Published online Sep 24, 2026. doi: 10.5306/wjco.123454
Revised: July 21, 2026
Accepted: August 20, 2026
Published online: September 24, 2026
Processing time: 127 Days and 17.5 Hours
For patients with intermediate-advanced hepatocellular carcinoma (HCC) who have contraindications to immune checkpoint inhibitors, effective alternative therapies are scarce. This case report contributes to the literature by documenting a multimodal regimen of transcatheter arterial embolization (TAE) followed by sequential oxaliplatin, raltitrexed, and anlotinib in a patient with active clonor
A 52-year-old male with chronic hepatitis B presented with a hepatic mass de
TAE-sequential chemo-targeted therapy may offer durable disease control for immunotherapy-ineligible advanced HCC patients.
Core Tip: This case reports a 52-year-old patient diagnosed with hepatocellular carcinoma (CNLC stage IIIB) complicated by active clonorchiasis—an immunotherapy contraindication. The patient received transcatheter arterial embolization followed by sequential oxaliplatin, raltitrexed, and anlotinib, achieving partial response and progression-free survival exceeding 50 months. This regimen may offer a viable alternative for immunotherapy-ineligible advanced hepatocellular carcinoma patients, although long-term efficacy requires further validation.
- Citation: Yu SL, Liu JE, Li CY, Ling H, Tao HY, Shen YQ. Efficacy of transcatheter arterial embolization plus targeted chemotherapy for advanced hepatocellular carcinoma: A case report and literature review. World J Clin Oncol 2026; 17(9): 123454
- URL: https://www.wjgnet.com/2218-4333/full/v17/i9/123454.htm
- DOI: https://dx.doi.org/10.5306/wjco.123454
Hepatocellular carcinoma (HCC) is one of the most prevalent primary malignant liver tumors worldwide. Its patho
In the Barcelona Clinic Liver Cancer (BCLC) staging system, patients with advanced-stage HCC (stage C) are recommended for frontline systemic immunotherapy combinations in contemporary guidelines. Notably, the BCLC framework has evolved to incorporate concepts such as “Treatment Stage Migration” and the Complexity, Uncertainty, Subjectivity, Emotion decision framework[10], which provide a useful lens for analyzing individualized treatment decisions in complex cases such as the one we report here.
A 52-year-old male with chronic hepatitis B presented with a hepatic mass detected on routine examination. The hepatic space-occupying lesion was detected two weeks previously.
On November 7, 2021, the patient underwent routine abdominal ultrasonography at a local hospital, which showed a solid hepatic mass, highly suggestive of HCC. Subsequent abdominal computed tomography (CT) at the same hospital revealed a space-occupying lesion in the right hepatic lobe with uncertain pathological nature. The patient experienced postprandial abdominal distension, without nausea, vomiting, abdominal pain, diarrhea, clay-colored stools, hema
The patient had a history of chronic HBV infection, with detailed diagnosis and treatment history unknown. He denied a history of hypertension, coronary heart disease, diabetes mellitus, cerebrovascular accident, and other chronic systemic diseases. He also denied a history of tuberculosis and other infectious diseases.
No significant abnormalities or positive family history of malignant tumors were noted.
On physical examination the following were observed: Body temperature: 36.2 °C, pulse rate: 76 beats/min, respiratory rate: 20 breaths/min, and blood pressure: 108/72 mmHg. The patient was conscious and alert. Breath sounds were rough in both lungs, without dry or moist rales. Heart rate was 76 beats/min with regular rhythm, and no pathological murmurs were heard on cardiac auscultation. The abdomen was flat and soft, with no tenderness or rebound tenderness, and no palpable abdominal mass. Bowel sounds of 4/min were detected. No percussion tenderness was noted over the hepatic region or bilateral renal regions. No edema of bilateral lower extremities was observed.
Stool examinations: Routine stool examination (occult blood): Eggs: Clonorchis sinensis eggs found (+); Stool parasite concentration microscopic examination: Clonorchis sinensis eggs found (+).
Biochemical indicators: Albumin: 34.1 g/L↓ (reference range: 40.0-55.0 g/L); alanine aminotransferase: 106 IU/L↑ (reference range: 9-50 IU/L); aspartate aminotransferase: 68 IU/L↑ (reference range: 15-40 IU/L); γ-glutamyl transpeptidase: 94 IU/L↑ (reference range: 10-60 IU/L); total bile acid: 17.6 μmol/L↑ (reference range: 0.0-10.0 μmol/L); glutamate dehydrogenase: 12.1 U/L↑ (reference range: ≤ 7.0 U/L); high-density lipoprotein cholesterol: 0.8 mmol/L↓ (reference range: 1.16-1.42 mmol/L); the remaining biochemical indicators were roughly normal.
Tumor markers: Neuron-specific enolase: 18.07 μg/L↑ (reference range: 0-16.50 μg/L); carbohydrate antigen 724: 15.4 IU/mL↑ (reference range: 0-7.00 IU/mL); alpha-fetoprotein: 4.74 ng/mL (reference range: 0-9.00 ng/mL); hepatitis B five items (quantitative); hepatitis B surface antigen: > 250 IU/mL↑ (reference range: 0-0.05 IU/mL); hepatitis B e antibody: > 5 PEIU/mL↑ (reference range: 0-0.15 PEIU/mL); hepatitis B core antibody: > 25 IU/mL↑ (reference range: 0-0.35 IU/mL); hepatitis B virus DNA (HBV-DNA) quantification: 2.58 × 106 IU/mL↑ (reference range: < 1.0 × 102 IU/mL); routine blood test, hepatitis three items, routine urine test, and coagulation function were roughly normal.
Serial laboratory monitoring during treatment: Table 1 shows dynamic changes in liver function during treatment: After February 15, 2022, liver function remained within normal limits throughout the remainder of treatment and follow-up. The patient received hepatoprotective therapy with glutathione, tiopronin, bicyclol, and silymarin during hospitalization, and chemotherapy was administered after transaminases returned to normal levels. Table 2 shows dynamic changes in HBV-DNA during treatment: The patient received long-term entecavir antiviral therapy. HBV-DNA was maintained at normal levels throughout the subsequent follow-up period.
| Date | ALT (IU/L) | AST (IU/L) | Clinical context |
| November 19, 2021 (Baseline) | 106 ↑ | 68 ↑ | Initial diagnosis, hepatic insufficiency |
| December 1, 2021 | 76 ↑ | 63 ↑ | Pre-TAE, hepatoprotective therapy initiated |
| December 2, 2021 | - | - | TAE procedure performed |
| December 5, 2021 | 148 ↑ | 73 ↑ | Post-TAE peak ALT |
| December 11, 2021 | 46 | 79 ↑ | Gradual recovery |
| December 29, 2021 | 130 ↑ | 144 ↑ | Before cycle 2, transient elevation |
| January 3, 2022 | 89 ↑ | 157 ↑ | Before cycle 2, AST peak |
| February 15, 2022 | 29 | 34 | Normalized, chemotherapy resumed |
| Date | HBV-DNA (IU/mL) | Reference range |
| November 19, 2021 (Baseline) | 2.58 × 106 | < 1.0 × 10² |
| December 29, 2021 | 8.04 × 10² | < 1.0 × 10² |
| January 24, 2022 | 1.31 × 10² | < 1.0 × 10² |
| February 15, 2022 | < 1.0 × 10² (normal) | < 1.0 × 10² |
Abdominal magnetic resonance imaging (MRI) (November 22, 2021) showed an abnormally enhanced lesion at the junction of segments S8 and S5 of the liver: Highly suggestive of small HCC, with a maximum cross-sectional size of approximately 4.6 cm × 3.9 cm. Multiple small hepatic cysts were noted, and follow-up was recommended to rule out individual metastatic tumors. Multiple lymph nodes were found in the hepatic hilar region, peripancreatic head region, retroperitoneum, pelvic cavity, bilateral iliac vascular regions, and bilateral inguinal regions, which were suspicious for metastasis; the largest node measured approximately 1.9 cm × 1.5 cm (Figures 1 and 2). CT: No imaging signs of tumor metastasis were observed.
HCC (CNLC stage IIIB, TNM stage T2N1M0, stage IIIB); chronic hepatitis B; clonorchiasis; hepatic insufficiency.
Combined with the patient’s medical history, physical examination, auxiliary examinations and pathological findings, the diagnosis of HCC (CNLC stage IIIB, TNM stage T2N1M0, stage IIIB) was confirmed. The patient also had the additional complication of active clonorchiasis infection. Stool examination revealed Clonorchis sinensis eggs, and the Infectious Disease Department was consulted. The consulting physicians recommended that the patient could be transferred for deworming therapy when his condition had stabilized; however, the patient declined deworming treatment due to personal reasons. Active clonorchiasis infection implied a potential risk of inducing severe adverse events or exacerbating underlying infection if immunotherapy was administered. Therefore, first-line immune combination therapy was not applicable in this patient. Considering the abundant tumor blood supply, hepatic functional reserve and treatment contraindications, after full communication with the patient and his family, the patient received initial TAE on December 2, 2021. Subsequently, the patient was given six cycles of sequential combination therapy: Oxaliplatin (OXA) 130 mg/m2 on day 1, raltitrexed (RTT) 3 mg/m2 on day 1, plus anlotinib (AL) 10 mg once daily on days 1-14, with cycles repeated every 21 days. Following combination chemotherapy, AL 10 mg (d1-14, q21d) was continuously administered as maintenance therapy. During the sixth cycle of chemotherapy, the patient developed suspected OXA hypersensitivity, manifested by scattered generalized skin rash accompanied by nausea and retching. Symptoms were relieved after anti-allergy and symptomatic supportive treatment, and no other adverse events occurred during the remaining treatment course. No dose adjustment of OXA was required throughout the entire treatment course. The patient received con
The patient completed TAE intervention plus six cycles of combination therapy with OXA (130 mg/m2, d1), RTT
On July 22, 2024 (31 months after treatment initiation), follow-up abdominal contrast-enhanced MRI revealed further shrinkage of the hepatic mass, with a maximum cross-section of 2.6 cm × 2.6 cm. No obvious changes were observed in multiple lymph nodes, and the size of the largest metastatic lymph node decreased to 1.4 cm × 0.9 cm. The therapeutic response was assessed as partial response.
On January 12, 2026 (last follow-up at another hospital), repeat abdominal contrast-enhanced MRI showed continuous stability of the hepatic lesion. A mass-like abnormal signal was observed at hepatic segments S8/5, measuring approximately 2.6 cm × 2.3 cm, without definite signs of disease progression. Several small lymph nodes of 5-7 mm in diameter were visible in the abdominal cavity; metastatic lymph nodes remained stable with no newly detected metastatic lesions (Figures 4 and 5).
HCC ranks among the most common primary malignant liver tumors worldwide, predominantly arising on the background of chronic liver diseases such as viral hepatitis, alcoholic liver disease, NAFLD, and liver cirrhosis[1]. In the global cancer burden, HCC is the sixth most common malignancy and the third leading cause of cancer-related mortality, with an overall 5-year survival rate of approximately 18% among affected patients[4]. In China, HCC pathogenesis is closely correlated with HBV infection, and more than half of patients are diagnosed at an advanced or unresectable stage at initial presentation[5]. The clinical manifestations of HCC are often atypical. Early-stage HCC is frequently asymp
Abdominal imaging examination is one of the core modalities for the diagnosis of HCC. The typical imaging hallmark of HCC on contrast-enhanced MRI is the characteristic “fast wash-in and fast wash-out” enhancement pattern, characterized by marked arterial-phase enhancement followed by rapid contrast washout in the portal venous and delayed phases[11]. For advanced HCC accompanied by lymph node metastasis, early metastatic lymph nodes typically demonstrate high signal intensity on diffusion-weighted imaging[12]. In this case, abdominal MRI clearly displayed the above imaging features of both the primary lesion and metastatic lymph nodes, providing crucial evidence for clinical diagnosis and tumor staging. Histopathology combined with immunohistochemistry remains the gold standard for the pathological diagnosis of HCC. The typical histological feature is tumor cells arranged in trabeculae of no less than two cell layers in thickness; the trabeculae are separated by hepatic sinusoids lined with a single layer of endothelial cells, without bile duct structures within the lesions[13]. CT-guided liver biopsy in this case confirmed the pathological features of well-differentiated HCC. By combining the patient's medical history, laboratory tests, typical imaging manifestations and pathological findings, the diagnosis of HCC was definitively established.
The patient in this case was diagnosed with unresectable HCC (CNLC stage IIIB, TNM stage T2N1M0, stage IIIB; corresponding to advanced-stage disease by contemporary staging standards) and complicated by active clonorchiasis, which constituted a contraindication to first-line immunotherapy. Accumulated studies have demonstrated that active parasitic infection can induce a Th2-type immune shift and an immunosuppressive microenvironment. The programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) signaling pathway is activated to restrain Th2-mediated immune responses[9]. Recent studies on Clonorchis sinensis have revealed that the parasite’s excretory/secretory products can upregulate immune checkpoints including cytotoxic T-lymphocyte antigen-4 and lymphocyte activation gene-3 in the tumor microenvironment[14]. Additionally, fatty acid synthase (FASN)-mediated fatty acid biosynthesis has been shown to remodel the immune environment in Clonorchis sinensis infection-related liver cancers, and treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy[15]. A comprehensive bibliometric analysis by Zhu et al[16] has mapped the PD-1/PD-L1 research landscape in HCC, highlighting the importance of understanding the tumor immune microenvironment for optimizing immunotherapy strategies. Furthermore, Wang et al[17] demonstrated that immune checkpoint inhibitors (ICIs) can induce intestinal epithelial injury and a senescence-like phenotype, underscoring the potential for off-target tissue damage when ICIs are used in patients with chronic infections. Under such circumstances, the application of ICIs may not only result in unsatisfactory therapeutic efficacy, but also trigger unpredictable severe immune-related adverse events or aggravate the underlying infection[9]. Therefore, it is of great clinical importance to explore effective alternative therapeutic regimens that avoid immunotherapy-related risks.
It is important to note that the patient was also diagnosed with active clonorchiasis, and the Infectious Disease Department was consulted for further management. The consulting physicians recommended that the patient could be transferred for deworming therapy once his condition stabilized. However, the patient declined deworming treatment due to personal reasons. This clinical scenario highlights the complexity of managing HCC patients with concurrent parasitic infections, where patient preferences and perceived risks must be carefully balanced against potential benefits. In this case, the patient's refusal of deworming therapy further reinforced the need for an effective alternative treatment strategy that could achieve tumor control without relying on immunotherapy.
It is also important to contextualize the potential contribution of entecavir therapy to the observed outcome. In this case, HBV-DNA declined from 2.58 × 106 IU/mL to undetectable within three months and remained suppressed throughout follow-up. Nucleos(t)ide analog therapy is known to improve survival and reduce recurrence in HBV-related HCC, primarily through suppression of necroinflammation, limitation of HBV integration-driven oncogenesis, and preservation of hepatic functional reserve[18]. In patients with HBV-related cirrhosis, entecavir has been associated with significantly lower post-resection late recurrence rates (1-, 3-, 5-, and 10-year: 26%, 49%, 65%, and 76% vs 29%, 69%, 87%, and 92% without antiviral therapy; P < 0.001), with late recurrence independently linked to HBV viral load in a dose-response manner[19]. A network meta-analysis further confirmed entecavir’s benefits over no antiviral therapy for overall survival (OS) [odds ratio (OR) = 2.14, 95%CI: 1.59-2.88] and late recurrence-free survival (OR = 1.96, 95%CI: 1.36-2.55)[18]. Nevertheless, the 50-month progression-free survival (PFS) and partial radiological response observed in this patient far exceed the reported benefits of antiviral therapy alone, and the reduction of both primary and metastatic lesions cannot be attributed to antiviral effects alone. We therefore propose that entecavir provided a permissive background—preserving liver function and reducing inflammation-driven tumor promotion—while the multimodal antitumor regimen delivered the primary cytoreductive effect. This case generates the hypothesis that in patients receiving intensive multimodal therapy for HBV-related HCC, the incremental benefit of antiviral therapy may be mediated primarily through preservation of hepatic reserve and modulation of the inflammatory microenvironment, rather than through direct antitumor activity—a hypothesis that warrants prospective validation with systematic virological monitoring.
In this case, TAE rather than transcatheter arterial chemoembolization (TACE) was selected based on the following considerations. On the one hand, chemotherapeutic agents administered in TACE may aggravate pre-existing hepatic insufficiency characterized by decreased albumin and elevated transaminases. As a pure embolization technique, TAE can effectively avoid chemotherapy-related hepatotoxicity[20]. A recent systematic review and meta-analysis comparing TAE and TACE in patients with unresectable HCC demonstrated that TAE achieved similar, if not superior, results compared with TACE in several randomized controlled trials[21]. The meta-analysis, which included six trials with 683 patients, found no significant differences between TACE and TAE for PFS [hazard ratio (HR) 0.83, 95%CI: 0.45-1.55; P = 0.57], OS (HR: 1.10, 95%CI: 0.90-1.35; P = 0.36), and objective response rate (OR: 1.17, 95%CI: 0.80-1.71; P = 0.42)[22]. The authors concluded that TAE was as effective as TACE, and as TAE is simpler, cheaper, and has fewer adverse effects than TACE, it should be a better choice in most cases where TACE is indicated for unresectable HCC[21]. The 2023 International Liver Cancer Association consensus statement notes that while the choice of drug in TACE is heterogeneous, TACE should be considered the first-line liver-directed treatment for patients with BCLC intermediate-stage HCC who are suitable for liver-directed therapy[22]. On the other hand, conventional single-agent chemotherapy adopted in TACE is difficult to implement regularly every 3-4 weeks, making it difficult to maintain optimal chemotherapy intensity and sustain effective plasma drug concentration[23]. In addition, the positive expression of CD34 in immunohistochemical staining indicated abundant tumor blood supply. TAE can rapidly induce tumor ischemic necrosis by embolizing the tumor feeding arteries, reduce local tumor burden, and create favorable conditions for subsequent systemic therapy. The choice of TAE in this case was explicitly due to the patient's hepatic reserve (albumin 34.1 g/L, elevated transaminases) and the intensive systemic regimen that followed.
The systemic therapeutic regimen consisted of OXA, RTT, and AL. The combined application compensates for the insufficient drug concentration and sustained efficacy limitation of conventional TACE, and exerts synergistic anti-tumor effects through distinct mechanisms. OXA and RTT mainly inhibit tumor progression by directly interfering with tumor cellular DNA metabolism and integrity. As a third-generation platinum agent, the active metabolites of OXA bind to DNA strands of tumor cells and form stable intrastrand crosslinks, resulting in severe distortion and damage of the DNA double helix structure. Such damage blocks DNA replication and transcription, and ultimately activates the cellular apoptotic program[24]. Furthermore, OXA-induced DNA adducts exhibit strong resistance to cellular repair systems, further enhancing its tumor cytotoxicity. RTT is a specific thymidylate synthase inhibitor. It is intracellularly converted into polyglutamate derivatives, which persistently and potently inhibit thymidylate synthase activity. This process depletes deoxythymidine triphosphate, an essential substrate for DNA synthesis, thereby inducing DNA synthesis arrest, S-phase cell cycle arrest, and eventual tumor cell death[25]. The combination of OXA and RTT damages DNA structure and depletes raw materials for DNA synthesis, respectively, synergistically attacking highly proliferative tumor cells and exerting prominent cytotoxic effects on high-burden tumors. Hepatic arterial infusion chemotherapy with OXA plus RTT has demonstrated antitumor activity and long-term survival benefits among patients with unresectable HCC.
However, the immunohistochemical finding of a Ki-67 index < 5% in this case warrants careful interpretation. Ki-67 is a classic nuclear marker of cell proliferation, and low Ki-67 expression has been consistently associated with favorable prognosis in HCC. Low Ki-67 expression is associated with favorable prognosis and better treatment response in patients with early recurrent HCC undergoing TACE. High Ki-67 risk stratification is closely associated with higher recurrence rates and worse outcomes following curative therapies in patients with HCC. The recurrence-free survival rate is significantly lower in the high Ki-67 expression group compared to the low expression group. Thus, while the > 50-month PFS achieved in this case is undoubtedly attributable to the multimodal treatment strategy combining TAE with targeted chemotherapy, the inherently indolent tumor biology represented by the extremely low Ki-67 expression may be an equally critical contributing factor[26]. The long-term disease control in this patient may rely more on TAE-induced ischemic necrosis (rapidly reducing local tumor burden) and the sustained anti-angiogenic maintenance effect of AL (inhibiting micrometastases and potential recurrence) rather than solely on the direct cytotoxicity of chemotherapy. This “locoregional debulking + long-term anti-angiogenic maintenance” model aligns well with the growth characteristics of low-proliferation tumors.
As an oral multi-target tyrosine kinase inhibitor, AL potently inhibits multiple critical targets including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). It exerts anti-tumor activities through multiple mechanisms, such as anti-angiogenesis, normalization of tumor vasculature, inhibition of tumor cell migration and invasion, and modulation of the tumor immune microenvironment[27]. The phase II ALTER-0802 study demonstrated that AL showed promising efficacy and safety as a first- or second-line treatment for advanced HCC[28]. In Cohort 1 (treatment-naive patients, n = 26), the 12-week PFS rate was 80.8% (95%CI: 59.8%-91.5%) and median time to progression (TTP) was 5.9 months (95%CI: 4.8-6.9). In Cohort 2 (previously treated patients, n = 24), the 12-week PFS rate was 72.5% (95%CI: 48.7%-86.6%) and median TTP was 4.6 months (95%CI: 2.7-10.0). The most common grade 3-5 adverse events were hypertension (8%), diarrhea (8%) and hand-foot syndrome (6%)[28]. This evidence supports the rationale for incorporating AL into the sequential regimen. A recent phase II randomized controlled trial further demonstrated that the addition of AL to TACE provided safe and effective therapeutic benefits for patients with intermediate or advanced-stage HCC[29]. The ALTER-H004 study, a multi-center phase II clinical trial, evaluated AL combined with TACE as adjuvant therapy in HCC patients at high risk of recurrence after surgery, and the updated results suggested that this combination exhibited promising clinical benefit and a favorable safety profile. In the present case, AL produced synergistic anti-tumor efficacy when combined with chemotherapy in the induction phase, and continuously suppressed residual lesions and micrometastases as single-agent maintenance therapy, serving as a key agent for maintaining long-term disease stability. Notably, the patient did not experience leukopenia or hypertension during the entire course of AL therapy, further supporting the favorable safety profile of AL in this clinical context.
Regarding the choice of AL over lenvatinib: Lenvatinib is currently the most widely used first-line single-agent anti-angiogenic therapy for advanced HCC in clinical practice[10]. However, the selection of AL in this case was based on several considerations. First, the overall treatment protocol was designed and implemented under the framework of a clinical research project funded by the Liuzhou Municipal Bureau of Science and Technology (No. 2019BJ10613), which prospectively determined TAE and sequential AL combined with OXA and RTT as the core treatment regimen, with AL pre-specified as the study drug. Second, the ALTER-0802 study demonstrated anlotinib's favorable efficacy and safety profile in advanced HCC[28]. Third, the distinct multi-target inhibition profile of AL (VEGFR, PDGFR, FGFR) may offer synergistic potential when combined with OXA and RTT, complementing the mechanisms of DNA damage and DNA synthesis inhibition. Fourth, as an oral agent with a manageable safety profile, AL is well-suited for long-term maintenance therapy following induction chemotherapy. It should be noted that while AL monotherapy has not yet been approved as a first-line standard of care for HCC, the accumulating evidence from clinical trials supports its clinical value in specific therapeutic contexts[28,29].
Compared with existing therapeutic regimens, the present protocol exhibits innovation and superiority in multiple aspects. Firstly, the fluorouracil/Leucovorin plus OXA (FOLFOX) regimen serves as a standard chemotherapy for advanced HCC, with an objective response rate of only 8%-15% and a median PFS of less than 4 months. Moreover, cumulative adverse reactions such as neurotoxicity and myelosuppression frequently limit its long-term clinical application[30]. Although studies on FOLFOX combined with targeted or immunotherapy have achieved certain progress, most of these triple regimens incorporate ICIs and are therefore not applicable in patients with immunotherapy contraindications. Phase II clinical trials of AL monotherapy as second-line treatment for advanced HCC reported a median PFS of 4.8 months and a median OS of 9.8 months[28]. By combining TAE with dual-drug chemotherapy, our regimen prolonged PFS to more than 50 months, over 10 times that of AL single-agent therapy, which fully demonstrates the synergistic efficacy of combined treatment. The interventional plus targeted model of TAE combined with sorafenib can extend median PFS to 7-9 months[31], which is still inferior to the outcome of the present regimen. In addition, latest studies have indicated that TACE combined with sorafenib yields no significant OS benefit[32].
As a landmark first-line immune combination regimen, the T+A regimen (atezolizumab plus bevacizumab) achieved a median PFS of 6.8 months and a median OS of 19.2 months in the IMbrave150 trial[7]. The EMERALD-1 trial (TACE + durvalumab + bevacizumab) demonstrated that adding systemic therapy to locoregional treatment can significantly improve PFS in patients with unresectable HCC[33]. Similarly, the LEAP-012 trial (TACE + lenvatinib + pembrolizumab) showed significant, clinically meaningful improvement in PFS compared with TACE plus placebo[34]. The TALENTACE trial (TACE + atezolizumab + bevacizumab) reported a median PFS of 10.3 months[35]. A recent systematic review and meta-analysis incorporating 12 retrospective studies with 1078 patients in the TACE+tyrosine kinase inhibitor (TKI)+PD-1 group and 1332 in the TACE+TKI group demonstrated that TACE+TKI+PD-1 significantly improved OS (RR = 7.39, 95%CI: 5.69-9.08, P < 0.001), PFS (RR = 3.89, 95%CI: 3.21-4.57, P < 0.001), and objective response rate (RR = 1.38, 95%CI: 1.26-1.51, P < 0.001), with the 1-year survival rate also significantly improved (RR = 5.92, 95%CI: 4.43-5.92, P < 0.001)[36]. These findings establish the “triple therapy” (TACE + TKI + ICI) as a current focus of global phase III trials. Nevertheless, the superior efficacy of these regimens must be carefully weighed against their safety profiles. The meta-analysis itself emphasized that patient selection is paramount, as the addition of ICIs to TACE and TKIs introduces a higher risk of immune-related adverse events, including immune-mediated hepatitis, pneumonitis, and colitis—toxicities that can be particularly problematic in patients with pre-existing hepatic insufficiency or chronic infections[36]. This is precisely the clinical context of our patient: With active clonorchiasis, which may not only limit the efficacy of PD-1/PD-L1 inhibitors but also increase the risk of severe immune-related adverse events, an intensive TKI + dual-chemotherapy regimen without immunotherapy was chosen. Notably, our regimen achieved a PFS of over 50 months in a patient with absolute immunotherapy contraindications, highlighting the value of multimodal synergistic therapy consisting of locoregional embolization, dual-drug chemotherapy, and targeted maintenance treatment—while entirely avoiding the safety concerns associated with immune checkpoint inhibition in this vulnerable population.
The innovations in this study are summarized as follows: Providing an effective alternative therapeutic strategy specifically for HCC patients with immunotherapy contraindications; Adopting TAE instead of TACE to rapidly reduce tumor burden via pure arterial embolization while avoiding additional chemotherapy-induced liver injury; The combination of OXA plus RTT exerts synergistic anti-tumor effects through dual mechanisms of DNA damage and DNA synthesis inhibition, with stronger cytotoxicity than single-agent chemotherapy; AL maintenance therapy continuously inhibits micrometastases via sustained anti-angiogenic effects; Individualized therapeutic decision-making based on the patient’s clinicopathological features embodies the concept of precision medicine. This regimen achieved markedly prolonged PFS without the application of immunotherapeutic agents, providing a novel therapeutic strategy and clinical reference for the management of advanced HCC.
Treatment-related adverse events were systematically graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 throughout the entire treatment course[37]: Table 3 shows treatment-related adverse events graded according to CTCAE v5.0. No grade 3 or higher treatment-related adverse events were observed throughout the entire treatment course. No dose adjustment of OXA was required. The patient did not experience leukopenia, hypertension, or hand-foot syndrome during AL therapy.
| Adverse event | CTCAE grade | Timing | Management | Outcome |
| Oxaliplatin hypersensitivity (generalized skin rash, nausea, retching) | Grade 2 | Cycle 6 | Anti-allergic and symptomatic treatment | Resolved |
| Elevated ALT (baseline 106 IU/L, peaked at 148 IU/L post-TAE, 130 IU/L during cycle 2) | Grade 1 | Throughout treatment | Hepatoprotective therapy (glutathione, tiopronin, bicyclol, silymarin) | Normalized |
| Elevated AST (baseline 68 IU/L, peaked at 157 IU/L during cycle 2) | Grade 1 | Throughout treatment | Hepatoprotective therapy | Normalized |
| Anlotinib-related adverse events (leukopenia, hypertension, hand-foot syndrome) | None | - | - | - |
In this case, sequential therapy with OXA, RTT plus AL following TAE may provide clinical benefits to treatment-naive patients with intermediate-advanced HCC, providing a valuable reference for exploring alternative intensified therapeutic regimens for advanced HCC. The BCLC 2025 concept of “Treatment Stage Migration” officially recognizes that patients may migrate between stages based on treatment response or contraindications—our patient effectively migrated from a systemic-first stage to a hybrid locoregional-intensive systemic sequence[10]. However, this case also has certain limitations: As a single case report, caution is necessary when extrapolating the conclusions to a broader population; the patient was concurrently complicated with HBV infection and received entecavir antiviral therapy, which may have played a role in controlling tumor recurrence, and its potential impact cannot be completely excluded. Regarding the interaction between antiviral therapy and tumor biology, it is important to note that sustained HBV suppression can reduce chronic inflammation and liver injury, thereby potentially lowering the risk of HCC recurrence. In this case, HBV-DNA was monitored throughout follow-up (baseline 2.58 × 106 IU/mL, decreased to 8.04 × 102 IU/mL at 1 month, 1.31 × 102 IU/mL at 2 months, and normalized by 3 months after entecavir initiation) and remained consistently suppressed thereafter. While the direct anti-tumor effect of entecavir is minimal, its role in maintaining hepatic functional reserve and reducing inflammation-driven tumor promotion should not be overlooked. The patient also declined deworming therapy for clonorchiasis despite infectious disease consultation recommending it, which reflects the complexity of shared decision-making in HCC management and further underscores the need for effective immunotherapy-free alternatives. The occurrence of OXA-induced allergic reaction during treatment indicates that close monitoring of adverse events is necessary; the ideal patient population that may benefit most from this regimen remains to be determined and warrants further investigation. In the future, prospective, multi-center clinical studies should be conducted to verify the universality of this regimen and explore its optimal applicable population.
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