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Initial Experience with Contrast-Enhanced Sonography of the Prostate

¹ Department of Radiology, Jefferson Prostate Center, Thomas Jefferson University, 132 S. 10th St., Philadelphia, PA 19107-5244.
² Alliance Pharmaceutical Corp., 3040 Science Park Rd., San Diego, CA 92121.
³ Department of Urology, Jefferson Prostate Center, Thomas Jefferson University, Philadelphia, PA 19107-5244.
⁴ Department of Radiology, University of California at San Diego, 200 N. Arbor Dr., San Diego, CA 92103.

Received August 18, 1999; accepted after revision November 3, 1999.

 
Supported in part by Alliance Pharmaceutical Corporation.

Address correspondence to E. J. Halpern.

Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBJECTIVE. We investigated the usefulness of contrast-enhanced sonography to depict vascularity in the prostate and improve the detection of prostatic cancer.

SUBJECTS AND METHODS. Twenty-six patients with an elevated prostate-specific antigen level (4 ng/ml) or an abnormal digital rectal examination were enrolled in a phase II study of an IV injected sonographic contrast agent. Continuous gray-scale, intermittent gray-scale, phase inversion gray-scale, and power Doppler sonography of the prostate were performed. Sonographic findings were correlated with sextant biopsy results.

RESULTS. After the administration of contrast material, gray-scale and Doppler images revealed visible enhancement (p < 0.05). Using intermittent imaging, we found focal enhancement in two isoechoic tumors that were not visible on baseline images. No definite focal area of enhancement was identified in any patient without cancer. Contrast-enhanced images revealed transient hemorrhage in the biopsy tracts of three patients.

CONCLUSION. Enhancement of the prostate can be seen on gray-scale and Doppler sonographic images after the administration of an IV contrast agent. Contrast-enhanced intermittent sonography of the prostate may be useful for the selective enhancement of malignant prostatic tissue.

Introduction

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In 1999, approximately 179,300 American men developed prostatic cancer [1]. Because approximately one third of patients sent for biopsy have cancer, we estimate that over 500,000 prostate biopsies are performed annually in the United States. Although most clinicians use sonography to guide needle placement for prostate biopsy, a recent review of the prostate sonography literature suggests that imaging has little advantage for the detection of malignant lesions [2]. Our own evaluation of gray-scale, color, and power Doppler sonography reveals that these techniques are minimally superior to chance in the detection of prostatic cancer [3]. An accurate noninvasive imaging study of prostatic cancer would allow limited targeted biopsy of suspicious sites and might reduce the number of patients subjected to biopsy of the prostate.

Increased microvessel density in prostatic cancer is reported to correlate with the presence of metastases [4], the stage of disease [5,6,7], and disease-specific survival [8,9]. In other words, microvessel density in prostatic cancer is predictive of clinically significant disease. Microbubble-based sonographic contrast agents may reveal prostatic cancer based on increased microvascularity. Although color Doppler enhancement of the prostate has been reported with contrast agents [10,11], no published study has revealed gray-scale parenchymal enhancement of the prostate. We used intermittent gray-scale imaging to evaluate contrast-enhanced imaging of the prostate and to selectively enhance the neovasculature associated with prostatic cancer.

Subjects and Methods

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Twenty-six patients with prior abnormal digital rectal exams or elevated (4 ng/ml) prostate-specific antigen levels were recruited for a phase II study of the contrast agent Imagent (AF0150; Alliance Pharmaceutical, San Diego, CA). Eligible patients were 18-80 years old and scheduled for transrectal sonography of the prostate with biopsy. Patient age ranged from 38 to 81 years (mean age, 64 years). The study included 18 Caucasians, six African-Americans, one Hispanic, and one Indian. The institutional review board approved this study, and written informed consent was obtained from each patient.

Study participants were prepared according to standard operating procedure for patients undergoing transrectal sonographically guided biopsy of the prostate. The use of aspirin or other anticoagulants was discontinued 1 week before the procedure. Antibiotic prophylaxis was orally administered (ofloxacin tablets, 300 mg) 1 hr before biopsy and continued for a total of six doses, taken twice daily.

Imagent is a sterile nonpyrogenic white to off-white powder of spray-dried microspheres. The microspheres contain perfluorohexane gas and consist of surfactants, buffers, salts, and a water-soluble structural agent that dissolves when reconstituted, forming a dispersion of stable and highly echogenic microbubbles in a buffered isoosmotic solution. These microbubbles remain in the circulation for several minutes after injection and reveal gray-scale and Doppler parenchymal organ enhancement [12].

Sonography was performed with a 6.5EC10 end-fire endocavitary probe on a Sonoline Elegra system (Siemens Medical Systems, Issaquah, WA). Gray-scale imaging was performed with a center probe frequency of 5.14-6.00 MHz, a dynamic range of 55 dB, and a persistence setting of two. Gray-scale gain was adjusted for baseline imaging and was not altered after contrast material injection. For power Doppler imaging, the center probe frequency was 4.0 MHz with a dynamic range of 30 dB, pulse repetition frequency of 868 Hz, and low wall filter. The Doppler window for power imaging was adjusted to include the entire gland. Power Doppler gain was adjusted at baseline to maximize signal but eliminate clutter from the prostate. Power gain was reduced after the administration of contrast material to eliminate blooming. The entire examination was recorded on a super-VHS videotape.

Sonographically guided biopsies were performed on all patients with an 18-gauge automated spring-loaded biopsy gun. Biopsy specimens were obtained in a sextant pattern; one specimen was obtained from the base, midportion, and apex of the outer gland, on both the right and left sides. When an abnormality was visible on gray-scale or Doppler imaging, either at the baseline or after contrast material administration, the corresponding sextant biopsy site was directed to the abnormality.

The first phase of the study protocol evaluated the enhancement of the prostate as a function of contrast dose with continuous gray-scale and Doppler imaging. Twelve patients were randomized to receive an IV contrast bolus of 0.05 ml/kg, 0.1 ml/kg, or 0.2 ml/kg, or to receive a continuous IV infusion of Imagent (maximum dose, 0.2 ml/kg). The prostate gland was imaged in the transverse and sagittal planes with gray-scale and power Doppler imaging at the baseline and after contrast material administration.

In the second phase of the study, 14 patients were evaluated with continuous and intermittent gray-scale imaging at the baseline and after contrast material administration. During intermittent imaging, the transducer was turned off for a specified interscan delay time. Preproduction (commercially unavailable) software on our Elegra system provided an adjustable interscan delay time. Intermittent imaging was repeated with interscan delay times of 1 sec, 2 sec, and 5 sec. Doppler sonography was not performed on these patients to allow more time for intermittent imaging. The first four patients in this group received a contrast dose that was randomized as previously described. To guarantee sufficient contrast enhancement for continuous and intermittent imaging (approximately 10 min), the final 10 patients received contrast infusion at a rate of 20-50 mg/min (1-2.5 ml/min). Phase inversion harmonic imaging became available on the endorectal probe toward the end of the study. The final five patients underwent phase inversion harmonic imaging.

A single examining physician rated each biopsy site as normal, indeterminate, or abnormal for each imaging method at the time of the examination. The physician also completed a series of visual analog scales to rate the enhancement of the prostate [13]. We used the standard visual analog scale without calibration markings because it is easily adapted to measure a continuous variable and reveal change over time. Visual analog scales were completed to measure gray-scale echogenicity and power Doppler signal at the baseline and after contrast material administration. Visual analog scale scores from baseline imaging and contrast-enhanced imaging were compared with a Wilcoxon's signed rank test. The biopsy site ratings and visual analog scales were prospectively completed at the time of the examination. Videotapes were subsequently reviewed to retrospectively correlate pathologic results with sonographic findings.

Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of 26 patients, six had an abnormal digital rectal examination and 20 had an elevated prostate-specific antigen level (range, 4.6-23.0 ng/ml; mean, 9.4 ng/ml). All patients completed the protocol with no significant adverse reactions, though technical problems limited the use of intermittent imaging in one patient.

The initial 12 patients included six patients who entered the study because of an abnormal digital rectal examination and six patients with elevated prostate-specific antigen levels. Enhancement of the prostate was revealed on gray-scale and power Doppler imaging in all 12 patients (p < 0.05 for Wilcoxon's signed rank test of visual analog scale scores at baseline versus visual analog scale scores after contrast material administration). Enhancement was more obvious at higher doses. Acoustic shadowing was observed at a dose of 4.0 mg/kg. Power Doppler gain was reduced by 30-43 dB after contrast material administration to control blooming (Fig. 1A,1B). There were 17 biopsy sites with cancer in eight of 12 patients. None of the biopsy sites with positive results were prospectively identified as focally enhancing after contrast material administration. A single biopsy site with positive results and enhanced Doppler flow was identified on retrospective review of the videotapes (Fig. 1B).

View larger version (129K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —77-year-old man with cancer (Gleason score, 6) in right base and mid gland (prostate-specific antigen, 5.5 ng/ml). Transverse power Doppler sonogram at baseline shows hypoechoic region in right base (short arrows) associated with minimal flow (long arrow).

View larger version (117K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —77-year-old man with cancer (Gleason score, 6) in right base and mid gland (prostate-specific antigen, 5.5 ng/ml). Contrast-enhanced power Doppler sonogram shows enhancement of periprostatic vessels and vessels in prostatic parenchyma at right base (arrows). Enhancement at right base was not prospectively appreciated. Power gain was reduced from 68 to 30 dB to eliminate blooming.

The final 14 patients, examined with intermittent (n = 14) and phase inversion (n = 5) imaging, had 11 biopsy sites with positive findings and cancer in three patients. In one of the three patients, the sites of cancer appeared suspicious on unenhanced images but revealed no focal enhancement on continuous contrast-enhanced gray-scale images. Unfortunately, the sonographic system running with preproduction software failed at the start of intermittent imaging, and we noted no visible contrast material remaining in the circulation when the system was rebooted. For the remaining two patients with positive biopsy results, we noted no visible cancer on baseline gray-scale images. After contrast material administration, contrast-enhanced flow was identified in vessels adjacent to the site of the tumor, but we noted no focal enhancement of the tumor with continuous gray-scale imaging. Focal parenchymal enhancement of tumor sites was revealed on intermittent imaging. Both patients had biopsies with positive results from base to apex on the left side of the prostate, one with Gleason scores of 5-6 and the other of 6-9. Both patients revealed similar enhancement patterns (Figs. 2A,2B and 3A,3B,3C,3D). With continuous imaging and 1-sec intermittent imaging, mild parenchymal enhancement was noted, but no tumors were visible. With an interscan delay of 2 sec, isodense tumors were clearly defined with focal enhancement (Figs. 2B and 3B). With an interscan delay of 4 sec, the prostatic parenchyma revealed homogeneous enhancement without focal enhancement of the tumors. All patients had parenchymal enhancement on intermittent imaging with interscan delays of 2-5 sec. However, no focal area of increased enhancement was identified in any of the 11 patients without cancer who were studied with intermittent imaging.

View larger version (119K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —61-year-old man with cancer (Gleason score, 6) along left side of prostate from base to apex (prostate-specific antigen, 9.1 ng/ml). Transverse sonographic image at baseline reveals homogeneous echotexture pattern.

View larger version (102K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —61-year-old man with cancer (Gleason score, 6) along left side of prostate from base to apex (prostate-specific antigen, 9.1 ng/ml). Contrast-enhanced intermittent image with 2-sec interscan delay shows focal enhancement at site of cancer in left base (arrows).

View larger version (123K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A. —61-year-old man with cancer (Gleason score, 9) along left side of prostate from base to apex (prostate-specific antigen, 10.4 ng/ml). Transverse sonographic image at baseline reveals no focal lesion.

View larger version (111K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B. —61-year-old man with cancer (Gleason score, 9) along left side of prostate from base to apex (prostate-specific antigen, 10.4 ng/ml). Contrast-enhanced intermittent image with 2-sec interscan delay shows focal enhancement at site of cancer in left mid gland (arrows).

View larger version (112K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3C. —61-year-old man with cancer (Gleason score, 9) along left side of prostate from base to apex (prostate-specific antigen, 10.4 ng/ml). Contrast-enhanced continuous image (obtained 20 sec after B) reveals no focal enhancement.

View larger version (106K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3D. —61-year-old man with cancer (Gleason score, 9) along left side of prostate from base to apex (prostate-specific antigen, 10.4 ng/ml). Contrast-enhanced intermittent image with 4-sec interscan delay (obtained 18 sec after C) reveals diffuse enhancement and no evidence of a focal enhancing cancer.

In three patients, flowing contrast material was visible along a biopsy tract in the prostate after the procedure. None of these patients had excessive bleeding at the rectum. The first two patients with this enhancement pattern were observed with sonography for several minutes, and enhancement in the biopsy tracts spontaneously stopped (Fig. 4A,4B,4C,4D). For the third patient, pressure was applied at the site of contrast enhancement to reduce flow. Contrast flow was not observed in the biopsy tract while pressure was applied.

View larger version (76K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A. —62-year-old man with visible bleeding after prostatic biopsy. Transverse sonographic image of prostate before needle biopsy.

View larger version (70K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B. —62-year-old man with visible bleeding after prostatic biopsy. Transverse sonographic image shows biopsy needle along lateral margin of right mid gland.

View larger version (74K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4C. —62-year-old man with visible bleeding after prostatic biopsy. Transverse sonographic image obtained 30 sec after biopsy reveals enhancement along biopsy tract.

View larger version (74K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4D. —62-year-old man with visible bleeding after prostatic biopsy. Transverse sonographic image obtained 90 sec after biopsy reveals continued enhancement along biopsy tract. Enhancement persisted for several minutes.

The final five patients were imaged with a phase inversion technique. Although there were no tumors found in this subgroup, the degree of parenchymal enhancement was greater with the phase inversion technique compared with imaging at the fundamental frequency (Fig. 5A,5B).

View larger version (93K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A. —73-year-old man with marked benign prostatic hyperplasia (prostate-specific antigen, 14.8 ng/ml). Contrast-enhanced intermittent image obtained during contrast material infusion using a 2-sec interscan delay reveals faint enhancement of inner gland (arrows).

View larger version (98K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B. —73-year-old man with marked benign prostatic hyperplasia (prostate-specific antigen, 14.8 ng/ml). Phase inversion image reveals enhancement of inner gland (arrows) brighter than that seen in A.

Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Currently available sonographic contrast agents have intravascular residence times of several minutes, pass through the pulmonary circulation, and may be used for parenchymal organ enhancement [14,15]. Some agents reveal only Doppler enhancement in the prostate, whereas others show both gray-scale and Doppler enhancement. Studies of one such contrast agent, EchoGen (QW3600; Sonus Pharmaceuticals, Bothell, WA), suggest that enhanced color flow with contrast material may be associated with the presence of prostatic cancer, though gray-scale enhancement was not revealed [10,11]. A dose-response relationship has been revealed for Doppler enhancement of the prostate with SonoVue (BR1; Bracco, Milan, Italy) [16]. A recent study of men with biopsyproven prostatic cancer suggests that power Doppler enhancement with the contrast agent Levovist (SHU508A; Schering, Berlin, Germany) is reduced after antiandrogen therapy [17]. In the present study, both gray-scale and Doppler enhancement of the prostate were observed after the administration of Imagent. However, our results suggest that contrast-enhanced continuous gray-scale and power Doppler sonography are insensitive for the detection of prostatic cancer.

To enhance the neovascularity associated with prostatic cancer, a contrast agent should be imaged in the microvasculature. If the contrast agent is destroyed before it can reach the microcirculation, the desired enhancement of tumor vessels will not be observed. Continuous sonographic imaging often delivers power levels that are sufficient to destroy contrast microbubbles, especially when using a high mechanical index. Because the typical gray-scale sonographic image is refreshed at 30 frames per second, the available contrast agent for each new image frame is the amount that enters the imaging plane in 1/30 sec. In this short time between frames, contrast material may enter larger vessels but generally will not reach the microcirculation. Intermittent imaging with reduced frame rates increases the enhancement provided by sonographic contrast agents [18,19,20]. With intermittent imaging, the sonography beam is turned off for longer periods between each image frame. Then, more contrast material may enter the imaging plane and have more time to traverse the capillary bed. Thus, intermittent imaging may provide a quantitative increase in contrast enhancement and a qualitative difference in the enhancement pattern of smaller vessels. By adjusting the interscan delay, radiologists can control the depth of penetration of contrast material in the capillary bed. Given a properly optimized interscan delay time, microbubbles will enter the microvasculature and provide more selective imaging of neovascularity. In this study, intermittent sonography provided focally increased tumor enhancement in two patients with prostatic cancer and a diffuse homogeneous enhancement pattern in 11 others who were free of disease.

Harmonic imaging represents yet another recent advance in contrast-enhanced sonography [21,22,23,24,25]. When microbubble contrast agents are imaged, their nonlinear reverberation creates harmonic frequencies different from the frequency of insonation. Because ordinary tissue predominantly reflects the sonographic pulse at the frequency of insonation, images generated from the harmonic frequencies will reveal reduced signal from ordinary tissues and improved imaging of contrast material. Phase inversion techniques use harmonic signals from microbubble contrast agents to improve contrast material visualization. None of the five patients who underwent phase inversion imaging had cancer; nevertheless, these patients' overall parenchymal enhancement was improved.

Our study design was limited by several factors. The total number of patients was small, and the protocol was altered after the first 12 patients to include intermittent imaging. The method of contrast material administration was standardized to infusion after the first 16 patients to ensure sufficient time for continuous and intermittent scanning. Phase inversion imaging was applied only to the last five patients, and only three patients who underwent intermittent imaging had cancer on biopsy. The small number of patients evaluated with intermittent imaging (n = 14) limits our ability to perform statistical analysis. Many of these limitations are related to the preliminary and exploratory nature this study.

In conclusion, there exists clear pathologic evidence that the vascular supply to malignant prostatic tissue is different from the vascular anatomy of normal prostatic tissue. Quantitative assessment of microvascular density may also provide important data to identify clinically significant cancer and guide therapeutic decisions [26]. Based on our limited experience, we suggest that intermittent imaging with sonographic contrast agents enhances the visualization of neovascularity associated with prostatic cancer. Our preliminary data serve as the groundwork for a more focused clinical trial on the use of intermittent and phase inversion imaging for prostatic cancer. If similar results can be reproduced in a larger population, contrast-enhanced intermittent imaging may be used to selectively identify patients with clinically significant prostatic cancer.

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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Halpern, E. J. Articles by Goldberg, B. B. Search for Related Content PubMed PubMed Citation Articles by Halpern, E. J. Articles by Goldberg, B. B. Social Bookmarking                      What's this?