nach oben

Current Hepatology Reports

Erschienen in:

07.11.2017 | Drug-Induced Liver Injury (F Bessone and R Andrade, Section Editors)

Hepatotoxicity of New Antitumor Agents

verfasst von: Nelia Hernandez

Erschienen in: Current Hepatology Reports | Ausgabe 4/2017

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

Cancer therapy had a noteworthy development in recent years, mostly focused in targeted therapies. Even if it is expected that these agents would be less harmful, their use has been associated with several side effects. This review focuses on hepatotoxicity concerning molecular targeted therapy particularly the tyrosine kinase inhibitors, monoclonal antibodies, and immune checkpoint inhibitors.

Recent Findings

The tyrosine kinase inhibitor hepatotoxicity is one of the serious class-related adverse events and has been linked to severe and fatal liver injury. The use of immune checkpoint inhibitors is associated with autoimmune-like side effects. The mechanism of liver injury is likely to be immunologically mediated, even if serum autoantibodies are not usually present, and responsiveness to corticosteroid therapy is reported.

Summary

New antitumor agents, mainly tyrosine kinase inhibitors and immune checkpoint inhibitors, are a significant cause of liver injury. Even if in most instances, molecular targeted therapy-induced hepatotoxicity is reversible, several of these agents have been linked to fatal liver injury.

• Ulcickas Yood UM, Bortolini M, Casso D, Beck Jean G, Oliveria SA, Wells K, et al. Incidence of liver injury among cancer patients receiving chemotherapy in an integrated health system. Pharmacoepidemiol Drug Saf. 2015;24:426–33. Using automated data, among 2788 chemotherapy-exposed patients, 3.3% had elevated LLTs suggestive of DILI. However, after a medical record review only two patients (0.07%) with chemotherapy have not another potential alternative cause of liver injury

• Chalasani N, Bonkovsky HL, Fontana RJ, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148:1340–52. Last update of cases of drug induced liver injury in the US, collected from 2004. CrossRefPubMedPubMedCentral

Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.CrossRefPubMed

Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8:3034–8.PubMed

Van Hootegem A, Verslype C, Van Seenbergen W. Sorafenib-induced liver failure: a case report and review of the literature. Case Rep Hepatol. 2011;2011:941395.

Guillen SS, Meijer M, de Jongh FE. Lethal acute liver failure in a patient treated with sunitinib. BMJ Case Rep. 2016;2016 https://doi.org/10.1136/bcr-2015-213624.

Klempner SJ, Choueiri TK, Yee E, Doyle LA, Schuppan D, Atkins MB. Severe pazopanib-induced hepatotoxicity: clinical and histologic course in two patients. J Clin Oncol. 2012;30:e264–8.CrossRefPubMed

Takeda M, Okamoto I, Fukuoka M, Nakagawa K. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol. 2010;28:e273–4.CrossRefPubMed

Peroukides S, Makatsoris T, Koutras A, Tsamandas A, Onyenadum A, Labropoulou-Karatza C, et al. Lapatinib-induced hepatitis: a case report. World J Gastroenterol. 2011;17:2349–52.CrossRefPubMedPubMedCentral

10.

Kapadia S, Hapani S, Choueiri TK, Wu S. Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients. Acta Oncol. 2013;52:1202–12.CrossRefPubMed

11.

• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503. Systematic review of the currently available information on the liver injury potential of tyrosine kinase inhibitors [crizotinib, imatinib, lapatinib, pazopanib, ponatinib, regorafenib, sunitinib]. CrossRefPubMed

12.

• Iacovelli R, Palazzo A, Procopio G, Santoni M, Trenta P, De Benedetto A, et al. Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy. Br J Clin Pharmacol. 2014;77:929–38. Meta analysis for phase III randomized trials with axitinib, pazopanib, sorafenib, sunitinib, regorafenib or vandetanib. A significant increase in the relative risk of grade 3–4 ALT increase was present for sorafenib and pazopanib but not for sunitinib

13.

Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev. 2013;39:199–206.

14.

• Teo YL, Ho HK, Chan A. Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review. Expert Opin Drug Metab Toxicol. 2015;11:231–42. Review of the literature of mechanism of action involved in tyrosine kinase inhibitor-induce hepatotocitiy and the strategies adopted to overcome this adverse event. The experts highlight the formation of reactive metabolites and its potential for liver toxicity

15.

Aliberti S, Grignani G, Allione P, Fizzotti M, Galatola G, Pisacane A, et al. An acute hepatitis resembling autoimmune hepatitis occurring during imatinib therapy in a gastrointestinal stromal tumor patient. Am J Clin Oncol. 2009;32:640–1.CrossRefPubMed

16.

Bonvin A, Mesnil A, Nicolini FE, Cotte L, Michallet M, Descortes J, et al. Dasatinib-induced acute hepatitis. Leuk Lymphoma. 2008;49:1630–2.CrossRefPubMed

17.

• Spraggs CF, Parham LR, Briley LP, Warren L, Williams LS, Fraser DJ, et al. Characterization of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes. Pharmacogenomics J. 2017; https://doi.org/10.1038/tpj.2017.39. Among 8381 patients with HER2- overexpressing primary breast cancer treated with lapatinib or trastuzumab or both, HLADRB1* 07:01 carriage was associated with serum ALT elevations in lapatinib-treated patients. The authors suggest that the use of genetic testing may support causality discrimination and safety risk management during the use of this therapy

18.

Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes MR, et al. Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. J Hepatol. 2011;54:1237–43.CrossRefPubMed

19.

• Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics. 2013;14:541–54. Review of genetic studies of lapatinib and pazopanib demonstrating different mechanisms of hepatotoxicity and the utility of genetic studies to improve safety management. CrossRefPubMed

20.

Westgeest HM, van Erp NP, Honeywell RJ, Hoekstra R, Peters GJ, Verheul HM. Successful treatment of renal cell carcinoma with sorafenib after effective but hepatotoxic sunitinib exposure. J Clin Oncol. 2013;31:e83–6.CrossRefPubMed

21.

Klinger M1, Eipeldauer S, Hacker S, Herberger B, Tamandl D, Dorfmeister M, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35:515–20.CrossRefPubMed

22.

Muñoz A, Carrera S, Ferreiro J, Ruiz de Lobera A, Mañe JM, Lopez-Vivanco G. Reversible liver toxicity with adjuvant trastuzumab for localized breast cancer. Ann Oncol. 2007;18:2045–6.CrossRefPubMed

23.

Vucicevic D, Carey EJ, Karlin NJ. Trastuzumab-induced hepatotoxicity: a case report. Breast Care. 2013;8:146–8.CrossRefPubMedPubMedCentral

24.

Srinivasan S, Parsa V, Liu CY, Fontana JA. Trastuzumab-induced hepatotoxicity. Ann Pharmacother. 2008;42:1497–501.CrossRefPubMed

25.

• Sadeghi S, Olevsky O, Hurvitz AS. Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine. Pharmagenomics Pers Med. 2014;15:329–38. Review of data relating to trastuzumab emtansine use for (HER2)-positive breast cancer. The most common toxicities described were thrombocytopenia and an elevation in liver transaminases

26.

• Force J, Saxena R, Schneider BP, Storniolo AM, Sledge GW Jr, Chalasani N, et al. Nodular regenerative hyperplasia after treatment with trastuzumab emtansine. J Clin Oncol. 2016;20:34:e9–12. Two women presented with ascites, varices, and low platelet 16 months after starting therapy with trastuzumab emtansine for metastatic breast cancer. Liver biopsy demonstrated nodular regenerative hyperplasia. Both patients were improving after the drug was interrupted.

27.

• Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One. 2016;11(7):e0160221. https://doi.org/10.1371/journal.pone.0160221. Systematic review of case reports describing immune-related adverse events in patients receiving ipilimumab, nivolumab, or pembroluzimab. Among 251 cases, the majority treated with ipilimumab (93.2%), autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported adverse event. Gastrointestinal adverse events were not reported in patients treated with pembrolizumab [10 cases] or nivolumab [7 cases]. CrossRefPubMedPubMedCentral

28.

Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40.CrossRefPubMedPubMedCentral

29.

• Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015;39:1075–84. Clinical and histological features of 11 patients with liver injury after 1 to 4 doses of ipilimumab; 10 men, median age 58 y. Nine biopsies showed active hepatitis with prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis (8 cases). Discontinuation of ipilimumab and immunosuppressive therapy resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation

30.

• Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7. Review of the immune-related adverse events associated with ipilimumab and their management. The authors recommend use of high doses of corticosteroids for 2 days followed by tapering doses to at least 30 days, and ipilimumab should not be restarted. CrossRefPubMed

31.

• Imafuku K, Yoshino K, Yamaguchi K, Tsuobi S, Ohara K, Hata H. Successful treatment of sudden hepatitis induced by long-term nivolumab administration. Case Rep Oncol. 2017;10:368–71. 57 year old man with metastatic melanoma developed asymptomatic hepatitis after 34 weeks of nivolumab. The AST/ALT level improved after the patient stopped taking nivolumab and was treated with 1.0 mg/kg/day of systemic cortico

32.

• Simonelli M, Di Tommaso L, Baretti M, Santoro A. Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Immunotherapy. 2016;8:1363–9. 68 years old man with glioblastoma developed colitis and hepatitis after 4 courses of nivolumab. The patient had promptly responsiveness to corticosteroid therapy and to suspension of nivolumab therapy but recurred after the tapering of corticosteroids. CrossRefPubMed

Titel: Hepatotoxicity of New Antitumor Agents
verfasst von: Nelia Hernandez
Publikationsdatum: 07.11.2017
Verlag: Springer US
Erschienen in: Current Hepatology Reports / Ausgabe 4/2017
Elektronische ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-017-0381-7

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Purpose of Review

Recent Findings

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2017

Managing HCC in NAFLD

The Management of Bleeding from Anorectal Varices

Non-alcoholic Fatty Liver Disease in Non-obese Patients

Role of Exercise in NAFLD/NASH: What is the Right Prescription?

Natural History of NAFLD/NASH