Conversion therapy for hepatocellular carcinoma to improve treatment strategies for intermediate and advanced stages

Abstract

This manuscript is based on a case reported by Song et al published in the World Journal of Clinical Cases. Several challenges remain in the field of hepatocellular carcinoma (HCC) conversion therapy. Consequently, only a limited number of patients with HCC accompanied by portal vein tumor thrombosis (PVTT) and hepatic vein tumor thrombosis (HVTT) are eligible for resection. This clinical case demonstrates that considering the complexity of the disease, a multimodal and multidisciplinary approach is essential for managing HCC accompanied by PVTT and HVTT. However, the outcomes of such surgeries remain controversial. In conclusion, research on HCC conversion therapy is extremely useful for improving treatment strategies for intermediate and advanced HCC, which currently have disappointing clinical outcomes.

Key Words: Hepatocellular carcinoma; Portal vein; Inferior vena cava; Tumor thrombus; Conversion surgery

Core Tip: Hepatocellular carcinoma accompanied by portal vein tumor thrombus and inferior vena cava tumor thrombus can be converted to surgical resection after multimodality and multidisciplinary treatments.

TO THE EDITOR

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the sixth most prevalent cancer worldwide, with an increasing incidence and mortality rate[1,2]. The high mortality rate and poor prognosis are hallmarks of HCC, largely owing to its diagnosis often occurring at an advanced stage, rendering surgery impractical. HCC frequently invades the vascular system, in particular, the portal venous system and hepatic veins[3]. At initial diagnosis, 10%-40% of patients with HCC exhibit vascular invasion[3,4]. This invasion significantly worsens the prognosis[3,4]. Macrovascular invasion can involve tumor thrombus in the portal vein (PVTT) and/or hepatic veins and inferior vena cava. PVTT is classified into four types, with grades III and IV characterized by invasion of the main portal trunk. Hepatic vein tumor thrombosis (HVTT) is divided into three types, with inferior vena cava invasion classified as type II–III[3].

According to the latest American Association for the Study of Liver Disease practice guidelines on the management of HCC, when HCC is accompanied by vascular invasion in patients with preserved liver function and performance status, the tumor is considered to be in the “advanced stage”, and treatment is based on systemic therapy[5,6]. However, these patients typically have a relatively poor median survival time. Conversely, the China Liver Cancer Staging system[7] classifies HCC with vascular invasion as advanced stage IIIa. Unlike Western countries, China recommends hepatectomy and loco-regional therapies, including transarterial chemoembolization, hepatic arterial infusion chemotherapy, or radiation therapy combined with systemic treatment for such patients. Compared with systematic or conservative treatment alone, a multimodal approach may improve prognosis[3,4].

Recent advances in systemic therapies have significantly improved oncological outcomes for intermediate and advanced HCC. In patients with initially unresectable HCC, a combination of loco-regional and systemic therapies appears to further facilitate downstaging, thereby increasing the number of patients eligible for surgical resection. Conversion therapy provides a second chance for patients with late-stage HCC who are no longer candidates for surgery by offering a means to downgrade initially unresectable HCC to a resectable condition through various treatment modalities[4,5]. Therefore, conversion therapy allows patients with advanced-stage HCC to transition from an initially unresectable state to a resectable one, thereby expanding their treatment options[4,5].

In the case reported by Song et al[8] in “Conversion therapy of a giant hepatocellular carcinoma with portal vein thrombus and inferior vena cava thrombus: A case report and review of literature”, the authors used multimodal and multidisciplinary treatments for conversion to surgery in a patient with a large HCC on cirrhosis along with PVTT and HVTT. Conversion therapy aims to downstage unresectable HCC to reduce the tumor burden through a combination of loco-regional and/or systemic therapies. If downstaging is successful, patients may become suitable for surgical resection[4,5]. In this clinical case, the patient was initially treated with transarterial chemoembolization, followed by radiotherapy and seven cycles of adjuvant treatment with atezolizumab, bevacizumab, and epimedium soft capsules[8]. Finally, polyvinyl alcohol embolization was performed again to enhance the efficacy of the treatment. In addition, oral entecavir was administered for chronic hepatitis B infection. After this multimodal approach, the patient’s prothrombin induced by vitamin K absence-II levels decreased from 32004 ng/mL to 31 ng/mL, and alpha-fetoprotein levels decreased from 110010 ng/mL to 8.8 ng/mL. Imaging revealed significant shrinkage of the tumor over 7 mo of treatment, with notable reductions in PVTT and HVTT. Therefore, the patient was deemed suitable for surgery, and a hemihepatectomy along with the removal of the vena cava tumor thrombus was performed. After 7 mo of follow-up, no recurrence was observed.

Reporting their clinical case, the authors described their employment of a comprehensive range of treatments that have shown adjuvant efficacy in advanced HCC with vascular invasion to achieve downstaging of the tumor in their patient, rendering them suitable for surgical resection. Although malignant cells can spread in and out of the liver from an oncological standpoint, the overall survival outcomes of patients with HCC with vascular invasion treated with a single treatment option are not as satisfactory as the outcomes of those treated with multimodal options, who have shown better survival rates. Transarterial chemoembolization has long been used as an adjuvant treatment option for patients with HCC with vascular invasion, alongside radiotherapy. The introduction of immunotherapy in advanced HCC has shown better results compared to initial treatments with sorafenib, and now systemic therapy with atezolizumab plus bevacizumab is recommended for HCC with VP3–4 PVTT[3,4].

However, many challenges remain in the field of HCC conversion therapy, including the following: The careful selection of patients, which includes considerations of preserved liver function, age, and portal hypertension that might require splenectomy; the formulation of optimal conversion therapy regimens; the determination of the optimal time for surgery; and the application of post-surgical adjuvant therapy. Owing to these factors, only a limited number of patients with HCC accompanied by PVTT and HVTT can be converted to resection.

Meanwhile, the majority of results have been obtained in patients with HCC combined with PVTT, and limited data are available in patients with HVTT or both[3]. This clinical case demonstrates that considering the complexity of the disease, a multimodal and multidisciplinary approach is necessary for managing HCC accompanied by PVTT and HVTT. It is important to note that the outcomes of such surgeries are controversial. For example, the optimal duration of neoadjuvant therapy to reduce recurrences remains unclear, necessitating more extensive data. Another issue is the reproducibility of the results in patients from different regions. In the Eastern regions, the etiology of HCC is primarily viral, whereas in the Western population, HCC is primarily associated with alcoholic and non-alcoholic steatohepatitis.

In conclusion, research on HCC conversion therapy is extremely useful for improving treatment strategies for intermediate and advanced HCC, which continue to have disappointing clinical outcomes.