Selektive interne Radiotherapie (Radioembolisation) und Strahlentherapie beim HCC – Stand und Perspektiven

Zusammenfassung

Die Mikrosphären- und Partikel-Technologie mit gezieltem Transport tumorizider Substanzen oder Strahlung repräsentiert eine neue Generation von Therapeutika in der interventionellen Onkologie. So erlaubt die intrahepatische Applikation von radioaktiven Mikrosphären über die Arteria hepatica eine lokal ablative Behandlung auch diffuser und multifokaler Lebertumoren, die bisher nur einer systemischen Therapie zugänglich waren. Derzeitiger Standard für eine solche selektive interne Radiotherapie (SIRT) oder Radioembolisation ist die Verwendung von Yttrium-90 angereicherten Glas- oder Kunstharz-Mikrosphären. Indikation, Technik und derzeitige Ergebnisse dieser Therapie beim hepatozellulären Karzinom (HCC) werden ausführlich diskutiert. Außer Yttrium-90-Mikrosphären sind in jüngster Vergangenheit aber auch andere Radiopharmaka wie 131-Jod- oder 188-Rhenium-Lipiodol für eine SIRT verwendet worden. Zusätzlich zur internen gewinnt aber jüngst auch die perkutane Strahlentherapie, vor allem begründet in der Verfügbarkeit neuer schonender Bestrahlungstechniken, bei der lokoregionären Therapie des HCCs zunehmend an Bedeutung.

Abstract

Microsphere and particle technologies for the selective transport of tumoricidal agents or radiation represent a new generation of therapeutics in interventional oncology. The intrahepatic application of radioactive microspheres via the hepatic artery, for instance, allows locoregional therapy of diffuse or multifocal liver tumours, for which to date systemic therapy was the only remaining option. Current standards for this selective internal radiotherapy or radioembolisation are 90-yttrium glass or resin microspheres. Indication, technique, and the current results are extensively discussed. In addition to 90-yttrium microspheres, other radiopharmaceuticals, such as 131-iodine or 188-rhenium lipiodol, have been successful used for SIRT. As a result of new, more selective radiation techniques, internal radiotherapy for the locoregional treatment of HCC has been recently complemented by an increasing use of percutaneous radiotherapy.

Schlüsselwörter

hepatozelluläres Karzinom - Radioembolisation - Radiotherapie - SIRT - lokoregionäre Therapie - Lebertumor

Key words

hepatocellular carcinoma - radioembolisation - radiotherapy - SIRT - locoregional therapy - liver tumours

Literatur

• 1 Nolan T R, Grady E D. Intravascular particulate radioisotope therapy: clinical observations of 76 patients with advanced cancer treated with 90-yttrium particles.  Am Surg. 1969;  35 (3) 181-188
• 2 Mantravadi R V, Spigos D G, Tan W S. et al . Intraarterial yttrium 90 in the treatment of hepatic malignancy.  Radiology. 1982;  142 (3) 783-786
• 3 Wollner I S, Knutsen C A, Ullrich K A. et al . Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs.  Cancer Res. 1987;  47 (12) 3285-3290
• 4 Wollner I, Knutsen C, Smith P. et al . Effects of hepatic arterial yttrium 90 glass microspheres in dogs.  Cancer. 1988;  61 (7) 1336-1344
• 5 Shepherd F A, Rotstein L E, Houle S. et al . A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma.  Cancer. 1992;  70 (9) 2250-2254
• 6 Andrews J C, Walker S C, Ackermann R J. et al . Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up.  J Nucl Med. 1994;  35 (10) 1637-1644
• 7 Bruix J, Sherman M, Llovet J M. et al . Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.  J Hepatol. 2001;  35 (3) 421-430
• 8 Llovet J M, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.  Semin Liver Dis. 1999;  19 (3) 329-338
• 9 Mazzaferro V, Regalia E, Doci R. et al . Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.  N Engl J Med. 1996;  334 (11) 693-699
• 10 Llovet J M, Ricci S, Mazzaferro V. et al . Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;  359 (4) 378-390
• 11 Ho C L, Chen S, Yeung D W. et al . Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma.  J Nucl Med. 2007;  48 (6) 902-909
• 12 Kennedy A, Nag S, Salem R. et al . Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium.  Int J Radiat Oncol Biol Phys. 2007;  68 (1) 13-23
• 13 Hung J C, Redfern M G, Mahoney D W. et al . Evaluation of macroaggregated albumin particle sizes for use in pulmonary shunt patient studies.  J Am Pharm Assoc (Wash). 2000;  40 (1) 46-51
• 14 Ho S, Lau W Y, Leung T W. et al . Tumour-to-normal uptake ratio of 90Y microspheres in hepatic cancer assessed with 99Tcm macroaggregated albumin.  Br J Radiol. 1997;  70 (836) 823-828
• 15 Ho S, Lau W Y, Leung T W. et al . Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours.  Eur J Nucl Med. 1996;  23 (8) 947-952
• 16 Ho S, Lau W Y, Leung T W. et al . 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 (3) 293-298
• 17 Murtha A D. Review of low-dose-rate radiobiology for clinicians.  Semin Radiat Oncol. 2000;  10 (2) 133-138
• 18 Campbell A M, Bailey I H, Burton M A. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy.  Phys Med Biol. 2001;  46 (2) 487-498
• 19 Emami B, Lyman J, Brown A. et al . Tolerance of normal tissue to therapeutic irradiation.  Int J Radiat Oncol Biol Phys. 1991;  21 (1) 109-122
• 20 Salem R, Thurston K G. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations.  J Vasc Interv Radiol. 2006;  17 (8) 1251-1278
• 21 Dawson L A, Ten Haken R K. Partial volume tolerance of the liver to radiation.  Semin Radiat Oncol. 2005;  15 (4) 279-283
• 22 Goin J E, Salem R, Carr B I. et al . Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis.  J Vasc Interv Radiol. 2005;  16 (2 Pt 1) 195-203
• 23 Lewandowski R J, Sato K T, Atassi B. et al . Radioembolization with 90Y microspheres: angiographic and technical considerations.  Cardiovasc Intervent Radiol. 2007;  30 (4) 571-592
• 24 Zavgorodni S F. A model for dose estimation in therapy of liver with intraarterial microspheres.  Phys Med Biol. 1996;  41 (11) 2463-2480
• 25 Sarfaraz M, Kennedy A S, Lodge M A. et al . Radiation absorbed dose distribution in a patient treated with yttrium-90 microspheres for hepatocellular carcinoma.  Med Phys. 2004;  31 (9) 2449-2453
• 26 Dancey J E, Shepherd F A, Paul K. et al . Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.  J Nucl Med. 2000;  41 (10) 1673-1681
• 27 Goin J E, Salem R, Carr B I. et al . Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities.  J Vasc Interv Radiol. 2005;  16 (2 Pt 1) 205-213
• 28 Salem R, Thurston K G, Carr B I. et al . Yttrium-90 microspheres: radiation therapy for unresectable liver cancer.  J Vasc Interv Radiol. 2002;  13 (9 Pt 2) S223-S229
• 29 Okuda K, Ohtsuki T, Obata H. et al . Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients.  Cancer. 1985;  56 (4) 918-928
• 30 Geschwind J F, Salem R, Carr B I. et al . Yttrium-90 microspheres for the treatment of hepatocellular carcinoma.  Gastroenterology. 2004;  127 (5 Suppl 1) S194-S205
• 31 Carr B I. Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.  Liver Transpl. 2004;  10 (2 Suppl 1) S107-S110
• 32 Kulik L M, Carr B I, Mulcahy M F. et al . Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.  Hepatology. 2008;  47 (1) 71-81
• 33 Raoul J L, Bourguet P, Bretagne J F. et al . Hepatic artery injection of I-131-labeled lipiodol. Part I. Biodistribution study results in patients with hepatocellular carcinoma and liver metastases.  Radiology. 1988;  168 (2) 541-545
• 34 Bretagne J F, Raoul J L, Bourguet P. et al . Hepatic artery injection of I-131-labeled lipiodol. Part II. Preliminary results of therapeutic use in patients with hepatocellular carcinoma and liver metastases.  Radiology. 1988;  168 (2) 547-550
• 35 Raoul J I, Bretagne J F, Caucanas J P. et al . Internal radiation therapy for hepatocellular carcinoma. Results of a French multicenter phase II trial of transarterial injection of iodine 131-labeled Lipiodol.  Cancer. 1992;  69 (2) 346-352
• 36 Bhattacharya S, Novell J R, Dusheiko G M. et al . Epirubicin-Lipiodol chemotherapy versus 131iodine-Lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma.  Cancer. 1995;  76 (11) 2202-2210
• 37 Rindani R B, Hugh T J, Roche J. et al . 131I lipiodol therapy for unresectable hepatocellular carcinoma.  ANZ J Surg. 2002;  72 (3) 210-214
• 38 Raoul J L, Guyader D, Bretagne J F. 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 (11) 1782-1787
• 39 Raoul J L, Guyader D, Bretagne J F. et al . Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma.  Hepatology. 1997;  26 (5) 1156-1161
• 40 Lau W Y, Leung T W, Ho S K. et al . Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial.  Lancet. 1999;  353 (9155) 797-801
• 41 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 (5) 1237-1241
• 42 Lau W Y, Lai E C, Leung T W. et al . Adjuvant Intra-arterial Iodine-131-labeled Lipiodol for Resectable Hepatocellular Carcinoma: A Prospective Randomized Trial-Update on 5-Year and 10-Year Survival.  Ann Surg. 2008;  247 (1) 43-48
• 43 Boucher E, Garin E, Guylligomarc’h A. et al . Intra-arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma.  Radiother Oncol. 2007;  82 (1) 76-82
• 44 Liepe K, Brogsitter C, Leonhard J. et al . Feasibility of high activity rhenium-188-microsphere in hepatic radioembolization.  Jpn J Clin Oncol. 2007;  37 (12) 942-950
• 45 Hafeli U O, Casillas S, Dietz D W. et al . Hepatic tumor radioembolization in a rat model using radioactive rhenium (186Re/ 188Re) glass microspheres.  Int J Radiat Oncol Biol Phys. 1999;  44 (1) 189-199
• 46 Lin Y C, Tsai S C, Hung G U. et al . Direct injection of (188)Re-microspheres in the treatment of hepatocellular carcinoma: compared with traditional percutaneous ethanol injection: an animal study.  Nuklearmedizin. 2005;  44 (3) 76-80
• 47 Wang S J, Lin W Y, Chen M N. et al . Intratumoral injection of rhenium-188 microspheres into an animal model of hepatoma.  J Nucl Med. 1998;  39 (10) 1752-1757
• 48 Lambert B, Bacher K, De K. et al . 188Re-HDD/lipiodol for treatment of hepatocellular carcinoma: a feasibility study in patients with advanced cirrhosis.  J Nucl Med. 2005;  46 (8) 1326-1332
• 49 Sundram F, Chau T C, Onkhuudai P. et al . Preliminary results of transarterial rhenium-188 HDD lipiodol in the treatment of inoperable primary hepatocellular carcinoma.  Eur J Nucl Med Mol Imaging. 2004;  31 (2) 250-257
• 50 Bernal P, Raoul J L, Vidmar G. et al . Intra-arterial rhenium-188 lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study.  Int J Radiat Oncol Biol Phys. 2007;  69 (5) 1448-1455
• 51 Seong J, Koom W S, Park H C. Radiotherapy for painful bone metastases from hepatocellular carcinoma.  Liver Int. 2005;  25 (2) 261-265
• 52 Kaizu T, Karasawa K, Tanaka Y. et al . Radiotherapy for osseous metastases from hepatocellular carcinoma: a retrospective study of 57 patients.  Am J Gastroenterol. 1998;  93 (11) 2167-2171
• 53 Wittig A, Stuschke M. Palliative Strahlentherapie von Knochenmetastasen im Bereich der Wirbelsäule.  Orthopäd Praxis. 2007;  43 (9) 489-493
• 54 Constine L S, Williams J P, Morris M. et al .Late effects of cancer treatment on normal tissues. Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK Principles and practice of radiation oncology Philadelphia; Lippincott Williams & Wilkins 2004: 397-390
• 55 Kaiser G M, Mueller A B, Sauerwein W. et al . Biliodigestive anastomosis after intraoperative irradiation in swine.  J Invest Surg. 2005;  18 (6) 305-313
• 56 Tse R V, Hawkins M, Lockwood G. et al . Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.  J Clin Oncol. 2008;  26 657-664
• 57 Eccles C, Brock K K, Bissonnette J P. et al . Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy.  Int J Radiat Oncol Biol Phys. 2006;  64 (3) 751-759
• 58 Thomas E, Chapet O, Kessler M L. et al . Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors.  Int J Radiat Oncol Biol Phys. 2005;  62 (2) 571-578
• 59 Fuss M, Salter B J, Herman T S. et al . External beam radiation therapy for hepatocellular carcinoma: potential of intensity-modulated and image-guided radiation therapy.  Gastroenterology. 2004;  127 (5 Suppl 1) S206-S217
• 60 Herfarth K K, Debus J, Wannenmacher M. Stereotactic radiation therapy of liver metastases: update of the initial phase-I/II trial.  Front Radiat Ther Oncol. 2004;  38 100-105
• 61 Cheng J C, Wu J K, Huang C M. et al . Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease.  Int J Radiat Oncol Biol Phys. 2003;  56 (1) 229-234
• 62 Guo W J, Yu E X, Liu L M. et al . Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma.  World J Gastroenterol. 2003;  9 (8) 1697-1701
• 63 Shim S J, Seong J, Han K H. et al . Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma.  Liver Int. 2005;  25 (6) 1189-1196
• 64 Zeng Z C, Tang Z Y, Yang B H. et al . Radiation therapy for the locoregional lymph node metastases from hepatocellular carcinoma, phase I clinical trial.  Hepatogastroenterology. 2004;  51 (55) 201-207
• 65 McGinn C J, Ten Haken R K, Ensminger W D. et al . Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model.  J Clin Oncol. 1998;  16 (6) 2246-2252
• 66 Wulf J, Guckenberger M, Haedinger U. et al . Stereotactic radiotherapy of primary liver cancer and hepatic metastases.  Acta Oncol. 2006;  45 (7) 838-847
• 67 Mornex F, Girard N, Beziat C. et al . Feasibility and efficacy of high-dose three-dimensional-conformal radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies – mature results of the French Phase II RTF-1 trial.  Int J Radiat Oncol Biol Phys. 2006;  66 (4) 1152-1158
• 68 Kato H, Tsujii H, Miyamoto T. et al . Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis.  Int J Radiat Oncol Biol Phys. 2004;  59 (5) 1468-1476
• 69 Kawashima M, Furuse J, Nishio T. et al . Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma.  J Clin Oncol. 2005;  23 (9) 1839-1846
• 70 Hata M, Tokuuye K, Sugahara S. et al . Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis.  Strahlenther Onkol. 2006;  182 (12) 713-720
• 71 Hata M, Tokuuye K, Sugahara S. et al . Proton beam therapy for aged patients with hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys. 2007;  69 (3) 805-812
• 72 Sauerwein W. Principles and history of neutron capture therapy.  Strahlenther Onkol. 1993;  169 (1) 1-6
• 73 Nievaart V A, Moss R L, Kloosterman J L. et al . Design of a rotating facility for extracorporal treatment of an explanted liver with disseminated metastases by boron neutron capture therapy with an epithermal neutron beam.  Radiat Res. 2006;  166 (1 Pt 1) 81-88
• 74 Wittig A, Malago M, Collette L. et al . Uptake of two 10B-compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11 001).  Int J Cancer. 2008;  122 (5) 1164-1171
• 75 Yamada K, Izaki K, Sugimoto K. et al . Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys. 2003;  57 (1) 113-119
• 76 Zeng Z C, Tang Z Y, Fan J. et al . A comparison of chemoembolization combination with and without radiotherapy for unresectable hepatocellular carcinoma.  Cancer J. 2004;  10 (5) 307-316
• 77 Lin C S, Jen Y M, Chiu S Y. et al . Treatment of portal vein tumor thrombosis of hepatoma patients with either stereotactic radiotherapy or three-dimensional conformal radiotherapy.  Jpn J Clin Oncol. 2006;  36 (4) 212-217
• 78 Ingold J A, Reed G B, Kaplan H S. et al . Radiation Hepatitis.  Am J Roentgenol Radium Ther Nucl Med. 1965;  93 200-208
• 79 Reed G B Jr, Cox A J Jr. The human liver after radiation injury. A form of veno-occlusive disease.  Am J Pathol. 1966;  48 (4) 597-611
• 80 Lawrence T S, Robertson J M, Anscher M S. et al . Hepatic toxicity resulting from cancer treatment.  Int J Radiat Oncol Biol Phys. 1995;  31 (5) 1237-1248
• 81 Unger E C, Lee J K, Weyman P J. CT and MR imaging of radiation hepatitis.  J Comput Assist Tomogr. 1987;  11 (2) 264-268
• 82 Garra B S, Shawker T H, Chang R. et al . The ultrasound appearance of radiation-induced hepatic injury. Correlation with computed tomography and magnetic resonance imaging.  J Ultrasound Med. 1988;  7 (11) 605-609
• 83 Yankelevitz D F, Knapp P H, Henschke C I. et al . MR appearance of radiation hepatitis.  Clin Imaging. 1992;  16 (2) 89-92