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Z Gastroenterol 2009; 47(1): 37-54
DOI: 10.1055/s-2008-1028002
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

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

Selective Internal Radiotherapy (Radioembolization) and Radiation Therapy for HCC – Current Status and PerspectivesP. Hilgard1, 2 , S. Müller3 , M. Hamami3 , W. S. Sauerwein4 , U. Haberkorn5 , G. Gerken1 , G. Antoch6
  • 1Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen
  • 2Medizinische Klinik, Ev. Krankenhaus, Mülheim a. d. Ruhr
  • 3Institut für Nuklearmedizin, Universitätsklinikum Essen
  • 4Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Essen
  • 5Klinik für Nuklearmedizin, Universitätsklinikum Heidelberg
  • 6Institut für diagnostische und interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen
Further Information

Publication History

Manuskript eingetroffen: 5.10.2008

Manuskript akzeptiert: 30.11.2008

Publication Date:
20 January 2009 (online)

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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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 8 Llovet J M, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.  Semin Liver Dis. 1999;  19 (3) 329-338
    Google Scholar
  • 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
    Google Scholar
  • 10 Llovet J M, Ricci S, Mazzaferro V. et al . Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;  359 (4) 378-390
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 17 Murtha A D. Review of low-dose-rate radiobiology for clinicians.  Semin Radiat Oncol. 2000;  10 (2) 133-138
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 21 Dawson L A, Ten Haken R K. Partial volume tolerance of the liver to radiation.  Semin Radiat Oncol. 2005;  15 (4) 279-283
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 24 Zavgorodni S F. A model for dose estimation in therapy of liver with intraarterial microspheres.  Phys Med Biol. 1996;  41 (11) 2463-2480
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 51 Seong J, Koom W S, Park H C. Radiotherapy for painful bone metastases from hepatocellular carcinoma.  Liver Int. 2005;  25 (2) 261-265
    Google Scholar
  • 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
    Google Scholar
  • 53 Wittig A, Stuschke M. Palliative Strahlentherapie von Knochenmetastasen im Bereich der Wirbelsäule.  Orthopäd Praxis. 2007;  43 (9) 489-493
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 72 Sauerwein W. Principles and history of neutron capture therapy.  Strahlenther Onkol. 1993;  169 (1) 1-6
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 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
    Google Scholar
  • 83 Yankelevitz D F, Knapp P H, Henschke C I. et al . MR appearance of radiation hepatitis.  Clin Imaging. 1992;  16 (2) 89-92
    Google Scholar

PD Dr. Philip Hilgard

Medizinische Klinik Abt. für Allg. Innere Medizin und Gastroenterologie

Wertgasse 30

45468 Mülheim a. d. R.

Phone: 02 08/3 09-26 00

Fax: 02 08/3 09-26 28

Email: philip.hilgard@evkmh.de

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