Elsevier

European Urology

Volume 70, Issue 5, November 2016, Pages 829-836
European Urology

Prostate Cancer
Simultaneous 68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer

https://doi.org/10.1016/j.eururo.2015.12.053Get rights and content

Abstract

Background

Ligands of the prostate-specific membrane antigen (PSMA) show promising results in positron emission tomography (PET) imaging of prostate cancer (PCa).

Objective

To compare the diagnostic performance of simultaneous gallium 68 (68Ga)-PSMA HBED-CC PET/magnetic resonance imaging (MRI) for localization of primary PCa with multiparametric magnetic resonance imaging (mpMRI) and PET alone.

Design, setting, and participants

We performed 68Ga-PSMA HBED-CC PET/MRI in 66 men with biopsy-proven PCa.

Intervention

PET, mpMRI, and combined 68Ga-PSMA HBED-CC PET/MRI were independently evaluated using Prostate Imaging Reporting and Data System criteria or a 5-point Likert scale.

Outcome measurements and statistical analysis

The prostate was divided into sextants for histopathology and coregistered with imaging. Diagnostic performance for localization of malignancy was calculated based on receiver operating characteristics analysis for each modality. Regional quantitative PET tracer uptake was recorded; uptake ratio was defined as the ratio of malignant to nonmalignant prostate tissue.

Results and limitations

A total of 53 of 66 patients were eligible for analysis. mpMRI, PET, and PET/MRI detected cancer in 66% (35 of 53), 92% (49 of 53), and 98% (52 of 53) of the patients, respectively. Overall, 202 of 318 sextants (63.5%) contained cancer at pathologic examination. Simultaneous PET/MRI statistically outperformed mpMRI (area under the curve [AUC]: 0.88 vs 0.73; p < 0.001) and PET imaging (AUC: 0.88 vs 0.83; p = 0.002) for localization of PCa. Compared with mpMRI, PET imaging was more accurate (AUC: 0.83 vs 0.73; p = 0.003). PET provided a high uptake ratio between malignant versus nonmalignant tissue (5.02 [range: 0.89–29.8]), but no significant correlation was observed between quantitative PET parameters and Gleason score or prostate-specific antigen value.

Conclusions

Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves diagnostic accuracy for PCa localization both compared with mpMRI and with PET imaging alone. Further prospective studies are warranted to evaluate its potential (eg, for biopsy guidance).

Patient summary

We examined gallium 68 (68Ga)-prostate-specific membrane antigen (PSMA) HBED-CC positron emission tomography/magnetic resonance imaging (PET/MRI) for primary prostate cancer (PCa) and compared it with multiparametric MRI and PET alone. Our results indicate a higher diagnostic accuracy for 68Ga-PSMA HBED-CC PET/MRI that may help localize PCa.

Introduction

Early detection and specific localization of prostate cancer (PCa) is expected to improve patient management [1]. Various imaging techniques are used to enhance detection and localization beyond digital rectal examination and assessment of serum prostate-specific antigen (PSA). Transrectal or perineal biopsies are currently associated with suboptimal diagnostic accuracy. Therefore, the clinical need for image-guided biopsies is well appreciated [2].

Recent data support the combined use of ultrasound and targeted magnetic resonance imaging (MRI) for guided biopsy, yielding significantly better diagnostic performance [3]. Multiparametric magnetic resonance imaging (mpMRI) combining T2-weighted and functional information from diffusion-weighted imaging (DWI) and dynamic contrast-enhanced sequences shows promising results for localizing PCa [4], [5]. However, widespread mpMRI application is compromised by lack of standardization and limited tumor detection (eg, in the transitional zone) [6]. Although not yet recommended for routine clinical use, mpMRI has been included in several guidelines and is preferred by various expert panels as the method of choice in patients with elevated PSA values but negative biopsy [7], [8].

Molecular imaging with positron emission tomography (PET) is regarded as a promising diagnostic approach [9]. Despite the relation of fluorodeoxyglucose-PET to tumor aggressiveness, its application in clinical practice is limited due to negative signal in low Gleason score cancers [10]. Choline derivatives visualizing the malignancy-induced upregulation of choline kinase are useful for localization of biochemically recurrent disease, but discrimination between benign and malignant intraprostatic tissue is hampered by low specificity [11], [12].

Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a significantly increased expression in PCa cells [13], recently selected as a target for molecular imaging approaches [14]. The introduction of gallium 68 (68Ga)-PSMA HBED-CC (Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)]) as an extracellular PSMA inhibitor for PET imaging demonstrated high specificity for PSMA-expressing tumor cells [15]. First clinical studies show high image contrast and improved detection rates of recurrent PCa in comparison with fluorine 18 (18F)-choline [16], [17]. In addition, recent data addressing preoperative lymph node staging of primary PCa suggest high specificity of 68Ga-PSMA-tracer uptake, demonstrated histopathologically [18].

Thus the purpose of this study was to apply the newly introduced technology of simultaneous 68Ga-PSMA HBED-CC PET/MRI combining mpMRI data acquisition with the most advanced molecular imaging approach using 68Ga-PSMA HBED-CC as a specific and sensitive ligand for localization of intraprostatic tumor in patients undergoing elective radical prostatectomy (RP). The imaging results were compared and coregistered with an established histologic work-up of the excised gland to define diagnostic accuracy of both mpMRI and PET separately as well as combined 68Ga-PSMA HBED-CC PET/MRI.

Section snippets

Patients

Between January 2013 and May 2014, 66 consecutive patients with histologically proven intermediate- or high-risk PCa were scheduled for simultaneous 68Ga-PSMA HBED-CC PET/MRI before RP. D’Amico criteria were used for classification into intermediate- and high-risk PCa [19]. Imaging was performed with a median interval of 40 d (interquartile range [IQR]: 21–102) following biopsy. The retrospective study was approved by the Ethics Committee of the Technical University Munich (permit 5665/13). All

Patients and pathologic findings

Of 66 possible candidates for analysis, 53 patients qualified to be included. Supplementary Figure 1 shows the flowchart of patient selection including the different reasons for dropout. Median interval between imaging and RP was 17 d (IQR: 13–29). Table 1 lists the patient characteristics including risk stratification. Overall, 202 of 318 sextants (64%) contained cancer. The median diameter of the largest tumor focus per sextant was 9 mm (IQR: 5–15). Tumor foci of up to 5 mm or Gleason score ≤6

Discussion

This is the first clinical study in humans demonstrating the added diagnostic value of simultaneous 68Ga-PSMA HBED-CC PET/MRI for localization of primary PCa compared with mpMRI alone, validated by histopathology. These promising data support the hypothesis that multimodal imaging using morphologic, functional, and molecular information enhances the diagnostic performance in patients with PCa.

PET/MRI in principle offers substantial advantages over PET/CT due to the high soft tissue contrast and

Conclusions

We found that 68Ga-PSMA HBED-CC PET/MRI increases the diagnostic accuracy for localization of PCa in patients selected for RP. Thus to evaluate the potential of this technique (eg, for biopsy guidance), further prospective studies are necessary and warranted.

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