Nuclear Medicine and Biology 42 (2015) 340–348

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18

F-fluoromethylcholine or 18F-fluoroethylcholine pet for prostate cancer imaging: which is better? A literature revision Laura Evangelista a,⁎, Anna Rita Cervino a, Andrea Guttilla b, Fabio Zattoni b, Vincenzo Cuccurullo c, Luigi Mansi c a b c

Radiotherapy and Nuclear Medicine Unit, Oncological Institute of Veneto IOV-IRCCS, Padua, Italy Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Italy Nuclear Medicine, Second University of Naples, Napoli, Italy

a r t i c l e

i n f o

Article history: Received 6 October 2014 Received in revised form 22 December 2014 Accepted 28 December 2014 Keywords: Diagnostic accuracy Fluoethylcholine Fluoromethylcholine PET imaging Prostate cancer

a b s t r a c t Introduction: The present review was conceived for describing the differences in biodistribution and diagnostic performance of two types of 18 F-radiolabeled choline for positron emission tomography (PET) imaging in prostate cancer (PCa), such as fluoromethylcholine (FCH) and fluoroethylcholine (FEC). Materials and methods: A collection of published data about two radiopharmaceutical agents was made by using PubMed, Web of Knowledge databases and Trip Database, and then a critical revision was discussed. Results: FCH was injected in 338 and 1164 patients, while FEC was injected in 20 and 139 patients, respectively for basal staging and re-staging. The diagnostic performances of FCH and FEC for the detection of lymph node metastasis before the surgical approach are typically around 50% or less and between 0% and 39%, respectively. Conversely, both the tracers appear useful for the detection of recurrent PCa in case of increase in absolute PSA value or in case of high levels of PSA velocity and PSA doubling time (sensitivity ranged between 42.9% and 96% for FCH and between 62% and 85.7% for FEC). Conclusions: In according with the available information, FCH appears to be a more appropriate radiocompound as compared to FEC, although more comparative data are mandatory. A well designed and prospective trial for the evaluation of biokinetic data and diagnostic performance of both radiopharmaceutical agents seems essential. Advances in knowledge and implication for patient care: FCH seems to be an appropriate radiopharmaceutical agent as compared to FEC. Anyway both the radiocompounds are useful in the evaluation of recurrent disease in case of a serial increase in PSA value and their performance improves when a correct preparation and acquisition protocol is employed. © 2015 Elsevier Inc. All rights reserved.

1. Introduction The use of positron emission tomography (PET) tracers for the evaluation of urogenital diseases has been expanding in recent years, particularly for prostate cancer (PCa). Although Magnetic Resonance (MR) may also play a clinical role, radionuclide functional imaging has generated great interest, being able to surpass the limits of conventional imaging, such as computed tomography (CT) and bone scan (BS). Thus, it is gaining importance for both clinical management and drug development for PCa. The currently available PET tracers for PCa include 18 F-sodium fluoride ( 18 F-NaF), 11C-acetate, 11C-choline, and 18 F-choline. Interest in radiolabeled-choline tracers for differentiating and for localizing malignancies has been increasing, because phosphocholine (Pcho)

⁎ Corresponding author. Radiotherapy and Nuclear Medicine Unit, Veneto Institute of Oncology IOV-IRCCS, Gattamelata Street, 64 Padova, Italy. Tel.: +39 049 821 7997; fax: +39 049 821 2205. E-mail address: [email protected] (L. Evangelista). http://dx.doi.org/10.1016/j.nucmedbio.2014.12.019 0969-8051/© 2015 Elsevier Inc. All rights reserved.

accumulates in a variety of tumor cells, including PCa. Radiolabeledcholine analogs are entrapped by PCa cells by choline transporters and are intracellularly phosphorylated by choline kinase (CK), which is strongly associated with phospholipid metabolism [1–4] (Fig. 1). Both 11 C-choline and 18 F-radiolabeled-choline have been extensively used for imaging applications in PCa patients, mostly in Europe and Japan [5]; further growth has been recorded after the approval of production and use of 11C-choline for PET imaging in recurrent PCa by the US Food and Drug Administration, announced on September 2012 [6]. Current use of 11C-choline PET/CT in PCa patients has mainly been aimed at the early detection of disease recurrence, leading to a possible change in patient management. In particular, it has been shown to improve the assessment of disease spreading with respect to local and distant metastasis as well as bone involvement [7] and to avoid the futile use of radiotherapy in the prostatic bed, thus reducing the rate of related morbidity [8]. Nevertheless, the use of 11C-choline is not a widely available option because it has a short half-life of 20 min. This limit has stimulated the development of 18 F-labeled choline. The practical advantages of working with 18 F (e.g. its longer half-life that allows long-time storage and long-distance transportation; its shorter

L. Evangelista et al. / Nuclear Medicine and Biology 42 (2015) 340–348

positron range gives a quality of image with a slightly higher spatial resolution) led Hara et al. [9] to synthesize and to evaluate 2-[ 18 F] fluoroethyldimethyl-2-hydroxyethylammonium (FEC) as a choline analog. They demonstrated in vitro that FEC is incorporated into tumor cells by an active transport, then phosphorylated inside the cells yielding phosphoryl- 18 F-FEC and finally integrated into phospholipids. Later, Hara et al. [10] showed in vivo no difference between FEC uptake and 11 C-choline uptake in PCa. Some years later, DeGrado et al. [11] synthesized fluoromethyl-dimethyl-2-hydroxyethylammonium (fluorocholine or FCH). FCH differs from FEC by a single methylene group between the nitrogen atom and the carbon bearing the fluorine atom (Fig. 2); this small structural difference is associated with an FEC uptake reduction of 80% in PC-3 prostate cancer cells. Furthermore, whereas FCH showed equivalent in vitro phosphorylation with choline, FEC was more poorly phosphorylated by CK. DeGrado et al. [11] reported a steric hindrance of CK-catalyzed phosphorylation for analogs with fluorine containing substituents larger than the fluoromethyl group. As further information affecting pharmacokinetics, Uusijärvi et al. [12] demonstrated a different biodistribution of 18 F-choline between 0 and 1 h after injection in 4 patients with PCa recurrence after radical prostatectomy: the uptake decreases in kidneys and in spleen while it increases in liver, salivary glands and in the tumor [12]. In any case, the authors reported no clear information about the type of 18 Flabeled choline compound. In the present review, we have selectively collected and critically evaluated published articles in order to assess the differences between FEC and FCH PET/CT scans in PCa patients, in both acquisition protocols and diagnostic performance.

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2. Materials and methods 2.1. Literature research A computer literature search of studies on FCH and/or FEC PET or PET/CT in PCa patients performed between January 2000 and September 2014 was carried out. MEDLINE databases, such as Pubmed, Web of Knowledge and TripDatabase, were consulted using the following key words: “fluoromethylcholine” AND “prostate”; “fluoroethylcholine” AND “prostate”. Moreover, some limits were applied to the search strategy, such as species (human), article type (original articles, comparative studies, multicenter study) and language (English). MEDLINE research produced 78 scientific papers: in particular, 53 with “fluoromethylcholine”, of which 28 also contained “prostate”, and 25 with “fluoroethylcholine”, of which four also contained “prostate”. Abstracts, reviews, clinical reports and editor comments were excluded. The references of articles found in the literature search were also examined to find additional reports that met the inclusion criteria. Only 28 articles met the inclusion criteria (Table 1). In particular, 20 studies included PET or PET/CT with FCH, three with FEC and one study with both tracers. On the contrary, five studies did not specify what type of 18 F-labeled choline compound was injected, indifferently reporting the acronym FCH or FC. For information about the source of radiopharmaceutical, the investigators were contacted. Fig. 3 illustrates the flowchart of selected studies. PET or PET/CT was performed for initial staging, re-staging, treatment monitoring and treatment planning. In most cases, prospective studies were included (n = 19), and therefore approved by the local

Cell membrane

Choline Choline transporters

Cytoplasm

SP1

PI3K

GPC-PDE

RALGDS

CH K

HIF1

1-acylglycerophosphocholine

AP1

SP1

RAS

RALGDS

GP C

Choline

RAF

PLA 2

PCho RAF

CC T

RAF

PC-PLD SP1

RAF

RAS

PLA 2 CDPCho

PI3K

FA

ERK JNK

DAG CHPT 1

SREBP

Cell membrane

Nucleus

Fig. 1. Choline metabolic pathway.

Ptd Cho

342

L. Evangelista et al. / Nuclear Medicine and Biology 42 (2015) 340–348

OH 18F-fluorocholine (FCH)

18F

N+

18F

18F-fluoroetylcholine (FEC)

OH N+

Fig. 2. Chemical structures of fluoethylcholine and fluoromethylcholine.

ethical committees. The selected articles were published from 2006 to 2014. A total of 2147 PCa patients were included and all of them well tolerated 18 F-radiolabeled-choline without reporting adverse events. Five-hundred thirty six patients were at initial staging, and 1611 at restaging or at treatment planning. FCH was injected in 338 and 1164 patients, while FEC was injected in 20 and 139 patients, respectively for basal staging and re-staging. For the residual 383 patients, the type of 18 F-labeled choline was not well addressed (178 and 308 patients at initial staging and at re-staging of disease, respectively). 3. Results Each article was evaluated on the basis of the study population (number of patients, patient preparation, injection time, acquisition protocol) and the study design (prospective, retrospective and comparative). 3.1. FEC PET or PET/CT in clinical practice FEC PET was employed in four original papers [13–16]. Graute et al. [13] performed PET/CT scans both with FEC and with FCH in 82 PCa patients (n = 25 with FCH and n = 57 with FEC). The authors declared that both FC compounds showed similar in vivo properties. They demonstrated a detection recurrence rate of 62% for FEC/FCH PET/CT. Two papers [14,15] evaluated the accuracy of FEC PET/CT in the detection of lymph node metastases in PCa patients; while the paper of Würschmidt et al. [16] was related to the planning of radiation treatment. In particular, Tilki et al. [14] and Steuber et al. [15] did not find any data supporting the use of FEC PET/CT in clinical practice for lymph node evaluation. The authors reported a sensitivity of 0% and 39.7%, respectively. In particular, Tilki et al. [14] found that the sensitivity of FEC PET/CT for lymph node assessment was higher when PSA level was N2 ng/mL as compared to a PSA level b2 ng/mL (42.4% vs. 28.3%, respectively). Steuber et al. [15] showed that FEC PET/CT missed lesions with a diameter b 10 mm and reported that the potential disadvantages for FEC in lymph node detection are, firstly, elevated secretion into urinary system and, secondly, the shorter residence time in the blood that may limit their diffusion into poorly perfused areas. Finally, Würschmidt et al. [16] clearly demonstrated the efficacy of PET/CT with FEC in planning radiotherapy. 3.2. FCH PET or PET/CT in clinical practice Since 2006, 16 prospective studies were published about FCH PET/ CT: five of them enrolled a large sample of patients (from 100 to 250; [17–21]), while the residual studies considered a limited number of subjects (from 15 to 56; [22–26]). The prospective studies with the largest population (number ranged between 100 and 250 patients) were

authored by Poulsen et al. [17], Beheshti et al. [18,19], and Husarik et al. [20], who reported an overall sensitivity of FCH PET/CT for the detection of primary or recurrent PCa of 73.2%, 66%, 59.5% and 83% respectively, while Cimitan et al. [21] did not report any data about sensitivity. Poulsen et al. [17] and Beheshti et al. [18] focused their attention on initial lymph node evaluation, demonstrating conflicting results. According to the first study, FCH PET/CT was not ideal for the lymph node staging (sensitivity = 56.2%; specificity = 94%), while on the basis of the second report, FCH PET/CT was considered a sensitive instrument for lymph node detection (sensitivity = 66%). Husarik et al. [20] showed the highest overall sensitivity (n = 111 subjects, 86%) for the recurrence of disease but they agreed with the low sensitivity in detecting lymph node metastases at initial staging (sensitivity = 20%). Wetter et al. [22] demonstrated that FCH PET/MR gives the advantage of combining high resolution images, functional studies and metabolic/molecular imaging in PCa patients, but the data are still preliminary. Similar to the previous results, the analysis of small sample studies demonstrated some disagreements in sensitivity. Poulsen et al. [23] attributed high sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for patient-based lymph node staging (100%, 95%, 75%, and 100%, respectively) to FCH PET/CT, while Hacker et al. [24] demonstrated that FCH PET/CT missed lymph node detection in nine patients, due to the limitation of the scanner’s spatial resolution. Last year, Buchegger et al. [26] reported an excellent agreement between FCH and 11 C-acetate PET/CT in recurrent PCa patients, thus demonstrating that both the radiopharmaceutical agents are interchangeable. Moreover, Kwee et al. [25] showed a link between volumetric measurement of tumor choline activity and the prognosis of metastatic PCa. As clear evidence of the importance of the inclusion criteria in determining a different diagnostic accuracy, it is interesting to compare the two papers published, at different times, by Poulsen et al. [17,23]. In the paper published in 2010, the authors reported values of 100%, 95%, 75%, and 100%, respectively in sensitivity, specificity, PPV and NPV for patient-based lymph node staging when evaluating 25 consecutive males with newly diagnosed PCa (Gleason score N 6, and/or PSA N 10 ng/mL, and/ or T3 cancer). Completely different results derived by the same group when analyzing a wider population including 210 intermediate or high-risk patients [17]. Sensitivity, specificity, PPV, and NPV were 73.2%, 87.6%, 58.8% and 93.1%, respectively. Corresponding values for LN-based analyses were 56.2%, 94%, 40.2%, and 96.8%, respectively, discouraging a routine use of FCH for primary lymph node staging in patients with PCa. Only four retrospective studies were considered in the present review [27–30]. All of them evaluated the role of FCH PET/CT for the detection of disease relapse on the basis of biochemical recurrence after primary treatment. Marzola et al. [27] demonstrated a detection rate of 54% in 233 patients previously treated by radical prostatectomy, while a slightly higher detection rate (n = 50; 64%) was obtained by Hodolic et al. [30]. Henninger et al. [28] demonstrated a sensibility of 80% and 50% (n = 35 subjects), respectively, in relation to the concomitant administration of androgen deprivation treatment (ADT) and no administration, while Oprea-Lager et al. [29] did not report any data related on sensitivity. Finally, Schillaci et al. [31], Soyka et al. [32], Pinkawa et al. [33], and recently Kjölhede et al. [34] and Gacci et al. [35] described the utility of 18 F-choline in PCa patients, although they did not clearly mention fluoride-labeled choline. Contact with each author revealed that the source of radiopharmaceutical was FCH. Schillaci et al. [31] investigating the relationship between PSA kinetic and PET/CT detection rate after radical prostatectomy, found that the sensitivity of FCH PET/CT was higher in patients with a PSA doubling time (PSAdt) of ≤ 6 months and especially in those with a PSA velocity (PSAvel) of N2 ng/ml per year. Kjölhede et al. [34] reported a high specificity (value = 92%) of FCH in depicting lymph node metastases in patients with high-risk PCa. Gacci et al. [35] established a cut-off of b6 months and N6 ng/mL/ month, respectively for PSAdt and PSAvel for the prediction of a positive

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343

Table 1 Characteristics of selected studies. Authors, ref

Journals, year

Study design

N of 18 F-labeled patients choline and PET scanner

Dosage

PET protocol

Key point of literature

1

Kwee et al., 25

JNM, 2014

Prospective

30

FCH PET/CT

2.6 MBq/kg

WBS at 12–15 min

2

Kjölhede et al., 34

World J Urol, 2014

Prospective

112

Not specified choline PET/CTa

4 MBq/kg

WBS at 60–90 min

3

Buchegger et al., 26 Gacci et al., 35

EJNMMI, 2014 Scand J Urol

Prospective

23

FCH PET/CT

Longitudinal

103

Not specified choline PET/CTa

307 ± 16 MBq/kg –

Dyn + WBS at 45 min Dyn + WBS at 60 min

AfsharOromieh et al., 40 Beheshti et al., 19

EJNMMI, 2014

Retrospective and comparative Prospective

37

FCH vs. 68GaPSMA PET/CT

3 MBq/kg

WBS at 60 min

Metabolic metastatic indices, such as metabolic tumor activity and total lesion activity are independently associated with a poor prognosis in castrate resistant prostate cancer patients PET/CT with radiolabeled choline has low accuracy in excluding local lymph node dissemination of disease, but has high performance in depicting metastasis outside the template of an extended pelvic lymph node dissection. 11C-acetate and FCH have the same sensitivity for the detection of early recurrent PCa. PET/CT with fluorocholine is able to detect the presence of disease in case of an absolute change in PSA between two consecutive PET scans N5 ng/mL, a PSAdt b 6 months and a PSAvel N6 ng/mL/month 68Ga-PMSA was more sensitive than FCH PET/CT in detection of lesions even at low PSA levels.

250

FCH PETCT

4.07 MBq/kg

Dyn + WBS at 10 min

Wetter et al., 22 Marzola et al., 27

Invest Radiol, 2013 Clin Nucl Med, 2013

Prospective

15

FCH PET/MRI

N.A.

Retrospective

331

FCH PET/CT

3 MBq/kg

Tilki et al., 14

European Urology, 2013

Retrospective

56

FEC PET/CT

Mean dose: 300 MBq

10 Poulsen et al., 17

BUJI, 2012

Prospective

210

FCH PET/CT

4 MBq/kg

11 Graute et al., 13 12 Panebianco et al., 39

EJNMMI, 2012 E J Radiol, 2012

Prospective

82

Prospective and Comparative

84

FEC and FCH PET/CT FCH PET/CT

Mean dose: 300 MBq 185–259 MBq

13 Henninger et al., 28

Nucl Med Commun, 2012

Retrospective

35

FCH PET

4 MBq/kg

14 OpreaLager et al., 29

PLOS ONE, 2012

Retrospective

25

FCH PET/CT

4 MBq/kg

15 Schillaci et al., 31

EJNMMI, 2012

Not specified

49

Not specified PET/CTa

370 MBq

16 Soyka et al., [32]

EJNMMI, 2012

Retrospective

156

Not specified PET/CTa

200–300 MBq

17 Wurschmidt Radiation et al., 16 Oncol, 2011

Prospective

26

FEC PET/CT

5 MBq/kg

18 Hodolic, 30

Radiol Oncol, 2011

Retrospective

50

FCH PET/CT

200–300 MBq

19 Steuber et al., 15 20 Pinkawa et al., 33

EJC, 2010

Prospective

20

FEC PET/CT

300–400 MBq

Strahlenther Prospective Onkol, 2010

66

Not specified PET/CTa

178–355 MBq

4

5

6

7 8

9

JNM, 2013

Trigger PSA and ADT are the two significant predictors of FCH-positive PET lesions. ADT seems to not impair FCH uptake in hormone-refractory prostate cancer patients. WBS at PET/MRI has the advantage of combining high resolution prostate 150 min images, functional studies, and metabolic/molecular imaging. Early pelvis The recurrence detection rate using FCH PET/CT static scan increased with the increase in trigger PSA value, (5–10 min) + and even more in those patients presenting with WBS at fast PSAdt and fast PSAvel. Moreover FCH PET/CT 60 min can detect disease relapse in more than 50% of PCa patients with biochemical relapse and negative CI WBS at FEC PET/CT is not adequately accurate for the exact 60 min localization of all metastatic lymph nodes. One third of affected lymph nodes was missed; lower sensitivity was recorded for retroperitoneal region. WBS at FCH PET/CT is not ideal for primary lymph node 60 min staging due to its low sensitivity (73.2% and 56.2% per patient-based and per lesion-based analysis) WBS at It is most likely to reveal disease sites when PSA level 60 min exceeds 1.74 ng/ml after radical prostatectomy. WBS at FCH PET/CT shows low sensitivity in detection of local 60 min recurrence when PSA value is lower than 2 ng/mL. Conversely, DCEMR shows a higher diagnostic accuracy also for a PSA value ranged between 0.2 and 2.0 ng/mL. Dyn It is an accurate method for detection of recurrences (1 min) + after radical prostatectomy in patients in WBS at ADT even at PSA value b4 ng/dL. 60 min Dyn (after An acquisition at 30 min after iv may be a reasonable 2 min) + alternative for predicting the nodal status. In particular, WBS at reactive nodes remained detectable for 30 min after iv. 30 min WBS at The detection rate was directly related to the 45 min absolute PSA values; in particular, the sensitivity of PET is higher in patients with PSAdt ≤ 6mo and PSAvel N 2 ng/mL per year. Early WBS at 18 F-Choline PET/CT in patients with recurrent PCa 3–4 min + had an important impact on therapeutic strategy and WBS at 15– it was able to help determine an appropriate treatment 20 min in these patients. Dyn (after FEC PET/CT could be helpful in dose escalation in 2 min) + PCa patients allowing boost dose N 60 Gy to WBS at metastatic lymph nodal regions if PET/CT-planned 60–90 min intensity modulated and image guided radiotherapy is used. Dyn (0–5 FCH PET/CT seems to be a useful imaging modality min) + WBS in patients with PCa; it can demonstrate spread at 60 min of the disease preoperatively and detect the local recurrence after RP. WBS at FEC PET/CT cannot be recommended for routine clinical use 60 min to detect occult LN metastasis prior to initial treatment. WBS at Treatment planning with FCH PET/CT allows the definition of 60 min an integrated boost in nearly all PCa patients without considerably increasing of equivalent uniform dose and normal-tissue complication probability. (continued on next page)

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Table 1 (continued) Authors, ref

Journals, year

Study design

N of 18 F-labeled patients choline and PET scanner

Dosage

PET protocol

Key point of literature

21 McCarthy et al., 36

EJNMMI, 2011

Prospective

26

FCH PET and PET/CT

200 MBq

Early pelvis static scan (5 min) + WBS at 5 min

22 Beheshti et al., 18

Radiology, 2010

Prospective

130

FCH PET/CT

4.07 MBq/kg

23 Poulsen et al., 23

BJUI, 2010

Prospective

25

FCH PET/CT

4 MBq/kg

24 Beheshti et al., 37

EJNMMI, 2008

Prospective and Comparative

38

FCH PET/CT vs. Fluoride PET/CT

6–7 WBSs after 10 min + late WBS at 90–120 min WBS at 15 min + WBS at 60 min Dyn (8 min) + WBS at 8 min

FCH PET demonstrated an overall concordance of 81% with BS and CT and an accuracy of 96% on a lesion-based analysis. In particular, it appears to differentiate malignant nodal involvement from reactive change on CT images. It could be a useful one-stop diagnostic procedure especially in high risk patients to exclude distant metastases when surgical approach is planned.

25 Pelosi et al., 41

Radiol med, 2008

Retrospective

56

FCH PET/CT

26 Husarik et al., 20

EJNMMI, 2008

Prospective

111

FCH PET/CT

27 Vees et al., 38

BJUI, 2007

Prospective and Comparative

11

FCH PET/CT vs. 11C-Acetate PET/CT

28 Hacker et al., 24

J Urol, 2006

Prospective

20

FCH PET/CT

29 Cimitan et al., 21

EJNMMI, 2006

Prospective

100

FCH PET/CT

The authors support the use of FCH PET/CT as a tool for lymph nodes staging in intermediate or high risk patients. 4.07 MBq/kg FCH PET/CT was less sensitive than 18 F-fluoride PET/CT for the detection of bone metastases. FCH has the potential to become a one-stop diagnostic procedure in high risk patients in particular for early detection of bone marrow metastases. 185–259 MBq WBS at It is a useful diagnostic modality in patient with 60 min PSA N 5 ng/mL (sensitivity = 81,8%). The detection rate is very low in patients with PSA b1 ng/mL (sensitivity = 20%), while it increases when PSA value is between 1 and 5 ng/mL (sensitivity = 44%). 200 MBq WBS at 2 min It is not suitable for the initial staging of PCa due its low sensitivity (=20%) in detecting lymph nodes metastases. On the contrary, it is the most accurate imaging modality to identify the location of recurrent disease, even though the sensitivity rate is rater moderate (=86%). 214 ± 14 MBq WBS at 2 min Even if labeled PET/CT succeeded in detecting local or recurrent disease, it cannot yet be recommended as a standard diagnostic tool for early relapse or suspicious of persistent disease after surgery. It may be indicated for high risk patients for distant relapse after radiotherapy also at low PSA value. 4.07 MBq/kg Dyn (8 min) + FCH is not useful in searching for occult lymph node WBS at metastasis in clinically advanced PCa, while sentinel 8 min guided PLND allows the detection of even small lymph node disease. 3.7–4.07 MBq/kg WBS at 5– FCH could be useful in patients with high PSA levels 15 min + (N4 ng/mL) and/or poorly differentiated PCa (GS N7) WBS at 60– to exclude distant metastases when salvage local 200 min treatment is intended.

WBS: whole-body scan; Dyn = dynamic acquisition; ADT: anti-androgen therapy; PSAdt: PSA doubling time; PSAvel: PSA velocity; CI: conventional imaging; DCEMR: dynamic contrastenhanced magnetic resonance imaging; BS: bone scan; CT: computed tomography; GS: gleason score. a Later confirmed, by a contact with the authors, to be FCH.

FCH PET/CT scan. The other two studies were about 1) the clinical impact of FCH in 156 PCa patients by the administration of a questionnaire [32] and 2) the use of FCH as guide for intensity-modulated radiotherapy planning [33]. This latter study showed that 18 F-labeled choline has an important impact on therapeutic strategy allowing the definition of an integrated boost without a considerable increase of the equivalent uniform dose and normal tissue complication. 3.3. FCH PET/CT vs. other imaging modalities Five studies compared FCH PET/CT with other imaging modalities: five were prospective and one retrospective. In detail, McCarthy et al. [36], Beheshti et al. [37], Vees et al. [38] and Panebianco et al. [39] compared FCH PET/CT with BS and CT, 18 F-NaF and MR spectroscopic imaging, respectively; conversely, Afshar-Oromieh et al. [40] compared FCH with Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] ( 68Ga-PSMA). In particular, McCarthy et al. [36] concluded that FCH imaging may better differentiate malignant nodal involvement from reactive change on CT and that it is also useful as an adjunct to BS in equivocal cases (trauma or degenerative change); furthermore, they demonstrated an overall

concordance for PET/CT with BS and CT. Beheshti et al. [37] showed that FCH and 18 F-NaF PET/CT had the same sensitivity for detecting bone metastases in PCa patients. In particular, the sensitivity, specificity and accuracy of PET/CT in detection of bone metastasis in 38 patients were 74%, 99% and 85% for FCH and 81%, 93% and 86% for 18 F-NaF, respectively. The discordant cases (FCH positive and 18 F-NaF negative) according to the authors were probably due to bone marrow metastases without significant bone reaction and remodeling, suggesting therefore that FCH PET/CT has an advantage in the early detection of medullary bone metastases. Vees et al. [38] prospectively investigated the diagnostic potential both of 11C-acetate and FCH PET/CT in the early detection of PCa recurrence after surgery at PSA levels of b 1 ng/mL. They demonstrated a sensitivity of 60% and 66% for FCH PET/CT and 11C-acetate PET, respectively. Recently, a similar study was conducted by Buchegger et al. [26] that compared the sensitivity of 11C-Acetate and 18 F-choline PET/CT, reporting a great concordance for both the radiopharmaceutical agents in patients with early recurrence of PCa. As stated by the authors, this finding suggests that both tracers visualize similar features of PCa cells on either tracer integration in lipid synthesis or catabolic energy provision. Panebianco et al. [39] compared the sensitivity of FCH PET/

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345

N° patients and setting of disease

Inclusion criteria

Medline research

“Fluoromethylcholine” AND “Prostate” “Fluoroethylcholine” AND “Prostate N=78

“Fluoromethylcholine” N=53 “Fluoromethylcholine” AND “Prostate” N=28

“Fluoroethylcholine” N=25 “Fluoroethylcholine” AND “Prostate” N=4

“Fluoromethylcoline” and “Fluorethylcholine” and “Prostate” N=29

Fluomethylcholine PET or PET/CT N=20

Fluoroethylcholine PET or PET/CT N=3

Fluoroethyl and Fluoromethylcholine PET or PET/CT N=1

No specified 18Flabeled choline PET or PET/CT N=5

Total number of patients: n=2147 staging: n=536 Restaging: n=1.611

Staging: n=338 Restaging: n=1.164

Staging: n=20 Restaging: n=139

Staging: n=178 Restaging: n=308

Fig. 3. Flow-diagram of selected studies.

CT and proton MR imaging in early detection of local recurrence in prostatic bed, recruiting 84 patients with a rise of PSA value after prostatectomy. They showed that diagnostic accuracy of MR was also higher in patients with low PSA value (ranged between 0.2 ng/mL and 2 ng/mL), while FCH PET/CT should be used only in patients with a PSA value N 2.0 ng/mL. The paper of Afshar-Oromieh et al. [40] was based on the comparison between 68Ga-PSMA and FCH for the detection of biochemical recurrence. To this aim, 37 male patients, undergoing both FCH and 68Ga-PSMA PET/CT within a time window of 30 days, were enrolled. 68Ga-PSMA and FCH PET/CT detected 78 lesions in 32 patients and 56 lesions in 26 patients, respectively. All lesions detected by FCH PET/CT were also seen by 68Ga-PSMA PET/CT. Although not a comparative study, Schillaci et al. [31] secondarily compared the results of PET alone with those of the diagnostic fulldose CT scan with contrast agent. PET alone was positive in 31 of 49 patients (63.3%), with identification of local and systemic relapse in four and 27 patients, respectively. Of these 31 patients with a positive PET scan, 14 had a negative CT scan. Therefore, the combination of 18 F-choline PET and diagnostic CT could be favorable.

3.4. Diagnostic performance, androgen deprivation therapy and PSA levels Considering the variability in sensitivity of 18 F-labeled choline PET or PET/CT, we made a separate analysis of available published data in relation to ADT and PSA levels. No information about the variation of diagnostic accuracies for FEC PET and concomitant administration of hormonal therapy was available from the retrieved literature. Both Steuber et al. [15] and Tilki et al. [14] excluded from the enrollment all patients who underwent ADT at the time of PET imaging. Moreover, only one study found a higher PPV for patients undergoing FEC PET/CT with a PSA value N 2 ng/mL (95.5% vs. 50%, respectively in case of PSA N 2 ng/mL vs. PSA b 2 ng/mL) [14]. Cimitan et al. [21] and Beheshti et al. [19] investigated the ability of FCH in detecting recurrence of PCa on the basis of PSA levels. Cimitan et al. [21] reported that FCH could be useful in patients with high PSA level (N4 ng/mL) and/or a poorly differentiated PCa (GS N 7). Conversely, Beheshti et al. [19] demonstrated that FCH can provide useful information even in the case of PSA level = 0.5 ng/mL (n = 250; sensitivity = 59.5%), especially in intermediate and high-risk patients and in patients who are under ADT (n =

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100; 85%). Husarik et al. [20] recorded a slight difference in sensitivity according to the value of PSA and ongoing ADT. In particular, the authors found a sensitivity of 87% at PSA levels of N2 μg/l, of 86% in the case of PSA N 2 μg/l without ADT and 84% at PSA N 2 μg/l and concomitant ADT. Henninger et al. [28] found that the sensitivity of FCH PET was higher in the ADT patient group than the group without (n = 35; 80% vs. 50%, respectively). The detection rate of FCH during ADT was equal to 67% in the study by Marzola et al. [27], being higher than that for those who were not under ADT (value = 44%), while the detection rate described by Pelosi et al. [41] was slightly lower (42,9%; n = 24/ 56). The potential influence of ADT, such as LH-RH analogues or bicalutamide in patients who undergo 11C-choline or 18 F-labeled choline analogs PET/CT is still an unresolved matter in literature. Hara et al. [42] demonstrated in cultured PCa cells that androgen depletion markedly suppresses the uptake of labeled choline analogs in androgen-sensitive PCa cells, suggesting a potential underestimation of choline metabolism when imaging is performed during ADT [42]. Similar conclusions were achieved by Fuccio et al. [43]. But, the increase in PSA levels during ADT is a marker of castration-resistance of PCa cells. 3.5. 18 F-choline analogs: patient preparation and acquisition protocol 3.5.1. Patient preparation Schillaci et al. [31] described a detailed preparation for the execution of 18 F-labeled choline PET scan. In particular, the authors suggested the avoidance of foods containing high levels of choline, such as asparagus, beans, soya, carrots, egg yolk, lamb, pig and calf liver, skimmed milk, peanuts, peanut butter, peas, spinach, turnip and wheat products during the week before the examination. Moreover, a fasting of 6 h before the examination was required. Similarly, some authors suggested fasting for 4–6 h before examination [23,27,30] or not performing FCH PET scan in patients with blood glucose level higher than 200 ml/L [15]. Conversely, no information concerning the preparation of patients was reported by Häcker et al. [24], Behesthi et al. [18,19], Husarik et al. [20], Panebianco et al. [39], McCarthy et al. [36], Pelosi et al. [41] and Gacci et al. [35]. According to Henninger et al. [28] fasting was not essential to perform FCH PET/CT. Buchegger et al. [26] and Kjölhede et al. [34] required a fasting for at least 4 h before PET/CT images. Marzola et al. [27] suggested a fasting of 6 h and 1-h avoidance of liquids to reduce bladder filling before tracer injection. Kwee et al. [25] educated all patients to refrain from eating and drinking at least 3 h before undergoing PET. Schillaci et al. [31] well hydrated their patients using a saline solution by intravenous administration to reduce the pool of tracer in the kidney. Moreover, approximately 600 ml of contrast-containing solution was administered orally to opacify the intestinal loops. A similar approach was described by Steuber et al. [15]. Finally, in the study by Würschmidt et al. [16], between early and late images, to significantly reduce bladder activity, patients received 20 mg furosemide and were instructed to drink 1–1.5 L of water for forced diuresis. 3.5.2. Acquisition protocol FCH PET and/or PET/CT acquisition protocols for PCa imaging were not standardized. Most authors performed an early imaging acquisition to avoid interference from bladder tracer accumulation. Early static or dynamic acquisition of pelvis followed by a whole-body PET or PET/CT acquisition was proposed as alternative to whole body scan (WBS) alone, for optimizing the detection of distant disease. Early time points for imaging (0–15 min post-intravenous injection) and/or delayed imaging time points (30, 40, 45, 60, 90–120 and 65–200 min postintravenous injection) were also described in some collected articles. Details about PET protocols are listed in Table 1. As illustrated, patient preparation and protocol acquisitions were not relative to the employed compound, either FCH or FEC. Moreover, as clearly reported in Table 1, in the majority of studies with FEC, a WBS after 60 min from tracer injection was made. Conversely, a huge variability was registered for FCH, due to both the larger number of studies and the main purposes of trials.

4. Discussion Considering the available data in literature, FCH may be considered a compound with high performance and a very promising tracer in patients with PCa, finding even today a primary role, mainly in the restaging and/or the recruitment of patients undergoing salvage radiotherapy [44]. The chemical structure of FCH differs from FEC just for a single methylene group between the nitrogen atom and the carbon bearing the fluorine atom (Fig. 2). This chemical structure confers both an 80% decrease in uptake for FEC in PC-3 prostate cancer cells and a reduction in CKmediated phosphorylation process. Recently, Takesh [45] described the kinetic modeling of FCH PET/CT in PCa, reporting that choline transport (K1) is more important than phosphorylation (K3) and that it can be considered the key factor for choline uptake. Therefore, with both K1 and K3 being higher for FCH than FEC, vascularity and the function of CK are better evaluated by FCH. This latter concept could have both therapeutical and prognostical consequences. From the analysis of collected data, it emerged that FCH PET/CT is widely used in different countries (n = 1502/1932; 78%), although a great variability in PET protocols and in patient preparation can be identified. In some studies, a fasting of at least 4 h, a diet including food with low levels of choline the week before the scan, or defined hydrating conditions are required, although no data about the effects of food and hydration on the biodistribution of the radiolabeled choline are currently available. Also, PET protocol represents an important limitation for a rigorous comparison between different studies. Acquisition times may vary. In the studies examined, we found: dynamic image from 1 to 8 min after injection of tracer, a very early WBS (after 8 min), moderately early WBS (after 30 min), a conventional WBS (after 60 min) or late WBS (after 120 min). The variability of PET image acquisition can alter the diagnostic performance of the examination and of the employed radiopharmaceutical agents. In fact, variations in the lesion/background ratio may be observed as consequence of the variability of many issues, dependent either on the subject or on the radiocompound (FCH versus FEC). For example, a different diagnostic accuracy could be connected with no standardized examinations, no consideration in optimizing the scan time to obtain the best lesion/background ratio, parameters such as temporal biodistribution of radiocholine, intracellular metabolism and catabolic rate, formation and kinetics of dissimilar radiochemical forms, and time and speed of filling of the bladder. In accordance with Kwee et al. [25], volumetric measurements of tumor choline activity are strong predictors of prognosis in metastatic PCa. Therefore, a well-defined and complete standardization in methodology, including patient acceptance criteria, dosing and imaging protocols, is mandatory for a more reliable evaluation of diagnostic accuracy in the clinical routine. Moreover, the setup of quantitative analysis, which also gives relevance to the information acquired by CT, could further improve the diagnostic accuracy, trying to decrease the number of false negatives, without increasing false positive results. To optimize both methodology and the quantitative approach, an important contribution could be achieved through a better understanding of in vivo pharmacokinetics in humans. In fact, there is a very high rate of metabolism in vivo producing betaine; therefore any analysis of 18 F rather than the chemical compound might overestimate the amount of phosphocholine produced [46]. To date, clinical reports have not yet been published that include the analysis of catabolites and/or of other in vivo produced fluorinated radiochemical forms. An experimental study, which also analyzes metabolites, preferably conducted in collaboration with a radiopharmacologist and a mathematician rather than with a clinician alone, could give a relevant contribution in defining a more rigorous diagnostic methodology. Furthermore, the achievement of more precise data for a prognostic stratification and/or an earlier and more effective evaluation of therapy

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347

Table 2 The diagnostic performances in similar studies with FCH and FEC. FEC

FCH

Authors, ref

Setting, n. pts

Sens.

Spec.

Acc.

Authors, ref

Setting, n. pts

Sens.

Spec.

Acc.

Tilki et al., 14b Wurschmidt et al.a, 16 Steuber et al., 15a

Restaging, 56 Restaging, 26 Staging, 20

68.4% 92.3% 0%

73.3% – 100%

70.2% – –

Pelosi et al., 41a McCarthy et al., 36b Poulsen et al., 23a

Restaging, 56 Restaging, 26 Staging, 25

82.7% 96% 100%

96.2% 96% 95%

89.2% 96% 96%

a b

Patient-based analysis. Lesion-based analysis.

response could be obtained. Few data about the differences between FCH and FEC, from a clinical point of view, are now available. From the analysis of the reports, it emerged that the diagnostic performances of FCH and FEC for the detection of lymph node metastasis before a surgical approach are generally low, with values typically around 50% or less for FCH and between 0% and 39% for FEC. Conversely, either of the tracers appears useful for the detection of recurrent PCa, in the case of increase in absolute PSA value or in the case of high levels of PSAvel and PSAdt (sensitivity ranged between 42.9% and 96% for FCH and between 62% and 85.7% for FEC). Table 2 reports the diagnostic performances in similar studies with FCH and FEC. To date, it is not possible to determine whether FCH is superior to FEC, or vice versa. The discrepancy between the number of studies based on FCH and those based on FEC is very important, with the number of FEC reports being very small (n = 3 versus n = 20, respectively for FEC and FCH). This limitation could affect the conclusions and our considerations. Nevertheless, from a comparison between similar studies involving a comparable number of patients and in the same setting of disease (see Table 2), it appears that FCH has a higher diagnostic performance than FEC, particularly for recurrence detection. Probably, this latter advantage could be linked with less uptake in the bowel of FCH as compared to FEC, which could reduce the detection of abdominal lymph nodes [47]. Furthermore, it has to be pointed out that Graute et al. [13], in their comparative study between FCH and FEC, conclude with the following sentence: “In fact, no systematic comparison (between FEC and FCH) has yet been made in vivo, but FCH may have slightly superior properties in vitro” [48]. 4.1. Implication for practice On the basis of our experience, also directed by the careful evaluation of the literature, we suggest different protocols in accordance to the requests of the oncologists, urologists or radiotherapists. Firstly, the patients should be advised to fast for a minimum of 6-h before the examination, to be well-hydrated and to void the bladder before the tracer injection and/

FEC and FCH PET protocols in prostate cancer patients

or PET examination. Secondly, in order to reduce the bowel uptake and a competitive uptake, patients should be invited in the 24 h before the scan to drink at least 1.5-2 l of water (or other fluids) and to avoid food containing choline (such as such as asparagus, beans, soya, carrots, egg yolk, lamb, pig and calf liver, skimmed milk, peanuts, peanut butter, peas, spinach, turnip and wheat products, as suggested by Schillaci et al. [31]). The acquisition protocol should be based on the clinical request. In particular, in the case of suspicious for prostatic fossae recurrence, a dynamic imaging (for at least 8 min from the injection of tracer) or a very early static imaging (maximum 2 min after the injection) with a duration of 5 min may be helpful. In case of suspicious for lymph node involvement, a late whole-body imaging is suggested (at least 30–60 min after injection; 3–4 min/bed). Finally, if distant skeletal and/or visceral metastases are suspected, a delayed whole-body scan (after 60 min from the injection; 3–4 min/bed) should be performed. In our experience, a delayed whole-body scan (after 60 min from the tracer injection) alone is recommended to increase the detection rate of PET/CT with FCH or FEC, for lymph node and distant organs involvement. A summary of a suggested protocol is shown in Fig. 4. 5. Conclusion In our opinion, FCH is already recruited in the toolbox for diagnosis of recurrence in patients with PCa. FCH seems to be a more appropriate radiopharmaceutical agent compared to FEC, although more comparative data are mandatory. The variability on patient preparation, imaging acquisition and the clinical setting makes it difficult to make a final decision. A well designed and prospective trial for the evaluation of biokinetic data and diagnostic performance of both radiopharmaceutical agents seems essential, because nowadays we are not able to determine the difference in clinical practice between FEC and FCH linked to the different chemical features. It will also be interesting to see how all PCa imaging agents fit into the current clinical standard of practice, which probably still contains 99Tc-MDP, subsequently substituted by 18 F-NaF. In the near future, radiolabeled PSMA radiotracers, which have already aroused great clinical interest in preliminary studies, will also be added to 18 F and 11C radiolabeled-choline agents. Conflict of interest Nothing to declare.

Prostatic fossae

Lymph nodes

Distant organs

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.nucmedbio.2014.12.019.

•

Dynamic imaging (for 8 minutes)

•

Early static scan (after 2 minutes from injection)

Delayed whole-body scan (after 30-60 minutes from the injection)

Fig. 4. A schematic summary of 18 F-FCH PET or PET/CT protocol.

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