RESULTS. of patients with T1 3 prostate cancer. To date no long-term data are available for patients who have had interstitial brachytherapy (IB) [5].

Transcription

1 Urological Oncology [ 11 C]-CHOLINE PET/CT FOR RECURRENT PROSTE CANCER RINNAB Evaluation of [ et al. 11 C]-choline positron-emission/computed tomography in patients with increasing prostate-specific antigen levels after primary treatment for prostate cancer Ludwig Rinnab, Felix M. Mottaghy*, Norbert M. Blumstein*, Sven N. Reske*, Richard E. Hautmann, Kathrin Hohl, Peter Möller, Thomas Wiegel, Rainer Kuefer and Juergen E. Gschwend Departments of Urology, *Nuclear Medicine, Biometry and Medical Documentation, Pathology and Radiation Oncology, University of Ulm, Department of Urology, Technical University, Munich, Germany, and Division of Nuclear Medicine, UZ Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium Accepted for publication 9 March 2007 R.K and J.E.G. contributed equally to the work Study Type Diagnostic (non consecutive cohort study) Level of Evidence 2b OBJECTIVE To evaluate [ 11 C]-choline positron-emission tomography (PET)/computed tomography (CT) for detecting clinical recurrence after primary treatment for prostate cancer. PIENTS AND METHODS In all, 50 patients with prostate cancer who had had initial therapy (radical prostatectomy in 40, external beam radiation in three and interstitial brachytherapy in seven) had PET/ CT using [ 11 C]-choline in the presence of an increased or increasing prostate-specific antigen () level. The mean (range) time to biochemical progression was 22 (2 136) months. Current levels were determined in all patients at the time of examination. The results were correlated with the histopathology reports after targeted biopsy or surgery, and with the clinical follow-up. RESULTS The mean (median, range) level in patients with positive PET/CT was 3.62 (2.42, ) ng/ml, and that in patients with a negative scan was 0.90 (0.95, ) ng/ ml. PET/CT was positive in seven of 13 patients with a level of <1.5 ng/ml, and histology was positive in this group in nine. In 17 patients with levels of ng/ml PET/CT was positive in all and the histology was positive in 13; in 11 men with a level of ng/ml PET/CT was positive in all 11 and the histology was positive in 10; in nine men with levels of >5 ng/ml PET/CT identified all as positive and the histology was positive in eight. The sensitivity at a level of <2.5 ng/ml of PET/CT for detecting recurrence was 91% (95% confidence interval, 71 99%) with a specificity of 50% (16 84)%. CONCLUSION [ 11 C]-choline PET/CT seems to be useful for restaging prostate cancer after curative therapy and with increasing levels; this was verified by histological examination. We recommend this method at levels of <2.5 ng/ml. KEYWORDS 11 C-choline PET, prostate cancer, re-staging,, follow-up INTRODUCTION Detecting local recurrence after a definitive treatment for prostate cancer is a well-known diagnostic challenge and is first indicated by an increase in the serum value of after reaching the nadir. It occurs in 30 50% of patients within 10 years after radical prostatectomy (RP) [1] and 16 35% of these patients receive second-line treatment within 5 years after surgery [2]. Patients with T1 2 disease after external beam radiotherapy (EBRT, 70 Gy) have a recurrence in up to 30 40% within 10 years [3,4], but biopsyconfirmed local recurrence occurs in 21 53% of patients with T1 3 prostate cancer. To date no long-term data are available for patients who have had interstitial brachytherapy (IB) [5]. However, detecting the recurrence presents a major problem in daily urological practice, particularly for increases of <20 ng/ml. Although several innovative imaging techniques are available (TRUS, CT, MRI, Prostascint TM ), they all fail to produce reliable results [6]. TRUS-guided biopsies have a limited sensitivity of 25 54%, particularly when the level is <1.0 ng/ml [7]. Perianastomotic biopsies are questionable, as a positive result does not exclude metastatic disease and a negative result does not exclude local recurrence [2]. Contrast-enhanced CT is not sufficiently sensitive for detecting local recurrence until the velocity is >20 ng/ ml/year [8]. Bone scans rarely detect skeletal metastases in men with a level of <30 ng/ ml [2,8]. Encouraging results were reported for endorectal MRI and MRI spectroscopy in small retrospective series [9]. Apart from these imaging methods, an increase in velocity is useful to distinguish local recurrence from distant metastasis [10]. Recent data suggest that [ 11 C]-acetate positron-emission tomography (PET) [11], and 786 JOURNAL COMPILION 2007 BJU INTERNIONAL 100, doi: /j x x

2 [ 11 C]-CHOLINE PET/CT FOR RECURRENT PROSTE CANCER FIG. 1. A 52-year-old patient, with a status after RP and PLA of pt3a pn0 cm0, G3, Gleason 9, stage III R1 prostate cancer. His level was 9.8 ng/ml before and 0.3 ng/ml at 6 months after surgery, rising to 0.7 ng/ ml and 1 month later to 2.4 ng/ml; he had no antiandrogen deprivation; conventional imaging (TRUS, CT, endorectal MRI) was negative. The PET/CT showed a histologically confirmed local recurrence and a presacral metastasis (red arrows). For therapy he had intensity-modulated RT. reported that [ 11 C]-choline PET cannot be used to visualize prostate cancer on re-staging at a level of <4.5 ng/ml. Considering these findings the question arises whether the use of [ 11 C]-choline PET/CT, with the advantage of precise tumour localization and delineation in patients with prostate cancer in the follow-up after initial therapy, should be limited to patients with a level of >5 ng/ml or whether the application of PET/CT is rational in men with levels of <5 ng/ml. In the present study we investigated the feasibility of [ 11 C]-choline PET/CT for detecting clinical recurrence after primary treatment with RP, EBRT or IB. PIENTS AND METHODS FIG. 2. A. Contrast-enhanced four-row helical CT (transaxial slice) of an operated area. The thick red arrow shows solid non-contrast-enhanced tissue; this structure was suspected to be either scar or isolated local relapse. B. PET image (transaxial slice) of focal [ 11 C]-choline uptake in the pelvis with no precise location (thin red arrow). C. Fused PET/CT image shows focal [ 11 C]-choline uptake in the rectal wall caused by local inflammation (thin red arrow), with no focal [ 11 C]-choline uptake in a suspected lesion (thick red arrow). Therefore PET/CT revealed no local relapse. TRUS-guided biopsy confirmed a local recurrence of prostate cancer, Gleason 8. A B C [ 11 C]-choline PET and PET/CT, are promising tools to detect a clinical relapse after primary therapy for prostate cancer [12 14]. Choline is one component of phosphatidylcholine, an essential entity of phospholipids in the cell membrane [15]. Malignant tumours are associated with increased cell proliferation and up-regulation of choline-kinase, an enzyme that catalyses the phosphorylation of choline. This up-regulation provides the rationale for the use of [ 11 C]-choline PET in oncology. As [ 11 C]-choline is not rapidly excreted in urine, [ 11 C]-choline PET has been reported to give clear images of the pelvic region, and of prostate cancer and pelvic lymph node metastases in the absence of urinary activity [16,17]. Although PET with [ 18 F]-fluorodeoxyglucose (FDG) shows increasing usefulness in clinical oncology for disease staging, prognostic stratification, planning and monitoring treatment, and early detection of recurrent tumour growth, its use in some tumours, including prostate cancer, is limited by a low sensitivity [18 20]. Recently Heinisch et al. [21] reported a [ 18 F]- fluorocholine PET/CT phase III study for restaging prostate cancer in 34 patients (RP in 31, EBRT in three), and they recommended using this technique at levels of <5 ng/ ml. In that study the results of [ 18 F]-choline were mostly compared with other imaging methods (CT and/or MRI), and only in a few cases was local tumour progression confirmed by biopsy and histology, as well as the course of disease. They found malignancy in seven of eight men positive on [ 18 F]- fluorocholine PET/CT and with levels of <5 ng/ml. By contrast, de Jong et al. [13] In all, 50 consecutive patients (mean age 65.9 years, median 67, range 52 79) with prostate cancer and referred for whole [ 11 C]- choline PET/CT for clinical re-staging after RP (40), EBRT (three) or IB (seven), were retrospectively evaluated. Nine of the RP group had received adjuvant EBRT. Written informed consent was obtained in all patients before PET/CT. The data were evaluated retrospectively after obtaining permission from the local ethics committee, and did not require a specific signature of the patients. The indication for PET/CT was a suspicion of local relapse or distant metastasis due to an increasing level. Patients with biochemical evidence of disease after RP were identified by a serum level of 0.2 ng/ml, and those after EBRT or IB were identified by three consecutive increase in serum level after the nadir, according to the American Society for Therapeutic Radiology and Oncology criteria [22,23]. The mean (median, range) level in all patients before primary therapy was 24.2 (14.3, ) ng/ml. All patients had their level measured on the same day as the PET/CT; the mean level of all patients was then 3.62 (2.42, ) ng/ml; that in patients with a negative PET/CT was 0.9 (0.95, ) ng/ml. Patients treated with EBRT and IB before PET/CT or with RP in the previous 3 months were excluded from the study. The bounce effect was also excluded. Four patients were under hormonal deprivation at the time of examination (nos 5, 32 and 39, Table 1, and no. 3, IB). 11 C-choline was synthesized according to the loop methylation method [24], and patients JOURNAL COMPILION 2007 BJU INTERNIONAL 787

3 RINNAB ET AL. TABLE 1 Patient details and results after RP, EBRT and IB No./ age, years 1 TNM stage 1/ pt3apn0cm0 G Gleason sum nadir Primary therapy (Gy) 2 PET/ CT Site of +ve U confirm by II RP 0.6 ve no U Bx result DRE Bone scan TRUS 2ry treatment 3 at FU, months +ve ns np s RT < / pt2cpn0cm0 III RP 0.41 ve no U Sa LA ve s ve s RT, HT <0.1 (NS) pelvic l 5ARI 19 3/61 17 pt3bpn0cm0 IIb RP 3.8 +ve U +ve ns np s RT 0.4 region Bx nd 4/ pt2cpn0cm0 I 6 1 RP (NS) ve U LN 1 no LU Sa LA 2 ve s np s RT /59 14 pt3b pn1cm0 (13/28) L1 III RP HT, RT (66) 8 +ve U LN 3 Sa LA aortic bifurcation +ve s np ns MAB /64 55 pt3b pnx cm0 IIb RP 1.6 +ve U LN 4 pelvic +ve ns np ns ww nd LA bilat 7/73 13 pt3b pn1 (2/19) cm0 III RP HT, RT 2.7 +ve U 2 LN 5 Sa LA 5 r EF +ve ns np ns HT RO 8/ pt4apn1cm0 II np 0.1 RP 2.2 +ve U 6 TURB +ve ns np s iht 2.5 R1 III DBW 29 9/ pt2bcnxcm0 II prp 2.2 +ve U LU Bx +ve s np s RT 0.5 U1LN 7 ve 7 10/68 21 pt3a pn0 cm0 II RP 1.1 ve U Bx ve s np s RT /71 12 pt3c pn1 cm0 (1997th ED) III RP adj Estrazyt 1.8 +ve U, LU sub vesical +ve ns np s Sa BT 12/ pt2b pn0 cm0 III RP 1.7 +ve U AR ve ns np ns iht <0.1 + SV l 25 13/68 65 pt3a pn0 cm0 II RP 4 +ve U +ve ns np s HT nd 14/69 25 pt3a pn0 cm0 II RP ve U ve ns np s ww nd 15/ pt2c pn0 cm0 II RP (NS) 2.8 +ve U +ve ns np s RT / pt3b pn1 cm0 R1 III RP ve U 8 +ve s +ve s RT 9 Zometa / pt3b pn0 cm0 II RP 1.3 +ve U 2 para iliacal LN bilat 10 open pla ve +ve ns np ns ww / pt3a pnx cm0 R1 II prp, HT RT (66) ve U LN 11 Sa pla +ve ns np ns ww /73 22 pt4a pn1 (4/9) III RP 2.4 +ve U LU +ve s np s Sa BT <0.1 cm0 HT 22 20/ pt4 pn0 cm0 III RP 1.2 +ve U prostate lobe +ve s 15 ve s RT / pt2b pn0 cm0 II np 0.2 RP 1.4 ve no U ve s np s RT /66 32 pt3b pn1 cm0 II RP 6.9 +ve U LU 13 +ve s +ve s HT 8 R1 RT 28 23/ pt2a pn0 cm0 I RP 0.5 +ve U prostate +ve s ve s RT 0.3 lobe 21 24/ pt3a pn0 cm0 III RP 3 +ve U LU +ve ns ve s HT >0.1 R1 RT (60) 34 25/ pt3a pn0 cm0 II RP 0.8 ve no U +ve s np s RT / pt2a pn0 cm0 II RP 3.7 +ve U +ve s ve s RT JOURNAL COMPILION 2007 BJU INTERNIONAL

4 [ 11 C]-CHOLINE PET/CT FOR RECURRENT PROSTE CANCER TABLE 1 Continued No./ age, TNM 2ry treat- years 1 stage G sum nadir (Gy) 2 CT +ve U by result DRE scan TRUS ment months 27/ pt3a pn0 cm0 III RP 1.9 +ve U LU +ve ns np s RT 0.71 subvesical 12 28/ pt2b pn0 cm0 II RP ve U +ve s np s RT 3.58 R / pt2a pn0 cm0 II RP 2.1 +ve U 1 LN Sa pla +ve s np s HT 0.46 l iliac l 13 30/ pt2b cn0 cm0 III RP 9.1 +ve U LU +ve ns ve s RT 0.4 R1 RT (66) r and SV nd 31/ pt2c cn0 cm0 II 7 0 RP 1.1 ve no U ve s ve ns ww / pt4 pn1 cm0 II RP 2.5 +ve U +ve ns ve ns HT 0.1 R2 RT (66) 60 33/ pt4 pn1 cm0 II RP 3.9 +ve U LU +ve s np s RT <0.1 R1 RT + SV l HT 23 34/ pt3a pn0 cm0 II RP 1.9 +ve U +ve ns ve ns BT 0.42 nd 35/62 22 pt2 pn0 cm0 I II prp 8.3 +ve U +ve ns ve ns RT <0.1 nd 36/ pt3b pn0 cm0 III RP RT (70.2) 2.4 +ve U LN iliac r Sa pla r ve ns np np HT nd 37/ pt3a pn1 cm0 R1 II RP HT 1.4 +ve U LN para aortal (LWK III) left Sa RLA +ve nd nd nd ww nd 38/ pt3a pn1 cm0 II RP, HT ve U LN Sa pla +ve nd nd nd HT 2.3 R1 RT (60) r 12 39/66 36 pt4 pn1 cmo R1 II RP HT ve U LN 14 para Sa RLA +ve nd ve nd docet thali multiple 40/ pt3b pn1 cm0 II RP 3.8 +ve U LN Sa LA ve s ve s MAB 4.4 HT presacral 15 presacral 6 EBRT 1/66 32 ct3 Nx cm0 II RT, adj HT 6 m ve U 16 Sa RP + pla +ve ab np ns HT < / ct2c cn1 cm0 II pla RT ve U prostate bilat P +ve ab np s RT nd 3/66 84 ct2b cn0 cm0 II RT, adj HT 6 m IB 1/ ct2a Nx cm0 II III Gleason Primary therapy LDR-IB adj HT 6 m 2/ ct3a Nx cm0 II LDR-IB adj HT 6 m ve U presacral l under HT 3.4 +ve U prostate basal + l SV of presacral tumour +ve ab ab s presacral P PCa ab np ns iht, 5ARI RT 21 nd 3.8 nd 2.8 +ve U prostate TURB 17 PCa ab np s HT >0.1 nd 3/ ct2a cnx cm0 I 4 1 LDR-IB 1.5 +ve U prostate SV bilat P SV bil PCa ab np s Breuss > / ct2b pn0 cm0 III orch, RT pelvic LA, LDR-IB 7.2 +ve U SV r P no Ca ab ve s HT /54 22 ct2a cnx cm0 II LDR-IB ve U SV r 18 P SV r PET/ Site of confirm Bone PCa ab ve np pelvic LA, Sa RP 19 adj HT 3 at FU, < JOURNAL COMPILION 2007 BJU INTERNIONAL 789

5 RINNAB ET AL. TABLE 1 Continued No./ age, TNM Gleason years 1 stage G sum nadir (Gy) 2 CT +ve U 6/ ct3a Nx cm0 II LDR-IB 2.8 +ve U local rec between seeds 7/ ct2a cn0 cm0 II LDR-IB 1 +ve U SV r + prostate 20 Primary therapy PET/ Site of confirm 2ry treat- by result DRE scan TRUS ment months TURP PCa ab np np LHRHa LN l Bone PCa ab np s LHRHa nd 3 at FU, U, uptake; FU, follow-up; EF, extended field; DBW, dorsal bladder wall; NS, nerve sparing; s, suspicious; ns, not suspicious; np, not performed; nd, no data; TURB, transurethral resection of bladder, 1, at diagnosis; 2, at PET/CT; 3, at follow-up after therapy; ww, watchful waiting; Breuss, alternative therapy; Bx, biopsy;, TRUS-guided biopsy;, anastomosis region; Sa, salvage; r, right; l, left; 5ARI, 5α-reductase inhibitor; bilat, bilateral; adj, adjuvant; SV, seminal vesicle; docet, docetaxel; thali, thalidomide; MAB, complete androgen deprivation; an, abnormal; n, normal; 1 V. iliac com. right; 2 pelvic/iliac/presacral right; 3 under and upper aortic bifurcation; 4 A. iliac com. left; 5 parailiac com. right; 6 DBW and suspect LU in SV; 7 glutea inf. left; 8 osteoplastic metastasis acetabulum right, os sacrum right; 9 including bone metastasis; 10 A. obtur. right and left; 11 A. obturatoria int. right, LN between M. psoas right and A. iliac ext.; 12 died from pancreatic cancer; 13 osteoplastic metastasis acetabulum right, os sacrum right; 14 parailiac and paraaortal; 15 abandoned because of frozen pelvis ; 16 apex prostate both sides, suspicious LU; 17 bladder neck, dorsal wall; 18 MRI showed a suspicious lesion on the right SV; 19 pt3b pn1 cm0 GII Gleason 7; 20 suspicious A. iliaca ext. LN left. underwent PET/CT after 5 8 h fasting on an integrated PET/CT scanner after and i.v. injection with 1056 ± 143 MBq of [ 11 C]- choline. PET images were acquired 5 10 min after the injection, starting from the distal margin of the pelvic floor with a 3-min acquisition time per bed position [25]. Contrast-enhanced CT (140 kv, 160 ma, pitch 1.5 mm) was acquired with 120 ml of nonionic contrast medium (i.v.) as a bolus (Ultravist, Schering, Germany) immediately before the PET acquisition. PET images were reconstructed with the iterative reconstruction ordered-subset expectation maximum likelihood algorithm of the manufacturer, after correction for attenuation based on the CT dataset. Consecutive transverse PET/CT slices of 4.25 mm thickness were generated. The images were assessed visually, by consensus, by a radiologist and a nuclearmedicine physician unaware of the clinical data and results of previous imaging studies. The criteria for diagnosing recurrent prostate cancer was an increased uptake of [ 11 C]- choline retrovesically and pre-rectally that had to be at least twice that of [ 11 C]-choline uptake in the periprostatic soft tissue or pararectal fat tissue, as determined by the standard uptake value. Any increased uptake in pelvic or para-aortal lymph nodes was determined as a local or distant lymph-node metastases, irrespective of the size of the lymph nodes. [ 11 C]-choline uptake in inguinal, mediastinal or hilar lymph nodes was defined as unspecific uptake. Bone metastases were suspected in patients with typical sclerotic lesions and or increased focal uptake of [ 11 C]- choline. Care was taken to differentiate prostatic [ 11 C]-choline uptake from rectal activity. Examples of imaging [ 11 C]-choline PET/CT scans are given in Figs 1 3. The biopsy and surgical specimens after pelvic lymphadenectomy were assessed histologically after salvage RP, TUR of the bladder or prostate, and TRUS-guided biopsies. The surgical specimens were processed according to standard methods. The primary histological diagnosis was made using haematoxylin and eosinstained sections, with additional immunohistochemical staining to optimize the pathological diagnosis. in the serum was determined at the central chemical laboratory of the University of Ulm using the Hybritech assay (Hybritech Inc., Beckman Coulter, Fullerton, CA, USA), with a lower detection limit (analytical sensitivity) of <0.01 ng/ml. To obtain an overall impression of the diagnostic value of [ 11 C]-choline PET/CT, the sensitivity, specificity and accuracy, with 95% CI, were calculated based on all patients. We also examined these characteristics for different subgroups of patients according to their value. RESULTS The clinical data of all patients and the results of PET/CT imaging are shown in Table 1; the mean level in PET/CT-positive patients was 3.62 (2.42, ) and in those PET/CTnegative was 0.9 (0.95, ) ng/ml. Table 2 compares the results of PET/CT and histology for patients with different ranges of level. The overall sensitivity and the positive predictive value (with 95% CI) of PET/ CT for detecting recurrence was 95 (83 99)% and 86 (73 95)%. The overall specificity was 40 (12 74)% with a negative predictive value of 67 (22 96)% and an accuracy of 84 (71 93)%. The sensitivity at a level of <2.5 ng/ml (including 30 patients) was 91 (71 99)% and the specificity 50 (16 84)%, respectively. Table 3 gives details of the sensitivity and specificity for each category. Six of the PET/CT results were negative, and two of the patients had a positive histology after targeted surgery or biopsy. The mean (median, range) level in this subgroup before PET/CT was 0.96 (1.1, ) ng/ml. DISCUSSION Currently, relapse after primary curative therapy of prostate cancer is a diagnostic and therapeutic challenge. The extent of the required diagnostic tools to date is controversial. Locating the relapse and the growth kinetics of the tumour are vitally 790 JOURNAL COMPILION 2007 BJU INTERNIONAL

6 [ 11 C]-CHOLINE PET/CT FOR RECURRENT PROSTE CANCER FIG. 3. PET/CT (transaxial slices) of a patient after RP for a pt3b pn1 (13/28) cm0 GIII Gleason 9 prostate cancer. Adjuvant therapy was by antiandrogen deprivation and EBRT in prostatic lobes, with a delivered dose of 66 Gy. A, a PET image (transaxial slice) B, the corresponding contrast-enhanced four-row helical CT (transaxial slice) and C, the fused PET/CT image; D, a PET image (coronal slice, maximum intensity projection) with several suspicious lymph nodes (red arrows). The level at the time of examination was 8.0 ng/ml; the scans show intensive focal uptake in the lymph nodes under and above the aortic bifurcation. The histology after salvage PLA confirmed the presence of lymph-node metastases. A B tumour size or metabolism. Moreover, although there are reports that choline uptake decreases after initiating hormone therapy, it is not known whether it influences choline metabolism and equally [31,32]. We cannot exclude that the [ 11 C]-choline PET signal is less influenced than the level under hormonal deprivation. In the present study, four patients were under hormonal therapy at the time of PET/CT and the other 46 were hormone-naive. C important for subsequent therapy. Although is the most sensitive tool for detecting recurrences, it cannot precisely distinguish between a local, regional or distant failure. Of patients with biochemical relapse after RP, 30 50% will also develop a local recurrence. The rate of local recurrence after RT or IB is less clear. Unfortunately, a physical examination and conventional techniques are not sensitive enough to detect recurrent disease. MRI and CT can identify lymph-node metastases with a sensitivity of 30 80% [9,26], although MRI is commonly used to assess extracapsular extension for local D staging [27 29]. However, in prostate cancer the use of FDG-PET is of limited value because of its high excretion into urine. Results were particularly disappointing for the diagnosis of recurrences [14,30]. Alternative tracers, among which acetate and choline are promising to have considerable clinical potential, have been developed. At present 11 C- and 18 F-choline are the most used radiopharmaceuticals in prostate cancer [14]. In patients who have been treated with hormone therapy the level is likely to be suppressed and might not correlate well with A recent Medline search yielded 10 studies reporting on PET and PET/CT for re-staging prostate cancer; to our knowledge the present is the first report which correlated all PET/CT results with histology. Yoshida et al. [33] reported in a phase III study of only eight patients that [ 11 C]-choline PET is a useful and promising tool in re-staging prostate cancer after RP (five men) and RT (three). The mean (range) level was 5.3 (2.3 11)ng/mL. The results were positive in six of the eight patients; five results were verified by other imaging techniques. De Jong et al. [13] obtained positive findings in the re-staging of patients with prostate cancer using [ 11 C]-choline PET at levels of <5 ng/ml. Picchio et al. [12] compared [ 11 C]- choline PET and FDG-PET for re-staging prostate cancer in 100 patients. logical confirmation was not available except for some cases of local recurrence; the neoplastic nature of the lesions was strongly suspected also by conventional imaging at PET and 1 year later, and by the follow-up. They reported positive findings using PET in three patients, even at low levels of 1.2 ng/ml, but provided no data on numbers of patients. In the present study PET/CT was positive at levels of <1.5 ng/ml in seven of 13 patients, with positive histology in this range in nine patients. The remaining four patients had neither a positive histology nor a positive PET/CT, despite elevated levels, and therefore had an occult prostate cancer relapse. In the group of patients with levels of <2.5 ng/ml, the sensitivity of PET/CT and the positive predictive value were high (91% and 86%, respectively), whereas the specificity and the negative predictive value were relatively low, at 50% and 66%, respectively. Similar values were obtained for the total sample. Thus PET/CT seems to be good at detecting clinical recurrence, but fails to identify those with no evidence of recurrence; this explains why the overall accuracy was only 84%. JOURNAL COMPILION 2007 BJU INTERNIONAL 791

7 RINNAB ET AL., ng/ml at PET/CT PET/CT +ve logy +ve PET/CT ve logy ve <1.5 7/13 9/13 6/13 4/ /17 13/17 0/17 4/ /11 10/11 0/11 1/11 >5 9/9 8/9 0/9 1/9 TABLE 2 Comparison of category vs PET/CT and histology findings should be recommended at levels of <2.5 ng/ml. The results show that this technique can be used to detect recurrences responsible for an increasing level, and is complementary to conventional imaging techniques, but with the advantage of staging the disease in one step., ng/ml at PET/CT n n/n, ratio (95% CI) Sensitivity In the present study we used an integrated contrast-enhanced PET/CT, whereas the former studies only used conventional PET scanners [12,13,33] Although PET visualises localized relapses or metastases, it has a considerable rate of false-positive results, due to the lack of anatomical information. In integrated PET/CT, the focal uptake of choline can be more easily assigned to anatomical structures, resulting in a higher accuracy. We found no correlation between the six negative PET/CT results and the Gleason score; the mean (median, range) level before PET/CT was 0.96 (1.1, ) ng/ml. Two of the six patients with a negative PET/CT result had a positive histology after targeted surgery/ biopsy. There are two possible reasons for false-negative cases: first, the metastases could be too small for detection; second, it could be explained by a blockage of choline uptake. Various nomograms exist to estimate the likelihood of a recurrence after local therapy [34]. There is also a need for nomograms that estimate the likelihood of treatment-related morbidity (e.g. urinary incontinence and erectile dysfunction). However, nomograms were developed to identify patients at high risk of having disease progression after RP, EBRT or IB, and they are useful for counselling patients. However, nomograms are far from perfect and cannot be applied to all men with prostate cancer. Ideally imaging methods could add information to existing clinical nomograms. The limitations of the present study are the relatively few patients and their Specificity < /9, 0.78 ( ) 4/4, 1.0 ( ) /13, 1.00 ( ) 0/4, 0 (0 0.60) < /22, 0.91 ( ) 4/8, 0.5 ( ) /10, 1.00 ( ) 0/1, 0 (0 1) >5 9 8/8, 1.00 ( ) 0/1, 0 (0 1) Total 50 38/40, 0.95 ( ) 4/10, 0.40 ( ) TABLE 3 The sensitivity and specificity of PET/CT in each category heterogeneous distribution. We also recognize that the highest clinical value would be given, e.g. to patients after RP and a level of <1.0 ng/ml, due to adjuvant treatment options. This aspect could not be further evaluated with so few patients in this setting. Most likely this needs to be assessed in a multicentre study design. Finally, the comparison with other imaging techniques and proof of a survival benefit for the patients are pending. Based on the present results we recommend using [ 11 C]-choline PET/CT, even at levels of <2.5 ng/ml, because early detection of recurrence can be an advantage for patients with increasing levels. In local recurrence after RP, RT with curative intent can be offered. Early radiation treatment, at a level of < ng/ml, has been shown to achieve better results. To date, imaging studies with CT, MRI or FDG-PET have failed to identify a small recurrence with high sensitivity and specificity. The present results showed that local recurrence or distant metastasis could be detected by PET/CT with an overall sensitivity and positive predictive value of 95% and 86%. The overall specificity was 40% with a negative predictive value of 67%. These results agree with those of other groups [12,13,33]. In the present study [ 11 C]-choline PET/CT was a valid and useful method for detecting recurrent prostate cancer. In conclusion, [ 11 C]-choline-PET/CT seems to be useful for re-staging men with prostate cancer and increasing serum levels, and CONFLICT OF INTEREST The authors state that there is no conflict of interest. REFERENCES 1 Morgan WR, Bergstralh EJ, Zincke H. Long-term evaluation of radical prostatectomy as treatment for clinical stage C (T3) prostate cancer. Urology 1993; 41: Bott SR. Management of recurrent disease after radical prostatectomy. Prostate Cancer Prostatic Dis 2004; 7: Stamey TA, Ferrari MK, Schmid HP. The value of serial prostate specific antigen determinations 5 years after radiotherapy: steeply increasing values characterize 80% of patients. J Urol 1993; 150: Boccon-Gibod L, Djavan WB, Hammerer P et al. Management of prostate-specific antigen relapse in prostate cancer: a European Consensus. Int J Clin Pract 2004; 58: Guedea F, Aguilo F, Polo A et al. 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