​The National Health Commission authoritatively released: the 2022 edition of the "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer", a comprehensive interpretation of the treatment update!

*Only for medical professionals to read and refer to the super practical, super new guideline update, this article is organized! On January 17, the official website of the National Health Commission released the latest version of the "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer", which was updated after 2019
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Due to the emergence of many high-level evidences in line with the principles of evidence-based medicine in the diagnosis, staging and treatment of liver cancer both domestically and externally, and especially the emergence of research results adapted to China's national conditions, the National Health Commission commissioned the Chinese Medical Association to combine the clinical diagnosis and treatment of liver cancer.
And the latest practice of research, revised and updated again to form the "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)"
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 The focus of the guideline update: systemic anti-tumor therapy The most important part of this guideline update is systemic anti-tumor therapy
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First-line antitumor regimens have added atezolizumab in combination with bevacizumab, sintilimab in combination with a bevacizumab analog (Dayotong), and donafenib
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The main indications for anti-tumor therapy of the China Clinical Staging of Liver Cancer (CNLC) and Therapeutic Roadmap System are: ① CNLC stage IIIa and IIIb liver cancer patients; ② CNLC stage IIb liver cancer patients who are not suitable for surgical resection or TACE treatment; ③ TACE treatment resistance or TACE treatment failed liver cancer patients
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01First-line systemic anti-tumor treatment regimen (1) Atezolizumab combined with bevacizumab Atezolizumab combined with bevacizumab is approved for unresectable liver cancer who has not received systemic therapy before patients (evidence level 2, recommendation A)
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The results of the IMbrave150 global multicenter phase III study showed that the median survival time and progression free survival (PFS) of the atezolizumab combined with bevacizumab group were significantly longer than those of the sorafenib group , a 34% lower risk of death and a 35% lower risk of disease progression
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For the Chinese subgroup, patients in the combination therapy group also had significant clinical benefit, with a 47% reduction in the risk of death and a 40% reduction in the risk of disease progression compared with sorafenib
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(2) Sintilimab combined with bevacizumab analogs Sintilimab combined with bevacizumab analogs has been approved in China for unresectable or metastatic patients who have not received systemic antitumor therapy before.
First-line treatment of liver cancer (evidence level 2, recommendation A)
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The results of the ORIENT32 national multi-center phase III study showed that the efficacy of sintilimab combined with bevacizumab analogs was significantly better than that of the sorafenib group.
Compared with the sorafenib group, the combined treatment group reduced the risk of death by 43% , the risk of disease progression decreased by 44%
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(3) Donafenib Donafenib has been approved in China for patients with unresectable liver cancer who have not received systemic antitumor therapy before (evidence level 2, recommendation A)
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Compared with sorafenib, donafenib can significantly prolong the median survival time of advanced liver cancer and reduce the risk of death by 17%; The Ni group has good safety and tolerability
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The most common adverse reactions were hand-foot skin reaction, increased aspartate aminotransferase, increased total bilirubin, decreased platelets, and diarrhea
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(4) Lenvatinib Lenvatinib is suitable for patients with unresectable liver function Child-Pugh A grade advanced liver cancer (evidence level 1, recommendation A)
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The REFLECT global multi-center clinical phase III controlled study showed that the median survival time was non-inferior to sorafenib, and the study reached the non-inferiority endpoint [HR 0.
92, 95% CI 0.
79-1.
06]
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Median PFS was significantly better in the lenvatinib group than in the sorafenib group, with a 34% reduction in the risk of disease progression
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(5) Sorafenib Sorafenib is the earliest molecularly targeted drug used in the systemic anti-tumor therapy of liver cancer
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A number of clinical studies have shown that sorafenib has certain survival benefits for patients with advanced liver cancer in different countries and backgrounds of liver disease (evidence level 1, recommendation A)
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Sorafenib can be used in patients with Child-Pugh A or B liver function, but compared with Child-Pugh B liver function, the survival benefit of Child-Pugh A patients is more obvious
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(6) Systemic chemotherapy FOLFOX4 regimen is approved in China for first-line treatment of locally advanced and metastatic liver cancer not suitable for surgical resection or local therapy (evidence level 2, recommendation A)
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(7) Progress in other first-line treatment Phase III clinical study of camrelizumab combined with apatinib (SHR-1210-III-310), phase III clinical study of lenvatinib combined with pembrolizumab (LEAP 002) Phase Ib clinical study of vatinib combined with nivolumab (Study117) CS1003 (PD-1 monoclonal antibody) combined with lenvatinib Phase III clinical study (CS1003-305) Toripalimab combined with lenvatinib III Phase III clinical study of camrelizumab combined with oxaliplatin-based systemic chemotherapy Phase III clinical study of duvalizumab combined with tremelimumab (HIMALAYA) Sintilimab combined with IBI310 (Anti-CTLA-4 monoclonal antibody) Phase III clinical study 02 Second-line systemic anti-tumor treatment regimen (1) Regorafenib Regorafenib is approved for patients with liver cancer who have previously received sorafenib treatment (evidence level 1, A) is recommended
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(2) Apatinib mesylate Apatinib is a small molecule targeted new drug independently developed in China, and has been approved as a single drug for patients with advanced disease that has failed or is intolerable after receiving at least first-line systemic antitumor therapy.
Patients with liver cancer (evidence level 2, recommendation A)
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(3) Camrelizumab has been approved for the treatment of patients with advanced liver cancer who have previously received sorafenib therapy and/or oxaliplatin-containing systemic chemotherapy (evidence level 4, recommended B)
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(4) Tislelizumab Tislelizumab is approved for the treatment of liver cancer patients who have undergone at least one systemic antitumor therapy (evidence level 4, recommendation B)
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 The focus of the guideline update: exploring the comprehensive treatment strategy of advanced liver cancer based on surgery Another focus of this guideline update is to give the main research direction in the field of liver cancer: to explore a new comprehensive treatment strategy based on surgery for middle and advanced liver cancer
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Based on the data of a large number of previous cases, although the overall survival after surgery for intermediate-advanced liver cancer (CNLC stage IIb, IIIa, and IIIb) is unsatisfactory, in the absence of other effective treatments, surgical resection can still allow some patients to recover.
benefit (evidence level 4, recommendation C)
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Combined with the latest progress in systemic anti-tumor therapy, the effect of systemic anti-tumor therapy and/or local therapy on tumor control can provide more possibilities for radical resection, reduction of postoperative recurrence and improvement of prognosis for patients with advanced liver cancer (evidence level 4, recommended B)
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Therefore, the strategy of direct surgical resection in patients with advanced HCC needs to be re-understood
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Conversion therapy is the transformation of unresectable liver cancer into resectable liver cancer, and it is one of the ways for patients with advanced liver cancer to obtain radical resection and long-term survival
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For potentially resectable liver cancer, a multimodal, high-intensity antitumor therapy strategy is recommended to promote its transformation
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 01 Transformational therapy for tumors (1) Systemic antitumor therapy: The single or combined application of systemic antitumor therapy is one of the main methods of transformation therapy for advanced liver cancer (evidence level 4, recommendation B)
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The depth, speed, and duration of remission in liver cancer, as well as organ-specific remission, are important factors affecting subsequent treatment decisions
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The effects of different drug combinations on liver tissue and the safety of subsequent surgery require more exploration
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(2) Local therapy: including TACE (evidence level 3, recommendation B), hepatic artery catheterization and continuous chemotherapy perfusion (evidence level 4, recommendation C) and other local therapy methods create potential surgical resection opportunities for patients with initially unresectable liver cancer, and can translates into survival benefit
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Radiation therapy combined with HAIC and HAIC combined with TACE can further improve the conversion rate
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Systemic antitumor therapy combined with local therapy is expected to achieve higher tumor remission and higher transformation resection rate (evidence level 4, recommendation B)
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 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 Guide Point 01 Screening and Diagnosis Points (1) Early screening of liver cancer with the help of liver ultrasound imaging combined with serum AFP, it is recommended that high-risk groups should be checked at least once every 6 months
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(2) Dynamic contrast-enhanced CT and multi-parameter MRI scanning are the preferred imaging methods for definite diagnosis of patients with abnormal liver ultrasound imaging and/or serum AFP screening
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(3) The imaging diagnosis of liver cancer is mainly based on the enhancement method of “fast in and fast out”
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(4) Multiparametric MRI of the liver is the preferred imaging technique for the clinical diagnosis, staging and efficacy evaluation of liver cancer
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(5) PET-CT scan is helpful for staging and efficacy evaluation of liver cancer
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(6) Serum AFP is a common and important indicator for the diagnosis of liver cancer and monitoring of curative effect
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For serum AFP-negative population, early diagnosis can be made with the help of PIVKAⅡ, miRNA detection kit, AFP-L3 and GALAD-like model
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(7) Patients with liver space-occupying lesions with typical imaging features of liver cancer who meet the clinical diagnostic criteria for liver cancer usually do not need biopsy of liver lesions for the purpose of diagnosis
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 02 Key points of liver resection (1) Hepatectomy is an important means for long-term survival of patients with liver cancer
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(2) The principle of liver resection is to completely remove the tumor and retain sufficient volume and functional liver tissue, so it is very important to complete the preoperative evaluation of liver reserve function and oncology
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(3) It is generally believed that liver function Child-Pugh A and ICG-R15<30% are necessary conditions for surgical resection; the remaining liver volume must account for more than 40% of the standard liver volume (with chronic liver disease, liver parenchyma damage or liver disease).
cirrhosis) or more than 30% (without liver fibrosis or cirrhosis), it is also a necessary condition for surgical resection
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Those with impaired liver function need to retain more residual liver volume
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Preoperative evaluation also includes the determination of liver stiffness and the degree of portal hypertension
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(4) Surgical resection is the preferred treatment for CNLC stage Ia, Ib and IIa liver cancer with good liver reserve
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In CNLC stage IIb and IIIa liver cancer patients, surgical resection is not the first choice, but some patients still have the opportunity to benefit from surgical resection after careful preoperative multidisciplinary evaluation
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(5) Into the liver (hepatic artery and portal vein) and out of the liver (hepatic vein) blood flow control technology is often used during liver resection; preoperative three-dimensional visualization technology helps to improve the accuracy of liver resection; laparoscopic technology helps to reduce Surgical trauma, but for patients with huge liver cancer, multiple liver cancer, liver cancer located in difficult parts and close to important ducts in the central area, and liver cancer complicated with severe liver cirrhosis, it is recommended to be performed by experienced physicians after strict selection
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(6) For potentially resectable liver cancer, a multimodal and high-intensity treatment strategy is recommended to promote its transformation
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For patients with small residual liver volume, ALPPS or PVE can be used to increase the resection rate by compensatory hyperplasia of the residual liver
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(7) The main goal of postoperative adjuvant therapy for liver cancer is to reduce recurrence
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TACE treatment for patients with high risk of postoperative recurrence can reduce recurrence and prolong survival; postoperative oral Huaier granules can also help reduce recurrence and prolong survival
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In addition, the use of nucleoside analogs for anti-HBV therapy and α-interferon after surgery can also inhibit recurrence and prolong survival
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(8) The application strategies of systemic anti-tumor therapy and local therapy alone or in combination in the perioperative period are being actively explored
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 03 Key points of liver transplantation (1) Liver transplantation is one of the curative treatment methods for liver cancer, especially for patients with small liver cancer who have decompensated liver function and are not suitable for surgical resection and ablation therapy
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(2) UCSF criteria are recommended as the indication criteria for liver transplantation for liver cancer in China
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(3) Early withdrawal/hormone-free regimen after liver transplantation for hepatocellular carcinoma, reducing the dosage of early calcineurin inhibitors after liver transplantation, and using mTOR inhibitors (such as rapamycin, everolimus)-based immunization.
Suppression regimens can help reduce tumor recurrence and improve survival
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(4) Once the tumor recurs and metastasizes after liver transplantation, the disease progresses rapidly.
Comprehensive treatment based on multidisciplinary diagnosis and treatment may prolong the survival time of patients
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 04 Key points of ablation therapy (1) Ablation therapy is suitable for CNLC stage Ia and some stage Ib liver cancer (ie, a single tumor with a diameter of ≤5cm; or 2 to 3 tumors with a maximum diameter of ≤3cm), and a radical treatment effect can be obtained
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For single or multiple tumors with a diameter of 3 to 7 cm that cannot be surgically removed, TACE can be combined
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(2) For patients with liver cancer with a diameter of £3cm, the tumor-free survival rate and overall survival rate of ablation therapy were similar to or slightly lower than those of surgical resection, but the complication rate and hospital stay were lower than those of surgical resection
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For a single HCC with a diameter of ≤2cm, the efficacy of ablation therapy is similar to that of surgical resection, especially for central HCC
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(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
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(4) The long-term effect of PEI on liver cancer with diameter ≤2cm is similar to that of RFA
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The advantage of PEI is safety, and it is especially suitable for cancer foci close to high-risk sites such as the hepatic hilum, gallbladder, and gastrointestinal tract, but requires multiple, multi-point punctures to achieve intratumoral diffusion of the drug
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(5) Regularly review dynamic contrast-enhanced CT, multi-parameter MRI scan, contrast-enhanced ultrasound and serological tumor markers after ablation treatment to evaluate the effect of ablation
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 05 Key points of transarterial chemoembolization (1) TACE is a commonly used non-surgical treatment for liver cancer, and is mainly suitable for CNLC IIb, IIIa and some IIIb stage liver cancer patients
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(2) Advocate precise TACE treatment to reduce tumor heterogeneity leading to differences in TACE efficacy
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(3) TACE treatment (including cTACE and DEB-TACE) must follow a standardized and individualized plan
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(4) Advocate TACE combined with ablation therapy, radiotherapy, surgery, molecular targeted drugs, immunotherapy and antiviral therapy to further improve the efficacy of TACE
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(5) For liver cancer with portal vein trunk or first-level branch tumor thrombus, portal vein stent placement combined with iodine-125 seed therapy or direct puncture implantation of iodine-125 seed can be used on the basis of TACE
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 06 Key points of radiotherapy (1) For CNLC stage IIIa liver cancer patients, liver cancer with resectable portal vein tumor thrombus can be treated with preoperative neoadjuvant radiation therapy or postoperative adjuvant radiation therapy to prolong survival; for those who cannot be surgically removed, palliative therapy can be performed.
Radiation therapy, or a combination of radiation therapy and TACE, prolongs patient survival
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(2) For CNLC stage IIIb liver cancer patients, some patients with oligometastases can undergo SBRT radiation therapy to prolong survival; external radiation therapy can also relieve symptoms such as pain, obstruction or bleeding caused by lymph node, lung, bone, brain or adrenal metastasis
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(3) Some patients can obtain the opportunity of surgical resection through radiotherapy conversion
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(4) Irradiation dose for liver tumors: Stereotactic radiotherapy is generally recommended ≥45-60Gy/3-10Fx, and conventional fractionated radiotherapy is generally 50-75Gy.
The irradiation dose is closely related to patient survival
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Some intrahepatic lesions or extrahepatic metastases can be treated with hypofractionated radiation therapy to increase the single dose and shorten the radiation therapy time
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(5) The tolerable dose of normal tissues must be considered: radiation therapy fractionation, Child-Pugh grading of liver function, normal liver (liver-tumor) volume, gastrointestinal blood 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
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(7) Internal radiation therapy is a method of local treatment of liver cancer
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07 Systematic treatment points (1) Indications for systemic anti-tumor therapy: CNLC stage IIIa and IIIb liver cancer patients, CNLC stage IIb liver cancer patients who are not suitable for surgical resection or TACE treatment, and liver cancer patients who are resistant to TACE treatment or fail TACE treatment
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(2) The first-line anti-tumor treatment options can be atezolizumab combined with bevacizumab, sintilimab combined with bevacizumab analogs (Dayotong), donafenib, lenvatinib Nitinol, sorafenib, or systemic chemotherapy with oxaliplatin
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(3) Second-line anti-tumor treatment options, in China, regorafenib, apatinib, camrelizumab or tislelizumab can be selected
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(4) According to the needs of the disease, traditional Chinese medicines such as Huaier granules can be applied
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(5) In addition to anti-tumor treatment, anti-viral treatment should be carried out throughout the whole process of treatment, while protecting the liver and gallbladder as appropriate, and supporting symptomatic treatment
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