Molekulare Bildgebung der Proliferation mit [¹⁸F]FLT-PET

Zusammenfassung

Eine gesteigerte Proliferationsrate ist ein wesentliches Charakteristikum maligne transformierter Zellen und daher für eine spezifische Darstellung bösartiger Tumore potentiell besser geeignet als Alterationen des Glukose-Stoffwechsels. Da therapeutische Ansätze in der Onkologie überwiegend auf eine gesteigerte Proliferation zielen, ist die nicht-invasive Bestimmung der proliferativen Aktivität auch zur Beurteilung des Therapieansprechens und frühzeitigen Erkennung einer Therapieresistenz von besonderem Interesse. In klinischen Studien zeigte sich eine spezifische Anreicherung des Radionukleosids 3′-Desoxy-3′-[¹⁸F]Fluorthymidin (FLT) in malignen Tumoren. Es konnte für eine Vielzahl solider Malignome gezeigt werden, dass mit FLT-PET eine nicht-invasive Beurteilung der proliferativen Aktivität möglich ist. Die lineare Regressionsanalyse der tumoralen FLT-Anreicherung und der immunhistochemisch ermittelten Proliferationsfraktion (PCNA, Ki-67 Index) ergab eine signifikante Korrelation (z. B. Lungenkarzinom, r=0,87, p<0,0001). Im direkten Vergleich mit dem Standardradiopharmakon FDG konnte gezeigt werden, dass FLT die histologisch bestimmte Proliferationsrate exakter widerspiegelt. Malignome mit geringer proliferativen Aktivität entgingen jedoch der Detektion mit FLT-PET. Bei malignen Lungentumoren wurde z. B. eine reduzierte Sensitivität von 86% beschrieben. Aufgrund der eingeschränkten Sensitivität ergibt sich für das Staging des Lungenkarzinoms oder kolorektaler Karzinome kein Vorteil für die spezifische Bildgebung der proliferativen Aktivität. Auch hinsichtlich der Detektion von lokoregionären Lymphknoten- und Fernmetastasen weist die FDG-PET eine höhere Sensitivität auf. Lediglich bei Hodgkin- und Non-Hodgkin-Lymphomen zeigte die FLT-PET eine vergleichbare Sensitivität. Eine Spezifität von 100% deutet darauf hin, dass mit FLT-PET eine Methode zur Verfügung steht, mit der nicht-invasiv die proliferative Aktivität sämtlicher Lymphom-Manifestationen beurteilt und gezielt Biopsien entnommen werden können. Dies hat potentiell eine Bedeutung für die Therapieplanung, da sämtliche Lokalisationen auf das Vorliegen einer gesteigerten Proliferationsrate und somit einer möglichen Transformation zu einer aggressiveren Histologie untersucht werden können. Da Chemotherapie und Strahlentherapie eine Schädigung der Zellen verursachen, welche zum Zeitpunkt der Therapie den Zellzyklus durchlaufen, könnte mit FLT-PET eine einfache und frühzeitige Beurteilung des Therapieerfolges ermöglicht werden. Erste In-vitro- und In-vivo-Studien konnten eine rasche Reduktion der FLT-Aufnahme nach Einleitung einer zytostatischen Therapie nachweisen. In Maus-Xenotransplantatmodellen war bereits 24 h nach Chemotherapie eine signifikante Reduktion der FLT-Anreicherung im Tumor messbar. Mit FLT-PET lässt sich somit die gesteigerte Proliferation als Charakteristikum maligner Tumore nicht-invasiv erfassen. Ob hiermit eine entscheidende Zusatzinformation im Vergleich zu dem Standard-Radiopharmakon FDG generiert werden kann, muss in weiteren In-vitro-Experimenten und klinischen Studien gezeigt werden.

Abstract

An increased proliferation fraction is a hallmark of malignant cells and a specific feature of malignant tumors which potentially allows more specific tumor imaging compared to increased glucose consumption (FDG-PET). The majority of therapeutic approaches aim at inhibition of proliferation or induction of apotposis. Accordingly, non-invasive assessment of the proliferation fraction is also of interest for montoring response to treatment and to early detect resistance to a specific kind of therapy. In clinical studies it has been demonstrated that the radiotracer 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) accumulates specifically in malignant tumors. Regression analysis of tumoral FLT-uptake and immunohistochemically detected proliferation fraction (PCNA, Ki-67) resulted in a significant correlation (e.g., in lung cancer, correlation coefficient r=0.87, p<0.0001). The possibility to non-invasively assess the proliferation fraction with FLT-PET has been shown in a variety of solid cancers. Compared to the standard radiotracer FDG, superior demonstration of the proliferative activity using FLT as the tracer has been demonstrated. On the other hand, accumulation of FLT was significantly lower compared to FDG. Malignant tumors with low proliferation rates did not present with increased FLT-uptake resulting in a reduced sensitivity. In lung cancer for example, the sensitivity was 86% of FLT-PET compared to 100% of FDG-PET. Also, regarding detection of locoregional lymph node metastases or distant metastases, FDG-PET was shown to have a higher sensitivity. Due to the reduced sensitivity, there is no advantage of specific imaging of tumor proliferation regarding tumor staging. In malignant lymphoma, FLT was similar effective for tumor staging as compared to FDG-PET. In a pilot study comprising 34 patients, both tracers showed a similar sensitivity regarding detection of lymphoma. An observed specificity of 100% indicates that FLT-PET represents a diagnostic test for non-invasive assessment of the proliferation fraction in malignant lymphoma which can be used to further guide biopsy of lesions and subsequent tumor grading. This has potential impact on the therapeutic decision making process since all localizations can be evaluated regarding an increased proliferation fraction and transformation to a more aggressive histology. Chemotherapy and radiotherapy induce damage to tumor cells which are passing through the cell cycle at the time point of treatment. Therefore, FLT-PET could be a suitable approach for early response monitoring. Initial in-vitro and in-vivo studies demonstrated a rapid reduction of tumoral FLT-uptake early in the course of cytostatic or cytotoxic treatment. In mouse xenotransplant models, cytostatic drug effects have been demonstrated by a marked reduction of the FLT-uptake as early as 24 h after initiation of therapy. FLT-PET therefore represents a suitable tool to non-invasively assess the increased proliferative activity which is a prerequisite of malignant tumors. Whether the radiotracer FLT offers incremental diagnosis information compared to FDG-PET remains to be determined.

Schlüsselwörter

Positronenemissionstomografie - Radionukleoside - [¹⁸F]FLT - Onkologie - Staging - Grading - therapeutisches Ansprechen - Therapiemanagement

Key words

positron emission tomography - radionucleosides - [¹⁸F]FLT - oncology - staging - grading - response monitoring - therapeutic management

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