Abstract
Background/Aim: We report on a case of locally advanced hepatocellular carcinoma (HCC) accompanied by an inferior vena cava tumor thrombus (IVCTT), treated successfully with proton-beam therapy (PBT). Case Report: A 63-year-old male presented with a primary, single HCC with IVCTT, without metastasis to the intrahepatic region, lymph nodes, or distant organs. The clinical staging was identified as T4N0M0 Stage IIIB. The patient’s liver function was classified as Child-Pugh class A (score: 6), with a modified albumin–bilirubin (mALBI) grade of 2a. The patient had liver cirrhosis due to non-alcoholic steatohepatitis. Magnetic resonance imaging revealed a nodular tumor measuring 13.2×8.9×9.8 cm across segments 1, 6, 7, and 8, along with IVCTT. The patient received PBT, with a total dose of 72.6 Gy (relative biological effectiveness) delivered in 22 fractions. Throughout the PBT treatment, the patient experienced no acute toxicities and completed the therapy as planned. Twelve months following PBT, the patient was alive without evidence of local recurrence, lymph node involvement, or distant organ metastasis. The only late toxicity observed was a mild worsening of the mALBI grade. Conclusion: We observed a favorable local response with manageable toxicities in a patient with locally advanced HCC and IVCTT treated with PBT. While this is a single case report, our findings suggest that PBT could be considered a viable treatment option for HCC with IVCTT.
- Hepatocellular carcinoma
- proton-beam therapy
- inferior vena cava tumor thrombus
- radiotherapy
- macroscopic vascular invasion
Treating hepatocellular carcinoma (HCC) that involves a main portal vein (Vp4) or inferior vena cava (Vv3) tumor thrombus (IVCTT) or invasion often presents considerable challenges. Although systemic treatments like multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors are the standard care for HCC with macroscopic vascular invasion (MVI) (1-4), these therapies alone might not achieve adequate tumor control (2-4). Liver resection could be an option for managing MVI, excluding Vp4 and Vv3 cases (5); however, for Vp4 and Vv3, it is often difficult due to liver function and tumor status.
Recent studies have identified radiotherapy (RT), including particle therapy, as a potential local treatment for HCC with MVI (6-8). Proton-beam therapy (PBT), a form of particle beam therapy, offers a substantial advantage over traditional X-ray RT due to its Bragg peak characteristic. This allows proton-beams to deliver concentrated doses to tumors while minimizing damage to surrounding healthy tissue. As a result, PBT has demonstrated promising clinical outcomes for HCC with MVI (7, 9, 10). However, literature on its efficacy, particularly in patients with HCC involving IVCTT, remains scarce.
Here, we present a case where PBT was applied to treat HCC with IVCTT, resulting in favorable local control and no associated severe toxicities.
Case Report
Patient. A 63-year-old Japanese male with primary single HCC with IVCTT and without metastasis to the intrahepatic region, lymph nodes, or distant organs was referred to the Department of Radiation Oncology at Shonan Kamakura General Hospital for PBT. The patient had liver cirrhosis resulting from non-alcoholic steatohepatitis. According to the Eastern Cooperative Oncology Group the patient’s performance status was 0. The liver function was classified as Child-Pugh class A (score: 6) and modified albumin–bilirubin (mALBI) grade 2a (score: −2.28). Laboratory test results, summarized in Table I, highlighted notably elevated alpha-fetoprotein (AFP) levels (36,720.1 ng/ml; normal range=0-10.0 ng/ml) and protein induced by vitamin K absence-II (PIVKA-II) levels (3,360 mAU/ml; normal range=0-33.3 mAU/ml). The indocyanine green retention rate at 15 min (ICG-R15) was 19.2%. Gadolinium–ethoxybenzyl–diethylenetriamine penta-acetic acid (Gd–EOB–DTPA)-enhanced magnetic resonance imaging (MRI) identified a tumor measuring 13.2×8.9×9.8 cm across liver segments 1, 6, 7, and 8, with characteristics including absence of early arterial phase enhancement, washout in the delayed phase, and higher signal intensity in diffusion-weighted imaging (DWI) (Figure 1A-C). 2-Deoxy-2-[18F]fluoroD-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed abnormal FDG uptake in the lesion, consistent with the findings on contrast-enhanced CT and MRI (Figure 1D and E). Both imaging modalities showed no ascites or evidence of lymph node or distant organ metastasis. A needle biopsy confirmed the diagnosis of HCC. The patient was staged as IIIB (clinical T4N0M0) according to the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM staging system. The patient’s medical history included diabetes, hypertension, dyslipidemia, and angina pectoris. Given the patient’s ineligibility for surgery and refusal of systemic therapy, PBT was selected as the local treatment approach.
Liver function parameters before and after the proton-beam therapy.
Gadolinium–ethoxybenzyl–diethylenetriamine penta-acetic acid enhanced magnetic resonance imaging and 2-Deoxy-2-[18F]fluoroD-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) before proton-beam therapy. These images detected a tumor (13.2×8.9×9.8 cm) in segments 1, 6, 7, and 8 of the liver, washout in the delayed phase of axial (A) and coronal (B) images, and higher signal intensity in the diffusion-weighted image (C). FDG- PET/CT showed abnormal FDG uptake of axial (D) and coronal (E) images.
Proton-beam therapy. Before undergoing PBT, the patient was immobilized with tailor-made fixation cushions and thermoplastic shells to capture treatment-planning CT images; both respiratory-gated and four-dimensional CT scans were performed. A fiducial marker was placed near the tumor prior to CT imaging. The movement of the marker was tracked using four-dimensional CT images to ensure PBT was administered within a 3 mm range of the marker’s peak expiratory movement. For the actual treatment, the gating level for respiratory-gated irradiation was set between 20% of the expiratory wave height near peak expiration and maximum expiration. The patient underwent PBT once daily, five days a week, from Monday to Friday.
The treatment planning CT images were combined with MRI scans to accurately outline the gross tumor volume (GTV). The clinical target volume (CTV) included a margin to encompass microscopic disease, while the planning target volume (PTV) comprised the CTV, an internal margin, and a setup margin. The prescribed PBT dose was 72.6 Gy [relative biological effectiveness (RBE)] of carbon-ion radiotherapy (C-ion RT) in 22 fractions, targeting at least 95% coverage of the CTV with this dose. The dose constraints were defined as the maximum gastrointestinal (GI) tract dose (Dmax) of <50 Gy (RBE), healthy liver (liver - GTV) volume receiving more than 5 Gy (RBE) <60%, and healthy liver volume receiving less than 2 Gy (RBE) >500 cm3. Figure 2 illustrates the dose distribution of the PBT. Toxicities were monitored using the Common Terminology Criteria for Adverse Effects (version 4.0) (11). Informed consent was obtained from the patient before starting the treatment.
Dose distribution of proton-beam therapy. Axial (A) and coronal (B) images. The area within the red outline is the gross tumor volume. Highlighted are 95% (red), 90% (orange), 80% (yellow), 65% (light green), 50% (light blue), and 20% (blue) isodose curves [100% was 72.6 Gy (RBE)].
Results
The patient completed PBT according to schedule and did not experience any acute toxicities. Twelve months after PBT, Gd–EOB–DTPA-enhanced MRI showed tumor shrinkage and a decrease in signal intensity on DWI (Figure 3). Additionally, AFP levels dropped to 2.3 ng/ml and PIVKA-II decreased to 11 mAU/ml. The laboratory test results post-PBT are detailed in Table I. The patient is alive and shows no evidence of local recurrence, lymph node involvement, or distant organ metastasis. In terms of late toxicities, the only issue noted was a mild deterioration in the mALBI grade, moving from 2a to 2b. Currently, the patient is not undergoing any adjuvant treatment following PBT.
Treatment response 12 months after proton-beam therapy. Axial (A) and coronal (B) in the delayed phase, and in the diffusion-weighted image (C) of magnetic resonance imaging. No evidence of local recurrence is seen.
Discussion
In this case of HCC with IVCTT treated with PBT, we observed a favorable clinical outcome without toxicities. Treatment strategies for HCC with IVCTT remain a subject of debate, except for systemic therapy (12). Furthermore, data on the efficacy and safety of PBT in this context are currently limited. Although this is a single case report, we are optimistic that our positive findings will contribute to the development of effective treatment strategies for HCC with IVCTT.
Studies have indicated that HCC patients with IVCTT who undergo surgery tend to have longer survival times than those who do not (5, 13), suggesting a recommendation for local treatment in these patients. Moreover, the median survival times reported for HCC patients with IVCTT in complete versus non-complete resection groups were 30.8 and 10.5 months, respectively, with a study on PBT showing a median survival time of 21 months (7, 14). These findings imply that local treatment should be considered as part of the treatment strategy for HCC with IVCTT, offering surgery as an option for cases amenable to complete resection and PBT for cases where complete resection is challenging. We hope this case report will aid in selecting appropriate treatments for HCC with IVCTT.
X-ray RT is recognized as a local treatment option for HCC with MVI (6). However, a previous study has demonstrated that the dose distribution for HCC treatment using X-ray RT is inferior to those with PBT, particularly in terms of the dose-volume histogram parameters for liver volume receiving more than 30 Gy (RBE) and the mean liver dose (15). This research suggests that the superior dose distribution characteristics of PBT could enable the delivery of higher doses to the tumor, improving tumor control while reducing toxicity. Furthermore, we posit that these benefits of PBT could facilitate repeat irradiation in cases of HCC recurrence, potentially extending patient survival. Thus, PBT may offer considerable advantages over X-ray RT, especially for patients who either refuse systemic therapy or are medically ineligible for it.
Regarding systemic therapy, the patient in question declined such treatment; thus, no systemic therapy was administered before or after PBT. Notably, new HCC lesions will emerge outside the initially irradiated field in the future. In such cases, early therapeutic intervention becomes crucial, underscoring the importance of vigilant follow-up. Ideally, when local treatment is an option, a combination of systemic and local therapies is recommended (5). If PBT is selected as the local treatment approach, incorporating systemic therapy prior to radiotherapy is advisable. Pre-radiotherapy systemic therapy could lead to tumor shrinkage, potentially reducing the necessary irradiation field and decreasing the likelihood of toxicities associated with PBT.
Conclusion
We experienced a case of HCC with IVCTT treated with PBT, with favorable local effects and tolerable toxicities. Our study findings suggest that PBT is a potential treatment option for patients with HCC with IVCTT.
Acknowledgements
The Authors would like to thank their colleagues at Shonan Kamakura General Hospital.
Footnotes
Authors’ Contributions
Conceptualization, S.Shiba; investigation, S.Shiba, K.T.; resources, S.Shiba, S.Shiraishi, and K.T.; patient treatment, S.Shiba, S.Shiraishi, K.T., and R.R.; writing—original draft preparation, S.Shiba; writing—review and editing, S.Shiba, S.Shiraishi, K.T., R.S., and M.O.; visualization, S.S.; supervision, K.T.; project administration, S.S. and K.T.
Funding
This research received no external funding.
Conflicts of Interest
All Authors have declared no conflicts of interest in relation to this study.
- Received April 16, 2024.
- Revision received April 25, 2024.
- Accepted April 26, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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