Molekulare Bildgebung in der Onkologie

Zusammenfassung

„Molekulare Bildgebung” wird im Allgemeinen definiert als nicht-invasive Darstellung von Makromolekülen oder biologischen Prozessen in lebenden Organismen. Ein wesentliches Kennzeichen der Molekularen Bildgebung ist ihr nicht-invasiver Charakter, wodurch wiederholte Untersuchungen an einem Patienten möglich sind, sodass biologische Prozesse im zeitlichen Verlauf darstellbar werden. Im Bereich der Onkologie ist die molekulare Bildgebung deshalb insbesondere für die Erfolgskontrolle bei der Behandlung maligner Tumoren geeignet. In experimentellen Studien können verschiedene Techniken für die molekulare Bildgebung eingesetzt werden. Dazu gehören optische Verfahren wie die Fluoreszenz- und Biolumineszenz-Bildgebung, die Magnetresonanztomografie (MRT) sowie nuklearmedizinische Untersuchungen. Klinisch stehen nuklearmedizinische Verfahren jedoch ganz im Vordergrund, da bislang nur mit radioaktiv markierten Tracern eine ausreichende Sensitivität erzielt werden kann, um die Expression und Funktion von biologisch relevanten Makromolekülen nicht-invasiv darzustellen. Mit Hilfe nuklearmedizinischer Verfahren läst sich am Patienten die Expression verschiedener Rezeptoren (Östrogen-, Androgen-, Somatostatinrezeptoren sowie Integrine) nachweisen. Außerdem stehen Tracer zur Untersuchung der Tumorhypoxie und Proliferation zur Verfügung. Der Schwerpunkt der molekularen Bildgebung in der Onkologie liegt jedoch im Bereich des Tumorstoffwechsels. Der gesteigerte Glukosestoffwechsel maligner Tumoren kann mit Hilfe der Positronen-Emissions-Tomografie mit dem Glukoseanalogon [¹⁸F]Fluordeoxyglukose (FDG-PET) dargestellt und quantitativ erfasst werden. Zahlreiche Studien haben dabei gezeigt, dass die Abnahme des Tumorglukosestoffwechsels unter Therapie eine frühe Vorhersage des Tumoransprechen und des Patientenüberlebens ermöglicht. In klinischen Studien wird derzeit überprüft, ob so mit Hilfe der FDG-PET die Therapie von malignen Tumoren individualisiert werden kann.

Abstract

Molecular imaging is generally defined as noninvasive and quantitative imaging of targeted macromolecules and biological processes in living organisms. A characteristic of molecular imaging is the ability to perform repeated studies and assess changes in biological processes over time. Thus molecular imaging lends itself well for monitoring the effectiveness of tumor therapy. In animal models a variety of techniques can be used for molecular imaging. These include optical imaging (bioluminescence and fluorescence imaging), magnetic resonance imaging (MRI) and nuclear medicine techniques. In the clinical setting, however, nuclear medicine techniques predominate, because so far only radioactive tracers provide the necessary sensitivity to study expression and function of macromolecules non-invasively in patients. Nuclear medicine techniques allows to study a variety of biological processes in patients. These include the expression of various receptors (estrogen, androgen, somatostatin receptors and integrins). In addition, tracers are available to study tumor cell proliferation and hypoxia. The by far most commonly used molecular imaging technique in oncology is, however, positron emission tomography (PET) with the glucose analog [¹⁸F]fluorodeoxyglucose (FDG-PET). FDG-PET permits non-invasive quantitative assessment of the accelerated exogenous glucose use of malignant tumors. Numerous studies have now shown that reduction of tumor FDG-uptake during therapy allows early prediction of tumor response and patient survival. Clinical studies are currently underway to determine whether FDG-PET can be used to individualize tumor therapy by signaling early in the course of therapy the need for therapeutic adjustments in patients with likely non-responding tumors.

Schlüsselwörter

molekulare Bildgebung - Therapiekontrolle - Positronen-Emissions-Tomografie

Key words

Molecular imaging - treatment monitoring - positron emission tomography

Literatur

• 1 Zasadzinski J A, Meyer R B. Molecular imaging of tobacco mosaic virus lyotropic nematic phases.  Physical Review Letters. 1986;  56 636-638
• 2 Jones T. The imaging science of positron emission tomography.  Eur J Nucl Med. 1996;  23 807-813
• 3 Weissleder R, Mahmood U. Molecular imaging.  Radiology. 2001;  219 316-333
• 4 Herschman H R. Molecular imaging: looking at problems, seeing solutions.  Science. 2003;  302 605-608
• 5 Tjuvajev J G, Stockhammer G, Desai R, Uehara H, Watanabe K, Gansbacher B, Blasberg R G. Imaging the expression of transfected genes in vivo.  Cancer Res. 1995;  55 6126-6132
• 6 Ntziachristos V, Ripoll J, Wang L V, Weissleder R. Looking and listening to light: the evolution of whole-body photonic imaging.  Nat Biotechnol. 2005;  23 313-320
• 7 Driehuys B. Chemistry. Toward molecular imaging with xenon MRI.  Science. 2006;  314 432-433
• 8 Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker.  J Clin Oncol. 2006;  24 3293-3298
• 9 Beer A J, Haubner R, Goebel M, Luderschmidt S, Spilker M E, Wester H J, Weber W A, Schwaiger M. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer ¹⁸F-galacto-RGD in cancer patients.  J Nucl Med. 2005;  46 1333-1341
• 10 Avril N. GLUT1 expression in tissue and (¹⁸)F-FDG uptake.  J Nucl Med. 2004;  45 930-932
• 11 Mortimer J E, Dehdashti F, Siegel B A, Trinkaus K, Katzenellenbogen J A, Welch M J. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.  J Clin Oncol. 2001;  19 2797-2803
• 12 Dehdashti F, Picus J, Michalski J M, Dence C S, Siegel B A, Katzenellenbogen J A, Welch M J. Positron tomographic assessment of androgen receptors in prostatic carcinoma.  Eur J Nucl Med Mol Imaging. 2005;  32 344-350
• 13 Meisetschlager G, Poethko T, Stahl A, Wolf I, Scheidhauer K, Schottelius M, Herz M, Wester H J, Schwaiger M. Gluc-Lys([¹⁸F]FP)-TOCA PET in patients with SSTR-positive tumors: biodistribution and diagnostic evaluation compared with [¹¹¹In]DTPA-octreotide.  J Nucl Med. 2006;  47 566-573
• 14 Hofmann M, Maecke H, Borner R, Weckesser E, Schoffski P, Oei L, Schumacher J, Henze M, Heppeler A, Meyer J, Knapp H. Biokinetics and imaging with the somatostatin receptor PET radioligand (⁶⁸)Ga-DOTATOC: preliminary data.  Eur J Nucl Med. 2001;  28 1751-1757
• 15 Eliceiri B P, Cheresh D A. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development.  J Clin Invest. 1999;  103 1227-1230
• 16 Haubner R H, Wester H J, Weber W A, Schwaiger M. Radiotracer-based strategies to image angiogenesis.  Q J Nucl Med. 2003;  47 189-199
• 17 Rajendran J G, Krohn K A. Imaging hypoxia and angiogenesis in tumors.  Radiol Clin North Am. 2005;  43 169-187
• 18 Miller A B, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment.  Cancer. 1981;  47 207-214
• 19 Moertel C G, Hanley J A. The effect of measuring error on the results of therapeutic trials in advanced cancer.  Cancer. 1976;  38 388-394
• 20 Buyse M, Thirion P, Carlson R W, Burzykowski T, Molenberghs G, Piedbois P. Meta-Analysis Group in Cancer . Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis.  Lancet. 2000;  356 373-378
• 21 Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval.  Clin Cancer Res. 2005;  11 5928-5934
• 22 Mandard A, Dalibard F, Mandard J, Marnay J, Henry-Amar M, Petiot J, Roussel A, Jacob J, Segol P, Samama G. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.  Cancer. 1994;  73 2680-2686
• 23 Mikhaeel N G. Use of FDG-PET to monitor response to chemotherapy and radiotherapy in patients with lymphomas.  Eur J Nucl Med Mol Imaging. 2006;  33 22-26
• 24 Weber W A, Wieder H. Monitoring chemotherapy and radiotherapy of solid tumors.  Eur J Nucl Med Mol Imaging. 2006;  33 Suppl 13 27-37
• 25 Wahl R L, Zasadny K, Helvie M, Hutchins G D, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation.  J Clin Oncol. 1993;  11 2101-2111
• 26 Kostakoglu L, Coleman M, Leonard J P, Kuji I, Zoe H, Goldsmith S J. PET predicts prognosis after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin's disease.  J Nucl Med. 2002;  43 1018-1027
• 27 Haioun C, Itti E, Rahmouni A, Brice P, Rain J D, Belhadj K, Gaulard P, Garderet L, Lepage E, Reyes F, Meignan M. [¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome.  Blood. 2005;  106 1376-1381
• 28 Mikhaeel N G, Hutchings M, Fields P A, O'Doherty M J, Timothy A R. FDG-PET after two to three cycles of chemotherapy predicts progression-free and overall survival in high-grade non-Hodgkin lymphoma.  Ann Oncol. 2005;  16 1514-1523
• 29 Hutchings M, Loft A, Hansen M, Pedersen L M, Buhl T, Jurlander J, Buus S, Keiding S, D'Amore F, Boesen A M, Berthelsen A K, Specht L. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma.  Blood. 2006;  107 52-59
• 30 Weber W A, Ott K, Becker K, Dittler H J, Helmberger H, Avril N E, Meisetschlager G, Busch R, Siewert J R, Schwaiger M, Fink U. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.  J Clin Oncol. 2001;  19 3058-3065
• 31 Wieder H A, Brucher B L, Zimmermann F, Becker K, Lordick F, Beer A, Schwaiger M, Fink U, Siewert J R, Stein H J, Weber W A. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment.  J Clin Oncol. 2004;  22 900-908
• 32 Ott K, Fink U, Becker K, Stahl A, Dittler H J, Busch R, Stein H, Lordick F, Link T, Schwaiger M, Siewert J R, Weber W A. Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial.  J Clin Oncol. 2003;  21 4604-4610
• 33 Brun E, Kjellen E, Tennvall J, Ohlsson T, Sandell A, Perfekt R, Wennerberg J, Strand S E. FDG PET studies during treatment: prediction of therapy outcome in head and neck squamous cell carcinoma.  Head Neck. 2002;  24 127-135
• 34 Avril N, Sassen S, Schmalfeldt B, Naehrig J, Rutke S, Weber W A, Werner M, Graeff H, Schwaiger M, Kuhn W. Prediction of response to neoadjuvant chemotherapy by sequential F-18-fluorodeoxyglucose positron emission tomography in patients with advanced-stage ovarian cancer.  J Clin Oncol. 2005;  23 7445-7453
• 35 Weber W A, Petersen V, Schmidt B, Tyndale-Hines L, Link T, Peschel C, Schwaiger M. Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use.  J Clin Oncol. 2003;  21 2651-2657
• 36 Hoekstra C J, Stroobants S G, Smit E F, Vansteenkiste J, van Tinteren H, Postmus P E, Golding R P, Biesma B, Schramel F J, van Zandwijk N, Lammertsma A A, Hoekstra O S. Prognostic relevance of response evaluation using [¹⁸F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer.  J Clin Oncol. 2005;  23 8362-8370
• 37 Ott K, Weber W A, Lordick F, Becker K, Busch R, Herrmann K, Wieder H, Fink U, Schwaiger M, Siewert J R. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction.  J Clin Oncol. 2006;  24 4692-4698
• 38 Haberkorn U, Morr I, Oberdorfer F, Bellemann M E, Blatter J, Altmann A, Kahn B, van Kaick G. Fluorodeoxyglucose uptake in vitro: aspects of method and effects of treatment with gemcitabine.  J Nucl Med. 1994;  35 1842-1850
• 39 Rozental J M, Levine R L, Nickles R J, Dobkin J A. Glucose uptake by gliomas after treatment. A positron emission tomographic study [see comments].  Arch Neurol. 1989;  46 1302-1307
• 40 Demetri G D, Mehren M von, Blanke C D, Van den Abbeele A D, Eisenberg B, Roberts P J, Heinrich M C, Tuveson D A, Singer S, Janicek M, Fletcher J A, Silverman S G, Silberman S L, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker B J, Corless C, Fletcher C D, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.  N Engl J Med. 2002;  347 472-480
• 41 Cullinane C, Dorow D S, Kansara M, Conus N, Binns D, Hicks R J, Ashman L K, McArthur G A, Thomas D M. An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development.  Cancer Res. 2005;  65 9633-9636
• 42 Su H, Bodenstein C, Dumont R A, Seimbille Y, Dubinett S, Phelps M E, Herschman H, Czernin J, Weber W. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors.  Clin Cancer Res. 2006;  12 5659-5667
• 43 Lordick F, Ott K, Weber W A, Stein H J, Becker K, Wieder H, Roethling N, Hennig M, Peschel C, Schwaiger M, Siewert J R. Individualized indication for neoadjuvant treatment based on metabolic response assessed by 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in adenocarcinoma of the esophago-gastric junction (AEG).  Journal of Clinical Oncology. 2005;  23 318S
• 44 Miller K D, Miller M, Mehrotra S, Agarwal B, Mock B H, Zheng Q H, Badve S, Hutchins G D, Sledge Jr G W. A physiologic imaging pilot study of breast cancer treated with AZD2171.  Clin Cancer Res. 2006;  12 281-288
• 45 Mankoff D A, Shields A F, Krohn K A. PET imaging of cellular proliferation.  Radiol Clin North Am. 2005;  43 153-167
• 46 Haas R L, de Jong D, Valdes Olmos R A, Hoefnagel C A, van den Heuvel I, Zerp S F, Bartelink H, Verheij M. In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients.  Int J Radiat Oncol Biol Phys. 2004;  59 782-787
• 47 Muhr C, Gudjonsson O, Lilja A, Hartman M, Zhang Z J, Langstrom B. Meningioma treated with interferon-alpha, evaluated with [(¹¹)C]-L-methionine positron emission tomography.  Clin Cancer Res. 2001;  7 2269-2276
• 48 Reske S N, Blumstein N M, Neumaier B, Gottfried H W, Finsterbusch F, Kocot D, Moller P, Glatting G, Perner S. Imaging prostate cancer with ¹¹C-choline PET/CT.  J Nucl Med. 2006;  47 1249-1254
• 49 Albrecht S, Buchegger F, Soloviev D, Zaidi H, Vees H, Khan H G, Keller A, Bischof Delaloye A, Ratib O, Miralbell R. (¹¹)C-acetate PET in the early evaluation of prostate cancer recurrence.  Eur J Nucl Med Mol Imaging. 2006;  ,  [Epub ahead of print]
• 50 Heinisch M, Dirisamer A, Loidl W, Stoiber F, Gruy B, Haim S, Langsteger W. Positron emission tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients: meaningful at PSA < 5 ng/ml?.  Mol Imaging Biol. 2006;  8 43-48
• 51 Liu D, Hutchinson O C, Osman S, Price P, Workman P, Aboagye E O. Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin.  Br J Cancer. 2002;  87 783-789