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Use of choline tracers in the prostate carcinoma management
Available online at
www.sciencedirect.com Médecine Nucléaire 37 (2013) 71–77
Review
Use of choline tracers in the prostate carcinoma management Utilisation de la choline marquée dans la prise en charge du cancer de la prostate A. Mestre-Fusco *, M. Suárez-Piñera Nuclear Medicine Department, Hospital del Mar, Parc de Salut Mar, Passeig Maritim 25-29 P-1, 08003 Barcelona, Spain Received 14 November 2012; accepted 23 November 2012 Available online 1st March 2013
Abstract Prostate cancer is the second most frequently diagnosed cancer in men. This incidence has increased because of the introduction of screening with prostate-specific antigen (PSA) and the use of improved biopsy techniques. Choline PET/CT cannot be recommended as a first-line screening procedure for primary prostate cancer. PET/CT has a limited sensitivity due to its dependency on tumor configuration and size, and a limited specificity in differentiation between prostate cancer and benign pathologies. PET/CT could be useful in the detection of malignant lymph nodes in case of nodes greater than 5 mm in diameter. An application of choline PET/CT may be to increase the detection rate of clinically suspected prostate cancer with multiple negative prostate biopsies. Choline PET/CT has proved to be useful for restaging patients with prostate cancer with biochemical failure. Studies have shown that the positive detection rate of choline PET/CT increases with increasing PSA values. The definition of a PSA cut-off value to refer prostate carcinoma with biochemical recurrence would be helpful for the clinical management of these patients. Several PSA cut-off values have been proposed by literature. The routine use of choline PET/CT cannot be recommended only in patients with an absolute PSA value of < 1 ng/mL. Moreover, the sensitivity of 18F-Fluorocholine (FCH) PET/CT is significantly higher in patients with a PSA velocity > 2 ng/mL per year or a PSA-doubling time 6 months. In case of early bone metastases 18F-FCH could be superior to 18F-sodium fluoride due to the absence of bone reaction and remodelling. # 2012 Elsevier Masson SAS. All rights reserved. Keywords: Prostate; Cancer; PET;
11
C-Choline;
18
F-FCH
Résumé Le cancer de la prostate est le deuxième cancer le plus fréquent chez l’homme. Cette prévalence a augmenté avec l’utilisation en dépistage du dosage de l’antigène prostatique spécifique (PSA) et l’amélioration des techniques des biopsies. La TEP-TDM à la choline marquée ne peut pas être recommandée comme procédure de première ligne de dépistage. La TEP-TDM a une sensibilité limitée car elle dépend de la configuration et de la taille tumorales, et une spécificité limitée dans sa capacité à différencier un cancer prostatique d’une pathologie bénigne. La TEP-TDM peut être utile dans la détection de ganglions métastatiques, si leur taille est supérieure à 5 mm. Une application de la TEP-TDM à la choline marquée est d’augmenter le taux de détection de cancers suspectés malgré de multiples biopsies négatives. La TEP-TDM à la choline marquée s’est révélée utile pour redéfinir le stade du cancer lors d’une récidive biologique. Des études ont montré que le taux de détection de la TEP-TDM à la choline marquée augmentait avec le taux de PSA. La définition d’une valeur seuil de PSA pour prédire une récurrence cancéreuse dans le cas d’une récidive biologique serait très utile dans la prise en charge de ces patients. Plusieurs valeurs seuils ont été proposées dans la littérature. Une utilisation en routine de la TEP-TDM à la choline marquée n’est pas recommandée chez des patients présentant un dosage de PSA inférieur à 1 ng/L. De plus, la sensibilité de la TEP-TDM à la choline marquée au fluor 18 est significativement supérieure chez les patients présentant une vélocité du PSA supérieur à 2 ng/mL par an, ou un temps de doublement du PSA inférieur ou égal à six mois. Pour la détection de métastases osseuses précoces, la fluorocholine-18F peut être supérieure au fluorure de sodium-18F en raison de l’absence de réaction et de remodelage osseux. # 2012 Elsevier Masson SAS. Tous droits réservés. Mots clés : Prostate ; Cancer ; TEP ; Choline -18F ; Choline -11C
* Corresponding author. E-mail address: [email protected] (A. Mestre-Fusco). 0928-1258/$ – see front matter # 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.mednuc.2012.11.004
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1. Introduction Prostate cancer (PCa) is the second most frequently diagnosed cancer, and the third most common cause of death from cancer in men in United States and Western Europe [1]. PCa is clinically a heterogeneous disease characterized by an overall long natural history in comparison to the other solid tumors, with a wide spectrum of biologic behavior that ranges from indolent to aggressive [2]. Clinically, PCa is diagnosed as local or advanced, and treatments range from surveillance to radical local treatment or androgen-deprivation treatment. Androgen deprivation reduces symptoms in about 70 to 80% of patients with advanced prostate cancer, but most tumours relapse within 2 years to an incurable androgen-independent state [1,3]. The incidence of prostate cancer has substantially increased in the past two decades, probably because of the introduction of screening with prostate-specific antigen (PSA) and the use of improved biopsy techniques for diagnosis. Commonly used diagnostic tools in the evaluation of prostate cancer are digital rectal examination (DRE), measurement of serum levels of prostate-specific antigen (PSA), transrectal ultrasound (TRUS) as well as TRUS-guided biopsies. A combination of TRUS and DRE findings seems to predict biopsy results best. Cancer recurrence detection seems to be predicted by TRUS and DRE findings, but not by PSA levels or pathological stage [4]. Gold standard for diagnosing PCa is based on histopathological examination of tissue specimens from the prostate gland core biopsies. The most commonly used system for grading adenocarcinoma of the prostate is the Gleason score. The system describes a score between 2 and 10, with 2 being the less aggressive and 10 the most aggressive [3–5]. Moreover, several molecular biomarkers of cancer pathogenic pathways including Ki-67 (proliferation), Bcl-2 (apoptosis), CD31 (angiogenesis), Her-2/neu (oncogene), PTEN (anti-oncogene), and AR (androgen receptor) were also involved in CaP. Chen et al. [6] evaluated whether the tracer 11 C-choline uptake, quantified as SUVmax-P/M ratio (ratio calculated as prostate lesions or target P and pelvis muscles non-target M) correlated with tumour stage, Gleason score, and expression levels of these biomarkers of aggressiveness. As a result, SUVmax-P/M ratio was also significantly higher in lesions with Gleason score of 4 + 3 or higher versus less than or equal to 3 + 4. SUVmax-P/M ratio was found significantly correlated with expression levels of Ki-67 and CD31 and a higher SUVmax-P/M ratio was demonstrated in Her-2/neu positive subgroup. Nevertheless, a correlation between SUVmax of 11C-choline and Ki-67 was not confirmed by other authors [7]. Pathological stage of PCa is based on TNM classification [8], emphasizing in T3: the tumor has spread through the prostatic capsule, N1: metastasis in regional lymph node(s), M1a: the cancer has spread to lymph nodes beyond the regional ones and M1b: the cancer has spread to bone. The choice of treatment for localized PCa, i.e. active surveillance, radical prostatectomy, or any type of radiotherapy,
depends on tumor characteristics, Gleason score, PSA value and the patient’s life expectancy. Treatment with intent to cure is not used in all patients with PCa since many cases of well to moderately differentiated PCa have a very indolent history [3]. In fact, prostatectomy did not prolong survival unless patients were younger than 65 years [7,9]. In PCa screening, it is known that there is no true PSA cutoff point distinguishing cancer from non-cancer. Some authors [10] suggest that providers consider individualized decision making when PSA levels fall in the indeterminate range of 2.5 ng/mL to 4.0 ng/mL, particularly for men at increased risk for high-grade cancer based on non-PSA risk factors. On the other hand, the first sign of failure after primary treatment with curative intent is generally a rising serum PSA level, occurring months to years before clinical symptoms or imaging signs of recurrent disease [3]. A biochemical failure or recurrence is defined by a detectable serum PSA level of at least two consecutive measurements of > 0.2 ng/mL after surgery [2] or by an increment of 2 ng/mL over nadir PSA after radiotherapy (RT) [11]. In general, local recurrence is characterized by a late PSA increase, a long PSA-doubling time, and a less aggressive disease at diagnosis with low Gleason score, and no invasion of the seminal vesicles or lymph nodes [3].
2. Imaging techniques in prostate carcinoma Panebianco et al. reported the emerging role for MRI, particularly multiparametric MRI combining T2 weighted imaging, diffusion weighted imaging, contrast-enhanced MR, and spectroscopy, as the most sensitive and specific tool available to evaluate prostate gland and imaging PCa [12]. MRI of patient with PCa affecting the left lobe of prostate gland is shown on Fig. 1. On the other hand, morphological imaging techniques such as TRUS, CT and MRI have demonstrated only limited accuracy for primary diagnosis of prostate cancer, recurrent disease as well as advanced disease. Furthermore, the detection of lymph node metastases is limited by CT and MRI; first, small lymph node metastases cannot be visualized; second, size as the only criterion might not be sufficient to detect metastatic involvement in lymph nodes. Combined molecular and morphological imaging techniques such as PET/ CT may improve the diagnostic accuracy in imaging prostate cancer. PET/CT based on increased glycolysis using 18Ffluorodeoxyglucose (FDG) has shown only limited sensitivity for the detection of PCa [5]. Evidence derived from imaging studies over the past many years suggest that use of different imaging modalities may need to be aligned with the clinical phase of the disease [13]. There has been considerable interest in the potential diagnostic utility of PET with radiolabeled 11C or 18F-choline in prostate cancer [2]. The biologic basis for radiolabeled choline uptake in tumors is the malignancy-induced upregulation of choline kinase, which leads to the incorporation and trapping of choline in the form of phosphatidylcholine in the tumor cell membrane.
[(Fig._ 1)TD$FIG]
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Fig. 1. Multiparametric MRI combining T2 weighted imaging (B), diffusion (C) and perfusion (D) weighted imaging, and spectroscopy (A), in patient with PCa affecting the left lobe of prostate gland. IRM multiparamétrique, associant les images pondérées T2 (B), de diffusion (C), de perfusion (D), et de spectroscopie (A) chez un patient présentant un cancer du lobe gauche de la prostate.
11
C-choline has a shorter half-life (20 min) that requires an onsite cyclotron. Normal biodistribution of 11C-choline demonstrates relatively high accumulation in the pancreas, liver, kidneys, and salivary glands and variable uptake in the bowel, with little urinary excretion [14]. 18F-fluorocholine (FCH) has a longer half-life (110 min). The normal biodistribution of 18F-FCH demonstrates relatively high accumulation in the pancreas, liver, spleen, and kidneys; variable uptake in the bowel; and urinary excretion of 18F-FCH is higher than 11 C-choline. Both of them have an uptake overlapping benign and malignant prostate tissues [2,3]. 3. Use of choline PET in initial diagnosis and local evaluation The value of PET and PET/CT using 11C and 18F labeled choline derivates for the initial diagnosis of primary PCa has been examined in several studies with controversial results. Behesthi et al. [15] assessed the value of 18F-FCH PET/CT in the preoperative staging of intermediate and high-risk patients with PCa. The authors evaluated 132 patients with PCa with intermediate or high risk of extracapsular disease. Overall, 912 lymph nodes were histopathologically examined, and an analysis revealed the sensitivity, specificity, and positive and negative predictive values of 18F-FCH PET/CT in the detection
of malignant lymph nodes were 45%, 96%, 82%, and 83%, respectively. In lymph nodes 5 mm in diameter or larger, the sensitivity, specificity, and positive and negative predictive values were 66%, 96%, 82%, and 92%, respectively. 18F-FCH PET/CT had limited value in the detection of malignant lymph nodes smaller than 5 mm in diameter. When considering the entire high-risk group, 20% of the patient population (17/83 patients) had findings that were upstaged after 18F-FCH PET/ CT. The following studies reported a high sensitivity for the detection of primary prostate cancer using PET and PET/CT with 11C-choline or 18F-FCH (Table 1). De Jong et al. [16] prospectively evaluated the visualization of primary PCa with 11 C-choline PET in patients with biopsy-proven prostate cancer in comparison with benign changes of the prostate. Normal prostate and prostate cancer tissue showed mean SUV of 2.3 (1.3–3.2) and 5 (2.4–9.5), respectively. In 24 patients out of 25, there was a focal increased choline uptake. Yoshida et al. [17] evaluated the use of 11C-choline in staging primary PCa. Tumoral lesion could be identified by means of increased choline uptake in five patients out of six (SUV mean of 4.21) and only in one patient with primary prostate cancer could not be identified correctly. Kwee et al. (2006) [18] evaluated the efficacy of delayed 18F-FCH PET imaging or imaging at two time points (dual point) for the localization of primary PCa
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Table 1 Diagnostic efficacy of 18F-choline (FCH) and 11C-choline PET and PET/CT in patients with primary Pca. Efficacite´ diagnostique de la TEP et TEP/TDM avec 18F-choline (FCH) et 11C-choline chez des patients pre´sentant un cancer prostatique primaire. Tracer
18F-FCH 11C-Choline 11C-Choline 18F-FCH 11C-Choline 18F-FCH 11C-Choline 11C-Choline 11C-Choline 11C-Choline
Reference
[15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Author
Beheshti et al. de Jong et al. Yoshida et al. Kwee et al. Reske et al. Husarik et al. Souvatzoglou et al. Yamaguchi et al. Martorana et al. Farsad et al.
Year
2010 2002 2005 2006 2006 2008 2011 2005 2006 2005
Modus
PET/CT PET PET PET PET/CT PET/CT PET/CT PET PET/CT PET/CT
Patients
130 25 13 26 26 43 43 20 43 36
Local tumor
Lymph nodes
Sensitivity (%)
Specificity (%)
Sensitivity (%)
Specificity (%)
no 100 no 100 100 98 79 100 66 66
84 81 no no no no no no no no
45 80 no no no 33 no no no no
96 95 no no no 100 no no no no
Modified from [5]. No: non available.
(7 min and 1 h). The mean SUVmax for malignant findings significantly increased from 7.6 to 8.6 between early and delayed acquisition while the mean SUVmax for presumably benign lesions significantly decreased between the initial and the late image (4.8 to 3.9). Reske et al. [19] found a SUVmax cut-off of 2.65 with an associated area under the curve of 0.89 0.01 in the ROC analysis for correct prediction of prostate cancer. Regions with PCa could be identified in all patients (26/26) using 11C-choline PET/CT, resulting in a sensitivity of 100%. Furthermore, the authors did not find a correlation between 11C-choline SUVmax and PSA value and Gleason score but found a correlation with T stage. Besides the limited sensitivity, the differentiation between benign prostatic hyperplasia (BPH), prostatitis or high-grade intraepithelial neoplasia (HGPIN) is not always possible in primary staging of PCa using choline PET/CT [3,5,20–24]. Beheshti et al. [15] concluded that differentiation between PCa and prostatitis was not possible due to intense FCH accumulation in inflammatory lesions. Souvatzoglou et al. [21] confirmed the results concerning limited specificity of choline PET/CT in primary staging of PCa. In their study, there was no statistically significant difference between SUVmax of prostate cancer, benign prostate hyperplasia (P = 0.102) or prostatitis (P = 0.054). They concluded that the detection and localization of PCa in the prostate with 11C-choline PET/CT is impaired by tumor configuration. Yamaguchi et al. [22] also confirmed these results by showing that there was a significant overlap of choline uptake between BPH and PCa which resulted in a limited specificity in the detection of primay PCa using choline PET/CT. Martorana et al. [23] showed that SUVmax was significantly higher in malignant lesions compared to benign lesion (P = 0.027). However, there was no statistically significant difference between false-positive and false-negative findings. Based on sextant biopsy, PET/CT had a slightly better sensitivity than transrectal ultrasound (66% vs. 61%, P = 0.434) but it was less specific (84% vs. 97%, P = 0.008). Farsad et al. [24] confirmed that benign entities also show a high choline uptake, and reported a specificity of 81% for the detection of primary prostate cancer that was not significantly different from that with HGPIN.
In summary, choline PET/CT cannot be recommended as a first-line screening procedure for the diagnosis of primary prostate cancer in men at risk. It might play a role in the detection of clinically suspected prostate cancer with repeatedly negative prostate biopsies [3,5]. 4. Use of choline PET in biochemical recurrence When a biochemical recurrence is observed in patients, accurate delineation of local versus metastatic disease is crucial for selection of appropriate therapy [3]. Several studies have reported both 11C-Choline and 18FFCH PET/CT to be useful for detecting recurrence in patients with PSA relapse [25–33]. However, a PSA cut-off value for which PCa patients should be referred to PET/CT has not been established yet. This threshold ranges from values as low as 1 ng/mL [25] to high as 5 ng/mL [20,26], In a large prospective study, Cimitan et al. [28] identified prostate cancer recurrence with 18F-FCH PET/CT in 53 patients out of 100 with PSA relapse; however, 89% of patients with presumably false-negative scans had a serum PSA level < 4 ng/ dL resulting in a lower sensitivity for 18F-FCH for detecting recurrent prostate cancer if the PSA was low. Similar results [29] have also been reported for choline PET/CT, with a low sensitivity in patients with a PSA less than 4 to 5 ng/mL. Krause et al. found a linear relationship between the absolute PSA value and identification of the site of relapse. Rinnab et al. [30] evaluated the detection of biochemical recurrence of prostate cancer after radical prostatectomy with 11 C-choline PET/CT in 41 patients, and reported a sensitivity value of 89% for patients with a PSA < 2.5 ng/mL. Castellucci et al. [31] investigated the effect of total PSA at the time of 11C-choline PET/CT (trigger PSA), PSA velocity (PSAve), and PSA-doubling time (PSAdt) on 11C-choline PET/ CT detection rate in patients (n = 190) treated with radical prostatectomy who showed biochemical recurrence (defined as PSA > 0.2 ng/mL; range, 0.2–25.4 ng/mL; mean, 4.2 ng/mL) during follow-up. The authors found that the likelihood of lesion detection by the non standard imaging evaluation with 11 C-choline PET was increased when PSA was higher than
[(Fig._ 2)TD$FIG] Nucléaire 37 (2013) 71–77 A. Mestre-Fusco, M. Suárez-Piñera / Médecine 2.4 ng/mL or when PSA was less than 2.4 ng/mL but that the PSAdt was lower than 3.4 months or PSAve was higher than 1 ng/mL/year. Giovacchini et al. [32] evaluated the detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by 11C-choline PET/CT. ROC analysis was used to assess the performance of 11C-choline PET/CT in relation to PSA levels in a study for 358 patients. The mean PSA level was 3.77 6.94 ng/mL. PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. Statistical significance (P < 0.05) was obtained for PSA levels, pathological stage, age and history of biochemical failure as a predictive factors. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/mL. Schillaci et al. [33] evaluate the accuracy of 18F-FCH PET/ CT in 49 restaging patients with PCa after radical prostatectomy in relation to PSA, PSAve and PSAdt. Rising PSA (mean 4.13 ng/mL) were divided into four groups according to PSA level: 1 ng/mL, 1 to 2 ng/mL, 2 to 4 ng/mL, and > 4 ng/mL. Based on their results, authors recommended PET/CT in patients with PSA > 2 ng/mL, PSAdt 6 months and PSAve > 2 ng/mL per year.
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Fig. 2. Comparison between PSA (ng/mL) and positive detection rate (%) using PET/CT 18F-FCH/11C-choline by authors. Comparaison entre le taux de PSA (ng/mL) et la sensibilité de détection PDR (%) en TEP/TDM avec choline marquée par le fluor 18 ou le carbone 11.
In summary, it appears that the sensitivity of PET may generally depend directly on serum PSA level, with the expectation that at higher PSA levels, the probability of lesion localization increases. Several PSA cut-off values have been proposed on the basis of choline PET/CT-Positive Detection Rate (Fig. 2). In our experience, there is a relationship between PSA level and presence of lymph node or metastatic disease in patients diagnosed and treated for PCa and biochemical failure (Figs. 3 and 4).
[(Fig._ 3)TD$FIG]
Fig. 3. Patient treated for PCa with biochemical recurrence, PSA mean = 7.8 ng/mL. PET/CT with 11C-choline demonstrated lymph node dissemination. Patient sous traitement d’un cancer prostatique, avec récidive biologique (PSA moyen = 7,8 ng/mL). La TEP/TDM avec 11C-choline montre des localisations secondaires ganglionnaires.
[(Fig._ 4)TD$FIG] 76
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Fig. 4. Patient treated for PCa with biochemical recurrence, PSA mean = 20.1 ng/ml. PET/CT with 11C-choline shows bone metastases. Patient sous traitement d’un cancer prostatique, avec récidive biologique (PSA moyen = 20,1 ng/mL). La TEP/TDM avec 11C-choline montre des métastases osseuses.
5. Use of choline PET in bone metastases
6. Conclusion
It has been estimated that > than 80% of men who die from PCa develop bone metastases. It is mainly osteoblastic, and is caused by a relative excess of osteoblast activity induced by adjacent cancer cells, leading to abnormal bone formation [3]. In a prospective study, Behesthi et al. [34] compared the potential value of 18F-FCH and 18F-sodium fluoride PET/CT for the detection of bone metastases from PCa. Thirty-eight patients were studied. Overall, 321 lesions were evaluated in this study. The sensitivity, specificity and accuracy of PET/ CT in the detection of bone metastases in PCa was 81%, 93% and 86% for 18F-sodium fluoride, and 74%, 99% (P = 0.01) and 85% for 18F-FCH, respectively. So, 18F-sodium fluoride PET/CT demonstrated higher raw sensitivity than 18F-FCH PET/CT for detection of bone metastases (not statistically significant). Hence, 18F-FCH PET/CT proved to be more specific than 18F-sodium fluoride PET/CT. For evaluation of bone metastases in PCa patients, 18F-FCH and 18F-sodium fluoride PET/CT were concordant in 80% of lesions. In the group with 18F-FCH positive/18F-sodium fluoride negative results, the findings may be due to bone marrow metastases without significant bone reaction and remodelling, which suggests that 18F-FCH PET/CT has an advantage in the early detection of bone metastases.
Choline PET/CT cannot be recommeded as a first-line screening procedure for primary PCa due to its limited sensitivity, its dependency on tumor configuration and its limited specificity in differentiation between prostate cancer and benign pathologies. Published data indicate an emerging role for MRI, combining T2 weighted imaging, diffusion weighted imaging, contrast-enhanced MR, and spectroscopy, as the most sensitive and specific tool available to evaluate prostate gland. On the other hand, choline PET/CT could be useful in the detection of malignant lymph nodes except in case of nodes smaller than 5 mm in diameter. In fact, an accurate detection of lymph-node metastases is essential to decide the treatment. So, pelvic lymph node metastases are the strongest predictor of disease recurrence and progression. Although CT and specially MRI are the main imaging tool for N-staging of PCa they has a relative low sensitivity and choline PET/CT may play a role in N-staging. In contrast, choline PET/CT has proved to be useful for restaging patients with prostate cancer with biochemical failure. Studies have shown that the positive detection rate of choline PET/CT increases with increasing PSA values. The definition of a PSA cut-off value to refer PCa with biochemical recurrence would be helpful for the clinical management of these patients. Several PSA cut-off values have been proposed
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on the basis of Choline PET/CT-Positive Detection Rate with discrepancies reported by authors. In addition, despite several studies over the last few years, there is currently no consensus on such a PSA cut-off value. The routine use of choline PET/CT cannot be recommended only in patients with an absolute PSA value < 1 ng/mL. Moreover, the sensitivity of 18F-FCH PET/ CT is significantly higher in patients with a PSAve > 2 ng/mL per year or a PSAdt 6 months. Similarly, 11C-choline PET/ CT detection rate is influenced by trigger PSA, PSAdt and PSAve. Other factors as advanced pathological stage, older age and history of biochemical failure are predictive factors of positive choline PET/CT findings and should be considered. In bone metastases evaluation, 18F-sodium fluoride PET/CT demonstrated higher raw sensitivity than 18F-FCH PET/CT for detection of bone metastases. In contrast, in case of early metastases 18F-FCH could be superior to 18F-sodium fluoride due to the absence of bone reaction and remodelling.
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[15] Beheshti M, Imamovic L, Broinger G, Vali R, Waldenberger P, Stoiber F, et al. 18F choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 patients. Radiology 2010;254:925. [16] de Jong IJ, Pruim J, Elsinga PH, et al. Visualization of prostate cancer with 11C-choline positron emission tomography. Eur Urol 2002;42:18–23. [17] Yoshida S, Nakagomi K, Goto S, et al. 11C-choline positron emission tomography in prostate cancer: primary staging and recurrent site staging. Urol Int 2005;74:214–20. [18] Kwee SA, Wei H, Sesterhenn I, et al. Localization of primary prostate cancer with dual-phase 18F-fluorocholine PET. J Nucl Med 2006;47: 262–9. [19] Reske SN, Blumstein NM, Neumaier B, et al. Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med 2006;47:1249–54. [20] Husarik DB, Miralbell R, Dubs M, et al. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:253–63. [21] Souvatzoglou M, Weirich G, Schwarzenboeck S, et al. The sensitivity of [11 C]Choline PET/CT to localize prostate cancer depends on the tumor configuration. Clin Cancer Res 2011;17:3751–9. [22] Yamaguchi T, Lee J, Uemura H, et al. Prostate cancer: a comparative study of 11C-choline PET and MR imaging combined with proton MR spectroscopy. Eur J Nucl Med Mol Imaging 2005;32:742–8. [23] Martorana G, Schiavina R, Corti B, et al. 11C-choline positron emission tomography/computerized tomography for tumor localization of primary prostate cancer in comparison with 12-core biopsy. J Urol 2006;176: 954–60. [24] Farsad M, Schiavina R, Castellucci P, et al. Detection and localization of prostate cancer: correlation of (11)C-choline PET/CT with histopathologic step-section analysis. J Nucl Med 2005;46:1642–9. [25] Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, et al. (18)F-choline and/or (11)C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostatespecific antigen values (< 1 ng/mL) after radical prostatectomy. BJU Int 2007;99:1415–20. [26] de Jong IJ, Pruim J, Elsinga PH, Vaalburg W, Mensink HJ. 11C-choline positron emission tomography for the evaluation after treatment of localized prostate cancer. Eur Urol 2003;44:32–8. [27] Husarik DB, Miralbell R, DubsM, John H, Giger OT, Gelet A, et al. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:253–63. [28] Cimitan M, Bortolus R, Morassut S, Canzonieri V, Garbeglio A, Baresic T, et al. [(18)F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging 2006;33:1387–98. [29] Krause BJ, Souvatzoglou M, Tuncel M, Herrmann K, Buck AK, Praus C, et al. The detection rate of [11 C]choline-PET/CT depends on the serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:18–23. [30] Rinnab L, Simon J, Hautmann RE, Cronauer MV, Hohl K, Buck AK, et al. [(11)C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy. World J Urol 2009;27:619. [31] Castellucci P, Fuccio C, Nanni C, et al. Influence of trigger PSA and PSA kinetics on 11C-choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med 2009;50:1394–400. [32] Giovacchini G, Picchio M, Coradeschi E, Bettinardi V, Gianolli L, Scattoni V, et al. Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging 2010;37:301–9. [33] Schillaci O, Calabria F, Tavolozza M, Caracciolo CR, Finazzi Agrò E, Miano R, et al. Influence of PSA, PSA velocity and PSA doubling time on contrast-enhanced 18F-choline PET/CT detection rate in patients with rising PSA after radical prostatectomy. Eur J Nucl Med Mol Imaging 2012;39:589–96. [34] Beheshti M, Vali R, Waldenberger P, Fitz F, Nader M, Loidl W, et al. Detection of bone metastases in patients with prostate cancer by (18)F fluorocholine and (18)F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging 2008;35:1766.
www.sciencedirect.com Médecine Nucléaire 37 (2013) 71–77
Review
Use of choline tracers in the prostate carcinoma management Utilisation de la choline marquée dans la prise en charge du cancer de la prostate A. Mestre-Fusco *, M. Suárez-Piñera Nuclear Medicine Department, Hospital del Mar, Parc de Salut Mar, Passeig Maritim 25-29 P-1, 08003 Barcelona, Spain Received 14 November 2012; accepted 23 November 2012 Available online 1st March 2013
Abstract Prostate cancer is the second most frequently diagnosed cancer in men. This incidence has increased because of the introduction of screening with prostate-specific antigen (PSA) and the use of improved biopsy techniques. Choline PET/CT cannot be recommended as a first-line screening procedure for primary prostate cancer. PET/CT has a limited sensitivity due to its dependency on tumor configuration and size, and a limited specificity in differentiation between prostate cancer and benign pathologies. PET/CT could be useful in the detection of malignant lymph nodes in case of nodes greater than 5 mm in diameter. An application of choline PET/CT may be to increase the detection rate of clinically suspected prostate cancer with multiple negative prostate biopsies. Choline PET/CT has proved to be useful for restaging patients with prostate cancer with biochemical failure. Studies have shown that the positive detection rate of choline PET/CT increases with increasing PSA values. The definition of a PSA cut-off value to refer prostate carcinoma with biochemical recurrence would be helpful for the clinical management of these patients. Several PSA cut-off values have been proposed by literature. The routine use of choline PET/CT cannot be recommended only in patients with an absolute PSA value of < 1 ng/mL. Moreover, the sensitivity of 18F-Fluorocholine (FCH) PET/CT is significantly higher in patients with a PSA velocity > 2 ng/mL per year or a PSA-doubling time 6 months. In case of early bone metastases 18F-FCH could be superior to 18F-sodium fluoride due to the absence of bone reaction and remodelling. # 2012 Elsevier Masson SAS. All rights reserved. Keywords: Prostate; Cancer; PET;
11
C-Choline;
18
F-FCH
Résumé Le cancer de la prostate est le deuxième cancer le plus fréquent chez l’homme. Cette prévalence a augmenté avec l’utilisation en dépistage du dosage de l’antigène prostatique spécifique (PSA) et l’amélioration des techniques des biopsies. La TEP-TDM à la choline marquée ne peut pas être recommandée comme procédure de première ligne de dépistage. La TEP-TDM a une sensibilité limitée car elle dépend de la configuration et de la taille tumorales, et une spécificité limitée dans sa capacité à différencier un cancer prostatique d’une pathologie bénigne. La TEP-TDM peut être utile dans la détection de ganglions métastatiques, si leur taille est supérieure à 5 mm. Une application de la TEP-TDM à la choline marquée est d’augmenter le taux de détection de cancers suspectés malgré de multiples biopsies négatives. La TEP-TDM à la choline marquée s’est révélée utile pour redéfinir le stade du cancer lors d’une récidive biologique. Des études ont montré que le taux de détection de la TEP-TDM à la choline marquée augmentait avec le taux de PSA. La définition d’une valeur seuil de PSA pour prédire une récurrence cancéreuse dans le cas d’une récidive biologique serait très utile dans la prise en charge de ces patients. Plusieurs valeurs seuils ont été proposées dans la littérature. Une utilisation en routine de la TEP-TDM à la choline marquée n’est pas recommandée chez des patients présentant un dosage de PSA inférieur à 1 ng/L. De plus, la sensibilité de la TEP-TDM à la choline marquée au fluor 18 est significativement supérieure chez les patients présentant une vélocité du PSA supérieur à 2 ng/mL par an, ou un temps de doublement du PSA inférieur ou égal à six mois. Pour la détection de métastases osseuses précoces, la fluorocholine-18F peut être supérieure au fluorure de sodium-18F en raison de l’absence de réaction et de remodelage osseux. # 2012 Elsevier Masson SAS. Tous droits réservés. Mots clés : Prostate ; Cancer ; TEP ; Choline -18F ; Choline -11C
* Corresponding author. E-mail address: [email protected] (A. Mestre-Fusco). 0928-1258/$ – see front matter # 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.mednuc.2012.11.004
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1. Introduction Prostate cancer (PCa) is the second most frequently diagnosed cancer, and the third most common cause of death from cancer in men in United States and Western Europe [1]. PCa is clinically a heterogeneous disease characterized by an overall long natural history in comparison to the other solid tumors, with a wide spectrum of biologic behavior that ranges from indolent to aggressive [2]. Clinically, PCa is diagnosed as local or advanced, and treatments range from surveillance to radical local treatment or androgen-deprivation treatment. Androgen deprivation reduces symptoms in about 70 to 80% of patients with advanced prostate cancer, but most tumours relapse within 2 years to an incurable androgen-independent state [1,3]. The incidence of prostate cancer has substantially increased in the past two decades, probably because of the introduction of screening with prostate-specific antigen (PSA) and the use of improved biopsy techniques for diagnosis. Commonly used diagnostic tools in the evaluation of prostate cancer are digital rectal examination (DRE), measurement of serum levels of prostate-specific antigen (PSA), transrectal ultrasound (TRUS) as well as TRUS-guided biopsies. A combination of TRUS and DRE findings seems to predict biopsy results best. Cancer recurrence detection seems to be predicted by TRUS and DRE findings, but not by PSA levels or pathological stage [4]. Gold standard for diagnosing PCa is based on histopathological examination of tissue specimens from the prostate gland core biopsies. The most commonly used system for grading adenocarcinoma of the prostate is the Gleason score. The system describes a score between 2 and 10, with 2 being the less aggressive and 10 the most aggressive [3–5]. Moreover, several molecular biomarkers of cancer pathogenic pathways including Ki-67 (proliferation), Bcl-2 (apoptosis), CD31 (angiogenesis), Her-2/neu (oncogene), PTEN (anti-oncogene), and AR (androgen receptor) were also involved in CaP. Chen et al. [6] evaluated whether the tracer 11 C-choline uptake, quantified as SUVmax-P/M ratio (ratio calculated as prostate lesions or target P and pelvis muscles non-target M) correlated with tumour stage, Gleason score, and expression levels of these biomarkers of aggressiveness. As a result, SUVmax-P/M ratio was also significantly higher in lesions with Gleason score of 4 + 3 or higher versus less than or equal to 3 + 4. SUVmax-P/M ratio was found significantly correlated with expression levels of Ki-67 and CD31 and a higher SUVmax-P/M ratio was demonstrated in Her-2/neu positive subgroup. Nevertheless, a correlation between SUVmax of 11C-choline and Ki-67 was not confirmed by other authors [7]. Pathological stage of PCa is based on TNM classification [8], emphasizing in T3: the tumor has spread through the prostatic capsule, N1: metastasis in regional lymph node(s), M1a: the cancer has spread to lymph nodes beyond the regional ones and M1b: the cancer has spread to bone. The choice of treatment for localized PCa, i.e. active surveillance, radical prostatectomy, or any type of radiotherapy,
depends on tumor characteristics, Gleason score, PSA value and the patient’s life expectancy. Treatment with intent to cure is not used in all patients with PCa since many cases of well to moderately differentiated PCa have a very indolent history [3]. In fact, prostatectomy did not prolong survival unless patients were younger than 65 years [7,9]. In PCa screening, it is known that there is no true PSA cutoff point distinguishing cancer from non-cancer. Some authors [10] suggest that providers consider individualized decision making when PSA levels fall in the indeterminate range of 2.5 ng/mL to 4.0 ng/mL, particularly for men at increased risk for high-grade cancer based on non-PSA risk factors. On the other hand, the first sign of failure after primary treatment with curative intent is generally a rising serum PSA level, occurring months to years before clinical symptoms or imaging signs of recurrent disease [3]. A biochemical failure or recurrence is defined by a detectable serum PSA level of at least two consecutive measurements of > 0.2 ng/mL after surgery [2] or by an increment of 2 ng/mL over nadir PSA after radiotherapy (RT) [11]. In general, local recurrence is characterized by a late PSA increase, a long PSA-doubling time, and a less aggressive disease at diagnosis with low Gleason score, and no invasion of the seminal vesicles or lymph nodes [3].
2. Imaging techniques in prostate carcinoma Panebianco et al. reported the emerging role for MRI, particularly multiparametric MRI combining T2 weighted imaging, diffusion weighted imaging, contrast-enhanced MR, and spectroscopy, as the most sensitive and specific tool available to evaluate prostate gland and imaging PCa [12]. MRI of patient with PCa affecting the left lobe of prostate gland is shown on Fig. 1. On the other hand, morphological imaging techniques such as TRUS, CT and MRI have demonstrated only limited accuracy for primary diagnosis of prostate cancer, recurrent disease as well as advanced disease. Furthermore, the detection of lymph node metastases is limited by CT and MRI; first, small lymph node metastases cannot be visualized; second, size as the only criterion might not be sufficient to detect metastatic involvement in lymph nodes. Combined molecular and morphological imaging techniques such as PET/ CT may improve the diagnostic accuracy in imaging prostate cancer. PET/CT based on increased glycolysis using 18Ffluorodeoxyglucose (FDG) has shown only limited sensitivity for the detection of PCa [5]. Evidence derived from imaging studies over the past many years suggest that use of different imaging modalities may need to be aligned with the clinical phase of the disease [13]. There has been considerable interest in the potential diagnostic utility of PET with radiolabeled 11C or 18F-choline in prostate cancer [2]. The biologic basis for radiolabeled choline uptake in tumors is the malignancy-induced upregulation of choline kinase, which leads to the incorporation and trapping of choline in the form of phosphatidylcholine in the tumor cell membrane.
[(Fig._ 1)TD$FIG]
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Fig. 1. Multiparametric MRI combining T2 weighted imaging (B), diffusion (C) and perfusion (D) weighted imaging, and spectroscopy (A), in patient with PCa affecting the left lobe of prostate gland. IRM multiparamétrique, associant les images pondérées T2 (B), de diffusion (C), de perfusion (D), et de spectroscopie (A) chez un patient présentant un cancer du lobe gauche de la prostate.
11
C-choline has a shorter half-life (20 min) that requires an onsite cyclotron. Normal biodistribution of 11C-choline demonstrates relatively high accumulation in the pancreas, liver, kidneys, and salivary glands and variable uptake in the bowel, with little urinary excretion [14]. 18F-fluorocholine (FCH) has a longer half-life (110 min). The normal biodistribution of 18F-FCH demonstrates relatively high accumulation in the pancreas, liver, spleen, and kidneys; variable uptake in the bowel; and urinary excretion of 18F-FCH is higher than 11 C-choline. Both of them have an uptake overlapping benign and malignant prostate tissues [2,3]. 3. Use of choline PET in initial diagnosis and local evaluation The value of PET and PET/CT using 11C and 18F labeled choline derivates for the initial diagnosis of primary PCa has been examined in several studies with controversial results. Behesthi et al. [15] assessed the value of 18F-FCH PET/CT in the preoperative staging of intermediate and high-risk patients with PCa. The authors evaluated 132 patients with PCa with intermediate or high risk of extracapsular disease. Overall, 912 lymph nodes were histopathologically examined, and an analysis revealed the sensitivity, specificity, and positive and negative predictive values of 18F-FCH PET/CT in the detection
of malignant lymph nodes were 45%, 96%, 82%, and 83%, respectively. In lymph nodes 5 mm in diameter or larger, the sensitivity, specificity, and positive and negative predictive values were 66%, 96%, 82%, and 92%, respectively. 18F-FCH PET/CT had limited value in the detection of malignant lymph nodes smaller than 5 mm in diameter. When considering the entire high-risk group, 20% of the patient population (17/83 patients) had findings that were upstaged after 18F-FCH PET/ CT. The following studies reported a high sensitivity for the detection of primary prostate cancer using PET and PET/CT with 11C-choline or 18F-FCH (Table 1). De Jong et al. [16] prospectively evaluated the visualization of primary PCa with 11 C-choline PET in patients with biopsy-proven prostate cancer in comparison with benign changes of the prostate. Normal prostate and prostate cancer tissue showed mean SUV of 2.3 (1.3–3.2) and 5 (2.4–9.5), respectively. In 24 patients out of 25, there was a focal increased choline uptake. Yoshida et al. [17] evaluated the use of 11C-choline in staging primary PCa. Tumoral lesion could be identified by means of increased choline uptake in five patients out of six (SUV mean of 4.21) and only in one patient with primary prostate cancer could not be identified correctly. Kwee et al. (2006) [18] evaluated the efficacy of delayed 18F-FCH PET imaging or imaging at two time points (dual point) for the localization of primary PCa
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Table 1 Diagnostic efficacy of 18F-choline (FCH) and 11C-choline PET and PET/CT in patients with primary Pca. Efficacite´ diagnostique de la TEP et TEP/TDM avec 18F-choline (FCH) et 11C-choline chez des patients pre´sentant un cancer prostatique primaire. Tracer
18F-FCH 11C-Choline 11C-Choline 18F-FCH 11C-Choline 18F-FCH 11C-Choline 11C-Choline 11C-Choline 11C-Choline
Reference
[15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Author
Beheshti et al. de Jong et al. Yoshida et al. Kwee et al. Reske et al. Husarik et al. Souvatzoglou et al. Yamaguchi et al. Martorana et al. Farsad et al.
Year
2010 2002 2005 2006 2006 2008 2011 2005 2006 2005
Modus
PET/CT PET PET PET PET/CT PET/CT PET/CT PET PET/CT PET/CT
Patients
130 25 13 26 26 43 43 20 43 36
Local tumor
Lymph nodes
Sensitivity (%)
Specificity (%)
Sensitivity (%)
Specificity (%)
no 100 no 100 100 98 79 100 66 66
84 81 no no no no no no no no
45 80 no no no 33 no no no no
96 95 no no no 100 no no no no
Modified from [5]. No: non available.
(7 min and 1 h). The mean SUVmax for malignant findings significantly increased from 7.6 to 8.6 between early and delayed acquisition while the mean SUVmax for presumably benign lesions significantly decreased between the initial and the late image (4.8 to 3.9). Reske et al. [19] found a SUVmax cut-off of 2.65 with an associated area under the curve of 0.89 0.01 in the ROC analysis for correct prediction of prostate cancer. Regions with PCa could be identified in all patients (26/26) using 11C-choline PET/CT, resulting in a sensitivity of 100%. Furthermore, the authors did not find a correlation between 11C-choline SUVmax and PSA value and Gleason score but found a correlation with T stage. Besides the limited sensitivity, the differentiation between benign prostatic hyperplasia (BPH), prostatitis or high-grade intraepithelial neoplasia (HGPIN) is not always possible in primary staging of PCa using choline PET/CT [3,5,20–24]. Beheshti et al. [15] concluded that differentiation between PCa and prostatitis was not possible due to intense FCH accumulation in inflammatory lesions. Souvatzoglou et al. [21] confirmed the results concerning limited specificity of choline PET/CT in primary staging of PCa. In their study, there was no statistically significant difference between SUVmax of prostate cancer, benign prostate hyperplasia (P = 0.102) or prostatitis (P = 0.054). They concluded that the detection and localization of PCa in the prostate with 11C-choline PET/CT is impaired by tumor configuration. Yamaguchi et al. [22] also confirmed these results by showing that there was a significant overlap of choline uptake between BPH and PCa which resulted in a limited specificity in the detection of primay PCa using choline PET/CT. Martorana et al. [23] showed that SUVmax was significantly higher in malignant lesions compared to benign lesion (P = 0.027). However, there was no statistically significant difference between false-positive and false-negative findings. Based on sextant biopsy, PET/CT had a slightly better sensitivity than transrectal ultrasound (66% vs. 61%, P = 0.434) but it was less specific (84% vs. 97%, P = 0.008). Farsad et al. [24] confirmed that benign entities also show a high choline uptake, and reported a specificity of 81% for the detection of primary prostate cancer that was not significantly different from that with HGPIN.
In summary, choline PET/CT cannot be recommended as a first-line screening procedure for the diagnosis of primary prostate cancer in men at risk. It might play a role in the detection of clinically suspected prostate cancer with repeatedly negative prostate biopsies [3,5]. 4. Use of choline PET in biochemical recurrence When a biochemical recurrence is observed in patients, accurate delineation of local versus metastatic disease is crucial for selection of appropriate therapy [3]. Several studies have reported both 11C-Choline and 18FFCH PET/CT to be useful for detecting recurrence in patients with PSA relapse [25–33]. However, a PSA cut-off value for which PCa patients should be referred to PET/CT has not been established yet. This threshold ranges from values as low as 1 ng/mL [25] to high as 5 ng/mL [20,26], In a large prospective study, Cimitan et al. [28] identified prostate cancer recurrence with 18F-FCH PET/CT in 53 patients out of 100 with PSA relapse; however, 89% of patients with presumably false-negative scans had a serum PSA level < 4 ng/ dL resulting in a lower sensitivity for 18F-FCH for detecting recurrent prostate cancer if the PSA was low. Similar results [29] have also been reported for choline PET/CT, with a low sensitivity in patients with a PSA less than 4 to 5 ng/mL. Krause et al. found a linear relationship between the absolute PSA value and identification of the site of relapse. Rinnab et al. [30] evaluated the detection of biochemical recurrence of prostate cancer after radical prostatectomy with 11 C-choline PET/CT in 41 patients, and reported a sensitivity value of 89% for patients with a PSA < 2.5 ng/mL. Castellucci et al. [31] investigated the effect of total PSA at the time of 11C-choline PET/CT (trigger PSA), PSA velocity (PSAve), and PSA-doubling time (PSAdt) on 11C-choline PET/ CT detection rate in patients (n = 190) treated with radical prostatectomy who showed biochemical recurrence (defined as PSA > 0.2 ng/mL; range, 0.2–25.4 ng/mL; mean, 4.2 ng/mL) during follow-up. The authors found that the likelihood of lesion detection by the non standard imaging evaluation with 11 C-choline PET was increased when PSA was higher than
[(Fig._ 2)TD$FIG] Nucléaire 37 (2013) 71–77 A. Mestre-Fusco, M. Suárez-Piñera / Médecine 2.4 ng/mL or when PSA was less than 2.4 ng/mL but that the PSAdt was lower than 3.4 months or PSAve was higher than 1 ng/mL/year. Giovacchini et al. [32] evaluated the detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by 11C-choline PET/CT. ROC analysis was used to assess the performance of 11C-choline PET/CT in relation to PSA levels in a study for 358 patients. The mean PSA level was 3.77 6.94 ng/mL. PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. Statistical significance (P < 0.05) was obtained for PSA levels, pathological stage, age and history of biochemical failure as a predictive factors. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/mL. Schillaci et al. [33] evaluate the accuracy of 18F-FCH PET/ CT in 49 restaging patients with PCa after radical prostatectomy in relation to PSA, PSAve and PSAdt. Rising PSA (mean 4.13 ng/mL) were divided into four groups according to PSA level: 1 ng/mL, 1 to 2 ng/mL, 2 to 4 ng/mL, and > 4 ng/mL. Based on their results, authors recommended PET/CT in patients with PSA > 2 ng/mL, PSAdt 6 months and PSAve > 2 ng/mL per year.
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Fig. 2. Comparison between PSA (ng/mL) and positive detection rate (%) using PET/CT 18F-FCH/11C-choline by authors. Comparaison entre le taux de PSA (ng/mL) et la sensibilité de détection PDR (%) en TEP/TDM avec choline marquée par le fluor 18 ou le carbone 11.
In summary, it appears that the sensitivity of PET may generally depend directly on serum PSA level, with the expectation that at higher PSA levels, the probability of lesion localization increases. Several PSA cut-off values have been proposed on the basis of choline PET/CT-Positive Detection Rate (Fig. 2). In our experience, there is a relationship between PSA level and presence of lymph node or metastatic disease in patients diagnosed and treated for PCa and biochemical failure (Figs. 3 and 4).
[(Fig._ 3)TD$FIG]
Fig. 3. Patient treated for PCa with biochemical recurrence, PSA mean = 7.8 ng/mL. PET/CT with 11C-choline demonstrated lymph node dissemination. Patient sous traitement d’un cancer prostatique, avec récidive biologique (PSA moyen = 7,8 ng/mL). La TEP/TDM avec 11C-choline montre des localisations secondaires ganglionnaires.
[(Fig._ 4)TD$FIG] 76
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Fig. 4. Patient treated for PCa with biochemical recurrence, PSA mean = 20.1 ng/ml. PET/CT with 11C-choline shows bone metastases. Patient sous traitement d’un cancer prostatique, avec récidive biologique (PSA moyen = 20,1 ng/mL). La TEP/TDM avec 11C-choline montre des métastases osseuses.
5. Use of choline PET in bone metastases
6. Conclusion
It has been estimated that > than 80% of men who die from PCa develop bone metastases. It is mainly osteoblastic, and is caused by a relative excess of osteoblast activity induced by adjacent cancer cells, leading to abnormal bone formation [3]. In a prospective study, Behesthi et al. [34] compared the potential value of 18F-FCH and 18F-sodium fluoride PET/CT for the detection of bone metastases from PCa. Thirty-eight patients were studied. Overall, 321 lesions were evaluated in this study. The sensitivity, specificity and accuracy of PET/ CT in the detection of bone metastases in PCa was 81%, 93% and 86% for 18F-sodium fluoride, and 74%, 99% (P = 0.01) and 85% for 18F-FCH, respectively. So, 18F-sodium fluoride PET/CT demonstrated higher raw sensitivity than 18F-FCH PET/CT for detection of bone metastases (not statistically significant). Hence, 18F-FCH PET/CT proved to be more specific than 18F-sodium fluoride PET/CT. For evaluation of bone metastases in PCa patients, 18F-FCH and 18F-sodium fluoride PET/CT were concordant in 80% of lesions. In the group with 18F-FCH positive/18F-sodium fluoride negative results, the findings may be due to bone marrow metastases without significant bone reaction and remodelling, which suggests that 18F-FCH PET/CT has an advantage in the early detection of bone metastases.
Choline PET/CT cannot be recommeded as a first-line screening procedure for primary PCa due to its limited sensitivity, its dependency on tumor configuration and its limited specificity in differentiation between prostate cancer and benign pathologies. Published data indicate an emerging role for MRI, combining T2 weighted imaging, diffusion weighted imaging, contrast-enhanced MR, and spectroscopy, as the most sensitive and specific tool available to evaluate prostate gland. On the other hand, choline PET/CT could be useful in the detection of malignant lymph nodes except in case of nodes smaller than 5 mm in diameter. In fact, an accurate detection of lymph-node metastases is essential to decide the treatment. So, pelvic lymph node metastases are the strongest predictor of disease recurrence and progression. Although CT and specially MRI are the main imaging tool for N-staging of PCa they has a relative low sensitivity and choline PET/CT may play a role in N-staging. In contrast, choline PET/CT has proved to be useful for restaging patients with prostate cancer with biochemical failure. Studies have shown that the positive detection rate of choline PET/CT increases with increasing PSA values. The definition of a PSA cut-off value to refer PCa with biochemical recurrence would be helpful for the clinical management of these patients. Several PSA cut-off values have been proposed
A. Mestre-Fusco, M. Suárez-Piñera / Médecine Nucléaire 37 (2013) 71–77
on the basis of Choline PET/CT-Positive Detection Rate with discrepancies reported by authors. In addition, despite several studies over the last few years, there is currently no consensus on such a PSA cut-off value. The routine use of choline PET/CT cannot be recommended only in patients with an absolute PSA value < 1 ng/mL. Moreover, the sensitivity of 18F-FCH PET/ CT is significantly higher in patients with a PSAve > 2 ng/mL per year or a PSAdt 6 months. Similarly, 11C-choline PET/ CT detection rate is influenced by trigger PSA, PSAdt and PSAve. Other factors as advanced pathological stage, older age and history of biochemical failure are predictive factors of positive choline PET/CT findings and should be considered. In bone metastases evaluation, 18F-sodium fluoride PET/CT demonstrated higher raw sensitivity than 18F-FCH PET/CT for detection of bone metastases. In contrast, in case of early metastases 18F-FCH could be superior to 18F-sodium fluoride due to the absence of bone reaction and remodelling.
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