Change in arterial tumor perfusion is an early biomarker of lenvatinib efficacy in patients with unresectable hepatocellular carcinoma
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摘要
BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.
BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.
BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.
引文
1 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379:1245-1255[PMID:22353262DOI:10.1016/S0140-6736(11)61347-0]
2 Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma:An update.Hepatol Res 2013; 43:147-154[PMID:23145926 DOI:10.1111/j.1872-034X.2012.01113.x]
3 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y,Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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[PMID:19095497 DOI:10 .1016/S1470-2045(08)70285-7]
4 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL,Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I,H?ussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359:378-390[PMID:18650514 DOI:10.1056/NEJMoa0708857]
5 Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, Minoshima Y, Iwata M,Funahashi Y. Antitumor activity of lenvatinib(e7080):an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014; 2014:638747[PMID:25295214 DOI:10.1155/2014/638747]
6 Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF,Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M,Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma:a randomised phase 3 non-inferiority trial. Lancet 2018; 391:1163-1173[PMID:29433850DOI:10.1016/S0140-6736(18)30207-1]
7 Kudo M. Systemic Therapy for Hepatocellular Carcinoma:Latest Advances. Cancers(Basel)2018; 10[PMID:30380773 DOI:10.3390/cancers10110412]
8 Lassau N, Bonastre J, Kind M, Vilgrain V, Lacroix J, Cuinet M, Taieb S, Aziza R, Sarran A, LabbeDevilliers C, Gallix B, Lucidarme O, Ptak Y, Rocher L, Caquot LM, Chagnon S, Marion D, Luciani A,Feutray S, Uzan-Augui J, Coiffier B, Benastou B, Koscielny S. Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors:the French multicenter support for innovative and expensive techniques study. Invest Radiol 2014; 49:794-800[PMID:24991866DOI:10.1097/RLI.0000000000000085]
9 Frampas E, Lassau N, Zappa M, Vullierme MP, Koscielny S, Vilgrain V. Advanced Hepatocellular Carcinoma:early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results. Eur J Radiol 2013; 82:e205-e211[PMID:23273822 DOI:10.1016/j.ejrad.2012.12.004]
10 Lencioni R, Llovet JM. Modified RECIST(m RECIST)assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52-60[PMID:20175033 DOI:10.1055/s-0030-1247132]
11 Shiozawa K, Watanabe M, Ikehara T, Shimizu R, Shinohara M, Igarashi Y, Sumino Y. Evaluation of sorafenib for advanced hepatocellular carcinoma with lowα-fetoprotein in arrival time parametric imaging using contrast-enhanced ultrasonography. J Med Ultrason(2001)2017; 44:101-107[PMID:27837395DOI:10.1007/s10396-016-0757-2]
12 Knieling F, Waldner MJ, Goertz RS, Strobel D. Quantification of dynamic contrast-enhanced ultrasound in HCC:prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma. BMJ Case Rep 2012; 2012[PMID:23257272 DOI:10.1136/bcr-2012-007576]
13 Shiozawa K, Watanabe M, Ikehara T, Kogame M, Kikuchi Y, Igarashi Y, Sumino Y. Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography:Preliminary result. Oncol Lett 2016; 12:579-584[PMID:27347183 DOI:10.3892/ol.2016.4669]
14 Sugimoto K, Moriyasu F, Saito K, Rognin N, Kamiyama N, Furuichi Y, Imai Y. Hepatocellular carcinoma treated with sorafenib:early detection of treatment response and major adverse events by contrast-enhanced US. Liver Int 2013; 33:605-615[PMID:23305331 DOI:10.1111/liv.12098]
15 Lamuraglia M, Escudier B, Chami L, Schwartz B, Leclère J, Roche A, Lassau N. To predict progressionfree survival and overall survival in metastatic renal cancer treated with sorafenib:pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 2006; 42:2472-2479[PMID:16965911DOI:10.1016/j.ejca.2006.04.023]
16 Ueda N, Nagira H, Sannomiya N, Ikunishi S, Hattori Y, Kamida A, Koyanagi Y, Shimabayashi K, Sato K,Saito H, Hirooka Y. Contrast-Enhanced Ultrasonography in Evaluation of the Therapeutic Effect of Chemotherapy for Patients with Liver Metastases. Yonago Acta Med 2016; 59:255-261[PMID:28070162]
2 Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma:An update.Hepatol Res 2013; 43:147-154[PMID:23145926 DOI:10.1111/j.1872-034X.2012.01113.x]
3 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y,Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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[PMID:19095497 DOI:10 .1016/S1470-2045(08)70285-7]
4 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL,Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I,H?ussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359:378-390[PMID:18650514 DOI:10.1056/NEJMoa0708857]
5 Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, Minoshima Y, Iwata M,Funahashi Y. Antitumor activity of lenvatinib(e7080):an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014; 2014:638747[PMID:25295214 DOI:10.1155/2014/638747]
6 Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF,Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M,Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma:a randomised phase 3 non-inferiority trial. Lancet 2018; 391:1163-1173[PMID:29433850DOI:10.1016/S0140-6736(18)30207-1]
7 Kudo M. Systemic Therapy for Hepatocellular Carcinoma:Latest Advances. Cancers(Basel)2018; 10[PMID:30380773 DOI:10.3390/cancers10110412]
8 Lassau N, Bonastre J, Kind M, Vilgrain V, Lacroix J, Cuinet M, Taieb S, Aziza R, Sarran A, LabbeDevilliers C, Gallix B, Lucidarme O, Ptak Y, Rocher L, Caquot LM, Chagnon S, Marion D, Luciani A,Feutray S, Uzan-Augui J, Coiffier B, Benastou B, Koscielny S. Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors:the French multicenter support for innovative and expensive techniques study. Invest Radiol 2014; 49:794-800[PMID:24991866DOI:10.1097/RLI.0000000000000085]
9 Frampas E, Lassau N, Zappa M, Vullierme MP, Koscielny S, Vilgrain V. Advanced Hepatocellular Carcinoma:early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results. Eur J Radiol 2013; 82:e205-e211[PMID:23273822 DOI:10.1016/j.ejrad.2012.12.004]
10 Lencioni R, Llovet JM. Modified RECIST(m RECIST)assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52-60[PMID:20175033 DOI:10.1055/s-0030-1247132]
11 Shiozawa K, Watanabe M, Ikehara T, Shimizu R, Shinohara M, Igarashi Y, Sumino Y. Evaluation of sorafenib for advanced hepatocellular carcinoma with lowα-fetoprotein in arrival time parametric imaging using contrast-enhanced ultrasonography. J Med Ultrason(2001)2017; 44:101-107[PMID:27837395DOI:10.1007/s10396-016-0757-2]
12 Knieling F, Waldner MJ, Goertz RS, Strobel D. Quantification of dynamic contrast-enhanced ultrasound in HCC:prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma. BMJ Case Rep 2012; 2012[PMID:23257272 DOI:10.1136/bcr-2012-007576]
13 Shiozawa K, Watanabe M, Ikehara T, Kogame M, Kikuchi Y, Igarashi Y, Sumino Y. Therapeutic evaluation of sorafenib for hepatocellular carcinoma using contrast-enhanced ultrasonography:Preliminary result. Oncol Lett 2016; 12:579-584[PMID:27347183 DOI:10.3892/ol.2016.4669]
14 Sugimoto K, Moriyasu F, Saito K, Rognin N, Kamiyama N, Furuichi Y, Imai Y. Hepatocellular carcinoma treated with sorafenib:early detection of treatment response and major adverse events by contrast-enhanced US. Liver Int 2013; 33:605-615[PMID:23305331 DOI:10.1111/liv.12098]
15 Lamuraglia M, Escudier B, Chami L, Schwartz B, Leclère J, Roche A, Lassau N. To predict progressionfree survival and overall survival in metastatic renal cancer treated with sorafenib:pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 2006; 42:2472-2479[PMID:16965911DOI:10.1016/j.ejca.2006.04.023]
16 Ueda N, Nagira H, Sannomiya N, Ikunishi S, Hattori Y, Kamida A, Koyanagi Y, Shimabayashi K, Sato K,Saito H, Hirooka Y. Contrast-Enhanced Ultrasonography in Evaluation of the Therapeutic Effect of Chemotherapy for Patients with Liver Metastases. Yonago Acta Med 2016; 59:255-261[PMID:28070162]