Five-year complete remission of super-giant hepatocellular carcinoma with hepatectomy followed by sorafenib plus camrelizumab: A case report

Abstract

BACKGROUND

Cirrhotic patients with super-giant hepatocellular carcinoma (HCC) and portal vein invasion generally have a poor prognosis. This paper presents a patient with super-giant HCC and portal vein invasion, who underwent hepatectomy followed by a combination of sorafenib and camrelizumab, resulting in complete remission (CR) for 5 years.

CASE SUMMARY

A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC, Barcelona Clinic Liver Cancer stage C. Enhanced computed tomography imaging revealed a 152 mm × 171 mm tumor in the right liver, invading the portal vein and hepatic vein. Liver function was normal. The patient successfully underwent hepatectomy on July 18, 2019. However, by December 2019, HCC recurrence with lung metastases and portal vein invasion were detected. He started treatment with sorafenib (200 mg twice daily) and camrelizumab (200 mg every 3 weeks). By May 12, 2020, the patient was confirmed to have CR. Camrelizumab was adjusted to 200 mg every 12 weeks from June 16, 2021, with the last infusion on March 29, 2024. Although no further tumor recurrence was observed, he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices, which were managed with endoscopic therapy. To date, the patient has remained in CR for 5 years.

CONCLUSION

The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with super-giant HCC and portal vein invasion. Further research is necessary to address these challenges and improve patient outcomes.

Key Words: Hepatectomy; Sorafenib; Camrelizumab; Super-giant hepatocellular carcinoma; Complete remission; Case report

Core Tip: Cirrhotic patients with super-giant hepatocellular carcinoma (HCC), accompanied by portal vein invasion, generally have a poor prognosis. We report a patient with super-giant HCC and portal vein invasion, who underwent hepatectomy followed by sorafenib plus camrelizumab, resulting in complete remission for 5 years. However, two critical issues are raised: One is how to screen and manage portal hypertension in HCC, and the other is related to the optimal treatment duration of tyrosine kinase inhibitors and immune checkpoint inhibitors in HCC patients who achieve complete remission. Further research is needed to address these challenges.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, originating from hepatocytes and intrahepatic cholangiocytes. It is the fourth most common malignancy and the second leading cause of cancer-related death in China, with hepatitis B virus (HBV) infection being a major causative factor[1]. According to the guidelines, patients with super-giant HCC, portal vein invasion, and extrahepatic spread are classified as having advanced stage (Barcelona Clinic Liver Cancer stage C)[2]. Despite treatment with liver resection and transcatheter arterial chemoembolization (TACE), the long-term prognosis for these patients remains extremely poor[3,4].

The advent of multi-targeted tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has provided new hope for these patients. Sorafenib, a multi-targeted kinase inhibitor, has been extensively validated for the treatment of advanced HCC[5]. Camrelizumab is a humanized monoclonal antibody that targets programmed cell death receptor 1 (PD-1), blocking its interaction with ligands PD-L1 and PD-L2, and restoring T-cell anti-tumor activity. Although many studies have demonstrated the efficacy and safety of sorafenib and camrelizumab in patients with advanced HCC[6,7], long-term complete remission (CR) remains rare. Here, we present the unique case of a patient with super-giant HCC and portal vein invasion. The patient underwent hepatectomy, followed by combination therapy of sorafenib and camrelizumab, achieving a sustained CR over a 5-year follow-up period.

CASE PRESENTATION

Chief complaints

A 40-year-old male presented to the hospital with the complaint of abdominal pain for one day.

History of present illness

One day ago, the patient developed persistent pain in the right upper abdomen. A subsequent abdominal computed tomography (CT) scan revealed a hepatic space-occupying lesion. Consequently, hospital admission was deemed necessary for further assessment and treatment.

History of past illness

The patient had no significant medical history.

Personal and family history

The patient had a family history of HBV infection.

Physical examination

Physical examination showed tenderness in the right upper abdomen.

Laboratory examinations

Laboratory tests indicated positive hepatitis B surface antigen, elevated HBV DNA (5.28 × 10³ IU/mL), elevated α-fetoprotein (AFP) (575.9 ng/mL), and elevated AFP-L3 (206.8 ng/mL), with normal blood cell counts, liver and renal function, and coagulation tests (Table 1). The indocyanine green retention rate at 15 minutes was 7.2%.

Table 1 Laboratory examinations at diagnosis and endpoint.

Variables		Baseline	Endpoint
CBC test	WBC (× 109/L)	7.51	3.19
	RBC (× 109/L)	5.17	4.83
	HGB (g/L)	155	135
	PLT (× 109/L)	314	96
Coagulation test	PT (s)	12.2	11.6
	INR	1.09	1.03
Biochemistry test	ALT (U/L)	25	28
	TBIL (μmol/L)	23.6	17.4
	ALP (U/L)	454	58
	γ-GT (U/L)	77	26
	ALB (g/L)	38.2	40.9
	CREA (μmol/L)	65	57
Tumor markers	AFP (ng/mL)	561.9	1.99
	AFP-L3 (ng/mL)	206.8	Less than 0.908
Serology test	HBV-DNA (IU/mL)	5280	Less than 10
	HBsAg	Positive	Negative
	HBsAb	Negative	Negative
	HBeAg	Negative	Negative
	HBcAb	Positive	Positive
	HBeAb	Positive	Positive

CBC: Complete blood count; WBC: White blood cell; RBC: Red blood cell; HGB: Hemoglobin; PLT: Platelet; PT: Prothrombin time; INR: International normalized ratio; ALT: Alanine transaminase; TBIL: Total bilirubin; ALP: Alkaline phosphatase; γ-GT: γ-glutamyltransferase; ALB: Albumin; CREA: Creatinine; AFP: α-fetoprotein; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBcAb: Hepatitis B core antibody; HBeAb: Hepatitis B e antibody.

Imaging examinations

Liver stiffness measurement (LSM) was 7.9 kPa. Enhanced CT revealed a 152 mm × 171 mm liver mass in the right lobe with satellite nodules, invading the right posterior branch of the portal vein and the right hepatic vein. Thoracic CT showed no metastasis (Figure 1A).

Figure 1 Contrast-enhanced abdominal computed tomography and contrast-free thoracic computed tomography. A: Computed tomography (CT) scans showed a super-giant tumor 152 mm × 171 mm in size in the right liver lobe, without lung metastasis; B: The postoperative CT scans showed that hepatocellular carcinoma was removed; C: CT scans showed multiple liver recurrences and lung metastasis in December 2019; D: CT scans showed complete remission of liver recurrence and lung metastasis on May 12, 2020.

FINAL DIAGNOSIS

The patient was diagnosed with HCC (Barcelona Clinic Liver Cancer stage C) and compensated hepatitis B-related cirrhosis (Child-Pugh class A, Eastern Cooperative Oncology Group Performance Status 0).

TREATMENT

The patient was administered entecavir for HBV infection and underwent hepatectomy on July 18, 2019 (Figures 1B and 2A). Pathological examination revealed moderately to poorly differentiated HCC with tumor thrombosis in most vessels, including the portal and right hepatic veins (Figure 2B). Immunohistochemical staining showed higher PD-1 expression in the tumor compared to surrounding tissue (Figure 2C-E). On September 4, 2019, the patient underwent TACE to reduce recurrence risk, confirming no tumor remnants.

Figure 2 Histopathology of the resected liver tumor. A: The specimen showed a giant hepatic tumor over 170 mm in size; B: Hematoxylin and eosin staining of hepatocellular carcinoma revealed that the tumor cells were arranged in a nest-like cluster at the junction with normal liver tissue, and the nuclear was large and deeply stained with atypical morphology (200 × magnification); C-E: Immunofluorescence staining of programmed cell death receptor 1 in tumor tissue showed more positive findings than in para-carcinoma tissues. The arrow indicates positive. PD-1: Programmed cell death receptor 1.

OUTCOME AND FOLLOW-UP

The patient recovered well after operation, and received regular follow-ups every 3 months. Serum AFP and enhanced CT scans showed no recurrence until December 2019. At that time, he reported respiratory distress and elevated serum AFP (134.7 ng/mL) and AFP-L3 (27.05 ng/mL). Enhanced CT scans identified multiple recurrent tumors in the liver and lungs (Figure 1C). The patient began treatment with sorafenib (200 mg twice daily) and camrelizumab (200 mg every 3 weeks) on December 23, 2019. Initially, he experienced mild desquamation of the feet and palms, nausea, and loss of appetite due to drug side effects but continued to improve throughout treatment. By February 12, 2020, enhanced CT scans showed significant remission with tumor markers returning to normal. CR was achieved on May 12, 2020 (Figures 1D and 3). From June 16, 2021, the dosage of camrelizumab was reduced to 200 mg every 12 weeks, with the final infusion administered on March 29, 2024.

Figure 3 Dynamic change in α-fetoprotein during the entire treatment period. AFP: α-fetoprotein.

During the follow-up period, the patient experienced two episodes of gastrointestinal bleeding due to esophagogastric varices on May 11, 2020 and July 11, 2021, respectively, which was treated with endoscopic variceal ligation and endoscopic tissue glue injection on May 29, 2020 and August 13, 2021, respectively (Figure 4). During these periods, both sorafenib and camrelizumab were temporarily discontinued. Encouragingly, the patient has maintained durable CR since May 12, 2020, with regular CT scans and tumor marker tests conducted every 6 months. The complete treatment timeline is shown in Figure 5, and the dynamic change in AFP is shown in Figure 3.

Figure 4 Endoscopy examinations. After two episodes of gastrointestinal bleeding, upper gastrointestinal endoscopy revealed mild esophagogastric varices without red color signs. The patient was subsequently treated with esophageal variceal ligation and endoscopic tissue glue injection. A: The endoscopy finds the first acute esophageal variceal bleeding on May 11, 2020; B: The patient accepted endoscopic variceal ligation treatment on May 29, 2020; C: The endoscopy found the gastric variceal bleeding without esophageal varices on July 11, 2021; D: The patient accepted endoscopic tissue glue injection treatment on August 13, 2021. AVB: Acute variceal bleeding; EVL: Endoscopic variceal ligation.

Figure 5 The entire treatment timeline. TACE: Transcatheter arterial chemoembolization; HCC: Hepatocellular carcinoma; AVB: Acute variceal bleeding; EVL: Endoscopic variceal ligation.

DISCUSSION

The treatment of HCC has significantly advanced with the introduction of combination therapy using TKIs and ICIs[8]. Despite this progress, patients with super-giant HCC and portal vein invasion typically have a poor prognosis, and achieving CR is rare, even with combination regimens. This case report describes a patient with super-giant HCC and portal vein invasion who achieved CR and a 5-year recurrence-free survival following hepatectomy and subsequent sorafenib plus camrelizumab therapy.

Both TKIs and ICIs have dramatically improved the feasibility and effectiveness of hepatectomy for patients with super-giant HCC. This case demonstrates that in the era of TKIs plus ICIs, patients with super-giant HCC can achieve CR and long-term recurrence-free survival following hepatectomy. Generally, patients with HCC tumors larger than 10 cm have poorer prognoses compared to those with smaller tumors. Within 5 years after liver resection, the recurrence rate can be as high as 84.9%, and the overall survival (OS) rate as low as 34.0%[9]. Consequently, some patients forgo hepatectomy in favor of TACE to manage HCC progression. However, for patients with giant HCC undergoing TACE, the progression-free survival is only about 9.5 months, and OS ranges from 10.6 to 19.3 months[10]. Due to the large size of super-giant HCC, these patients are at high risk for various complications following TACE. Currently, TKIs plus ICIs is considered the first-line treatment for advanced HCC. However, as demonstrated in the COSMIC-312 study, not all combination regimens achieve OS benefits[11]. Therefore, exploring new combination treatment regimens that extend OS for super-giant HCC patients is essential. Sorafenib, a multikinase inhibitor, promotes apoptosis, reduces angiogenesis, and inhibits tumor progression. Prior to 2020, it was the only effective first-line treatment for HCC. Studies have shown that sorafenib may exert antitumor effects by normalizing tumor vasculature[12], altering macrophage polarization[13], and reducing the number of CD4+PD-1+ and CD8+PD-1+ T cells[14]. Camrelizumab, a high-affinity humanized PD-1 monoclonal antibody, can alleviate the immunosuppressive state of CD8+ T cells. These factors collectively support the idea that the combination of sorafenib and camrelizumab could benefit HCC patients by modulating antitumor immunity. Existing research has also confirmed the safety and efficacy of the combined use of sorafenib and camrelizumab in HCC patients. In a 2022 retrospective study, recurrence-free survival was significantly extended to 10.2 months in the group receiving sorafenib combined with camrelizumab, compared to 6.1 months in the sorafenib monotherapy group[7]. Despite its potential, identifying which patients will respond best to this combination remains a challenge. PD-1 inhibitors are theoretically more effective in patients with high PD-1 expression, making PD-1 levels in tumor tissues a potentially optimal biomarker for predicting treatment response[15]. In this case, we report a patient with super-giant HCC who achieved CR and long-term survival through surgical resection of the primary tumor, followed by sorafenib and camrelizumab for recurrent disease. Early in the treatment, immunohistochemistry revealed higher PD-1 expression in the tumor compared to surrounding healthy tissues, supporting the rationale for using camrelizumab. This underscores that hepatectomy can substantially reduce tumor burden, improving the sensitivity and effectiveness of subsequent sorafenib and camrelizumab combination for super-giant HCC patients. In addition, PD-1 expression levels in tumor tissues may serve as a predictive indicator for selecting patients who are likely to respond to camrelizumab therapy.

In the era of TKIs and ICIs, managing portal hypertension in HCC patients is crucial. This patient experienced bleeding twice due to mild gastroesophageal varices during systemic therapies, indicating that the Barveno VII criteria may not be appropriate for predicting esophagogastric varices or bleeding in HCC patients with compensated cirrhosis undergoing targeted therapy and immunotherapy. Based on Barveno VII criteria, patients with LSM ≤ 15 kPa and platelets (PLT) ≥ 150 × 10⁹/L can be diagnosed without clinically significant portal hypertension and avoid endoscopy[16]. However, HCC can worsen portal hypertension and increase bleeding risk in cirrhotic patients, related to the development of arteriovenous shunts, structural liver changes, and portal vein tumor invasion[17]. There is growing concern about the potential for TKIs and ICIs to increase gastrointestinal bleeding in HCC patients. Vascular endothelial growth factor receptor inhibitors are believed to increase bleeding risk by reducing endothelial cell regenerative capacity, inhibiting angiogenesis, and decreasing collateral vessel proliferation[18-20]. This patient was not advised to undergo screening endoscopy initially because his LSM was ≤ 15 kPa and PLT were ≥ 150 × 10⁹/L. However, he experienced esophagogastric variceal bleeding twice despite an excellent tumor response and stable liver function, with no further bleeding after endoscopic therapy. Therefore, our report suggests that the Barveno VII criteria are inadequate for screening portal hypertension in HCC patients treated with TKIs and ICIs. We recommend that HCC patients, even with LSM ≤ 15 kPa and PLT ≥ 150 × 10⁹/L, undergo screening endoscopy before starting TKIs and ICIs. To ensure continuous and effective TKIs plus ICIs, regular gastroscopy intervals should be shortened during treatment, and necessary prophylactic treatment of esophagogastric varices should be actively pursued.

Determining the optimal duration and discontinuation strategy for TKIs plus ICIs remains challenging for clinicians. HCC patients typically discontinue TKIs and ICIs due to disease progression, drug resistance, or serious adverse events such as hand-foot skin reactions, diarrhea, liver dysfunction, and upper gastrointestinal hemorrhage[21]. With the advent of TKIs plus ICIs, CR is possible but rare in advanced HCC patients, with rates as low as 1.3% in the targeted therapies group and 2.7% in the ICIs group[22,23]. However, for patients who achieve CR, there are no guidelines on the optimal duration of TKIs plus ICIs[24]. Additionally, it remains uncertain whether HCC patients will still benefit from their original treatment regimen if the tumor recurs after discontinuation. Indefinite-duration treatment could reduce recurrence but might also lead to significant economic waste and the accumulation of drug toxicity. In this case, sorafenib plus camrelizumab has been administered continuously for over 4 years, except during periods of variceal bleeding, with favorable outcomes. The emerging issue for clinicians is determining when and how to safely discontinue the treatment of sorafenib plus camrelizumab, a topic worth discussing and investigating.

CONCLUSION

Overall, the combination of hepatectomy with sorafenib plus camrelizumab is a potentially effective treatment for super-giant HCC patients with portal vein invasion. This approach can significantly reduce tumor burden, enhance systemic therapy efficacy, and achieve CR. However, extensive use of TKIs plus ICIs combination therapy raises two critical issues: How to perform endoscopic screening and manage portal hypertension in HCC patients, and how to determine the optimal treatment duration of TKIs plus ICIs and safely discontinue the drugs in HCC patients who achieve CR. Further research is needed to address these challenges and improve patient outcomes.