Systematic anti-tumor treatment for primary liver cancer, saving patients in Yuanchi

Author: Wang Mingming Chief Physician Shandong Provincial Public Health Clinical Center (formerly Jinan Infectious Disease Hospital) This article is authorized by the author to publish the medical pulse pass, please do not reprint
without authorization.

Primary liver cancer includes hepatocellular carcinoma, intrahepatic cholangiocarcinoma and a mixture of the two, collectively referred to as liver cancer
.
Liver cancer accounts for the 4th largest number of malignant tumors in China, and the 2nd place
in the cause of tumor death.
Treatment includes tumor resection, liver transplantation, ablation therapy, hepatic artery intubation chemoembolism (TACE), radiotherapy, and systemic antitumor therapy, with different treatments
depending on the stage.
Systemic antitumor therapy includes targeted therapy, immunotherapy and chemotherapy, traditional Chinese medicine therapy, and treatment of underlying liver cancer (such as antiviral therapy, hepatoprotective choleretics, and supportive symptomatic therapy
).
Systemic antitumor therapy is suitable for: (1) CNLC III.
a, III.
b stage patients; (2) CNLC stage II.
b patients who are not suitable for surgical resection or TACE treatment; (3) Patients who resist TACE therapy or fail
TACE therapy.
Traditional Chinese medicine treatment and treatment of basic diseases of liver cancer are omitted
from this article.

First, targeted therapy for tumor therapy
is to inhibit the proliferation of tumor cells by acting on a specific target related to tumor growth by the drug (this target can not be the tumor cell itself), and the targeted drug is highly selective
.
The targeted therapy drugs used in liver cancer are mainly aimed at the signal pathways related to tumor angiogenesis, which affect the angiogenesis required by the tumor by inhibiting the expression of receptors, and play an anti-tumor role
.
(1) Multi-target tyrosine kinase inhibitors: including lenvatinib, sorafenib, regofinib, sunitinib, etc.
; (2) VEGFR antagonists: including apatinib, axitinib, etc.
; (3) VEGF/VEGFR monoclonal antibody: including bevacizumab, remo reglumumab, etc
.
The above targeted drugs are mainly used in the advanced or advanced stage of liver cancer, and the recommended first-line drugs are lenvatinib and sorafenib
.

Lendvatinib selectively blocks the proliferation of hepatocellular carcinoma cells and is a multi-target inhibitor including VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, which was approved for listing
in China in 2018 。 Phase III clinical trials have shown that lenvatinib significantly improves the objective remission rate (40.
6% vs 12.
4%) and progression-free survival (7.
3 vs 3.
6 months) in patients with advanced liver cancer compared with sorafenib.
In patients with advanced liver cancer in China, lenvatinib can improve overall survival (15.
0 vs 10.
2 months) and reduce the risk
of death by 50%.

Sorafenib is the earliest molecularly targeted drug for the treatment of liver cancer, approved for domestic marketing in August 2009, and is also a multi-target, multi-kinase inhibitor, which can block tumor angiogenesis by inhibiting the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDG-FR), and can also inhibit tumor cell proliferation
by blocking the RAF/MEK/ERK signaling pathway 。 Sorafenib can be used in patients with Child-Pugh grade A or B in liver function, but the survival benefit is more pronounced
in patients with Child-Pugh grade B with liver function.

Second, immunotherapy for liver cancer immunotherapy
includes PD-1 inhibitors and PD-L1 inhibitors
.
PD-1 Chinese full name is programmed cell death protein-1, PD-L1 is a ligand of PD-1
.
PD-1 is mainly expressed in activated T cells and B cells, PD-L binds to PD-L1, conducts signals that suppress immunity, reduces or reduces the activation of immune cells, stabilizes immune function, avoids autoimmune diseases
due to immune dysfunction.
Tumor cells overexpress PD-L1 and bind to PD-1 on the membrane of T cells, inactivating T cells and producing immune escape
.
PD-1 inhibitors and PD-L1 inhibitors can block or inhibit the binding of PD-L1 to PD-1 in tumor cells, restore the activity of T cells, and enhance the recognition and killing ability
of T cells to tumor cells.

PD-1 inhibitors are pabolizumab, navurizumab, carilizumab; PD-L1 inhibitors have antilizumab
.
Recommended first-line treatments are: (1) atilizumab + bevacizumab
.
Artelizumab plus bevacizumab is approved for use in patients with
unresectable liver cancer who have not received systemic systemic therapy.
The results of the IMbrave150 global multicenter phase III study showed that the median survival time and progression-free survival of the attilizumab plus bevacizumab group were significantly longer than those of the sorafenib group, with a 34% lower risk of death and a 35%
lower risk of disease progression.
There was also a clear clinical benefit for patients in the Chinese subpopulation, with a 47% lower risk of death and a 40%
lower risk of disease progression compared with sorafenib.
Combination therapy may also delay the deterioration in the patient's median quality of life
.
Common adverse effects of combination therapy include hypertension, proteinuria, abnormal liver function, hypothyroidism, diarrhea, and decreased appetite
.
(2) Xindilizumab + bevacizumab analogue
.
The Cidilizumab plus bevacizumab analogue has been approved for first-line treatment for unresectable or metastatic liver cancer in patients who have not previously received systemic antitumor therapy
.
The results of the ORIENT32 national multicenter phase III study showed that the efficacy of the Xindilizumab plus bevacizumab analogue was significantly better than that of the sorafenib group, and the risk of death and disease progression was reduced by 43% in the combination group compared with the sorafenib group
.
The combination regimen is safe, and the most common adverse reactions in the combination treatment group are proteinuria, thrombocytopenia, elevated liver enzymes, hypertension, and hypothyroidism
.

Third, chemotherapy
is the use of chemosynthetic drug therapy
.
The FOLFOX4 regimen (oxaliplatin + fluorouracil + calcium folinate) has been approved in China for the first-line treatment of locally advanced and metastatic liver cancer
that is not suitable for surgical resection or topical treatment.
An early multicenter, open-label, randomized clinical phase III study compared with a doxorubicin control suggested that median overall survival (OS) was 6.
40 months and 4.
97 months in the foxorubicin group, 2.
93 months in the FOLFOX4 regimen group, and 1.
77 months
in the doxorubicin group.
The response rate (RR) was 8.
15% in the FOLFOX4 protocol group and 2.
67%
in the doxorubicin group.

Arsenic trioxide injection was officially approved by the State Food and Drug Administration in 2004, increasing the indications for advanced liver cancer and having a certain palliative effect on advanced liver cancer
.
Studies have shown that arsenic trioxide can induce apoptosis of liver cancer cells, inhibit the proliferation of liver cancer cells, and inhibit the formation of tumor neovascularization, thus playing an anti-liver cancer effect
.
The phase II multicenter study carried out by Chinese scholars shows that arsenic trioxide has a certain efficacy and analgesic effect on advanced liver cancer, but its toxic effect
should be closely monitored in clinical application.


References:[1] Medical Administration Bureau of the National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of primary liver cancer, Chinese Journal of Practical Surgery, 2022; 42(3):241-273.
[2] Cheng AL, Qin SK, Ikeda M, et al.
Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs.
sorafenib for unresectable hepatocellular carcinoma.
J Hepatol.
2022; 76(4):862-873.
[3] Ren ZG, Xu JI, Bai YX, et al.
Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
Lancet Oncol.
2021; 22(7):977-990.
Qu Fenglian, Hao Xuezhi, Qin Shukui, et al.
Phase II Multicenter Clinical Study of Arsenite Acid Injection in the Treatment of Primary Liver Cancer, Chinese Journal of Oncology, 2011; 33(9):697-671.
Du Jiahang, Chen Dong, Chen Yaoting.
Anti-liver cancer mechanism of arsenic trioxide and its study in the treatment of liver cancer, International SwellingJournal of Oncology, 2021; 48(9):572-574.