Integrating Surgical and Systemic Approaches to HCC

An “explosion of therapies” over the last few years has enabled progess in the effective combination of medical therapies and surgical intervention for hepatocellular carcinoma (HCC), resulting in “relatively long overall survival,” Vatche G. Agopian, MD, said in his address to the International Society of Gastrointestinal Cancer meeting on October 13.

Dr Agopian is a professor of surgery and pharmacology and director of the Dumont-UCLA Liver Cancer Center at the David Geffen School of Medicine at UCLA in Los Angeles, California.

Among the important issues surrounding treatment of HCC are the role of neoadjuvant and adjuvant therapy among patients undergoing resection or ablation. While some previous studies of adjuvant therapy for patients with HCC demonstrated no improvement in survival following resection or ablation, the IMBrave-050 trial was an “exciting, positive study” of the efficacy of adjuvant therapy with atezolizumab plus bevacizumab for resectable HCC, he stated.

The combination of the PD-L1 checkpoint inhibitor atezolizumab and the VEGF inhibitor bevacizumab had previously demonstrated significant improvement in overall survival, progression-free survival, and overall response for unresectable HCC. The IMBrave-050 trial was designed to determine if the dual PD-L1/VEGF blockade might prove equally effective in reducing the recurrence of HCC among high-risk patients with resectable HCC. A presentation at the American Association for Cancer Research earlier this year revealed a recurrence-free survival rate of 78% among patients treated with the combination as adjuvant therapy vs 65% with active surveillance.

Neoadjuvant and perioperative therapy are thought to potentially improve surgical outcomes by affecting the immune component of the liver microenvironment and also by inhibiting the growth of micrometastases. In what Dr Agopian referred to as a “holy grail” study by Patel et al among patients with melanoma published in the New England Journal of Medicine, significantly improved survival was seen among patients with melanoma in the neoadjuvant arm. However, Dr Agopian noted, “It is important to point out that no studies are proving improvement of overall survival” although progression-free survival improvement has been seen, and studies are ongoing to determine if neoadjuvant therapy provides significant benefits in HCC.

Downstaging patients with more advanced liver cancer to enable resection or liver transplant requires the careful balancing of ablation therapies, systemic and locoregional treatment, and timing in the use of immunotherapies to mitigate complications. Dr Agopian provided a case study of a patient with a “well encapsulated tumor with some microvascular intrusion.” This patient received systemic lenvatinib, a tyrosine kinase inhibitor (TKI), which resulted in “a much more defined, nonviable tumor and showed incredible radiographic response.” When the patient underwent resection, “most of the tumor was dead,” he explained. At 14 months post-surgery, the patient is doing well.

The combination of lenvatinib plus the immune checkpoint inhibitor pembrolizumab “led to significantly longer progression-free survival and overall survival than chemotherapy,” marking it as a promising agent for treatment of HCC, according to research. Yet, Dr Agopian pointed out, the safety of using checkpoint inhibitors close to the time of liver transplant remains a concern. “The rate of rejection is not insignificant, at 30-40%,” he noted, among patients who receive these therapies following liver transplantation to protect against HCC recurrence.

It is also important to gauge carefully when to discontinue immunotherapy prior to liver transplant, Dr Agopian said. Discontinuing too soon can result in an advance of disease that could make the patient no longer eligible for transplant; waiting too long can increase the risk of post-transplant rejection.

Following downstaging, another question that may arise is whether patients with vascular invasion of tumors should be referred for transplant. Conceding that he does refer select patients, Dr Agopian concluded, “It can be tough to know how to choose the right patients. Some have well defined tumors, no microvascular invasion while others have less well-defined tumor and some microvascular invasion.

“Not all high-risk patients are the same.”