Professor Qin Shukui: Consolidating the "Great Power Status" of Liver Cancer Diagnosis and Treatment and Research with "Chinese Wisdom"

BOC/BOA 2024 Preview丨Professor Qin Shukui: Strengthening the "Great Power Status" of Liver Cancer Diagnosis and Treatment and Research with "Chinese Wisdom"

Editor's note: In recent years, there have been two significant changes in the field of liver cancer. On the one hand, with the development of treatment technology, the prognosis of liver cancer patients has improved significantly, and the title of "king of cancer" has gradually faded. On the other hand, the rapid development of liver cancer diagnosis and treatment and research in China has contributed a series of "Chinese solutions" and "Chinese wisdom" for liver cancer prevention and treatment to the world. On the eve of the "2024 China Annual Progress Symposium on Clinical Oncology (BOC) and Best of ASCO 2024 China" conference, Tumor Outlook interviewed Professor Qin Shukui, a well-known clinical oncology expert, from Nanjing Tianyinshan Hospital affiliated to China Pharmaceutical University, briefly reviewing the achievements of liver cancer prevention and treatment research in mainland China and sharing the latest progress in systemic treatment of liver cancer.

Professor Qin Shukui said, "The treatment of malignant tumors is progressing with each passing day. The treatment of primary liver cancer has entered a new era dominated by immunotherapy. At this BOC/BOA conference, it is worth looking forward to the learning and sharing of new research results on target-free and double-free combination therapy for liver cancer. 2024 BOC/BOA, meet you in Guangzhou, see you or leave! ”

From "Follower" to "Leader"

China has made remarkable achievements in the diagnosis and treatment and research of liver cancer

Tumor Outlook: The mainland is a "big country for liver cancer" in the world, but has the innovative research on the treatment of liver cancer in the mainland also reached the "level of a big country"? What challenges do you think still exists in the clinical diagnosis and treatment and research of liver cancer in mainland China?

Prof. Qin Shukui: Primary liver cancer, mainly hepatocellular carcinoma, is one of the most common malignant tumors in the world, especially in Asia and China. There are many factors associated with the development of liver cancer, including viral hepatitis infection, drinking water pollution (blue-green algae toxins), aflatoxin, alcohol abuse and smoking. In recent years, the incidence of liver cancer associated with non-alcoholic liver disease, such as fatty liver, has also increased. The continent has a population of more than 1.4 billion, accounting for less than 20% of the world's total population; However, the incidence and mortality of liver cancer in mainland China have reached more than 40% of the world's total, resulting in a serious disease burden. In order to achieve the goals of the Healthy China 2030 Plan, we need to pay attention to the diagnosis and treatment and research of liver cancer. Compared with European and American countries, the occurrence and development of liver cancer in mainland China are quite different and highly heterogeneous, which also requires us to blaze a trail with "Chinese characteristics" in the diagnosis and treatment and research of liver cancer. While actively learning from the advanced experience and diagnosis and treatment techniques of European and American countries, we should also formulate a plan that is more in line with the needs of practice in combination with the national conditions and the characteristics of patients in mainland China, so as to avoid rigid copying.

Over the years, under the leadership and guidance of the older generation of experts such as Academician Wu Mengchao, Academician Tang Zhaoyou and Academician Sun Yan, and through the joint efforts of multidisciplinary experts in hepatobiliary surgery, medical oncology, interventional medicine, hepatology, etc., the diagnosis and treatment and research of liver cancer in mainland China have made remarkable progress.

In the field of liver surgery, a group of experts such as Fan Jia, Dong Jiahong, Zheng Shusen, Wang Xuehao, Chen Xiaoping, Shen Feng, Zhou Jian, and other experts have made outstanding achievements in the development of new surgical technologies, surgical innovation, and even clinical, basic and translational research on liver cancer.

In the field of interventional therapy, although transarterial chemoembolization (TACE) and other technologies were first carried out in Japan and other countries, interventional experts in mainland China have done a lot of work on this basis, and Academician Teng Gaojun, Professor Li Huai and Professor Wang Jianhua have rich practical experience and active exploration, especially the interventional team of the Cancer Center of Sun Yat-sen University in Guangzhou has achieved gratifying results in the treatment of liver cancer using hepatic arterial continuous perfusion chemotherapy (HAIC).

In the field of medical oncology, our research on new drugs and systemic therapies was relatively weak in the past, but since 2000, we have actively participated in international multi-center clinical trials, and have now entered the fast lane of development. According to my incomplete statistics, the NMPA has approved 15 new drugs/combination regimens for the first- or second-line treatment of liver cancer, and the vast majority of new drug registration trials have the active participation of Chinese expert teams. In recent years, a number of new drugs/regimens that originated in China have been approved for marketing into clinical practice in liver cancer through rigorous clinical trials, including small molecule tyrosine kinase inhibitors (TKIs) such as donafenib and apatinib, immune checkpoint inhibitors (ICIs) such as camrelizumab, sintilimab and tislelizumab, and systemic chemotherapy regimens such as oxaliplatin-containing FOLFOX4. In addition, the combination of traditional Chinese and Western medicine in the treatment of liver cancer also has obvious characteristics, including modern Chinese medicine such as acoladine, elemene and Tongguan vine preparation (Xiaomao Ping) are also widely used in clinical practice. With the support and help of a group of hepatologists such as Jia Jidong, Wei Lai, Hou Jinlin and Chen Chengwei, we pay more attention to the management of underlying liver diseases, which is of great significance for the treatment of liver cancer.

In short, our country has made remarkable progress in the diagnosis, treatment and research of liver cancer, and has gradually grown from a "follower" and "trickster" in the international research team to a "leader" and "trendsetter". These achievements are due to the great attention paid by our party and the state to the prevention and treatment of liver cancer, and the strong support of relevant departments such as the National Health Commission, the State Food and Drug Administration, and the Ministry of Science and Technology. At the same time, I would like to express my heartfelt thanks to the older generation of experts for their guidance and guidance to young and middle-aged medical staff. However, we must also be soberly aware that compared with lung cancer and breast cancer, there is still a certain gap in the research and development of innovative drugs for liver cancer. Compared with international counterparts, there are also many things to learn and learn from. Therefore, we must maintain a modest and cautious attitude, guard against arrogance and rashness, and make unremitting efforts to overcome liver cancer as soon as possible and make more contributions to the global fight against cancer. In the future, we need to continue to increase investment in scientific research, strengthen international cooperation and exchanges, and promote new breakthroughs in the diagnosis, treatment and research of liver cancer. At the same time, we will also pay attention to the actual needs of liver cancer patients, strive to improve the early diagnosis and early treatment rate of liver cancer, reduce the mortality rate of liver cancer, bring better survival benefits and quality of life to patients, and contribute to the realization of the great blueprint of "Healthy China".

Based on the national conditions, cohesion

Explore the prevention and treatment of liver cancer with "Chinese characteristics".

Tumor Outlook: You have just introduced some important achievements in the field of liver cancer in mainland China, can you talk about what achievements with "Chinese characteristics" we have made in the prevention and treatment of liver cancer?

Professor Qin Shukui: The prevention of liver cancer in mainland China has very distinct "Chinese characteristics", and a relatively complete primary to tertiary prevention system has been formulated from public health to clinical medicine, especially the primary prevention of liver cancer can be summarized as the seven-character policy of "water improvement, mildew prevention, and vaccination".

"Water improvement" is because drinking water pollution caused by blue-green algal toxins in wells and rivers is one of the risk factors for the occurrence and development of liver cancer, and blue-green algal toxin pollution can be reduced through measures such as village-to-village tap water projects and drinking water quality optimization.

"Mold prevention" is to prevent food mildew through extensive health science popularization and improve grain storage technology, so as to reduce the incidence of liver cancer caused by aflatoxin.

In terms of "vaccines", the country has included hepatitis B vaccine in the immunization program in 2002, and increased immunization of newborns, cooks and other special occupational groups. At present, the carrier rate of hepatitis B surface antigen in mainland China has dropped to about 8%, and that of children under 10 years old has been reduced to less than 5%, effectively reducing the occurrence and development of viral hepatitis B and related liver cancer.

On the other hand, we have explored and established a set of relatively complete standards for liver cancer surveillance, screening, and diagnosis and treatment. For example, as early as the 1970s, in Qidong, Jiangsu Province and other areas with a high incidence of liver cancer, field investigations of alpha-fetoprotein (AFP) began to be conducted, so as to determine that it was used as a marker for liver cancer screening in mainland China. In order to improve the standardized diagnosis and treatment of liver cancer, the National Health Commission has promulgated several editions of the Standard for the Diagnosis and Treatment of Primary Liver Cancer, and the Chinese Society of Clinical Oncology (CSCO) also updates the Guidelines for the Diagnosis and Treatment of CSCO Primary Liver Cancer every two years. These screening strategies and diagnosis and treatment standards have condensed the collective wisdom of multidisciplinary physicians such as public health, hepatobiliary surgery, medical oncology, radiotherapy, interventional medicine, hepatology, and integrated traditional Chinese and Western medicine, and have played a huge role in improving the level of early diagnosis and early treatment of liver cancer in mainland China.

As mentioned above, we have made remarkable achievements in the medical treatment of liver cancer, but the early years of research have been full of blue threads. In 2006, under the guidance of Academician Sun Yan, we co-sponsored the international multicenter EACH study in the Asia-Pacific region, which confirmed the efficacy and safety of oxaliplatin-containing FOLFOX4 regimens compared with doxorubicin monotherapy for advanced hepatocellular carcinoma. This regimen has been widely recognized internationally and is recommended as a commonly used systemic therapy in Asia (China, Japan, and South Korea, etc.). In recent years, we have also made many achievements in the R&D and clinical trials of new drugs such as molecularly targeted drugs and immunity, including a new generation of TKIs donafenib, apatinib, and camrelizumab and other anti-PD-1/L1 immune checkpoint inhibitors, among which the "double Ai" combination of target-immune combination (apatinib combined with camrelizumab) has become one of the standard regimens for first-line treatment, and has achieved a median overall survival (mOS) of 23.8 months, which is obvious to all peers in the world.

Chinese wisdom, Chinese solutions

Promote the adjuvant therapy of liver cancer into the era of immunity

Oncology Outlook: In the early and mid-stage treatment of liver cancer, you published the global multicenter IMbrave050 study in The Lancet as the first author and chair of the Global Scientific Steering Committee. Can you share with us about the progress of your research?

Prof. Qin Shukui: Last year, we published two Phase 3 clinical studies in The Lancet, namely the CARES-310 study of the combination of "double Ai" for the first-line treatment of advanced stage, and the IMbrave050 study of the "T+A" regimen (atezolizumab + bevacizumab) for the postoperative adjuvant treatment of early- to medium-to-high-risk liver cancer. The latter has opened the door to adjuvant immunotherapy for liver cancer, which is expected to promote the emergence of a series of research results.

The IMbrave050 study is the world's first phase 3 clinical trial to report interim positive results of adjuvant immunotherapy for liver cancer, which is a milestone in the global liver cancer treatment journey, and Professor Pierce Chow and I are the co-chairs of the global scientific steering committee of the study, and 37 centers in mainland China are actively participating in it, contributing a lot of "Chinese wisdom" and "Chinese data". The results of the interim analysis showed that "T+A" significantly improved recurrence-free survival compared with active surveillance (RFS: HR 0.72, P=0.012). However, after the sponsor announced the results of the first interim analysis early last year, many patients randomized to the active monitoring group requested to switch to "T+A" adjuvant therapy, which will bring great interference and adverse effects to the final results, which is an unanticipated problem in the initial study and reflects the challenge of adjuvant therapy research for liver cancer.

On the other hand, there are some potential "Chinese protocols" for adjuvant immunotherapy for liver cancer. For example, the phase 2 study of sintilimab monotherapy adjuvant therapy for liver cancer led by Professor Cheng Shuqun also obtained positive results and reduced the risk of recurrence (HR 0.534 for PFS, P=0.002), and the related paper has been published in the journal Nature Medicine. It is foreseeable that more studies on adjuvant immunotherapy for liver cancer will be carried out in the future. The pivotal phase 3 study of "Shuangai Combination" adjuvant therapy co-led by Academician Fan Jia and I has also completed patient recruitment, and we look forward to achieving positive results and adding new treatment options for liver cancer patients.

At present, molecularly targeted drugs, immune checkpoint inhibitors, and oxaliplatin-containing systemic chemotherapy are mainly used for the systemic treatment of advanced liver cancer. As efficacy improves, we hope to be able to move the threshold forward, i.e., to allow these new therapies/regimens to work in neoadjuvant, adjuvant and perioperative therapies to increase the patient's chance of cure. Surgical and interventional experts in the field of liver cancer in mainland China have and are conducting a lot of research and exploration, such as increasing the number of patients who have been converted to surgery through hepatic artery intervention and systemic therapy, and exploring different adjuvant regimens to reduce the risk of recurrence. Academician Fan Jia has been actively exploring mechanisms such as omics evolution and immune regulation of liver cancer in basic and translational research of liver cancer, providing a basis for optimizing targeted and immunotherapy for liver cancer. Academician Dong Jiahong has made systematic explorations in the paradigm and technical system of precision liver surgery, and actively carried out yttrium-90 resin microspheres for the treatment of liver cancer. In addition, the above-mentioned liver disease experts are also actively exploring more reasonable antiviral treatment regimens, more accurate liver cancer risk assessment models, and more feasible liver cancer surveillance programs, hoping to block the occurrence and progression of liver cancer. We medical oncologists need to learn from these experts seriously, and the combination of multidisciplinary and multi-means will also be the characteristics of early comprehensive treatment of liver cancer in China.

Keep moving forward

Break through the bottleneck of the benefit of advanced liver cancer treatment

Oncology Perspectives: In the field of advanced liver cancer, the international study of CARES-310, which you lead, has been published in The Lancet, and the final OS results were further reported at the just-concluded 2024 ASCO Congress. Can you tell us about the current status of this research and immunotherapy for liver cancer? How do you think that the original research protocol in China affects clinical practice?

Prof. Qin Shukui: In the past decade, breakthroughs have been made in the use of immune checkpoint inhibitors in a variety of solid tumors, bringing extensive changes to the strategy and landscape of anti-tumor treatment. The liver is a blood-rich immune organ, rich in Kupffer cells, macrophages and lymphocytes, which lays the foundation for immunotherapy, so endless progress has been made in the field of liver cancer, including a variety of new drugs and protocols original in China. From last year to this year, there have been two phase 3 clinical studies for the first-line treatment of liver cancer, which have attracted great attention from the global academic community.

The results of the interim analysis of the CARES-310 study, which was published last year in the world's top academic journal The Lancet, have demonstrated that the combination can significantly improve median progression-free survival (mPFS, HR 0.52, P<0.0001) and mOS (HR 0.62, P<0.0001). At ASCO 2024 in June this year, we further updated our final analysis of the OS, which reached 23.8 months of mOS. This is the longest mOS obtained in the phase 3 clinical trial for the first-line treatment of liver cancer so far, which has attracted great attention and praise from the global medical community. It is very commendable that this program can achieve such results, and it has extended the mOS of advanced liver cancer from about 6 months in the past to nearly 2 years, which is comparable to the efficacy of lung cancer, breast cancer and gastric cancer. This is an original protocol entirely from China, and Chinese researchers and national pharmaceutical companies have worked together to overcome all kinds of difficulties, carefully designed, and strictly controlled to achieve the expected results, and bring such exciting innovations and treatment options to liver cancer patients in China and around the world.

Another international study, CheckMate-9DW, which is also the focus of the HCC field, was also reported at this year's ASCO Congress, and I myself participated as a member of the Global Scientific Committee (SC) and a Leading PI in China. Prior to this, the HIMALAYA study has demonstrated the efficacy and safety of the double-free first-line treatment of liver cancer, namely the "STRIDE regimen"; The "Y+O" dual-immune first-line treatment in the CheckMate-9DW study also achieved positive results, with an mOS of up to 23.7 months and a significant reduction in mortality risk of 21% compared with the control group (HR 0.79, P=0.018), thus further consolidating the position of first-line dual-immune therapy for liver cancer.

The first-line treatment of advanced liver cancer is still emerging, and domestic pharmaceutical companies have recently disclosed that the phase 3 study of toripalimab combined with bevacizumab for first-line treatment has also obtained positive results, and the data will be shared at major academic conferences in the future. From actively participating in and leading global multi-center research initiated by international pharmaceutical companies, to actively participating in and organizing international and domestic multi-center research initiated by national pharmaceutical companies, Chinese scholars have continuously achieved fruitful results in the field of clinical research of liver cancer drugs. This is inseparable from the full cooperation of pharmacology, biostatistics, clinical monitoring, coordination and management teams, as well as the trust and cooperation of the sponsor, so as to show more China's strength and wisdom to the world.

However, we must not rest on our laurels for the present. The unavoidable problem is that today's first-line drug treatment for liver cancer seems to have reached a "bottleneck period", and it is difficult to break through the median overall survival of 24 months and the objective response rate of about 30%. In order to further break through the bottleneck, it is necessary to optimize the current target-immune therapy or develop more drugs with new mechanisms. As mentioned above, Fan Jia, Academician Dong Jiahong, Shen Feng and Professor Zhou Jian have made many explorations in basic and translational research and even clinical trials of liver cancer, setting an example for us. It is expected that with the concerted efforts of colleagues across the country, more and better innovative therapeutic drugs or solutions can be promoted in clinical practice to benefit more liver cancer patients.

Professor Qin Shukui

Academic Advisor and Chief Physician of the First Affiliated Hospital of China Pharmaceutical University (Nanjing Tianyinshan Hospital).

Editor-in-chief of the Journal of Clinical Oncology, a national statistical source journal

Professor and doctoral supervisor of China Pharmaceutical University, Nanjing Medical University and Nanjing University of Traditional Chinese Medicine

He is engaged in the clinical diagnosis and treatment of tumors and research, and is a diagnosis expert of the Central Health Commission

He is also the executive director of the Asian Federation of Clinical Oncology (FACO), the International Society for Immuno-Oncology (SITC) and the Asian Society of Clinical Oncology (ACOS).

Vice President of the Chinese Society of Clinical Oncology (CSCO).

Chairman of the Board of Supervisors of Beijing CSCO Foundation

He is a core expert of the Hematology and Oncology Drug Advisory Committee of the State Food and Drug Administration

Chairman of the Expert Committee on Oncology Capacity Building and Continuing Education of the National Health Commission

He is the president-elect of Jiangsu Anti-Cancer Association and other academic positions