On MVA, the volume of underdosed tumor (GTV receiving less than 100 Gy) was the only significant dosimetric predictor for CR (p = 0.0004) and overall survival (OS, p = 0.003). All targets with less than CR (n = 39) had more than 20 cc of underdosed tumor. D70 (p = 0.038) correlated with OR, with mean D70 of 95 Gy for responders and 60 Gy for non-responders (p = 0.042). On MVA, mean dose to nontumorous liver trended toward significant association with grade 3+ toxicity (p = 0.09) and correlated with delivered activity (p < 0.001) and burden of disease (p = 0.05). Dosimetric models supplied area under the curve estimates of > 0.80 predicting CR, OR, and ≥grade 3 acute toxicity. Dosimetric parameters derived from the retrospective analysis of post-TARE Y-90 bremsstrahlung SPECT/CT after lobar treatment of HCC suggest that volumetric coverage of GTV, not a high mean or median dose, is the driving factor in treatment response and that this is best assessed through the analysis of actual Y-90 biodistribution.