Abstract
Background:
This study observed the clinical outcome of radiotherapy to extensive intrahepatic targets for advanced hepatocellular carcinoma (HCC) in a single institution.
Methods:
From September 2009 to July 2021, patients who underwent fractionated radiotherapy to a planning target volume (PTV) of over 100 ml with biological effective dose >30 Gy10 for advanced HCC were enrolled. Overall survival (OS) and radiation-induced liver toxicity (RILD) were evaluated. RILD was defined as an increase in Child-Pugh (CP) score ≥2 or liver function tests ≥2.5 times at 3 months after the end of radiotherapy.
Results:
A total of 136 patients were evaluated. Eighty-nine patients had portal vein tumor thrombus (PVTT), 37 patients were in CP B stage, and the median radiation dose to PTV was 48.8 Gy10. The median OS was 12.3 months. The factors most affecting OS were PVTT (P = 0.001), PTV (>500 ml, P = 0.001), incomplete coverage of the intrahepatic tumor (P = 0.004), and CP B (P = 0.006) in Cox regression. RILD occurred in 22.4% of the patients and was affected by PVTT (P = 0.003), PTV (P = 0.010), pretreatment bilirubin levels (>1.5 mg/ml, P = 0.016), and the mean normal liver dose (MNLD) (≥ EQD2 18 Gy3, P = 0.021) in binary logistic regression. As the PTV was in excess of >500 ml, RILD developed in 30.2% of patients and the prognostic importance of pretreatment bilirubin levels (P = 0.006) and the MNLD (P = 0.014) increased.
Conclusions:
As PTV is more extensive, the bilirubin level and the MNLD have to be taken into consideration for safe radiotherapy, in addition to the traditional prognostic factors.
Keywords: Hepatocellular carcinoma, planning target volume, portal vein tumor thrombus, radiation-induced liver disease, radiotherapy
INTRODUCTION
Hepatocellular carcinoma (HCC), with the second highest mortality rate in 2019 according to Korean statics,[1] has a poor prognosis, presenting with an expected 5-year survival rate of 42.4%.[2] HCC is common in endemic areas of hepatitis B or C virus, and alcohol is one of the main causes in the Western world.[3] Due to underlying liver conditions, patients with HCC generally have unfavorable liver functional reserve. In fact, it has been reported that approximately one-third belong to Child-Pugh (CP) class B or C.[4]
In early stage HCC, partial surgical resection or a liver transplantation could be considered as curative options. Radiofrequency ablation (RFA) is also attempted in tumors of a limited size. However, a significant number of patients with HCC are diagnosed in advanced stages, showing 32.6%, 40.2%, and 24.3% with multiple tumors of ≥4 numbers, a large size of >5 cm, and portal vein tumor thrombus (PVTT), respectively, in recent Korean data.[5] In these advanced HCCs, various treatments such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and new rising systemic agents of targeted therapy and immunotherapy could be considered. In addition, a multidisciplinary approach has been used to improve survival outcomes.
Radiotherapy (RT) has developed into intensity-modified radiation therapy (IMRT) after undergoing computerized tomography (CT)-based simulation and three-dimensional conformal radiotherapy (3DCRT). As there is a shift in the understanding that RT can preserve the normal liver through a recent technique of elaborate dose distribution and precise dose delivery, RT has occupied an axis of a multidisciplinary approach in combination with other treatments. In fact, there have been various clinical trials showing feasible outcomes when combined with TACE,[6,7] HAIC,[8] and target therapy.[9,10] However, concerns remain about tumor control and side effects of the combined treatment when applying RT to an extensive field due to advanced HCC. Therefore, RT for HCC has a wide range of different applications depending on the experience of each institution and physician.[11] It suggests that the clinical experience should be supported by showing the benefit against the loss of extensive-field RT to the liver. This study observed the clinical outcomes of survival and toxicity of extensive-field RT in a single institution for advanced HCC.
PATIENTS AND METHODS
This study retrospectively collected the medical records of patients who received RT for treatment of HCC in the Korea University, Ansan Hospital from September 2009 to July 2021. The inclusion criteria were as follows: (1) HCC was diagnosed based on the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC) practice guidelines at that time[12]; (2) an Eastern Cooperative Oncology Group performance score of 0–2; (3) CP class A or B; (4) RT was performed on the liver over a biological effective dose (BED) of 30 Gy10 when the α/β ratio was assumed to be 10 Gy; and (5) a planning target volume (PTV) >100 ml (approximately 6 cm sphere). The exclusion criteria were as follows: (1) patients who missed their follow-up evaluation at the end of RT; (2) stereotactic radiotherapy (SBRT) was done with <10 fractions; (3) disseminated distant metastases (the number of metastases ≥5 on ≥3 organs); and (4) inferior vena cava invasion or heart invasion. This study was approved by the Institutional Review Board of Ansan Hospital, Korea University (K-2022-1792) on 2022-08-30. Written informed consent was waived due to the retrospective nature of the study.
For RT, CT images with a 2 or 3 mm thickness were acquired using Big Bore CT simulation (Philips Medical System, The Netherlands). CT images were taken under free breathing with respiratory gating images. 3DCRT or IMRT was planned through the Eclipse radiotherapy planning system (Varian Medical system, Palo Alto, CA, USA). Magnetic resonance (MR) images were registered to simulation CT images to draw gross target volume (GTV). Referring to the images of respiratory gating, GTV was extended to internal target volume (ITV) and then 3–5 mm was added from ITV to make PTV. RT planning was developed to meet the KLCSG and NCC guideline of RT if possible.[12] Depending on the patients, the cone-down or simultaneous integrated boost (SIB) technique was applied. In these cases, if the PTV of a larger target volume exceeded 100 ml and > BED 30 Gy10 was irradiated, it was considered a valid case for this study.
Our clinical factors were classified with three categories of personal (age, sex, hepatitis status, and liver function), tumor (stage, specific characteristics of intrahepatic tumor and tumor marker), and radiotherapy information. For radiotherapy information, combined therapies with RT, the prescribed dose, the coverage of intrahepatic tumor, the PTV, the RT technique, and the irradiated liver dose were recorded. Normal liver volume was defined as the total liver volume minus the PTV. Mean doses of the liver were converted 2 Gy per fraction equivalent dose (EQD2), assuming the α/β ratio of liver was 3 Gy.
The status of survival, intrahepatic tumor recurrence of in-field and out-field of the PTV, and distant metastases were noted as factors affecting tumor control. The overall survival (OS) was calculated from the date of imaging diagnosis, when the need for RT would be raised, to the date of death or available follow-up. RILD was evaluated after a 3-month period following the end of RT according to the elevation of CP score (≥2 of baseline CP score) or liver function tests (LFTs) [2.5 times of maximal normal range (if baseline LFT is within the normal range) or initial liver function test (if baseline LFT is over the normal range)].
The main end points were the OS and the RILD. The OS was evaluated by the Kaplan–Meier method. The log-rank tests were used for the comparison of survival differences in terms of various factors within the subgroups. For RILD, the distribution difference was evaluated by the X2 tests. The prognostic factors with a P value of less than 0.1 in the univariate analyses entered the multivariate analyses of the Cox regression for the OS and the logistic regression analyses for RILD using the backward elimination method. Those values were indicated as hazard ratio (HR) and odds ratio (OR) with 95% confidential interval (95% CI), respectively. A P value of <0.05 was considered significant. The Statistical Package for the Social Sciences (SPSS version 21.0) was used to perform all statistical analyses (IBM Corp., Armonk, NY, USA).
RESULTS
Patient characteristics
A total of 136 patients were evaluated. The median age was 56 years (range 34–84 years), and 69.9% were below 65 years. For the baseline liver function, 91 patients (66.9%) had hepatitis B virus and 99 patients (72.8%) were in CP class A. For HCC, 83 patients (61.0%) and 89 patients (65.4%) had a tumor maximal diameter >8 cm and PVTT, respectively. For all except 13 patients, RT was combined with TACE 58.8%, HAIC 20.6%, and targeted therapy 11%. The median prescribed radiation dose to PTV was BED 48.8 Gy10 (range 31.3–80 Gy10). The median PTV was 356 ml (range 101–3563 ml), and the cohort was divided into two groups of moderate and marked PTV according to the cutoff value of 500 ml (approximately 10 cm sphere) [Table 1].
Table 1.
Patient characteristics
| Characteristics | Subgroups | n=136 |
|---|---|---|
| Personal information | ||
| Sex | Male: Female | 125: 11 |
| Age (years) 125: 11 | < 65: ≥65 | 95: 41 |
| Cause | HBV: HCV: Alcohol: Other | 91:11: 18: 16 |
| Child-Pugh class | A: B | 99: 37 |
| Liver function test | Normal: Elevated | 22: 114 |
| Bilirubin (mg/ml) | <1.5: ≥1.5 | 101: 35 |
| Ascites | No: Yes | 95: 41 |
| Tumor information | ||
| Size | ≤8: >8 | 53: 83 |
| Location (lobe) | Unilateral: Bilateral | 75: 61 |
| Number | 1: 2-5: ≥6 | 30: 72: 34 |
| Portal vein tumor thrombus | No: Yes | 47: 89 |
| Main branch invasion | No: Yes | 39: 50 |
| Total occlusion | No: Yes | 38: 51 |
| mUICC | T2: T3: T4 | 14: 43: 79 |
| mUICC | N0 and M0: N1 or M1 | 106: 30 |
| AFP (ng/ml) | <500: ≥500 | 68: 68 |
| PIVKA-II (mAU/ml) | <2000: ≥2000: unknown | 58: 74: 4 |
| Radiotherapy information | ||
| Combined therapy | TACE: HAIC: Systemic: No | 80: 28: 15: 13 |
| Planning target volume (ml) | 101-500: >500 | 83: 53 |
| Technique | 3DCRT: IMRT | 63:73 |
| Coverage of intrahepatic tumor | Entire: Partial: | 49: 87 |
| Mean total liver dose (EQD2, Gy) | <27: ≥27 | 81: 55 |
| Mean normal liver dose (EQD2, Gy) | <18: ≥18 | 94: 42 |
HBV=hepatitis B virus, HCV=hepatitis C virus, mUICC=Modified Union for International Cancer Control, AFP=α-feto protein, PIVKA-II=protein induced by vitamin K absence or antagonist-II, EQD2=equivalent dose in 2 Gy fraction, TACE=transarterial chemoembolization, HAIC=hepatic arterial infusion chemotherapy, 3DCRT=3-dimensional conformal radiotherapy, IMRT=intensity-modulated radiotherapy
Survival outcomes
The median OS was 12.3 months. The recurrence free rates of PTV, intrahepatic tumor, and distant metastases were 64.0%, 31.5%, and 57.8%, respectively, in 1 year and 48.9%, 22.6%, and 48.8% respectively, in 2 years. The factors most affecting a poor OS were PVTT [P = 0.001, HR = 2.09 (CI 95% 1.36–3.22)], marked PTV of >500 ml [P = 0.001, HR = 2.04 (CI 95% 1.35–3.07)], incomplete coverage of intrahepatic tumor [P = 0.004, HR = 1.95 (CI 95% 1.24–3.08)], and CP class B [P = 0.006, HR = 1.79 (CI 95% 1.18–2.71)] in Cox regression analysis [Table 2]. The median OS was 26.1 months (95% CI 17.8–34.4 months) and 9.7 months (95% CI 8.1–11.3 months) according to PVTT. The median OS of CP class A without PVTT was 32.1 months versus 10.8 months according to the extent of PVT (P = 0.021). The median OS of CP class B with PVTT was 8.6 months versus 4.2 months according to the extent of PVT (P = 0.001, Figure 1).
Table 2.
Prognostic factors of overall survival (univariate analyses by log-rank test and multivariate analyses by Cox regression)
| Characteristics | Subgroups | Median survival (CI 95%) | Univariate P | Multivariate P HR (CI 95%) |
|---|---|---|---|---|
| Sex | Male | 11.6 (7.9-15.3) | 0.140 | |
| Female | 19.4 (1.5-37.3) | |||
| Age (years) | <65 | 10.3 (8.9-11.7) | 0.250 | |
| ≥65 | 17.5 (13.3-21.7) | |||
| Cause | HBV | 11.2 (6.6-15.8) | 0.167 | |
| Other | 16.0 (5.6-26.3) | |||
| Child-Pugh class | A | 16.6 (14.2-19.0) | < | 0.006 |
| B | 7.9 (6.3-9.5) | 0.001* | 1.79 (1.18 – 2.71) | |
| Liver function test | Normal | 20.4 (16.0-24.8) | 0.024* | |
| Elevated | 10.3 (8.1-12.5) | |||
| Bilirubin (mg/ml) | <1.5 | 16.0 (11.8-20.2) | 0.159 | |
| ≥1.5 | 7.9 (5.4-10.4) | |||
| Ascites | No | 17.3 (14.9-19.7) | < | |
| Yes | 8.6 (7.1-10.1) | 0.001* | ||
| Albumin (mg/ml) | >3.5 | 16.0 (11.4-20.6) | 0113 | |
| ≤3.5 | 8.7 (6.1-11.3) | |||
| Tumor Size (cm) | ≤8 | 19.0 (16.0-22.0) | 0.009* | |
| >8 | 9.7 (8.0-11.4) | |||
| Number | 1-5 ≥6 | 15.4 (10.4-20.4) 10.3 (7.2-13.4) | 0.023* | 202408 |
| Portal vein tumor thrombus | No | 26.1 (17.8-34.4) | < | 0.001 |
| Yes | 9.7 (8.1-11.3) | 0.001* | 2.09 (1.36-3.22) | |
| AFP (ng/ml) | <500 | 17.5 (13.0-22.0) | 0.032* | |
| ≥500 | 10.1 (8.3-11.9) | |||
| PIVKA-II (mAU/ml) | <2000 ≥2000 | 18.7 (9.3-28.1) 10.2 (7.6-12.8) | 0.012* | |
| Planning target volume (ml) | 101-500 | 15.4 (10.0-20.8) | 0.025* | 0.001 |
| >500 | 9.7 (7.6-11.8) | 2.04 (1.35-3.07) | ||
| Technique | 3DCRT | 10.2 (9.1-11.3) | 0.417 | |
| IMRT | 15.4 (10.9-19.9) | |||
| Coverage of intrahepatic tumor | Entire | 26.1 (16.6-35.6) | < | 0.004 |
| Partial | 10.1 (8.6-11.6) | 0.001* | 1.95 (1.24-3.08) |
*Those factors are included in the multivariate analyses. HBV=hepatitis B virus, AFP=α-feto protein, PIVKA-II=protein induced by vitamin K absence or antagonist-II, 3DCRT=3-dimensional conformal radiotherapy, IMRT=intensity-modulated radiotherapy
Figure 1.
Overall survival. (a) Survival difference according to portal vein tumor thrombus (median survival 26.1 months vs 9.7 months, P < 0.001). (b) Survival difference of CP class A without PVTT according to radiation volume (median survival 21.1 months vs. 10.8 months, P = 0.021). (c) Survival difference of CP class A with PVTT according to radiation volume (median survival 14.9 months vs. 12.4 months, P = 0.281). (d) Survival difference of CP class B with PVTT according to radiation volume (median survival 8.6 months vs. 4.2 months, P = 0.014)
Liver toxicity
It was possible to evaluate RILD in 116 patients except patients with disease progression or loss of periodic examination at 3 months following the end of RT, and it was found that RILD had occurred in 26 patients (22.4%). Factors affecting RILD include a PVTT [P = 0.003, OR = 12.98 (CI 95% 2.42–69.64)], a marked PTV [P = 0.010, OR = 4.93 (CI 95% 1.46–16.64)], a pretreatment bilirubin level of >1.5 mg/ml [P = 0.016, OR = 4.39 (CI 95% 1.31–14.64)], a mean normal liver dose of ≥18 Gy3 (EQD2) [P = 0.021, OR = 3.67 (CI 95% 1.22–11.04)], and multiple tumors of ≥6 [P = 0.026, OR = 3.93 (CI 95% 1.18–13.09)] in binary logistic regression analyses [Table 3]. RILD occurred in more than half of cases (11/21 cases) with two RT factors being the mean normal liver dose (≥18 Gy3, EQD2) and marked PTV (Figure 2). Patients who experienced RILD showed a poor prognosis, and all but two patients died within 9 months of the end of RT. Four cases of gastrointestinal bleeding were observed due to varix. However, duodenal bleeding related to RT was not observed.
Table 3.
Prognostic factors of RILD (univariate analyses by X2 test and multivariate analyses by binary logistic regression)
| Characteristics | Subgroups | n=116 No: Yes | Univariate P | Multivariate P OR (CI 95%) |
|---|---|---|---|---|
| Sex | Male | 82: 26 | 0.115 | |
| Female | 8: 0 | |||
| Age (years) | <65 | 59: 22 | 0.062* | |
| ≥65 | 31: 4 | |||
| Cause | HBV | 57:21 | 0.095* | |
| Other | 33: 5 | |||
| Child-Pugh class | A | 72: 17 | 0.192 | |
| B | 18: 9 | |||
| Liver function test | Normal | 20: 1 | 0.032* | |
| Elevated | 70: 25 | |||
| Bilirubin (mg/ml) | <1.5 | 74: 14 | 0.003* | 0.016 |
| ≥1.5 | 16: 12 | 4.39 (1.31-14.64) | ||
| Ascites | No | 69:17 | 0.247 | |
| Yes | 21: 9 | |||
| Size | ≤8 | 44: 6 | 0.019* | |
| >8 | 16: 20 | |||
| Number | 1-5 | 73: 16 | 0.057* | 0.026 |
| ≥6 | 17: 10 | 3.92 (1.18-13.09) | ||
| Portal vein tumor thrombus | No | 42: 2 | <0.001* | 0.003 |
| Yes | 48: 24 | 12.98 (2.42-69.64) | ||
| Total liver volume (ml) | > 750 | 39: 14 | 0.343 | |
| ≤1750 | 51: 12 | |||
| Normal Liver volume (ml) | >1250 | 48: 9 | 0.093* | |
| ≤1250 | 43: 17 | |||
| Planning target volume (ml) | 101-500 | 61: 12 | 0.044* | 0.010 |
| >500 | 29: 14 | 4.93 (1.46-16.64) | ||
| Technique | 3DCRT | 41: 12 | 0.957 | |
| IMRT | 49: 14 | |||
| Coverage of intrahepatic tumor | Entire | 35: 5 | 0.063* | |
| Partial | 55: 21 | |||
| Mean total liver dose (EQD2, Gy) | <27 | 59: 9 | 0.005* | |
| ≥27 | 31: 17 | |||
| Mean normal liver dose (EQD2, Gy) | <18 | 59: 9 | 0.005* | 0.021 |
| ≥18 | 31: 17 | 3.67 (1.22-11.04) |
*Those factors are included in the multivariate analyses. HBV=hepatitis B virus, EQD2=equivalent dose in 2 Gy fraction, 3DCRT=3-dimensional conformal radiotherapy, IMRT=intensity-modulated radiotherapy
Figure 2.
RILD according to normal liver mean dose and planning target volume. In the area of normal liver mean dose ≥18 Gy and planning target volume > 500 ml, RILD was observed in 52.4% of patients (11/21)
Marked PTV
A marked PTV was necessary in advanced HCC. Therefore, PVTT, tumor maximal diameter >8 cm, and multiple tumors of ≥6 were 58.1%, 90.7%, and 48.8%, respectively. For OS, incomplete coverage of intrahepatic tumor [P = 0.003, HR = 2.67 (95% CI 1.18–4.37)] and PVTT [P = 0.014, HR = 2.67 (95% CI 1.40–5.08)] was still significant in marked PTV group. However, the importance of CP class became weak. RILD developed in 30.2% of patients, and pretreatment bilirubin levels of >1.5 mg/ml [P = 0.006, OR = 179.02 (95% CI 4.23–7468.43)] and the mean normal liver dose of ≥18 Gy3 (EQD2) [P = 0.014, OR = 23.75 (95% CI 1.92–294.48)] showed significant values, followed by PVTT [P = 0.042, OR = 21.17 (95% CI 1.12–401.00)] and age of younger group <65 years [P = 0.047, OR = 20.41 (95% CI 1.04–500.00)].
DISCUSSION
For HCC with a limited size, SBRT has shown promising results. In a phase II clinical trial for a median tumor size of 2.4 cm, 3-year OS was 76%.[13] In another phase II trial for a median tumor size of 1.3 cm, 5-year OS was 77.6% with local control over 90%.[14] These studies showed that SBRT could sufficiently be considered as the alternative therapy of RFA. However, the role of conventional fractionated RT was important in the case of widespread HCC, which is more common in actual practice. This study would help establish RT plan by presenting the clinical outcomes in the group of patients who need extensive PTV of more than 6 cm in diameter. Especially, as the effect of concurrent RT with a few systemic therapies of atezolizumab plus bevacizumb,[15] nivolumab,[16] and lenvatinib[17] is expected, it would be appropriate to check the previous RT outcomes for locally advanced HCC.
PVTT and CP class are regarded as major factors in Barcelona Clinic Liver Cancer, Japan Integrated, and Hong Kong Liver Cancer staging systems, and their importance was shown even in cases of advanced HCC in this study. Most of the PVTT included in this study had wide invasiveness of the main portal trunk and first-order branching of the right or left sides. However, details regarding main trunk invasion and the complete occlusion of blood flow did not affect the prognosis. For our cohort, most patients with PVTT applied the liver-directed therapy with RT. In a recent retrospective study of 10 institutions, the group of liver-directed therapy plus RT was favorable to sorafenib plus RT, and median OS of 10.6 months (95% CI 9.2–12.0) for liver-directed therapy plus RT was similar with our median OS of 9.7 months (95% CI 8.1–11.3).[18] For patients of CP class B, RT and the combined therapies were also performed in consideration of general performance. In regard to baseline liver status, ascites and an increased liver function test showed a worse prognosis in the univariate analyses; however, the CP class acted as a more important factor indicating the baseline liver status. In a retrospective study of 13 institutions, the fractionated RT was feasible with median OS of 9.4 months and normal liver volume was meaningful for toxicity after RT.[19] Our median OS of 7.9 months (95% CI 6.3–9.5) was poor compared to the previous study because patients requiring a relatively extensive PTV were included.
Factors of HCC such as tumor size, multiplicity, distribution, and vascular invasion affect the determination of the RT target. The patient’s underlying liver status and general performance might be factors. It is also necessary to comply with the following recommendation of dose distribution that the liver volume receiving ≤30 Gy must be ≥40% of the total liver volume.[20] Although this study showed that complete inclusion of intrahepatic tumor in PTV was significant to OS, various aspects including tumor location and normal liver volume and dose should be carefully considered to decide the target of RT. Comparing the rival RT plannings according to different PTV and using the SIB technique could be helpful to establish final RT planning. In addition, marked PTV was related to RILD and it is necessary to divide the area to be treated with RT and to be replaced with other modalities. In terms of RT technique, this study did not demonstrate that IMRT is better than 3DCRT in the OS or RILD. However, a few dosimetric studies showed that IMRT has a better dose distribution in comparison with 3DCRT. The index of V20 and V30 and the conformal index decreased, and the possibility of dose escalation was suggested.[21,22]
RILD occurred in 22.4% of patients, except for 20 patients who were excluded because they died or experienced intrahepatic progression and ceased the periodic examination at 3 months following the end of RT. Patients with RILD tend to have a poor clinical outcome. In the cohort of advanced HCC, it is presumed that the presence of RILD inhibits the timing of proper consequent therapies. In terms of PVTT, there have been reports of increased biliary toxicity in RT of HCC, located around the portal vein. The increase in radiation dose near major blood vessels and bile ducts located in the central part of the liver is related to RILD.[23] A recent deep learning study drew a contour map of the radiation dose distribution in the portal vein, and it could predict RILD effectively.[24] This study showed that the baseline bilirubin level was usefully evaluated along with other values showing the status of liver function. Although CP class B was not a major factor in RILD in this study, due to premature progression after RT, the baseline CP score ≤7 was an important factor in tolerating RILD in previous studies.[25,26]
This study confirmed that RILD occurred more frequently in the group with marked PTV of 500 ml and the relationship between normal liver dose and initial bilirubin level. The marked PTV group consisted of 43 patients, and there are aspects that require verification through additional research in the future. For hypofractionation study, normal liver volume should be limited to ≤ EQD2 28 Gy.[27] In this study, the occurrence of RILD was shown based on a mean normal liver dose of EQD2 18 Gy3, and it was shown that more strict dose distribution is required when fractionated RT is performed over an extensive target. Proton therapy is expected to be favorable for RT in marked PTV as it has a protective effect of normal liver by utilizing Bragg peak.[28] A retrospective study for HCC with >5 cm showed the improved progression-free survival and OS with lower RILD and gastrointestinal bleeding.[29] It is necessary to demonstrate effectiveness of proton over photon through prospective clinical trials in near future.
This study had limitations as a retrospective study. The first is that the technique of RT and combined therapies for HCC changed during the 12-year period of this study. The IMRT technique has become common, and the radiation schedule, target delineation, and so on have been gradually changed over time. The second is in the process of obtaining information. The laboratory tests and imaging examinations were observed with a more generous window period than the controlled clinical study. Third, some factors that influence a physician’s decisions would be difficult to control. The patient’s overall condition would affect the intensity of RT, which is far from controllable in retrospective studies. Although the correlation between significant factors in multivariate analysis was not moderate, there may be confounders that we did not expect. Finally, this study is limited to RILD immediately after RT, and long-term toxicity would also need to be considered in future studies.
This study summarized the clinical outcomes of RT performing extensive PTV in HCC through retrospective studies and examined significant clinical factors for OS and RILD. When RT is applied to an extensive field of the liver, the OS and RILD could be mainly affected by PVTT and PTV. In addition, it was confirmed that the target volume of RT was more extensive; the bilirubin level and the radiation dose in the normal liver could affect the hepatotoxicity. It is necessary to pay attention to these factors and establish a plan for RT.
Financial support and sponsorship
This work was supported by Korea University (Grant number K2409151).
Conflicts of interest
There are no conflicts of interest.
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