The impact of pazopanib and extremity radiotherapy on transaminase elevations in soft tissue sarcoma
DOI:
https://doi.org/10.2340/1651-226X.2026.46196Keywords:
radiotherapy, pazopanib, transaminase elevations, soft-tissue sarcoma, heptatotoxicityAbstract
Background and purpose: Unexpected high rates of grade ≥ 3 transaminase elevations were observed in patients receiving pazopanib and extremity radiotherapy. Although alanine transaminase (ALT) and aspartate transaminase (AST) primarily originate from the liver, both are also present in muscle tissue. In extremity soft tissue sarcomas (STS), where large muscle volumes are within the radiation field, radiation-induced muscle damage may contribute to these elevations. This study evaluated the impact of extremity radiotherapy, pazopanib, and their combination on the incidence and degree of ALT/AST elevations in STS patients.
Patients and methods: A prospective cohort treated with extremity radiotherapy alone was combined with a retrospective cohort treated with pazopanib alone or in combination. Patient characteristics, treatment details, and laboratory values (liver enzymes and muscle injury biomarkers) were collected. Descriptive analyses and logistic regression were conducted to evaluate the association with grade ≥ 3 ALT/AST elevations.
Results: Among 154 patients (10 radiotherapy, 108 pazopanib, 36 radiotherapy plus pazopanib), none of the radiotherapy-only patients experienced grade ≥ 3 elevations. Post-irradiation ALT/AST, creatine kinase and myoglobin elevations were minimal. Grade ≥ 3 elevations occurred in 6% of patients receiving pazopanib and 36% of those receiving both radiotherapy and pazopanib. All elevations typically resolved after pazopanib discontinuation. Grade ≥ 3 elevations were significantly associated with pazopanib, and modestly associated with pazopanib trough levels (odds ratio [OR]: 1.43 per 10 mg/L, 95% confidence interval [CI]: 1.12–1.90), but not with radiotherapy.
Interpretation: Adding pazopanib to radiotherapy in localised extremity sarcoma significantly increases the rate of AST/ALT elevations. Extremity radiotherapy alone does not induce clinically relevant transaminase elevations. Grade ≥ 3 elevations were associated with pazopanib treatment. The mechanism underlying the substantially higher incidence of transaminase elevations with combined pazopanib and radiotherapy, compared with pazopanib alone, remains unknown.
Downloads
References
SEER*Explorer. SEER incidence data soft tissue [Internet]. National Cancer Institute; 2025 [cited 2025 Dec 24]. Available from: https://seer.cancer.gov/statistics-network/explorer/
Blay JY, Le Cesne A, Penel N, Bompas E, Chevreau C, Duffaud F, et al. 1397O – the nationwide cohort of 26,883 patients with sarcomas treated in NETSARC reference network between 2010 and 2015 in France: major impact of multidisciplinary board presentation prior to 1st treatment. Ann Oncol. 2016;27:vi483 DOI: https://doi.org/10.1093/annonc/mdw388.03
Haas RLM, Gelderblom H, Sleijfer S, van Boven HH, Scholten A, Dewit L, et al. A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities. Acta Oncol. 2015;54:1195–201 DOI: https://doi.org/10.3109/0284186X.2015.1037404
van Meekeren M, Bovee JVMG, van Coevorden F, van Houdt W, Schrage Y, Koenen AM, et al. A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma. Acta Oncol. 2021;60:1557–64 DOI: https://doi.org/10.1080/0284186X.2021.1971294
Van Riet BHG, Van Meekeren M, Fiocco M, Miah A, De Pree I, Wiltink LM, et al. Long-term survival of participants in the PASART-1 and PASART-2 trials of neo-adjuvant pazopanib and radiotherapy in soft tissue sarcoma. Acta Oncol. 2025;64:69-77 DOI: https://doi.org/10.2340/1651-226X.2025.42333
van der Graaf WTA, Blay J-Y, Chawla SP, Kim D-W, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–86 DOI: https://doi.org/10.1016/S0140-6736(12)60651-5
Powles T, Bracarda S, Chen M, Norry E, Compton N, Heise M, et al. Characterisation of liver chemistry abnormalities associated with pazopanib monotherapy: a systematic review and meta-analysis of clinical trials in advanced cancer patients. Eur J Cancer. 2015;51:1293–302 DOI: https://doi.org/10.1016/j.ejca.2015.03.019
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 DOI: https://doi.org/10.3109/0284186X.2013.782103
Nakamura T, Matsumine A, Kawai A, Araki N, Goto T, Yonemoto T, et al. The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: a Japanese Musculoskeletal Oncology Group (JMOG) study. Cancer. 2016;122:1408–16 DOI: https://doi.org/10.1002/cncr.29961
European Medicines Agency. VOTRIENT (pazopanib): summary of product characteristics [Internet]. 2021 [cited 2025 Dec 24]; 60 p. Available from: https://www.ema.europa.eu/en/documents/product-information/votrient-epar-product-information_en.pdf
Wang X, Chen R, Liu J, Wang E, Luo H. Liver injury related to vascular endothelial growth factor tyrosine kinase inhibitors: a pharmacovigilance analysis of the USA FDA adverse event reporting system (FAERS) database. Expert Opin Drug Saf. 2026;25(7):1351-59 DOI: https://doi.org/10.1080/14740338.2025.2460449
LiverTox: clinical and research information on drug-induced liver injury [Internet]. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2012 [cited 2025 Dec 24]. Consulted entries: pazopanib, imatinib, lapatinib, crizotinib. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547852/
Tan Z, Völler S, Yin A, Rieborn A, Gelderblom H, van der Hulle T, et al. Model-informed dose optimization of pazopanib in real-world patients with cancer. Clin Pharmacokinet. 2025;64:715–28 DOI: https://doi.org/10.1007/s40262-025-01504-5
Noda S, Yoshida T, Hira D, Murai R, Tomita K, Tsuru T, et al. Exploratory investigation of target pazopanib concentration range for patients with renal cell carcinoma. Clin Genitourin Cancer. 2019;17:e306–13 DOI: https://doi.org/10.1016/j.clgc.2018.12.001
Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, et al. Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer. 2014;111:1909–16 DOI: https://doi.org/10.1038/bjc.2014.503
Minot-This MS, Boudou-Rouquette P, Jouinot A, de Percin S, Balakirouchenane D, Khoudour N, et al. Relation between plasma trough concentration of pazopanib and progression-free survival in metastatic soft tissue sarcoma patients. Pharmaceutics. 2022;14:1234 DOI: https://doi.org/10.22541/au.164916726.61084520/v1
Moriles KE, Azer SA. Alanine amino transferase. Treasure Island, FL: StatPearls Publishing; 2020 [cited 2025 Dec 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559278/
Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18–35 DOI: https://doi.org/10.1038/ajg.2016.517
Lecina M, Castellar C, Pradas F, López-Laval I. 768-km multi-stage ultra-trail case study-muscle damage, biochemical alterations and strength loss on lower limbs. Int J Environ Res Public Health. 2022;19:876 DOI: https://doi.org/10.3390/ijerph19020876
Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Safety. 2006;15:241-43 DOI: https://doi.org/10.1002/pds.1211
Wang Y, Chia YL, Nedelman J, Schran H, Mahon FX, Molimard M. A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther Drug Monit. 2009;31:579–84 DOI: https://doi.org/10.1097/FTD.0b013e3181b2c8cf
Herbrink M, de Vries N, Rosing H, Huitema AD, Nuijen B, Schellens JH, et al. Quantification of 11 therapeutic kinase inhibitors in human plasma for therapeutic drug monitoring using liquid chromatography coupled with tandem mass spectrometry. Ther Drug Monit. 2016;38:649–56 DOI: https://doi.org/10.1097/FTD.0000000000000349
U.S. Food and Drug Administration. VOTRIENT (pazopanib) prescribing information [Internet]. 2024 [cited 2025 Dec 24]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022465s036lbl.pdf
R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. Available from: https://www.R-project.org/
Miyake K, Miyake N, Kondo S, Tabe Y, Ohsaka A, Miida T. Seasonal variation in liver function tests: a time-series analysis of outpatient data. Ann Clin Biochem. 2009;46:377–84 DOI: https://doi.org/10.1258/acb.2009.008203
Carobene A, Røraas T, Sølvik U, Sylte MS, Sandberg S, Guerra E, et al. Biological variation estimates obtained from 91 healthy study participants for 9 enzymes in serum. Clin Chem. 2017;63:1141–50 DOI: https://doi.org/10.1373/clinchem.2016.269811
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45 DOI: https://doi.org/10.1038/clpt.1981.154
Maillard M, Arellano C, Vachoux C, Chevreau C, Cabaton NJ, Pont F, et al. Biological role of pazopanib and sunitinib aldehyde derivatives in drug-induced liver injury. Metabolites. 2022;12:852 DOI: https://doi.org/10.3390/metabo12090852
Wang YK, Yang XN, Liang WQ, Xiao Y, Zhao Q, Xiao XR, et al. A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice. Xenobiotica. 2019;49:655–70 DOI: https://doi.org/10.1080/00498254.2018.1489167
Chen J, Zhu T, Deng Y, Chen J, Jiang G, He Q. Activation of HSPA5 contributes to pazopanib-induced hepatotoxicity through l-ornithine metabolism pathway and endoplasmic reticulum stress. J Pharm Pharmacol. 2025;77:564–81 DOI: https://doi.org/10.1093/jpp/rgae130
Verheijen RB, Beijnen JH, Schellens JHM, Huitema ADR, Steeghs N. Clinical pharmacokinetics and pharmacodynamics of pazopanib: towards optimized dosing. Clin Pharmacokinet. 2017;56:987–97. https://doi.org/10.1007/s40262-017-0510-z DOI: https://doi.org/10.1007/s40262-017-0510-z
Westerdijk K, Krens SD, Steeghs N, van der Graaf WTA, Tjwa E, Westdorp H, et al. Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients. Cancer Chemother Pharmacol. 2024;93:353–64 DOI: https://doi.org/10.1007/s00280-023-04615-7
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 DOI: https://doi.org/10.1200/JCO.2011.41.0332
Choi JW, Yoo JJ, Kim SG, Kim YS, Chin S. Pazopanib-induced severe acute liver injury: a case report. Medicine. 2021;100:e27731 DOI: https://doi.org/10.1097/MD.0000000000027731
Zhu B-k, Chen S-Y, Li X, Huang S-Y, Luo Z-Y, Zhang W. Real-world pharmacovigilance study of drug-induced autoimmune hepatitis from the FAERS database. Sci Rep. 2025;15:4783 DOI: https://doi.org/10.1038/s41598-025-89272-x
Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56:958–76 DOI: https://doi.org/10.1007/s10620-011-1611-4
Xu CF, Johnson T, Wang X, Carpenter C, Graves AP, Warren L, et al. HLA-B*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer. Clin Cancer Res. 2016;22:1371–7 DOI: https://doi.org/10.1158/1078-0432.CCR-15-2044
Orkin C, Wang J, Bergin C, Molina J-M, Lazzarin A, Cavassini M, et al. An epidemiologic study to determine the prevalence of the HLA-B*5701 allele among HIV-positive patients in Europe. Pharmacogenet Genomics. 2010;20:307–14 DOI: https://doi.org/10.1097/FPC.0b013e3283390666
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 DOI: https://doi.org/10.1016/j.jhep.2010.09.028
van Aken ESM, Devnani B, Prelaj A, Castelo-Branco L, Marijnen CAM, Martins-Branco D, et al. ESMO-ESTRO consensus statements on the safety of combining radiotherapy with immune checkpoint inhibitors, VEGF(R) inhibitors, or multitargeted tyrosine kinase inhibitors. Ann Oncol. 2026;37(1):17–32 DOI: https://doi.org/10.1016/j.annonc.2025.09.008
Additional Files
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2026 Bauke H. G. van Riet, Shermarke Hassan, Thomas R. de Wijkerslooth, Tom T. P. Seijkens, Alwin D. R. Huitema, Neeltje Steeghs, Rick L. Haas
This work is licensed under a Creative Commons Attribution 4.0 International License.
