Drug-Induced Liver Injury and the Likelihood of Hepatocellular Carcinoma During Chemotherapy for Colorectal Cancer (Meta-Analysis)
https://doi.org/10.22416/1382-4376-2025-35-3-94-103
Abstract
Tumor diseases are one of the leading causes of death worldwide. Neoadjuvant and adjuvant chemotherapy can potentially lead to drug-induced liver injury and carcinoma. According to the literature review and meta-analysis, the mean weighted incidence of drug-induced liver injuries for all drugs among patients receiving neoadjuvant chemotherapy for colorectal cancer with liver metastases is 63.2 %. The mean weighted incidence of severe liver injury is 37.2 %. However, we have not found clinical reports of liver carcinoma formation due to chemotherapy. At present, we can say that, despite the theoretical possibility, chemotherapy for colorectal cancer is not accompanied by the development of hepatocellular carcinoma.
About the Authors
T. N. Garmanova
M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
Tatyana N. Garmanova — Cand. Sci. (Med.), Associate Professor of the Department of Surgical Diseases, Leading Researcher of the Department of Surgery and Oncology, Medical Research and Educational Institute
119991, Moscow, Leninskie gory, 1
D. R. Markaryan
M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
Daniil R. Markaryan — Cand. Sci. (Med.), Senior Researcher at the Department of Surgery and Oncology, Head of the Department of Abdominal and Thoracic Oncology, Medical Research and Educational Institute
119991, Moscow, Leninskie gory, 1
E. A. Kazachenko
M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
Ekaterina A. Kazachenko — Postgraduate of the Department of Surgical Diseases, Medical Research and Educational Institute
119991, Moscow, Leninskie gory, 1
G. V. Tishkin
M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
German V. Tishkin — Resident of the Department of Surgical Diseases, Medical Research and Educational Institute
119991, Moscow, Leninskie gory, 1
R. V. Ishchenko
M.V. Lomonosov Moscow State University
Russian Federation
Russian Federation
Roman V. Ishchenko — Dr. Sci. (Med.), Professor of the Department of Surgical Diseases, Medical Research and Educational Institute
119991, Moscow, Leninskie gory, 1
References
1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca A Cancer Journal for Clinicians. 2021;71(3):209–49. DOI: 10.3322/caac.21660
2. Björnsson E.S., Stephens C., Atallah E., Robles-Diaz M., Alvarez-Alvarez I., Gerbes A., et al. A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry. Liver Int. 2023;43(1):115–26. DOI: 10.1111/liv.15378
3. Han J., Liu J., Yu Z., Huang R., Zhao L., Xu Y., et al. Risk factors for irinotecan-induced liver injury: A retrospective multicentre cross-sectional study in China. BMJ open. 2023;13(6):e069794. DOI: 10.1136/bmjopen-2022-069794
4. Zeien J., Qiu W., Triay M., Dhaibar H.A., Cruz-Topete D., Cornett E.M., et al. Clinical implications of chemotherapeutic agent organ toxicity on perioperative care. Biomed Pharmacother. 2022;146:112503. DOI: 10.1016/j.biopha.2021.112503
5. Arjmand A., Tsipouras M.G., Tzallas A.T., Forlano R., Manousou P., Giannakeas N. Quantification of liver fibrosis — A comparative study. Applied Sciences. 2020;10(2):447. DOI: 10.3390/app10020447
6. Narita M., Oussoultzoglou E., Chenard M.P., Fuchshuber P., Rather M., Rosso E., et al. Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol. 2012;19(7):2230–7. DOI: 10.1245/s10434-011-2112-6
7. Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Rev Panam Salud Publica. 2022;46:e112. DOI: 10.26633/rpsp.2022.112
8. Saracoglu I., Akin E., Aydin Dincer G.B. Efficacy of adding pain neuroscience education to a multimodal treatment in fibromyalgia: A systematic review and meta-analysis. Int J Rheum Dis. 2022;25(4):394–404. DOI: 10.1111/1756-185X.14293
9. Zhang Y., Huang L., Wang D., Ren P., Hong Q., Kang D. The ROBINS-I and the NOS had similar reliability but differed in applicability: A random sampling observational studies of systematic reviews/meta-analysis. J Evid Based Med. 2021;14(2):112–22. DOI: 10.1111/jebm.12427
10. Luchini C., Veronese N., Nottegar A., Shin J.I., Gentile G., Granziol U., et al. Assessing the quality of studies in meta-research: Review/guidelines on the most important quality assessment tools. Pharm Stat. 2021;20(1):185–95. DOI: 10.1002/pst.2068
11. Soubrane O., Brouquet A., Zalinski S., Terris B., Brézault C., Mallet V., et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: Correlation with post-hepatectomy outcome. Ann Surg. 2010;251(3):454–60. DOI: 10.1097/SLA.0b013e3181c79403
12. Mehta N.N., Ravikumar R., Coldham C.A., Buckels J.A.C., Hubscher S.G., Bramhall S.R., et al. Effect of preoperative chemotherapy on liver resection for colorectal liver metastases. Eur J Surg Oncol. 2008;34(7):782–6. DOI: 10.1016/j.ejso.2007.09.007
13. Rubbia-Brandt L., Lauwers G.Y., Wang H., Majno P.E., Tanabe K., X Zhu A. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56(4):430–9. DOI: 10.1111/j.1365-2559.2010.03511.x
14. Nordlinger B., Benoist S., Penna C. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;244(5):835.
15. Narita M., Oussoultzoglou E., Jaeck D. Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18(Suppl. 3):S310. DOI: 10.1245/s10434-011-1936-4
16. Viganò L., Capussotti L., De Rosa G., De Saussure W.O., Mentha G., Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: Impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731–42. DOI: 10.1097/SLA.0b013e-3182a6183e
17. Miura K., Nakano H., Sakurai J., Kobayashi S., Koizumi S., Arai T., et al. Splenomegaly in FOLFOX-naïve stage IV or recurrent colorectal cancer patients due to chemotherapy-associated hepatotoxicity can be predicted by the aspartate aminotransferase to platelet ratio before chemotherapy. Int J Clin Oncol. 2011;16(3):257–63. DOI: 10.1007/s10147-010-0176-0
18. Karoui M., Penna C., Amin-Hashem M., Mitry E., Benoist S., Franc B., et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243(1):1–7. DOI: 10.1097/01.sla.0000193603.26265.c3
19. Tamandl D., Klinger M., Eipeldauer S., Herberger B., Kaczirek K., Gruenberger B., et al. Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18(2):421–30. DOI: 10.1245/s10434-010-1317-4
20. Galimova S.F. Drug-induced liver injuries (part I). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2012;22(3):38–48. (In Russ.).
21. Real M., Barnhill M.S., Higley C., Rosenberg J., Lewis J.H. Drug-induced liver injury: Highlights of the recent literature. Drug Safety. 2019;42(3):365–87. DOI: 10.1007/s40264-018-0743-2
22. Sun Y.K., Zhang Y.F., Xie L., Rong F., Zhu X.Y., Xie J., et al. Progress in the treatment of drug-induced liver injury with natural products. Pharmacol Res. 2022;183:106361. DOI: 10.1016/j.phrs.2022.106361
23. Garcia-Cortes M., Robles-Diaz M., Stephens C., OrtegaAlonso A., Lucena M.I., Andrade R.J. Drug induced liver injury: An update. Arch Toxicol. 2020;94(10):3381–407. DOI: 10.1007/s00204-020-02885-1
24. Li X., Tang J., Mao Y. Incidence and risk factors of drug-induced liver injury. Liver Int. 2022;42(9):1999–2014. DOI: 10.1111/liv.15262
25. Björnsson H.K., Björnsson E.S. Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management. Eur J Intern Med. 2022;97:26–31. DOI: 10.1016/j.ejim.2021.10.035
26. Andrade R.J., Chalasani N., Björnsson E.S., Suzuki A., Kullak-Ublick G.A., Watkins P.B., et al. Druginduced liver injury. Nat Rev Dis Primers. 2019;5(1):58. DOI: 10.1038/s41572-019-0105-0
27. Strobach D., Benesic A. Drug-induced liver injury. Krankenhauspharmazie. 2023;44(1):3–9.
28. Ragab M., Schlichting H., Hicken M., Mester P., Hirose M., Almeida L.N., et al. Azathioprine promotes intestinal epithelial cell differentiation into Paneth cells and alleviates ileal Crohn’s disease severity. Sci Rep. 2024;14(1):12879. DOI: 10.1038/s41598-024-63730-4
29. Shojaie L., Iorga A., Dara L. Cell death in liver diseases: A review. Int J Mol Sci. 2020;21(24):9682. DOI: 10.3390/ijms21249682
30. Weber S., Gerbes A.L. Challenges and future of drug-induced liver injury research — Laboratory tests. Int J Mol Sci. 2022;23(11):6049. DOI: 10.3390/ijms23116049
31. Devarbhavi H., Aithal G., Treeprasertsuk S., Takikawa H., Mao Y., Shasthry S.M.; Asia Pacific Association of Study of Liver. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines. Hepatol Int. 2020;15(2):258–82. DOI: 10.1007/s12072-021-10144-3
32. Gijbels E., Vilas-Boas V., Deferm N., Devisscher L., Jaeschke H., Annaert P., et al. Mechanisms and in vitro models of drug-induced cholestasis. Arch Toxicol. 2019;93(5):1169–86. DOI: 10.1007/s00204-019-02437-2
33. Hwang D.B., Seo Y., Lee E., Won D.H., Kim C., Kang M.H., et al. Diagnostic potential of serum miR-532-3p as a circulating biomarker for experimental intrinsic drug-induced liver injury by acetaminophen and cisplatin in rats. Food Chem Toxicol. 2023;178:113890. DOI: 10.1016/j.fct.2023.113890
34. Chen R., Li W., Li R., Ai S., Zhu H., Lin W. Cysteine-activated fluorescence/photoacoustic integrated probe for non-invasive diagnosis of drug-induced liver injury. Chinese Chemical Letters. 2023;34(5):107845. DOI: 10.1016/j.cclet.2022.107845
35. Ramachandran R., Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol. 2009;62(6):481–92. DOI: 10.1136/jcp.2008.058248
36. Ivashkin V.T., Raikhelson K.L., Palgova L.K., Maevskaya M.V., Gerasimova O.A., Kondrashina E.A., et al. Drug-induced liver injury in cancer patients. Oncohematology. 2020;15(3):80–94. (In Russ.). DOI: 10.17650/1818-8346-2020-15-3-80-94
37. Yang X.Q., Ye J., Li X., Li Q., Song Y. Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: Pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes. World J Gastroenterol. 2019;25(28):3753–63. DOI: 10.3748/wjg.v25.i28.3753
38. Corbacioglu S., Jabbour E.J., Mohty M. Risk factors for development of and progression of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Biol Blood Marrow Transplant. 2019;25(7):1271–80. DOI: 10.1016/j.bbmt.2019.02.018
39. Weiss B.M., Sawinski D. Sinusoidal obstruction syndrome. Onco-Nephrology E-Book. 2019;40(4):99–106.e4.
40. Nakano H., Oussoultzoglou E., Rosso E., Casnedi S., Chenard-Neu M.P., Dufour P., et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247(1):118–24. DOI: 10.1097/SLA.0b013e31815774de
41. Zhu C., Ren X., Liu D., Zhang C. Oxaliplatin-induced hepatic sinusoidal obstruction syndrome. Toxicology. 2021;460:152882. DOI: 10.1016/j.tox.2021.152882
42. Teng Y.X., Xie S., Guo P.P., Deng Z.J., Zhang Z.Y., Gao W., et al. Hepatocellular carcinoma in non-alcoholic fatty liver disease: Current progresses and challenges. J Clin Transl Hepatol. 2022;10(5):955–64. DOI: 10.14218/JCTH.2021.00586
43. Chidambaranathan-Reghupaty S., Fisher P.B., Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1–61. DOI: 10.1016/bs.acr.2020.10.001
44. Müller M., Bird T.G., Nault J.C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020;72(5):990–1002. DOI: 10.1016/j.jhep.2020.01.019
45. Semendyaeva M.I., Merculov I.A., Pastukhov A.I., Gaydascheva E.V., Lesnyak V.N., Schutova O.V. Hepatocellular carcinoma today. Journal of Clinical Practice. 2013;2(14):35–49. (In Russ.).
46. Wang W., Gao W., Zhu Q., Alasbahi A., Seki E., Yang L. TAK1: A molecular link between liver inflammation, fibrosis, steatosis, and carcinogenesis. Front Cell Dev Biol. 2021;9:734749. DOI: 10.3389/fcell.2021.734749
47. Dhar D., Baglieri J., Kisseleva T., Brenner D.A. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood). 2020;245(2):96–108. DOI: 10.1177/1535370219898141
Supplementary files
Review
For citations:
Garmanova T.N., Markaryan D.R., Kazachenko E.A., Tishkin G.V., Ishchenko R.V. Drug-Induced Liver Injury and the Likelihood of Hepatocellular Carcinoma During Chemotherapy for Colorectal Cancer (Meta-Analysis). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2025;35(3):94-103. https://doi.org/10.22416/1382-4376-2025-35-3-94-103
Views:
16
Email this article 
