Immunotherapy First Versus Upfront Surgery in Liver Cancer

Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for approximately 80% of cases. It is also the sixth most common cancer in the United States and the fourth most common cause of cancer death.

In treating advanced liver cancer, immunotherapy is now among the main approaches, while surgery remains the only primary curative treatment for early-stage disease.

However, complete tumor removal with negative surgical margins may not be possible because of spread outside the liver, tumor involvement of major blood vessels, inadequate liver function and/or anatomical factors. These circumstances affect approximately 30% of patients with liver cancer, who are considered ineligible for surgery under current medical guidelines.

Most patients treated surgically also experience cancer recurrence within the first 5 years after surgery.

A New Era in Early-Stage Liver Cancer Treatment

Nakazawa and colleagues reported in Cancer Research Communications on August 15, 2024 that patients with high-risk localized hepatocellular carcinoma (HCC), including those who do not meet standard surgical eligibility criteria because their cancers have spread to surrounding tissue or extended into blood vessels, can receive preoperative immunotherapy and successfully undergo negative-margin resection, removing all cancerous tissue.

A negative-margin lesion indicates that the cancerous tissue has been completely removed surgically and that the surrounding healthy tissue margins are clear. This reduces the risk of local recurrence and generally increases the patient's chances of long-term survival.

Furthermore, patients receiving neoadjuvant immunotherapy for high-risk localized (liver-confined) HCC can achieve long-term outcomes similar to those undergoing upfront surgery. These findings suggest potential benefits of preoperative immunotherapy, particularly in high-risk localized liver cancer.

Study Design

Researchers retrospectively reviewed outcomes for 92 patients who underwent liver cancer surgery at Johns Hopkins Hospital between January 2017 and December 2023. Of these, 36 had received immune checkpoint inhibitor-based therapy under clinical trial protocols evaluating the feasibility and efficacy of preoperative immunotherapy. Before immunotherapy, 61% would not have qualified for surgery under conventional resection criteria.

Results

• Patients receiving neoadjuvant immune checkpoint inhibitors had higher-risk disease features than those undergoing upfront surgery. These included elevated serum alpha-fetoprotein, tumors larger than 5 cm (P = .001), portal vein invasion (P = .001) and multifocality (P < .001).
• Patients receiving neoadjuvant immunotherapy achieved negative-margin resection at rates similar to those undergoing upfront surgery (P = .47).
• They also had similar recurrence-free survival outcomes (median recurrence-free survival: 44.8 versus 49.3 months; P = .66).
• Among patients whose tumors had largely disappeared (70% or more), the immunotherapy group showed slightly better time without recurrence, although the difference was not significant.

Commentary

This study shows that our criteria for identifying suitable treatment candidates in liver cancer are too restrictive. The findings suggest systemic treatment may change approaches in early-stage as well as advanced disease. Today, some patients with high-risk liver cancer can achieve long-term survival through surgery after intensive systemic treatment.

Prospective clinical trials are needed to better understand the role preoperative immunotherapy could play in conventionally resectable and high-risk localized hepatocellular carcinoma.