Editor's note: Hepatocellular Carcinoma (HCC) is a common malignant tumor that seriously threatens human health. In recent years, with the great progress of systematic treatment, the survival of patients with advanced HCC has been significantly improved. With the gradual deepening of clinical research, the application of systemic therapy to patients with Intermediate-Stage HCC has also become a hot topic in this field. At the 32nd annual meeting of the Asia-Pacific Association for Liver Research (APASL), the journal invited Professor Masatoshi Kudo of the Medical College of Jindai University in Japan to conduct an exclusive interview, and asked him to share with us the current treatment status of patients with Intermediate-Stage HCC in Japan and the emerging treatment strategies, and how to choose the best treatment strategy for patients with Intermediate-Stage HCC, what are the unmet needs for clinical treatment of liver cancer at present, and the treatment concept for future development, etc.
IH：First of all, would you please share the current treatment status of patients with Intermediate-Stage HCC in Japan ?
Dr Kudo: In the past, TACE has been standard-of-care for the treatment of intermediate-stage HCC. However, recently in Japan, the combination of systemic therapy and TACE became standard-of-care. The development of very effective drugs changed the treatment strategy for intermediate-stage HCC. Of note, lenvatinib had a very high response rate in clinical trials - 40.6% by mRECIST. Also, it is very well known that a vascular endothelial growth factor (VEGF) inhibitor normalizes the tumor vessels so upfront lenvatinib can improve TACE efficacy. Even in cases of resistant tumors, such as the confluent multi nodular type or poorly differentiated HCC, upfront lenvatinib can improve TACE efficacy. That is called lenvatinib-TACE (LEN-TACE) sequential therapy. LEN-TACE sequential therapy can prolong overall survival in intermediate-stage HCC. Another important systemic therapy is combination immunotherapy - atezolizumab plus bevacizumab (Atezo/Bev), an anti-PD1 antibody plus an anti-VEGF agent. The response rate with Atezo/Bev in intermediate-stage HCC is about 44% per RECIST v1.1. That is very high, and tumor shrinkage can occur. After tumor shrinkage on Atezo/Bev, intermediate-stage HCC can be curatively treated by ablation or resection. So conversion therapy is possible. Even if tumor shrinkage is not obtained, in stable disease, progressive disease (PD), partial response (PR) and complete response (CR), TACE can achieve tumor mass reduction and also release tumor antigen so the atezolizumab plus bevacizumab followed by TACE can achieve a complete response, and sometimes drug-free status. The cancer-free drug-free status is very close to pathological complete response, so a real cure is obtained in intermediate-stage HCC. Those two treatment strategies are very novel approaches in Japan.
IH：In order to further improve the clinical efficacy and prognosis of patients with Intermediate-Stage HCC, what new treatment strategies have emerged at present? How do you think we can choose the best treatment strategy for patients?
Dr Kudo: As I mentioned for the previous question, lenvatinib-TACE sequential therapy and Atezo/Bev followed by curative conversion is the novel treatment option for intermediate-stage HCC. How do we select the treatment strategy for LEN-TACE, Atezo/Bev and conversion therapy (called ABC conversion therapy)? For the relative early intermediate stage, such as up-to-7 in criteria patients, low tumor burden or simple nodular type HCC, these are candidates for LEN-TACE sequential therapy. TACE alone is not so effective, but sequential therapy can achieve complete response, sometime drug-free. In that sense, for early intermediate-stage, maybe we should select LEN-TACE sequential therapy. For late intermediate-stage, such as high tumor burden exceeding up-to-7 criteria, those patients may get atezolizumab plus bevacizumab upfront, followed by selective TACE can achieve a complete response or prolong overall survival. Also upfront Atezo/Bev can sometimes achieve curative conversion with resection or ablation. So the selection of the treatment strategy would LEN-TACE in early intermediate disease, and in late intermediate disease, Atezo/Bev followed by curative conversion.
IH：With the vigorous development of multidisciplinary treatment of liver cancer, do you think the treatment of patients with medium-term liver cancer is still based on surgery and supplemented by other treatments? Or is it possible that the traditional surgical led treatment concept will change?
Dr Kudo: In intermediate-stage HCC, un-resectable HCC can be changed to resectable HCC by upfront systemic therapy using lenvatinib or Atezo/Bev. Of course, surgical resection is the most important curative treatment, and ablation as well. But in our experience, upfront Atezo/Bev followed by LEN-TACE can achieve complete response without resection or ablation. In that sense, not only surgical resection and ablation and TACE, but LEN-TACE and Atezo/Bev can be combined. Upfront Atezo/Bev followed by LEN-TACE can achieve a complete response. This is what we call ABC Sandwich therapy - Atezo/Bev followed by TACE, then Atezo/Bev is continued. TACE is sandwiched by Atezo/Bev. Those sequential therapies can achieve a complete response. In these cases, there may be no viable tumor in the resected specimen, meaning resection is sometimes not necessary. In that sense, the treatment paradigm is changing, not only for surgery, but also ABC/TACE or ABC/LEN-TACE therapy can achieve a complete response that is drug-free or pathological CR. The treatment paradigm is changing
IH：In order to realize the individualized multidisciplinary comprehensive treatment strategy, what unmet needs do you think we have at present? What further research will we do next?
Dr Kudo: An unmet need is still present with the response rate to Atezo/Bev not being enough - 44% in the intermediate stage. I think the response rate can be higher, even 50% to 70% in the intermediate stage. That way, more patients could achieve a complete response or real cure. What further research will we do next? Maybe other combinations, such as not only Atezo/Bev, but also triple therapy like PD-1/PD-L1 antibody plus CTLA4 antibody plus TKI (such as lenvatinib). Triple therapy may be effective. Phase III trials are now ongoing with PD-L1s plus anti-VEGFs (bevacizumab), as well as PD-L1 antibody plus CTLA4 antibody plus lenvatinib. Theoretically, that is the strongest combination, and we are now conducting a global study. We will conduct and finish this trial, and this will change the treatment strategy for intermediate-stage HCC.
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