To the Editor: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and an important cause of cancer-related death.1 Approximately 40.0–66.2% of patients with HCC develop portal vein tumor thrombus (PVTT), and their median survival is only 2–5 months.2 Transcatheter arterial chemoembolization (TACE), a minimally invasive, nonsurgical intervention widely used in the treatment of liver cancer, is currently considered a standard therapeutic option for patients with intermediate-stage HCC.3 In the present study, a retrospective cohort study, we used the double spring coil TACE (DSC-TACE) approach, which was developed to test the therapeutic potential of this novel strategy namely, to increase iodized oil deposition within PVTT, improve portal vein blood flow, and ultimately reduce the risk of mortality. A total of 94 patients with unresectable HCC and PVTT treated at Shandong Cancer Hospital and Institute between May 1, 2015, and December 31, 2021, were retrospectively enrolled in this study. This retrospective study using anonymized clinical data was granted ethical exemption by the review board of Cancer Hospital of Shandong First Medical University. All procedures were performed in accordance with the Declaration of Helsinki. The study was also registered at Chictr.org.cn (Registration No: ChiCTR2200055193). To assess the therapeutic effect of DSC-TACE in the treatment of HCC, patients with HCC were divided into four groups, including the conventional TACE (c-TACE) group (26 patients), the sorafenib group (18 patients), the c-TACE plus sorafenib group (26 patients), and the DSC-TACE plus sorafenib group (24 patients). The major clinicopathological features of the enrolled patients are shown in Supplementary Table 1, https://links.lww.com/CM9/C894. Successful chemoembolization of PVTT is dependent upon the precise identification of its feeding arteries. The hepatic artery-derived feeder of PVTT was first reported by Okuda in the 1970s.4 This hepatic artery-derived branch of the artery penetrates the thrombus and creates an arteriovenous fistula through its anastomosis with the portal venous system. Although c-TACE cannot effectively occlude these feeding arteries, DSC-TACE was developed specifically to address this limitation. Using computed tomography angiography, DSC-TACE is a dual-phase embolization approach to achieve targeted arterial occlusion: embolization of the primary hepatic lesion followed by focused embolization of the tumor thrombus Figure 1A. When the artery supplying PVTT could be successfully superselected, a mixed emulsion of lipiodol and epirubicin hydrochloride (30 mg), totaling 2–10 mL, was infused through a microcatheter for the outline of the microvascular network. This was then followed by embolization using gelatin sponge particles or coils Figure 1B–G.Figure 1: Specific operations of DSC-TACE surgery. (A) The flowchart of the DSC-TACE procedure. (B) DSA illustrates the feeding artery (white arrow) of the PVTT originating from the right hepatic artery, with a schematic displaying the small branch (black arrowhead) penetrating the portal vein to supply the PVTT. (C) Angiography through a microcatheter (black arrow) provides a detailed view of the tumor’s vascular blood supply. (D) Lipiodol emulsion adequately fills the PVTT (white arrows). (E) A microcoil occludes the main trunk of the PVTT feeding artery (white arrowheads). (F and G) The PVTT, hypoattenuating compared with the normal adjacent liver parenchyma during the portal venous phase on transverse computed tomography before embolization (yellow arrowheads), demonstrates successful intervention with replacement by high-density lipiodol deposition at 1 month postembolization (purple arrowheads). (H and I) The transverse computed tomographic scan revealed the feeding artery of the PVTT during the arterial phase (white arrow in H) and displayed a large heterogeneous mass during the portal venous phase (white arrows in I). (J) The primary lesion was adequately embolized (white arrowheads), but the PVTT was not distinctly visualized on the follow-up angiography. (K) The feeding artery was precisely visualized (white arrows), along with the PVTT (black arrows), following occlusion of the main lesion’s supply artery by a microcoil (black arrowheads). (L) Significant lipiodol deposition was observed in the PVTT (white arrows) and its feeding artery (white arrowhead). The black arrowhead indicates the first microcoil. (M) A second microcoil was deployed to embolize the proximal feeding artery of the primary lesion (white arrowhead). The black arrowhead marks the position of the first microcoil, and the white arrows indicates the PVTT. (N and O) During the procedure, computed tomography revealed a well-embolized PVTT (white arrows) along with the presence of two microcoils (black and white arrowheads), maintaining effective occlusion at 1 month postembolization. (P) Kaplan–Meier survival curves of HCC patients with PVTT. The values below indicate the number of patients at risk at each follow-up time point, with colors distinguishing different treatment groups. CBCT: Cone-beam computed tomography; DSA: Digital subtraction angiography; DSC-TACE: Double spring coil transcatheter arterial chemoembolization; HCC: Hepatocellular carcinoma; HRCT: High-resolution computed tomography; OP: Operation; PVTT: Portal vein tumor thrombus.Alternatively, when superselection of the PVTT-supplying artery was not possible, a double coil embolization technique was used Figure 1H–O, which consisted of the following steps: (1) identification of the PVTT feeding artery; (2) placement of the first spring coil at the distal end of the hepatic arterial branch supplying the thrombus to block blood flow to the hepatic sinusoids; (3) infusion of the lipiodol–epirubicin emulsion to embolize the PVTT feeding artery until complete cessation of blood flow; and (4) deployment of the second coil at the proximal segment of the same vessel, cone-beam computed tomography (CBCT) was then carried out to assess lipiodol deposition after embolization. TACE procedures were tailored to the individual patient, with approximately two to three procedures performed to achieve the desired embolization endpoint, usually at intervals of 1–1.5 months. For patients with hepatic artery–portal vein shunts, embolization of the dominant shunt or multiple secondary shunts was performed after embolization of the arterial supply to the primary tumor Supplementary Figures 1 and 2, https://links.lww.com/CM9/C894. In the TACE-sorafenib group, patients received oral sorafenib (400 mg twice daily), starting 3–5 days after the first TACE session. Treatment was continued until administration of the second TACE procedure. Dose reduction to 400 mg once daily was used in cases of grade 3/4 adverse events based on the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, including hematologic, dermatologic, gastrointestinal toxicities and hypertension or hepatic dysfunction. Sorafenib was discontinued when severe adverse events were not resolved by dose reduction and was resumed only after the toxicities were resolved. Compared with conventional therapies, DSC-TACE plus sorafenib showed comparable treatment-related adverse event rates Supplementary Table 2, https://links.lww.com/CM9/C894 but superior clinical outcomes. To assess liver function, we evaluated the changes in albumin and total bilirubin levels before and after treatment. The results showed that both postoperative albumin and total bilirubin levels in the DSC-TACE group exhibited no significant differences compared with other treatment groups, which suggests that DSC-TACE did not cause additional damage to the core hepatic metabolic function Supplementary Figure 3, https://links.lww.com/CM9/C894. When evaluated by curative effect and overall response rate (ORR), the DSC-TACE plus sorafenib group showed significantly better results, with ORR of 75.0% (18/24), complete response (CR) rate of 12.5% (3/24), partial response rate of 62.5% (15/24), and disease control rate of 87.5% (21/24), which was better than all other treatment groups Supplementary Tables 3 and 4, https://links.lww.com/CM9/C894. Furthermore, Cox regression analysis assessing the effect of various treatment modalities on mortality showed that DSC-TACE plus sorafenib significantly decreased the risk of death in HCC patients with PVTT Supplementary Table 5, https://links.lww.com/CM9/C894. Survival analyses further showed that the median progression-free survival (PFS) and median overall survival (OS) of DSC-TACE plus sorafenib group were 13 months (P <0.001) and 15 months (P <0.001), which were significantly longer than in the other three groups Figure 1P. Collectively, these results suggest that DSC-TACE with sorafenib has better clinical benefits than c-TACE and significantly improves the prognosis of HCC patients with PVTT. This retrospective cohort study established and validated a DSC-TACE procedure for the treatment of HCC patients with PVTT. This novel approach, which was specifically developed to overcome the limitations of c-TACE in terms of accurately identifying the PVTT arterial supply and reducing nontarget embolization, resulted in significant improvement of both OS and PFS. Remarkably, the combination of DSC-TACE and sorafenib achieved a median OS that was higher than the reported median OS of TACE (6 months) and hepatic arterial infusion chemotherapy (HAIC) (10.1 months) in the Asia-Pacific region.5 Taken together, these results indicate the potential of DSC-TACE to improve CR rate and ORR and reduce the risk of mortality, making it a promising therapeutic option for HCC patients with PVTT. The rational choice of embolic agents is a key determinant of therapeutic success. The feeding arteries of PVTT are generally small branches of the hepatic arteries with unstable hemodynamics and significant anatomical variability, which is in sharp contrast to the inherent limitations of traditional particulate embolic materials. In contrast, coils provide vascular occlusion by direct mechanical obstruction and are not affected by variations in the blood flow. Under the guidance of imaging, they can be deployed with high precision to achieve a “double-point anchoring” effect, allowing the embolization endpoint to be controlled in real time and with high accuracy. These advantages render coil-based embolization especially suitable for patients with moderate-to-severe PVTT. Optimal candidates for this treatment are patients with a good hepatic functional reserve (Child-Pugh class A or early-stage B) and patients in whom PVTT poses an immediate threat to survival (moderate-to-severe portal vein obstruction, high risk of complications, or rapidly progressing thrombus) for whom the potential benefits of treatment outweigh the potential risks. Conversely, patients with impaired liver function (Child-Pugh class C), extensive tumor thrombus load, or severely impaired general health condition are more suitable candidates for systemic therapies such as targeted therapy or immunotherapy. Regarding the possible development of collateral vessels after repeated embolization of the arteries, the present study established a systematic management protocol in its staged treatment design. Before each TACE session, detailed imaging evaluations were performed to assess vascular anatomical changes and intraoperative digital subtraction angiography (DSA) was used to accurately identify newly developed collateral vessels, including aberrant branches supplying the tumor or PVTT. When the collateral blood supply was proven, microcatheter superselective techniques were used for precise embolization to prevent these vessels from harboring residual or recurrent tumor growth while reducing the risk of nontarget embolization. Despite the promising results, there are several limitations to this study that should be noted. Its single-center retrospective design, relatively small sample size, and uneven distribution of the groups may limit the generalizability and robustness of the results. Irreversible arterial occlusion secondary to coil embolization may limit the availability of some vascular pathways for future interventions. Moreover, the long-term consequences of collateral vessel formation have to be elucidated using extended follow-up. It is also important to note that sorafenib, the systemic therapy used in this study, is becoming more outdated in the current landscape of HCC treatment. Emerging clinical evidence suggests that a combination of TACE with next-generation targeted therapies or immune checkpoint inhibitors (e.g., programmed cell death protein 1/programmed death-ligand 1 inhibitors) achieves superior tumor control. Integrating such novel agents with our DSC-TACE strategy could potentially further improve therapeutic efficacy, and this highlights a limitation in the direct clinical translation of our findings. These limitations may be partially overcome by careful patient selection, individual treatment planning, and the availability of several therapeutic options. Future multicenter, large-sample, prospective trials incorporating next-generation targeted or immunotherapeutic agents are warranted to validate and strengthen the efficacy and safety profile of this treatment strategy. In conclusion, this retrospective cohort study demonstrates that DSC-TACE is associated with improved survival outcomes in HCC patients with PVTT in our cohort. Further validation by multicenter trials and study of novel combination therapies are indicated to improve survival outcomes in patients with advanced HCC. Conflicts of interest None.
Ning et al. (Wed,) studied this question.