CC BY
4
nvw; ) JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN ..... Short Communication
(E-ISSN 2313-1519)
Actual issues of secondary prevention of liver cancer in Kazakhstan
Niyaz Malayev12, Saparbayev Samat3, Saule Kubekova4, Nurlan Zhampeissov5
'Department of Oncology, Marat Ospanov West Kazakhstan Medical University, Aktobe, Kazakhstan 2Department of General and Thoracic Surgery, National Scientific Medical Center, Astana, Kazakhstan 3Department of Surgery, Astana Medical University, Astana, Kazakhstan 4Department of Cardiology, Astana Medical University, Astana, Kazakhstan
5Department of Radiation Diagnostics and Ultrasound Imaging, National Scientific Medical Center, Astana, Kazakhstan
Abstract
Liver cancer is characterized by high mortality and low survival rates in most countries of the world. According to the WHO data, more than 1.3 million people with liver cancer die annually in the world and according to the data of the 9th volume of "Cancer on five continents" - the highest standardized incidence rates are in Korea - 44.9 per 100 thousand population as well as in Thailand, Japan, China. Low rates were in Algeria, India, Belgium and the Netherlands. In Russia 61.5% of patients die of liver cancer progression in the first year after diagnosis [1,2].
Information on the global burden of cancer in 2018 showed that the specific weight of liver cancer in the structure of malignant neoplasms (MN) is 8.2%, and in 2020 - 8.3% [3].
The worldwide peculiarity of liver cancer is its late diagnosis. Several evidence-based treatment options for liver cancer are currently available: liver transplantation for hepatocellular liver cancer (HCC) (according to the Milan criteria), radiofrequency ablation as a radical treatment option (RFA), chemoembolization for intrahepatic cholangiocarcinoma (TACE), and the administration of Sorafenib as systemic therapy [4].
Current approaches for the treatment of early-stage primary liver cancer are represented by hepatic RFA, and the efficacy of this approach depends on the subjective attentiveness and visual acuity of the clinician. The latest technique used in liver RFA is the hyperspectral imaging which utilize objective assessment [2].
Ultrasound is usually used to detect liver lesions, but the detection rate is low for many reasons, such as clinician skills and technical capabilities. Modern approaches of diagnostic capabilities, such as contrast-enhanced ultrasound integrated imaging (CEUS) and comprehensive ultrasound imaging - contrast-enhanced CT (CECT) or contrast-enhanced MRI (CEMRI) for visualization of focal liver lesions (FLL) - increase the confidence of the interventional physician so it should be recommended for use as a routine procedure [5-6].
The ratio of morbidity and mortality in many countries reaches 91.6%, which represents the third most important cause of cancer deaths [7-9]. Keywords: liver cancer, prevalence, incidence, regions of Kazakhstan
Received: 2023-11-03. Accepted: 2023-11-22
© ®
This work is licensed under a Creative Commons Attribution 4.0 International License
J Clin Med Kaz 2023; 20(6):66-72
Corresponding author: Saule Kubekova. E-mail: dr.kubekova@gmail.com, ORCID: 0000-0001-5358-3690
Introduction
Late diagnosis is the peculiarity of liver cancer worldwide. Information on the global burden of cancer in 2018 showed that the specific weight of liver cancer in the structure of malignant neoplasms (MN) - 8.2%, and in 2020 - 8.3%. In Kazakhstan in 2021 - 2.8%.
The incidence of liver cancer in the world reaches up to 44.6 per 100 thousand population and in Kazakhstan - 4.7 in 2021.
Objective: To study the prevalence of liver cancer in Kazakhstan.
Material and methods
A search in the databases ofPubMed, GoogleScholar, Rinz, statistical and analytical indicators materials of oncological service of Kazakhstan for 2019-2021 was conducted. The method of research is desk-based, retrospective.
Results and discussion
In 2021, the incidence of malignant neoplasms (MN) increased by 7.6% and amounted to 170.3, compared to 2020 -157.3. The growth rate increased over two years +8.3%. In the structure of malignant neoplasms, liver cancer ranked 15 th with a positive growth rate of +3.1% (Table 1).
Incidence of liver cancer in the structure of MNs of the population in Kazakhstan
Localization Indicators Growth rate, %
abs. number to 100 000. 2020 2021
2020 2021 2019 2020 2021
All MNs, including 29701 32572 174,8 157,3 170,3 -10,3 8,3
Mouth 76 119 0,7 0,4 0,6 -42,9 54,6
Oral cavity 481 520 2,8 2,5 2,7 -4,8 6,7
Salivary gland 112 143 0,6 0,6 0,7 - 26,1
Nasopharynx 70 76 0,4 0,4 0,4 - 7,2
Throat 164 169 0,8 0,9 0,9 -20,0 1,7
Esophagus 1082 1130 6,3 5,7 5,9 -7,3 3,1
Stomach 2497 2576 14,4 13,2 13,5 -8,5 1,9
Colon 1645 1686 9,2 8,7 8,8 -4,9 1,2
Rectum 1471 1604 8,7 7,8 8,4 -11,5 7,7
Liver 861 899 5,4 4,6 4,7 -16,3 3,1
Pancreas 1143 1128 6,0 6,1 5,9 1,9 -2,6
Larynx 339 365 2,3 1,8 1,9 -20,0 6,3
Lungs 3375 3615 20,1 17,9 18,9 -11,6 5,8
Bones 141 143 0,8 0,7 0,7 -12,5 0,1
Soft tissues 381 439 2,2 2,0 2,3 -5,0 13,8
Skin melanoma 283 360 1,9 1,5 1,9 -23,5 25,6
Mammary gland 4307 5021 26,6 22,8 26,3 -14,9 15,1
Uterine cervix 1672 1804 9,6 8,9 9,4 -8,1 6,5
Uterine corpus 1074 1240 6,4 5,7 6,5 -11,9 14,0
Ovary 1010 1249 6,2 5,3 6,5 -12,0 22,1
Prostate 970 1169 6,6 5,1 6,1 -23,6 19,0
Kidneys 1029 1292 6,7 5,5 6,8 -18,3 24,0
Bladder 667 737 4,1 3,5 3,9 -13,5 9,1
Nervous system 785 765 3,8 4,2 4,0 11,4 -3,8
Thyroid 612 712 4,3 3,2 3,7 -25,6 14,9
Blood 1702 1713 8,3 9,0 9,0 9,1 -0,6
Lymphoma 837 886 4,4 4,4 4,6 9,1 4,5
Leukemia 865 827 3,8 4,6 4,3 9,1 -0,6
Figure 1 - Growth rate of liver cancer incidence in the structure of the population in Kazakhstan, Gr.
^vvvv.
J? " ^
For economically developed countries the standardized indicator of the population morbidity with MN is within 250350, for developing countries - 100-120. According to these benchmarks, Kazakhstan is striving to reach the levels of indicators of economically developed countries in recent years.
Graphical analysis of the growth rate of liver cancer in the structure of MN in Kazakhstan showed that liver cancer is characterized by low intensity of detection compared to the previous year, despite the positive growth rate (Figure 1).
Analysis of regional peculiarities of 2021 in the structure of MN in Kazakhstan allowed to single out regions with high morbidity rates - the highest rate of MN is breast cancer in Pavlodar region - 48.0, East Kazakhstan (EKR) - 40.0 and lung cancer in North Kazakhstan - 39.0 (SKR) (Table 2).
Regions with high liver cancer incidence rates are Pavlodar region - 7.0, East-Kazakhstan - 6.8 and Atyrau region - 6.3; with low rates - Turkestan region - 2.6, Kostanay region - 2.7, North Kazakhstan - 3.7 (Figure 2).
Figure 2 - Liver cancer incidence in the regions of Kazakhstan
The analysis of regional peculiarities in 2021 of MN structure in Kazakhstan showed that the highest specific weight of liver cancer in Zhambyl and Mangystau regions - 4.9% and 4.5%, Atyrau region 4.1% and Kyzylorda region - 3.9%, and less specific weight in Kostanay region -1.1%, North Kazakhstan -1.3% (Figure 3).
Figure 3 - Specific weight of liver cancer in the structure of MN by regions of Kazakhstan, 2021, %
Analysis of regions with a high proportion of stage 4 liver cancer in 2020-2021 showed that the most disadvantaged region is Akmola region - 38.9/61.1%, SKO - 38.9%, and Pavlodar region - 27.7% (Figure 4).
Incidence of liver cancer in the structure of MN in the population of the Republic of Kazakhstan in 2021, per 100 thousand population.
MN localization Name of regions
Kazakhstan Republic Akmola Aktobe Almaty region Atyrau East Kazakhstan Zhambyl West Kazakstan Karaganda Kyzylorda Kostanay Mangystau Pavlodar North Kazakhstan Turkestan Nur-Sultan city Almaty city Shymkent city
Total 170 216 177 119 152 255 123 192 244 137 245 110 281 287 71 166 193 109
Oral cavity 2.7 4.1 3.4 1.6 3.4 4.7 2.3 3.0 3.1 1.8 4.4 1.1 5.2 6.9 0.9 2.3 2.6 1.3
Esophagus 5.9 6.5 10 4.1 8.1 5.3 5.9 11 6.6 12 6.3 8.1 5.0 6.3 4.5 4.1 3.6 4.2
Stomach 13 17 19 11 14 18 10 19 18 12 16 9.7 17 25 6.7 13 12 7.4
Colon 8.8 10 9.0 4.7 8.7 13 5.8 10 15 4.6 16 4.9 15 13 2.7 9.0 12 4.0
Rectum 8.4 13 8.1 5.6 6.3 14 5.1 9.8 12 5.3 16 2.8 18 15 2.7 9.0 7.8 5.0
Liver 4.7 5.2 5.7 3.1 6.3 6.8 6.0 6.0 5.9 5.3 2.7 4.9 7.0 3.7 2.6 4.4 4.4 4.2
Pancreas 5.9 9.1 6.3 3.8 5.8 8.7 5.4 6.9 9.0 5.1 8.4 3.2 9.8 7.1 2.3 5.6 6.4 3.6
Lungs 19 32 20 10 21 31 14 25 29 15 25 9 35 39 7 17 17 10
Bones 0.7 1.1 1.3 0.5 1.0 0.2 0.6 0.8 0.6 2.2 0.7 0.4 0.8 2.0 0.3 0.8 0.8 0.4
Connective tissues 2.3 1.5 2.4 1.9 1.5 2.3 3.0 3.5 2.8 2.8 4.7 1.2 4.1 3.9 0.9 1.5 2.4 1.7
Melanoma 1.9 2.0 1.1 1.1 0.7 3.8 0.9 0.9 3.1 1.0 3.7 1.5 3.9 5.4 0.4 1.1 2.9 0.6
Mammary gland 26 30 24 17 16 40 15 28 40 14 36 17 48 38 12 28 35 22
Uterine cervix 9.4 12 12 9.5 12 11 5.7 11 12 8.2 11 10 17 10 5 7 8 7
Uterine corpus 6.5 9.3 6.1 4.7 4.2 10 4.6 5.7 9.6 4.8 9.4 3.1 10 15 1.3 6.5 8.5 4.3
Ovary 6.5 6.9 6.4 5.4 6.7 7.2 4.3 7.2 7.5 8.3 9.6 3.2 9.4 6.3 3.5 7.7 9.3 4.1
Prostate 6.1 7.1 3.6 4.3 1.6 14 4.4 5.6 10 1.0 12 2.7 11 16 1.0 4.3 7.6 3.1
Kidneys 6.8 0.4 6.6 4.0 6.9 9.4 4.1 4.5 9.5 3.9 10 4.9 12 14 2.5 9.4 8.4 3.1
Bladder 3.9 5.7 3.2 2.8 2.1 7.0 2.8 3.6 6.4 2.7 5.7 2.0 6.4 7.6 1.1 2.6 4.8 2.3
CNS 4.0 4.8 5.2 4.1 3.3 4.1 4.2 4.1 3.1 4.5 3.6 3.1 6.3 5.2 2.3 4.3 5.7 1.7
Thyroid 3.7 3.8 3.4 3.0 0.6 5.8 2.1 3.8 4.8 4.1 2.9 1.9 5.2 8.0 0.5 6.3 5.9 2.6
Blood 9.0 6.9 6.7 6.3 7.2 13 5.0 8.1 16 6.8 11 6.9 14 19 5.0 9.3 12 4.8
Kazakhstan - 4.2 per 100 thousand population (rough indicators).
Regions with low mortality rate from liver cancer in 2020: Almaty city - 1.8; Atyrau region - 2.1; Aktobe region - 2.2. In 2021: Kostanay region - 1.6; Kyzylorda region - 1.7; Almaty region - 1.9 per 100 thousand population (rough indicators) (Figure 5).
For the indicator by regions: morbidity, mortality, postmortem (Figure 6).
Figure 4 - Specific weight of stage 4 liver cancer in Kazakhstan, %
Analysis of regions with low specific weight of stage 1 liver cancer in 2020-2021 showed that the most unfavorable region is Akmola - 38.9/61.1%, North Kazakhstan - 38.9%, and Pavlodar region - 27.7% (Figure 5).
Regions with high mortality rate from liver cancer in 2020: East Kazakhstan and West Kazakhstan - 4.8; Pavlodar region -4.4. In 2021: East Kazakhstan - 5.4; Pavlodar region - 4.7; West
Figure 5 - Specific weight of stage 1 and 4 liver cancer in Kazakhstan, %
In 2020, a high ratio was observed in Akmola region, Turkestan region and Shymkent city, and in 2021 - Turkestan region, East Kazakhstan and Pavlodar region.
It is important to estimate the proportion of postmortem detected patients for the quality indicator of lifetime diagnostics of liver cancer.
The highest share of postmortem-detected cancer patients in Kazakhstan was recorded for 2019-2021 for liver cancer and amounted to - 7.3-7.5-6.2%. The minimum share is within 0-0.9% for 12 localizations, average - from 1 to 3% for localizations and above average from 3-7.5% for 6 localizations (Figure 9).
Figure 5 - Mortality of Kazakhstan population from liver cancer by regions, per 100 thousand population.
Figure 6 - Morbidity and mortality of liver cancer in Kazakhstan by region.
Analyzing the data of morbidity and mortality rates by regions, attention is drawn to the indicators of high morbidity and low mortality in the regions: Atyrau, Zhambyl, Aktobe and Kyzylorda and North Kazakhstan.
The ratio of incidence and mortality from liver cancer in Kazakhstan in 2020-2021 is 67.4/59.57. By region, this indicator varies from 33.3 to 100: regions with high ratio - Akmola in 2020 100, in 2021 - 57.7; Turkestan 85.4/84.6, East Kazakhstan 81.4/79.4, Pavlodar region 80.0/67.4. With low ratio - Atyrau 45.7/33.3; Aktobe 41.5/38.6; Kyzylorda 54.1/32.1 (Figure 8).
-2019
-2020 -i-2021
Figure 8 - Ratio of liver cancer incidence and mortality in Kazakhstan by region
Figure 9 - Share of liver cancer deaths not registered with oncology organizations, %
Full 100% confirmation of the postmortem diagnosis by autopsy in 2020 was provided by oncological organizations of Zhambyl, Karaganda, Kostanay regions and Almaty city. Autopsies were not performed in 2020 and 2021 in Aktobe and Turkestan regions. In Kazakhstan, the overall rate of posthumously detected patients was -1.8% in 2019, 2.0% in 2020, and 1.6% in 2021. If we compare it with the indicators in Russia, the average indicator is 5.3% [The state of oncological care in Russia in 2019].
The ratio of one-year mortality and neglect (stage 4) in the republic in 2019-2021 was 1,9 - 1,8 - 1,7 , the recommended indicator is 1.0. In the first place of the worst indicator was taken by the central nervous system, but, liver cancer was in 6th place (Figure 10).
For the period 2019-2021, liver cancer in the ratio between one-year mortality and stage 4 negatively is ranked sixth place.
Analyzing liver cancer rates by gender for the study period, there is a positive indicator in the decreasing the incidence in men - Increase rate of -14.3% in 2029 and a significant increase in incidence rate of +7.3% in 2021. At the same time, mortality is steadily decreasing by -9.7% (Table 3).
The growth rate of morbidity and mortality shows how fast the indicator is increasing or decreasing in comparison with previous year. The values used for calculation are current value and comparable value according to the formula: current value/ comparable value x 100%. 543/634 х 100% - 100%
Indicators of diagnosis liver cancer in Kazakhstan among women for the first time their life, rough indicators
__
~~—___-—
~ ___
r —
2019 2020 2021
-male morbidity standardised rates 7,5 6,2 6,6
-male morbidity 7 5,9 6,3
mortality 4,4 4,1 3,7
mortality standardised rates 4,7 4,3 3,8
Figure 11 - Features of morbidity and mortality of liver cancer in Kazakhstan in men, per 100 thousand population.
Indicators of first-time diagnosis of liver cancer in Kazakhstan in men, rough indicators
Men
Indicators abs. number to 100 000. growth rate
years
2019 2020 2021 2019 2020 2021 2020 2021
Morbidity 634 543 583 7,0 5,9 6,3 -14,3 +7,3
Mortality 397 373 341 4,4 4,1 3,7 -6,8 -9,7
Women
Indicators abs. number to 100 000. growth rate
years
2019 2020 2021 2019 2020 2021 2020 2021
Morbidity 378 318 316 3,9 3,3 3,2 -15,9 -0,6
Mortality 245 207 197 2,6 2,1 2,0 -19,2 -4,7
can lead to unreasonable funding. To analyze a negative growth rate, other indicators need to be analyzed: the status of liver cancer detection in population screenings and post-mortem liver cancer detection rates.
Liver cancer rates for men were 7.0 - 5.9 - 6.3 per 100,000 population, for women, respectively, 3.9 - 3.3 - 3.2 in 2019-2021 (Figure 12).
Figure 10 - Correlation between one-year mortality and liver cancer neglect in the structure of MN in Kazakhstan (stage 4).
Figure 12 - Features of liver cancer morbidity and mortality in women in Kazakhstan, per 100 thousand population.
By analyzing the data of liver cancer by sex, no significant difference was found in results (p<0.05).
The mortality rate from MN decreased in both sexes by 4.5%, from 74.9 to 71.5 per 100,000 population, and the standardized mortality rate decreased by 5.1% in 2021.
The ratio of the standardized mortality rate from MN of men to that of women is stable at 1.6:1.0. The ratio of standardized liver cancer mortality rate is 2.5:1.0 in 2021, while there is a decrease in mortality in women over the three years to 4.4 in 2019, 4.1 in 2020 and 3.7 in 2021. Males also show a decrease in mortality rate of 4.4-4.1-3.7, respectively (Figure 13).
The incidence of MN population in the males was 151.3 or 14048 cases (2020 142.3 - 13036 cases) per 100,000 and in females was 171.5 and 188.3 in 2021.
Liver cancer in males were 7.0 - 5.9 - 6.3 per 100,000 population and in females were 4.4 - 4.1 - 3.7 respectively (Figure 11) in 2019-2021.
For women, growth rate of morbidity decreased -15.9 in 2019, and -0.6% in 2021, and mortality were19.2% and -4.7%, respectively (Table 4).
The morbidity of the male population of MN is 151.3 or 14048 cases (2020 142.3 - 13036 cases) per 100,000 population and in females 171.5 and 188.3 in 2021.
What are the dangers of fast and slow rates? Fast positive rates can lead to unrealistic expectations and negative fast rates
Figure 13 - Liver cancer mortality by sex, per 100,000 population.
In 2021, the number of patients with MN decreased from 647 to 562 deaths, or by 13%, and was 1.6%, in 2020 - 2.0%. Comparatively, in Russia this indicator in 2020 was 6.9%.
By regions of Kazakhstan mortality rates from MN show dependence on the sex and age composition of the population. The specific weight of liver cancer in the structure of MN in Kazakhstan for 2019-2021 ranked 5/8 in men and 12/12 in women.
The most consistently low five-year survival rate of patients with MN in Kazakhstan with liver and pancreatic cancer, and high - MN of bones and articular cartilage and larynopharynx (Figure 14).
v v////// *///'///////
<V ■J' rv
/ / /
Figure 14 - Five-year survivability of patients with liver cancer in Kazakhstan, %
^ <i> £ J
The five-year survivability of liver cancer is the lowest -this is another factor confirming liver cancer in the early stages. Official statistical compilations do not take into account the coverage of special treatment in oncology. The radical treatment of liver cancer is interventional method in the early stages in Kazakhstan (Figure 15).
- 4.8, Pavlodar - 4.4; the three lowest indicators were identified: Almaty city - 1.8; Atyrau - 2.1; Aktobe and Astana - 2.2.
The number of deaths from malignant neoplasms not registered with oncological organizations - liver cancer in the first place in 2019 and 2020, blood cancer in the second place, pancreatic cancer in the third place.
The top three diseases with the highest one-year mortality rates are pancreatic cancer at 59.6%, liver cancer at 46.9% and oesophageal cancer at 43.4% in 2020. At the same time, compared to 2019, liver cancer showed a worsening of this indicator by 17.7%. The leading negative place over 2 years for the ratio between one-year mortality and neglect (stage 4) belonged to malignant neoplasms of the central nervous system
- 5.5 and 7.8 The positive ratio (1.0) was breast cancer in 2019 and bone and articular cartilage cancer - 1.1 in 2020.
In Kazakhstan, the lowest five-year survival rate for liver cancer patients was 23.8 % in 2019 and 26.2 %in 2020. Pancreatic cancer has a slightly better statistics like 33.5% and 32.3%, and also, blood cancer numbers at 53.7% and 54.4%.
Conclusion
In Kazakhstan, standardized indicators of liver cancer incidence are low, and in the structure of morbidity they are not among the top ten of the number of registered malignant diseases, while liver cancer is in first place among the deceased who are not registered at the dispensary during 2019 and 2020. Also, liver cancer is one of the three stable anti-leaders of malignant neoplasms with mortality within a year and low five-year survival
It is necessary to introduce new modern approaches to early diagnosis and modern treatment of liver cancer in Kazakhstan.
It is necessary to include in the monitoring of liver cancer treatment methods - an interventional method that is used worldwide in routine practice for early diagnosis of liver cancer.
Disclosures: There is no conflict of interest for all authors.
Acknowledgements: None. Funding: None.
Figure 15 - Coverage of specialized treatment for liver cancer patients in the Republic of Kazakhstan
Results and discussion
For the period 2019-2020, liver cancer ranked 7th in the structure of standardized morbidity rates in men and its specific weight was 7.5% in 2019, and 6.2% and 9th in 2020, growth rate = -17.3 in the structure of malignant neoplasms (MN) morbidity in Kazakhstan. In females it is 3.1/2.5, growth rate = -19.3.
Standardized incidence rates of liver cancer were 4.9 per 100,000 population in 2019 and 4.1 in 2020, growth rate = -16.3.
Mortality from liver cancer was 3.4 per 100,000 population in 2019 and 3.1 in 2020: in men 4.4/4.1 and in women 2.6/2.1 respectively. Place in mortality structure was 10th place - in 2019; and 8th in 2020.
In 2020, the top three regions with high mortality rates from liver cancer were East Kazakhstan - 4.8. West-Kazakhstan
References
1. Chekmazov I.A., Ivanikov I.O. et al. Liver cancer: etiology, pathogenesis, results of clinical and epidemiological observation. Evidence-based Gastroenterology. 2019; 8(1):5-15. https://doi.org/10.17116/dokgastro201980115
2. Abdlaty R, Abbass MA, Awadallah AM. Radiofrequency ablation for liver: Comparison between expert eye and hyperspectral imaging assessment. PhotodiagnosisPhotodyn Ther. 2022; 37:102699. https://doi.org/10.1016/j.pdpdt.2021.102699
3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. https://doi.org/10.3322/ caac.21660
4. Bruix J, Han KH, Gores G, Llovet JM, Mazzaferro V. Liver cancer: Approaching a personalized care. J Hepatol. 2015; 62(1 Suppl):144-56. https://doi.org/10.1016/jjhep.2015.02.007
5. Bo XW, Xu HX, Wang D, Guo LH, Sun LP, Li XL, Zhao CK, He YP, Liu BJ, Li DD, Zhang K. Fusion imaging of contrast-enhanced ultrasound and contrast-enhanced CT or MRI before radiofrequency ablation for liver cancers. Br J Radiol. 2016; 89(1067):20160379. https://doi.org/10.1259/bjr.20160379
6. Minami Y, Kudo M. Image Guidance in Ablation for Hepatocellular Carcinoma: Contrast-Enhanced Ultrasound and Fusion Imaging. Front Oncol. 2021; 11:593636. https://doi.org/10.3389/fonc.2021.593636
7. Carloni R, Rizzo A, Cusmai A, Palloni A, Federico AD, Marco MD, Massafra R, Fanizzi A, Palmiotti G, Brandi G. Advances in novel systemic therapies for advanced hepatocellular carcinoma. Future Med Chem. 2022; 14(20):1455-1470. https://doi.org/10.4155/fmc-2022-0045
8. Wong KM, King GG, Harris WP. The Treatment Landscape of Advanced Hepatocellular Carcinoma. Curr Oncol Rep. 2022; 24(7):917-927. https://doi.org/10.1007/s11912-022-01247-7
9. Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol. 2023; 29(17):2571-2599. https://doi. org/10.3748/wjg.v29.i17.2571
