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DOI: 10.1055/s-0033-1355834
Early Prediction of Treatment Response to Sorafenib with Elastosonography in a Mice Xenograft Model of Hepatocellular Carcinoma: A Proof-of-Concept Study
Elastosonografie zum Nachweis eines frühen Ansprechens des hepatozellulären Karzinoms auf die Behandlung mit Sorafenib im Maus-Xenotransplantat-Modell: Eine Studie zur Überprüfung des TherapiekonzeptsPublication History
19 December 2012
27 September 2013
Publication Date:
16 October 2013 (online)
![](https://www.thieme-connect.de/media/ultraschall/201306/lookinside/thumbnails/10.1055-s-0033-1355834-1.jpg)
Abstract
Purpose: Sorafenib is the reference therapy for advanced hepatocellular carcinoma (HCC). There is no method for predicting in the early period subsequent individual response. Starting from the clinical experience in humans that subcutaneous metastases may rapidly change consistency under sorafenib and that elastosonography allows assessment of tissue elasticity, we investigated the role of this ultrasound-based technique in the early prediction of tumor response to sorafenib in a HCC mice model.
Materials and Methods: HCC subcutaneous xenografting in mice was utilized. Mice were randomized to vehicle (17 mice) or treatment with sorafenib (19 mice). Strain elastosonography (Esaote, Italy) of the tumor mass was performed at different time points (day 0, + 2 and + 14 from treatment start) until the mice were sacrificed (day + 14). At the same time points, the volume was calculated with ultrasonography.
Results: Sorafenib-treated mice showed a smaller increase in tumor size on day + 14 in comparison to vehicle-treated mice (tumor volume increase + 175 % vs. + 382 %, p = 0.009). The median tumor elasticity increased in both groups on day + 2 (+ 5.65 % and + 3.86 %, respectively) and decreased on day + 14 (–3.86 % and –3.63 %, respectively). However, among Sorafenib-treated tumors, 13 mice with a growth percentage delta < 200 % (considered as good treatment response) showed an increase in elasticity on day + 2 (+ 8.9 %, range –12.6 – + 64) while the other 6 with a growth percentage delta > 300 % (considered as poor treatment response) showed a decrease in elasticity (–17 %, range –30.2 – + 15.3) (p = 0.044).
Conclusion: Elastosonography appears to be a promising noninvasive new technique for the early treatment prediction of HCC tumor response to sorafenib. Specifically, an early increase in tumor elasticity (corresponding to tumors becoming softer) is associated with a good response.
Zusammenfassung
Ziel: Sorafenib ist die Referenz-Therapie für das fortgeschrittene hepatozelluläre Karzinom (HCC). In der Frühphase gibt es keine Methode, um das individuelle Ansprechen auf die Therapie vorherzusagen. Ausgehend von der klinischen Erfahrung beim Menschen, dass subkutane Metastasen ihre Konsistenz unter Sorafenib sehr schnell verändern können und dass die Elastosonografie die Bewertung der Gewebe-Elastizität ermöglicht, untersuchten wir diese Technik zur Untersuchung des frühen Ansprechens des Tumors auf Sorafenib im HCC-Mausmodell.
Material und Methoden: Es wurde ein subkutanes HCC-Xenotransplantat in Mäusen durchgeführt. Die Mäuse wurden randomisiert und entweder mit Trägersubstanz (17 Mäuse) oder Sorafenib (19 Mäuse) behandelt. Die Strain-Elastosonografie (Esaote, Italy) der Tumormasse erfolgte zu bestimmten Zeitpunkten (Tag 0, + 2 und + 14 ab Therapiebeginn) bis Autopsie der Mäuse (Tag + 14). Jeweils zum gleichen Zeitpunkt wurde auch das Volumen sonografisch errechnet.
Ergebnisse: Sorafenib-behandelte Mäuse zeigten eine geringere Zunahme der Tumorgröße am Tag + 14 im Vergleich zu Mäusen, die Trägersubstanz erhielten (+ 175 % vs. + 382 %, p = 0,009). In beiden Gruppen stieg der Median der Tumor-Elastizität am Tag + 2 an (+ 5,65 % mit Sorafenib, + 3,86 % mit Trägersubstanz) und sank am Tag + 14 ab (–3,86 % mit Sorafenib, –3,63 % mit Trägersubstanz). Allerdings zeigten 13 Mäuse aus der Gruppe der sorafenib-behandelten Tumore mit einer Größenzunahme delta < 200 % (als gutes Therapieansprechen zu bewerten) eine Erhöhung der Elastizität am Tag + 2 (+ 8,9 %, Bereich – 12,6 – + 64), während die 6 anderen Mäuse eine Wachstumszunahme von delta > 300 % (entsprechend einem schlechten Therapieansprechen) eine Verminderung der Elastizität (–17 %, Bereich –30,2 – + 15,3) (p = 0,044) aufwiesen.
Schlussfolgerung: Die Elastosonografie scheint eine viel versprechende, nicht-invasive neue Methode zu sein, die ein frühes Ansprechen der Behandlung eines HCC auf Sorafenib ermöglicht. Insbesondere geht ein früher Anstieg der Elastizität des Tumors (in Übereinstimmung mit Tumoren, die weicher werden) mit einem guten Ansprechen einher.
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References
- 1 Wilhelm S, Carter C, Lynch M et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5: 835-844
- 2 EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-943
- 3 Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390
- 4 Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205-216
- 5 Italian Association for the Study of the Liver (AISF). Position paper of the Italian Association for the Study of the Liver (AISF): The multidisciplinary clinical approach to hepatocellular carcinoma. Dig Liver Dis 2013; Epub ahead of print DOI: 10.1016/j.dld.2013.01.012.
- 6 Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52-60
- 7 Iavarone M, Cabibbo G, Piscaglia F et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011; 54: 2055-2063
- 8 Lassau N, Chapotot L, Benatsou B et al. Standardization of dynamic contrast-enhanced ultrasound for the evaluation of antiangiogenic therapies: the French multicenter Support for Innovative and Expensive Techniques Study. Invest Radiol 2012; 47: 711-716
- 9 Raoul JL, Bruix J, Greten TF et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol 2012; 56: 1080-1088
- 10 Llovet JM, Pena CE, Lathia CD et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012; 18: 2290-2300
- 11 Furukawa MK, Furukawa M. Diagnosis of lymph node metastases of head and neck cancer and evaluation of effects of chemoradiotherapy using ultrasonography. Int J Clin Oncol 2010; 15: 23-32
- 12 Copeman M. Prolonged response to first-line erlotinib for advanced lung adenocarcinoma. J Exp Clin Cancer Res 2008; 4: 27-59
- 13 Reich S, Overberg-Schmidt US, Buhrer C et al. Low-dose chemotherapy with vinblastine and methotrexate in childhood desmoid tumors. J Clin Oncol 1999; 17: 1086
- 14 Oshino S, Saitoh Y, Kasayama S et al. Short-term preoperative octreotide treatment of GH-secreting pituitary adenoma: predictors of tumor shrinkage. Endocr J 2006; 53: 125-132
- 15 Ravaud A, Legrand E, Delaunay MM et al. A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma. Br J Cancer 1995; 71: 331-336
- 16 Judson I, Leahy M, Whelan J et al. A Guideline for the Management of Gastrointestinal Stromal Tumour (GIST). Sarcoma 2002; 6: 83-87
- 17 Bamber J, Cosgrove D, Dietrich CF et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: basic principles and technology. Ultraschall in Med 2013; 34: 169-184
- 18 Bojunga J, Herrmann E, Meyer G et al. Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 2010; 20: 1145-1150
- 19 Berg WA, Cosgrove DO, Dore CJ et al. Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses. Radiology 2012; 262: 435-449
- 20 Stachs A, Hartmann S, Stubert J et al. Differentiating between malignant and bening breast masses: factors limiting sonoelastographic strain ratio. Ultraschall in Med 2013; 34: 131-136
- 21 Wojcinski A, Farrokh A, Weber S et al. Multicenter study of ultrasound real-time tissue elastography in 779 cases for the assessment of breast lesions: improved diagnostic performance by combining the BI-RADS®-US classification system with sonoelastography. Ultraschall in Med 2010; 5: 484-491
- 22 Hu DM, Gong TT, Zhu Q. Endoscopic ultrasound elastography for differential diagnosis of pancreatic masses: a meta-analysis. Dig Dis Sci 2013; 58: 1125-1131
- 23 Wojcinski S, Dupont J, Schmidt W et al. Real time ultrasound elastography in 180 axillary lymph nodes: elasticity distribution in healthy lymph nodes and prediction of breast cancer metastases. BMC Medical Imaging 2012; 12: 35
- 24 Wilhelm SM, Carter C, Tang L et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109
- 25 Cheng AL, Kang YK, Chen Z et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34
- 26 Miyahara K, Nouso K, Tomoda T et al. Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2011; 26: 1604-1611
- 27 Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359: 1757-1765
- 28 Strobel D, Bernatik T, Blank W et al. Diagnostic accuracy of CEUS in the differential diagnosis of small (≤ 20 mm) and subcentimetric (≤ 10 mm) focal liver lesions in comparison with histology. Results of the DEGUM multicenter trial. Ultraschall in Med 2011; 32: 593-597
- 29 Lassau N, Koscielny S, Chami L et al. Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification--preliminary results. Radiology 2011; 258: 291-300
- 30 Shiozawa K, Watanabe M, Kikuchi Y et al. Evaluation of sorafenib for hepatocellular carcinoma by contrast-enhanced ultrasonography: a pilot study. World J Gastroenterol 2012; 18: 5753-5758
- 31 Knieling F, Waldner MJ, Goertz RS et al. Early response to anti-tumoral treatment in hepatocellular carcinoma – can quantitative contrast-enhanced ultrasound predict outcome?. Ultraschall in Med 2013; 34: 38-46
- 32 Claudon M, Dietrich CF, Choi BI et al. Guidelines and good clinical practice recommendayions for contrast enhanced ultrasound (CEUS) in the liver – Update 2012. Ultraschall in Med 2013; 39: 187-210
- 33 Piscaglia F, Nolsøe C, Dietrich CF et al. The EFSUMB Guidelines and Recommendations on the Clinical Practice of Contrast Enhanced Ultrasound (CEUS). Update 2011 on non-hepatic applications. Ultraschall in Med 2012; 33: 33-59
- 34 Barr RG, Destounis S, Lackey LB et al. Evaluation of breast lesions using sonographic elasticity imaging: a multicenter trial. J Ultrasound Med 2012; 31: 281-287
- 35 Cosgrove D, Piscaglia F, Dietrich CF et al. EFSUMB guidelines and recommendations on the clinical use of elastography. Part 2: clinical applications. Ultraschall in Med 2013; 34: 238-253
- 36 Tuch BE, Casamento FM. Outcome of xenografted fetal porcine pancreatic tissue is superior in inbred scid (C.B-17/Icr-scid/scid) compared to outbred nude (CD-1-nu/nu) mice. Cell Transplant 1999; 8: 259-264
- 37 Bonekamp S, Kamel I, Solga S et al. Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately?. J Hepatol 2009; 50: 17-35
- 38 Friedrich-Rust M, Schwarz A, Ong M et al. Real-time tissue elastography versus Fibroscan for non invasive assessment of liver fibrosis in chronic liver disease. Ultraschall in Med 2009; 5: 478-484
- 39 Sporea I, Bota S, Peck-Radosavljevic M et al. Acoustic Radiation Force Impulse elastography for fibrosis evaluation in patients with chronic hepatitis C; an international multicenter study. Eur J Radiol 2012; 12: 4112-4118
- 40 Piscaglia F, Salvatore V, Di Donato R et al. Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall in Med 2011; 2: 167-175
- 41 Merz M, Komljenovic D, Semmler W et al. Quantitative contrast-enhanced ultrasound for imaging antiangiogenic treatment response in experimental osteolytic breast cancer bone metastases. Invest Radiol 2012; 47: 422-429