Editor’s note:
Liver cancer has become the 6th most common and the 3rd leading cause of cancer deaths worldwide. For liver cancer patients, surgery is the preferred method to completely eliminate tumors and achieve long-term survival. However, the majority of liver cancer patients still face late diagnoses and low survival rates. In recent years, the systemic treatment of liver cancer has progressed rapidly, with new immunotherapies and targeted drugs emerging, promoting continuous innovation in liver cancer treatment concepts and schemes. From July 6-8, 2023, the 13th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2023) was grandly held in Seoul, South Korea. At the conference, Dr. Hanchong Toh from the National Cancer Centre Singapore shared the latest developments in immune adjuvant therapy for liver cancer.
Hepatology Digest: For patients with hepatocellular carcinoma that cannot be surgically removed or with portal vein tumor thrombus, surgery often poses risks. Can local treatments such as TACE and radiofrequency ablation significantly improve the survival of these patients?
Dr. Toh: Liver cancer patients with concurrent portal vein thrombosis typically have a poor prognosis, and achieving radical cure through surgery is very challenging. Nonetheless, surgeons from both China and other parts of Asia tend to advocate for aggressive surgical treatments. The question is: can we shrink the tumor as much as possible and clear the tumor thrombus before surgery? The answer is yes. Radiofrequency ablation is usually used for smaller tumors. It’s quite straightforward for tumors 3 cm or smaller. Preoperative TACE or transarterial radioembolization (TARE) can significantly reduce tumor size and clear visible tumor thrombi. However, with the rapid progress of systemic treatment for liver cancer in recent years, many promising new drugs have emerged, including immune checkpoint inhibitors represented by PD-1/PD-L1 inhibitors, which have performed impressively in clinical practice. An increasing number of patients are choosing systemic treatments before surgery to shrink the cancer, and this approach is gaining popularity.
Hepatology Digest: How do you evaluate the role of immune checkpoint inhibitors in neo-adjuvant therapy for liver cancer?
Dr. Toh: For locally advanced liver cancer that can still potentially be surgically removed, we opt for neo-adjuvant treatments. What is neo-adjuvant therapy? It involves systemic or local treatments to shrink the tumor before surgery, for technically resectable liver cancer patients with high-risk recurrence factors, in order to eliminate invisible microscopic lesions or increase the likelihood of negative surgical margins, thereby reducing postoperative recurrence. This means we need to create a tumor-free environment. Currently, we see an increasing number of clinical studies related to immune checkpoint inhibitors in this area. Whether it’s monotherapy with immune checkpoint inhibitors, combinations of them, or combinations with tyrosine kinase inhibitors (TKIs), we notice two distinct trends: better therapeutic responses in patients, with significant pathological responses in many; and surgeries becoming easier, potentially even improving long-term patient outcomes. In the future, we need large-scale clinical trials to prove this.
Hepatology Digest: How do you view the role of lenvatinib in neo-adjuvant therapy for liver cancer?
Dr. Toh: A clinical trial is currently underway exploring the role of multi-targeted tyrosine kinase inhibitors like lenvatinib in neo-adjuvant therapy for liver cancer. The primary endpoint of this study is achieving an R0 resection (meaning no cancer cells are found on the pathology margin). Compared to some TKIs, lenvatinib indeed has a fairly good objective response rate (ORR) and a very favorable progression-free survival rate (PFS). We need to wait for the data to mature to see if it can shrink the cancer enough for surgery, but it’s indeed a promising option.
Hepatology Digest: Combining targeted therapy and immunotherapy has been a hot direction in liver cancer clinical research in recent years. For unresectable liver cancer patients, how do you choose the neo-adjuvant treatment strategy? Is it immunotherapy, targeted therapy, or a combination?
Dr. Toh: Regarding the combination of immunotherapies like immune checkpoint inhibitors and targeted therapies as neo-adjuvant treatment for liver cancer, several large clinical studies are currently underway. One of them, led by Dr. Shukui Qin’s team from Nanjing, China, has been published. The results show that the combination of camrelizumab (a PD-1 monoclonal antibody) and apatinib (a VEGF receptor-targeted TKI) demonstrated good pathological responses. In this study, pathological analyses indicated that tumor necrosis is associated with better patient outcomes.
Another study from the MD Anderson Cancer Center in the U.S. also indicates that either nivolumab monotherapy or nivolumab combined with epilimumab can significantly reduce the surgical tumor size.
Furthermore, a study from Johns Hopkins University in the U.S. reveals that the combination of nivolumab and the oral TKI cabozantinib might even convert unresectable liver cancers into resectable ones. However, it’s essential to emphasize that all these studies involve fewer than 30 subjects and aren’t large-scale clinical research. Still, this early data suggests that combining targeted drugs with immunotherapies might provide clinical benefits for more liver cancer patients, potentially becoming a choice for neo-adjuvant treatment for liver cancer.
