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DOI: 10.1148/radiol.2352040494
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(Radiology 2005;235:623-628.)
© RSNA, 2005


Technical Developments

Fluorocholine PET/CT in Patients with Prostate Cancer: Initial Experience1

Daniel T. Schmid, MD, Hubert John, MD, Roland Zweifel, MD, Tibor Cservenyak, MS, Gerrit Westera, PhD, Gerhard W. Goerres, MD, Gustav K. von Schulthess, MD, PhD and Thomas F. Hany, MD

1 From the Departments of Nuclear Medicine (D.T.S., G.W.G., G.K.v.S., T.F.H.), Urology (H.J.), and Pathology (R.Z.), University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland; and Center for Radiopharmaceutical Science of Eidgenössisch Technische Hochschule, University Hospital Zurich, and Paul Scherrer Institut, Villingen, Switzerland (T.C., G.W.). Received March 22, 2004; revision requested June 2; revision received July 6; accepted August 5. Address correspondence to T.F.H. (e-mail: thomas.hany@usz.ch).


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Institutional review board approval and written informed consent were obtained. Patients with newly diagnosed prostate cancer and patients suspected of having recurrent prostate cancer were prospectively evaluated with fluorine 18 fluorocholine (FCH) combined in-line positron emission tomography (PET) and computed tomography (CT). In 19 patients (mean age, 67 years ± 8; range, 57–85 years), standardized uptake values of FCH in 17 different tissues were determined by using volumes of interest. In nine patients evaluated at initial staging, histologic findings of the resected prostate were compared to FCH uptake. Only small variations of physiologic tracer accumulation were measured in all organs but the kidneys. Differentiation of benign hyperplasia from cancerous prostate lesions was not possible with FCH PET/CT. However, in patients with recurrent prostate cancer, FCH PET/CT is a promising imaging modality for detecting local recurrence and lymph node metastases.

© RSNA, 2005


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Prostate cancer is the most commonly diagnosed cancer in men in the United States and in many other countries (1). Prostate-specific antigen (PSA) testing and digital rectal examination allow early detection of prostate cancer, which is confirmed in most patients with transrectal biopsy of the prostate. In recent years, radical prostatectomy with curative intent has become a considerable alternative to radiation treatment procedures, especially in younger patients (2). Some of the patients treated with curative intent by using either surgery or irradiation may experience relapse. Relapse is detected in most patients as a result of increasing PSA levels, which trigger a number of imaging tests that are often inconclusive.

For initial T staging of prostate cancer, transrectal ultrasonography (US) and magnetic resonance (MR) imaging are the established imaging studies in many institutions. The use of computed tomography (CT) and MR imaging for N staging is of limited value because of the low sensitivity in the detection of lymph node metastases (3). It has been shown that lymph node size does not correlate with the presence of prostate cancer metastases (4).

In patients with biochemical evidence of recurrence of prostate cancer, differentiation of local scar tissue from recurrent disease with conventional imaging techniques is often not possible. Metabolic imaging with fluorodeoxyglucose positron emission tomography (PET) is of limited use for staging and restaging of prostate cancer because of a very low sensitivity (57). Recent developments of new PET ligands such as carbon 11 (11C)- and fluorine 18 (18F)-labeled choline analogues, 11C-acetate, and 18F-fluorodihydrotestosterone have shown promising results in the detection of malignant lesions in prostate cancer (811). The rationale of using PET imaging with radiolabeled choline analogues is the role of choline as a precursor for the biosynthesis of phosphatidylcholine and other phospholipids, which are the major components of cell membranes (12). Carcinogenesis is characterized by elevated cell proliferation rates, and, therefore, higher demands on phospholipids. In vitro uptake and phosphorylation of fluorocholine (FCH) are similar to those of carbon 14–labeled choline and superior to those of other choline analogues (13). Accumulation of FCH is not expected to differ essentially from that of other choline analogues.

The purpose of our study was to prospectively evaluate 18F FCH for combined in-line PET/CT imaging in patients with newly diagnosed prostate cancer and in patients suspected of having recurrent prostate cancer.


    Materials and Methods
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Patients
Data obtained from FCH PET/CT performed in 19 male patients (mean age, 67 years ± 8 [standard deviation]; range, 57–85 years) with histologically confirmed adenocarcinoma of the prostate were evaluated. Ten consecutive patients seen at our institution between March and July 2003 had a newly diagnosed prostate cancer and were scanned preoperatively in addition to undergoing routine staging examinations (biopsy, CT, and bone scanning in patients with PSA level >20 ng/mL). Free serum PSA levels in these patients were 6.4 ng/mL ± 4 (mean ± standard deviation), with an average interval of 35 days (range, 1–63 days) between PSA measurement and PET/CT. Nine patients were scanned for recurrent prostate cancer. All but one of these patients had previously undergone surgical radical prostatectomy. One patient underwent radiation treatment with curative intent. The mean interval between treatment and FCH PET/CT was 49.4 months ± 25.6. None of these patients received androgen deprivation therapy within the previous 6 months. The free serum PSA levels of these nine patients were 14.1 ng/mL ± 15.3, with an average interval of 38 days (range, 12–81 days) between PSA measurement and PET/CT. In eight of these patients, scanning was performed because of increasing PSA levels and negative conventional imaging results (whole-body bone scintigraphy, contrast material–enhanced CT of the abdomen, MR imaging, and US). The remaining patient with known osseous metastases underwent PET/CT to evaluate the extent of pelvic metastases. The institutional review board approved the study protocol, and written informed consent was obtained from all patients.

Synthesis of FCH
18F FCH (fluorocholinefluoromethyl-dimethyl-2-hydroxyethylammonium) was produced by using the method described by Cservenyak et al (14). 18F FCH was prepared by means of a reaction of 18F fluoromethyltriflate with dimethylaminoethanol. 18F fluoride was made by using a 16.8-MeV cyclotron (PET Trace 2000; GE Medical Systems, Uppsala, Sweden). It was azeotropically dried with two washes of 0.7 mL of acetonitrile and was reacted with dibromomethane in acetonitrile in the presence of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix 2.2.2; Merck-Schuchardt, Darmstadt, Germany) at 110°C to give 18F fluorobromomethane, which was purified with distillation followed by passage over a series of four silica cartridges (Sep-Pak Plus; Waters, Milford, Mass) (15). 18F fluoromethyltriflate was made by passing 18F bromofluoromethane over a silver trifluoromethanesulfonate column (Graphpac GC; Waters) at 180°C. 18F fluoromethyltriflate was then used for the N-alkylation of 2-dimethylaminoethanol immobilized on a Sep-Pak Plus C-18 cartridge (a solution of 200 µL of 2-dimethylaminoethanol and 600 µL of ethanol was placed on the cartridge) to quantitatively yield the desired product. For purification, 18F FCH was selectively trapped on a Sep-Pak Accel CM cartridge, washed with water, and removed with saline and a sterile filter added to the patient’s bottle with 4 mL of saline, 0.5 mL of 10% NaCl, and 70 µL of NaHCO3. Quality control was achieved with high-pressure liquid chromatography over a 250 x 4.6 mm, 5-mm pore size, cation-exchange column (Supelcosil LC-SCX; Sigma-Aldrich, St Louis, Mo) eluted with 0.15 M NaH2PO4 in 1000 mL of water and 0.08 mL of pyridine and adjusted to pH of 2.37 with 70% H3PO4 (16).

Imaging Protocol
All patients were scanned with an in-line PET/CT scanner (Discovery LS; GE Medical Systems, Waukesha, Wis) that consisted of a full-ring PET scanner with a 14.6-cm transverse field of view and an in-plane resolution of 4.8 mm full width at half maximum at the center of the field of view and a multisection CT scanner. First, an unenhanced CT scan (80 mA, 0.5 second per rotation, 140 kV, 4.25-mm reconstructed section thickness) was obtained from the head to the pelvic floor. Subsequently, the table position was moved axially to the initial position for the PET scanning so that the first field of view covered the pelvic floor and the bladder. PET scanning was initiated 120 seconds after intravenous injection of 214 MBq ± 14 FCH. Seven cradle positions were scanned, with an acquisition time of 3 minutes for the emission scan per cradle position. PET attenuation data were measured by using CT data (17). To reduce attenuation artifacts, a breathing protocol was used during the CT acquisition, which has been previously described (18). The PET images were reconstructed with standard iterative reconstruction ordered-subset expectation maximization iterative algorithm (two iterative steps) and were reformatted into transverse, coronal, and sagittal views.

FCH Uptake Measurements
Standardized uptake value (SUV) measurement was performed to assess semiquantitative uptake of FCH in different structures. A personal scale (Tanita, model 2001; Tanita, Tokyo, Japan) with an integrated foot-to-foot bioelectric impedance analyzer was used to determine the lean body mass (LBM) of the patients. The manufacturer-supplied equations for this model incorporate sex, mass, height, and a measured impedance value to determine the percentage of body fat and for calculation of LBM. Recent study findings have shown that body fat can be accurately determined by using this device compared with dual-energy x-ray absorptiometry and underwater weighing (1921). By using attenuation-corrected PET data, SUVs were calculated with the following equation: SUV = (LBM · CFCH)/Dose, where LBM is measured in grams, CFCH is the concentration of FCH in becquerels per milliliter, and Dose is the injected dose measured in becquerels.

In a fluorodeoxyglucose PET study (22), SUV calculated with LBM has shown less weight dependence than SUV calculated with body mass. Because SUV calculation based on body mass is more established in many institutions, it was also calculated. Therefore, the same equation was used, except LBM was replaced with body mass (in grams).

Quantitative analysis of FCH uptake was evaluated for the following structures: liver, spleen, kidneys, bladder, pancreas, abdominal aorta, bone (lumbar spine), lungs, left ventricular myocardium, thyroid, submandibular and parotid glands, brain cortex, cerebellum, hypophysis, skeletal muscle (gluteus maximus muscle), and gluteal subcutaneous fat. Since anatomic landmarks are poor on FCH PET scans and some of the mentioned structures could not be easily identified on PET sections, volumes of interest were defined on the CT scan and were subsequently transferred onto the corresponding PET scan by using a software package (PMOD Technologies, Zurich, Switzerland). Pathologic findings on the unenhanced CT sections in one of the aforementioned structures (eg, low-attenuating liver lesions, kidney cysts, opacifications in the lung, suspected bone metastases, movement artifacts) were excluded from the volumes of interest. In all patients, each structure-specific SUV was calculated as mean ± standard deviation. Definition of volumes of interest and calculation of SUVs were performed in consensus by a radiologist (T.F.H.) with 10 years of experience and a nuclear medicine physician (D.T.S.) with 4 years of experience.

To determine the maximum SUV in the prostate or the primary tumor, a volume of interest covering the entire prostate gland was drawn (T.F.H., D.T.S.). The average value of the five voxels with the highest activity was calculated to minimize overestimation of the maximum SUV caused by a single high-activity voxel.

Image Interpretation
Image readout was performed on screen by using PET/CT review software (Entegra, version 2.5; GE Medical Systems, Haifa, Israel), which allows simultaneous scrolling through the corresponding PET, CT, and fused sections in transverse, coronal, and sagittal planes. Two nuclear medicine physicians (D.T.S. and G.W.G. with 4 and 10 years of experience, respectively) and at least one board-certified radiologist (T.F.H. with 10 years of experience) read all PET/CT images in consensus. Pathologic findings identified on CT scans and suspicious tumor lesions identified on PET images were discussed with the referring urologist.

Histopathologic Correlation
In nine patients who underwent radical prostate surgery, areas with the highest tracer accumulation within the prostate on transverse PET/CT images were visually compared with the largest tumor location and extension on histopathologic thin slices. The surgically resected specimens were fixed in formalin. After fixation, the prostate specimens were then step sectioned at 0.5-cm intervals perpendicular to the long axis (apical to basal) of the gland. Histologic sections were obtained from at least two slices of tissue. The paraffin-embedded sections were routinely stained with hematoxylin and eosin. Exact location and extension of carcinomatous tissue were determined independently by a board-certified pathologist (R.Z.). Additional visual comparison with FCH PET/CT findings was performed in consensus (R.Z., T.F.H., D.T.S.).

In patients suspected of having recurrent disease, surgical and/or histopathologic specimens were only obtained from patients with limited lymph node involvement (one to two lymph nodes).

Evaluation of Additional Findings
PET/CT images were analyzed for additional FCH uptake in locations other than those aforementioned. All findings were evaluated in consensus (D.T.S., T.F.H., G.W.G., G.K.v.S.) and were compared with clinical information. All lesions suspicious for malignancy were further evaluated with other imaging modalities.


    Results
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
FCH Uptake Measurements
In the abdomen, avid FCH uptake was found in the liver, spleen, kidneys, and pancreas and in widely varying amount and locations in parts of the bowel. Mean SUVs calculated by using LBM and body mass for the evaluated structures are listed in Table 1. Assessment of physiologic uptake values in the prostate was not possible due to known prostate cancer, benign prostate hyperplasia, or status after prostatectomy.


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TABLE 1. FCH Uptake in Different Organs

 
Patients with Newly Diagnosed Cancer
In patients scanned for staging of a newly diagnosed and untreated prostate cancer, the maximum SUVs calculated by using LBM and body mass measured in the prostate were 3.5 ± 0.9 (range, 2.2–5.3) and 4.3 ± 1.1 (range, 2.5–6.5), respectively. In only one patient did the PET findings in the prostate match well with the histopathologic location and extent of the tumor (Fig 1, A). In the remaining eight patients, FCH accumulation was found in the region of the tumor and in the vicinity and also in areas without histopathologic evidence of malignancy. In these areas, signs of prostate hyperplasia were found. In two of the eight patients, histologic examination revealed only multiple autonomous small cancer lesions within the prostate with a maximum diameter of 2 mm, which are below the spatial resolution of PET. However, heterogeneous FCH uptake was also present in these patients (Fig 1, B). PET/CT scans showed no evidence of pelvic lymph node metastases in these patients. Histopathologic work-up of 35 sampled lymph nodes from all nine patients confirmed the PET/CT findings in all patients.



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Figure 1. Histopathologic thin slices of the prostate perpendicular to the long axis of the prostate at low (x4) magnification (top images) and at a higher (x100 in A and x50 in B) magnification (bottom left image in A and B). (Hematoxylin and eosin stain.) A, Images in a 61-year-old patient with tumor infiltration mainly of the right posterior part of the prostate (largest diameter, 20 mm) correlate well with the FCH uptake (arrowhead) on fused PET/CT image (bottom right). B, Images in a 65-year-old patient with a multiple separated lesions of tumor infiltration (largest diameter, 2 mm) and signs of benign hyperplasia of the prostate gland demonstrate avid and heterogeneous FCH accumulation (arrows) on fused PET/CT image (bottom right).

 
Patients Suspected of Having Recurrent Cancer
In all nine patients with biochemical evidence of recurrence of prostate cancer, FCH PET/CT findings were highly suggestive of local recurrence, lymph node metastases, or bone involvement. In four of nine patients, PET/CT findings indicated local recurrent tumor in the prostate bed. In another four patients, there was no evidence of local recurrence, but pelvic lymph node metastases were identified (Fig 2). In one patient, local recurrence and unilateral iliac lymph node metastases were detected. In the remaining patient, multiple bone metastases were visualized in accordance with a recent whole-body bone scan. However, none of these metastases were pathologically proved. SUVs of tumorous lesions are listed in Table 2.



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Figure 2. Transverse CT (left), FCH PET (middle), and fused PET/CT (right) images in a 62-year-old patient with biochemical evidence of recurrence of prostate cancer (PSA level, 6.19 ng/mL) and a negative bone scan. Avid focal FCH accumulation (arrowheads) was found in left paraaortic lymph node (top row) and in right iliac lymph node (bottom row), corresponding to metastases as confirmed histologically.

 

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TABLE 2. FCH Uptake Expressed as Maximum SUV in Patients with Biochemical Recurrent Disease

 
In two of the patients suspected of having lymph node metastases and no other suspicious lesions, lymphadenectomy was performed. Histopathologic work-up of the resected lymph nodes confirmed the PET/CT findings in all four resected nodes. Of the other seven patients, six received androgen deprivation therapy with or without local radiation treatment and one patient refrained from any further treatment.

Additional Findings
In one patient with known sarcoidosis, high accumulation of FCH was found in multiple mediastinal and peribronchial lymph nodes, with a maximum SUV calculated by using LBM of 4.46 and a maximum SUV calculated by using body mass of 4.9. In another patient scanned for recurrent prostate cancer, a lesion with increased tracer accumulation (maximum SUV with LBM, 2.8; maximum SUV with body mass, 3.4) was found in the left frontal lobe, which turned out to be a meningioma at MR imaging. In all patients, bilateral mild uptake (maximum SUV with LBM, 0.8–1.6; maximum SUV with body mass, 0.9–1.9) was found in inguinal lymph nodes. CT morphology of these lymph nodes showed no pathologic enlargement. In addition, in one patient with a chronic venous ulcer of the calf, a unilateral more pronounced uptake was found (maximum SUV with LBM, 3.2; maximum SUV with body mass, 3.9).


    Discussion
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
On the basis of our data, FCH PET/CT seems not to be suited for T staging of prostate cancer because of the inability to differentiate benign prostate hyperplasia from cancerous lesions. However, FCH PET/CT for the detection of recurrent disease or metastases after radical prostatectomy is a promising field in patients with only biochemical evidence of recurrence but otherwise unremarkable imaging findings.

A PSA level greater than 0.2 ng/mL has recently been reported as an appropriate cutoff for the definition of tumor recurrence after radical prostatectomy (23). PSA doubling time as a predictor of tumor progression proved a more consistent criterion to determine intervention (24,25). Unfortunately, there is no consensus regarding further diagnostic work-up in patients with biochemical evidence of recurrence. When salvage radiation treatment is intended, a number of imaging tests that include bone scanning, CT, and MR imaging are therefore typically initiated either for localization of tumor recurrence or to exclude distant metastases. In many patients, these tests are unable to define local or distant tumor recurrence. For example, the likelihood of a positive bone scan in patients with a PSA level lower than 40 ng/mL is less than 5% (26). The usefulness of salvage irradiation remains unclear in patients in whom detection of recurrent tumor tissue is not achieved.

Our results are promising in that FCH PET/CT could improve therapeutic care of patients with biochemical evidence of recurrence of prostate cancer. In our small series of patients, localization of recurrent tumor tissue was possible in all patients. These results are comparable with previously reported series by de Jong et al (27) of 22 patients with increasing PSA levels who were scanned with 11C-choline PET. Interestingly, tumor detection was also possible in patients with a PSA level lower than 5 ng/mL, where de Jong et al found no positive PET scans. A possible explanation for this could be the crucial information provided by coregistered CT data, allowing differentiation of physiologic uptake in bowel and ureter from that in diseased lymph nodes.

Primary staging of prostate cancer includes transrectal US and biopsy. Performance of MR imaging in the detection of prostate cancer seems to be heterogeneous but helpful in the definition of extracapsular disease (28). Our data suggest that FCH PET/CT is of limited use since benign prostate hyperplasia cannot be differentiated from prostate cancer tissue. However, FCH PET/CT could be useful in a selected patient population with higher PSA levels for lymph node staging.

Today, widely performed PSA tests for screening allow early detection of prostate cancer, often before the tumor has metastasized into pelvic lymph nodes. Distant metastases at this time are also rare. FCH PET imaging, therefore, has no role as a screening imaging modality.

Whole-body distribution of FCH did not show essential differences compared with distribution of 11C-choline. High tracer accumulation into various tissues is present for all choline analogues used with PET imaging. These include mainly liver, spleen, kidneys, pancreas, and other exocrine organs. Only small variations of physiologic tracer accumulation were measured in all organs but the kidneys, since choline is excreted renally. Therefore, a nonparametric visual interpretation of FCH uptake is possible, and standardized measurement is not crucial for image interpretation.

Even though other malignant tumors such as breast cancer have been described to be FCH avid, evaluation of these organs regarding metastases may not be possible because uptake in liver metastases may be indistinguishable from physiologic uptake of normal liver tissue. Besides tumorous uptake, FCH uptake in inflammatory tissue was recently reported by Wyss et al (29) in an animal model. Similarly, in one patient with known sarcoidosis, avid FCH uptake was seen in mediastinal and peribronchial lymph nodes. In all patients, bilateral mild uptake was found in inguinal lymph nodes. However, CT morphology of these lymph nodes showed no pathologic enlargement and was, therefore, interpreted as possible reactive uptake. In addition, in one patient with a chronic venous ulcer of the calf, a unilateral more pronounced uptake was found. By using the described PET imaging protocol, dynamic imaging of the pelvic region is not necessary since urinary activity does not interfere with image interpretation at this early time point. In addition, the coregistered CT data allow reliable localization of tracer accumulation such as that in the bladder. Furthermore, missing anatomic landmarks on FCH PET images underlines the necessity of combined PET/CT imaging.

The major advantage of 18F- versus 11C-labeled choline tracers is the substantially longer half-life of the FCH compound, which allows the distribution of this tracer to PET institutions without an on-site cyclotron, very much like the common distribution of fluorodeoxyglucose.

There were limitations in this study. First, the numbers of patients in both groups were small. Second, in most patients with recurrent prostate cancer, histopathologic confirmation of tumor recurrence cannot be assessed for a number of reasons, but particularly for ethical considerations.

In conclusion, FCH PET/CT is a technically feasible and reliable imaging technique. The potential use is the detection of recurrent tumor tissue in patients with biochemical evidence of recurrence of prostate cancer. For local T staging of primary prostate cancer, FCH PET/CT seems to be of limited value since there is accumulation in tumor tissue, as well as in benign hyperplasia.


    FOOTNOTES
 
Abbreviations: FCH = fluorocholine, LBM = lean body mass, PSA = prostate-specific antigen, SUV = standardized uptake value

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, T.F.H., G.K.v.S.; study concepts, T.F.H., D.T.S.; study design, G.W.G., H.J., R.Z.; literature research, D.T.S., T.F.H., G.W., T.C.; clinical studies, D.T.S., T.F.H., G.W.G., G.K.v.S.; data acquisition, D.T.S., T.F.H., G.W.G., H.J., R.Z.; data analysis/interpretation, D.T.S., T.F.H.; manuscript preparation, D.T.S., T.F.H., G.W.G., H.J., R.Z., T.C., G.W.; manuscript definition of intellectual content, T.F.H., D.T.S., G.K.v.S., G.W.; manuscript editing, D.T.S., T.F.H.; manuscript revision/review and final version approval, all authors


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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