Two cases of unresectable hepatocellular carcinoma treated via atezolizumab and bevacizumab combination therapy

Case 1

The patient was a 71-year-old man with a history of chronic alcoholic liver disease, hypertension, dyslipidemia, diabetes, and asthma. In March 2021, during routine follow-up, a medical examination revealed liver dysfunction, and computed tomography (CT) showed a large liver tumor. The patient was referred to our department for further diagnosis and management.

Blood tests performed at his first visit revealed an elevated alanine aminotransferase level of 75 U/L, aspartate aminotransferase level of 51 IU/L, and total bilirubin level of 1.7 mg/dL. Albumin level (4.2 d/dL) and prothrombin time level (84.6%) were normal. Serum alpha-fetoprotein (AFP) level was 106.6 ng/mL, and that of des-gamma carboxyprothrombin (DCP) was 67,200 mAU/mL. He had a Child–Pugh score of 5 (Child–Pugh grade A) and no hepatic encephalopathy or ascites (Table 1). Contrast-enhanced CT showed an internally enhanced 120-mm tumor in the S4 area of the liver, which touched the right hepatic hilum, compressing the right portal vein and bile duct. Intrahepatic dilation of the lateral and anterior segments of the liver was also observed (Fig. 2A). The patient was diagnosed with Barcelona Clinic Liver Cancer stage A HCC, but the tumor was extensive in the right lobe, and left tri-segmentectomy was required to achieve radical resection. Remnant liver function was assessed using remnant (rem) KICG (= KICG × volume rate) and rem 99mTc–GSA scintigraphy (KGSA) (= KGSA × functional rate) indices; hepatectomy was considered unsafe for values < 0.05. The patient’s liver volume was 1053 ml, and effective liver resection rate of 65.3%. The remnant liver volume was 365 ml, and the remnant liver function was 0.048521 in rem KICG and 0.055739 in rem KGSA, considering it unresectable because of the difficulty in maintaining remnant liver function after tri-segmentectomy of the liver.

Table 1 Laboratory investigation in Case 1

According to the fourth edition in 2020, including the 2017 edition of the Japanese Society of Hepatology Guidelines, atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) was administered as one course over 3 weeks without any adverse effects. After the tenth course, the serum levels of AFP and DCP were within the normal range (Fig. 1), the intrahepatic HCC had shrunk to 73 mm with regression of the right hepatic hilum tumor contact (Fig. 2B), and the patient was diagnosed with a partial response to the modified RECIST. R0 resection with left hemihepatectomy is considered feasible with a sufficient surgical margin. In the left hemihepatectomy, the remnant liver volume was 78.4% and rem KICG was 0.077616, and the remnant liver function was 0.084348 in rem KICG, and 0.10263192 in KGSA.

Fig. 1figure 1

Time line of chemotherapy and changes in levels of DCP and AFP in case 1. The circle numbers are administration courses. AFP alph-fetoprotein, DCP des-gamma carboxyprothrombin

Fig. 2figure 2

Computed tomography of case 1. A Neoplastic lesion in S4 at the time of diagnosis. Yellow arrows show dilatation of intrahepatic bile duct in anterior, and lateral segment. Red arrows show tumor contact with right hilum region. B Neoplastic lesion in S4 after course of ATEZO/BEV. Tumor contact with hilum region regressed to only left hilum (red allows)

In November 2021, segmentectomy of S4 and cholecystectomy were performed following a 5-week period since the last administration of ATZ + BEV. The duration of surgery was 4 h 13 min; blood loss was 1280 mL, and intraoperative and postoperative blood transfusions (4 units of fresh frozen plasma) were required. Intraoperative ultrasonography was used to confirm the location of the tumor, and sufficient surgical margin was obtained. The pathological diagnosis was necrosis without viable HCC cells. There was only a small amount of background liver tissue and little or no invasion into the portal vein. The resection margins were negative and R0 resection was confirmed (Fig. 3). The patient was discharged 10 days after the surgery without postoperative complications. There was no recurrence within one year of surgery.

Fig. 3figure 3

A Surgical findings. B Resection specimen obtained after conversion surgery. C–E Hematoxylin and eosin (H&E) stain. No viable hepatocellular carcinoma was detected

Case 2

The patient was a 72-year-old man who visited his family doctor complaining of upper abdominal pain and was referred to our department after a liver tumor was detected on abdominal ultrasonography. The patient had no medical history of viral hepatitis or metabolic disorders.

Blood tests at his first visit revealed an elevated alanine aminotransferase level of 254 U/L, an aspartate aminotransferase level of 230 IU/L, and a total bilirubin level of 3.7 mg/dL. Albumin level (3.9 d/dL) and prothrombin time level (90.8%) were normal. The serum level of alpha-fetoprotein (AFP) was 570.6 ng/mL and that of des-gamma carboxyprothrombin (DCP) was 65,143 mAU/ml. He had a Child–Pugh score of 6 (Child–Pugh grade A) and no hepatic encephalopathy or ascites (Table 2). Contrast-enhanced CT showed an internally enhanced 120-mm tumor in the S4 area of the liver, which was in contact with the right hilum region, and intrahepatic dilation of the left and anterior segments of the liver (Fig. 5A).

Table 2 Laboratory investigation in Case 2

The patient was diagnosed with Barcelona Clinic Liver Cancer stage A HCC, accompanied by right hepatic hilum involvement. As in Case 1, left tri-segmentectomy was needed to achieve radical resection, but the remnant liver volume was 21.1% (410 ml) and rem KICG was 0.02235 after tri-segmentectomy, indicating surgical resection to be impossible. Endoscopic retrograde cholangiopancreatography was performed to relieve jaundice, and atezolizumab (1200 mg) and bevacizumab (15 mg/kg) were administered as one course of 3 weeks without any adverse effects. After the seventh course, the serum levels of AFP and DCP were within the normal range (Fig. 4), the intrahepatic HCC had shrunk to 70 mm with regression of the hilum tumor contact, and the patient was diagnosed with a partial response to the modified RECIST (Fig. 5B). R0 resection with left hemihepatectomy is considered feasible with a sufficient surgical margin. With left hemihepatectomy, the remnant liver volume was 65.5% (1275 ml) and rem KICG was 0.06943, and the remnant liver function was 0.10263912 in rem KICG and 0.077616 in KGSA.

Fig. 4figure 4

Time line of chemotherapy and changes in levels of DCP and AFP in case 2. The circle numbers are administration courses. AFP  alph-fetoprotein, DCP  des-gamma carboxyprothrombin

Fig. 5figure 5

Computed tomography of case 2. A Neoplastic lesion in S4 at the time of diagnosis. Yellow arrows show dilatation of intrahepatic bile duct in anterior, and lateral segment. Red arrows show tumor contact with right hilum region. B Neoplastic lesion in S4 after course of ATEZO/BEV. Tumor contact with hilum region regressed (red allows)

In December 2022, a left hepatectomy was performed after a 5-week period following the last ATZ + BEV administration. The duration of surgery was 4 h 16 min; blood loss was 1810 ml, and intraoperative and postoperative blood transfusions (red blood cells, 4 units; fresh frozen plasma, 4 units; and blood platelets, 10 units) were performed. Intraoperative ultrasonography confirmed the absence of tumor invasion into hepatic hilum, and sufficient surgical margin was obtained. The pathological diagnosis was moderately differentiated HCC, with most of the tissues being necrotic, possibly because of preoperative treatment. Although the tumor tissues were present outside the capsule, the margins were negative, and R0 resection was confirmed (Fig. 6). The patient was discharged 8 days after surgery without postoperative complications. There was no recurrence up to 5 months after surgery.

Fig. 6figure 6

A Surgical findings. B Resection specimen obtained after conversion surgery. C, D Hematoxylin and eosin (H&E) stain. A primary tumor composed of moderately differentiated cancer cells with most of these tissues necrotic

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