Three effective cases of transcatheter arterial embolization after atezolizumab and bevacizumab treatment for hepatocellular carcinoma: a case report

Abstract

Background

The Barcelona Clinic Liver Cancer staging system classifies hepatocellular carcinoma on the basis of tumor characteristics, liver function, and Eastern Cooperative Oncology Group performance status. Hepatocellular carcinoma is divided into five stages, and the treatment options for intermediate-stage hepatocellular carcinoma have evolved in recent years. Transcatheter arterial chemoembolization remains the standard treatment for intermediate-stage (stage B) hepatocellular carcinoma. However, the concepts of transcatheter-arterial-chemoembolization-unsuitable and transcatheter-arterial-chemoembolization-refractory tumors have emerged. The authors herein describe three Japanese patients with hepatocellular carcinoma who were treated with atezolizumab and bevacizumab followed by transcatheter arterial embolization or transcatheter arterial chemoembolization. Cases 1 and 2 were transcatheter-arterial-chemoembolization-unsuitable, and Case 3 was transcatheter-arterial-chemoembolization-refractory. All patients achieved a complete response, assessed according to the modified Response Evaluation Criteria in Solid Tumors guidelines.

Case presentation

The first patient was a 65-year-old Japanese man with a primary 11 cm hepatocellular carcinoma. He started treatment with atezolizumab and bevacizumab but developed grade 3 liver injury after two courses, leading to the discontinuation of these drugs and subsequent bland transcatheter arterial embolization. The second patient was an 82-year-old Japanese woman with multiple primary hepatocellular carcinomas. After one course of atezolizumab and bevacizumab, the treatment was interrupted because of grade 3 proteinuria. Bland transcatheter arterial embolization was performed after completing one course of atezolizumab and bevacizumab and one course of atezolizumab alone. The third patient was an 83-year-old Japanese man with recurrent multiple hepatocellular carcinomas. Despite 12 courses of atezolizumab and bevacizumab, the tumor in segment 4 of the liver increased in size and showed arterial-phase enhancement. Transcatheter arterial chemoembolization was performed to treat this tumor. All three patients achieved a complete response based on the modified Response Evaluation Criteria in Solid Tumors guidelines.

Conclusion

Atezolizumab and bevacizumab followed by transcatheter arterial embolization may be an effective treatment strategy for patients with intermediate-stage hepatocellular carcinoma that is transcatheter-arterial-chemoembolization-refractory or transcatheter-arterial-chemoembolization-unsuitable.

Background

In recent years, treatment options for intermediate-stage hepatocellular carcinoma (HCC) have been changing. Transcatheter arterial chemoembolization (TACE) is the standard treatment for intermediate-stage HCC [1,2,3]. However, the concepts of TACE-unsuitable tumors [4, 5] and TACE-refractory tumors [6, 7] have been proposed. Combination therapy with molecular-targeted drugs or immunotherapy has recently been expanding. Combination therapies involving molecular-targeted drugs and immunotherapies have also gained prominence. Several therapeutic agents, such as the molecular-targeted drugs sorafenib [8] and lenvatinib [9], have been approved.

The latest version of the Barcelona Clinic Liver Cancer (BCLC) staging system, released in 2022, further stratifies stage B into three subgroups. Stage B now includes patients with diffuse, infiltrative, or extensive liver involvement, for whom TACE is not beneficial, making systemic therapy the recommended option [10, 11]. These drugs can be used to reduce the tumor volume and achieve a cure with the addition of hepatectomy, radiofrequency ablation (RFA), and TACE. A proof-of-concept study demonstrated that patients with HCC beyond the “up-to-7 criteria” (which are met when the sum of the number of tumors and the total diameter of all tumors in centimeters is ≥ 7) respond better to upfront lenvatinib followed by selective TACE (LEN-TACE) [12].

Additionally, a combination of the immune checkpoint inhibitor atezolizumab and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Atez/Bev) has been used as first-line therapy for advanced-stage HCC [13]. Atez/Bev curative (ABC) conversion therapy, which aims to achieve a cancer-free or drug-free state with Atez/Bev treatment followed by surgery, RFA, or TACE, has been proposed [14]. Atez/Bev followed by TACE has been suggested to be potentially as effective as LEN-TACE.

We herein report three cases of TACE-refractory HCC (one case) or TACE-unsuitable HCC (two cases) that were effectively treated with Atez/Bev followed by transarterial embolization (TAE) or TACE.

Case presentation

Case 1

A 65-year-old Japanese man was referred to the authors’ hospital because of upper abdominal pain, and computed tomography (CT) showed a tumor in the liver. He had been diagnosed with chronic hepatitis C and achieved a sustained virological response after 12 weeks of treatment with the combination of elbasvir and grazoprevir hydrate about 5 years prior. He had stopped visiting the hospital after achieving a sustained virological response.

The patient’s clinical course is shown in Fig. 1. Dynamic CT detected a tumor approximately 11 cm in diameter in the right lobe of the liver. The lesion showed enhancement in the arterial phase and washout on the portal phase. An irregular hypodense region was present within the tumor (Fig. 2a, d). The patient’s des-γ-carboxy prothrombin (DCP) level was elevated at 2355 mAU/mL, and he was diagnosed with HCC. The tumor was too large for surgical removal and was classified as BCLC stage B HCC with TACE-unsuitable characteristics. Because of the patient’s well-preserved liver function (Child–Pugh A) and adequate hematologic and organ function (Table 1, Case 1), he began treatment with 1200 mg of Atez plus 15 mg/kg of Bev.

Fig. 1

Clinical course of Case 1. Black arrows: atezolizumab and bevacizumab; and white arrows: bland transarterial embolization

Fig. 2

Contrast-enhanced computed tomography of Case 1 detecting a tumor of approximately 11 cm in diameter located in the right lobe of the liver. The lesion showed enhancement in the arterial phase and washout in the portal phase. An irregular hypodense region was present within the tumor. a Arterial phase. b Early-phase computed tomography during hepatic arteriography. c Arterial phase. d Late-phase computed tomography during hepatic arteriography of Case 1 revealing a decrease in vascularity after two courses of atezolizumab and bevacizumab treatment, although the size of the tumor had not changed. e Late-phase computed tomography during hepatic arteriography. Contrast-enhanced computed tomography of Case 1 showed that the tumor had decreased in size from 11 to 5 cm in diameter; it was hypodense in the arterial phase atezolizumab and bevacizumab treatment followed by bland transarterial embolization. f Late phase

Table 1 Laboratory data from cases

However, the Atez/Bev treatment was interrupted after two courses because of grade 3 liver injury, which was suspected to be immune-related. A liver biopsy was performed, which revealed mild lymphocytic infiltration in the portal and lobular areas; however, the cause could not be identified. It is known that Atez/Bev therapy can result in elevated aspartate aminotransferase in 14.0% of cases, with grade 3/4 adverse events occurring in 3.6% of cases [13]. The patient was treated with stronger neo-minophagen C, and steroids were considered for use if the liver injury did not improve [15]. Fortunately, his liver function gradually improved.

Given the large size of the tumor, bland TAE was performed to minimize adverse events [16, 17]. TACE was considered for use if hyperenhancement persisted. CT during abdominal angiography revealed a decrease in the vascularity of the tumor after two courses of Atez/Bev treatment, although the size of the tumor remained unchanged (Fig. 2b, e). A total of 1 year after bland TAE, the tumor achieved a complete response (CR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines (Fig. 2c, f). Liver function remained stable after TAE.

Case 2

A 82-year-old Japanese woman was referred to our hospital because an abdominal ultrasound revealed a tumor in the liver. She had no symptoms. The patient’s clinical course is shown in Fig. 3. Dynamic CT detected a tumor approximately 5 cm in diameter in the left lobe of the liver. The lesion showed enhancement in the arterial phase and washout in the portal phase. CT also detected tumors of approximately 1.5 and 2.5 cm in diameter located in segments 4 and 8 of the liver. The lesions showed little enhancement in the arterial phase and hypodensity in the portal phase (Fig. 4a–c). The tumors were positive on fluorodeoxyglucose positron emission tomography (FDG-PET) (Fig. 4d), and the patient’s α-fetoprotein (1440 ng/mL) and DCP (1232 mAU/mL) levels were elevated. She was diagnosed with BCLC stage B HCC with TACE-unsuitability.

Fig. 3

Clinical course of Case 2. Black arrows: atezolizumab and bevacizumab; striped arrows: atezolizumab; and white arrows: bland transarterial embolization

Fig. 4

Contrast-enhanced computed tomography and fluorodeoxyglucose-positron emission tomography of Case 2. Dynamic computed tomography detected a tumor of approximately 5 cm in diameter located in the left lobe of the liver; the lesion showed enhancement in the arterial phase and washout in the portal phase. Computed tomography also detected tumors of approximately 1.5 and 2.5 cm in diameter located in segments 4 and 8 of the liver; the lesions showed little enhancement in the arterial phase and hypodensity in the portal phase. The lesions were positive on fluorodeoxyglucose positron emission tomography (orange arrow). a–c Arterial phase. d Fluorodeoxyglucose positron emission tomography; black arrows denote the tumor. Computed tomography during hepatic arteriography of Case 2 revealing that only the hepatocellular carcinoma in the left lobe of the liver showed enhancement in the early phase. e Early-phase computed tomography during hepatic arteriography. Contrast-enhanced computed tomography of Case 2 showing that the tumor size had decreased; it was hypodense in the arterial phase after atezolizumab and bevacizumab treatment followed by bland transarterial embolization. f Arterial phase

Because of her well-preserved liver function (Child–Pugh A) and adequate hematologic and organ function (Table 1, Case 2), the patient began treatment with 1200 mg of Atez plus 15 mg/kg of Bev. One course of Atez/Bev treatment was administered. However, Bev treatment was then interrupted because of grade 3 proteinuria (≥ 2 g/24 hours). Proteinuria is a known major adverse event associated with Atez/Bev therapy in patients with HCC, with the IMbrave150 trial reporting an incidence of 20.1% [13]. The current standard management for proteinuria in patients receiving Bev recommends performing a 24-hour urine protein test if a dipstick test shows ≥ 2+ proteinuria, and Bev should be interrupted if protein levels reach ≥ 2 g/24 hours [18]. On the basis of this, Bev was discontinued.

Bland TAE was performed after one course of Atez/Bev treatment and one course of Atez treatment. Abdominal angiography revealed that only the HCC in the left lobe of the liver showed enhancement on early-phase CT during hepatic arteriography (CTHA) (Fig. 4e). The authors performed bland TAE of only the HCC in the left lobe of the liver because it was located in the liver periphery, and TAE was used to prevent bleeding. Liver function remained stable after TAE. After 12 courses of Atez/Bev treatment, the tumor achieved CR according to the mRECIST guidelines (Fig. 4f).

Case 3

A 83-year-old Japanese man underwent RFA of the liver for hepatitis B-associated HCC (3.0 and 2.0 cm in diameter) 17 years prior. However, he developed repeated intrahepatic recurrences. Posterior segmentectomy of the liver was performed three times, RFA was performed once, and TACE was performed four times. However, dynamic CT detected tumors of approximately 1.2 cm in maximum diameter located in segments 2, 4, and 8. The lesions showed enhancement in the arterial phase and washout in the portal phase (Fig. 5a–c). The patient’s α-fetoprotein and DCP (2355 mAU/mL) levels were elevated, and he was diagnosed with refractory BCLC stage B HCC. Because of his well-preserved liver function (Child–Pugh A) and adequate hematologic and organ function (Table 1, Case 3), he began treatment with 1200 mg of Atez plus 15 mg/kg of Bev.

Fig. 5

Contrast-enhanced computed tomography of Case 3 detecting a tumor of approximately 1.2 cm in maximum diameter located in segments 2, 4, and 8; the lesion showed enhancement in the arterial phase. a–c Arterial phase. Contrast-enhanced computed tomography revealed that the hepatocellular carcinoma in segment 4 of the liver showed enhancement in the arterial phase and that the other hepatocellular carcinomas had decreased in size after atezolizumab and bevacizumab treatment. d Arterial phase. Computed tomography during hepatic arteriography of Case 3 revealing that the hepatocellular carcinoma in segment 4 of the liver showed enhancement. e Early-phase computed tomography during hepatic arteriography. Contrast-enhanced computed tomography of Case 3 showing lipiodol uptake in segment 4 of liver 4 months after transarterial chemoembolization. f Arterial phase; black arrows denote tumor

The patient’s clinical course is shown in Fig. 6. After 12 courses of Atez/Bev, dynamic CT showed that the tumors in segments 2 and 8 had decreased in size, but the tumor in segment 4 had increased in size and still showed enhancement in the arterial phase (Fig. 5d). The Bev treatment had been interrupted because of grade 3 proteinuria (≥ 2000 mg/day) and was discontinued 3 weeks before TACE. Following 15 courses of Atez/Bev, the authors performed TACE because the tumor could not be located via abdominal ultrasonography. Abdominal angiography revealed that the HCC in segment 4 of the liver showed enhancement in early-phase CTHA (Fig. 5e). Additionally, a small nodule in segment 7 of the liver showed enhancement in early-phase CTHA. However, no ring-like dark staining reaction (corona) was observed in late-phase CTHA, and the nodule in segment 7 was considered to be a shunt. Because HCC could not be completely ruled out, we performed TACE to treat the tumors in segments 4 and 7.

Fig. 6

Clinical course of Case 3. Black arrows: atezolizumab and bevacizumab; striped arrows: atezolizumab; and white arrows: transarterial chemoembolization

Four months after TACE, the tumor response reached CR according to the mRECIST guidelines (Fig. 5f). Liver function remained stable after TACE.

Discussion

In the BCLC staging system, HCC is classified by tumor conditions, liver reserve, and Eastern Cooperative Oncology Group performance status (ECOG-PS). HCC is divided into five stages: very early (stage 0), early (stage A), intermediate (stage B), advanced (stage C), and terminal (stage D) [3, 19]. In the European Association for the Study of the Liver Clinical Practice Guidelines, early-stage (BCLC stage A) HCC is defined as a single tumor of > 2 cm or no more than three nodules of < 3 cm in diameter in patients with an ECOG-PS of 0 and preserved liver function (Child–Pugh A without ascites). Intermediate-stage HCC is defined as the presence of multinodular asymptomatic tumors without vascular invasion or extrahepatic spread in patients with an ECOG-PS of 0 and preserved liver function [19]. The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus defined intermediate-stage HCC as a single tumor with a maximum size of 5 cm classified as BCLC stage A or B because both of these stages are good candidates for TACE in unresectable HCCs [5].

Although TACE is the standard treatment for intermediate-stage HCC [1,2,3], intermediate-stage HCC is characterized by a wide variety of tumor conditions. Thus, TACE is not an unconditional first-line treatment for intermediate-stage HCC. In recent years, treatment options for intermediate-stage HCC have been changing.

The concepts of TACE-unsuitable tumors [4, 5] and TACE-refractory tumors [6, 7] have been proposed. A TACE-unsuitable tumor is characterized by each of the following three clinical conditions that either prevent a survival benefit from TACE or render TACE harmful: First, the tumor is unlikely to respond to TACE. Such tumors include the confluent multinodular type, massive or infiltrative type, simple nodular type with extranodular growth, poorly differentiated type, intrahepatic multiple disseminated nodules, or those with sarcomatous changes after TACE. Second, the tumor is likely to develop TACE failure/refractoriness. Such tumors do not meet the “up-to-7 criteria,” which are met when the sum of the number of tumors and the total diameter of all tumors in centimeters is ≤ 7 [20]. Third, the patient is likely to develop Child–Pugh B or C liver disease after TACE. This is seen in patients who do not meet the up-to-7 criteria (especially patients with bilobar multifocal HCC) and those with modified albumin–bilirubin (ALBI) grade 2b HCC [5].

TACE-refractory is defined as the presence of intrahepatic lesions that are difficult to control even if TACE is performed twice, including efforts such as changing the drug and reconsidering other blood vessels for treatment. Additionally, the levels of tumor markers either do not decrease or persistently increase, which is indicative of vascular invasion or distant metastasis [7, 21]. The updated clinical practice guidelines from the European Society for Medical Oncology recently recommended upfront systemic therapy for patients who are ineligible for TACE [22]. Switching to molecular-targeted therapy at the point of TACE refractoriness reportedly improves the prognosis [23].

Several therapeutic agents have been approved, including the molecular-targeted drug sorafenib in 2009 [8] and lenvatinib in 2020 [9]. Lenvatinib has also shown efficacy in TACE-refractory tumors, such as the multinodular type, simple nodular type with extranodular growth, and poorly differentiated type [24, 25]. For patients with HCC exceeding the up-to-7 criteria and Child–Pugh A liver function, who typically do not benefit from TACE, lenvatinib offers more favorable outcomes. In fact, overall survival (OS) was significantly longer in the group receiving LEN-TACE than in those treated with TACE alone. The OS in the LEN-TACE group was 37.9 months, compared with only 21.3 months in the TACE-alone group (hazard ratio, 0.48; 95% confidence interval, 0.16–0.79; p < 0.01), indicating the efficacy of LEN-TACE [12].

Molecular-targeted drugs with anti-VEGF effects act on tumor blood vessels by improving vascular permeability, reducing tumor interstitial pressure, enhancing drug delivery, and boosting treatment efficacy [26,27,28,29]. The combination of an immune checkpoint inhibitor with VEGF inhibitors, such as Atez/Bev, is now used as first-line treatment for advanced-stage HCC. CR rates have been reported at 10.2% (according to HCC mRECIST) in patients receiving Atez/Bev [8]. ABC conversion therapy, which aims to achieve a cancer-free or drug-free state with Atez/Bev therapy followed by surgery, RFA, or TACE, has been proposed. Curative therapy becomes feasible, and a drug-free status can be achieved by combining Atez/Bev with locoregional treatment or resection, resulting in a radiological CR rate of approximately 30% in patients with TACE-unsuitable intermediate-stage HCC.

Atez/Bev followed by selective TACE has been suggested to be potentially as effective as LEN-TACE. Atez/Bev mainly induces tumor shrinkage, whereas lenvatinib mainly induces tumor necrosis by reducing blood flow [9]. The VEGF-inhibitory action of Bev may enhance the effects of TACE, or TACE may improve the efficacy of Atez by releasing cancer antigens [21]. In a previous report of 21 cases treated with TACE combined with Atez/Bev, the overall response rate was 61.9%, and the disease control rate was 100% according to mRECIST. The median OS was not reached, but the 1-year OS rate was 90.5% [30]. Similar to our report, the patients demonstrated a favorable clinical course.

TACE combined with Bev may increase the risk of severe, and potentially lethal, septic and vascular side effects [31]. However, in the abovementioned report, the most common adverse events were mild and included fever, elevated levels of aspartate aminotransferase and alanine aminotransferase, fatigue, and abdominal pain [30]. In our cases, although side effects were observed with Atez/Bev treatment, no additional adverse effects were noted with the addition of TACE or TAE.

In the present report, Case 1 was considered TACE-unsuitable, because the tumor did not meet the up-to-7 criteria. Although TACE is often used for large HCCs, the efficacy of radiotherapy combined with TACE has been reported to result in a 5-year OS rate of only 3% [17]. In our case, there was a possibility that the tumor would be difficult to control with TACE alone. While the tumor size remained unchanged, the tumor marker levels and tumor vascularity decreased following Atez/Bev treatment.

Case 2 was also considered TACE-unsuitable because of failure to meet the up-to-7 criteria, and the tumors were suspected to be the confluent multinodular and poorly differentiated types. Most FDG-PET-positive HCCs are poorly differentiated tumors [32,33,34], but the authors were able to control multiple FDG-PET-positive HCCs in this case.

In Case 3, the patient had TACE-refractory HCC and was switched to Atez/Bev. We performed TACE to treat the HCC, allowing us to control multiple HCCs.

This study has limitations, primarily the small sample size (three cases), which limits the generalizability of the findings. Larger studies are needed to confirm these results.

Conclusion

We have herein described three Japanese patients with TACE-unsuitable or TACE-refractory HCC treated with Atez/Bev followed by TAE or TACE. All three patients achieved a complete response as evaluated using the mRECIST. These results suggest that, after Atez/Bev treatment, TAE may be effective in patients with uncontrolled TACE-unsuitable or TACE-refractory HCC. A Phase III IMPACT trial comparing a group receiving Atez/Bev followed by curative conversion or on-demand TACE in combination with Atez/Bev, versus an Atez/Bev monotherapy group, was initiated in Japan in July 2023 (registration no.: jRCTs051230037).