Neoadjuvant and Adjuvant Treatment Approaches for Hepatocellular Carcinoma

Future Outlook

Ibrahim Halil Sahin; Lana Khalil; Ralph Millett; Ahmed Kaseb


Chin Clin Oncol. 2021;10(1):7 

In This Article

Abstract and Introduction


Hepatocellular carcinoma (HCC) is a highly aggressive and chemotherapy resistant cancer with unique biologic characteristics which makes this disease highly different than other gastrointestinal cancers. The mainstay of curative treatment in HCC is surgical resection, ablation, and transplantation. However, rates of recurrence are high and many patients are not initially candidates for these curative approaches. This paper discusses predictors of recurrence of HCC in patients who have undergone surgical resection and addresses adjuvant therapies aimed at decreasing recurrence risk and improving overall survival (OS) outcomes, including traditional cytotoxic chemotherapies, tyrosine kinase inhibitors (TKIs), and immunotherapy. This article also discusses neoadjuvant strategies aimed at improving recurrence rate and OS as well as downstaging advanced HCC to enable surgical disease, including locoregional therapies, systemic chemotherapy, TKIs, and immune checkpoint inhibitors. Finally, this article addresses potential future directions for both adjuvant and neoadjuvant therapies that may change the treatment paradigm of HCC in the near future.


Hepatocellular carcinoma (HCC) is the second leading cause of cancer related mortality worldwide with an estimated global incidence of between 500,000–1,000,000 and an attributable 600,000 deaths annually.[1] Unfortunately, HCC is also increasing faster than any other cancer for both men and women in the United States despite the fact that roughly 70% of cases develop secondary to modifiable risk factors (e.g., alcohol use, chronic viral hepatitis infections, obesity, and smoking).[2] Of unique challenge in the treatment HCC is the high co-occurrence of underlying liver disease which inherently limits potential systemic therapeutic approaches, and despite progress in the management and treatment options of HCC in the last decades, the prognosis remains dismal with a 5-year survival of less than 5%.[3]

While treatment of HCC is multidisciplinary, at present the only therapies directed at cure are aimed at physical removal or destruction of local disease. In patients with relatively preserved liver function, surgical resection is the mainstay treatment but is often limited by the size and anatomy of the disease.[4,5] In patients with end-stage liver disease (ESLD), liver transplantation (LT) is considered the optimal treatment option as it addresses both the malignancy and the underlying cirrhosis.[6] Transplanted patients with localized HCC have a have 5-year survival rates of between 65–80% with a tumor recurrence rate between of 8–15%.[7] Unfortunately, most patients with HCC are ineligible for transplantation by Milan Criteria at the time of presentation and organ procurement remains a challenge even for those who are initially transplant candidates.[6–8] As a result, many of the treatment options discussed in this paper are directed at downstaging or stabilization of disease in advance of potential resection or transplantation, in many cases by applying therapies otherwise approved for the systemic treatment of unresectable or metastatic HCC.

In this review article, we discuss predictors of recurrence among surgically resected patients with HCC and present an overview of the recent progress in different therapeutic approaches aimed at reducing the risk of recurrence and improving overall survival (OS) outcomes. We also evaluate the efficacy of neoadjuvant and adjuvant approaches with novel approaches including immunotherapy as well as targeted therapies and provide a perspective on the likely future direction of clinical trials and treatment options in this highly challenging cancer.