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Super practical, super new guide update, this article is sorted out!
On January 17, the official website of the National Health Commission released the latest version of the "Primary Liver Cancer Diagnosis and Treatment Specifications", which is updated again after 2019. Due to the emergence of many high-level evidence in the diagnosis, staging and treatment of domestic and extrinsic liver cancer that conform to the principles of evidence-based medicine, especially the research results adapted to China's national conditions, the National Health Commission entrusted the Chinese Medical Association to revise and update the "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)" in combination with the latest practice of clinical diagnosis and treatment and research of liver cancer.
Guideline update focus: Systemic antineoplastic therapy
The most important thing in this guideline update is systemic antineoplastic therapy.
First-line antineoplastic regimens include atenizumab plus bevacizumab, sindilizumab plus bevacizumab analogues (davus), and donafenib.
Clinical staging (CNLC) and treatment roadmap for liver cancer in China
The indications for systemic antineoplastic therapy are: (1) patients with CNLC STAGE III.a and III .b liver cancer; (2) patients with CNLC stage II .b liver cancer who are not suitable for surgical resection or TACE therapy; and (3) patients with liver cancer whose TACE treatment resistance or TACE treatment has failed.
01 First-line systemic anti-tumor treatment options
(1) Atenizumab combined with bevacizumab
Atenizumab plus bevacizumab is approved for use in patients with unresectable liver cancer who have not previously received systemic therapy (evidence level 2, recommendation A). The results of the IMbrave150 global multicenter Phase III study showed that the median survival time and progression free survival (PFS) in the atenizumab and bevacizumab group were significantly longer than those in the Sorafenib group, with a 34% lower risk of death and a 35% lower risk of disease progression. For the Chinese subpopulation, patients in the combination therapy group also had a clear clinical benefit, with a 47% lower risk of death and a 40% lower risk of disease progression compared with sorafenib.
(2) Sindili maclub combined with bevacizumab analogue (Dayoutong)
Sindilimab plus bevacizumab analogues (Dayoutong) has been approved in mainland China for first-line treatment of unresectable or metastatic liver cancer that has not previously received systemic antineoplastic therapy (evidence level 2, recommendation A). Orient32 The results of the National Multicenter Phase III study showed that the efficacy of sindilimab combined with bevacizumab analogues (Dayoutong) was significantly better than that of the sorafenib group, and the risk of death and the risk of disease progression decreased by 43% in the combination treatment group compared with the sorafenib group.
(3) Donafenib
Donafenib has been approved in mainland China for use in patients with unresectable liver cancer who have not previously received systemic antitumor therapy (evidence level 2, recommendation A). Compared with sorafenib, donafenib was able to significantly prolong median survival time and reduce the risk of death by 17%; the median PFS of the two groups of donatinic and sorafenib was similar, but the donafenib group had good safety and tolerability. The most common adverse reactions are hand-foot skin reactions, elevated aspartate aminotransferase, elevated total bilirubin, decreased platelets, and diarrhea.
(4) Lunvatinib
Lenvatinib is indicated in patients with advanced liver cancer of non-resectable liver function Child-Pugh class A (evidence level 1, recommendation A). Reflect Global Multicenter Clinical Phase III controlled study showed that the mid-term survival time was not inferior to sorafenib, and the study achieved a non-inferior efficacy endpoint [HR 0.92, 95% CI 0.79-1.06]. The median PFS in the renvatinib group was significantly better than that in the sorafenib group, with a 34% reduction in the risk of disease progression.
(5) Sorafenib
Sorafenib was the earliest molecularly targeted drug for antitumor therapy in the liver cancer system. Multiple clinical studies have shown that sorafenib has a certain survival benefit for patients with advanced liver cancer in different countries and regions and in different liver disease backgrounds (evidence level 1, recommendation A). Sorafenib can be used in patients with liver function Child-Pugh grade A or B, but the survival benefit is significant in patients with Child-Pugh Grade A compared with Child-Pugh Grade B of liver function.
(6) Systemic chemotherapy
The FOLFOX4 regimen is approved in mainland China for the first-line treatment of locally advanced and metastatic liver cancers that are not suitable for surgical resection or topical therapy (evidence level 2, recommendation A).
(7) Progression of other first-line treatments
- Carellizumab combined with apatinib Phase III clinical study (SHR-1210-III.-310)
- Phase III clinical study of lenvatinib combined with pambolizumab (LEAP 002)
- Phase I clinical study of lenvatinib combined with navuliyumab.b I (Study117)
- CS1003 (PD-1 monoclonal antibody) combined with rumpatinib Phase III clinical study (CS1003-305)
- Triprimumab combined with rumpatinib phase III clinical study
- Phase III clinical study of carellizumab combined with oxaliplatin-based systemic chemotherapy
- Phase III clinical study of duvalliumab combined with trimemizumab (HIMALAYA)
- Sindilimab combined with IBI310 (anti-CTLA-4 monoclonal antibody) Phase III clinical study
02 Second-line system antineoplastic treatment regimens
(1) Rigofenib
Regofenib is approved for use in patients with liver cancer who have previously received treatment with sorafenib (level of evidence 1, recommendation A).
(2) Apatinib
Apatinib mesylate is a small molecule targeted new drug independently developed in mainland China, which has been approved as a single drug for patients with advanced liver cancer who have failed or become intolerable after receiving at least one-line systemic anti-tumor therapy in the past (evidence level 2, recommendation A).
(3) Carellizumab
Carellizumab has been approved for the treatment of patients with advanced liver cancer who have previously received sorafenib and/or chemotherapy with oxaliplatin-containing systems (evidence level 4, recommendation B).
(4) Tirelizumab
Tirelizumab is approved for the treatment of patients with liver cancer who have undergone at least one systemic antitumor therapy (evidence level 4, recommendation B).
Guideline update focus: Exploring comprehensive surgically-based treatment strategies for advanced liver cancer
Another focus of this guideline update is to give the most important research direction in the field of liver cancer: to explore a new strategy for the comprehensive treatment of intermediate and advanced liver cancer based on surgery.
Based on data from previous large cases, overall survival after surgery for advanced and moderately advanced liver cancer (CNLC STAGE II.b, III.a, III.b) is not satisfactory, but surgical resection may benefit some patients in the absence of other effective treatments (evidence level 4, recommendation C). Combined with the latest advances in current systemic antineoplastic therapy, the effect of systemic antineoplastic therapy and/or topical therapy in controlling tumors may provide more possibilities for radical resection, reducing postoperative recurrence, and improving prognosis in patients with advanced liver cancer (evidence level 4, recommendation B). Therefore, the strategy of direct surgical resection in patients with intermediate and advanced liver cancer needs to be re-understood.
Conversion therapy, which converts unresectable liver cancer into resectable liver cancer, is one of the ways for patients with advanced liver cancer to achieve radical resection and long-term survival. For potentially resectable liver cancer, a multimodal, high-intensity antineoplastic therapy strategy is recommended to promote its transformation.
01 Translational therapy for tumors
(1) Systemic antitumor therapy: single or combined application of systemic antineoplastic therapy is one of the main ways of translational therapy for advanced liver cancer (evidence level 4, recommendation B). The depth, speed and duration of liver cancer remission, as well as organ-specific remission, are important factors influencing subsequent treatment decisions. The effects of different drug combinations on liver tissue and the safety of subsequent surgeries need to be explored more.
(2) Local treatment: local treatment including TACE (evidence level 3, recommendation B) and hepatic artery catheter continuous chemotherapy perfusion (evidence level 4, recommendation C) and other local treatment methods create potential surgical resection opportunities for patients with initially unresectable liver cancer, and can be translated into survival benefits. Radiation therapy combined with HAIC, HAIC and TACE can further improve the conversion rate. Systemic antineoplastic therapy combined with topical therapy is expected to achieve higher tumor remission and higher conversion resection rates (evidence level 4, recommendation B).
02 Conversion therapy for insufficient residual liver volume
(1) Portal vein embolization (PVE)
(2) Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)
2022 Edition Guide Essentials
01 Screening and diagnostic points
(1) With the help of liver ultrasound imaging combined with serum AFP for early screening of liver cancer, it is recommended that high-risk groups be examined at least once every 6 months.
(2) Dynamic enhanced CT and multiparameter MRI scans are the preferred imaging tests for the definitive diagnosis of patients with liver ultrasound imaging and/or serum AFP screening abnormalities.
(3) The imaging diagnosis of liver cancer is mainly based on the reinforcement method of "fast-forward and fast-out".
(4) Liver multiparameter MRI examination is the preferred imaging technology for clinical diagnosis, staging and efficacy evaluation of liver cancer.
(5) PET-CT scan is helpful for staging and efficacy evaluation of liver cancer.
(6) Serum AFP is a commonly used and important indicator for the diagnosis of liver cancer and the monitoring of efficacy. Early diagnosis can be made in serum AFP-negative populations using PIVKAII., miRNA detection kits, AFP-L3, and GALAD-like models.
(7) Patients with hepatic mass lesions with typical imaging characteristics of liver cancer, patients who meet the clinical diagnostic criteria for liver cancer usually do not need puncture biopsy for the purpose of diagnosis.
02 Hepatic resection points
(1) Hepatic resection is an important means for liver cancer patients to obtain long-term survival.
(2) The principle of hepatic resection is to completely remove the tumor and retain sufficient volume and functional liver tissue, so it is very important to improve the preoperative liver reserve function assessment and oncological assessment.
(3) It is generally considered that 30% of liver function Child-Pugh Class A, ICG-R15< is necessary for the implementation of surgical resection; the remaining liver volume must account for more than 40% of the standard liver volume (with chronic liver disease, liver parenchymal injury or cirrhosis) or more than 30% (without liver fibrosis or cirrhosis), which is also a necessary condition for surgical resection. People with liver impairment need to retain more of the remaining liver volume. Preoperative evaluation also includes the determination of liver hardness and portal hypertension.
(4) The preferred treatment for CNLC stage I.a, stage I.b and stage II.a liver cancer with good liver reserve function is surgical resection. Surgical resection is not appropriate in patients with CNLC stage II.b and stage III.a liver cancer, but some patients still have the opportunity to benefit from surgical resection after careful preoperative multidisciplinary evaluation.
(5) Hepatic resection often uses blood flow control techniques into the liver (hepatic artery and portal vein) and out of the liver (hepatic vein); preoperative three-dimensional visualization technology helps to improve the accuracy of liver resection; laparoscopic technique helps to reduce surgical trauma, but for large liver cancer, multiple liver cancer, liver cancer located in difficult areas and central areas adjacent to important pipelines, liver cancer and liver cancer complicated by severe cirrhosis, it is recommended to be implemented by experienced physicians after strict selection.
(6) For potentially resectable liver cancer, it is recommended to adopt multi-mode, high-intensity treatment strategies to promote its transformation. For patients with smaller remaining liver volumes, ALPPS or PVE can be used to compensate for residual liver hyperplasia to improve resection rates.
(7) Postoperative adjuvant therapy for liver cancer takes reducing recurrence as the main goal. TACE treatment in patients at high risk of postoperative recurrence can reduce recurrence and prolong survival, and postoperative oral locust ear granules can also help reduce recurrence and prolong survival. In addition, postoperative use of nucleoside analogues anti-HBV therapy and α-interferon also have the effect of inhibiting recurrence and prolonging survival.
(8) The application strategy of systemic anti-tumor therapy and local treatment alone or in combination in the perioperative period is being actively explored.
03 Liver transplantation points
(1) Liver transplantation is one of the radical treatment methods for liver cancer, especially for patients with small liver cancer who are decompensated and not suitable for surgical resection and ablation treatment.
(2) Recommend the UCSF standard as the indication standard for liver transplantation in Chinese liver cancer.
(3) Early withdrawal/hormone-free regimen after liver cancer liver transplantation, reducing the amount of calcineurin inhibitors in the early post-liver transplantation, and using immunosuppressive regimens based on mTOR inhibitors (such as rapamycin and everolimus) can help reduce tumor recurrence and improve survival.
(4) Once the tumor recurs and metastasizes after liver cancer liver transplantation, the disease progresses rapidly, and comprehensive treatment on the basis of multidisciplinary diagnosis and treatment may prolong the survival time of patients.
04 Ablation treatment points
(1) Ablation therapy is suitable for CNLC stage I.a and some stage I.b liver cancer (that is, a single tumor, ≤ 5 cm in diameter; or 2 to 3 tumors, the maximum diameter ≤ 3 cm), and a radical therapeutic effect can be obtained. Single or multiple tumours with a diameter of 3 to 7 cm that cannot be surgically resected can be treated in combination with TACE.
(2) For liver cancer patients with a diameter of ≤3cm, the tumor-free survival rate and overall survival rate of ablation therapy are similar or slightly lower than that of surgical resection, but the complication rate and hospital stay time are lower than that of surgical resection. For a single liver cancer ≤2 cm in diameter, ablation therapy is similar to surgical resection, particularly central liver cancer.
(3) There is no significant difference between RFA and MWA in terms of local efficacy, complication rate and long-term survival, and can be selected according to the size and location of the tumor.
(4) The long-term efficacy of PEI on liver cancer with a diameter of ≤2 cm is similar to that of RFA. Pei has the advantage of being safe, especially suitable for cancer lesions close to high-risk areas such as the hepatic hilar, gallbladder and gastrointestinal tissue, but multiple punctures are required to achieve intratumor diffusion of the drug.
(5) Dynamic enhancement CT, multiparameter MRI scan, ultrasound and serological tumor markers are regularly reviewed after ablation therapy to evaluate the effect of ablation.
05 Transarterial chemotherapy embolization points
(1) TACE is a commonly used non-surgical treatment method for liver cancer, which is mainly suitable for patients with CNLC II.b, III.a and some stage III .b liver cancer.
(2) Advocate fine TACE treatment to reduce the heterogeneity of tumors leading to differences in TACE efficacy.
(3) TACE treatment (including cTACE and DEB-TACE) must follow a standardized and individualized protocol.
(4) Advocate comprehensive treatments such as TACE combined ablation therapy, radiation therapy, surgery, molecular targeted drugs, immunotherapy and antiviral therapy to further improve the efficacy of TACE.
(5) Liver cancer with portal vein trunk or primary branch carcinoma plug can be treated on the basis of TACE in combination with portal vein stenting combined with iodine-125 particle therapy or direct puncture implantation of iodine-125 particles.
06 Key points of radiation therapy
(1) In patients with CNLC stage III.a liver cancer, liver cancer with resectable portal artery carcinoma suppositories can undergo preoperative neoadjuvant radiation therapy or postoperative auxiliary radiation therapy to prolong survival; for those who cannot be surgically removed, palliative radiation therapy can be performed, or radiation therapy can be combined with TACE and other therapy to prolong the survival of patients.
(2) In patients with CNLC III .b liver cancer, some patients with oligometastatic lesions can undergo SBRT radiation therapy to prolong survival; external radiation therapy can also alleviate symptoms such as pain, obstruction or bleeding caused by lymph node, lung, bone, brain or adrenal metastases.
(3) Some patients can obtain surgical resection opportunities through radiation therapy conversion.
(4) Liver tumor irradiation dose: stereotactic radiation therapy is generally recommended ≥ 45 ~ 60Gy/3 ~ 10Fx, conventional segmented radiation therapy is generally 50 ~ 75Gy, and the irradiation dose is closely related to the survival of patients. Some intrahepatic lesions or extrahepatic metastases may be treated with low-segment radiation therapy to increase a single dose and shorten the duration of radiation therapy.
(5) The tolerated dose of normal tissues must be considered: radiation therapy segmentation, liver function Child-Pugh grading, normal liver (liver-tumor) volume, gastrointestinal stasis and coagulation function status, etc.
(6) IGRT is superior to three-dimensional conformal radiation therapy or intensity-modulated radiation therapy, and stereotactic radiation therapy must be performed under IGRT.
(7) Internal radiation therapy is a method of local treatment of liver cancer.
07 Points of systematic treatment
(1) Indications for systemic antitumor therapy: CNLC III.a, III.b liver cancer patients, CNLC II .b liver cancer patients who are not suitable for surgical resection or TACE treatment, TACE treatment resistance or TACE treatment failure of liver cancer patients.
(2) First-line anti-tumor treatment options can choose attilizumab plus bevacizumab, sindilimab plus bevacizumab analogue (dayoutong), donifinib, lenvatinib, sorafenib or systemic chemotherapy containing oxaliplatin.
(3) Second-line anti-tumor treatment program, in the mainland can choose regofenib, apatinib, carrelizumab or tiralizumab.
(4) According to the needs of the condition, traditional Chinese medicine can be applied, such as locust ear granules.
(5) At the same time as anti-tumor therapy, antiviral therapy should run through the whole process of treatment, and at the same time, hepatoprotective choleretic and supportive symptomatic therapy should be carried out as appropriate.
This article was first published: Medical Oncology Channel
This article is written by Li Rentao
Editor-in-Charge: Sweet
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