Onkopipeline

, Volume 3, Issue 2, pp 99–105 | Cite as

Nichtkleinzelliges Bronchialkarzinom

Molekulare Bildgebung mittels PET und translationale Forschung
  • Markus Dietlein
  • Carsten Kobe
  • Bernd Neumaier
  • Roland Ullrich
GRAND ROUNDS

Zusammenfassung

US-amerikanische Daten belegen, dass die Hinzunahme der Fluordesoxyglucose- Positronenemissionstomographie (FDG-PET) im initialen Staging des nichtkleinzelligen Bronchialkarzinoms (NSCLC) zu einem Stadienshift geführt hat. Dabei wurde ein Stadium III (lokal fortgeschrittenes NSCLC) seltener diagnostiziert, umgekehrt ein Stadium IV (Fernmetastasen) häufiger. Zwei randomisierte Studien aus den Niederlanden und zuletzt aus Dänemark zeigten in gleicher Weise, dass nach einer additiv durchgeführten FDG-PET etwa bei jedem fünften Patienten eine „frustrane“ Thorakotomie vermieden werden kann. Hierunter wurden Thorakotomien verstanden, die binnen Jahresfrist wegen Rezidiv, Fernmetastasen oder Tod ohne anhaltenden Erfolg blieben, bzw. Thorakotomien mit dem unerwarteten Nachweis eines N2-Status. Die Bildgebung bezüglich des mediastinalen Lymphknotenstatus besitzt Grenzen. Sind die Ergebnisse in der Computertomographie und in der FDG-PET konkordant pathologisch, ist die Spezifität begrenzt, und die histopathologische Abklärung bleibt erforderlich, sofern im Fall einer N0- oder N1-Situation ein operativ-kurativer Behandlungsansatz möglich wäre.

Neben dem Therapiemonitoring einer Chemotherapie mittels PET ist die frühzeitige Beurteilung des Therapieansprechens auf „targeted therapies“ Gegenstand der Forschung. Als PET-Tracer kommt neben FDG (Glucosemetabolismus) Fluorthymidin (FLT) als In-vivo-Marker der Zellproliferation in Betracht. In Mäusen mit einem NSCLC konnte die FLT-PET die gezielte Inhibiton des epidermalen Wachstumsfaktor-Rezeptors (EGFR) bereits 48 h nach Therapiebeginn zeigen. Umgekehrt verhindert die Resistenzmutation T790M die Bindung des EGFR-Tyrosinkinase-(TK-)Inhibitors Erlotinib an die Adenosintriphosphat-(ATP-)Tasche der EGFR-TK. Solche Resistenzmutationen treten im Verlauf einer Therapie mit einem EGFR-Inhibitor häufig auf und wurden im Tiermodell mittels der FLT-PET erkannt. Diese präklinische Studie ist Grundlage für klinische Studien zur FLT-PET in der Vorhersage des Therapieansprechens auf Erlotinib beim NSCLC. Die radiochemische Forschung konzentriert sich auf PET-Tracer, die – wie die pharmakodynamisch wirksamen TK-Inhibitoren – mit ATP um die Bindung an die Enzymtasche der TK konkurrieren. Dadurch werden Veränderungen auf Ebene der TK-Aktivität sehr sensitiv messbar. Allerdings sind die pharmakokinetischen Eigenschaften der bislang getesten Biomarker für die klinische Anwendung noch nicht ausgereift.

Schlüsselwörter:

Bronchialkarzinom Positronenemissionstomographie Fluordesoxyglucose Fluorthymidin „Targeted therapy“ 

Non-Small Cell Lung Cancer. Molecular Imaging with PET and Translational Research

Abstract

Data from the USA have demonstrated that fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of non-small cell lung cancer (NSCLC) is responsible for stage migration. There was a decline in the number of patients with stage III (locally advanced NSCLC) and an increase in the number of patients with stage IV disease (distant metastases). Two randomized trials from the Netherlands and from Denmark have shown that a futile thoracotomy can be avoided in one out of five patients by use of FDG-PET. Futile thoracotomies were defined as relapse, distant metastases, death from any cause within the 1st year after surgery, or a thoracotomy with the unexpected finding of mediastinal lymph node metastases. Imaging for mediastinal lymph nodes has some limitations. When computed tomography and FDG-PET are both pathologic, the specificity is limited and histopathologic verification is necessary, as far as – in case of N0 or N1 – a curative treatment would be possible.

Besides therapy monitoring of chemotherapy early interim PET for response evaluation of targeted therapies is a new field of research. PET tracers are FDG (glucose metabolism) as well as 18F-fluorothymidine (FLT) as an in vivo marker of cell proliferation. In mice with NSCLC, FLT-PET could detect the specific epidermal growth factor receptor (EGFR) inhibition 48 h after the start of therapy. The mutation T790M (resistance factor) prevents the EGFR tyrosine kinase (TK) inhibitor erlotinib from binding to the adenosine triphosphate-(ATP-)binding pocket of the EGFR-TK. This mutation develops frequently in the course of therapy with an EGFR inhibitor, and detection by FLT-PET was possible in the animal model. The animal study was the basis for clinical trials to evaluate FLT-PET in the prediction of response to erlotinib in NSCLC. The radiopharmaceutical research is focused on new PET tracers, which are competitive to ATP for binding to the ATP-binding pocket of the EGFR-TK like the therapeutic TK inhibitors. This principle will allow a very sensitive measurement of the activity of TK. At the moment, the pharmacokinetic characteristic of the tested tracers is not suitable for clinical trials.

Key Words:

Lung cancer Positron emission tomography Fluorodeoxyglucose Fluorothymidine Targeted therapy 

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Copyright information

© Springer 2010

Authors and Affiliations

  • Markus Dietlein
    • 1
    • 2
    • 4
  • Carsten Kobe
    • 1
    • 2
  • Bernd Neumaier
    • 2
    • 3
  • Roland Ullrich
    • 2
    • 3
  1. 1.Klinik und Poliklinik für NuklearmedizinUniversitätsklinikum KölnKölnGermany
  2. 2.Centrum für Integrierte Onkologie Köln BonnUniversitätsklinikum KölnKölnGermany
  3. 3.Max-Planck-Institut für Neurologische ForschungKölnGermany
  4. 4.Klinik und Poliklinik für NuklearmedizinUniversitätsklinikum KölnKölnGermany

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