Evaluation of liver functionality after liver stereotactic body radiation therapy (SBRT) using blood tests and imaging examinations

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide [1].HCC has a high recurrence rate, rendering its treatment modalities and the assessment of liver function after therapy of signi cant interest to the medical community [2].Currently, although there are many treatment methods for hepatocellular carcinoma, radiation therapy, surgery, and radiofrequency ablation are among the treatments that are used locally to treat this cancer [3,4,5].
Radiation-induced liver disease (RILD) determines the liver tolerance dose of radiotherapy for liver cancer.
RILD is a radiation liver injury characterized by brous occlusion of the small hepatic veins caused by radiation, resulting in congestion and hepatocellular depletion, and presenting within 3 months of radiotherapy [3,4].If these changes occur over a wide area, they lead to liver failure; however, if they occur only partially, they merely leave atrophic scars in that part of the organ, and liver failure can be avoided.
Previously, it was believed that the maximum tolerable radiation dose to the liver was about 30 Gy.This guideline was based on past reports of whole-liver irradiation, and it was considered impossible to administer radical doses.However, recent research revealed that, for stereotactic body radiation therapy (SBRT), the tolerable dose is higher, especially in the case of partial liver irradiation.
SBRT is a computer-controlled treatment that concentrates doses from multiple directions.The success of this treatment has led to its application not only to the brain, but also to tumors of the body, such as those of the lung.However, because SBRT emits beams from multiple directions, it also damages the normal liver tissue that surrounds the tumor.Theoretically, it is considered a local treatment for liver cancer, similar to liver resection.Therefore, it can be used as a pretreatment evaluation method for SBRT, in addition to the preoperative indocyanine green retention test 15 minutes (ICG-R15) and galactosyl human serum albumin (GSA) scintigraphy [6,7,8,9,10,11,12,13].In the case of liver resection, deterioration of liver function is observed at the time of surgery using blood tests (ALBI, GSA, and ICG-R15).However, in the case of SBRT, post-treatment computed tomography (CT) cannot measure local functional deterioration of the liver.This is because the Houns eld units are similar in non-enhanced CT for both normal and functionally impaired partial livers.However, it has been reported that decreased accumulation of GSA by radiation therapy and abnormal signals can be detected by magnetic resonance imaging (MRI) [14,15,16,17,18].Functional imaging is useful for planning the second SBRT or liver resection for new hepatocellular carcinoma [6,7,8,9,10].At present, there are many uncertainties in the planning of SBRT of the liver based on GSA and MRI alone.The goal of this study was to examine the relationship between blood tests (ALBI and ICG-R15) measuring total liver function pre and post SBRT in liver cancer and GSA images re ecting functional images (CT and MRI with and without EOB enhancement).

Materials And Methods
In this study, we assessed the following: 1) changes over time in Child-Pugh classi cation, ICG-R15, and ALBI values before and after SBRT (overall liver evaluation); 2) the correlation between the changes in GSA count and ICG-R15 over time (correlation); and 3) the optimal MRI sequence for recognizing radiation hepatitis.

Patients
This study was approved by the Institutional Review Board, and the national registration number is UMIN000035026.Of the 23 patients who underwent liver SBRT at our hospital between 2019 and 2022, 11 received only imaging examinations (GSA, CT, and MRI) and blood tests before treatment, 1 month after treatment, and 3 months after treatment; and 12 received ALBI and ICG-R15 in addition to the imaging.Moreover, 10 of the 12 patients had to undergo trans arterial chemoembolization (TACE) within 1 month before SBRT.At our hospital, we rst perform TACE on HCC, and then perform SBRT on areas where embolization was not possible.The patient backgrounds are shown in Table 1.

Imaging
An Elekta Synergy Linear Accelerator (Elekta AB, Stockholm, Sweden) with coplanar volume-modulated arc therapy was used for all patients.This approach delivers personalized, safe, e cient, and high-quality radiation with enhanced dose conformance appropriate to the tumor's size, shape, and pathology.Each patient was immobilized in a stereotaxic frame and underwent a 4-dimensional CT scan with 2 mm sections.Scanning was performed using an external respiration monitoring system (Apex Medical, Inc., Tokyo, Japan) during breath-holding.Respiratory phase data were transferred to a treatment planning system (MOSAIQ; Elekta AB).For some patients, ducial markers were not used.

Radiotherapy planning
The small intestine (including the duodenum), stomach, pancreas, kidneys, and spinal cord were set as OARs.The GTV was the entire tumor; the clinical tumor volume (CTV) added a 2-mm margin to the GTV.
The planning target volume (PTV) was the same as the CTV.The prescription dose for PTV was 40 Gy/4fx (4 days).The treatment plan was carried out by a medical physicist with 15 years of experience and was approved by a radiation oncologist.

Statistical analyses
Wilcoxon signed-rank test for statistical analyses of the recorded data were performed using the Excel statistical software package (Excel-statistics 2015; Social Survey Research Information Co., Ltd., Tokyo, Japan).A p-value of < 0.05 was regarded as a statistically signi cant difference.

Results
Table 2, Figure 1, and Figure 2 depict the changes in liver function over time in patients who underwent SBRT.
2) The ICG-R15 values were 14.4 before RT, 17.1 after 1 month, and 17.6 after 3 months, which indicated a worsening at 1 month, but a similar result after 3 months (Figure 1).
3) The ALBI values were −2.61 before RT, −2.67 after 1 month, and −2.71 after 3 months.ALBl worsened slightly over time (Figure 2).Changes over time in the imaging of the site at which SBRT was performed Figure 3 shows the changes over time in CT and MRI between before and after the treatment.After SBRT, contrast-enhanced CT showed focal enhancement in the arterial phase and low intensity on Gd-EOB-DTPA-enhanced MRI (EOB).Regarding EOB, the low intensity persisted for a long time after treatment; however, in many cases, the hyperintense areas disappeared on contrast-enhanced CT.Abnormal signals were observed on MRI, consistent with the accumulation defect sites on GSA scintigraphy (Figure 4).However, the most useful sequence among the four sequences was EOB (15 min), followed by fat suppression-T2-weighted imaging (Table 3).

Correlations between GSA scintigraphy and blood tests
We assessed the correlation between imaging examinations (GSA) and blood tests (ICG-R15 and ALBI) re ecting liver function.There was no correlation between GSA counts and ICG-R15 values (Figure 5).

Blood tests and time course of liver reserve after SBRT
The goal in this study was to determine the method that can evaluate the future liver reserve capacity locally and globally.From this investigation we observed that the ICG-R15 blood test worsened by an average of 2.8 at 1 month of treatment, but changed by only 0.5 between 1 and 3 months after the end of treatment.The effects of radiotherapy usually become apparent after 1-3 months.Because the liver has a high regenerative capacity, the effects of radiation may already have disappeared after 3 months.Speci cally, although Patients 4 and 6 in the present study underwent SBRT more than once, there was almost no difference between the ICG values at 3 months after the rst treatment and those detected after the second treatment.It is possible that a phenomenon similar to the enlargement of the liver after liver resection may occur.Twelve patients were included in this analysis, and no statistically signi cant difference was observed using the Wilcoxon signed-rank test.It is expected that differences will become apparent if the number of cases is increased.
The standard deviation was large because the pretreatment ICG values were inconsistent.In the future, it would be worthwhile to increase the number of cases and divide the ICG before treatment into three groups (e.g., 0-10, 10-20, and 20-30) and observe the changes.Similarly, changes in the signal delivered to the liver depending on the size (mm) of the tumor and the range/dose of the irradiation are signi cant.
In regions that received low-dose irradiation, GSA accumulation and MRI abnormal signals become gradations, thus rendering boundaries unclear.Because the liver has a high regenerative capacity, its regeneration can be expected if there is little damage.The low-dose region of this gradation may be a reproducible part.In this way, the effects of radiotherapy change over time, and the responses of organs change accordingly.
In recent years, the number of reports on the usefulness of re-irradiation has increased.We believe that a variety of modalities can be used to plan re-irradiation, as determined based on liver imaging and blood tests [6,8,10,11].

Imaging
SBRT is a computer-controlled treatment that concentrates doses from multiple directions.The success of this treatment has led to its application not only to the brain, but also to tumors of the body, such as those of the lung.SBRT is also theoretically a local therapy; i.e., it is the same as RFA (Radiofrequency Ablation),, TACE, and surgery, and is a treatment that damages the normal liver, to some extent.This is why pretreatment ICG-R15 is necessary for surgical resection, and has been found to be useful for SBRT.ICG-R15 detects the deterioration of liver function immediately after surgery, whereas liver damage caused by radiation becomes apparent later.However, RILD appears within 3 months, and, conversely, liver function is thought to plateau after 3 months [3,4].Therefore, the following changes were observed on imaging in this study as changes pre and post SBRT.: a. GSA: a decrease in counts was observed consistent with the irradiated site.b.Contrast-enhanced MRI (comparison of the four sequences): a decrease in signal was observed in EOB imaging consistent with the irradiated area.EOB images were the most useful.However, FS-T2WI was useful when contrast imaging was not possible.c.Contrast-enhanced CT: contrast-enhanced effects in the hepatic arterial phase were observed in some cases, consistent with the irradiated area; however, the darkened area disappeared over time (the duration of this effect is unknown).
GSA indicates a decrease in normal hepatocyte counts, and EOB similarly re ects a decrease in normal hepatocyte counts.Although the mechanism of hepatic arterial phase enhancement in contrast-enhanced CT is unknown, the follow-up of hepatocellular carcinoma is often performed using MRI, because this modality is more sensitive than CT [4,5,13,14,15,16].Nevertheless, because there are patients who cannot undergo MRI, it is necessary to discover the mechanism of contrast-enhanced CT in the future.

Limitations
We could not perform evaluations in all patients, because contrast-enhanced CT was not used in all patients.Contrast-enhanced CT may have an early contrast-enhancing effect, which, if combined with the MRI signal, will allow the determination of further post-treatment changes.
To date, although the usefulness of functional imaging (GSA and MRI) to assess radiation hepatitis has been reported, there are no studies including blood tests.HCC often recurs, and SBRT is used more frequently than TACE and RFA.It is desirable to evaluate the changes in imaging after each treatment in greater detail in a larger number of patients.Because the small number of cases in each study, it is necessary to consider increasing the number of cases in future studies for better elucidation of the potential connection between changes in GSA counts and blood test results (ICG-R15, ALBI).

Conclusion
ICG-R15 assessment at 1 month after SBRT may be a su cient blood test to determine post-SBRT liver function after treatment.However, the changes in ICG-R15 levels were most drastic at only after 1 month after the treatment ended.MRI assessment of radiation hepatitis was clearest at EOB. Contrast-enhanced CT revealed a contrast-enhancing effect in the early phase, matching the site of post-treatment radiation hepatitis in some cases, but disappeared after more than 1 year in some cases.Abnormal signals in EOB were detectable at more than 1 year after treatment.1) Contrast is the difference in visual signal between the lesion and normal tissue.

Abbreviations
2) Borderline is the clarity of the distinction between the lesion and normal tissue.
3) Area is the degree of recognition of the site with the lesion.
Changes in ICG before radiation therapy (Pre), 1 month after radiation therapy (1 month), and 3 months after radiation therapy (3 months) The mean ICG-R15 was 14.4 before radiotherapy, 17.1 1 month after the treatment, and 17.6 3 months after the treatment.
Although there was no signi cant difference between the values obtained before radiotherapy and those obtained at 1 month after radiotherapy (P = 0.071), deterioration of liver function was observed.
Although there was no signi cant difference between the values obtained before radiotherapy and those obtained at 3 months after radiotherapy (P = 0.10), deterioration of liver function was observed.
There was no signi cant difference between the values obtained at 1 and 3 months after radiotherapy (P = 0.81).
Changes in ALBI before radiation therapy (Pre), 1 month after radiation therapy (1 month), and 3 months after radiation therapy (3 months) The mean ALBI was −2.61 before radiotherapy, −2.67 at 1 month after the treatment, and −2.71 at 3 months after the treatment.However, no signi cant difference was observed among the three groups.C, MR image (EOB); A decrease in signal is observed consistent with the radiation-irradiated sites.
score change (baseline to 3 months after treatment) ICG-R15 score change (baseline to 3 months after treatment) to −3.44) ALBI score change (baseline to 3 months after treatment) ALBI score change (baseline to 3 months after treatment) >1 CP; Child-Pugh classi cation, ICG-R15: Indocyanine green retention test (15 minutes) ALBI; albumin-bilirubin (ALBI) grade ALBI score (log10 bilirubin (μmol/L) × 0.66) (albumin(g/L) × −0.085) Grade 1: £ 2.60; Grade 2: −2.60 to £ 1.39; Grade 3: −1.39 Table 3 MRI evaluation Two medical physicists evaluated the four imaging sequences shown below, with a score of 1 indicating the worst imaging quality and a score of 5 indicating the best imaging quality; a score of 3 indicated a level of imaging that can be recognized by an average radiotherapist or medical physicist, a score of 2 represented a middle value between 1 and 3, and 4 represented a middle value between 3 and 5.

Figure 3 Changes
Figure 3

Figure 4 A
Figure 4

Table 1
Huang XB, Zhu XD, Zhang WD, Cai L, Huang HZ, et al.Dosimetric predictor identi cation for radiation-induced liver disease after hypofractionated conformal radiotherapy for primary liver carcinoma patients with Child-Pugh Grade A cirrhosis.Radiother Oncol.2011;98:265-9.15.Son SH, Kay CS, Song JH, Lee SW, Choi BO, Kang YN, et al.Dosimetric parameter predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally Baseline patient characteristics.