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Uterine Cervical Carcinoma: Comparison of Standard and Pharmacokinetic Analysis of Time-Intensity Curves for Assessment of Tumor Angiogenesis and Patient Survival

Department of Radiological Diagnostics, German Cancer Research Center, D-69120 Heidelberg [H. H., M. V. K., G. B., I. Z., S. O. S., M. E., G. v. K.], and Department of Obstetrics and Gynecology [P. G. K., W. W.] and Institute of Physiology and Pathophysiology [P. V.], University of Mainz, D-55101 Mainz, Germany

Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as for therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this study to: (a) examine the association of standard and pharmacokinetic analysis of time-intensity curves in dynamic MRI with histomorphological markers of tumor angiogenesis [microvessel density (MVD) and vascular endothelial growth factor (VEGF)]; and (b) determine the ultimate value of a histomorphological and a dynamic MRI approach by the correlation of those data with disease outcome in patients with primary cancer of the uterine cervix.

Pharmacokinetic parameters (amplitude, A; exchange rate constant, k₂₁) and standard parameters [the maximum signal intensity increase over baseline (SI-I) and the steepest signal intensity-upslope per second (SI-U/s)] were calculated from a contrast-enhanced dynamic MRI series in 37 patients with biopsy-proven primary cervical cancer. On the surgical whole mount specimens, histomorphological markers of tumor angiogenesis (MVD and VEGF) were compared to MRI-derived parameters. For MRI and histomorphological data, Kaplan-Meier survival curves were calculated and compared using log-rank statistics.

A significant association was found between MVD and A (P < 0.01) and SI-I (P < 0.05). No significant relationships were observed between VEGF expression and all dynamic MRI parameters. Kaplan-Meier curves based on k₂₁ and SI-U/s showed that tumors with high k₂₁ and SI-U/s values had a significantly (P < 0.05 and 0.001, respectively) worse disease outcome than did tumors with low k₂₁ and SI-U/s values. None of the histomorphological gold standard markers for assessing tumor angiogenesis (MVD and VEGF) had any significant power to predict patient survival.

It is concluded that in patients with uterine cervical cancer: (a) the pathophysiological basis for differences in dynamic MRI is MVD but not VEGF expression; (b) a functional, dynamic MRI approach (both standard and pharmacokinetic analysis) may be better suited to assess angiogenic activity in terms of patient survival than are the current histomorphological-based markers of tumor angiogenesis; and (c) compared with standard analysis, a simple pharmacokinetic analysis of time-intensity curves is not superior to assess MVD or patient survival.

¹ To whom requests for reprints should be addressed, at Department of Radiological Diagnostics and Therapy, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-6221-422525; Fax: 49-6221-422531; E-mail: H.Hawighorst@dkfz-heidelberg.de.

Received 2/27/98. Accepted 6/16/98.

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