Eur J Nucl Med Mol Imaging (2012) 39:271–282 DOI 10.1007/s00259-011-1970-2

ORIGINAL ARTICLE

Relationship between PSA kinetics and [18F]fluorocholine PET/CT detection rates of recurrence in patients with prostate cancer after total prostatectomy Vera Graute & Nathalie Jansen & Christopher Übleis & Michael Seitz & Markus Hartenbach & Michael Karl Scherr & Sven Thieme & Paul Cumming & Katharina Klanke & Reinhold Tiling & Peter Bartenstein & Marcus Hacker

Received: 8 June 2011 / Accepted: 7 October 2011 / Published online: 16 November 2011 # Springer-Verlag 2011

Abstract Purpose The aim of the present study was to identify prostate-specific antigen (PSA) threshold levels, as well as PSA velocity, progression rate and doubling time in relation to the detectability and localization of recurrent lesions with [18F]fluorocholine (FC) PET/CT in patients after radical prostatectomy. Methods The study group comprised 82 consecutive patients with biochemical relapse after radical prostatectomy. PSA levels measured at the time of imaging were correlated with the FC PET/CT detection rates in the entire group with PSA velocity (in 48 patients), with PSA doubling time (in 47 patients) and with PSA progression (in 29 patients). Results FC PET/CT detected recurrent lesions in 51 of the 82 patients (62%). The median PSA value was significantly higher in PET-positive than in PET-negative patients (4.3 ng/ml vs. 1.0 ng/ml; p<0.01). The optimal PSA threshold from ROC analysis for the detection of recurrent prostate

cancer lesions was 1.74 ng/ml (AUC 0.818, 82% sensitivity, 74% specificity). Significant differences between PETpositive and PET-negative patients were found for median PSA velocity (6.4 vs. 1.1 ng/ml per year; p<0.01) and PSA progression (5.0 vs. 0.3 ng/ml per year, p<0.01) with corresponding optimal thresholds of 1.27 ng/ml per year and 1.28 ng/ml per year, respectively. The PSA doubling time suggested a threshold of 3.2 months, but this just failed to reach statistical significance (p=0.071). Conclusion In a study cohort of patients with biochemical recurrence of prostate cancer after radical prostatectomy there emerged clear PSA thresholds for the presence of FC PET/CT-detectable lesions. Keywords Prostate-specific antigen . [18F]Fluorocholine PET/CT . Total prostatectomy . Recurrence . Detection rate

Introduction V. Graute : N. Jansen : C. Übleis : P. Cumming : K. Klanke : R. Tiling : P. Bartenstein : M. Hacker (*) Department of Nuclear Medicine, University of Munich, Marchioninistr. 15, 81377 Munich, Germany e-mail: [email protected] M. Seitz Department of Urology, University of Munich, Munich, Germany M. Hartenbach Department of Nuclear Medicine, Bundeswehrkrankenhaus Ulm, Ulm, Germany M. K. Scherr : S. Thieme Institute of Clinical Radiology, University of Munich, Munich, Germany

Prostate cancer (PC) is the most common cancer and one of the leading causes of death in men [1]. In 2008, nearly a million men were diagnosed with PC worldwide, of whom more than two-thirds were diagnosed in developed countries [2]. The life-time risk for the diagnosis of PC in developed countries is currently estimated to be 16%, and one in six of these patients will die of their disease, despite aggressive treatment. In recent years, there has been a substantial increase in the incidence of PC, which may largely be attributed to incidental discovery arising from the advent of prostate-specific antigen (PSA) testing. Fortunately, most patients are diagnosed at an early tumour stage characterized by local disease, for which the primary therapeutic approaches are either radical prostatectomy or

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radiation therapy. While indisputably beneficial in prolonging life, these treatments suffer from high recurrence rates. During a 10-year follow-up after prostatectomy, the recurrence rate has been found to be 20–30% [3, 4], as compared to 50% during a 5-year follow-up after radiation therapy [5]. Consequently, patients must be closely followed for an extended period, for which PSA is admirably sensitive. However, serum PSA levels after radical prostatectomy do not enable precise differentiation between local, regional and distant disease. Some 25–35% of men with increasing serum PSA levels will develop locally recurrent disease, 20–25% will develop metastatic disease, and 45– 55% will develop both local recurrence and metastatic disease [6, 7]. The distinction between local and distant recurrence is of paramount importance in clinical practice because of the differing therapeutic strategies [8]. The recurrence of PC and its restaging is facilitated by modern imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy (BS), and more recently, positron emission tomography (PET), especially in conjunction with CT (PET/CT). Appropriate PET tracers for the assessment of PC include [18F]fluoride for the detection of bone metastases, and metabolic tracers such as [11C]acetate, and [11C]methionine, [11C]choline and the fluorinated choline (FC) tracers [18F]fluorocholine and [18F]fluoroethylcholine, all of which rely on the elevated lipid and protein synthesis characteristic of PC. However, the otherwise eminently useful metabolic tracer [18F]FDG has limited use in detecting PC lesions due to the low glycolytic activity of this tumour. The particular sensitivity of [11C]choline and FC is related to the increased cell proliferation and upregulation of choline kinase in PC cells. Indeed, these two tracers have a diagnostic efficacy of approximately 71% in patients with recurrent PC [9]. Due to the brief (20-min) half-life of the radioisotope, the use of [11C]choline is limited to PET centres with an adjacent cyclotron/radiochemistry facility. The brief half-life also impedes the acquisition of late frames, when the optimal tumour-to-blood ratio for sensitive PC detection is obtained. Thus, [18F]fluorocholine permits late frame recordings, when there is likely to be a higher binding ratio. The detection rate with [11C]choline PET/CT in patients with relapse is related to plasma PSA levels and kinetics [10, 11], such that unnecessary imaging procedures can often be avoided on the basis of inexpensive blood tests. However, no comparable PSA thresholds are currently available for FC PET/CT. Therefore, we proposed in the present study to evaluate the detection rate of FC PET/CT for local PC recurrence, nodal metastases and distal spread in relation to PSA kinetics in a retrospective series of patients with recurrence after radical prostatectomy, as indicated by increasing PSA levels.

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Material and methods Patients From February 2007 to January 2011, 82 consecutive patients (67.1±7.0 years, range 49.3–81.4 years) with histopathologically proven primary PC were enrolled in the present study. The inclusion criteria for the performance of a FC PET/CT scan were a detectable PSA level and clinical suspicion of recurrence. All patients had been previously treated with radical prostatectomy. Of the 82 patients, 21 were additionally treated with radiotherapy, and 8 with hormone therapy. Hormone therapy had been discontinued at 14.5±34.5 months prior to the PET scan. After completion of the primary therapy, all patients had a PSA level under the detection threshold. At 54.0 ± 50.1 months after radical prostatectomy, patients with increasing PSA levels were referred for a PET/CT scan with either [18F]fluorocholine (n=25) or [18F]fluoroethylcholine (n=57), according to tracer availability. All patients gave written informed consent for the examination. Determination of PSA and PSA kinetics The free serum PSA level at the time of the PET/CT scan was available in all patients. In addition, PSA kinetics were calculated as described previously [10–13]. In 48 patients, at least two consecutive PSA values were available for calculation of the PSA velocity according to the formula: (PSA2−PSA1)/Δ time. In 29 patients, three consecutive PSA values were available extending over a more prolonged period, allowing calculation of PSA progression using the formula: [(PSA2−PSA1/ Δ time)+(PSA3−PSA2/ Δ time)]/2. Furthermore, the PSA doubling time could be calculated in 47 patients as: ln(2) × Δ time/[ln(PSA2)−ln(PSA1)]. [18F]Choline PET/CT Whole-body PET scans extending from the proximal femurs to the base of the skull were acquired in 3-D mode (3 min per bed position) using a Biograph 64 TruePoint PET/CT scanner (Siemens Medical Solutions). Prior to the CT scan, mean weight-adapted 120 ml of iodine-containing contrast agent (Iopromide, Imeron 300; Bracco) was intravenously administered at a rate of 2.5 ml/s. Initiation of the high-dose CT scan (200–250 mA, 120 kV, 5×5 and 3×3 mm collimation, pitch 0.6) was delayed by 50 s after starting contrast agent infusion in order to depict the venous contrast medium phase. The emission sequence was initiated 60 min after intravenous injection of FC ([18F] fluorocholine, n=25, or [18F]fluoroethylcholine, n=57). The mean radiochemical dose was 300 MBq, normalized to body mass. Directly prior to the PET/CT scan, patients

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were asked to empty their bladder so as to minimize tracer accumulation. Emission data were reconstructed with attenuation correction derived from the CT scan. Two nuclear medicine and two radiology specialists working side-by-side evaluated the PET/CT images in consensus using a dedicated software package (Syngo Leonardo; Siemens Medical Solutions, Erlangen, Germany). All readers were aware of the patients’ PSA values. Increased FC uptake in the PET/CT fusion image of suspicious lymph nodes, bones, prostatic fossa or other tissues was identified as local recurrence or metastatic tissue.

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(p=0.94). There were no statistically significant differences between FC PET-positive and FC PET-negative patients for tumour grading (p=0.50) and Gleason scores (p=0.41 for Gleason <7 vs. Gleason ≥7). However, we did find a significant difference in the TNM classification (p=0.003). The risk of positive PET/CT findings was significantly higher in T3 and T4 patients than in T1 and T2 patients (p= 0.003). The patients’ baseline characteristics stratified in terms of PET negativity and positivity are summarized in Table 1. PET findings

Follow-up During follow-up, FC PET findings were verified as truepositive by high-dose CT (82 patients), bone scintigraphy (8 patients), follow-up PET/CT (24 patients), or MRI (2 patients). Additional follow-up information was obtained from clinical charts. For the assessment of patient outcomes, the patients and their referring urologists were interviewed by telephone by a physician who was blind to the patients’ test results. Only true-positive findings on PET/CT were included for PSA correlation.

Of the 51 PET-positive patients, local recurrence was found in 12 (24%) and locoregional tumour manifestation in 17 (33%). Of these 17 patients, 15 showed lymph node metastases, most often in the paraaortal and iliacal regions, and two showed local recurrence and locoregional lymph node metastases. Distant spread was detected in 22 patients (43%), of whom one had lung metastases, and 14 had bone metastases. Six patients had lymph node and bone metastases, and one patient had lymph node, bone and lung metastases.

Statistical analysis

Positive PET findings in relation to PSA kinetics

Statistical analyses were performed using the SPSS software package (version 17.0). An uncorrected p value of less than 0.05 was assumed to be statistically significant. Comparisons of variables between PET/CT-positive and PET/CT-negative patients were performed using the t-test for parametric data, the Mann-Whitney U-test for nonparametric data or the Kruskal Wallis test for PET lesion location in relation to PSA kinetics. All patients had undergone radical prostatectomy, so any detectable serum PSA level was considered as evidence of disease recurrence. The receiver operating characteristic (ROC) analysis was generated by plotting sensitivity versus 1−specificity, with judgement of the optimal cut-off values for PSA and PSA kinetics to predict positive PET/CT scan results. Other clinical results are presented as means±standard deviation and range unless otherwise indicated.

The mean elevated free serum PSA level at the time of the PET/CT scan was 4.4±5.7 ng/ml (range 0.03–36.0 ng/ml). The mean baseline PSA level was higher in the PETpositive patients than in the PET-negative patients (6.0 vs. 1.7 ng/ml; p<0.01; Table 2). ROC analysis identified the optimal threshold for discriminating PET-positive and PETnegative findings as 1.74 ng/ml (AUC 0.818), resulting in a sensitivity of 82% and a specificity of 74%. Of the patients with a PSA level exceeding this threshold, eight (16%) had a nonsuspicious PET/CT scan. Of those with a PSA level below this threshold, nine (28%) showed recurrence lesions (Fig. 1). PSA velocity ranged from 0.0 to 95.5 ng/ml per year. Mean PSA velocity was 15.3 ng/ml per year in patients with PET-positive scans versus 1.4 ng/ml per year in those with PET-negative scans (p<0.01). ROC analysis revealed that the optimal cut-off of PSA velocity for the prediction of a positive PET/CT scan was 1.27 ng/ml per year (AUC 0.850), which resulted in a sensitivity of 84% and a specificity of 69%. Of patients with a PSA velocity exceeding this cut-off, five (16%) had a nonsuspicious PET/CT scan, whereas of those with a PSA velocity below this cut-off five (31%) showed recurrence lesions (Fig. 2). The PSA progression rate, which was measured over a median time of 6.2 months, ranged from 0.13 to 39.8 ng/ml per year. Mean progression was 10.7 ng/ml per year (range 0.43 – 39.8 ng/ml per year) in PET-positive patients and

Results Patient characteristics In the 82 patients, the mean time between prostatectomy and recurrence was 54±50 months. FC PET/CT yielded positive findings in 51 of the 82 patients (62%). Time intervals did not differ between the PET-negative (52± 50 months) and the PET-positive (55±51 months) patients

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Table 1 Patient characteristics Characteristic

All patients (n=82)

PET/CT-positive patients (n=51)

PET/CT-negative patients (n=31)

p value

67.1±7.0 49.3–81.4 8 21

66.2±7.0 49.3–77.8 6 15

68.6±6.7 53.8–81.4 2 6

0.22

0 1 15 1 23 5

0 0 5 0 17 4

0 1 10 1 6 1

0.003 (T1/T2 vs. T3/T4); 1.0 (N0 vs. N1)

T4 N0/Nx M0/Mx T4 N1 M0/Mx Grade (%) 2 3 Gleason score (n)

2 1

1 1

1 0

24 41

9 26

0.50

5 6 7 8 9 Time prostatectomy to PET/CT

1 4 16 10 10 (months)

0 1 7 5 8

1 3 9 5 2

0.14 (score ≤ 7 vs. >7)

54±50 3–211

55±51 3–185

52±50 3–211

0.94

Age (years) Mean±SD Range Previous hormone therapy (n) Previous radiotherapy (n) TNM stage (n) T1 T1 T2 T2 T3 T3

N0/Nx M0/Mx N1 M0/Mx N0/Nx M0/Mx N1 M0/Mx N0/Nx M0/Mx N1 M0/Mx

Mean±SD Range

Table 2 PSA and PSA kinetics All patients PSA (ng/ml) Mean±SD 4.4±5.7 Median 2.4 Range 0.03–36.0 No. of patients 82 PSA velocity (ng/ml per year) Mean±SD 10.7±19.1 Median 2.3 Range 0.0–95.5 No. of patients 48 PSA progression (ng/ml per year) Mean±SD 8.3±11.1 Median 3.7 Range 0.13–39.8 No. of patients 29 PSA doubling time (months) Mean±SD 7.5±8.4 Median 4.8 Range 0.5–34.5 No. of patients 47

PET/CT-positive patients

PET/CT-negative patients

p value

6.0±6.6 4.3 0.43–36.0 51

1.7±2.2 1.0 0.03–9.3 31

<0.01

15.3±22.1 6.4 0.42–95.5 32

1.4±1.6 1.1 0.0–5.8 16

<0.01

10.7±11.8 5.0 0.43–39.8 22

0.7±1.0 0.3 0.13–2.9 7

<0.01

6.7±8.4 2.9 0.5–34.5 32

9.3±8.6 6.1 1.5–30.4 15

0.07

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Fig. 1 PSA cut-off at 1.74 ng/ml. FC PET/CT detection rates (a) and location of the detected recurrences in relation to PSA value (b)

0.7 ng/ml per year (range 0.13–2.9 ng/ml per year) in PETnegative patients (p<0.01). The ROC analysis yielded an optimal cut-off of 1.28 ng/ml per year (AUC 0.955). Of patients with PSA progression exceeding this cut-off, one (5%) had a nonsuspicious PET/CT scan, whereas of those with PSA progression below this cut-off, five (45%) showed recurrence lesions (Fig. 3). PSA doubling time ranged between 0.5 and 34.5 months, with a mean of 6.7 months in PET-positive patients and 9.3 months in PET-negative patients (p=0.071). The near significance notwithstanding, the ROC analysis yielded an optimal cut-off when the doubling time was less than 3.2 months (Fig. 4).

PET lesion location in relation to PSA kinetics Among the PET-positive patients, we calculated the PSA baseline and kinetics in four patient subgroups: local recurrence only (12 patients), lymph node metastasis only (15 patients), bone metastasis only (14 patients), and metastases in at least two different organ systems (10 patients; Table 3). Patients in the last of these subgroups had significantly higher baseline PSA values than those in the other three subgroups (p<0.01; Fig. 1). Patients in the subgroup with only local recurrence had lower PSA velocity and PSA progression than those suffering only from lymph node metastasis. The PSA doubling time was

Fig. 2 PSA velocity cut-off at 1.27 ng/ml per year. FC PET/CT detection rates (a) and location of the detected recurrences in relation to PSA velocity (b)

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Fig. 3 PSA progression rate cut-off at 1.28 ng/ml per year. FC PET/CT detection rates (a) and location of the detected recurrences in relation to the PSA progression (b)

significantly longer in patients in the subgroup with only local recurrence than in those with tumour manifestations in at least two organ systems (Table 3, and Figs. 1b, 2b, 3b and 4b).

Discussion It is mandatory to know the location of PC recurrence in patients with radical prostatectomy and biochemical relapse of serum PSA for therapy planning, as the optimal choice of therapy must be informed by the differentiation between

local, regional and systemic disease (Figs. 5 and 6). It has previously been established that [11C]choline PET/CT is a sensitive method for detecting recurrence and distant metastases, and that positive [11C]choline PET/CT findings are associated with a certain threshold of PSA levels at the time of scanning [8–10, 14–21]. However, for the reasons discussed above, the use of [11C]choline is possible only when there is a cyclotron/radiochemistry facility on-site. Therefore, we elected to investigate for the first time the relationship between PSA kinetics and the threshold for detection of PC recurrence and location of metastases by PET/CT with FC, which is potentially more widely available.

Fig. 4 PSA doubling time cut-off at <3.2 months. FC PET/CT detection rates (a) and location of the detected recurrences in relation to the PSA doubling time (b)

Eur J Nucl Med Mol Imaging (2012) 39:271–282 Table 3 PET lesion location in relation to PSA and PSA kinetics in PET/ CT-positive patients

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Local recurrence only

Lymph node metastasis only

Bone metastasis only

Metastases in two or more organs

4.5±2.9 4.2 0.5–10.9 15

5.3±6.7 3.9 0.4–26.7 14

12.3±9.3 10.8 4.3–36.0 10

11.3±8.3 8.9 1.9–25.1 8

6.6±11.8 2.0 0.6–30.7 6

36.0±31.7 24.3 3.5–95.5 9

7.8±4.2 6.3 3.71–13.1 7

14.5±15.6 11.4 1.0–34.3 4

24.1±15.2 25.5 5.5–39.8 4

5.7±7.6 2.1 0.6–21.8

3.6±1.7 2.9 1.9–6.4

2.8±2.3 1.3 0.5–6.5

8

6

9

PSA (ng/ml) Mean±SD 3.5±4.0 Median 2.2 Range 0.6–15.5 No. of patients 12 PSA velocity (ng/ml per year) Mean±SD 4.1±6.4 Median 1.3 Range 0.4–20.2 No. of patients 9 PSA progression (ng/ml per year) Mean±SD 3.8±6.3 Median 1.0 Range 0.4–17.8 No. of patients 7 PSA doubling time (mo) Mean±SD 13.5±11.6 Median 11.5 Range 0.9–34.5 No. of patients

9

A single previously published study in a series of 56 patients examined the relationship between PSA level and positive findings on FC PET/CT after radical prostatectomy [20]. In that study, the sensitivity for tumour detection was correlated with serum PSA level, yielding sensitivities increasing from 20% in patients with PSA ≤1 ng/ml, to 44% for PSA ≤5 ng/ml, and 82% for PSA >5 ng/ml. The overall detection rate for FC PET with low-dose CT was 43%, as compared to 62% in the present study. Superior sensitivity could plausibly be attributed to our use of highdose CT in conjunction with contrast agent, which may have favoured the allocation of focal FC uptake to diseased anatomical structures. FC and its labelled metabolites undergo renal elimination, such that variable amounts of radioactivity accumulate in the kidneys, urinary bladder und ureters, especially in acquisitions delayed for 1 h. The rates for the detection of local recurrence and especially regional metastatic disease can be negatively influenced by this physiological uptake. Therefore, it is mandatory, especially in patients with small lymph node metastases or local recurrence, that the recurrence be located precisely. With the administration of CT contrast agent, anatomical allocation is much easier, which is especially important is recurrence involving organs and structures in the lesser pelvis, especially lymph nodes lying close to urinary structures. In 10 of the present 82 patients, the use of CT contrast agent enabled the differentiation of physiological urinary activity and FC uptake. Moreover, in these patients

the use of contrast agent was also helpful for excluding the possibility of infiltration of adjacent organs such as the bladder and rectum. Furthermore, in six patients we were able to identify small lymph node metastases with only marginal to moderate tracer uptake lying in close proximity to pelvic vessels or intestinal structures. Based on our experience and the findings of this study, we suggest using contrast agent whenever possible in daily practice, i.e. unless specifically contraindicated, because of the substantial benefits it brings to ease and reliability of PET interpretation. FC is characterized by higher urinary excretion than is typically found with [11C]choline. The interpretation of pelvic imaging is particularly vulnerable to accumulation of radioactivity in the bladder, such that improved CT contrast is especially important for correct assignment of possible metastases or recurrences. However, we did not report any lesion as positive on the basis only of contrast-enhanced CT, and in the absence of significant uptake in the PET image. However, the additional information provided by contrast-enhanced CT may well be advantageous in rare cases of PC in which tumour manifestations are not choline-avid. In their [11C]choline PET/CT study, Pelosi et al. found that PSA levels were significantly higher (p=0.034) in the patients with a positive PET scan (7.2±9.8 ng/ml) than in those with a negative or false-positive PET scan (2.6± 5.5 ng/ml). In accordance with the findings of Pelosi et al., with FC we found almost identical mean PSA

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values (6.0±6.6 ng/ml vs. 1.7±2.2 ng/ml), but with a considerably higher level of significance (p < 0.01). Whereas Pelosi et al. did not calculate a cut-off PSA value for tumour detection, ROC analysis in the present study indicated an optimal threshold of 1.74 ng/ml (AUC 0.818), which yielded a high sensitivity (82%) and specificity (74%). Similarly, in a recent [11C]choline study of 358 patients following radical prostatectomy, the cutoff PSA value was 1.4 ng/ml, which also yielded a high sensitivity (73%) and specificity (72%) [21]. The marginally higher sensitivity and specificity in the present FC study may reflect our slightly higher PSA cut-off value. However, in an earlier [11C]choline study of patients with biochemical recurrence, Castellucci et al. [10] found a still higher cut-off PSA value (2.43 ng/ml), albeit with nearly identical sensitivity and specificity to that reported by Giovacchini et al. [21]. The limited available results suggest that a trade-off between PSA cut-off and PET sensitivity may be favoured by the use of FC, but proof of this conjecture would require a within-group comparison of FC and [11C]choline PET. In another study by Castellucci et al. [11], the role of 11 [ C]choline PET/CT was examined in a large patient group. Encouragingly, our findings are in close agreement with those of that study, in which 28% of patients showed positive findings when the PSA level was below 1.5 ng/ml. In our setting, recurrence lesions were present in 28% of patients with PSA below our threshold of 1.74 ng/ml. Castellucci et al. pointed out that the likelihood of a high detection rate is greater in the presence of fast PSA kinetics, such that the detection rate increased to 58% in association with a PSA doubling time of less than 7.25 months. Overall, there is general agreement that local or distant recurrence can be detected even if the PSA level is initially low or below our threshold, as long as PSA kinetics is sufficiently rapid. If the PSA level is low the early detection of recurrent disease is very important for decisions about therapeutic management, as the likelihood of only a limited local recurrence is very high in these patients. In this circumstance, secondary radiation treatment to the prostatic fossa should be initiated. However, PET/CT with choline tracers can also detect unexpected distant tumour manifestations in patients with a low PSA level, resulting in fundamentally different therapeutic management and prognosis. In patients with distant tumour manifestation, systemic treatment is preferred to local radiotherapy, thus avoiding morbidity arising from that procedure. Castellucci et al. also considered the relationship between PSA kinetics and [11C]choline PET detection rates [10], finding an optimal cut-off point at a velocity of 1.1 ng/ml per year, only slightly less than the PSA velocity and progression (1.28 ng/ml per year) cut-off in the present FC study. Whereas Giovacchini et al. [22] and

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Castellucci et al. [10] both highlighted a significant relationship between the PSA doubling time and [11C] choline PET findings, this relationship just failed to attain significance in the present FC study, perhaps due to our relatively small group size compared to those in the earlier studies. The utility of PSA doubling time depends strictly on patient population characteristics. Castellucci et al. [11] demonstrated that if a patient group with low PSA values (<1.5 ng/ml) is selected, either PSA velocity or free PSA loose their statistical significance and only PSA doubling time will be statistically significant. Nonetheless, our apparent doubling times (6.7 months for PET-positive vs. 9.3 months for PET-negative) are close to those found in the earlier [11C]choline studies. The optimal tracer for PET imaging of patients with PC has been a matter of debate. A recent review found that 11 C- and 18F-labelled choline afforded similar tumour detection in different clinical settings [6]. Since [11C] choline is chemically identical to the endogenous compound, its use might be preferred, as has been argued for the case of [11C]DOPA versus [18F]fluoroDOPA [23]. The rapid and extensive clearance of the several radiolabeled cholines from blood following intravenous injection allows early PET acquisition for the pelvis, prior to extensive tracer accumulation in the urinary bladder. Whereas the urinary excretion of FC seems to exceed that of [11C] choline, the latter tracer also exhibits early accumulation in the bowel, which may also interfere with the interpretation of pelvic imaging [20, 24, 25]. However, the main practical difference between these tracers is the fivefold longer physical half-life of 18F, which makes FC potentially available to institutions lacking a cyclotron/radiochemistry facility. In addition, the longer half-life allows more delayed acquisitions, which are likely to provide superior lesion-to-blood pool ratios than are provided by [11C] choline, and the rapid washout of FC leads, in the course of a more delayed recording, to more favourable tumour-tobackground ratios, notwithstanding the potential interference from urinary accumulation mentioned above. The tumour-to-background ratios of FC and [11C]choline have not yet been systemically compared. Within-group comparisons of FC and [11C]choline PET are needed to definitively demonstrate their relative sensitivities. Of our 82 patients, 31 (38%) had a negative PET scan, which was associated with significantly lower baseline PSA levels, velocity, and progression, and a trend towards a longer doubling time. In general, PSA levels are an indication of the net PC load, presumably the product of tumour volume and metabolic activity [3, 4, 10, 26]. This relationship contributes to the value of PSA levels and kinetics for predicting tumour detectability by PET, thus allowing accurate prediction of the outcome of costly imaging on the basis of a blood test.

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Limitations In general, the spatial resolution of PET (4 mm) must limit the identification of small tumour lesions. Our study design did not entail the histological analysis of recurrent or metastatic tumours. Thus, the PET/CT findings were not validated using histological criteria. Because of practical and ethical issues, it is not always reasonable and feasible in clinical daily practice to confirm tumour manifestation by biopsy. Especially when the clinical follow-up and the imaging results are conclusive, a biopsy is not indicated, thus sparing the patient further surgical intervention. Of course, histological validation would have been preferable in this study, although we note that in patients with local relapse the rate of positive findings on TRUS-guided biopsy is moderate, such that even multiple biopsies do not completely exclude the possibility of local recurrence. However, our diagnoses were frequently substantiated by patient follow-up, high-dose CT, bone scintigraphy or MRI. We used either [18F]fluorocholine or [18F]fluoroethylcholine, depending on availability, and combined results for these two tracers so as to optimize the group size, based on Fig. 5 A 53-year-old patient with moderately differentiated PC (pT3b pN0 (0/11) L0 V0 R0) identified as grade 2, Gleason score 8 (4/4), who underwent FC PET/CT 32 months after prostatectomy. His baseline PSA level (7.0 ng/ml), and PSA kinetics (velocity 25.1 ng/ml per year, progression rate 12.8 ng/ml per year) exceeded the corresponding thresholds, and the doubling time (0.6 months) fell below the threshold. The FC PET/CT scan revealed pathological uptake in an iliacal lymph node metastasis of 13 mm diameter, lying in proximity to the intestinal loop

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the assumption of roughly similar properties in vivo for these closely related FC compounds. In fact no systematic comparison has yet been made in vivo, but [18F]fluorocholine may have slightly superior properties in vitro [27]. We included in our study two patients with PSA values of only 0.03 ng/ml, below the usual cut-off level indicating the need for PET/CT. However, one of these patients experienced a sudden increase in PSA to this level, following repeated findings of PSA levels below the detection limit (<0.001 ng/ml) for more than 39 months after prostatectomy. Furthermore, MRI revealed a suspect interaortocaval lymph node. Due to the concurrence of these two suspicious findings, the PET/CT scan was performed. This proved to be inconspicuous (in detail the lymph node did not show any uptake). In a follow up of 20.6 months the patient’s PSA value did not further increase, but had declined to 0.01 ng/ml at 20.6 months. The second patient also showed an increase in PSA value, which nonetheless still remained low at the time of the PET/CT scan, which did not show any pathological uptake. At 9.5 months after his PET/CT scan, an MRI scan was performed to reassess the PSA velocity, despite its slight

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magnitude. However, the MRI showed neither local recurrence nor distant spread. A final limitation arises from the history of previous hormone therapy in eight of our patients. Indeed, choline uptake in vitro is sensitive to chemotherapeutic and antiandrogenic substances [28]. Furthermore, Giovacchini et al. [29] found reduced [11C]choline in the prostate gland of patients with PC under treatment with nonsteroidal androgen antagonists. Our patients all showed increasing PSA levels, predicting reduced responsiveness to hormone therapy. Nonetheless, hormone therapy is conventional, and our somewhat heterogeneous patient group is representative Fig. 6 A 73-year-old patient with moderately differentiated PC (pT3b pN0 pM0) identified as grade 3, Gleason score 7, who underwent FC PET/CT 90 months after prostatectomy. His baseline PSA value (4.3 ng/ml) and PSA kinetics (velocity 2.0 ng/ml per year, progression rate 1.6 ng/ml per year, and doubling time 15 months) all exceeded the corresponding thresholds. The FC PET/CT scan showed a PET-positive local recurrence in the prostatic fossa, with infiltration of the vesica. The CT scan showed pathological contrast agent accumulation in the same region. There was no evidence of metastases

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of daily clinical routine. However, hormone therapy had been discontinued approximately 1 year prior to the PET scan, so that the potential effects of this confounding factor would have been minimal. Conclusion We found that FC PET/CT is most likely to reveal and localize tumours in PC patients with biochemical relapse after radical prostatectomy when their PSA level exceeds 1.74 ng/ml. Kinetics analysis of PSA gave thresholds of 1.28 ng/ml per year for velocity and

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progression, and suggested a threshold doubling time greater than 3.2 months. We found that FC PET has slightly higher sensitivity and specificity than found in previous studies with [11C]choline, and conclude that PSA levels and kinetics are entirely suitable for selecting patients likely to benefit from PET/CT imaging using FC. Conflicts of interest None.

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