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In the warm spring season, there is a grand event, and guests are welcomed at the foot of Baiyun Mountain. Recently, the "2024 Greater Bay Area International Forum on Liver Disease and Viral Hepatitis Eradication Conference" was successfully held in Guangzhou! Professor Yang Yongping of the Fifth Medical Center of the General Hospital of the Chinese People's Liberation Army gave an academic sharing on "Hepatocellular Carcinoma Treatment Dilemma and Solution Strategy: Beyond the Known Frontier", and the hepatobiliary photographic platform/liver cancer online specially compiled the essence into a text for clinicians' reference.
01
Epidemiology of liver cancer in China[1-3]
Primary liver cancer is currently the fifth most common malignant tumor and the second leading cause of cancer mortality in mainland China. In 2020, there were 410,000 new cases of liver cancer in China, accounting for 45.3% of the world's new liver cancer cases. There were 391,000 deaths, accounting for 47.1% of global liver cancer deaths. China ranks first in the world in terms of the number of cases and deaths from liver cancer, and by 2040, the number of new cases and deaths of liver cancer in mainland China will increase by 55%.
Overall, 70% of new liver cancer patients in China are in the middle and advanced stages. In terms of survival rate, the 5-year relative survival rate of Chinese cancer patients showed a significant increasing trend, from 30.9% in 2003-2005 to 40.5% in 2012-2015, but the 5-year relative survival rate of liver cancer only increased from 10.1% to 12.1%, which was a slow improvement.
02
Causative factors of liver cancer
Many factors can contribute to the occurrence of liver cancer, such as viral infection, environmental/lifestyle factors, self-diseases (diabetes, obesity), and genetic factors (such as autoimmune hepatitis) [4].
Among them, viral infections are the most important factor. Globally, more than 70% of liver cancers occur in relation to viral infections. In the mainland, HBV infection is a major risk factor; In Japan and East Asia, HCV infection is a major risk factor. In Africa and East Asia, liver cancer is mainly due to aflatoxin exposure. At the same time, environmental/lifestyle factors, such as smoking and alcohol abuse, are the main risk factors in areas with low incidence of liver cancer.
03
Molecular targeting and immunotherapy have profoundly changed
The whole process management pattern of liver cancer
At present, a number of molecularly targeted drugs and immune checkpoint inhibitors have been approved by the FDA/NMPA, and there are several phase III studies that have not yet been approved but have obtained positive results, thus driving a huge change in the whole process management landscape of liver cancer.
As we all know, the tumor microenvironment undergoes immunosuppressive changes with the development of the disease, and theoretically, the tumor microenvironment in the early stage of the disease is more conducive to T cell infiltration and killing tumor cells. Thus, the earlier immunotherapy is administered, the greater the benefit may be greater [5-6].
At present, immune checkpoint inhibitors are used in the postoperative adjuvant therapy of liver cancer and preoperative neoadjuvant therapy for liver cancer.
Studies [7] have shown that elevated PD-L1 expression is significantly associated with a high risk of postoperative recurrence. High immune scores were associated with significantly lower recurrence rates and longer recurrence-free survival (RFS) in HCC. Another study [8] confirmed that early recurrent hepatocellular carcinoma cells up-regulated the expression of CD47, PD-L1, CTLA-4 and other immune escape molecules, inhibited the ability of dendritic cells to activate CD8+ T cells, and ICIs could relieve immunosuppression, induce necrosis of residual satellite lesions in the liver, and reduce postoperative recurrence.
After radical treatment for liver cancer, active postoperative adjuvant therapy is recommended if the following 6 conditions exist:
1) Cancer cells were occasionally found at the incision edge under the microscope in the postoperative pathology report;
2) Vascular cancer thrombus was found under the microscope in the postoperative pathology report;
3) There was invasion of the membrane in the postoperative pathology report;
4) Postoperative pathological report with nerve or lymph node invasion;
5) Postoperative pathological report as grade 3 or 4 tumor;
6)有轻微大血管侵犯Vp1/Vp2。
The IMbrave050 study (atezolizumab in combination with bevacizumab, T+A) is the first Phase III clinical study in the world to achieve a positive primary endpoint for adjuvant therapy for postoperative hepatocellular carcinoma (HCC). Results from the study [9] showed that adjuvant T+A therapy improved RFS compared with active surveillance in patients at high risk of HCC recurrence after radical resection or ablation (HR 0.72, 95% CI: 0.56-0.93; P=0.0120).
At the same time, other clinical studies of adjuvant immunotherapy after surgery for liver cancer are also being explored, and there are currently a number of large-scale phase III studies. Molecularly targeted and immunotherapy has opened a new chapter in the systemic treatment of advanced liver cancer.
Conversion therapy is one of the ways to achieve radical resection and long-term survival for patients with advanced liver cancer, and for potentially resectable liver cancer, it is recommended to adopt a multimodal and high-intensity anti-tumor therapy strategy to promote the transformation, while taking into account the safety and quality of life of treatment [10].
At present, the new strategy of surgery-based conversion therapy for locally advanced/advanced HCC has become the focus of clinical attention, and the release of consensus related to conversion therapy for liver cancer such as the Chinese Expert Consensus on Conversion Therapy for Liver Cancer (2021 Edition) provides an important reference for the transformation therapy of liver cancer.
Professor Lu Shichun's team conducted a single-arm phase II trial of lenvatinib combined with anti-PD-1 antibody conversion therapy for unresectable intermediate and advanced HCC: [11]. The study included 56 eligible enrolled patients, of whom 53 (94.6%) had large vascular invasion and 16 (28.6%) had extrahepatic metastases, with a median follow-up of 23.5 months.
The conversion success rate in the study was 55.4% (31/56). The ORRs were 53.6% (mRECIST) and 44.6% (RECIST 1.1), respectively. mPFS was 8.9m and mOS was 23.9m. Among the 31 patients who were successfully transformed, 21 patients underwent surgery, and the R0 resection rate was 85.7%, the pathological complete response rate was 38.1%, and the 12-month RFS rate was 47.6%. ≥Grade 3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis showed that CD8+ T cells were significantly enriched in responders compared with non-responders (p=0.03).
The results of this study confirm that the combination of lenvatinib and PD-1 inhibitors is well tolerated and effective in patients with unresectable intermediate and advanced HCC, and that pre-existing CD8+ T cells are biomarkers of response to this treatment regimen.
04
Immunotherapy combined with topical therapy changes
Treatment pattern for mid-to-advanced HCC
Local treatment of HCC can shape tumor immunity by altering the composition of the tumor microenvironment. Hyperthermia or local cryoablation through percutaneous local ablation techniques can cause tumor cell necrosis to release tumor antigens, which can promote dendritic cells to enter the microenvironment and activate. This effect can be exploited to transform an immunosuppressive microenvironment that is unfavorable for checkpoint inhibitor therapy into an environment conducive to immune support, potentially making systemic therapy more effective [12-13].
Local ablation treatments for liver cancer include radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation (nanoknife), each of which has its own advantages and limitations [14], and should be reasonably selected in clinical practice.
Principles of cryoablation [15]:
■Ice crystal formation, cell dehydration and mechanical damage to tumor cells
■Blood embolism causes tumor tissue to die of hypoxia
■Reversible damage, causing apoptosis
■Freezing stimulates immune modulation and produces a waterfall ectopic tumor inhibition effect
Cryoablation and PD-1 antibodies have potential synergistic anti-tumor effects, and their combination therapy can bring benefits to HCC patients.
Case Study
The patient, a 45-year-old female, had a history of chronic hepatitis B and had been on entecavir antiviral therapy for 7 years.
The results of the re-examination on February 22, 2016 were normal; HBsAg, HBeAb and HBcAb were positive, and HBV DNA was negative. AFP 153.60ng/ml； Abdominal MRI showed that there were tumor lesions with a size and diameter of 4.62 cm in the S8 segment, peripheral enhancement in the arterial phase, obvious loss in the portal phase, cast cancer thrombus in the main trunk and right posterior branch of the portal vein, widening of the liver fissure, esophageal varices, and splenomegaly.
Diagnosis:
- Progressive primary HCC (portal trunk and right posterior branch cast cancer thrombus);
- Hepatitis cirrhosis type B compensated.
Treatment regimen: local cryoablation combined with PD-1 inhibitor (2mg/kg, w/time).
On February 28, 2016, cryoablation of S8 segment tumor lesions was performed, and on March 1, 2016, AFP was 121.70ng/ml, and the results of abdominal MRI reexamination are shown in the figure below, and PD-1 inhibitor 100mg (patient weight 53kg) was injected intravenously on March 4, 2016.
On August 9, AFP was 27.10ng/ml, and the results of abdominal MRI showed that the active lesion at the anterior edge of the lesion was enlarged, and the thrombotic activity of the main portal trunk and right posterior branch cancer disappeared. It was decided to perform cryoablation on the active lesion again on August 10.
On August 16, the AFP was 4.36ng/ml, and the results of abdominal MRI showed that the activity of the leading edge of the lesion was completely necrotic, and the thrombosis of the main portal trunk and right posterior branch cancer disappeared.
Follow-up MRI was performed on 16 August
The EMERALD-1 study [16] is a randomized, double-blind, placebo-controlled, multicenter, Phase III study evaluating the efficacy and safety of TACE (including conventional TACE and drug-loaded microsphere TACE) in combination with durvalumab + bevacizumab in patients with HCC. The results of the study showed that durvalumab + TACE + bevacizumab achieved both statistically and clinically significant improvement compared with TACE alone (median PFS: 15.0 versus 8.2 months), which marked the treatment of locally advanced HCC from the TACE era of nearly 30 years to the era of TACE combined immunization.
EMERALD-1 STUDY RESULTS
A prospective study of Airport Hospital, Tianjin Cancer Hospital, collected a total of 29 second-line or late-line HCC patients treated with cadonilimab (PD-1/CTLA-4 bispecific antibody) + regorafenib from October 2022 to February 2023, and highlighted the safety and tolerability of this regimen. The incidence of grade 3 TRAEs in the study was only 14 percent, and no grade 4 to 5 TRAEs were observed, suggesting that cadonilimab + regorafenib > the second line of HCC was well tolerated [17].
The ability of triple therapy to inhibit tumor progression in the long term was further demonstrated by data on time to progression (TTP), with TTP of 22.0 months in the moderate valumab + TACE + bevacizumab arm and 10.0 months in the TACE arm.
05
Combination therapy is the general trend
Systemic treatment of advanced HCC should focus on safety
Based on the success of the CheckMate 040 cohort 4 study, nivolumab (drug O) in combination with ipilimumab (drug Y) (PD-1+CTLA-4) has been approved for the second line of advanced HCC; Based on the success of the HIMALAYA study, durvalumab (D) + tremelimumab (T) (PD-L1 + CTLA-4) has become a new first-line treatment option for aHCC, and a variety of combination regimens have demonstrated the potential for HCC treatment.
In August 2023, JAMA Oncology published a review of "Systematic treatment of advanced HCC as recommended by critical evaluation guidelines" [18], recommending the use of recognized indicators such as the European Society of Oncology Clinical Benefit Scale (ESMO-MCBS)) to evaluate the clinical benefit of each drug in first- and second-line treatments. The ESMO-MCBS score ranges from 1 to 5, with a score of 4 or 5 indicating a clinically substantial benefit, 3 indicating moderate, and 1 or 2 indicating a low degree.
In the first-line treatment, T+A, sintilimab combined with bevacizumab obtained the highest score of 5, with substantial clinical benefit; camrelizumab plus apatinib was scored 4 points (one point was deducted due to safety concerns); Tsimumab plus durvalumab is worth 3 points.
In terms of security, T+A is used as a comparator. The risk of TRAEs in T+A is significantly reduced compared with camrelizumab + apatinib, sintilimab + IBI305 (bevacizumab analogue), and sorafenib, which is similar to that of tisimumab plus durvalumab.
In addition, when comparing > grade 3 severe TRAEs, camrelizumab + apatinib was significantly higher > the RR of grade 3 TRAEs compared with T+A (RR, 1.59, 95%CI: 1.25~2.03; P<0.001).
In a meta-analysis of first-line immunotherapy combinations, the investigators included four clinical trials with a total of 2397 patients comparing T+A, sintilimab plus IBI305, tisimumab plus durvalumab, camrelizumab plus apatinib with sorafenib. The results showed that compared with sorafenib, the mOs of patients was significantly prolonged in all four immunization regimens, but there was no significant difference in mOs between the first-line combination regimens.
In conclusion, there is no significant difference in mOS between the first-line combination regimens of HCC, but there may be differences in safety, which needs to be paid attention to clinically.
06
Patients with unresectable liver cancer with refractory ascites
A holistic, non-surgical, multidisciplinary approach should be adopted
Professor Yang Yongping pointed out that pre-emptive TIPS are recommended for patients with liver cancer with irrefractory ascites, human blood albumin level is not very low (>29g), normal bilirubin level, platelet level > 80,000, and basically normal coagulation function.
Case Study
The patient, a 60-year-old man with a long-term history of heavy drinking, developed low-grade fever, liver discomfort, and progressive abdominal distension in June 2017. Laboratory tests showed normal liver function, AFP 25360ng/ml, PLT 196x109/L.
Abdominal MRI showed that there were tumor lesions with a diameter of 4.62 cm in S8 segment, cast cancer thrombus in the main trunk of the portal vein and right posterior branch, widened liver fissure, esophageal varices, splenomegaly, and moderate or above ascites around the liver.
Diagnosis:
- Progressive primary HCC (portal trunk and right posterior branch cast cancer thrombus);
- Decompensated alcoholic cirrhosis.
Patient characteristics:
(1) After regular diuresis, ascites, and blood albumin supplementation for nearly 3 weeks, ascites did not decrease significantly, and progressive abdominal distension aggravated;
(2) the patient's portal cancer thrombus has developed to the lower cavity, which is the key to be solved at present;
(3) The reserve function of the patient's liver is better.
Holistic Treatment Plan:
- Do portal shunts;
- The application of multi-drug combination therapy centered on immune checkpoint inhibitors combined with sorafenib;
- Local ablation is done if necessary.
After initial treatment, the patient's ascites and abdominal distension disappeared, but the S8 lesion was progressing, and the AFP level was still high (AFP: 19860ng/ml).
Imaging results after initial treatment
Considering that the patient's ECOG PS: 0~1 and the liver reserve function was good, it was decided to perform local cryoablation therapy and liver biopsy at the same time.
On November 1, 2017, AFP was 286 ng/ml, and the treatment regimen was PD-1 inhibitor 3 mg/kg.w, intravenous infusion, once every two weeks, and sorafenib: 0.4, oral, twice daily.
How to deal with upper gastrointestinal bleeding after TKI treatment for advanced liver cancer to ensure that patients continue to receive target-immune therapy?
Since the advent of sorafenib, there have been more and more first-line treatment drugs for advanced liver cancer, and whether upper gastrointestinal bleeding in advanced liver cancer complicated with portal hypertension is still a contraindication to TIPS has become a hot topic of international debate.
Professor Yang Yongping's team compared the advantages and disadvantages of two prevention methods for variceal rebleeding in TKI-treated patients with advanced HCC, namely TIPS and endoscopy combined with β-receptor blockers. In the study [19], 106 patients with advanced HCC treated with TKIs were randomly assigned to receive TIPS (n=52) or endoscopic therapy in combination with β-blockers (n=54) for rebleeding prevention. The primary endpoint was variceal rebleeding.
During a median follow-up of 16 months, there were 14 patients in the endoscopic plus β-blocker group and 3 patients in the TIPS group with rebleeding p<0.001. Forty-nine patients died (38 patients were treated with endoscopy combined with β-blockers, and 11 patients were in the TIPS group, p<0.001). The overall survival rates at 6 months, 12 months, and 18 months were 95%, 81%, and 73%, respectively, in the TIPS group, and 35%, 21%, and 15% with endoscopic combination β-blocker therapy (p<0.001).
Eight patients treated with endoscopy combined with β-blockers received TIPS as salvage therapy, and two of them died. TKI was discontinued in 32 patients, including 24 patients treated with endoscopy combined with β-blockers and 8 patients in the TIPS group (p<0.001). No significant differences were observed between the two groups in terms of serious adverse events.
The results showed that in patients with advanced HCC who received TKI treatment and had variceal bleeding, TIPS could better prevent rebleeding, improve TKI treatment compliance, and prolong survival.
Can endoscopy be used for the secondary prevention of upper gastrointestinal bleeding in HCC?
Professor Yang Yongping said that endoscopic therapy for secondary prevention requires serial treatment, and serial therapy requires patients to continue fasting, which will cause poor tolerance of patients, and fasting requires discontinuation of TKI inhibitors, so that anti-tumor therapy is interrupted or delayed. In addition, multiple endoscopic treatments can produce new ascites, or worsen the original ascites, reduce the Child-Pugh score and stage, and lead to reduced TKI compliance, so endoscopy is not suitable for the secondary prevention of upper gastrointestinal bleeding in liver cancer portal hypertension.
07
The future direction of precision treatment of liver cancer
The future direction of precision treatment for liver cancer is as follows:
1. Continuous development of new therapeutics: therapeutic breakthroughs including proteolytic targeting chimeras (PROTACs), antibody drugs (ADCs) and mRNA vaccines;
2. Biomarker-driven clinical trials: Liver cancer patients can be stratified by considering the heterogeneity between tumors, so as to optimize resource allocation and improve the effectiveness of new methods;
3. Realize personalized treatment of liver cancer patients through functional experiments, and use liver cancer patient-derived tumor models (including PDXs, PDOs and explants) for functional testing such as drug screening.
08
summary
The perioperative treatment of HCC has become the focus of attention, the combination of target and immunity therapy is in the ascendant, and the combination of HCC targets needs to take into account safety in the era of precision tumor treatment, and bispecific antibodies provide more treatment options for HCC patients.
References Swipe up to read
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Prof. Yongping Yang
The Fifth Medical Center of the General Hospital of the Chinese People's Liberation Army
Chief Physician, Professor, Doctoral Supervisor
He is a silver star of science and technology and a recipient of special allowances from the State Council
Chairman of the Hepatology Committee of the Chinese Association of Research Hospitals
Member of the Expert Committee of the China Hepatitis Foundation
Vice Chairman of the Hepatology Committee of the Beijing Branch of the Chinese Medical Association
Vice Chairman of the Liver Disease Professional Committee of the Beijing Association of Integrative Medicine
Vice Chairman of Chinese Cryotherapy Association
Member of the Standing Committee of the All-Army Oncology Professional Committee
Member of the Standing Committee of the Chinese Infectious Diseases and Immunization Professional Committee
Leading the national "13th and 12th Five-Year Plan" major special projects, the "12th Five-Year Plan" key projects of the military and the key projects of military-civilian integration of the Beijing Municipal Science and Technology Commission; He has won 1 National Science and Technology Progress Award, 1 first prize of Beijing Science and Technology Progress Award, and 6 second prizes of Military Science and Technology Progress Award
Source: Liver Cancer Online