A patient who underwent conversion surgery after atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein thrombosis and perihepatic lymph node metastases achieved a pathological complete response

Abstract

Here, we present a patient with hepatocellular carcinoma complicated by tumor thrombosis into the main portal trunk and perihepatic lymph node metastases who was treated with atezolizumab plus bevacizumab. Shrinkage of the main tumor, portal vein thrombosis, and lymph node metastases were achieved; therefore, hepatectomy with lymphadenectomy could be performed. Final pathology indicated a complete pathological response in the main tumor, portal vein thrombosis, and perihepatic lymph nodes. The patient is currently alive with no evidence of recurrence on radiological assessment at 3 months after surgery.

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death [1]. Although potential curative therapies include resection, liver transplantation, and local ablation for early-stage HCC and transarterial chemoembolization (TACE) for intermediate-stage HCC [2, 3], many patients with HCC already have advanced or metastatic disease at diagnosis and are indicated for systemic chemotherapy, such as atezolizumab plus bevacizumab (atezo + bev) and durvalumab plus tremelimumab [4–6]. Conversion therapy is the primary treatment strategy used to achieve tumor downstaging and to provide patients with initially unresectable or borderline resectable tumors with the opportunity to undergo curative local treatment. Conversion therapy has been widely adopted for the treatment of various solid tumors, such as metastatic colorectal cancer and pancreatic cancer. In addition, the feasibility and efficacy of conversion surgery for unresectable HCC patients have recently been reported. Atezo + bev showed a high objective response rate of approximately 30%, and atezo + bev therapy is expected to contribute to a high conversion rate and a pathological response and lead to prolonged overall survival [7]. However, it is unclear whether objective response is associated with amenability to conversion surgery and pathological response, especially in patients with macroscopic vascular invasion and/or extrahepatic metastases. Here, we report a case of pathological complete response of a primary tumor, portal vein tumor thrombosis (PVTT), and perihepatic lymph node metastasis (PHLM) confirmed by conversion hepatectomy, portal vein thrombectomy, and lymphadenectomy after atezo + bev therapy.

Case report

An 83-year-old man without a history of hepatitis viral infection and excess alcohol intake was incidentally found to have elevated alpha fetoprotein (AFP) levels at medical check-up and was subsequently referred to a hepatologist at a secondary care hospital. He had not undergone routine liver cancer screening. He had no symptoms and no particular findings on physical examination. Blood examination revealed normal leukocyte and platelet counts and a normal hemoglobin concentration. The patient’s total bilirubin was 0.7 mg/dL, aspartate aminotransferase was 33 IU/L, alanine transaminase was 25 IU/L, albumin was 4.5 g/dL, prothrombin time was 11.0 s, AFP was 339 ng/mL, and des-γ-carboxy prothrombin (DCP) was 12,453 mAU/mL. Dynamic contrast-enhanced computed tomography (CT) revealed a 63 mm mass in the left lateral section with high density in the arterial phase and low density in the venous phase, forming portal vein tumor thrombosis reaching the main portal trunk (Vp4 according to the Japanese classification). Round, swollen lymph nodes with suspected lymph node metastases were also identified along the common hepatic artery (Station 8), around the celiac axis (Station 9), and along the lesser curvature (Station 3) (Fig. 1) [8]. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed a 67 × 56 mm lesion with enhancement in the early phase, non-enhancement in the portal and delayed phases, and greater signal intensity than in the normal liver on diffusion-weighted imaging (DWI). A higher signal intensity of the PHLM and PVTT in the left portal branch and main trunk was also observed on DWI-MRI (Fig. 2). The intrahepatic tumor had mild abnormal ¹⁸F-fluorodeoxyglucose (FDG) uptake with a standard maximum uptake value of 5.27 on FDG positron emission tomography (PET). No abnormal uptake at swollen lymph nodes detected on CT was detected on FDG-PET (Fig. 3). As no ascites on CT and MR images and no encephalopathy were observed, his Child‒Pugh classification was class A. Finally, HCC with Barcelona Clinic Liver Cancer prognosis and treatment strategy (BCLC) stage C owing to tumor thrombosis into the main portal trunk and PHLM was diagnosed.

Fig. 1.

CT images before atezolizumab plus bevacizumab therapy (a, d, g: arterial phase; b, e, h: portal phase; c, f, i: venous phase). An intrahepatic mass 63 mm in diameter at the lateral section with enhancement at the arterial phase (a) and washout at the venous phase (c) was observed at the left lateral section. Portal vein tumor thrombosis at the main portal trunk (arrow) and lymph node swelling with early enhancement and washout (arrowhead) at Station 9 (a, b, c), Station 8 (d, e, f), and Station 3 (g, h, i) were also observed

Fig. 2.

MR images before atezolizumab plus bevacizumab therapy. A 67 × 56 mm lesion in the left lateral section with enhancement in the early phase (a), non-enhancement in the portal (b) and late phases (c), and a higher signal intensity than that in the normal liver on diffusion-weighted imaging (d). Higher signal intensity in the PHLM (arrowhead) and PVTT (arrow) in the left portal branch and main portal trunk

Fig. 3.

18F-fluorodeoxyglucose (FDG)-PET revealed mild abnormal uptake of FDG with a maximum standard uptake of 5.27 in an intrahepatic tumor in the left lateral section and weak uptake in the portal vein tumor thrombosis (arrow). No abnormal uptake at perihepatic lymph nodes was observed

As his disease was considered oncologically unresectable, systemic therapy with atezolizumab (1200 mg/body) plus bevacizumab (15 mg/kg) every 3 weeks was started. The primary tumor and lymph node metastases strongly responded to a total of 3 cycles of atezo + bev therapy, although the patient needed to discontinue atezo + bev therapy due to immune-related colitis that needed steroid therapy. His AFP level decreased to within the normal range (from 339.0 to 1.4 ng/mL), and his DCP level decreased from 12,453 to 1082 mAU/mL (Fig. 4). On dynamic CT after atezo + bev therapy, the size and vascularity of the primary tumor decreased indicating partial response based on response evaluation criteria in solid tumors (RECIST) and modified RECIST [9, 10], and the PVTT shrank from the main portal trunk to the left portal branch. The swelling of perihepatic lymph nodes regressed or disappeared (Fig. 5). EOB-DTPA-MRI also revealed tumor regression, a shrunken portal thrombosis, and no high signal intensity in the lymph nodes on DWI. Because of the marked response to atezo + bev therapy and the presence of immune-related adverse effects, the patient underwent surgical intervention after 3 cycles of atezo + bev.

Fig. 4.

Treatment course of atezolizumab plus bevacizumab (atezo + bev) and surgery. The levels of alpha fetoprotein (AFP, ng/mL) and des-γ-carboxy prothrombin (DCP, mAU/mL) were markedly decreased after 3 cycles of atezo + bev. Conversion surgery was performed 12 weeks after the final administration of atezo + bev. Immunoreactivity-related colitis that required prednisolone therapy occurred after 3 cycles of atezo + bev

Fig. 5.

CT images after atezolizumab plus bevacizumab therapy (a, e, f: arterial phase; b, d: portal phase; c: venous phase). The size of the intrahepatic mass in the left lateral section was reduced to 30 mm in diameter with partial hypervascularity in the arterial phase (a). The portal vein tumor thrombosis shrank to the left portal branch (allow) (d). The perihepatic lymph nodes shrink, and hypervascularity disappears (arrowhead) (e, f)

Left hepatectomy and caudate lobectomy with lymphadenectomy at Stations 8 and 9 and portal vein thrombectomy were performed 12 weeks after the final administration of atezo + bev (Fig. 4). As swelling of lymph node Station 3 was not identified during the surgery, lymphadenectomy of Station 3 was not performed. Portal vein tumor thrombosis was extended to the left portal branch by intraoperative ultrasonography. Therefore, the right portal branch and main portal trunk were clumped, and tumor thrombectomy was performed by opening the left portal branch. The surgery lasted 7 h 15 min, with an estimated blood loss of 285 mL. He was discharged on postoperative day 10 without morbidity. Final pathology indicated no residual carcinoma in the resected intrahepatic tumor, PVTT, or lymph nodes. Microscopic pathological assessment revealed hyalinization, chronic inflammatory infiltration, hemosiderin accumulation, and angiogenesis, indicating a pathological complete response to preoperative atezo + bev (Fig. 6).

Fig. 6.

Macroscopic findings of the resected liver specimen (a, dorsal side; b, cut surface) and microscopic findings of the liver tumor (c), portal vein thrombosis (PVTT) (d) and lymph node (e). a, b Macroscopically, a 4.8 × 2.5 cm tumor involving the umbilical portion of the left portal tract with PVTT was observed. c The interior part of the fibrous capsule includes hyalinization, chronic inflammatory infiltration, hemosiderin accumulation and angiogenesis without residual cancer cells, indicating a pathological complete response to preoperative atezolizumab plus bevacizumab therapy (hematoxylin and eosin staining, magnification ×1). d Infiltration of chronic inflammatory cells and accumulation of hemosiderin-phagocytic cells are observed in the PVTT (hematoxylin and eosin staining, magnification ×10). e No residual cancer cells were observed in the perihepatic lymph node at Station 8 (hematoxylin and eosin staining, magnification ×2)

He has transitioned to surveillance with cross-sectional imaging and has not received adjuvant chemotherapy. His last follow-up was at 3 months after surgical resection, at which time CT scans of the chest, abdomen, and pelvis showed no obvious recurrent disease.

Discussion

The present patient had HCC with PVTT reaching the main portal trunk (Vp4) and PHLM at diagnosis and was considered to have oncologically unresectable disease based on the BCLC staging system and Japanese clinical practice guidelines for HCC[2, 3]. The patient remarkably responded to 3 cycles of atezo + bev; therefore, we decided to perform conversion surgery, including hepatectomy, portal vein thrombectomy, and perihepatic lymphadenectomy. Pathological assessment of surgically resected specimens indicated no residual cancer cells, indicating a pathological complete response to atezo + bev.

Systemic therapy based on the BCLC staging system is the standard therapy for patients with advanced-stage HCC, such as portal invasion and/or extrahepatic spread [2]. The Japanese Clinical Practice Guidelines for HCC also recommend systemic therapy for patients with extrahepatic metastases, although patients with vascular invasion are candidates for surgical resection [3]. Atezolizumab (anti-programmed death-ligand 1 [PD-L1] antibody) plus bevacizumab (anti-vascular endothelial growth factor antibody) therapy or durvalumab (anti-PD-L1 antibody) plus tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) therapy are recommended as first-line systemic therapies [5, 6]. In addition, patients with TACE-unsuitable intermediate-stage HCC are also candidates for such combination immunotherapies [2, 11]. Kudo et al. reported that atezo + bev followed by locoregional therapies, including TACE, ablation and surgery, achieved a 35% clinical or pathological complete response rate in patients with TACE-unsuitable intermediate-stage HCC [12]. However, as surgical resection was achieved in only 7 of the 38 patients who achieved clinical or pathological complete response in that study, the true complete response rate after atezo + bev therapy was uncertain. In addition, the efficacy of atezo + bev for portal invasion or extrahepatic metastasis is not well understood because that study investigated only patients with intermediate-stage HCC. To the best of our knowledge, there are only 4 case reports regarding pathological complete response confirmed by conversion surgery after atezo + bev therapy for advanced-stage HCC harboring PVTT, lung metastasis, adrenal metastasis, or peritoneal metastasis (Table 1) [13–16]. Therefore, this is the first report of a patient who achieved a pathological complete response to atezo + bev therapy in a patient with concurrent extrahepatic metastasis and PVTT or a patient with PHLM.

Table 1.

Prior reports undergoing conversion surgery after atezolizumab plus bevacizumab for advanced stage of hepatocellular carcinoma achieved a pathological complete response

Author	Year	Age	Sex	Background liver disease	Macrovascular invasion	Extrahepatic metastases	Number of cycles	Follow-up (months)	Outcome
Hoshino [13]	2022	77	M	HBV	IVC	Adrenal grand	9	3	Alive without recurrence
Kurisaki [14]	2023	60s	M	HBV	PV	None	5	16	Alive without recurrence
Fukunaga [15]	2023	77	M	Alcoholic liver disease	None	Lung	7	8	Alive without recurrence
Miyata [16]	2023	75	M	–	None	Peritoneum	15	7	Alive without recurrence
Current report	–	83	M	Non-viral, non-alcoholic	PV	Perihepatic lymph node	3	3	Alive without recurrence

M male, HBV hepatitis B virus, IVC inferior vena cava, PV portal vein

There is interest in the timing and indications for conversion surgery after atezo + bev therapy for oncologists and liver surgeons. Patients should be able to obtain stable disease, partial response or complete response based on RECIST or modified RECIST when considering conversion surgery in patients with advanced-stage HCC [9, 10]. In addition, decreases in tumor markers, including AFP and DCP, may be considered favorable biomarkers. Shindoh et al. reported that a downward trend in DCP levels was associated with R0 conversion resection after lenvatinib treatment [17]. Our group recently showed that decreases in AFP levels during lenvatinib treatment were associated with longer recurrence-free survival and overall survival after conversion surgery [18]. In this context, the current patient might be a favorable candidate for conversion surgery. In addition, it is uncertain whether patients who achieve a clinical complete response should be treated with additional interventions, including surgery, TACE, or ablation therapy. The current case indicates that there may be patients who achieved a pathological complete response to atezo + bev even if they had macrovascular invasion or extrahepatic metastases. However, locoregional therapies should be administered even if a complete response is considered to be achieved after atezo + bev therapy because we do not have the way to confirm the disappearance of cancer cells in such patients. As surgical resection is the only way to prove a pathological response to systemic therapy, especially in patients with macrovascular invasion or extrahepatic metastases, we believe that surgical resection should be considered for a better prognosis as well as for the accumulation of evidence.

The limitation of this report is the diagnostic accuracy of lymph node metastases before atezo + bev because the pathological diagnosis was not obtained. Although more than 1 cm has been reported to be the cut-off of lymph node swelling suspecting metastases [19, 20], the size of lymph node in the current case with approximately 1 cm in diameter was on the borderline. However, suspected lymph nodes in this case also had an enhancement in the early phase and a washout in the delayed phase on dynamic CE-CT, and a higher signal intensity on DWI-MRI, while abnormal uptake on FDG-PET was not observed. In addition, the size and vascularity of suspected lymph nodes on CE-CT after atezo + bev decreased, and no high signal intensity in the lymph nodes was observed on DWI after atezo +  bev, indicating response to atezo + bev. Therefore, we believe that this case had lymph node metastases.

In conclusion, we report the case of an HCC patient with PVTT and lymph node metastases who achieved a pathological complete response to atezo + bev therapy confirmed by conversion surgery. This case report may increase patients’ motivation to undergo systemic therapy even if they have advanced-stage HCC with macrovascular invasion and/or extrahepatic metastases.

Funding

This study was partly supported by JSPS KAKENHI (grant number 21K16486).

Data availability

The dataset generated and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

Informed consent was obtained from the individual participants included in the study.