Redefining Intermediate-Stage HCC Treatment in the Era of Immune Therapies

Gagandeep Brar, MD; Andrew Kesselman, MD; Anuj Malhotra, MD; Manish A. Shah, MD


J Oncol Pract. 2022;18(1):35-41. 

In This Article

Abstract and Introduction


Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. At diagnosis, most patients are ineligible for curative surgery, and approximately 20% of patients are diagnosed with advanced-stage disease. A significant proportion of patients fall under an unresectable or intermediate-stage disease who have liver-limited disease but are not surgical candidates because of large tumor size, number of lesions, or technically inoperable disease. In this unique intermediate-stage patient population, locoregional therapies have been the de facto mainstay of treatment because of high local response rates and favorable safety profile, especially in the context of minimally effective systemic therapies. However, not all patients who receive locoregional therapy for incurable disease have improved survival, and importantly, some of these patients never receive systemic therapy because of disease progression or further decline in hepatic function. Meanwhile, with the remarkable progress that has been made with systemic therapy in the past few years, revisiting the treatment of intermediate-stage HCC seems prudent. In this review, we will highlight current and emerging strategies for treating patients with unresectable, liver-limited HCC.


Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality and is increasing in prevalence in the United States. In 2020, there will be an estimated 42,810 new cases and 30,160 deaths related to liver cancer in the United States.[1] Surgical resection and transplantation remain standard-of-care curative options for patients with disease limited to the liver, with 5-year survival rates > 50%. However, the majority of patients who are newly diagnosed with HCC are ineligible for these curative surgical options, because either they are not candidates for liver transplant or do not have disease amenable to curative resection.[2–4] The Barcelona Clinic Liver Cancer algorithm is the most widely accepted staging system in HCC and incorporates treatment recommendations and prognosis on the basis of patient and tumor characteristics as well as underlying liver function.[5] Intermediate-stage HCC is defined as multinodular HCC in patients with preserved liver function and functional status; however, this corresponds to a heterogenous patient population. In patients with unresectable, liver-limited HCC, locoregional therapies (LRTs) have been the mainstay of treatment and have achieved success in downstaging or bridging patients to undergo surgery. However, the use of LRT in patients with larger (≥ 5 cm) or multiple and infiltrative hepatic tumors is associated with limited success, but it is used nonetheless in large part due to ineffective systemic therapies.[6] In addition, there have been recent attempts to redefine the treatment landscape of unresectable or intermediate-stage HCC. For example, Kudo et al[7] attempted to define a population of transarterial chemoembolization (TACE) failure or refractoriness that would be eligible for systemic treatment.

With recent advances in systemic therapies, redefining the management of unresectable disease may further improve outcomes for patients with HCC. In this review, we highlight the current commonly used locoregional therapeutic strategies for unresectable HCC and the emerging systemic strategies that have shown considerable efficacy. We propose that, with the development of better systemic strategies, it is time to move these strategies earlier in the treatment course of patients with intermediate-stage unresectable HCC.