Efficacy of Hepatic Artery Infusion Chemotherapy with Bevacizumab and Sintilimab in Advanced Hepatocellular Carcinoma: A Case Report

Introduction

Primary liver cancer is the sixth most prevalent malignant tumor and the third leading cause of cancer-related mortality globally, 75–85% of which are hepatocellular carcinoma (HCC) [1]. Many patients have developed vascular invasion or distant metastasis at diagnosis, both of which are hallmarks of advanced HCC (Barcelona Clinic for Liver Cancer [BCLC] Stage C), meaning a poor prognosis [2]. The incidence of portal vein tumor thrombosis (PVTT) ranges from 44% to 62.2%, and the median survival time (MST) of untreated patients is 2.7–4.0 months [3]. Hepatic vein tumor thrombosis (HVTT) is rarer (1.4–4.9%) than PVTT, but it can lead to severe complications due to metastasis to the inferior vena cava (IVC) and right atrium (RA), and the MST of untreated patients with IVC/RA tumor thrombosis is 1.0–5.0 months [4,5].

The guidelines from the United States and Europe, such as the American Association for the Study of the Liver Diseases (AASLD)/European Association for the Study of the Liver (EASL)/European Society for Medical Oncology (ESMO), recommend systemic therapies only for advanced HCC [2,6–8]. Moreover, the Japan Society of Hepatology (JSH) guidelines and the China liver cancer (CNLC) guidelines state that in addition to systemic therapy, transarterial chemoembolization (TACE)/hepatic artery infusion chemotherapy (HAIC)/stereotactic body radiation therapy (SBRT) can also provide survival benefit for HCC patients with vascular invasion [9,10].

Conversion therapy seeks to achieve tumor downstaging through local regional therapy with systemic therapy. Currently, there is no consensus on which conversion therapy regimens to choose for HCC with vascular invasion [11]. As a regional chemotherapy approach, HAIC delivers anti-tumor agents directly into tumors through the hepatic artery, thereby improving anti-tumor efficacy and reducing systemic toxicity. Compared to TACE, HAIC has advantages in treating unresectable large HCC, particularly those exceeding 10 cm in diameter or with vascular invasion [12]. Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF), which can inhibit angiogenesis and enhance anti-tumor immunity [13,14]. Sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, restores CD8+ T cell function, improves immune surveillance, and activates anti-tumor immune responses [15]. The ORIENT-32 trial showed satisfactory overall survival (OS) and progression-free survival (PFS) in Chinese unresectable HCC patients treated with a bevacizumab biosimilar (IBI305) and sintilimab [16]. However, few studies have reported the efficacy of HAIC combined with bevacizumab and sintilimab in the treatment of HCC with tumor thrombosis. Tian et al reported a case of advanced HCC accompanied by PVTT treated with modified HAIC combined with Lenvatinib and camrelizumab, in which the patient achieved complete response after 4 cycles of triple combined therapy [17]. Peng et al reported a case of colorectal cancer liver metastases treated with HAIC combined with sintilimab and Lenvatinib, and the patient was subsequently qualified for radical surgical resection [18]. Liu et al conducted a prospective, single-arm phase II trial to explore the efficacy of HAIC combined with bevacizumab biosimilar and sintilimab for unresectable HCC, reporting that 17 (58.6%) of 29 patients reached objective response after therapy [19]. This present report describes a 50-year-old man with advanced HCC associated with multiple venous tumor thromboses treated with triple combined conversion therapy of HAIC, bevacizumab, and sintilimab.

Case Report

A 50-year-old man with a history of hepatitis B virus (HBV)-related cirrhosis since 2018, managed consistently with entecavir, was admitted to our hospital in July 2022 due to an elevated alpha-fetoprotein (AFP) level, which was 60 381 ng/mL. Ten days later, his AFP level increased to 71 920.5 ng/mL, while the protein induced by vitamin K absence-II (PIVKA-II) reached >75 000 mAU/mL. His aspartate transaminase (AST) level was 136 U/L and his Child-Pugh score was 6 (grade A). The hepatitis B surface antigen was 1096.25 IU/mL, and HBV-DNA was 3.80×102 IU/mL. Abdominal computed tomography angiography (CTA) showed a large tumor (12.32×11.67 cm) in the right lobe of the liver, and multiple tumor thromboses formed in the right branch of the portal vein (PV) and right hepatic vein (HV) extending into the IVC (Figure 1A). At the same time, pulmonary CTA detected embolism in the main right pulmonary artery and its 2 branches, with multiple solid nodules (Figure 2). The patient occasionally felt abdominal distension, without jaundice, fever, or weight loss. The physical examination result was normal, and the Eastern Cooperative Oncology Group (ECOG) performance status was 0.

After a comprehensive assessment of his general conditions by the multidisciplinary treatment (MDT) group, he was diagnosed with advanced large HCC with PVTT and HVTT. The HCC was classified as BCLC stage C and CNLC stage IIIa [2,10]. According to the Japanese staging system, PVTT was classified as Vp4, and HVTT was classified as Vv3 [20]. Based on these findings, the patient had no surgical indication. Since he was treatment-naive, we recommended triple combined therapy consisting of bevacizumab (500 mg intravenously every 3 weeks) and sintilimab (200 mg intravenously every 3 weeks), followed by FOLFOX-HAIC (oxaliplatin 85 mg/m2, calcium levofolinate 100 mg/m2, fluorouracil 400 mg/m2 bolus, and 2400 mg/m2 continuous infusion via femoral artery catheterization every 3 weeks) (Figure 3A). His platelet count dropped to less than 50×109/L during therapy, appropriately leading to postponement of HAIC. Given the absence of apparent pulmonary discomfort and the high risk of bleeding from the large HCC, anticoagulation was not used to treat the pulmonary embolism incipiently. We also avoided radiotherapy to prevent exacerbation of pulmonary embolism. The first cycle of triple combined therapy resulted in shrinkage of the HCC and tumor thromboses (Figure 1B). In November 2022, after 3 cycles, both pulmonary embolism and nodules demonstrated remission, and abdominal magnetic resonance imaging (MRI) showed significant HCC shrinkage and necrosis (Figure 3B). Furthermore, AFP and PIVKA-II showed sustained decreases (Figure 3B). According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, the patient achieved partial response (PR) [21].

By January 2023, HCC and tumor thromboses had decreased by 45.04% and 46.59%, respectively. In March 2023, the intrahepatic lesions continued to shrink, but some pulmonary nodules were enlarged, with an AFP level of 1983.9 ng/mL and a PIVKA-II level of 613 mAU/mL, both of which were increased (Figure 2). Positron emission tomography/computed tomography (PET/CT) revealed pulmonary metastases. Subsequently, the patient received a TACE combined with bevacizumab and sintilimab, as well as SBRT precisely targeting pulmonary metastatic nodules, which was an effective local therapy that controlled the development of pulmonary metastases, but had caused radiation pneumonia as an adverse effect. When he was examined again in March 2024, brain MRI revealed that a metastatic lesion was located in the right parietal bone and extended to the right parietal lobe, requiring further local radiotherapy as palliative care (Figure 4).

With follow-up until September 2024, the patient has survived for over 26 months with a PFS of 8 months. HCC and multiple tumor thromboses responded well to HAIC combined with bevacizumab and sintilimab, and distant metastases were well controlled under local radiotherapy.

Discussion

HCC is a type of malignant tumor that threatens human health globally. Vascular invasion is a critical risk factor for unfavorable prognosis of HCC [22]; tumor cells can form thrombosis in the venous system, influencing hemodynamics and promoting distant metastasis. For HCC with tumor thrombosis, there are few opportunities for surgery, but local or systemic therapy can both be chosen or combined as conversion therapy to improve the prognosis. Cases of HCC with coincident PVTT and HVTT have rarely been reported. Here, we present a case of a 50-year-old man with multiple venous tumor thromboses in the PV, HV, and IVC, who received HAIC combined with bevacizumab and sintilimab conversion therapy to treat intrahepatic lesions and local radiotherapy as complementary therapy to control the extrahepatic metastases, emphasizing the importance of rational combined therapy for advanced HCC with tumor thrombosis.

Most patients with advanced HCC will receive local therapy and systemic therapy [23]. FOLFOX, composed of oxaliplatin, leucovorin, and fluorouracil, is one of the most common chemotherapeutic regimens [24]. The continuous infusion of FOLFOX agents by HAIC can ensure an adequate local drug concentration in the liver, and avoid the complications due to embolization to reduce the damage to liver function [25]. Lyu et al found that for advanced HCC with large tumor size (8.5–13.7 cm), FOLFOX-HAIC provided a longer median OS than sorafenib (13.9 months vs 8.2 months; P<.001) [26]. When patients with advanced HCC receive HAIC combined with systemic therapy, they can achieve a higher tumor regression rate and manageable adverse effects [27]. However, HAIC should be discontinued if intrahepatic lesions progress, neutrophil or platelet counts are significantly reduced, or total bilirubin or serum creatinine levels are elevated [24]. Another treatment approach for advanced HCC is systemic therapy. Nevertheless, as an immune tolerance organ, the liver can avoid the stimulation of dietary and microbial antigens in a physiological environment. The literature shows that HCC can reduce the effectiveness of immunotherapy, and only 15–20% of patients have an objective response to immunotherapy alone (CheckMate-040 phase II trials: 20%; KEYNOTE-224 phase II trials: 17%). Moreover, immune-monotherapy failed to improve overall survival benefits [28]. The main factor related to immunotherapy resistance is the immunosuppressive tumor microenvironment (TME), which includes low expression or absence of immune checkpoints, absence of neoantigens, dysfunction of antigen presentation, mutation of WNT/β-catenin/STAT3 genes, immunosuppressive cells and molecules (eg, Kupffer cells, tumor-associated macrophages, Tregs, and myeloid-derived suppressor cells), and HCC-derived exosomes [29,30]. Due to the low response rate of immune-monotherapy, combined therapy has become the predominant treatment modality, which can not only improve the tumor response but also alleviate immunotherapy resistance [31]. Some molecular-targeted therapies can block cancer-intrinsic pathways, such as MAPK, WNT-β-catenin, CDK4/6, and/or PI3K-PTEN signaling, to increase T cell infiltration, tumor antigen presentation, and interferon signaling, turning “cold” tumors into “hot” tumors that are more sensitive to immunotherapy [32], as proven by clinical trials. IMBrave150 demonstrated that combining atezolizumab with bevacizumab improved the median OS to 19.2 (17.0–23.7) months, with a 30% objective response rate (ORR) [33]. Similarly, the ORIENT-32 trial showed that sintilimab combined with bevacizumab biosimilar (IBI305) achieved comparable results in Chinese patients with HCC [16]. At present, the combination of molecular-targeted therapy and immunotherapy is the superior first-line treatment for advanced HCC.

Angiogenesis and immune evasion are the 2 key pathogenic hallmarks of HCC. Combination of HAIC, molecular-targeted therapy, and immunotherapy have synergistic anti-HCC efficacy. HAIC can induce HCC cell hypoxia, leading to elevated VEGF expression for angiogenesis [34]. Then, upregulated VEGF levels reshape an immunosuppressive TME, hindering dendritic cell maturation and function, and increasing T regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cell recruitment [35]. Finally, HAIC prompts the release of tumor antigen and cytokines to further foster immunogenic cell death. Consequently, there is potential to restore anti-angiogenesis activity and enhance the efficacy of immunotherapy by targeting VEGF [36]. Bevacizumab is a VEGF inhibitor that can transiently normalize the tumor vasculature to increase the delivery of therapeutic agents, enhance infiltration of T lymphocytes, and convert the immunosuppressive TME to the immunosupportive one, synergistically increasing the anti-tumor efficacy of immunotherapy [34,37]. As a PD-1 inhibitor, sintilimab prolonged the recurrence-free survival (median, 27.7 months) of resected high-risk HCC patients with microvascular invasion [38], showing the advantage of sintilimab. A prospective, single-arm, phase II trial also evaluated the function of HAIC combined with bevacizumab biosimilar and sintilimab for unresectable HCC, in which the ORR was 58.6% and the conversion surgery rate was 48.3% [19]. Peng et al reported a case of colorectal cancer liver metastases undergoing radical surgical resection after HAIC combined with sintilimab and Lenvatinib conversion therapy [18]. In this case, the patient was diagnosed with advanced large HCC and multiple tumor thromboses in the PV, HV, and IVC, and received triple combined therapy of HAIC, bevacizumab, and sintilimab as primary therapy. The dosage of bevacizumab was halved to reduce adverse effects without compromising overall efficacy [37]. In the early period of therapy, all lesions showed remission, reaching PR successfully according to the mRECIST criteria.

However, although intrahepatic lesions responded well, pulmonary metastases appeared, and during bevacizumab and sintilimab maintenance therapy, skull metastasis eventually occurred. Radiotherapy was used to target the metastatic lesions. The case of advanced HCC with PVTT reported by Tian Y et al showed tumor progression after reaching complete response [17], revealing the limitation of combined therapy. On the one hand, the mechanisms of HCC metastasis are complicated, and pulmonary metastasis is one of the most common HCC metastases, which involves the abnormalities of cancer-associated fibroblasts (CAFs), fibrillarin, tumor-derived exosomes (TEDs), and other cytokines [39–41]. Failure of combined therapy to cover these abnormal targets may result in the distant metastasis. On the other hand, the abscopal effect may be the reason for this transformation of metastases. The abscopal effect refers to the phenomenon that the local therapy at one tumor site can trigger the regression of distant metastases. It was first discovered in radiotherapy but has also been noted with other local treatments like TACE [42]. Systemic tumor regression caused by the abscopal effect often relies on the immune system, mediated by an anti-tumor immune response. Tumors treated by local therapy can generate tumor-associated antigens (TAAs) to present to CD8+ T cells to recognize and attack tumors, and release cellular danger-associated molecular patterns and cytokines to enhance traffic of immune cells, leading to systemic tumor regression. Hence, discontinuing local therapy might promote the development of distant metastasis. For patients with oligometastatic progression, the EASL guidelines recommends local therapy to treat progressive lesions while continuing systemic therapy if patients demonstrate a sustained response to systemic therapy [7].

By conducting a comprehensive literature review, we identified 11 case reports on the treatments of advanced HCC with tumor thrombosis and metastasis. As shown in Table 1 [43–53], intrahepatic metastasis and extrahepatic metastasis (eg, lymph node, adrenal gland, and lung) can both occur. In most HCC patients with metastasis, tumor thrombosis invades the main trunk or first branch of the hepatic or portal veins. Two patients received surgical resection directly, but one died, and another had progression of metastasis. Neoadjuvant therapies or adjuvant therapies, including chemotherapy, radiotherapy, and systemic therapy, could help improve the postoperative prognosis of patients. In addition, for such advanced-stage patients, especially those without surgery, the rates of HCC recurrence or metastasis were high. Even so, a rational combination of different anti-tumor treatments is important to prolong the survival time of patients.

Our advanced HCC patient with multiple tumor thromboses had surprisingly long survival. The main reasons might be as follows: firstly, HAIC combined with bevacizumab and sintilimab conversion therapy was effective in treating the primary HCC because it enabled remission of HCC and tumor thromboses; secondly, the distant metastases had also been quickly and effectively controlled through using radiotherapy, greatly delaying the disease process. These show the importance of formulating appropriate combined regimens, which may provide novel insights for clinical treatment.

Conclusions

HAIC combined with bevacizumab and sintilimab can alleviate primary HCC and tumor thromboses, and local radiotherapy can control the progression of distant metastases, prolonging the survival time of patients with advanced HCC.