The median age was 71 years (Q1 63 years; Q3 79 years), with 72% male and 28% female patients. Fifty percent of the patients had prior therapy, of which 50% received TACE, 38% surgical resection, 22% RFA (Radiofrequency Ablation) and 5% each SIRT (selective internal radiotherapy), IRE (irreversible electroporation) and MWA (microwave ablation), respectively. Median size of irradiated lesions was 3.5 cm (Range: 1.3–9.6 cm). Median CTV and PTV were 49.8 cm3 (range 8.7–502.1 cm3) and 141.2 cm3 (range 36.6–919.6 cm3), respectively. Mean healthy liver dose was 7 Gy RBE (range 2.6 – 16.3 Gy RBE). Among the treated HCC patients, most patients had a tumor in BCLC stage C (52%), followed by BCLC stage A (42%). Fifty percent of all patients had cirrhosis, of whom 78% had CHILD Pugh Score A and 22% had CHILD Pugh Score B cirrhosis. Chronic Hepatitis C (HCV) and Hepatitis B (HBV) was known in 27% and 15% of the patients. Detailed patient- and tumor- and treatment characteristics are shown in Tables 1, 2, and 3.

The median total dose of CIRT was 38 Gy RBE (Range: 32.4–42 Gy RBE), divided into 4 single doses every other day. One- and 2-year LC rate (LCR) were 100% and 92.3% respectively (Fig. 1A). Patients receiving ≥ median dosages of radiation had a LCR of 100% (Fig. 1B). After a median follow up of 19.5 months (range 3.2–137.2 months) only two patients experienced local progression of the irradiated lesion. Both of these patients suffered from HCC and were irradiated with a total dose of only 35.2 Gy RBE (4 × 8.8 Gy RBE) and received an additional CIRT upon progress on the same lesion without additional toxicity. One of the patients had another local progression within a year, whereas the other patient has been stable since. Median D-PFS was 37.6 months (Fig. 1C). Overall Local Treatment Response Rate (PR, CR) was 64.8%. Median OS was 3.2 years (range 0.15–11 years, Fig. 1D). An univariate cox proportional hazard model showed a significant association of OS with sex (better OS for male patients, p = 0.0344, Table 4). No correlation of clinicopathological characteristics and D-PFS could be seen (Table S1).

Kaplan-Meyer analysis of local control, D-PFS and overall survival after CIRT. 1- and 2-year local control rate were 100% and 92.3% respectively (A), separation of the cohort after median total dose revealed a 100% Local control rate of patients receiving ≥ median total dose of 38 Gy RBE (B). Distant progression free survival was 37.6 months (C) and overall survival was 3.2 years (D)

Between 2014 and 2022, 20 patients with primary liver cancer (16 HCC, 4 CCA) received photon-based SBRT with a total median BED of 83 Gy divided into 8 fractions (BED range 48–150 Gy in total, divided into 3–10 fractions). The most common prescription was 50 Gy in 5 fractions, prescribed to the 80% isodose. Median size of irradiated lesions was 3.2 cm (Range: 1.4–6.8 cm). Median CTV and PTV were 74 cm3 (range 19.5–639.7 cm3) and 135.4 cm3 (range 42.6–799.7 cm3), respectively. Liver cirrhosis was present in 85%, of which 88% were classified as CHILD A cirrhosis. After a median follow-up of 17 months (range 1–54.9 months) only one patient (CCA) experienced local progression within the radiation field. Detailed patient characteristics are listed in Table S2–S4. Univariate analysis of clinicopathological data revealed a significant correlation between survival and BMI level with better survival rates with BMI ≥ median with better overall survival for patients being slightly overweight (BMI 24.8–39.6) (Table S5).

Comparison of oncological outcomes in the two cohorts revealed a significant better D-PFS for CIRT versus photon-based SBRT (Fig. 2A, 3.1 versus 0.9 years, p = 0.006). Overall survival was significantly better for patients receiving CIRT compared to Photon-SBRT (Fig. 2B, 3.2 versus 1.7 years, p = 0.0014). 2-year local control rate was comparable (92.3% for CIRT versus 95.2% for photon-based SBRT). No significant differences in patient-, tumor- or treatment characteristics could be observed (Table 5). For a more profound analysis, a matched pair analysis between two cohorts was performed. Patients were matched for sex, age (± 5 years), tumor entity and size of lesion (± 2 cm). 17 patients of each treatment modality could be included in the matched pair cohort. Overall survival (2-year OS 100% versus 59.6%, p = 0.0398) and D-PFS (2-year D-PFS 75.7% versus 22.9%, p = 0.0006) were significantly better for the CIRT cohort in both cases (Fig. 2C, D).

Kaplan-Meyer analysis of overall survival and distant progression free survival in the matched-pair analysis. Comparison of CIRT and Photon-SBRT for distant progression free survival (PFS) and Overall survival between the whole cohorts (A, B) or as matched-pair analysis (C, D)

No dose-limiting toxicities were reported in either cohort. In the CIRT cohort, 73 adverse events (AEs) grade I—III occurred, distributed among 78% (28/36) of all patients. In the Photon-SBRT cohort, toxicities grade I—III occurred in all patients, totaling 59 AEs (Table 6). No significant difference in frequency of grade I / II or III toxicities could be observed in-between cohorts (p = 0.4923, χ2 = 1.417). The most common grade I radiation-related toxicity in both cohorts was fatigue (22.5% versus 11.6%). All cases of anemia, leukopenia and thrombocytopenia occurred either as long-term toxicity—most likely due to subsequent systemic treatments or on the basis of pre-existing cytopenia. All patients who were found to have grade III toxicities had these attributes prior to initiation of radiotherapy hence no therapy-related grade III toxicities occurred in neither CIRT nor Photon-SBRT cohort. Of note, liver function was not affected by radiation (no Grade > 2 elevation of liver enzymes, no > Grade 1 Ascites, no change in Child Pugh Score). Remarkably, within the CIRT cohort, four patients received re-radiation within 32.4 months (range 8.2–50.6 months) following the same protocol, of which two patients even had the same target volume. Again, no dose limiting toxicities and no significant impairment of liver function could be observed. Overall, both treatment regimen showed only slight differences in toxicities and did not cause persistent toxicities.