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Molecular imaging Positron tomographic assessment of androgen receptors in prostatic carcinoma Farrokh Dehdashti1, 4, Joel Picus1, 2, Jeff M. Michalski1, 3, Carmen S. Dence4, Barry A. Siegel1, 4, John A. Katzenellenbogen5, Michael J. Welch1, 4 1 2 3 4 5

The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA Department of Internal Medicine, Washington University School of Medicine, St. Louis MO, 63110, USA Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, 63110, USA Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA Department of Chemistry, University of Illinois, Urbana IL 61801, USA

Received: 2 September 2004 / Accepted: 7 January 2005 / Published online: 22 February 2005 © Springer-Verlag 2005

Abstract. Purpose: The purpose of this study was to evaluate the feasibility of androgen receptor (AR) imaging with 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) by positron emission tomography (PET) and to assess the binding selectivity of FDHT to AR in patients with prostate cancer. Methods: Twenty men (age range 56–87 years) with advanced prostate cancer were studied. All except one had metastatic disease confirmed by biopsy and/or radiological studies. One patient who had radiological findings suggesting a single hepatic metastasis was found to have focal fatty infiltration on biopsy obtained after FDHT-PET and was excluded from further data analysis. FDHT uptake was assessed semiquantitatively by determination of the standardized uptake value (SUV) and tumor-to-muscle ratio (T/M). Additionally, to assess the AR binding selectivity of FDHT, patients with one or more foci of abnormally increased FDHT accumulation were studied after administration of an AR antagonist (flutamide). Results: Conventional imaging demonstrated innumerable lesions in two patients and 43 lesions in the remaining 17 patients with advanced prostate cancer. FDHT-PET was positive in 12 of 19 patients (sensitivity of 63%), including the two patients with innumerable lesions. FDHT-PET detected 24 of 28 known lesions (86%) in the remaining ten patients. In addition, FDHT-PET detected 17 unsuspected lesions in five of these ten patients. All 12 patients with positive FDHT-PET underwent a repeat PET study after receiving flutamide for 1 day (250 mg t.i.d.). In all of these patients, there was a decrease in tumor FDHT uptake after flutamide; the mean (± standard deviation) SUV and T/M decreased from 7.0±4.7 and 6.9±3.9, respectively, to 3.0± 1.5 and 3.0±1.6, respectively (p=0.002). The mean PSA in Farrokh Dehdashti (*) The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA e-mail: [email protected] Tel.: +1-314-362-7418, Fax: +1-314-362-5428

patients with positive FDHT-PET was significantly higher than that in patients with negative FDHT-PET (p=0.006). Conclusion: Our results document the feasibility of PET imaging of prostate cancer with FDHT and suggest that tumor uptake of FDHT is a receptor-mediated process. Positive PET studies were associated with higher PSA levels and thus, presumably, with greater tumor burden. Keywords: PET – Prosteate – Cancer – Androgen – Receptor Eur J Nucl Med Mol Imaging (2005) 32:344–350 DOI 10.1007/s00259-005-1764-5

Introduction The treatment of metastatic and recurrent prostate cancer has long been based on the knowledge that the majority of malignant prostate epithelial cells are hormone (androgen) sensitive. The tumor cells will either die or cease dividing when androgen is removed from their environment. Thus, the mainstays of treatment of metastatic/recurrent prostate carcinoma have been either orchiectomy to remove the major source of the most physiologically active androgen hormone or administration of drugs to suppress androgen production [1–3]. Unfortunately, these methods are often not well tolerated by patients, and more importantly are not curative, with almost all patients ultimately developing progressive hormone-refractory prostate cancer despite continued treatment. Relapse is felt to be secondary to a number of factors, not least of which are continued androgen production by the adrenal gland and the presence of a population of androgen-independent cells that do not respond to hormonal therapy. In addition, there are data suggesting that changes may occur in the androgen receptor

European Journal of Nuclear Medicine and Molecular Imaging Vol. 32, No. 3, March 2005

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(AR) itself, causing cells that were once hormone dependent or sensitive to become hormone independent. Hormonal therapy of breast cancer is guided by in vitro methods for detecting and quantifying estrogen receptors. However, until recently there was no effective way of assessing tumor ARs in vitro and, thus, hormonal therapy of prostate cancer has been rather more empirically based. In fact, the availability of an in vitro method for the assessment of ARs has not greatly altered clinical management strategies for prostate cancer. At least in part this reflects the inherent limitations of in vitro assays, including the requirement for tumor tissue and the potential for sampling errors. Accordingly, there has been considerable interest in the development of in vivo techniques that would make noninvasive assessment of receptors possible. Tumor receptor imaging with positron emission tomography (PET) has been widely studied in breast cancer [4–9]. 16β-[18F] fluoro-17α-estradiol is an agent that has been successfully used to assess estrogen receptor levels and function in women with breast cancer [4–9]. A new imaging agent that binds to ARs, 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT), has recently been developed [10]. FDHT, an androgen analog, has been shown to accumulate in the prostate gland of nonhuman primates. In addition, the biodistribution and radiation dosimetry of FDHT in nonhuman primates suggest that this agent holds promise for studying AR in human prostate carcinoma. The aim of this study was to evaluate the feasibility of AR imaging with FDHT-PET, and also to assess AR binding selectivity of FDHT in patients with prostate cancer. Materials and methods

from 4 to 117 months before PET). Three of the 14 patients also underwent orchiectomy. It was difficult to determine the hormonal status of the 14 patients who had previously received or were on hormonal therapy at the time of FDHT-PET owing to uncertainly regarding the functional status of AR activity. Patients presumed to be hormone refractory may respond to a new combination of hormonal therapy or to discontinuation of hormonal therapy. The goal of this study was not to assess the relationship of FDHT-PET results and responsiveness to hormonal therapy; future studies are required to investigate this issue in a uniform group of patients. To assess the AR binding selectivity of FDHT, 12 patients with one or more foci of abnormally increased FDHT accumulation were studied both before and after administration of an AR antagonist (flutamide; 250 mg t.i.d. for 1 day).

PET imaging PET imaging was performed with an ECAT EXACT HR+ scanner (Siemens-CTI, Knoxville, TN, USA) beginning approximately 90 min after intravenous administration of approximately 10 mCi (370 MBq) of FDHT. A series of four to six static PET images were obtained, each lasting 5 min in duration and covering 15.5 cm axially, beginning at the upper thighs and proceeding cranially to the neck. Transmission scans, each 2 min in duration, were performed at each bed position to allow for segmented attenuation correction of the emission images. The PET images were reconstructed with an iterative algorithm (OSEM) with use of an 8-mm Gaussian filter. Images were viewed on the computer display monitor in three orthogonal projections and as whole-body maximum-pixel-intensity reprojection images for visual interpretation. In patients who underwent two PET imaging studies, efforts were made to keep the imaging sessions similar with regard to the injected dose of FDHT, initiation of imaging after injection of FDHT, and scan duration.

Radiopharmaceutical synthesis

Patients We prospectively studied 20 men (age range 56–87) with advanced prostate cancer. The study was approved by the Washington University Institutional Review Board and Radioactive Drug Research Committee. All patients gave written informed consent for study participation. One patient who had radiological findings suspicious for a single hepatic metastasis was found to have focal fatty infiltration on biopsy obtained after FDHT-PET and was excluded from further data analysis. All of the other 19 patients had metastatic or recurrent prostatic adenocarcinoma confirmed by biopsy or conventional imaging studies (bone scintigraphy or CT). Patients were required to have evaluable disease seen on bone scintigraphy or measurable (>1.0 cm) disease seen on CT, MRI, or plain radiographs. All patients had elevated or rising prostate-specific antigen (PSA) levels. One of the 19 patients (patient 8) had metastatic disease at diagnosis, whereas the remaining patients had distant metastatic or recurrent disease following initial therapy. Patients being treated with luteinizing hormone releasing hormone (LHRH) agonists had to have been receiving such therapy for at least 1 month to be eligible in order to avoid the flare reaction that occurs early during this type of treatment. Patients who were being treated with antiandrogen drugs, such as flutamide, bicalutamide, nilutamide, or cyproterone acetate, were not eligible. Five patients had never undergone hormonal therapy, six had stopped hormonal therapy (LHRH therapy ranging from 9 days to 7 years and antiandrogen therapy from 2 to 31 months) before FDHT-PET, and eight underwent FDHT-PET during treatment with an LHRH agonist (with the duration of hormonal therapy ranging

FDHT was produced in the Washington University Medical School cyclotron, as previously described [11]. The resultant FDHT has high specific activity, high binding affinity for ARs, and high selective uptake by androgen target tissue in vivo [11]. The synthesis of FDHT has recently been adapted to a robotic hand to decrease radiation exposure to the radiochemist.

Image analysis All FDHT-PETimages were evaluated qualitatively by an experienced nuclear medicine physician who was blinded to the results of conventional imaging studies and other clinical information (other than knowledge that each patient had recurrent or metastatic prostatic carcinoma). The PET images were subsequently correlated with bone scintigraphy and/or CT images. Regions of interest (ROIs) were drawn around identified lesions in multiple planes, guided by CTand/or bone scintigraphy. Similar ROIs were drawn on paravertebral muscle. The overall tumor uptake of FDHT was assessed semiquantitatively by determining the tumor-to-muscle activity ratio (T/M) using the maximum pixel value for the tumor and the average value for muscle. The maximum standardized uptake value (SUVmax) was also determined. The SUV is the ratio of the decay-corrected activity per unit volume of tissue (nCi/ml) to the administered activity per unit of body weight (nCi/g) [12]. In patients who underwent PET before and after flutamide, the initial SUV and T/M, as well as the percent changes in SUV and T/M after flutamide, were recorded. In patients with


346 Table 1. Summary of clinical data, imaging data, and follow-up in patients with metastatic/recurrent prostate cancer Patient no.

PSA (ng/ml)

Gleason score

1 2 3 4 5 6b 7 8b 9 10 11 12 13 14b 15 16b 17b 18 19

55 14.4 388 187 29 37 286 37 50 51 30 91 157 3.6 8.7 13.3 20 123 68

7 9 3 6 7 6 7 8 7 10 8 7 10 7 9 7 7 5 8

a

Baseline SUV

Baseline T/M

18.0 a

6.9 a

9.4

% change SUV −70

a

7.8

−68

% change T/M −61

a

−65

a

a

a

a

a

a

a

a

2.0 6.3 3.2 2.2 5.3 5.6 12.0 2.7

2.4 9.0 4.1 2.7 4.6 13.6 13.3 3.0

a

a

−20 −57 −15 −9 −24 −68 −58 −52

−26 −25 −19 −18 −74 −88 −40 −60

a

a

a

a

a

a

a

a

a

a

a

a

−45 −63

−57 −65

10.2 7.8

a

4.2 5.5

a

No uptake Hormone naïve

b

multiple lesions, the SUVs and T/Ms of all the lesions seen on the PET images were determined and the overall average values for all lesions in a given patient were recorded; these overall average values were used in the comparison of pre- and postflutamide PET studies.

Statistical analysis The semiquantitative measures of tumor FDHT uptake before and after flutamide were compared by use of a paired t test. The PSA levels in patients with positive and negative FDHT-PET studies were compared by use of a nonparametric Mann-Whitney test. P values less than 0.05 were considered statistically significant.

Results The Gleason scores of all patients at initial presentation are shown in Table 1. One or more foci of abnormal FDHT uptake were seen in the PET images of 12 of the 19 patients (sensitivity 63%) with known metastatic or recurrent disease (Fig. 1). Fourteen patients had received (n=6) or were on (n=8) hormonal therapy at the time FDHT-PET; ten had positive FDHT-PET. The remaining five patients never received hormonal therapy (hormone naïve); two of these patients had positive and three had negative FDHT-PET. Two patients had innumerable lesions on both FDHTPET and correlative imaging studies; one had diffuse osseous metastatic disease, and the other had diffuse nodal metastatic disease (Table 2). The remaining 17 patients had 43 lesions (27 nodal and 16 osseous lesions). FDHT-PET was positive in ten of these patients, and detected 24 (11

nodal and 13 osseous) of the 28 lesions (86%) demonstrated by conventional imaging (Table 2). In addition, FDHT-PET detected 17 unsuspected lesions (14 nodal and 3 osseous) in five of these ten patients (Table 2). All patients with unsuspected additional metastatic lesions had known metastatic or recurrent disease and, therefore, pathologic confirmation of these additional PET findings was not warranted clinically. The mean (± standard deviation) PSA level in the 19 patients was 86.9±102.8 ng/ml. The mean PSA level in patients with positive FDHT-PET (114.4±112.7 ng/ml) was significantly higher than that in patients with negative FDHT-PET (39.4±65.6 ng/ml) (p=0.006). All 12 patients with positive FDHT-PET underwent repeat imaging after receiving flutamide for 1 day (Fig. 1). In all of these patients, there was a decrease from baseline in tumor FDHT uptake after flutamide (ranging from 18% to 88% for T/M and from 9% to 70% for SUV). The mean (± standard deviation) SUV and T/M decreased from 7.0± 4.7 and 6.9±3.9, respectively, to 3.0±1.5 and 3.0±1.6, respectively (p=0.002 for both by paired t test) (Figs. 2, 3). Discussion Prostate cancer is the most common cancer in men in the USA. It has been estimated that 232,090 men will be diagnosed with prostate cancer in 2005 [13]. Prostate cancer is the second leading cause of cancer death in American men and will claim 30,350 lives in 2005. Metastatic disease remains the major cause of death in prostate cancer.


347 Fig. 1. Anterior (left upper) and posterior (right upper) FDHT-PET images at baseline show increased FDHT uptake in several lymph nodes in the supraclavicular, prevascular, paratracheal, precarinal, and several retroperitoneal regions (arrows). Anterior (left lower) and posterior (right lower) FDHT-PET images performed after flutamide show almost complete blockade of FDHT uptake in the previously seen lymph nodes

The AR has been recognized to be an important factor in the initial development and progression of prostate cancer. The initial treatment of patients who are diagnosed with or subsequently develop metastatic disease is androgen deprivation, either by surgery (orchiectomy) or by administration of drugs to suppress androgen production (medical castration). Despite an initial good response in up to 90% of patients with metastatic prostate cancer, the disease will eventually progress [14, 15]. The exact mechanisms responsible for failure of androgen deprivation therapy are unknown; however, a link between the AR gene and failure of androgen deprivation therapy has been suggested [16]. Several studies have demonstrated that resistance to hormonal therapy is not due to loss of AR expression, as there is evidence that ARs are expressed in essentially all metastatic tumors, including those that continue to grow following androgen ablation [17, 18]. Resistance to androgen ablation may rather develop as a consequence of a deregulated androgen signaling axis resulting from amplification or mutation of the AR gene or a ligand-independent activation of the AR by growth factors and cytokines [19–23]. However, a reliable and practical in vivo or in vitro method is needed to better understand the mechanism(s) of progression of prostate cancer and to determine the level and

activity of ARs in order to monitor therapeutics that target ARs. There has been considerable interest in development of an in vivo method for the detection and quantification of tumor ARs as a means to help understand the role of ARs in patients with prostate cancer. We have developed and tested several fluorinated AR ligands and selected FDHT for evaluation in patients with prostate cancer. Bonasera et al. have shown that FDHT has a high binding affinity and selectivity for ARs. This tracer accumulated avidly in the baboon prostate and this uptake was blocked by administration of testosterone [10]. Based on biodistribution data in baboons, the estimated radiation exposure from administration of FDHT to human subjects was judged to be acceptable [critical organ dose (gall bladder) 2.35 rem/mCi (8.7 mSv/MBq)] and effective dose equivalent 0.75 rem/ mCi (2.8 mSv/MBq) (unpublished data). In this study, we demonstrated that metastatic and recurrent prostate cancer lesions can be detected by PET with FDHT. The sensitivity of FDHT-PET on a patient-bypatient basis was 63% (12 of 19 patients) and on a lesionby-lesion basis, 86% (24 of 28 lesions) (excluding the two patients with diffuse disease from this analysis). Similar results have been reported by Larson et al.; they found


348 Table 2. Summary of the number and sites of metastatic disease in patients with metastatic/recurrent prostate cancer Patient no.

Bone scintigraphy (site/no. of lesions)‘

CT (site/no. of lesions)

FDHT-PET (site/no. of lesions)

1 2 3 4 5 6 7 8 9 10 11

a

Retroperitoneal LN/1 Hilar LN/1

a

12 13 14 15 16 17 18 19

a

Mediastinal and retroperitoneal LNs/6

Spine/1

a

Spine/1

a

Retroperitoneal and pelvic LNs/4 Pelvic LNs/2

a

Spine and pelvis/2 Diffuse osseous metastases

a

a

Pelvic LN/1

Spine and pelvis/2

a

a

Inguinal and pelvic LNs/2

Spine/1

a

a

Diffuse LN metastases Pelvic and inguinal LNs/2

Spine and pelvis/2 Diffuse osseous metastases Pelvic LN/1 Spine and pelvis/3 Inguinal, retroperitoneal, and pelvic LNs/4 Mediastinal and retroperitoneal LNs/6 Spine/2 Diffuse LN metastases Spine, scapula, rib, humerus/6 Pelvic and inguinal LNs/2

a

Spine, scapula, rib, humerus/6 a a a

Spine/1 Ribs/2 Spine/1

a

Retroperitoneal and pelvic LNs/3 Pelvic LN/1 Cervical LNs/2 Retroperitoneal LNs/1 Retroperitoneal and pelvic LNs/4 Mediastinal, retroperitoneal and pelvic LNs/3

a

a a a a

Retroperitoneal and pelvic LNs/2 Mediastinal, retroperitoneal, and pelvic LNs/4 Spine/2

LN lymph node a No abnormality

that FDHT-PET detected 78% (46/59) of the lesions identified by conventional imaging in seven patients with advanced prostate cancer [24]. In our study, FDHT-PET also disclosed 17 additional, previously unknown foci of tracer uptake most consistent with metastatic disease in five

patients. PSA levels were significantly higher in patients with positive FDHT-PET than in patients with negative FDHT-PET (p=0.006). This may be indicative of a greater disease volume in patients with positive FDHT-PET than in those with negative FDHT-PET. In this study, three of the

Fig. 2. Effect of flutamide on FDHT uptake (T/M ratio) in primary and/or metastatic prostate cancer (n=12)

Fig. 3. Effect of flutamide on FDHT uptake (SUV) in primary and/ or metastatic prostate cancer (n=12)


349

five hormone-naïve patients who had never received hormonal therapy had negative FDHT-PET. This raises the possibility that some prostate cancers may be hormone refractory before being exposed to hormonal therapy. Although this issue could not be adequately addressed in this study, our findings suggest that determination of AR status of prostate cancer prior to initiation of hormonal therapy may be beneficial in order to individualize therapy and to avoid the unnecessary expense and morbidity associated with ineffective therapy. The issue of hormonal therapy and AR activity in prostate cancer is very complicated, and well-controlled studies comparing the availability and functional status of AR, as measured by FDHT-PET and the patient’s clinical response to hormonal therapy, are needed in order to define whether tumor FDHT uptake is predictive of prostate cancer responsiveness to hormonal therapy. In this study we demonstrated a definite reduction in the FDHT uptake in all lesions after patients had been treated acutely with the antiandrogen drug flutamide. Similar blockade of FDHT uptake in the baboon prostate gland by antiandrogens has been reported [10]. Flutamide is expected to block the intracellular binding of FDHT to the AR. Accordingly, this effect of antiandrogens on tumor uptake of FDHT in human prostate cancer provides important evidence that the uptake of FDHT is via a specific interaction of the ligand with the AR. There are several important limitations of this study. First is the lack of knowledge about tumor AR content based on in vitro assays. In vitro assessment of tumor AR is not obtained routinely, as it is assumed that all prostate cancers will respond to hormonal therapy initially. Therefore, we were unable to determine the correlation between the FDHT uptake and the AR concentration in prostate cancer lesions. Second is the lack of a robust reference standard, other than the results of conventional imaging, for defining the extent of disease and for determining the sensitivity of FDHT-PET. Thus, the 17 unsuspected lesions detected only by FDHT-PET were not included in the calculation of sensitivity. In summary, we have shown that noninvasive assessment of AR in prostate cancer is possible with PET. Imaging with FDHT-PET has a potential use for evaluating the availability and functional status of tumor ARs. Future studies are needed to investigate whether AR availability as assessed by FDHT-PET is predictive of response to hormonal therapy in patients with prostate cancer. Acknowledgments. This work was supported by Department of Energy grants DE-FG02-86ER60401 and DE-FG0284ER60218.

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