ABSTRACT
Aims
To explore a safe and effective treatment modality for unresectable huge (≥ 10 cm) hepatocellular carcinoma with portal vein thrombosis. And to provide more data on the synergistic antitumor effects of radiotherapy combined with immune checkpoint inhibitors and antiangiogenic therapy.
Materials and Methods
This study compared the clinical outcomes in 63 patients with unresectable huge hepatocellular carcinoma and portal vein thrombosis who were treated with either γ‐ray body radiotherapy or linear accelerator radiotherapy (the RTγ and RTa groups, respectively), both combined with immune checkpoint inhibitors and antiangiogenic therapy.
Results
The median progress‐free survival (PFS) and median overall survival (OS) in the RTγ group were 12.1 and 14.3 months, respectively. And those in the RTa group were 6.6 and 8.1 months, respectively. The 1‐, 2‐, and 3‐year PFS were 43.2%, 24.3%, 10.8% in the RTγ group and 11.5%, 3.8%, 0% in the RTa group, respectively. The OS at the same intervals were 56.7%, 40.5%, and 18.9% in the RTγ group, and those were 23.1%, 7.7%, and 0% in the RTa group, respectively. The percentage of normal liver volume (NLV) in whole liver volume (WLV) > 60% and negative viral infection are significant independent factors for superior PFS and OS. Severe radiation‐induced liver disease was observed in 23.1% (n = 6) of patients in the RTa group, compared to none in the RTγ group.
Conclusions
RTγ combined with immune checkpoint inhibitors and antiangiogenic therapy is an effective and safe treatment modality for unresectable huge hepatocellular carcinoma with portal vein thrombosis. An NLV/WLV ratio > 60% and negative viral infection independently predicted better PFS and OS.
Keywords: clinical outcome, γ‐Ray, hepatocellular carcinoma, portal vein thrombosis, radiotherapy
1. Introduction
The incidence of hepatocellular carcinoma (HCC) has been steadily increasing on a global scale [1, 2, 3]. It is also one of the three leading causes of cancer‐related deaths worldwide [4]. The similarity between incidence and mortality underlines the dismal prognosis associated with this disease [5]. Most HCC develops from persistent hepatitis viral infection, alcohol abuse, nonalcoholic steatohepatitis, and aflatoxin exposure [6]. HCC predominantly occurs in males [7]. Since HCC is often absent of characteristic symptoms and signs, some patients are initially diagnosed at advanced stages with huge (10 cm or more in diameter) tumors (H‐HCC) [8]. The percentage of these patients, with huge tumors, in all HCC cases is approximately 20% [9]. Additionally, H‐HCC could often be found in clinical practice with the portal vein tumor thrombus (PVTT) that is often formed by HCC extending to the portal vein branches [10]. The HCC would be classified, according to the Barcelona Clinic Liver Cancer (BCLC) staging system, into advanced stage C once the PVTT has been formed. It was reported that the percentage of HCC with PVTT in all HCCs at initial diagnosis was approximately 55% [11]. Of note, the PVTT is associated with a poor prognosis for HCC patients [12].
Several treatment modalities would be the options for small to medium‐sized HCC patients today. Such as radiofrequency ablation (RFA), transarterial chemoembolization (TACE) [13, 14], and hepatic resection [15]. However, RFA is an effective treatment option only for early HCC [16]. Although adjuvant TACE has shown benefits for HCC [17, 18], TACE can merely achieve the objective response rates of 40%–60% when it is used alone in the treatment of large HCC [19]. The efficacy of TACE as a standalone treatment for H‐HCC is generally suboptimal [20]. To date, surgical resection remains the primary curative treatment for H‐HCC [21, 22]. However, the high recurrence rate following a successful resection is a factor that cannot be neglected. The 2‐ and 5‐year recurrence rates of 60.3% and 70% were reported by Cailing X et al. [23] and Marrero JA et al. [24], respectively. Moreover, resection is a viable option only for a highly selected group of H‐HCC patients, with fewer than 30% considered suitable candidates for surgical tumor removal [25, 26]. Although the combination of immune checkpoint inhibitors (ICI) and antiangiogenic therapy (AT) has been recommended in the management of advanced HCC [27]. There is still much room for improving the clinical outcomes. The retrospective study exhibited the efficacy of radiation therapy (RT) in the management of unresectable H‐HCC (UH‐HCC) [28]. RT not only destroys the DNA in tumors but also causes immunogenic cell death [29]. ICI can reverse the RT—induced exhaustion of T cells [30]. Therefore, rationally, RT combined with ICI and AT would be a great option for UH‐HCC patients. However, the data on the synergistic antitumor effect of RT combined with ICI and AT for UH‐HCC with PVTT is lacking. Additionally, to date, no studies have compared the clinical outcomes between UH‐HCC with PVTT patients treated by γ‐ray body RT combined with ICIs and AT and those treated with linear accelerator RT combined with ICIs and AT.
In this study, the clinical outcomes of γ‐ray body RT vs. linear accelerator RT (both combined with ICIs and AT) for UH‐HCC with PVTT were compared as one aim to explore a safe and effective treatment modality for UH‐HCC with PVTT. To provide more data on the synergistic antitumor effects of RT combined with ICIs and AT was the second aim of this study.
2. Materials and Methods
2.1. Patient Cohort
This study was conducted with the approval of the 900th Hospital of the Chinese People's Liberation Army Ethics Committee (approval no. 2023046), and prior informed consent to participate was obtained from all patients. The study adhered to the World Medical Association Declaration of Helsinki. A total of 413 HCC patients were treated at our department from January 2015 to December 2023. The eligibility criteria of this study were as following: (1) Diagnosis of UH‐HCC (≥ 10 cm in diameter); (2) No previous history of liver radiotherapy; (3) No extrahepatic metastasis; (4) Classified as Barcelona Clinic Liver Cancer (BCLC) stage C (HCC with PVTT); (5) ≥ 18 years old; and (6) RT combined with ICI and AT as the treatment modality. Patients were treated in supine and prone positions alternately when RT was delivered by a γ‐ray body radiotherapy device (RTγ), whereas they were solely in the supine position when RT was administered by linear accelerator (RTa). Patients were randomly assigned to receive either RTa or RTγ treatment. Ultimately, a total of 63 patients treated by RT combined with ICI and AT were eligible for inclusion in this study. According to the delivery methods of RT, 37 patients were treated by RTγ combined with ICI and AT, and 26 patients by RTa combined with ICI and AT, respectively.
2.2. Treatment
All patients underwent 4‐dimensional contrast CT with abdominal compression. The RT was administered using a γ‐ray body radiotherapy device (Tech (Shenzhen) Co. Ltd., China, OUR‐QGD) or a TrueBeam accelerator of Varian Medical System. RTa patients received treatment in the supine position alone, whereas RTγ patients received treatment in both supine and prone positions alternately. The reasons for RTγ patients treated in supine and prone alternately were elaborated in our previous work [28]. NLV and WLV were defined as the normal liver volume and whole liver volume (normal liver volume plus tumor volume), respectively. NLV/WLV was the percentage of normal liver volume in the whole liver volume. The treatment plans for RTγ patients have to meet the following criteria: (1) Well‐tolerance of normal tissues; (2) Planning target volume (PTV) enveloped totally by 50% or 55% isodose lines; (3) Presence of ≥ 70% isodose curves within the gross tumor volume (GTV); (4) prescription dose normalized at the 50% isodose curve. (5) The 60% isodose curve encompassing at least 90% of the PTV; (6) The 70% isodose curve encompassing at least 60% of the PTV; and (7) One plan for the prostrate position and the other for the prone position. Whereas the treatment plans for patients undergoing RTa meeting the following criteria were eligible, including: (a) Well‐tolerance of normal tissues; (b) 85% isodose line covering at least 95% of the PTV; (c) prescription dose normalized at the 85% isodose curve. The remaining liver tissue function, the predicted toxicities of the gastrointestinal tract, and other normal tissues were the main factors taken into consideration when the prescription dose was determined. Liver constraints were: Mean NLV dose ≤ 15 Gy or ≥ 700 mL of the NLV receiving dose < 15 Gy. For serial gastrointestinal organs, the maximum dose to 0.5 cc was constrained to ≤ 30 Gy for the stomach, duodenum, and small bowel, and to ≤ 32 Gy for the esophagus and large bowel. These dose constraints were in line with the study of Miften M et al. [31]. The schedule of radiation therapy was one fraction of radiation therapy per day, with a one‐day interval for each patient to rest after every six consecutive fractions, resulting in a prescription dose of 36.4–44.2 Gy delivered in 12 to 14 days.
ICI includes pembrolizumab, sintilimab, atezolizumab, and camrelizumab. An antiangiogenic agent is initiated simultaneously with ICI. Antiangiogenic agents include sorafenib, lenvatinib, donafenib, bevacizumab, and apatinib. To choose the appropriate ICI, AT, and RT regimens, several factors were taken into consideration, such as joint assessment of physicians, preference, the financial situation of patients, and the coverage of medical insurance. In this study, atezolizumab plus bevacizumab was the most commonly employed regimen. Sintilimab plus bevacizumab was another commonly used regimen. Camrelizumab combined with apatinib was also used in this study. All patients received concurrent ICI and AT during radiotherapy. Upon completion of radiotherapy, all patients received 1–4 further cycles of ICI and AT, and no other post‐treatment was administered. Once serious or unacceptable side effects occurred, the treatments would be withdrawn or interrupted with the joint evaluation of physicians.
2.3. Statistical Analysis
The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used in the evaluation of tumor response by comparing the initial tumor volume and the volume after treatment. The date between the first day of treatment and the last follow‐up or death was calculated as the time of overall survival (OS). Accordingly, progression‐free survival (PFS) was calculated starting from the first day of treatment to the event of interest. The event of interest was defined as disease progression or death for PFS. Kaplan–Meier curves were employed in the assessment of OS and PFS. A comparison of survival outcomes between patients treated by RTγ vs. RTa (both in combination with ICIs and AT) was performed by utilizing the log‐rank test. The forward stepwise Cox regression model was employed to analyze the relationship between OS (or PFS) and various parameters in multivariate analysis. A two‐tailed p value of < 0.05 was statistically determined significant. Spearman correlation or Cramer's V coefficients were employed to evaluate the association among covariates. The software of SPSS version 22 (SPSS Inc., Chicago, IL) was used in the process of statistical analysis.
3. Results
The clinical characteristics of patients treated by RT combined with ICI and AT are summarized in Table 1. HCC was diagnosed based on histological or cytological confirmation (n = 53), elevated alpha‐fetoprotein (AFP) levels (> 400 ng/mL) combined with radiological findings (n = 4), or at least two types of radiological evidence (n = 6). The median marginal dose, median mean dose, and median fractional dose of the PTVs in the RTγ group were 38.4 Gy, 49.6 Gy, and 3.2 Gy, respectively. And those were 36.6 Gy, 37.8 Gy, and 3.0 Gy for the PTVs in the RTa group, respectively. Detailed RT regimens are presented in Table 2.
TABLE 1.
Characteristics of the patients.
| Characteristics | RTγ (n = 37) | RTa (n = 26) | P |
|---|---|---|---|
| Gender | 1.000 | ||
| Male (n, %) | 33 (89.2) | 23 (88.5) | |
| Female (n, %) | 4 (10.8) | 3 (11.5) | |
| Age | 1.000 | ||
| Median | 57 | 51 | |
| Range | 23–81 | 26–78 | |
| Tumor size (cm) | 0.873 | ||
| Median | 13.6 | 12.8 | |
| Range | 10.3–17.2 | 10.2–16.7 | |
| Virus infection | 0.786 | ||
| Positive (n, %) | 32 (86.5) | 23 (88.5) | |
| Negative (n, %) | 5 (13.5) | 3 (11.5) | |
| NLV (cc) | 0.684 | ||
| Median | 763.4 | 767.8 | |
| Range | 578.8–1089.6 | 584.2–1103.4 | |
| WLV (cc) | 0.783 | ||
| Median | 1365.6 | 1382.8 | |
| Range | 893.7–2067.8 | 889.7–2106.3 | |
| NLV/WLV (%) | 0.724 | ||
| Median | 67.3 | 68.8 | |
| Range | 51.2–77.4 | 52.6–79.4 | |
| BCLC stage | 0.615 | ||
| C | 37 | 26 | |
| AFP (ng/mL) | 0.712 | ||
| > 400 (n, %) | 29 (78.4) | 20 (76.9) | |
| ≤ 400 (n, %) | 8 (21.6) | 6 (23.1) | |
| C/H confirmation | 1.000 | ||
| Yes (n, %) | 31 (83.8) | 22 (84.6) | |
| No (n, %) | 6 (16.2) | 4 (15.4) |
Abbreviations: AFP, alpha‐fetoprotein; BCLC, Barcelona Clinic Liver Cancer; C/H, cytology/histology; NLV, normal liver volume; NLV/WLV, percentage of NLV in WLV; WLV, whole liver volume (normal liver volume plus target volume).
TABLE 2.
RT regimen (n = 63).
| Parameters | RTγ (n = 37) | RTa (n = 26) |
|---|---|---|
| Prescribed fractional dose (Gy) | ||
| Median | 3.2 | 3.0 |
| Range | 2.8–3.4 | 2.8–3.2 |
| Prescribed total dose (Gy) | ||
| Median | 38.4 | 39 |
| Range | 36.4–44.2 | 38.4–40.8 |
| ICNPD | 50%–55% | 85% |
| PTVCPD | 100% | 95% |
| Marginal dose of PTV (Gy) | ||
| Median | 38.4 | 36.6 |
| Range | 36.8–47.8 | 36.5–38.8 |
| Mean dose of PTV | ||
| Median | 49.6 | 37.8 |
| Range | 47.8–57.3 | 37.8–39.3 |
| P70 | ||
| Median | 62.8% | 100% |
| Range | 60.6%–73.4% | 100% |
Abbreviations: ICNPD, isodose curve normalized by prescription dose; P70, percentage of tumor volume covered by 70% isodose curve in whole tumor; PTV, planning target volume; PTVCPD, percentage of tumor volume covered by prescription dose in whole tumor; RT, radiation therapy.
During treatment, all patients underwent weekly routine blood tests and liver function assessments. In the first 3 months after completing treatment, patients underwent monthly abdominal magnetic resonance imaging (MRI) scans and liver function evaluations; thereafter, these assessments were performed at 3–6 months intervals.
In the RTa group, five patients (19.2%) were unable to complete the treatment due to Grade 3 non‐classic radiation‐induced liver disease (RILD), as graded by the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. RILD is clinically categorized into classic and non‐classic subtypes. Classic RILD is a clinical syndrome resembling hepatic veno‐occlusive disease/sinusoidal obstruction syndrome, occurring after hepatic irradiation. Non‐classic RILD is a hepatitic‐type injury pattern dominated by acute hepatocellular damage, often associated with combined‐modality therapy. For the grade 3 non‐classic RILD patients in the RTa group, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels exceeded 5 times the upper limit of normal after 7–9 radiation fractions. Additionally, one more patient in the RTa group developed Grade 3 non‐classic RILD after completing treatment. Notably, ALT and AST levels failed to recover to normal in all RTa patients who experienced Grade 3 RILD. In contrast, no cases of Grade 3 or more severe RILD were observed in the RTγ group, and all patients in this group completed treatment successfully. The receiver operating characteristic (ROC) curve (Figure 1) analysis for RTa group patients indicated that a higher risk of Grade 3 non‐classic RILD was associated with a smaller percentage of NLV in WLV. The area under the curve (AUC) was 0.874 (95% confidence interval (CI), 0.809–0.968; p < 0.001).
FIGURE 1.
The receiver operating characteristic (ROC) curve evaluating the predictive value of the percentage of normal liver volume for severe radiation‐induced liver disease following linear accelerator radiotherapy.
All enrolled patients exhibited varying degrees of leukopenia during treatment. Most patients also developed thrombocytopenia and lymphopenia either during treatment or 1–2 weeks post‐treatment completion. Although the incidence of Grade ≥ III thrombocytopenia was significantly higher in the RTγ group than in the RTa group (18.9% vs. 7.7%, HR = 0.38; p = 0.008), all cases of thrombocytopenia (regardless of grade) resolved either spontaneously or with appropriate intervention. Similarly, leukocyte and lymphocyte counts recovered to normal levels either spontaneously or following proper management. Other adverse events were observed, but none exceeded Grade 3 in severity. Furthermore, except for Grade 3 RILD, all adverse events resolved either spontaneously or with appropriate intervention.
These findings demonstrate that, in terms of adverse events, patients in the RTγ group showed a more acceptable toxicity profile compared to the RTa group. The main adverse events observed in all patients are summarized in Table 3.
TABLE 3.
Treatment‐related side effects.
| Side effect | RTγ group (n = 37) | Rta group (n = 26) | P | ||
|---|---|---|---|---|---|
| No | % | No | % | ||
| Leukopenia | |||||
| Mild | 17 | 45.9 | 11 | 42.3 | 1.000 |
| Moderate | 14 | 37.8 | 11 | 42.3 | 0.312 |
| Severe | 6 | 16.2 | 4 | 15.4 | 1.000 |
| Thrombocytopenia | |||||
| Grade I | 11 | 29.7 | 7 | 26.9 | 1.000 |
| Grade II | 8 | 21.6 | 6 | 23.1 | 0.227 |
| Grade≥III | 7 | 18.9 | 2 | 7.7 | 0.038 |
| Lymphopenia | |||||
| Mild | 15 | 40.5 | 9 | 34.6 | 1.000 |
| Moderate | 12 | 32.4 | 10 | 42.3 | 0.424 |
| Severe | 3 | 8.1 | 2 | 7.7 | 0.508 |
| ALT/AST increased | |||||
| Mildly | 6 | 16.2 | 4 | 15.4 | 0.052 |
| Moderately | 3 | 8.1 | 4 | 15.4 | 0.017 |
| Severely | 0 | 0 | 6 | 23.1 | 0.008 |
| Total bilirubin increased | |||||
| Mildly | 6 | 16.2 | 3 | 11.5 | 0.044 |
| Moderately | 2 | 5.4 | 6 | 23.1 | 0.006 |
| Severely | 0 | 0 | 5 | 19.2 | 0.001 |
| Radiation‐induced dermatitis | |||||
| Grade I | 5 | 13.5 | 3 | 11.5 | 1.000 |
| Grade II | 8 | 21.6 | 4 | 15.4 | 1.000 |
| Grade≥III | 1 | 2.7 | 0 | 0 | 1.000 |
| Diarrhea | |||||
| Grade I | 5 | 13.5 | 3 | 11.5 | 1.000 |
| Grade II | 3 | 8.1 | 2 | 7.7 | 1.000 |
| Grade≥III | 0 | 0 | 0 | 0 | 1.000 |
| Anorexia | 12 | 32.4 | 8 | 30.8 | 1.000 |
| Nausea | 10 | 27 | 7 | 26.9 | 1.000 |
| Fever | 16 | 43.2 | 10 | 38.5 | 1.000 |
| Gastric ulcer | 1 | 2.7 | 0 | 0 | 0.476 |
| Duodenal ulcer | 1 | 2.7 | 0 | 0 | 0.384 |
| Dizziness | 14 | 37.8 | 10 | 38.4 | 1.000 |
| Malaise | 18 | 48.6 | 12 | 46.2 | 1.000 |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Within 6 months of follow‐up, the enrolled patients achieved an objective response rate (ORR) of 68.2% (n = 43), consisting of 9.5% (n = 6) complete response (CR) and 58.7% (n = 37) partial response (PR). During the same period, 17.5% (n = 11) of patients exhibited stable disease (SD), while 14.3% (n = 9) showed progressive disease (PD). When analysis was restricted to PVTT recanalization alone, a rate of 78.4% (n = 29) was achieved in the RTγ group, in contrast to 38.5% (n = 10) in the RTa group during 6 months of follow‐up. Notably, significant differences in ORR, CR, PR, SD, and PD were also observed between the RTγ and RTa groups, with the RTγ group demonstrating superior tumor response outcomes. Specifically:
RTγ group: Achieved an ORR of 86.5%, including 16.2% CR and 70.3% PR; SD was 13.5%, and no patients (0%) developed PD.
RTa group: Had a substantially lower ORR of 42.3% (accounted for by 42.3% PR, with 0% CR); SD was 23.1%, and PD occurred in 34.6% of patients.
These results indicated that patients in the RTγ group derived greater clinical benefits from treatment compared to those in the RTa group. The tumor response profiles of patients treated with RTγ and RTa are presented in Figure 2.
FIGURE 2.
The comparison of tumor response for patients treated by γ‐knife and linear accelerator radiotherapy.
Patients in the RTγ group indicated longer tumor progression‐free survival (PFS) outcomes compared to those in the RTa group. The median PFS was 12.1 months (95% CI, 7.0–23.2) in the RTγ group, significantly longer than the 6.6 months (95% CI, 5.1–8.2) observed in the RTa group. The hazard ratio (HR) was 0.54 (95% CI, 0.32–0.85; p = 0.004).
Notably, the 1‐year, 2‐year, and 3‐year PFS rates were also higher in the RTγ group than in the RTa group. Specifically, the RTγ group achieved 1‐year, 2‐year, and 3‐year PFS rates of 43.2%, 24.3%, and 10.8%, respectively; in contrast, the corresponding rates in the RTa group were 11.5%, 3.8%, and 0%. These findings indicate that patients treated with RTγ may achieve better PFS outcomes than those treated with RTa. A direct comparison of the PFS between the two groups is shown in Figure 3A.
FIGURE 3.
The comparison of progression‐free survival (A) and overall survival (B) for patients treated by γ‐knife and linear accelerator radiotherapy.
A difference in overall survival (OS) was also observed between the RTγ and RTa groups. The median OS was 14.3 months (95% CI, 7.7–26.9) for the RTγ group, compared to 8.1 months (95% CI, 6.1–10.1) for the RTa group. The OS benefit was confirmed by a significant reduction in the risk of death, with an HR of 0.56 (95% CI, 0.38–0.82; p < 0.001).
Furthermore, the 1‐year, 2‐year, and 3‐year OS rates were significantly higher in the RTγ group than in the RTa group: 56.7%, 40.5%, and 18.9% vs. 23.1%, 7.7%, and 0%, respectively. These findings suggest that RTγ may confer a potential survival advantage over RTa in the treatment of UH‐HCC with PVTT. A comparison of the OS between the two groups is provided in Figure 3B.
Univariate Cox Proportional Hazard Regression analysis revealed RTa group (compared to the RTγ group) (p < 0.001 for both PFS and OS), NLV/WLV < 60% (p = 0.003 for PFS, p < 0.001 for OS), tumor size ≥ 15 cm (p = 0.044 for PFS, p = 0.037 for OS), age ≥ 65 years (p = 0.031 for PFS, p = 0.042 for OS) and positive viral infection (p = 0.032 for PFS, p = 0.026 for OS) were significantly associated with inferior PFS and OS.
On multivariate analysis, the RTγ group (compared to the RTa group) was identified as a significant independent predictor of superior PFS (p < 0.001) and OS (p < 0.001). Moreover, both NLV/WLV < 60% (p = 0.027 for PFS, p < 0.034 for OS) and positive viral infection (p = 0.033 for PFS, p = 0.028 for OS) were significantly associated with worse PFS and OS. Notably, neither tumor size ≥ 15 cm (p = 0.057 for PFS, p = 0.061 for OS) nor age ≥ 65 years (p = 0.071 for PFS, p = 0.056 for OS) reached statistical significance as independent predictors of PFS or OS. The results of the Cox regression analyses of factors associated with PFS and OS are presented in Figure 4A,b, respectively.
FIGURE 4.
The forest plot of Cox regression analysis for progression‐free survival (PFS) (A) and overall survival (B).
4. Discussion
The findings suggest that combining RTγ (as opposed to RTa) with ICI and AT may improve clinical outcomes in UH‐HCC patients with PVTT.
The incidence of Grade ≥ III thrombocytopenia was higher in the RTγ group compared to the RTα group. However, all thrombocytopenia cases (regardless of grade) resolved either spontaneously or with appropriate intervention. Similarly, with the exception of Grade 3 non‐classic RILD, all other adverse events also resolved spontaneously or with appropriate intervention. Notably, RTγ could confer an advantage over RTa in protecting the normal liver. In the RTa group, 6 patients experienced Grade 3 non‐classic RILD, while no such cases were observed in the RTγ group. The difference in field formation between RTγ and RTa may explain why RTγ is superior to RTa in protecting the normal liver. The radiation field of RTγ is formed by the rotational focusing of 30 narrow radiation beams. This rotational focusing method can generate a dose distribution at the center of the tumor similar to the Bragg peak, which is produced by charged particle beams, resulting in a sharp dose drop‐off at the tumor edges [31]. Figure 5A shows the Bragg‐peak‐like dose distribution of a single field of RTγ (marked with a triangle). Figure 5B,C show the iso‐dose line and dose color wash distribution for the tumor treated with RTγ. However, the radiation field of RTa is directly formed by the MLC (Multileaf Collimator) according to the shape of the tumor. Figure 5D shows the dose distribution of a single RTa field. Figure 5E,F show the iso‐dose line and dose color wash distribution for the tumor treated with RTa. A comparison of the dose distribution between RTγ and RTa is shown in Figure 5. Figure 5 shows that, in RTγ therapy, the dose delivered to the tumor was much higher than the prescription dose and was distributed non‐uniformly. In contrast, in RTa therapy, the dose was much closer to the prescription dose and was relatively uniform. For a single RTa field, the normal liver tissues along the irradiation path may receive a higher radiation dose than the tumor itself. The dose drop‐off is less steep than that of RTγ. Therefore, RTγ could confer an advantage over RTa in the protection of the normal liver. Hsieh CE et al. suggested that a higher radiation dose to the normal liver was associated with higher rates of hepatic toxicity [32]. This may explain why no grade 3 or more severe RILD was observed in the RTγ group, while 6 patients were observed in the RTa group.
FIGURE 5.
Comparison of dose distribution between γ‐ray body radiotherapy (A–C) and linear accelerator radiotherapy (D, F). (A, D) Single‐field dose distribution profiles. (B, E) Isodose line distributions. For γ‐ray body radiotherapy (B): Green line, prescription dose; dotted blue line, tumor contour; yellow, red, and black lines represent 120%, 140%, and 160% of the prescription dose, respectively. For linear accelerator radiotherapy (E): Black line, 80% of the prescription dose; red line, 90%; blue line, tumor contour; yellow line, prescription dose. (C, F) Dose color‐wash distributions. For γ‐ray body radiotherapy (C): Green area, prescription dose; dotted blue line, tumor contour; yellow, pink, and black areas correspond to 120%, 140%, and 160% of the prescription dose, respectively. For linear accelerator radiotherapy (F): Color wash representation as shown.
The clinical efficacy outcomes of the RTγ group are also different from those of the RTa group. Notably, certain key metrics in the RTγ group—such as the ORR and median OS—were comparable to those reported in other studies [33, 34]. The median PFS and OS in the RTγ group were comparable to those of surgical treatment for giant HCC reported by Wee JJ et al. [35]. Despite the median diameter of HCC in the research of Wee JJ et al. being a little larger than that in our study, the outcomes of our study remain comparable to theirs, considering our cohort consisted of UH‐HCC with PVTT, a factor absent in their study. The clinical outcomes observed in the RTγ group were also similar to the previous report of the outcomes of stereotactic body radiotherapy for HCC with PVTT [37]. The authors argue that the main reason RTγ outperforms RTa as a treatment modality lies in a more inhomogeneous dose distribution of RTγ. A more inhomogeneous dose distribution may lead to increased dose delivery to the tumor. While the marginal doses of RTγ and RTa were nearly identical, the maximal doses in the RTγ group were twice the marginal doses, attributable to the 50% isodose curves encompassing the tumors. In contrast, the maximal doses in the RTa group were significantly lower than those in the RTγ group, as the tumors were encompassed by the 85% isodose curves. For the same reason, the mean doses of the RTa group were also significantly lower than those of the RTγ group. The increased dose delivery of RTγ resulted in superior therapeutic effects. This finding is consistent with the results of Chonlakiet K et al. [36]. Moreover, a more inhomogeneous dose distribution may activate the immune system of the body, which may further enhance the therapeutic outcomes of ICI and AT. Thereby, the therapeutic efficacy is naturally improved through these factors' synergistic effects. The ability of inhomogeneous dose distribution to trigger the immune system in the body is a key mechanism underlying spatially fractionated radiation therapy [37, 38].
The findings in this study did not indicate tumor size as an independent prognostic factor for PFS or OS, which is inconsistent with previous findings [39]. The authors postulate that the reason for this result is the limited differences between tumor sizes. However, NLV/WLV < 60% and positive viral infection were the independent prognostic factors for inferior PFS and OS. These findings are consistent with those of previous studies [40, 41, 42].
This study has inevitable limitations due to its retrospective design. Additionally, the sample size was modest. Therefore, prospective, multi‐center studies are required to confirm our findings.
5. Conclusions
This study supports RTγ combined with ICI and AT as an effective and safe treatment modality for UH‐HCC with PVTT patients. This retrospective analysis also shows a promising trend: Patients with UH‐HCC and PVTT subjected to RTγ combined with ICI and AT may benefit more than those subjected to RTa combined with ICI and AT, including higher rates of CR and ORR, prolonged PFS and OS, and a more favorable toxicity profile. Additionally, the percentage of NLV/WLV > 60% and negative viral infection are independent factors for superior PFS and OS.
Author Contributions
ZengLiang Huang: Drafted the work, approval of the submitted version; JuanJuan Shen: Revised the work, approval of the submitted version; NanBao Zhong: Design of the work, approval of the submitted version; ZhongHua Chen: Data acquisition, approval of the submitted version; JianHai Lin: Data analysis and interpretation, approval of the submitted version; ShiLong Den: Revised the work, approval of the submitted version.
Funding
The authors have nothing to report.
Disclosure
The authors have nothing to report.
Ethics Statement
Ethics approval was obtained from our Hospital Ethics Committee (approval no. 2023046). Informed consent to participate was obtained from all of the participants. The study adhered to the Declaration of Helsinki.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
We express our gratitude to all patients and participating clinicians for their invaluable support in this study.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.