Patients

A total of 102 patients (85 men, 17 women; mean age, 53.8 ± 10.4 years [range, 28–79 years]) with 102 HCCs were included. The details of the study population are presented in Table 1. The mean tumor size was 22.2 ± 10.0 mm (median, 18.5 mm; range, 7–50 mm).

Table 1 Characteristics of the patients

The median follow-up time was 15 months (range, 6–52 months). Seventy-eight and 70 patients had follow-up times > 6 months and ≥ 12 months, respectively. According to the diagnostic standard, the 102 lesions were divided into two groups: with (n = 6) and without (n = 96) local progression. The progression rate was 5.9% (6 cases).

Tumor size in group without local progression

Ten of 96 (10.4%) HCCs increased in size in the initial months post-SBRT. These lesions either decreased in size (n = 9) or remained stable (n = 1) during the follow-up period.

The most obvious HCC size reduction was observed within 3 months post-SBRT (Fig. 2a). During the 3-month follow-up MRI, the median HCC size reduction was 40.5% (mean, 36.0%), and the sizes of 67 of the 96 treated HCCs (69.8%) had decreased by ≥ 30%. By the end of the study period, the median proportion of maximum decrease was 60.0% (mean, 56.0; range, 9.0–86.0%). Seventy-two of 96 treated HCCs (75.0%) showed a size reduction ≥ 50%, while eighty-five of 96 showed a size reduction ≥ 30%. Moreover, 71 of 78 HCCs (91.1%) had stable sizes at 6 months post-SBRT, exhibiting a decrease in size ≤ 5 mm at the last follow-up compared with that measured at 6 months post-SBRT.

Fig. 2

Change in maximum tumor diameter in the first 12 months for hepatocellular carcinoma (HCCs) undergoing stereotactic body radiation therapy (SBRT). a Change in maximum tumor diameter in the first 12 months for HCCs undergoing SBRT. b Change in alpha-fetoprotein (AFP) levels in the first 12 months for HCCs undergoing SBRT. Patients with a baseline elevation (AFP level > 25 IU/mL) were included. Dots represent means, while lines represent 95% confidence intervals

Enhancement patterns in group without local progression

At baseline, all lesions exhibited APHE and washout. Within the first month post-SBRT, 59.4% (57/96) of the HCCs still exhibited APHE and washout. At 3 months, the proportion of HCCs exhibiting delayed enhancement (54.2% [52/96]) was higher than that of HCCs exhibiting APHE and washout (26.0% [25/96]). Meanwhile, p values derived from two-by-two comparisons between the three enhancement patterns were all < 0.05. From 6 months post-SBRT, the main enhancement pattern was converted to delayed enhancement, followed by non-enhancement.

Most (92.7% [89/96]) of the HCCs showed a conversion from the APHE and washout pattern to the other two enhancement patterns (Table 2), and the number of cases with pattern conversion within 3 months post-SBRT was the highest. At the end of the study, 71.9% (69/96) and 20.8% (20/96) of the HCCs demonstrated conversion to delayed enhancement (Fig. 3) and non-enhancement (Fig. 4) patterns, respectively, while seven cases demonstrated a persistence in the APHE and washout pattern until the time of the last follow-up (median, 9 months; range, 6–21 months) (Fig. 5). The median time for complete resolution of the APHE and washout pattern was 3 months (mean, 3.4 months; range, 1–21 months). In most (91.7% [88/96]) HCCs, the APHE and washout pattern persisted ≤ 6 months. The enhancement patterns became stable 9 months post-SBRT.

Table 2 Temporal evolution of MR imaging in tumors without progressionFig. 3

SBRT-treated HCC with conversion from APHE and washout before SBRT to delayed enhancement immediately after SBRT. A 44-year-old man with HBV-related cirrhosis and a 1.5-cm HCC in the seventh segment of the liver (arrow). At baseline, the lesion exhibited APHE and washout (a, b). Additionally, the lesion was hyperintense on T2WI (c) and DWI (d). At 1-month post-SBRT, the lesion demonstrated conversion to delayed enhancement (hypoenhancement on arterial phase imaging with increasing enhancement) (e, f) with a decrease in size, measuring 1.1 cm and a decrease in signal intensity on T2WI (g) and DWI (h). At 3 months post-SBRT, the lesion presented persistent delayed enhancement (i, j). Furthermore, at 3 months post-SBRT, there was wedge-like parenchymal arterial phase hypoenhancement and an increase in delayed phase images in the surrounding treated zone (asterisk). The lesion was categorized as CR and LR-TR nonviable based on m-RECIST and LI-RADS. SBRT stereotactic body radiation therapy; A arterial phase; V portal venous phase; T2WI T2-weighted imaging; DWI diffusion-weighted imaging; 6 min, delayed phase (6 min); CR complete response; APHE arterial phase hyperenhancement; HCC hepatocellular carcinoma; m-RECIST Modified Response Evaluation Criteria in Solid Tumors; LI-RADS Liver Reporting and Data System

Fig. 4

SBRT-treated HCC with conversion from APHE and washout pre-SBRT to non-enhancement immediately following SBRT. A 55-year-old man with HBV-related cirrhosis and a 3.0-cm cm HCC in the seventh segment of the liver (arrow). At baseline, the lesion exhibited APHE and washout (a, b). At 1-month post-SBRT, the lesion still exhibited APHE and washout with a decrease in size (c, d), measuring 2.5 cm. The lesion was categorized as PR and LR-TR equivocal based on m-RECIST and LI-RADS. At 3 months post-SBRT, the lesion had decreased in size, measuring 2.3 cm, with non-enhancement on multi-phased images (e, f), which persisted until the last follow-up MRI (13 months post-SBRT) (g, h). The lesion was categorized as CR and LR-TR nonviable based on m-RECIST and LI-RADS after 3 months. Additionally, at 3 months post-SBRT, there was a wedge-like parenchymal hyperenhancement with mild volume loss, which persisted until the last MRI (asterisk). SBRT stereotactic body radiation therapy; A arterial phase; 3 min, delayed phase (3 min); PR partial response; CR complete response; APHE arterial phase hyperenhancement; HCC hepatocellular carcinoma; m-RECIST Modified Response Evaluation Criteria in Solid Tumors; LI-RADS Liver Reporting and Data System; MRI magnetic resonance imaging

Fig. 5

SBRT-treated HCC with persistent APHE and washout. A 66-year-old man with HBV-related cirrhosis and a 1.8-cm HCC in the eighth segment of the liver (arrow). At baseline, the lesion exhibited APHE and washout (a, b). At 1-month post-SBRT, the lesion exhibited APHE and washout (c, d) with a decrease in size, measuring 1.3 cm. The lesion showed persistent APHE and washout at 6 months (e, f) and 18 months post-SBRT (g). At the last follow-up MRI (21 months post-SBRT), the lesion showed persistent APHE and washout (h, i) with a size of 0.8 cm. Moreover, the surrounding parenchyma exhibited delayed phase enhancement with capsular retraction. The lesion was categorized as PR and LR-TR equivocal based on m-RECIST and LI-RADS after SBRT until the last follow up MRI. SBRT stereotactic body radiation therapy; A arterial phase; 3-min, delayed phase (3 min); PR partial response; APHE arterial phase hyperenhancement; HCC hepatocellular carcinoma; m-RECIST Modified Response Evaluation Criteria in Solid Tumors; LI-RADS Liver Reporting and Data System; MRI magnetic resonance imaging

Details of hepatobiliary phase images after SBRT are provided in Supplementary Material 4.

T1WI, T2WI, and DWI in group without local progression

Most HCCs (99.0% [95/96]) showed a progressive increase in signal intensity on T1WI. At the end of the study period, the signal intensities of 70 and 25 HCCs increased to iso-hypointensity and isointensity, respectively. The signal intensity on T1WI was stable after 6 months The median time for T1WI hypointensity was 1 month (mean, 1.9 months; range, 1–12 months). No tumor demonstrated decreased T1WI signal intensity.

Most (97.9% [94/96]) HCCs showed a progressive decrease in signal intensity on T2WI. Within the first month post-SBRT, the proportion of HCCs exhibiting iso-hyperintensity on T2WI (47.9% [46/96]) was slightly higher than that of HCCs exhibiting hyperintensity (45.8% [44/96]). Over time, the proportion of HCCs exhibiting T2WI isointensity progressively increased. From the 9-month follow-up MRI, T2WI isointensity became the main imaging finding, followed by iso-hyperintensity. The signal intensities of most HCCs (96.9% [93/96]) on T2WI were stable after 9 months post-SBRT and those of three HCCs were stable after 12 months. At the end of the study period, the signal intensities of 41 and 53 HCCs decreased to iso-hyperintensity and isointensity, respectively. The median time for T2WI hyperintensity was 1 month (mean, 2.4 months; range, 1–9 months). No tumor demonstrated increased T2WI signal intensity.

Most (99.0% [95/96]) HCCs showed a progressive decrease in signal intensity on DWI. Within the first month post-SBRT, most HCCs (60.4% [58/96]) showed iso-hyperintensity on DWI. Over time, the proportion of HCCs exhibiting DWI isointensity progressively increased. From the 6-month follow-up MRI, no lesion demonstrated DWI hyperintensity, and DWI isointensity became the main imaging finding, followed by iso-hyperintensity. The signal intensity on DWI was stable after 9 months. At the end of the study period, the signal intensity of 14 and 81 HCCs decreased to iso-hyperintensity and isointensity, respectively. The median time for DWI hyperintensity was 1 month (mean, 1.8 months; range, 1–6 months). No tumor demonstrated increased DWI signal intensity.

Details of the changes in signal intensity on T1WI, T2WI, and DWI are shown in Supplementary Material 5.

Lesions with local progression

Of the six progressive tumors, two were diagnosed by pathology after surgical resection and four were diagnosed using imaging appearance and AFP levels. The median time for tumor progression was 6 months (range, 6–20 months).

The specific imaging appearances of tumors with local progression are shown in Table 3. The imaging findings of these six progressive tumors before progression are shown in Supplementary Material 6. At the time of progression, these six tumors exhibited the following findings: tumor growth (median, 7 mm; range, 5–11 mm), increased T2WI and DWI signal intensities, unchanged T1WI signal intensity, and APHE and washout pattern (Fig. 6).

Table 3 Magnetic resonance imaging manifestations in recurrent tumorsFig. 6

SBRT-treated HCC with persistent APHE and washout developed local progression. A 46-year-old man with HBV-related cirrhosis and a 3.5-cm cm HCC in the eighth segment of the liver (arrow). At baseline, the lesion exhibited APHE (a) with hyperintensity on T2WI (b) and DWI (c). At 3 months post-SBRT, the lesion showed APHE (d) with a decrease in size, measuring 1.7 cm, and iso-hyperintensity on T2WI (e) and DWI (f). At 6 months post-SBRT, the lesion increased in size, measuring 2.2 cm with annular enhancement (g) and hyperintensity on DWI (i) and T2WI (h). There was a decrease in wedge-like delayed phase parenchymal hyperenhancement with capsular retraction. The lesion was categorized as PD and LR-TR viable based on m-RECIST and LI-RADS. At the last follow-up MRI (9 months post-SBRT), the lesion continued to increase in size, measuring 4.0 cm (j, k). Eventually, the patient underwent surgical resection, and the lesion was confirmed pathologically. SBRT stereotactic body radiation therapy; A arterial phase; T2WI T2-weighted imaging; DWI diffusion-weighted imaging; PD progressive disease; APHE arterial phase hyperenhancement; HCC hepatocellular carcinoma; m-RECIST Modified Response Evaluation Criteria in Solid Tumors; LI-RADS Liver Reporting and Data System; MRI, magnetic resonance imaging

The results showed excellent agreement between the two observers (κ = 0.85–0.95) (Supplementary Table 1).

Treatment response evaluation

A total of 96 HCCs without progression were evaluated via the m-RECIST, LI-RADS TRA version 2018, and modified LI-RADS TRA, respectively (Table 4). Based on the m-RECIST, 10% (10/96) of the tumors met the CR criteria within the first month post-SBRT. Ten lesions met the PD criteria due to increase in size; 52% (50/96) and 64% (42/66) of the HCCs demonstrated CR at 6 and 12 months post-SBRT, respectively. The proportions of HCCs with PR + SD were 48% (46/96) and 36% (24/66) at 6 and 12 months, respectively.

Table 4 Response evaluation of patients after SBRT

Besides, when using the original LI-RADS TRA version 2018 criteria for the 96 HCCs without progression, at 3 months, 46% (35/96) of the tumors met the criteria for LR-TR nonviable. The proportion of HCCs categorized as LR-TR nonviable reached up to 52% (50/96) and 64% (42/66) at 6 and 12 months post-SBRT, respectively.

Furthermore, based on the modified LI-RADS with new definition of LR-TR nonviable, At 3 months, 74% (71/96) of the tumors met the criteria for LR-TR nonviable. Over time, the proportion of HCCs categorized as LR-TR nonviable progressively increased, reaching up to 89% (85/96) and 95% (63/66) at 6 and 12 months post-SBRT, respectively.

Surrounding parenchymal changes post-treatment

Within 1–3 months post-SBRT, 99% (101/102) of the tumors exhibited band-like or wedge-like changes. These post-treatment changes included hypointensity on T1WI and T2WI, mild APHE, and delayed phase hyperenhancement. Details are shown in Supplementary Material 7.

AFP levels in patients without local progression

Seventy-two patients were treated for only one lesion and had no extrahepatic metastasis or intrahepatic progression through the course of follow-up. Among these patients, 30 had elevated AFP levels (> 25 IU/mL) at baseline with a mean value of 877.2 ± 1146.5 IU/mL (range, 40.9–4549.0 IU/mL). The temporal evolution of AFP levels is shown in Fig. 2b. The most obvious decline in AFP levels (median, 96.5%; mean, 93.9%; range, 55.6–99.8%) was observed within 3 months post-treatment. At the 15-month follow-up, the AFP levels of the 30 patients declined to normal values. The median time for normalization was 3 months (range, 1–15 months). The AFP levels rapidly decreased in patients with baseline AFP level elevation (Fig. 2b).