Liver injury and recovery following radiation therapy for hepatocellular carcinoma: insights from functional liver imaging

Abstract

Aim: A critical need for hepatocellular carcinoma (HCC) management is understanding how the liver recovers following radiotherapy (RT). We hypothesized that functional liver imaging with ^99mTc-sulfur colloid (SC) SPECT/CT provides additional information on liver injury and recovery after RT compared to conventional imaging.

Methods: The liver function of patients with HCC was assessed using ^99mTc-SC SPECT/CT imaging before and after definitive RT. The anatomical liver volume (ALV) was segmented on CT imaging. Liver function was measured as the total liver function (TLF) encompassing 30% of maximum SC uptake. Changes in ALV and TLF were compared to clinical characteristics.

Results: Of 31 patients with evaluable post-RT SC SPECT/CT scans (total of 32), 23 had pre-treatment Child-Pugh (CP)-A and 9 had CP-B/C scores. The median follow-up post-RT was 57 days. The median change in ALV was -1.7% with no significant difference between CP-A and CP-B/C patients (P = 0.26) or between short- (32-99 days) and long-term (271-1120 days) follow-up imaging groups (P = 0.28). The median change in TLF post-RT was -24% and was significantly different between short- and long-term groups (-39% vs. 2%, P = 0.001) and between CP-A and CP-B/C patients (-19% vs. -57%, P = 0.002). TLF significantly decreased following treatment at all radiation dose levels, with the decline correlating with the dose (P < 0.001).

Conclusion: Functional imaging provides additional information regarding liver injury and recovery following RT that conventional imaging cannot reveal. Patients with CP-A liver status showed less decline following RT and most had liver function near or above pre-treatment levels.

Keywords

HCC / child-pugh / SPECT / IMRT / SBRT / proton therapy / recovery / reirradiation

References

[1] Cheng JC,Huang CM.Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description.Radiother Oncol2002;63:41-5

[2] Hsin IF,Huang HC.Liver failure after transarterial chemoembolization for patients with hepatocellular carcinoma and ascites: incidence, risk factors, and prognostic prediction.J Clin Gastroenterol2011;45:556-62

[3] Liang SX,Xu ZY.Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance.Int J Radiat Oncol Biol Phys2006;65:426-34

[4] Salem R,Mulcahy MF.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology2010;138:52-64

[5] Teh SH,Stevens SR.Risk factors for mortality after surgery in patients with cirrhosis.Gastroenterology2007;132:1261-9

[6] Higgins G.Experimental pathology of liver: restoration of liver in white rat following partial surgical removal.Arch Path1931;202Avaliable from: https://www.scienceopen.com/document?vid=57858414-5eff-4c8d-a028-ccb3fc1c44a6.[Last accessed on 9 Sep 2024].

[7] Bucher NLR,Aub JC.Regeneration of the liver in parabiotic rats.Cancer Res1951;11:457-65

[8] Wenneker AS.Regeneration of liver tissue following partial hepatectomy in parabiotic rats.Proc Soc Exp Biol Med1951;76:683-6

[9] Moolten FL.Regeneration of rat liver: transfer of humoral agent by cross circulation.Science1967;158:272-4

[10] Bucher NL.Liver regeneration: an overview.J Gastroenterol Hepatol1991;6:615-24

[11] Fausto N,Riehle KJ.Liver regeneration.Hepatology2006;43:S45-53

[12] Fausto N,Riehle KJ.Liver regeneration.J Hepatol2012;57:692-4

[13] Andersen KJ,Kannerup AS.The natural history of liver regeneration in rats: description of an animal model for liver regeneration studies.Int J Surg2013;11:903-8

[14] Hadjittofi C,Martin J,Huguet E.Liver regeneration biology: Implications for liver tumour therapies.World J Clin Oncol2021;12:1101-56 PMCID:PMC8716989

[15] Lasley FD,Johnson CS.Treatment variables related to liver toxicity in patients with hepatocellular carcinoma, child-pugh class a and b enrolled in a phase 1-2 trial of stereotactic body radiation therapy.Pract Radiat Oncol2015;5:e443-9

[16] Mizumoto M,Hashimoto T.Evaluation of liver function after proton beam therapy for hepatocellular carcinoma.Int J Radiat Oncol Biol Phys2012;82:e529-35

[17] Bennink RJ,Erdogan D.Preoperative assessment of postoperative remnant liver function using hepatobiliary scintigraphy.Nucl Med2004;45:965-71.Avaliable from: https://jnm.snmjournals.org/content/45/6/965.short.[Last accessed on 9 Sep 2024].

[18] Su TS,Liang SX.A prospective study of liver regeneration after radiotherapy based on a new (Su’s) target area delineaton.Front Oncol2021;11:680303 PMCID:PMC8426619

[19] Bowen SR,Chapman TR.Differential hepatic avoidance radiation therapy: proof of concept in hepatocellular carcinoma patients.Radiother Oncol2015;115:203-10 PMCID:PMC4587568

[20] Bowen SR,Borgman J.Measuring total liver function on sulfur colloid SPECT/CT for improved risk stratification and outcome prediction of hepatocellular carcinoma patients.EJNMMI Res2016;6:57 PMCID:PMC4923007

[21] Hoefs JC,Kanel G.Functional measurement of nonfibrotic hepatic mass in cirrhotic patients.Am J Gastroenterol1997;92:2054-8.

[22] Zuckerman E,Sabo E,Naschitz JE.Quantitative liver-spleen scan using single photon emission computerized tomography (SPECT) for assessment of hepatic function in cirrhotic patients.J Hepatol2003;39:326-32

[23] Everson GT,Hoefs JC.HALT-C trial groupquantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis trial.Hepatology2012;55:1019-29 PMCID:PMC3298578

[24] Groshar D,Zuckerman E.Quantitation of liver and spleen uptake of ^99mTc-phytate colloid using SPECT: detection of liver cirrhosis.J Nucl Med2002;43:312-17

[25] Price RG,Schaub SK.Regional radiation dose-response modeling of functional liver in hepatocellular carcinoma patients with longitudinal sulfur colloid SPECT/CT: a proof of concept.Int J Radiat Oncol Biol Phys2018;102:1349-56

[26] Schaub SK,Price RG.Functional liver imaging and dosimetry to predict hepatotoxicity risk in cirrhotic patients with primary liver cancer.Int J Radiat Oncol Biol Phys2018;102:1339-48

[27] R Core Team. R: a language and environment for statistical computing. Avaliable from: https://www.R-project.org/.[Last accessed on 9 Sep 2024]

[28] Rim CH,Woo JY.Compensatory hypertrophy of the liver after external beam radiotherapy for primary liver cancer.Strahlenther Onkol2018;194:1017-29

[29] Adachi T,Shibuya K.Partial liver irradiation in rats induces the hypertrophy of nonirradiated liver lobes through hepatocyte proliferation†.J Radiat Res2023;64:693-701 PMCID:PMC10354842

[30] de Graaf W,Dinant S.Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection.J Gastrointest Surg2010;14:369-78 PMCID:PMC2809979

[31] Gong WF,Lu Z.Evaluation of liver regeneration and post-hepatectomy liver failure after hemihepatectomy in patients with hepatocellular carcinoma.Biosci Rep2019;39:BSR20190088 PMCID:PMC6706596

[32] Richman RA,Pilkis SJ.Hormonal stimulation of DNA synthesis in primary cultures of adult rat hepatocytes.Proc Natl Acad Sci1976;73:3589-93 PMCID:PMC431163

[33] Liu L,Nishikawa T.The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis.Hepatology2012;55:1529-39 PMCID:PMC3700584

[34] Chuong MD,Khan F.Consensus report from the miami liver proton therapy conference.Front Oncol2019;9:457 PMCID:PMC6557299

[35] Zaki P,Schaub SK,Ibrahim M.Proton beam therapy and photon-based magnetic resonance image-guided radiation therapy: the next frontiers of radiation therapy for hepatocellular carcinoma.Technol Cancer Res Treat2023;22:15330338231206335 PMCID:PMC10621304