Intratumoral Dose Escalation Using Lattice Radiotherapy for Hepatocellular Carcinoma with Unfavorable Size and Location

Purpose/Objective(s)Stereotactic body radiation therapy (SBRT) is a standard of care for unresectable hepatocellular carcinoma (HCC). However, its safe delivery is limited by tumor size and adjacent organs-at-risk (OARs). RTOG 1112 showed a survival benefit with local control in advanced HCC, but median dose was limited to 35 Gy in 5 fractions due to OARs. Here, we demonstrate the dosimetric feasibility of lattice radiation therapy (LRT) for dose escalation in advanced HCC.Materials/MethodsFive-fraction volumetric arc-based (VMAT) LRT plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, or 50 Gy. Valley dose target volumes over a range of 2 to 45 Gy were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was applied to generate a final plan. The planning target volume (PTV) was a 5-mm uniform expansion from the GTV. All plans were generated at maximum inspiration on 4D-CT. OAR parameters were compared against a standard 5-fraction SBRT plan using Wilcoxon signed-rank testing.ResultsGTV and PTV measured 593 (23%) and 804 (32%) cm3, respectively, of a total liver volume of 2525 cm3. The minimum distance of GTV from stomach and duodenum was 6 mm and 2 mm, respectively. Plans were evaluated as per RTOG 1112 with stepwise reduction from a maximum PTV dose of 50 Gy based upon ability to meet mean liver dose (MLD, defined as liver-GTV) constraints; the 30 Gy threshold was the highest achievable. Of 7 eligible LRT plans, 5 with ablative 50 Gy peak doses were analyzed. Associated valley doses were 15 or 20 Gy. Median values of mean GTV and PTV doses for these plans were 36.2 (IQR, 34.6 - 37.8) and 32.9 (IQR, 31.3 - 33.4) Gy, respectively. A median of 12.4% (IQR, 7.4 - 28.4) of the GTV received a dose of 50 Gy. Median doses to 0.5 cc of stomach and duodenum were 16.7 Gy (range, 15.6 - 19.6) and 14.4 Gy (range, 12.3 - 23.9), respectively. The median value for MLD was 13.9 Gy (range, 13.6 to 14.8) and the median volume of normal liver spared 15 Gy was 1114 cm3 (range, 969 to 1154). These hepatic parameters were significantly decreased compared to a standard 30 Gy SBRT plan (18.1 Gy and 611.3 cc spared, p = 0.043 for both) which did not meet constraints.ConclusionDose escalation of advanced HCC using LRT is dosimetrically feasible. Though mean target doses remained limited by MLD, LRT allowed delivery of ablative dose to 12.4% of the GTV while meeting critical OAR constraints. Intratumoral dose-escalation may improve local control in advanced HCC patients. Stereotactic body radiation therapy (SBRT) is a standard of care for unresectable hepatocellular carcinoma (HCC). However, its safe delivery is limited by tumor size and adjacent organs-at-risk (OARs). RTOG 1112 showed a survival benefit with local control in advanced HCC, but median dose was limited to 35 Gy in 5 fractions due to OARs. Here, we demonstrate the dosimetric feasibility of lattice radiation therapy (LRT) for dose escalation in advanced HCC. Five-fraction volumetric arc-based (VMAT) LRT plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, or 50 Gy. Valley dose target volumes over a range of 2 to 45 Gy were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was applied to generate a final plan. The planning target volume (PTV) was a 5-mm uniform expansion from the GTV. All plans were generated at maximum inspiration on 4D-CT. OAR parameters were compared against a standard 5-fraction SBRT plan using Wilcoxon signed-rank testing. GTV and PTV measured 593 (23%) and 804 (32%) cm3, respectively, of a total liver volume of 2525 cm3. The minimum distance of GTV from stomach and duodenum was 6 mm and 2 mm, respectively. Plans were evaluated as per RTOG 1112 with stepwise reduction from a maximum PTV dose of 50 Gy based upon ability to meet mean liver dose (MLD, defined as liver-GTV) constraints; the 30 Gy threshold was the highest achievable. Of 7 eligible LRT plans, 5 with ablative 50 Gy peak doses were analyzed. Associated valley doses were 15 or 20 Gy. Median values of mean GTV and PTV doses for these plans were 36.2 (IQR, 34.6 - 37.8) and 32.9 (IQR, 31.3 - 33.4) Gy, respectively. A median of 12.4% (IQR, 7.4 - 28.4) of the GTV received a dose of 50 Gy. Median doses to 0.5 cc of stomach and duodenum were 16.7 Gy (range, 15.6 - 19.6) and 14.4 Gy (range, 12.3 - 23.9), respectively. The median value for MLD was 13.9 Gy (range, 13.6 to 14.8) and the median volume of normal liver spared 15 Gy was 1114 cm3 (range, 969 to 1154). These hepatic parameters were significantly decreased compared to a standard 30 Gy SBRT plan (18.1 Gy and 611.3 cc spared, p = 0.043 for both) which did not meet constraints. Dose escalation of advanced HCC using LRT is dosimetrically feasible. Though mean target doses remained limited by MLD, LRT allowed delivery of ablative dose to 12.4% of the GTV while meeting critical OAR constraints. Intratumoral dose-escalation may improve local control in advanced HCC patients.