Choline PET/CT for imaging prostate cancer: an update

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1 DOI /s REVIEW ARTICLE Choline PET/CT for imaging prostate cancer: an update Kazuhiro Kitajima Robert C. Murphy Mark A. Nathan Received: 12 February 2013 / Accepted: 16 April 2013 Ó The Japanese Society of Nuclear Medicine 2013 Abstract Whole-body positron emission tomography/ computed tomography (PET/CT) with [ 11 C]- and [ 18 F]- labeled choline derivates has emerged as a promising molecular imaging modality for the evaluation of prostate cancer. 11 C- and 18 F-choline PET/CT are used successfully for restaging prostate cancer in patients with biochemical recurrence of disease after definitive therapy, especially when the serum prostate-specific antigen level is [1.0 ng/ ml. 11 C- and 18 F-choline PET/CT have more limited roles for the initial staging of prostate cancer and for the detection of tiny lymph node metastases due to the low spatial resolution inherent to PET. Overall, these modalities are most useful in patients with a high pre-test suspicion of metastatic disease. The following is a review of the current clinical roles of 11 C- and 18 F-choline PET/CT in the management of prostate cancer. Keywords Prostate cancer Staging Restaging 11 C-choline 18 F-fluorocholine Positron emission tomography/computed tomography (PET/CT) Introduction Prostate cancer is the most common malignancy of nonskin origin among males and the second leading cause of K. Kitajima (&) Department of Radiology, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe , Japan kitajima@med.kobe-u.ac.jp; kazu @yahoo.co.jp R. C. Murphy M. A. Nathan Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA cancer mortality among men in most Western countries [1]. Management of newly diagnosed patients strongly depends on accurate initial assessment of the tumor (T) stage, presence or absence of regional lymph node (N) involvement, and the presence or absence of non-regional metastases (M). This is accomplished through data acquired by physical examination, biochemical assessment, non-invasive imaging, the use of clinical risk tables, and surgery [2]. Multiple options are available for the treatment of disease confined to the prostate gland, such as radical prostatectomy (RP), external-beam radiation therapy (RT), brachytherapy, and cryoablation [3]. Some men choose observation only. In general, men with metastatic disease at initial diagnosis undergo systemic androgen-deprivation therapy. A persistently rising serum prostate-specific antigen (PSA) level (biochemical disease recurrence) is typically the first sign of relapse in patients previously treated for prostate cancer. Therapeutic management depends on whether the recurrence is local, regional, or distant. Local and regional recurrence can often be managed with surgery and/or radiation. Distant recurrence, most often bone and node metastases, requires systemic therapy with or without palliative radiation to painful skeletal metastases. Imaging plays a primary role in the restaging of prostate cancer, and a combination of computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy is the standard regimen used. Choline positron emission tomography/computed tomography (PET/CT) (the subject of this review) is now commonly performed in certain European centers and is becoming the preferred method for restaging in some of these locations. Integrated PET/CT allows for the acquisition of both metabolic and anatomic imaging data using a single device in a single diagnostic session. In just a few years, this

2 technique has become central to clinical oncologic imaging. The glucose analog, 18 F-fluorodeoxyglucose ( 18 F- FDG), is the most commonly used radiopharmaceutical for clinical PET/CT. Many cancers have high glucose avidity and are visible on PET scans as areas of concentrated 18 F- FDG uptake. The addition of co-registered CT allows for excellent anatomic localization of FDG avid disease and for the differentiation of abnormal areas of 18 F-FDG concentration from potential confounders such as physiologic bowel activity. Certain malignancies such as pancreatic islet cell cancers, carcinoid tumors, and well-differentiated renal cell cancers typically do not have significant 18 F-FDG uptake and are thus poorly visualized on PET scans using this radiotracer. Unfortunately, the majority of prostate cancers fall into this category; this makes 18 F-FDG PET of limited use for imaging management. In addition, 18 F-FDG is normally highly concentrated in the urine, and pelvic pathology can be obscured or mimicked by urinary radiotracer activity (particularly in thin patients). For prostate carcinoma, this can be particularly problematic when urine activity is present in the prostatic urethra or in a transurethral prostatectomy defect. Such limitations continue to fuel the search for alternative PET agents for this highly prevalent disease. 11 C- and 18 F-choline have emerged as the most promising PET agents for the evaluation of prostate cancer. Hara et al. [4] first described the use of 11 C-choline PET for the evaluation of prostate cancer. A major advantage of this radiotracer is its rapid blood clearance (*5 min) and rapid uptake within prostate tissue (3 5 min). This allows for early imaging prior to excretion of the radiotracer into the urine. Thus, the pelvis can be viewed before significant excretory activity becomes a potential confounder. Unfortunately, the 20 min half-life of 11 C restricts the use of 11 C- choline to centers with an onsite cyclotron. In contrast, the longer half-life of 18 F(*110 min) allows transportation of 18 F-fluorocholine to centers without a cyclotron. In addition, the shorter positron range of 18 F over 11 C produces slightly higher image quality [5]. However, 18 F-choline has higher urinary excretion than 11 C-choline [5]. Prostate cancer cells show increased phosphocholine levels and elevated turnover of the cell membrane phospholipid, phosphatidylcholine [6]. A high-affinity transporter system imports choline into the cell where it is phosphorylated by choline kinase in the first step of the Kennedy cycle. Key enzymes in choline metabolism, such as choline kinase, are up-regulated in prostate cancers. This Table 1 Summary of the literature of studies using 11 C- and 18 F-choline PET/CT in the evaluation of detecting untreated prostate cancer Tracer Authors Years N PSA, median (range) (ng/ml) Sen (%) Spe (%) Acc (%) Modality 11 C-Cho Farsad et al. [7] (2 70) PET/CT Yamaguchi et al. [8] ( ) 100 PET 60 MRI (T2WI) 65 MRS Martorana et al. [9] (2.5 70) PET/CT TRUS Reske et al. [10] ( ) PET/CT Scher et al. [11] ( ) PET (25) and PET/CT (33) Testa et al. [12] (2.5 70) PET/CT MRI (T2WI) MRS Giovacchini et al. [13] (0.2 33) PET/CT Watanabe et al. [14] ( ) PET F-FDG PET MRI (T2WI? DCEI) Van den Bergh et al. [15] ( ) PET/CT MRI (T2WI) 18 F-FCho Kwee et al. [20] ( ) PET Husarik et al. [21] ( ) 98 PET/CT Kwee et al. [22] ( ) PET Igerc et al. [23] ( ) PET/CT Cho choline, FCho fluorocholine, N number, PSA prostatic specific antigen, Sen sensitivity, Spe specificity, Acc accuracy, MRI magnetic resonance imaging, T2WI T2-weighted imaging, MRS magnetic resonance spectroscopy, TRUS transrectal ultrasound, 18 F-FDG 18 F-fluorodeoxyglucose, DCEI dynamic contrast-enhanced imaging

3 b Fig. 1 A 63-year-old man with prostate cancer. PSA level of 12.6 ng/ml. a T2-weighted MRI obtained with an endorectal coil shows a cm mass in the left peripheral zone (arrow) which extends through the prostate capsule and involves the left seminal vesicle and the left neurovascular bundle. b 11 C-choline PET/CT and c CT at the almost same level as a. There is intense 11 C-choline uptake by the mass. The MRI is superior to the PET/CT for assessment of the integrity of the prostate capsule is likely the primary reason prostate cancers concentrate 11 C- and 18 F-choline. This article serves to provide an in-depth review of the roles of 11 C- and 18 F-choline for the staging and restaging of prostate cancer. The usefulness and limitations of 11 C- and 18 F-choline PET/CT compared to conventional imaging (MRI, CT, and bone scintigraphy) are discussed. 11 C-choline and 18 F-fluorocholine PET/CT for local disease evaluation The local detection of untreated prostate cancer by 11 C- choline PET/CT is reported to have a sensitivity of %, a specificity of %, and an accuracy of % in patient-based analyses (Table 1) [7 15]. Sensitivity is related to lesion size. Martorana and colleagues [9] demonstrated that sensitivity is 83 % for lesions [5 mm and only 4 % for lesions \5 mm. This is not unexpected since the spatial resolution of clinical PET scanners is about 5 mm. In addition, the partial volume effect could be another cause for failure to detect small lesions [16]. Reduced specificity for prostate cancer is related to confounding uptake by high-grade prostatic intraepithelial neoplasia, prostatitis, benign prostatic hypertrophy, urinary excreted activity in the base of the bladder or urethra, and by normal tissues surrounding the prostate gland (mainly pelvic sling musculature and rectum) [17]. With a few exceptions [9, 18], most groups have not found a significant correlation between 11 C-choline uptake by localized prostate cancer and serum PSA levels, Gleason score, or tumor grade [7, 8, 10, 15, 19]. The local detection of untreated prostate cancer by 18 F- fluorocholine PET/CT is reported to have a sensitivity of % and a specificity of % in patient-based analyses (Table 1) [20 23]. Kwee and colleagues [22] showed that 18 F-fluorocholine PET/CT reliably localizes dominant areas of prostate malignancy as determined by subsequent step-section pathologic analysis of prostate glands removed from 15 men with prostate cancer. Beheshti and colleagues [24] imaged 130 prostate cancer patients determined to be at intermediate and high risk for extracapsular disease and showed good correlation (r = 0.68; p \ 0.001) between sextants with maximal 18 F-fluorocholine uptake prior to surgery and post-prostatectomy sextants

4 with maximal tumor burden. These authors also found no significant correlation between the maximum standard uptake values (SUV max) of 18 F-fluorocholine localization in the prostate cancers and the serum PSA levels (p = 0.10) or Gleason scores (p = 0.28). MRI using T2-weighted imaging (T2WI) combined with dynamic contrast-enhanced imaging (DCEI) shows superior sensitivity and specificity for initial local assessment of prostate cancer compared to 11 C-choline PET/CT [8, 12, 14].Forexample,inastudybyMartorana et al. [9] sensitivity for the detection of extracapsular extension was 63 % for MRI and 22 % for 11 C-choline PET/CT. Concerning localized prostate cancer recurrence, Castelluci et al. [25] showed 11 C-choline PET/CT to have a sensitivity of 54 % in patients with a PSA \1.5 ng/ml following RP. 11 C-choline PET/CT was able to detect biopsy proven localized prostate cancer recurrence in 70 % of patients in a study by Reske and colleagues [26]. Panebianco et al. [27] evaluated 84 post-rp patients with suspected local disease recurrence and compared endorectal coil dynamic contrast-enhanced MRI/magnetic resonance spectroscopy (MRS) to 18 F-fluorocholine PET/CT; receiver operating characteristics (ROC) analysis showed the area under the curve to be for MRI and for PET/CT. Vees et al. [28] examined 11 post- RP patients with relapsed PSA levels \0.8 ng/ml using endorectal coil MRI and 18 F-fluorocholine PET/CT and found the sensitivity of MRI to be 89 % compared to 60 % for PET/CT. Summary MRI using an endorectal coil remains the optimal imaging method for evaluating the prostate gland and prostate bed for local primary and local recurrent prostate cancer. In addition, MRI is superior for the detection of imaging factors that would alter prognosis or management such as Fig. 2 A 71-year-old man with local recurrence of prostate cancer 34 months after radical prostatectomy. PSA level of 1.3 ng/ml. a Axial T2-weighted MRI obtained with an endorectal coil shows a mm nodule (arrow) at the left lateral bladder neck near the vesicourethral anastomosis suggesting local recurrence. b Apparent diffusion coefficient (ADC) map at the same level as a shows the same lesion as a focus of low signal intensity (arrow). c Dynamic contrast-enhanced MRI at the same level as a shows early and strong enhancement of the nodule (arrow) confirming the presence of local recurrence. d 11 C-choline PET/CT image at the almost same level as a shows moderate 11 C-choline uptake at the left lateral bladder neck (arrow) indicating local recurrence

5 subtle extracapsular invasion and seminal vesicle invasion. Figure 1 shows a prostate cancer patient initially staged with 11 C-choline PET/CT and endorectal coil MRI. Figures 2 and 3 are examples of multiparametric MRI and 11 C-choline PET/CT used to assess locally recurrent prostate cancer. 11 C-choline and 18 F-fluorocholine PET/CT for detection of lymph node metastases Two studies reported sensitivities of 60 and 78 % and specificities of 82 and 98 % for 11 C-choline PET/CT on a perpatient basis, and sensitivities of 41 and 52 % and specificities of 97 and 98 % on a per lesion basis, for the detection of pathologically confirmed metastatic pelvic lymph nodes in patients with untreated prostate cancer (Table 2) [29, 30]. In patients at high clinical risk for lymph node metastases, but who were negative by contrast-enhanced CT, Budiharto and colleagues [31] showed 11 C choline PET/CT to have a per patient sensitivity of 19 % and specificity of 95 %, and a per lesion sensitivity of 9 % and specificity of 99 %, for the detection of metastatic lymph nodes. The sensitivity of 11 C choline PET/CT for nodal prostate cancer metastases appears to be related to the sizes of pathologic nodes. Two groups [29, 30] showed a 0 % detection rate for nodes \2 mm in size, % detection for mm nodes, % detection for mm nodes, and % detection for nodes measuring 10 mm and larger. The reported diagnostic accuracy of 18 F-fluorocholine PET/CT also varies (Table 2)[21, 24, 32 34]. In one study, the per patient sensitivity and specificity were 45 and 96 % in 130 intermediate and high-risk prostate cancer patients who underwent RP and pelvic node dissection (912 nodes total) [24]; the sensitivity improved to 66 % and the specificity remained at 96 % when only lymph nodes 5 mm or greater were considered. The per patient sensitivity and specificity were 73 and 88 % in another study involving 210 intermediate and high-risk patients who underwent RP and pelvic node dissection [34]; the per node sensitivity and specificity were 56 and 94 %. Scattoni and colleagues [35] evaluated 11 C-choline PET/ CT for the evaluation of recurrent prostate cancer in pelvic and retroperitoneal lymph nodes in 25 patients following RP and reported a lesion-based sensitivity, specificity, and Fig. 3 An 80-year-old man with local recurrence of prostate cancer 24 months after completion of external-beam radiation therapy. PSA level of 5.3 ng/ml. a Axial T2-weighted MRI obtained with an endorectal coil shows diffusely low signal intensity of the prostate with loss of normal zonal anatomy. No suspicious morphologic mass is evident. b Dynamic contrast-enhanced MRI at the same level as a shows an enhancing area in the right anterior side of the transition zone (arrow) suggesting recurrent prostate cancer. c ADC map at the same level shows the lesion (arrow) as a focus of low signal intensity confirming presence of recurrent prostate cancer. d 11 C-choline PET/ CT image and e CT image at the almost same level as a. There is intense 11 C-choline uptake in the right anterior side of the transition zone (arrow) suggesting local recurrence

6 Table 2 Summary of the literature of studies using 11 C- and 18 F-choline PET/CT in the evaluation of pelvic lymph node staging in untreated prostate cancer Tracer Authors Years N PSA, median (range) (ng/ml) Sen (%) Spe (%) Analysis 11 C-Cho Schiavina et al. [29] (0.6 70) Patient-based Node-based Contractor et al. [30] ( ) Patient-based Node-based Budiharto et al. [31] ( ) Patient-based 9 99 Node-based 18 F-FCho Hacker et al. [32] ( ) Patient-based Husarik et al. [21] (0.6*162) Patient-based Node-based Steuber et al. [33] (8.1 27) Node-based Beheshti et al. [24] ( ) Patient-based Poulsen et al. [34] (1 108) Patient-based Node-based Cho choline, FCho fluorocholine, N number, PSA prostatic specific antigen, Sen sensitivity, Spe specificity Fig. 4 A 60-year-old man with pathologically proven lymph node c metastasis of prostate cancer after radical prostatectomy. PSA level of 3.9 ng/ml. a 11 C-choline PET/CT image and b CT image show a tiny right external iliac lymph node with intense 11 C-choline uptake (arrow) suggesting lymph node metastasis despite its small size accuracy of 64, 90, and 77 %, and a patient-based sensitivity, specificity, and accuracy of 66, 100, and 92 %. Meta-analysis of CT and MRI data showed a pooled sensitivity of 39 % and a pooled specificity of 82 % [36]. Summary 11 C-choline and 18 F-fluorocholine PET/CT demonstrate better performance than conventional imaging for staging of locoregional lymph nodes. Unfortunately, PET/CT accuracy is not sufficient to replace pelvic nodal dissection for initial staging: the Achilles heel again appears to be the limited spatial resolution of PET/CT leading to reduced sensitivity for detecting small pathologic nodes. On the other hand, choline PET/CT is recommended for the restaging of lymph nodes since there is currently no other better test. Other techniques, such as MRI using ultrasmall superparamagnetic iron oxide (USPIO), may provide better diagnostic accuracy after further refinement [37]. Figure 4 shows an example of 11 C-choline PET/CT for restaging nodal recurrence in prostate cancer. 11 C-choline and 18 F-fluorocholine PET/CT for detection of skeletal metastases Using 18 F-fluorocholine PET/CT, Poulsen and colleagues [34] foundbonemetastasesin18of210untreatedintermediateand high-risk prostate cancer patients. Likewise, Beheshti et al. [24] found 43 skeletal metastases in 13 of 130 intermediate and high-risk untreated prostate cancer patients also using 18 F-fluorocholine PET/CT; 2 of the 13 patients were negative by traditional bone scintigraphy. Picchio et al. [38] directly

7 Fig. 5 A 67-year-old man with bone metastasis of prostate cancer after radical prostatectomy. PSA level of 2.5 ng/ml. a 11 C-choline PET/CT image and b CT image show 11 C-choline avid sclerotic abnormality in the T2 vertebral body consistent with a skeletal metastasis compared 11 C-choline PET/CT and bone scintigraphy for detection of bone metastasis in 78 patients with PSA progression after primary treatment, and demonstrated that 11 C-choline PET/CT exhibited a lower sensitivity but a higher specificity than those of bone scintigraphy. Patient-based sensitivity, specificity, and accuracy of 11 C-choline PET/CT were 89, , and %, respectively, and those corresponding figures of bone scintigraphy were , , and %, respectively. Osteoblastic lesions identified by bone scintigraphy once in a while show no choline uptake (falsenegative PET result) [38, 39], and therefore it is important to find any osteoblastic change on CT part of PET/CT. Beheshti et al. [40] showed a sensitivity, specificity, and accuracy of 79, 97, and 84 % for 18 F-fluorocholine PET/ CT detection of bone metastases in 70 patients undergoing either initial staging or restaging. These authors also noted that choline activity tended to vary inversely with the degree of lesion sclerosis; the SUVmax for lytic lesions was 11 ± 3.2, and the SUVmax for sclerotic lesions was 7.8 ± 3.0. The lesions with densest scleroses on CT ([825 Hounsfield Units) had no choline activity and were mainly observed in patients being treated with hormone therapy, thus suggesting healed bone metastases. Summary Choline PET/CT is an optimal imaging modality for the assessment of viable prostate cancer burden in the skeleton. Table 3 Summary of the literature of studies using 11 C- and 18 F-choline PET/CT in the evaluation of restaging prostate cancer Tracer Authors Years Site N (therapy) PSA, mean (range) (ng/ml) Sen (%) Spe (%) Acc (%) 11 C-Cho Rinnab et al. [41] 2007 LR, LNM, BM 50 (RP 40, brachy 7, RT 3) 2.42 ( ) Scattoni et al. [35] 2007 LNM 25 (RP 25) 1.98 ( ) Krause et al. [42] 2008 LR, LNM, BM 63 (RP 42, RT 21) 2.15 (0.2 39) 56 Reske et al. [26] 2008 LR 46 (RP 46) 2.0 ( ) Rinnab et al. [43] 2009 LR, LNM, BM 41 (RP 41) 2.1 ( ) Richter et al. [45] 2010 LR, LNM, BM 73 (RP 49, RT 24) 2.9 ( ) 61 Giovacchini et al. [46] 2010 LR, LNM, BM 358 (RP 358) 1.27 ( ) Breeuwsma et al. [47] 2010 LR, LNM, BM 80 (RT 80) 9.1 ( ) Picchio et al. [38] 2012 BM 78 (RP 66, RT 12) 2.4 ( ) F-FCho Schmid et al. [48] 2005 LR, LNM, BM 9 (RP 8, RT 1) 14.1 ( ) 100 Cimitan et al. [49] 2006 LR, LNM, BM 100 (RP 58, RT 21, AT 21) ( ) Heinisch et al. [50] 2006 LR, LNM, BM 17 (RP 15, RT 2) (\5) 41 Vees et al. [28] 2007 LR 10 (RP 10) 0.35 ( ) 60 Husarik et al. [21] 2008 LR, LNM, BM 68 (RP 47, RT 17) (36 100) 86 Beheshti et al. [40] 2009 BM 70 (pre 32, post 38) 39.7 ( ) Schillaci et al. [51] 2012 LR, LNM, BM 49 (RP 49) 4.13 ( ) Kwee et al. [52] 2012 LR, LNM, BM 50 (RP 28, RT 13, brachy 9) 5.2 ( ) 62 Cho choline, FCho fluorocholine, N number, PSA prostatic specific antigen, Sen sensitivity, Spe specificity, Acc accuracy, LR local recurrence, LNM lymph node metastasis, BM bone metastasis, RP radical prostatectomy, Brachy brachytherapy, RT external-beam radiotherapy, AT androgen-deprivation therapy, Pre pre-therapy, Post post-therapy

8 Whether bone scintigraphy could be omitted or not has not been clarified yet. Figure 5 shows an example of 11 C- choline PET/CT for restaging skeletal metastasis in prostate cancer. 11 C-choline and 18 F-fluorocholine PET/CT-overall performance for the detection of prostate cancer recurrence 11 C-choline PET/CT is reported to have a sensitivity of %, a specificity of %, and an accuracy of % for restaging prostate cancer on a per-patient basis (Table 3) [25, 26, 35, 38, 41 43, 45 47]. The sensitivity is dependent on PSA level. In 190 patients previously treated with RP, Castelluci and colleagues [44] observed that detection of recurrent disease by 11 C-choline PET/CT was 19 % for a PSA\1 ng/ml, 25 % for a PSA of 1 2 ng/ ml, 41 % for a PSA of 2 5 ng/ml, and 67 % for a PSA [5 ng/ml. ROC analysis showed an optimal PSA of 2.43 ng/ml (sensitivity 73 %, specificity 69 %, area under the curve 0.76) for disease detection. Giovacchini et al. [46] found that 11 C-choline PET/CT had a patient-based sensitivity of 85 %, specificity of 93 %, and accuracy of 89 % for the detection of recurrent prostate cancer in 358 previously treated patients. They noted that the percentage of positive scans was 19 % for a PSA of ng/ml, 46 % for a PSA 1 3 ng/ml, and 82 % for a PSA [3 ng/ ml. The optimal PSA level was 1.4 ng/ml (sensitivity 73 %, specificity 72 %). Advanced age, initial pathological stage, and prior biochemical failure were associated with an increased likelihood of a positive scan. Castelluci et al. [25] found that 11 C-choline PET/CT was positive in almost one-third (28 %) of 102 patients who had only a slight PSA increase (\1.5 ng/ml). Seven patients had local recurrence, 13 patients had bone metastases, and 9 patients had lymph node metastases. 18 F-fluorocholine PET/CT is reported to have a sensitivity of %, a specificity of %, and an accuracy of % for restaging prostate cancer on a per-patient basis (Table 3) [21, 28, 40, 48 52]. Pelosi and colleagues [53] assessed 56 patients with prior RP and showed scan detection rates of 20 % for a PSA\1 ng/ml, 44 % for a PSA of 1 5 ng/ml, and 82 % for a PSA[5 ng/ ml. Schillaci et al. [51] examined 49 patients with prior RP and showed scan detection rates of 20 % for a PSA\1 ng/ ml, 55 % for a PSA of 1 2 ng/ml, 80 % for a PSA of 2 4 ng/ml, and 87 % for a PSA [4 ng/ml. ROC analysis on 82 patients by Graute et al. [54] suggested an optimal PSA of 1.74 ng/ml for imaging disease (82 % sensitivity, 74 % specificity, area under the ROC curve 0.818). Ceci et al. [55] clarified 11 C-choline PET/CT was able to detect relapsed disease in a large study of 157 patients with hormone-resistant prostate cancer during hormone therapy and suggested that hormone therapy withdrawal before performing 11 C-choline PET/CT scan may not be necessary for restaging. Kwee et al. [56] demonstrated that tissue lesions measurable by response evaluation criteria in solid tumors (RECIST) were found on the basis of increased 18 F-fluorocholine at PET/CT scans in 14 of 30 patients (47 %) with hormone-refractory prostate cancer and comparisons with RECIST appear feasible for evaluations of 18 F-fluorocholine PET/CT as a therapeutic response marker for hormone-refractory prostate cancer. Summary Choline PET/CT appears to be a reasonably sensitive and specific means by which to restage prostate cancer, particularly as the PSA becomes significantly elevated. Conclusion Initial staging In the era of PSA testing, the majority of newly diagnosed prostate cancer patients have disease localized to the pelvis. In this population, some of the most important prognostic factors include the Gleason score and whether or not the cancer has spread beyond the prostate capsule. Saturation biopsy is needed to establish the pre-therapy Gleason score. MRI using an endorectal coil excels at determining the direct extracapsular spread of tumor into periprostatic tissues. Surgery remains the gold standard method to initially stage pelvic lymph nodes. As such, choline PET/CT currently has no role for the initial workup of the vast majority of men with newly diagnosed prostate cancer. However, choline PET/CT may be useful in the minority of newly diagnosed patients with high clinical suspicion of distant metastatic disease (e.g., serum PSA [20 ng/ml, Gleason scores of 8 10, locally advanced tumor by palpation and/or MRI) [24, 34]. In those situations, it would be highly desirable to identify those men with distant disease before they are exposed to the morbidity of localized therapies that may not be beneficial. Beheshti et al. [24] estimated that the results of pre-treatment 18 F-fluorocholine PET/CT would result in a therapy change in 20 % of their high-risk study patients. Restaging Choline PET/CT is a powerful tool for the restaging of biochemically recurrent prostate cancer, particularly for those patients in whom standard imaging (CT, MRI and

9 bone scan) has failed to identify the site of recurrence. In the authors experience at Mayo Clinic, this sub-select group of patients frequently has one or more lymph node metastases in the pelvis that are normal in size by anatomic imaging; alternatively, one or more non-sclerotic skeletal metastases are identified that are beyond the field of view of the pelvic MRI [17]. Soyka et al. [57] observed that the results of 18 F-fluorocholine PET/CT caused a change in the treatment plan for 75 of 156 patients (48 %) with recurrent prostate cancer (110 had prior RP, 39 had prior RT, and 7 had prior combined RP and RT). As discussed above, the chance that a choline PET/CT scan will be positive is directly related to the PSA level at the time of the scan. The trigger PSA level for a restaging choline PET/CT scan in biochemically recurrent prostate cancer is controversial. A scan done at too low a PSA level has a high likelihood of negativity and exposes a patient to unnecessary radiation and cost; as noted above, at least 80 % choline PET scans are negative for PSA levels \1 ng/ml in the setting of biochemical recurrence [44, 46, 51, 52]. On the other hand, waiting for the PSA to rise to too high a level before doing a scan could delay salvage therapy unnecessarily. Picchio et al. [58] concluded that the routine use of 11 C-choline PET/CT to restage biochemically recurrent prostate cancer following RP could not be recommended for PSA levels \1 ng/ml. Unfortunately, there is even less guidance concerning the appropriate PSA level to trigger a scan in patients previously treated with pelvic radiation. Such patients almost always have a persistently detectable PSA, and recurrence is suggested by a steady rise over time. Conflict of interest All co-authors declare no financial support or relationship that may pose conflict of interest. References 1. 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