Aktuelle Urol 2017; 48(02): 132-139
DOI: 10.1055/s-0042-121338
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Magnetische Detektion von Sentinel-Lymphknoten beim Prostatakarzinom nach intraprostatischer Injektion von superparamagnetischen Eisenoxid-Nanopartikeln

Magnetic Sentinel Lymph Node Detection in Prostate Cancer after intraprostatic Injection of Superparamagnetic Iron Oxide Nanoparticles
Alexander Winter
1   Universitätsklinik für Urologie, Klinikum Oldenburg, Fakultät für Medizin und Gesundheitswissenschaften, Carl von Ossietzky Universität Oldenburg
,
Svenja Engels
1   Universitätsklinik für Urologie, Klinikum Oldenburg, Fakultät für Medizin und Gesundheitswissenschaften, Carl von Ossietzky Universität Oldenburg
,
Tobias Kowald
2   Institut für Diagnostische und Interventionelle Radiologie, Klinikum Oldenburg, Oldenburg
,
Tina Susanne Paulo
2   Institut für Diagnostische und Interventionelle Radiologie, Klinikum Oldenburg, Oldenburg
,
Holger Gerullis
1   Universitätsklinik für Urologie, Klinikum Oldenburg, Fakultät für Medizin und Gesundheitswissenschaften, Carl von Ossietzky Universität Oldenburg
,
Ajay Chavan
2   Institut für Diagnostische und Interventionelle Radiologie, Klinikum Oldenburg, Oldenburg
,
Friedhelm Wawroschek
1   Universitätsklinik für Urologie, Klinikum Oldenburg, Fakultät für Medizin und Gesundheitswissenschaften, Carl von Ossietzky Universität Oldenburg
› Author Affiliations
Further Information

Publication History

Publication Date:
21 March 2017 (online)

Zusammenfassung

Eine zuverlässige Information über den Lymphknotenstatus ist beim Prostatakarzinom für ein akkurates Staging bzw. eine hierauf abgestimmte optimale Therapieplanung von großer Bedeutung. Trotz deutlicher Fortschritte in der Bildgebung stellt der histologische Metastasennachweis bzw. die pelvine Lymphadenektomie (PLND) weiterhin das zuverlässigste Verfahren für das Lymphknotenstaging beim klinisch lokalisierten Prostatakarzinom dar, insbesondere wegen des möglichen Nachweises von kleinen bzw. Mikrometastasen. Die Radioisotop-gesteuerte Sentinel-PLND (sPLND) weist beim Prostatakarzinom eine hohe Sensitivität im Nachweis von Lymphknotenmetastasen und dabei aufgrund der zielgerichteten Entfernung von vergleichsweise wenigen Lymphknoten eine geringe Morbidität auf. Dem stehen jedoch bedingt durch die radioaktive Markierung prinzipielle Limitationen wie z. B. die einzuhaltenden strikten gesetzlichen Regularien, die Erfordernis einer Nuklearmedizin und die radioaktive Exposition von Patienten und medizinischem Personal gegenüber. Um die Vorteile des zielgerichteten Sentinel-Verfahrens weiter zu nutzen, aber die Nachteile der radioaktiven Markierung zu umgehen, wurde beim Mammakarzinom die Markierung von Sentinel-Lymphknoten (SLNs) mittels superparamagnetischen Eisenoxid-Nanopartikeln (SPIONs) überprüft und die Nichtunterlegenheit gegenüber der etablierten Markierung mittels 99mTechnetium-Nanokolloid gezeigt. Wie ehemals die radioaktive Markierung konnte dieses innovative neue magnetische Markierungsverfahren und die intraoperative Identifizierung von SLNs mittels eines Hand-Magnetometers erfolgreich auf das Prostatakarzinom übertragen und in ersten Untersuchungen eine hohe Sensitivität in der Detektion Lymphknoten-positiver Patienten gezeigt werden. Dabei bietet die Methode außerdem den Vorteil, sicher und vergleichsweise einfach von einem Urologen alleine unabhängig durchgeführt werden zu können. Zudem kann die Visualisierung der SPION-markierten SLNs mittels Magnetresonanztomografie vergleichbar zur Lymphszintigraphie beim radioaktiven Verfahren eine präzise präoperative SLN-Identifizierung und damit eine vollständig strahlungsfreie prä- und intraoperative Identifikation der SLNs bei Patienten mit Prostatakarzinom ermöglichen.

Abstract

In prostate cancer, reliable information about the lymph node status is of great importance for accurate staging and the optimal planning of treatment. Despite recent advances in imaging, the histological detection of metastases, or pelvic lymphadenectomy (PLND), continues to be the most reliable method for lymph node staging in clinically localised prostate cancer, especially as this procedure enables the detection of small or micrometastases. Radioisotope-guided sentinel PLND (sPLND) demonstrates high sensitivity in the detection of lymph node metastases as well as low morbidity in prostate cancer because of the targeted removal of a relatively small number of lymph nodes. However, radioactive labelling is associated with limitations such as strict legal regulations, the need for a nuclear medicine department and the radioactive exposure of patients and medical staff. In order to take advantage of the targeted sentinel method while avoiding the disadvantages of radioactive labelling, the identification of sentinel lymph nodes (SLNs) by means of superparamagnetic iron oxide nanoparticles (SPIONs) was studied in breast carcinoma, and its non-inferiority compared with the established procedure with 99mtechnetium nanocolloid was demonstrated. Just like the radioactive identification of SLNs, this innovative new method for magnetic labelling and the intraoperative identification of SLNs using a hand-held magnetometer were successfully transferred to prostate cancer. Initial studies demonstrated high sensitivity in the detection of lymph node-positive patients. This method offers the additional advantage of being safe and easy to perform for a single urologist. In addition, the visualisation of SPION-marked SLNs through magnetic resonance tomography enables a precise preoperative SLN identification comparable to lymphoscintigraphy in the radioactive approach. Therefore, SLNs can be identified before and during surgical procedures in prostate cancer patients without exposure to irradiation.

 
  • Literatur

  • 1 Joniau S, Briganti A, Gontero P. et al. Stratification of high-risk prostate cancer into prognostic categories: A European multi-institutional study. Eur Urol 2015; 67: 157-164
  • 2 Seiler R, Studer UE, Tschan K. et al. Removal of limited nodal disease in patients undergoing radical prostatectomy: Long-term results confirm a chance for cure. J Urol 2014; 191: 1280-1285
  • 3 Winter A, Henke RP, Wawroschek F. Targeted salvage lymphadenectomy in patients treated with radical prostatectomy with biochemical recurrence: complete biochemical response without adjuvant therapy in patients with low volume lymph node recurrence during long-term follow-up. BMC Urol 2015; 15: 10 doi: 10.1186/s12894-015-0004-y
  • 4 Hovels AM, Heesakkers RA, Adang EM. et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: A metanalysis. Clin Radiol 2008; 63: 387-395
  • 5 Maurer T, Gschwend JE, Rauscher I. et al. Diagnostic efficacy of (68)Gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer. J Urol 2016; 195: 1436-1443
  • 6 Bader P, Burkhard FC, Markwalder R. et al. Is a limited lymph node dissection an adequate staging procedure for prostate cancer?. J Urol 2002; 168: 514-518
  • 7 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF). Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, http://leitlinienprogrammonkologie de/Leitlinien.7.0.html; Stand 15.09.2016
  • 8 Mottet N, Bellmunt J, Briers E et al. The European Association of Urology Prostate Cancer Guidelines 2016. Im Internet: https://uroweb.org/guideline/prostate-cancer/ Stand 9.11.2016
  • 9 Musch M, Klevecka V, Roggenbuck U. et al. Complications of pelvic lymphadenectomy in 1380 patients undergoing radical retropubic prostatectomy between 1993 and 2006. J Urol 2008; 179: 923-928
  • 10 Winter A, Vogt C, Weckermann D. et al. Complications of pelvic lymphadenectomy in clinically localised prostate cancer: Different techniques in comparison and dependency on the number of removed lymph nodes. Aktuelle Urol 2011; 42: 179-183
  • 11 Zeidmann I, Buss JM. Experimental studies of the spread of cancer in the lymphatic system. Cancer Res 1954; 14: 403-405
  • 12 Gould EA, Winship T, Philbin PH. et al. Observations on a "sentinel node" in cancer of the parotid. Cancer 1960; 13: 77-78
  • 13 Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456-466
  • 14 Morton DL, Wen DR, Cochran AJ. Pathophysiology of regional lymph node metastases in early melanoma studied by intraoperative mapping of the cutaneous lymphatics. Second International Conference on Melanoma. October 1989, Venice, 131
  • 15 Van der Veen H, Hoekstra OS, Paul MA. et al. Gamma probe-guiged sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg 1994; 81: 1769-1770
  • 16 Horenblas S, Jansen L, Meinhardt W. et al. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000; 163: 100-104
  • 17 Wawroschek F, Vogt H, Bachter D. et al. First experience with gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 2000; 28: 246-249
  • 18 Giuliano AE, Kirgan DM, Guenther JM. et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220: 391-398
  • 19 Hakenberg OW, Compérat EM, Minhas S. et al. EAU Guidelines on Penile Cancer: 2014 Update. Eur Urol 2015; 67: 142-150
  • 20 Schubert T, Uphoff J, Henke RP. et al. Reliability of radioisotope-guided sentinel lymph node biopsy in penile cancer: verification in consideration of the European guidelines. BMC Urol 2015; 15: 98
  • 21 Morton DL, Thompson JF, Cochran AJ. et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014; 370: 599-609
  • 22 Land SR, Kopec JA, Julian TB. et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. J Clin Oncol 2010; 28: 3929-3936
  • 23 Menon M, Menon S, Strauss HW. et al. Demonstration of the existence of canine prostatic lymphatics by radioisotope technique. J Urol 1977; 118: 274-277
  • 24 Kaplan WD, Whitemore WF, Gittes RF. Visualization of canine and human prostatic lymph nodes following intraprostatic injection of technetium 99 m antimony sulphide colloid. Invest Radiol 1980; 15: 34-38
  • 25 Zuckier LS, Finkelstein M, Kreutzer ER. et al. Technetium-99m antimony sulphide colloid lymphoscintigraphy of the prostate by direct transrectal injection. Nucl Med Commun 1990; 11: 589-596
  • 26 Wawroschek F, Wengenmair H, Senekowitsch-Schmidtke R. et al. Prostate lymphoscintigraphy for sentinel lymph node identification in canines: reproducibility, uptake, and biokinetics depending on different injection strategies. Urol Res 2003; 31: 152-158
  • 27 Wawroschek F, Vogt H, Weckermann D. et al. The sentinel lymph node concept in prostate cancer – First results of gamma probe-guided sentinel lymph node identification. Eur Urol 1999; 36: 595-600
  • 28 Wawroschek F, Vogt H, Wengenmair H. et al. Prostate lymphoscintigraphy and radio-guided surgery for sentinel lymph node identification in prostate cancer. Technique and results of the first 350 cases. Urol Int 2003; 70: 303-310
  • 29 Holl G, Dorn R, Wengenmair H. et al. Validation of sentinel lymph node dissection in prostate cancer: Experience in more than 2000 patients. Eur J Nucl Med Mol Imaging. 2009; 36: 1377-1382
  • 30 Sadeghi R, Tabasi KT, Bazaz SM. et al. Sentinel node mapping in the prostate cancer. Meta-analysis. Nuklearmedizin 2011; 50: 107-115
  • 31 Wit EM, Acar C, Grivas N. et al. Sentinel Node Procedure in Prostate Cancer: A Systematic Review to Assess Diagnostic Accuracy. Eur Urol 2016; DOI: 10.1016/j.eururo.2016.09.007.
  • 32 Winter A, Kneib T, Henke RP. et al. Sentinel lymph node dissection in more than 1200 prostate cancer cases: Rate and prediction of lymph node involvement depending on preoperative tumor characteristics. Int J Urol 2014; 21: 58-63
  • 33 Makarov DV, Trock BJ, Humphreys EB. et al. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007; 69: 1095-1101
  • 34 Godoy G, Chong KT, Cronin A. et al. Extent of pelvic lymph node dissection and the impact of standard template dissection on nomogram prediction of lymph node involvement. Eur Urol 2011; 60: 195-201
  • 35 Briganti A, Larcher A, Abdollah F. et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: The essential importance of percentage of positive cores. Eur Urol 2012; 61: 480-487
  • 36 Abdollah F, Suardi N, Gallina A. et al. Extended pelvic lymph node dissection in prostate cancer: A 20-year audit in a single center. Ann Oncol 2013; 24: 1459-1466
  • 37 Winter A, Engels S, Süykers M. et al. Radioisotope guided sentinel lymph node dissection in prostate cancer: Rate of Lymph node involvment depending on preoperative tumor characteristics in more than 2100 patients. SM J Urol 2015; 1: 1002
  • 38 KleinJan GH, van den Berg NS, de Jong J. et al. Multimodal hybrid imaging agents for sentinel node mapping as a means to (re)connect nuclear medicine to advances made in robot-assisted surgery. Eur J Nucl Med Mol Imaging 2016; 43: 1278-1287
  • 39 Acar C, Kleinjan GH, van den Berg NS. et al. Advances in sentinel node dissection in prostate cancer from a technical perspective. Int J Urol 2015; 22: 898-909
  • 40 Faries MB, Bedrosian I, Reynolds C. et al. Active macromolecule uptake by lymph node antigen-presenting cells: A novel mechanism in determining sentinel lymph node status. Ann Surg Oncol 2000; 7: 98-105
  • 41 Brouwer OR, van den Berg NS, Mathéron HM. et al. A hybrid radioactive and fluorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. Eur Urol 2014; 65: 600-609
  • 42 Ahmed M, de Rosales RT, Douek M. Preclinical studies of the role of iron oxide magnetic nanoparticles for nonpalpable lesion localization in breast cancer. J Surg Res 2013; 185: 27-35
  • 43 Johnson L, Pinder SE, Douek M. Deposition of superparamagnetic iron-oxide nanoparticles in axillary sentinel lymph nodes following subcutaneous injection. Histopathology 2013; 62: 481-486
  • 44 Douek M, Klaase J, Monypenny I. et al. Sentinel node biopsy using a magnetic tracer versus standard technique: The SentiMAG Multicentre Trial. Ann Surg Oncol 2014; 21: 1237-1245
  • 45 Winter A, Woenkhaus J, Wawroschek F. A novel method for intraoperative sentinel lymph node detection in prostate cancer patients using superparamagnetic iron oxide nanoparticles and a handheld magnetometer: The initial clinical experience. Ann Surg Oncol 2014; 21: 4390-4396
  • 46 Buckle T, Brouwer OR, Valdés Olmos RA. et al. Relationship between intraprostatic tracer deposits and sentinel lymph node mapping in prostate cancer patients. J Nucl Med 2012; 53: 1026-1033
  • 47 Winter A, Engels S, Goos Ph. et al. Magnetometer guided sentinel lymphadenectomy after intraprostatic injection of super-paramagnetic iron oxide nanoparticles in intermediare and high risk prostate cancer patients. J Urol 2016; 195 (Suppl. 04) e987
  • 48 Stark DD, Weissleder R, Elizondo G. et al. Superparamagnetic iron oxide: Clinical application as a contrast agent for MR imaging of the liver. Radiology 1988; 168: 297-301
  • 49 Iida S, Imai K, Matsuda S. et al. In vivo identification of sentinel lymph nodes using MRI and size-controlled and monodispersed magnetite nanoparticles. Journal of magnetic resonance imaging. J Magn Reson Imaging 2013; 38: 1346-1355
  • 50 Turkbey B, Agarwal HK, Shih J. et al. A phase I dosing study of ferumoxytol for MR lymphography at 3T in patients with prostate cancer. AJR Am J Roentgenol 2015; 205: 64-69
  • 51 Winter A, Kowald T, Paulo TS. et al. Magnetic resonance sentinel lymph node imaging in prostate cancer using intraprostatic injection of superparamagnetic iron oxide nanoparticles: The first in-human results. Eur Urol Suppl 2016; 15 (Suppl. 03) 1060