HCC tumor response following 90Y-radioembolization with prospective voxel dosimetry in RAPY90D clinical trial

Introduction: To report interim analysis of hepatocellular carcinoma (HCC) tumor responses following patient-specific voxel-dosimetry-based treatment planning in a single-arm single-center prospective ⁹⁰Y-glass radioembolization clinical trial (RAPY90D, NCT03896646). The primary endpoint was measurement of the localized mRECIST objective response rate (ORR). The secondary objectives included evaluation of disease control rate (DCR), complete response rate (CRR), and characterization of tumor responses.

Methods: The study has completed enrollment (n=40). Eligibility criteria included all adult HCC patients with non-infiltrative tumor diameters ≥3 cm that are otherwise eligible for ⁹⁰Y-glass radioembolization. All patients underwent hepatic angiography with in-room fan-beam CT (AngioCT), received ^99mTc-MAA injections at all planned sites of treatment, and were imaged with SPECT/CT. AngioCT and ^99mTc-MAA SPECT/CT were used to determine the volume of the perfused treated territories and to develop patient-specific, voxel-dosimetry-based treatment plans targeting a tumor mean dose ≥200 Gy and normal liver mean dose ≤100 Gy. In cases that involved ≤2 segments, treatment plans were developed using single-compartment dosimetry targeting a mean dose ≥200 Gy. Image-based tumor responses (localized mRECIST) were determined at 3- and 6-month follow-up (+3mo, +6mo). Post-treatment dose verification was performed within 24 hours using ⁹⁰Y-SPECT/CT and ⁹⁰Y-PET/CT. We report summary statistics, DCR, ORR, and CRR on 33 patients (43 tumors) who have completed +3mo and +6mo evaluations. We characterized the relationship of tumor size (defined as the effective diameter) and tumor dose on tumor response, and the relationship of tumor dose and dose heterogeneity (defined as the ratio of standard deviation to mean) on tumor size.

Results: The median (range) size of 43 tumors was 4.5 (2.9-12.3) cm: 16 (37%) < 4 cm, 27 (63%) < 6 cm, and 6 (14%) > 8 cm. The median (range) voxel-dosimetry tumor mean dose delivered was 351 (172-981) Gy; with 42/43 (98%) > 200 Gy, 32/43 (74%) > 300 Gy, and 15/43 (35%) > 400 Gy. DCR of 100% was achieved at both +3mo and +6mo. At +3mo and +6mo, the measured ORR was 70% and 95%, and the CRR was 42% and 58%, respectively. The 2 (5%) stable disease tumors at +6mo had initial sizes/doses of 10.7 cm/255 Gy and 11.0 cm/362 Gy. Compared to their measured mRECIST category at +3mo, tumors at +6mo showed either the same (26/43=60%) or improved (17/43=40%) response status. Tumors that did not achieve complete response (CR) did not receive a significantly lower dose (363 Gy vs. 427 Gy, p=0.15, Welch’s t-test), but were found to be significantly larger in size at treatment time (7.0 cm vs. 4.4 cm, p=0.0016). A multi-variate logistic regression showed that only tumor size was prognostic of CR at +6mo with an odds ratio of 0.58 (95%CI: 0.36-0.81) and a ROC AUC of 0.79 (95%CI: 0.65-0.94, p=0.0013). The threshold size for CR was estimated as <5.6 cm with sensitivity of 88% and specificity of 72%; and tumors size <5.6 cm, on average, received a significantly higher mean dose (437 Gy vs. 336 Gy, p=0.018, Welch’s t-test). Tumor mean dose and dose heterogeneity were found not to be correlated with tumor size.

Conclusions: Interim analysis of the RAPY90D trial data has demonstrated the feasibility and benefits of prospective, patient-specific, ^99mTc-MAA SPECT/CT-based voxel dosimetry treatment planning for ⁹⁰Y-radioembilization of HCC, even for the treatments of large bulky tumors (>6 cm). Target mean tumor dose of >200 Gy was achieved in 98% cases, resulting in DCR=100%, ORR=95%, and CRR=58%. These RAPY90D trial results show marked improvement over prior retrospective studies that achieved ORR of only 55%-60% using package-insert (single-compartment) dosimetry. ORR did not regress between +3mo and +6mo follow-ups and response status improved in 40% of cases. Within this prospectively planned cohort with verified mean tumor doses >200 Gy mean doses, CR was significantly associated with tumor size below 5.6 cm.

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