Assessment of response to liver directed radiation-based therapies: Current guidelines, challenges, and future directions

Abstract

Radiation-based local-regional therapies for hepatocellular carcinoma (HCC) have gained wide acceptance due to promising rates of tumor response, survival, and safety profiles. After treatment, it is important to assess tumor response to determine further management, patient prognosis, and endpoint outcomes for clinical trials. To standardize imaging interpretation and reporting of HCC response to local-regional treatment, a few imaging-based response assessment systems were developed. Two of them have emerged as the most used: the Liver Imaging Reporting and Data System (LI-RADS) Treatment Response Algorithm (LR-TRA) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST). While these systems have been validated for the assessment of response to ablative locoregional therapies, assessment of response to radiation-based therapies can be challenged by persistent or evolving imaging features and is still an area of active research. Following the advances in technology and a better understanding of tumor biology that allowed for the increased application of radiation-based local-regional therapies for the treatment of HCC, research is still needed to address the limitations of current imaging criteria for assessing tumor response to these novel techniques. In this review, we describe radiation-based liver-directed treatment options, examine imaging criteria for assessing treatment response, discuss practical limitations and gaps in knowledge when applying these response criteria, and address future directions that may help to improve accuracy and outcomes when assessing response to radiation-based HCC treatment.

Keywords

Hepatocellular carcinoma / LI-RADS / mRECIST / Radioembolization / Y-90 / Radiation

References

[1] WHO Health Statistics. Cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer [Last accessed on 3 Jan 2023]

[2] Balogh J,Asham EH.Hepatocellular carcinoma: a review.J Hepatocell Carcinoma2016;3:41-53 PMCID:PMC5063561

[3] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases.Hepatology2018;68:723-50

[4] Llovet JM,Villanueva A.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[5] Heimbach JK,Finn RS.AASLD guidelines for the treatment of hepatocellular carcinoma.Hepatology2018;67:358-80

[6] Rizzo A,Gadaleta-Caldarola G.First-line immune checkpoint inhibitor-based combinations in unresectable hepatocellular carcinoma: current management and future challenges.Expert Rev Gastroenterol Hepatol2021;15:1245-51

[7] Jácome AA,Vasconcelos JPS.Efficacy and safety associated with immune checkpoint inhibitors in unresectable hepatocellular carcinoma: a meta-analysis.JAMA Netw Open2021;4:e2136128 PMCID:PMC8649834

[8] Sapisochin G,Doherty M.Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis.J Hepatol2017;67:92-9

[9] Marqueen KE,Ang C,Buckstein M.Cost-effectiveness analysis of selective internal radiotherapy with Yttrium-90 versus sorafenib in locally advanced hepatocellular carcinoma.JCO Oncol Pract2021;17:e266-77 PMCID:PMC8258013

[10] Williams SJ,White SB.Quality of life and cost considerations: Y-90 radioembolization.Semin Intervent Radiol2021;38:482-7 PMCID:PMC8497083

[11] Dhondt E,Hermie L.⁹⁰Y radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phase II randomized controlled trial.Radiology2022;303:699-710

[12] Salem R,Roberts C.Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis.J Vasc Interv Radiol2004;15:335-45

[13] Abouchaleh N,Ali R.⁹⁰Y radioembolization for locally advanced hepatocellular carcinoma with portal vein thrombosis: long-term outcomes in a 185-patient cohort.J Nucl Med2018;59:1042-8

[14] Garin E,Guiu B.Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial.Lancet Gastroenterol Hepatol2021;6:17-29

[15] Chen CP.Role of external beam radiotherapy in hepatocellular carcinoma.Clin Liver Dis2020;24:701-17

[16] Saini A,Alzubaidi S.History and evolution of Yttrium-90 radioembolization for hepatocellular carcinoma.J Clin Med2019;8:55 PMCID:PMC6352151

[17] Kielar A,Lewis S.Locoregional therapies for hepatocellular carcinoma and the new LI-RADS treatment response algorithm.Abdom Radiol (NY)2018;43:218-30 PMCID:PMC5771991

[18] Woerner AJ.Advances in Y-90 radioembolization for the treatment of hepatocellular carcinoma.HR2022;

[19] Murthy R,Szklaruk J.Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, technical considerations, and potential complications.Radiographics2005;25 Suppl 1:S41-55

[20] Salem R,Mouli S.Y-90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma.Gastroenterology2016;151:1155-1163.e2

[21] Boston Scientific Clinical Trials. Bridging and downstaging to surgery hepatology: liver transplantation following Y-90 for HCC. Available from: https://www.bostonscientific.com/en-US/medical-specialties/interventional-radiology/interventional-oncology/cancer-therapies-ablation/therasphere/proven-results/bridging-and-downstaging-to-surgery.html [Last accessed on 3 Jan 2023]

[22] Riaz A,Salem R.Side effects of Yttrium-90 radioembolization.Front Oncol2014;4:198 PMCID:PMC4114299

[23] Gerum S,Roeder F.Stereotactic body radiation therapy in patients with hepatocellular carcinoma: a mini-review.World J Gastrointest Oncol2019;11:367-76 PMCID:PMC6522765

[24] Qiu H,Milano MT,Katz AW.SBRT for hepatocellular carcinoma: 8-year experience from a regional transplant center.J Gastrointest Cancer2018;49:463-9

[25] Rim CH,Yang DS.Comparison of radiation therapy modalities for hepatocellular carcinoma with portal vein thrombosis: a meta-analysis and systematic review.Radiother Oncol2018;129:112-22

[26] Montazeri SA,Lewis AR.Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors.Eur J Nucl Med Mol Imaging2022;49:3892-7

[27] Okada M,Nihonmatsu H.Pathological appearance of focal liver reactions after radiotherapy for hepatocellular carcinoma.Diagnostics (Basel)2022;12:1072 PMCID:PMC9139971

[28] Aslam A,Kambadakone A.Hepatocellular carcinoma liver imaging reporting and data systems treatment response assessment: lessons learned and future directions.World J Hepatol2020;12:738-53 PMCID:PMC7643220

[29] Voizard N,Assad A.Assessment of hepatocellular carcinoma treatment response with LI-RADS: a pictorial review.Insights Imaging2019;10:121 PMCID:PMC6920285

[30] Ram R,Shenoy-Bhangle AS,Kielar AZ.LI-RADS treatment response lexicon: review, refresh and resolve with emerging data.Abdom Radiol (NY)2021;46:3549-57

[31] Sato Y,Sone M.Japan Interventional Radiology in Oncology Study Group-JIVROSGTumor response evaluation criteria for HCC (hepatocellular carcinoma) treated using TACE (transcatheter arterial chemoembolization): RECIST (response evaluation criteria in solid tumors) version 1.1 and mRECIST (modified RECIST): JIVROSG-0602.Ups J Med Sci2013;118:16-22 PMCID:PMC3572665

[32] Chaudhry M,Mervak B.The LI-RADS version 2018 MRI treatment response algorithm: evaluation of ablated hepatocellular carcinoma.Radiology2020;294:320-6

[33] Shropshire EL,Miller CM.LI-RADS treatment response algorithm: performance and diagnostic accuracy.Radiology2019;292:226-34 PMCID:PMC6614909

[34] Kim SW,Kim HC.LI-RADS treatment response categorization on gadoxetic acid-enhanced MRI: diagnostic performance compared to mRECIST and added value of ancillary features.Eur Radiol2020;30:2861-70

[35] Mendiratta-Lala M,Maturen KE.LI-RADS treatment response algorithm: performance and diagnostic accuracy with radiologic-pathologic explant correlation in patients with sbrt-treated hepatocellular carcinoma.Int J Radiat Oncol Biol Phys2022;112:704-14 PMCID:PMC9400832

[36] Yoon J,Shin J,Kim GM.LI-RADS version 2018 treatment response algorithm: diagnostic performance after transarterial radioembolization for hepatocellular carcinoma.Korean J Radiol2021;22:1279-88 PMCID:PMC8316770

[37] Lencioni R.Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.Semin Liver Dis2010;30:52-60

[38] Fournier L,Thiam R.Imaging criteria for assessing tumour response: RECIST, mRECIST, Cheson.Diagn Interv Imaging2014;95:689-703

[39] Shim JH,Kim SO.Which response criteria best help predict survival of patients with hepatocellular carcinoma following chemoembolization?.Radiology2012;262:708-18

[40] Xu M,Garcia-Aroz S. Predictive value of mRECIST in HCC response to the neoadjuvant locoregional therapies and prognosis affected by the peak afp level before liver transplantation. Available from: https://atcmeetingabstracts.com/abstract/predictive-value-of-mrecist-in-hcc-response-to-the-neoadjuvant-locoregional-therapies-and-prognosis-affected-by-the-peak-afp-level-before-liver-transplantation/ [Last accessed on 3 Jan 2023]

[41] Salem R,Kim E.Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study.Hepatology2021;74:2342-52 PMCID:PMC8596669

[42] Toskich B,Olson MT.Pathologic response of hepatocellular carcinoma treated with yttrium-90 glass microsphere radiation segmentectomy prior to liver transplantation: a validation Study.J Vasc Interv Radiol2021;32:518-526.e1

[43] Park S,Lee DH.Diagnostic performance of LI-RADS treatment response algorithm for hepatocellular carcinoma: adding ancillary features to mri compared with enhancement patterns at CT and MRI.Radiology2020;296:554-61

[44] Ibrahim SM,Miller FH.Radiologic findings following Y-90 radioembolization for primary liver malignancies.Abdom Imaging2009;34:566-81

[45] Mendiratta-Lala M,Shankar PR.Magnetic resonance imaging evaluation of hepatocellular carcinoma treated with stereotactic body radiation therapy: long term imaging follow-up.Int J Radiat Oncol Biol Phys2019;103:169-79 PMCID:PMC6301102

[46] Mendiratta-Lala M,Shampain K.MRI assessment of hepatocellular carcinoma after local-regional therapy: a comprehensive review.Radiol Imaging Cancer2020;2:e190024 PMCID:PMC7983779

[47] Riaz A,Lewandowski RJ.Radiologic-pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres.Hepatology2009;49:1185-93

[48] Yu MH,Park HS,Jeon HJ.Imaging patterns of intratumoral calcification in the abdominopelvic cavity.Korean J Radiol2017;18:323-35 PMCID:PMC5313520

[49] Sharma RA,Morgan B.Radioembolization of liver metastases from colorectal cancer using Yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy.J Clin Oncol2007;25:1099-106

[50] Park HJ,Jang KM.Added value of diffusion-weighted MRI for evaluating viable tumor of hepatocellular carcinomas treated with radiotherapy in patients with chronic liver disease.AJR Am J Roentgenol2014;202:92-101

[51] Altenbernd J,Forsting M.Treatment response after radioembolisation in patients with hepatocellular carcinoma-An evaluation with dual energy computed-tomography.Eur J Radiol Open2016;3:230-5 PMCID:PMC5009187

[52] Funaoka A,Takeda A.Use of contrast-enhanced ultrasound with sonazoid for evaluating the radiotherapy efficacy for hepatocellular carcinoma.Diagnostics (Basel)2021;11:486 PMCID:PMC7998355

[53] Delaney LJ,Wessner CE.Predicting long-term hepatocellular carcinoma response to transarterial radioembolization using contrast-enhanced ultrasound: initial experiences.Ultrasound Med Biol2021;47:2523-31 PMCID:PMC8355136

[54] Eisenbrey JR,Wessner CE.US-triggered microbubble destruction for augmenting hepatocellular carcinoma response to transarterial radioembolization: a randomized pilot clinical trial.Radiology2021;298:450-7 PMCID:PMC7850263

[55] Chen G,He W,Zhao LQ.Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol2008;14:5738-43 PMCID:PMC2748211

[56] Ippolito D,Bonaffini PA.Quantitative evaluation of CT-perfusion map as indicator of tumor response to transarterial chemoembolization and radiofrequency ablation in HCC patients.Eur J Radiol2014;83:1665-71

[57] Llovet JM,Lathia CD,Meinhardt G.SHARP investigators study groupplasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma.Clin Cancer Res2012;18:2290-300

[58] Nam JY,Bae J.Novel model to predict HCC recurrence after liver transplantation obtained using deep learning: a multicenter study.Cancers (Basel)2020;12:2791 PMCID:PMC7650768

[59] Abajian A,Savic LJ.Predicting treatment response to intra-arterial therapies for hepatocellular carcinoma with the use of supervised machine learning-an artificial intelligence concept.J Vasc Interv Radiol2018;29:850-857.e1 PMCID:PMC5970021

[60] Morshid A,Khalaf AM.A machine learning model to predict hepatocellular carcinoma response to transcatheter arterial chemoembolization.Radiol Artif Intell2019;1:e180021 PMCID:PMC6920060