Abstract
Several techniques have been developed for radionuclide therapy of hepatocellular carcinoma (HCC). Medical literature databases (Pubmed, Medline) were screened for available literature and articles were critically analysed as to their scientific relevance. In a palliative setting, intra-arterial administration of 131I-Lipiodol yields responses in 17–92% of patients. According to a randomised study, 131I-Lipiodol was far better tolerated than classic chemo-embolisation. The additive value of a single 131I-Lipiodol administration following partial liver resection for HCC was evaluated and evidence is available that adjuvant radionuclide treatment reduces the recurrence rate. Data concerning the role of 131I-Lipiodol in bridging patient to liver transplantation are scarce but suggest a potential benefit in terms of reducing the drop-out rate while patients are listed for transplantation. 188Re- and 90Y-labelled conjugates are emerging and initial clinical data are promising. Treatment of HCC with 90Y-labelled microspheres is likely as efficacious as treatment with radiolabelled Lipiodol but pretreatment 99mTc-MAA scintigraphy is required in order to exclude patients with significant lung shunting. Several antibodies targeting antigens expressed on HCC have been radiolabelled, almost exclusively with 131I, and evaluated in a preclinical or clinical setting. The use of radiolabelled Lipiodol and microspheres allows for selective targeting of HCC with limited toxicity. Prospective, randomised controlled trials demonstrating that both treatment modalities may provide a survival benefit in a palliative setting are mandatory. In addition, future research should focus on the complementary role of radionuclide treatment in patients at risk for recurrent disease following partial liver resection or while awaiting liver transplantation.
Similar content being viewed by others
References
Röcken C, Carll-McGrath S. Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis 2001;19:269–78
Parkin MD, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: globocan 2000. Int J Cancer 2001;94:153–6
Monto A, Wright TL. The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol 2001;28:441–9
Sherman M. Surveillance for hepatocellular carcinoma. Semin Oncol 2001;28:450–9
Coackley FV, Schwartz LH. Imaging of hepatocellular carcinima: a practical approach. Semin Oncol 2001;28:460–73
Ward J, Robinson PJ. How to detect hepatocellular carcinoma in cirrhosis. Eur Radiol 2002;12:2258–72
Caturelli E, Ghittoni G, Roselli P, De Palo M, Anti M. Fine needle biopsy of focal liver lesions: the hepatologist’s point of view. Liver Transplant 2004;10:S26–9
Llovet JM, Fuster J, Bruix J, Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplant 2004;10:S115–20
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Eng J Med 1996;334:693–699
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–42
Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17
Dusheiko GM, Hobbs KE, Dick R, Burroughs AK. Treatment of small hepatocellular carcinomas. Lancet 1992;340:285–8
Castells A, Bruix J, Bru C, et al. Treatment of hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993;18:1121–6
Livraghi T, Bolondi L, Buscarini L, et al. No treatment, resection and ethanol injection in hepatocellular carcinoma: a retrospective analysis of survival in 391 patients with cirrhosis. J Hepatol 1995;22:522–6
Yamamoto J, Okada S, Shimada K, et al. Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 2001;34:707–13
Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolisation for unresectable hepatocellular carcinoma: meta-analysis of randomised controlled trials. Radiology 2002;224:47–54
Reidy DL, Schwartz JD. Therapy for unresectable hepatocellular carcinoma: review of the randomized clinical trials—I: hepatic arterial embolization and embolization-based therapies in unresectable hepatocellular carcinoma. Anticancer Drugs 2004;15:427–37
Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 2002;3:593–603
Lin DY, Lin SM, Liaw YF. Non-surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol 1997;12:S319–28
Treiber G. Systemic treatment of hepatocellular carcinoma. Dig Dis 2001;19:311–23
Aguayo A, Patt YZ. Nonsurgical treatment of hepatocellular carcinoma. Semin Oncol 2001;28:503–13
Leung TW, Johnson PJ. Systemic therapy for hepatocellular carinoma. Semin Oncol 2001;28:514–20
Mathurin P, Rixe O, Bernards B, et al. Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta-analysis? Aliment Pharmacol Ther 1998;12:111–26
Schwartz JD, Beutler AS. Therapy for unresectable hepatocellular carcinoma: review of the randomized clinical trials—II: systemic and local non-embolization-based therapies in unresectable and advanced hepatocellular carcinoma. Anticancer Drugs 2004;15:439–52
Cheng JC, Chuang VP, Cheng SH, et al. Unresectable hepatocellular carcinoma treated with radiotherapy and/or chemo-embolisation. Int J Cancer 2001;96:243–52
Cheng JC, Wud JK, Huanga CM, et al. Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description. Radiother Oncol 2002;63:41–5
Cheng SH, Lin YM, Chuang VP, et al. A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol 1999;14:1025–33
Seong J, Park HS, Han KH, et al. Local radiotherapy for unresectable hepatocellular carcinoma patients who failed with arterial chemoembolization. Int J Radiat Oncol Biol Phys 2000;47:1331–5
Nakakuma K, Tashiro S, Hiraoka T, Ogata K, Ootsuka K. Hepatocellular carcinoma and metastatic cancer detected by iodized oil. Radiology 1985;154:15–7
Bhattacharya S, Dhillon AP, Winslet MC, et al. Human liver cells and endothelial cells incorporate iodised oil. Br J Cancer 1996;73:877–81
Al-Mufti RA, Pedley RB, Marshall D, et al. In vitro assessment of Lipiodol-targeted radiotherapy for liver and colorectal cancer cell lines. Br J Cancer 1999;79:1665–71
Ho S, Lau WY, Leung TWT, Johnson PJ. Internal radiation therapy for patients with primary or metastatic hepatic cancer. Cancer 1998;83:1894–907
Risse JH, Grünwald F, Kersjes W, et al. Intraarterial HCC therapy with I-131-Lipiodol. Cancer Biother Radiopharm 2000;15:65–70
Rindani R, Hugh T, Roche J, Roach PJ, Smith RC. 131I Lipiodol therapy for unresectable hepatocellular carcinoma. Aust NZ J Surg 2002;72:210–4
Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intraarterial injection of 131I-labeled iodized oil in the treatment of hepatocellular carcinoma. Hepatology 1997;26:1156–61
Bhattacharya S, Novell JR, Dusheiko GM, Hilson AJ, Dick R, Hobbs KE. Epirubicin-Lipiodol chemotherapy versus 131iodine-Lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma. Cancer 1995;76:2202–10
Raoul JL, Guyader D, Bretagne JF, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med 1994;35:1782–7
Brans B, Van Laere K, Gemmel F, et al. Combining iodine-131 Lipiodol therapy with low-dose cisplatin as a radiosensitiser: preliminary results in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2002;29:928–32
Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218:145–51
Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial Lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomized trial. Lancet 1999,353:797–801
Pocock S, White I. Trials stopped too early: too good to be true? Lancet 1999;353:943–4
Partensky C, Sassolas G, Henry L, Paliard P, Maddern G. Intra-arterial iodine 131-labeled Lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma. A phase 2 clinical study. Arch Surg 2000;135:1298–300
Raoul JL, Messner M, Boucher E, Bretagne JF, Campion JP, Boudjema K. Preoperative treatment of hepatocellular carcinoma with intra-arterial injection of I131-labelled Lipiodol. Br J Surg 2003;90:1379–83
Boucher E, Corbinais S, Rolland Y, et al. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003;38:1237–41
Brans B, De Winter F, Defreyne L, et al. The anti-tumoural activity of neoadjuvant intra-arterial 131I-Lipiodol treatment for hepatocellular carcinoma: a pilot study. Cancer Biother Radiopharm 2001;16:333–8
Wall WJ, Marotta PJ. Surgery and transplantation for hepatocellular cancer. Liver Transplant 2000;6:S16–22
Monsieurs M, Bacher K, Brans B, et al. Patient dosimetry for 131-I-Lipiodol therapy. Eur J Nucl Med Mol Imaging 2003;30:554–61
Garin E, Laffont S, Rolland Y, et al. Safe radiation exposure of medical personnel by using simple methods of radioprotection while administering 131I-Lipiodol therapy for hepatocellular carcinoma. Nucl Med Commun 2003;24:671–8
Wang SJ, Lin WY, Chen MN, Shen LH, Tsai ZT, Ting G. Preparation and biodistribution of yttrium-90 Lipiodol in rats following hepatic arterial injection. Eur J Nucl Med 1995;22:233–6
Wang SJ, Lin WY, Lui WY, Chen MN, Tsai ZT, Ting G. Hepatic artery injection of yttrium-90-Lipiodol: biodistribution in rats with hepatoma. J Nucl Med 1996;37:332–5
Yu J, Häfeli UO, Sands M, Dong Y. 90Y-oxine-ethiodol, a potential radiopharmaceutical for the treatment of liver cancer. Appl Radiat Isotopes 2003;58:567–73
Wang SJ, Lin WY, Chen MN, et al. Radiolabelling of Lipiodol with generator-produced 188Re for hepatic tumour therapy. Appl Radiat Isotopes 1996;47:267–71
Wang SJ, Lin WY, Chen MN, et al. Biodistribution of rhenium-188 Lipiodol infused via the hepatic artery of rats with hepatic tumours. Eur J Nucl Med 1996;23:13–7
Jeong JM, Kim YJ, Lee YS, et al. Lipiodol solution of a lipophilic agent, 188Re-TDD, for the treatment of liver cancer. Nucl Med Biol 2001;28:197–204
Lee YS, Jeong JM, Kim YJ, et al. Synthesis of 188Re-labelled long chain alkyl diaminedithiol for therapy of liver cancer. Nucl Med Commun 2002;23:237–42
Sundram FX, Jeong J-M, Zanzonico P, et al. Trans-arterial rhenium-188 Lipiodol in the treatment of inoperable hepatocellular carcinoma. An IAEA sponsored multi-centre phase 1 study. World J Nucl Med 2002;1:5–11
Sundram F, Chau TC, Onkhuudai P, Bernal P, Padhy AK. Preliminary results of transarterial rhenium-188 HDD Lipiodol in the treatment of inoperable primary hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2004;31:250–7
Lambert B, Bacher K, Defreyne L, et al. 188Re-HDD/Lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial. J Nucl Med 2005;46:60–6
Garin E, Noiret N, Malbert C, et al. Development and biodistribution of 188Re-SSS Lipiodol following injection into the hepatic artery of healthy pigs. Eur J of Nucl Med Mol Imaging 2004;31:542–6
Boschi A, Uccelli L, Duatti A, et al. A kit formulation for the preparation of 188Re-Lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. Nucl Med Commun 2004;25:691–9
Houle S, Yip TK, Shepherd FA, et al. Hepatocellular carcinoma: pilot trial of treatment with Y-90 microspheres. Radiology 1989;172:857–60
Shepherd FA, Rotstein LE, Houle S, Yip TC, Paul K, Sniderman KW. A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma. Cancer 1992;70:2250–4
Carr BI. Hepatic arterial 90ytrrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients. Liver Transplant 2004;10:S107–10
Geschwind JF, Salem R, Carr BI, et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology 2004;127:S194–205
Lau WY, Leung WT, Ho S, et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study. Br J Cancer 1994;70:994–9
Goin JE, Salem R, Carr BI, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis. J Vasc Interv Radiol 2005;16:195–203
Goin JE, Salem R, Carr BI, et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities. J Vasc Interv Radiol 2005;16:205–13
Ho S, Lau WY, Leung TW, Chan M, Johnson PJ, Li AK. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med 1997;24:293–8
Leung TW, Lau WY, Ho SK, et al. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90 yttrium-microspheres for inoperable hepatic tumours. Int J Radiat Oncol Biol Phys 1995;33:919–24
Salem R, Lewandowski R, Roberts C, et al. Use of yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol 2004;15:335–45
Liu L, Jiang Z, Teng GJ, et al. Clinical and experimental study on regional administration of phosphorus 32 microspheres in treating hepatic carcinoma. World J Gastroenterol 1999;5:492–505
Häfeli UO, Casillas S, Dietz DW, et al. Hepatic tumour radioembolization in a rat model using radioactive rhenium (Re-186/Re-188) glass microspheres. Int J Radiat Oncol Biol Phys 1999;44:189–99
Häfeli UO, Roberts WK, Pauer GJ, Kraeft ST, Macklis RM. Stability of biodegradable radioactive rhenium (Re-186 and Re-188) microspheres after neutron-activation. Appl Radiat Isotopes 2001;54:869–79
Mumper RJ, Ryo UY, Jay M. Neutron-activated holmium-166-poly (L-lactic acid) microspheres: a potential agent for the internal radiation therapy of hepatic tumours. J Nucl Med 1991;32:2139–43
Nijsen F, Rook D, Brandt C, et al. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study. Eur J Nucl Med 2001;28:743–49
Zeng ZC, Tang ZY, Xie H, et al. Radioimmunotherapy for unresectable hepatocellular carcinoma using 131I-Hepama-1 mAb: preliminary results. J Cancer Res Clin Oncol 1993;119:257–9
Zeng ZC, Tang ZY, Liu KD, Lu JZ, Xie H, Yao Z. Improved long-term survival for unresectable hepatocellular carcinoma (HCC) with a combination of surgery and intrahepatic arterial infusion of 131I-anti-HCC mAb. Phase I/II clinical trials. J Cancer Res Clin Oncol 1998;124:275–80
Zeng ZC, Tang ZY, Yang BH, et al. Comparison between radioimmunotherapy and external beam radiation therapy for patients with hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2002;29:1657–68
Order S, Pajak T, Leibel S, et al. A randomized prospective trial comparing full dose chemotherapy to 131I antiferritin: an RTOG study. Int J Radiat Oncol Biol Phys 1991;20:953–63
Liu KD, Tang ZY, Bao YM, et al. Radioimmunotherapy for hepatocellular carcinoma (HCC) using 131I-anti HCC isoferritin IgG: preliminary results of experimental and clinical studies. Int J Radiat Oncol Biol Phys 1989;16:319–23
Uraki J, Yamakado K, Nakatsuka A, Takeda K. Transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma invading the portal veins: therapeutic effects and prognostic factors. Eur J Radiol 2004;51:12–8
Ho S, Lau JW, Leung TW. Intrahepatic 90Y-microspheres for hepatocellular carcinoma. J Nucl Med 2001;42:1587–9
Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998;40:583–92
Van de Wiele C, Revets H, Mertens N. Radioimmunoimaging. Advances and prospects. Q J Nucl Med Mol Imaging 2004;48:317–25
Roselli M, Greiner JW, Nieroda CA, Guzdagni F. New biological strategies to improve radioimmunodetection/therapy effectiveness. In: Riva P, editor. Cancer radioimmunotherapy. Harwood Academic Publishers; 1999. pp. 103–22
Acknowledgements
Bieke Lambert is funded by the ‘Bijzonderonderzoeks Fonds (Ghent University, No 011D9501)’ and Christophe Van de Wiele by the ‘Nationaal Fonds voor Wetenschappelijk Onderzoek’.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lambert, B., Van de Wiele, C. Treatment of hepatocellular carcinoma by means of radiopharmaceuticals. Eur J Nucl Med Mol Imaging 32, 980–989 (2005). https://doi.org/10.1007/s00259-005-1859-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-005-1859-z