REVIEW URRENT C OPINION
Advances in imaging modalities in prostate cancer Kirsten Bouchelouche a, Baris Turkbey b, and Peter L. Choyke b
Purpose of review Imaging plays an important role in the clinical management of prostate cancer (PCa). Thus, much effort has gone into improving imaging modalities in PCa. This review focuses on the recent advancements in transrectal ultrasound, MRI and PET during the past year. Recent findings Contrast-enhanced transrectal ultrasound with microbubbles may be useful in PCa, but needs further evaluation before more widespread use. Multiparametric MRI has emerged as a valuable tool to assist clinical management of PCa, and great progress has been made in the past year. Several radionuclides for PET/computed tomography have been tested in clinical trials; most of the studies have used radiolabeled choline. However, new PET tracers such as 18F-1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid and 68Ga-labeled prostate-specific membrane antigen ligands are demonstrating promising results. PET/MRI may further improve imaging in PCa, but this imaging modality needs to be evaluated further. Summary Several advances in the imaging of PCa have been made during the past year. In particular, important clinical developments have been reported in multiparametric MRI, PET/computed tomography, and PET/MRI. The continuing development of imaging techniques in PCa has the potential to optimize treatment of PCa. However, the optimal imaging strategies for each of the major clinical scenarios in PCa have not yet been identified. Keywords MRI, PET/CT, PET/MRI, prostate cancer, transrectal ultrasound
INTRODUCTION Prostate cancer (PCa) is the most frequently diagnosed cancer in men [1]. Appropriate imaging of PCa is a crucial component of detection, staging, restaging, and therapy. Thus, it is important at primary diagnosis, at follow-up and recurrence, and in the presence of metastases to obtain accurate assessment of the disease in order to provide the best treatment strategies. For the purpose of this review, we consider the following major clinical scenarios: PCa detection and diagnosis, staging of PCa, detection of recurrent disease, and detection and monitoring of metastatic disease. The purpose of this review is to highlight the most important developments in transrectal ultrasound (TRUS), multiparametric MRI (mpMRI), and PET reported in the past year.
TRANSRECTAL ULTRASOUND TRUS is the most commonly used imaging technique for the prostate. The primary role of TRUS is in guiding biopsies of the prostate gland. TRUS has www.co-oncology.com
limited ability in detecting PCa; thus, these biopsies are considered ‘blind’ or ‘random’ because they are not targeted to a specific abnormality. Recently, contrast-enhanced TRUS (CE-TRUS) using gas-filled microbubbles has been reported to provide higher sensitivity for tumor detection than conventional unenhanced TRUS. Cornelis et al. [2] retrospectively evaluated the diagnostic accuracy of real-time CE-TRUS-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA). These patients (n ¼ 178) had previously negative TRUS-guided biopsies, but positive MRI findings.
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Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark and bMolecular Imaging Program, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA Correspondence to Kirsten Bouchelouche, Chief Physician, MD, DMSc, Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, Aarhus DK-8200, Denmark. Tel: +45 20 29 19 03; e-mail: [email protected] Curr Opin Oncol 2015, 27:224–231 DOI:10.1097/CCO.0000000000000174 Volume 27 Number 3 May 2015
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KEY POINTS Imaging plays an increasingly important role in the clinical management of PCa, and research has focused on new and more accurate imaging modalities. Contrast-enhanced TRUS with microbubbles may be useful in PCa, but needs further evaluation before more widespread use. Significant progress has been made in improving image acquisition and interpretation of mpMRI, and the role of mpMRI is shifting from local staging toward lesion detection and biopsy guidance. Several PET tracers (predominantly choline) have been tested in PCa, and new PET tracers such as 18F-FACBC and 68Ga-PSMA are demonstrating promising results in recurrent and metastatic PCa. PET/MRI may improve PCa imaging but the exact clinical role of PET/MRI remains to be elucidated.
CE-TRUS-targeted biopsies (TBx) were performed in regions that were suspicious for cancer by MRI, followed by 12-core random TRUS-guided biopsies. TBx had a positive overall detection rate of 30.9%, whereas the overall detection was only 6.9% with the 12-core TRUS-guided biopsies [2]. Nontargeted ultrasound microbubbles were studied by Uemura et al. [3] who performed targeted prostate biopsies with microbubbles in 71 patients. Although there was a significant difference in cancer detection rate by TBx between two cohorts with PSA less than 10 ng/ml (22.9%) and PSA of at least 10 ng/ml (52.2%), the added value of CE-TRUS was relatively small [3]. Thus, the literature in CE-TRUS appears promising but somewhat contradictory. Confirmation of the role of CE-TRUS awaits more widespread use, but this will require off-label use of the microbubble agent. Furthermore, the transient nature of the enhancement, lack of expertise with this method, operator dependence, and a tradition in most ultrasound departments for not using intravenous contrast agents have inhibited progress in this field.
MULTIPARAMETRIC MRI MpMRI combines both anatomical and functional pulse sequences consisting of T1-weighted MRI, T2weighted MRI, diffusion-weighted MRI (DW-MRI), dynamic contrast-enhanced MRI (DCE MRI), and, in some cases, magnetic resonance (MR) spectroscopy imaging (MRSI). MRI is particularly useful in identifying clinically significant lesions that are missed on routine TRUS biopsy, but fails to detect most
small low-grade cancers that likely do not warrant treatment. As a result, there is a shift toward use of mpMRI for guiding biopsy. Salami et al. [4] compared the performance of the Prostate Cancer Prevention Trial risk calculator for high-grade PCa with MRI for detecting PCa. The area under the receiver-operating characteristic curve for Prostate Cancer Prevention Trial risk calculator for high grade in detecting high-grade PCa was 0.676, for MRI was 0.769, and for mpMRI was 0.812, respectively [4]. Therefore, mpMRI appears to predict clinically significant PCa with higher accuracy than standard clinical nomograms. Once the decision to perform a biopsy is made, various methods for combining MRI and TRUS have been proposed. Jambor et al. [5] evaluated the diagnostic accuracy of mpMRI and mpMRI-targeted TRUS-guided biopsy using ‘cognitive fusion’. In ‘cognitive fusion’, the operator performs a TRUS biopsy based on the estimated location on the corresponding MRI. This method relies on substantial experience in reconciling the location of an abnormality on TRUS with the abnormality seen more clearly on MRI. The sensitivity, specificity, accuracy, and area under the curve (AUC) values for MRdirected biopsy in the detection of clinically relevant PCa on a sextant basis were 72, 89, 85%, and 0.81, respectively [5], which conforms with the most recent studies using state-of-the-art equipment. A limitation of this study is that ‘cognitive fusion’ is quite operator dependent. It is also currently not clear whether MRI can be improved to increase sensitivity to approximately 90% and replace 12-core random biopsies. Although mpMRI is considered an advance in the diagnosis of PCa, concerns have been raised about its costs. Thus, methods that might reduce the cost while maintaining efficacy are of interest. Rais-Bahrami et al. [6] determined the diagnostic yield of biparametric (T2-weighted and diffusionweighted) MRI for PCa detection compared with digital rectal exploration and PSA-based screening. Biparametric MRI reduced costs by shortening scan time and avoiding costs associated with contrast media. The AUC for cancer detection for biparametric MRI, PSA, and PSA density were 0.80, 0.66, and 0.74, respectively, which is comparable to mpMRI [6]. Another means of reducing costs and discomfort would be to eliminate the use of the endorectal coil (ERC). Turkbey et al. [7] performed a study in which patients had mpMRI with and without ERC in the same session and then underwent radical prostatectomy. Overall sensitivity of the ERC mpMRI and non-ERC mpMRI were 0.76 and 0.45, respectively. Among the 20 index cancers, ERC mpMRI was able to detect 85%, whereas non-ERC mpMRI detected
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75% of the cancers [7]. Thus, the majority of the extra tumors detected by ERC mpMRI were low grade and probably not clinically significant. These results are encouraging; however, they warrant further prospective randomized studies. Another method of reducing costs is to be more patient selective. Shakir et al. [8 ] performed a study in 1003 patients who underwent mpMRI, TRUS, and MRI/TRUS-guided biopsies. Targeted biopsy led to significantly more upgrading to clinically significant disease compared with 12-core biopsy. However, this difference only became significant when the PSA was more than 5.4 ng/ml in which 90% of the upgrading by targeted biopsy was captured. Therefore, MRI was only of significant benefit in 64% of the patients who underwent mpMRI and subsequent MRI/TRUS fusion biopsy. Conversely, 36% of patients with lower PSA did not benefit from mpMRI; therefore, this procedure could be avoided in such patients [8 ]. Larger trials are needed to confirm these outcomes; however, it is evident that mpMRI might not be needed in every patient, therefore lowering costs. Thus, the combination of increased selectivity of mpMRI candidates, shorter examination times, and eliminating the ERC may lower the cost of mpMRI. The promising results with mpMRI have led to its increased use for biopsy planning and targeting. Many groups have reported equivalent or superior tumor detection rates for mpMRI-guided biopsies compared with random TRUS-guided biopsies. Quentin et al. [9] performed a prospective study in 132 biopsy naı¨ve men with increased PSA more than >4 ng/dl. TRUS and in-bore MRI-guided biopsies provided the same 53.1% overall tumor detection rate, including 79.4 and 85.3%, respectively, for significant PCa. However, in-bore MRI-guided biopsy achieved these results with significantly fewer cores and revealed a higher percentage of cancer involvement per biopsy core [9]. This study confirms a clear advantage of mpMRI-guided biopsies. However, the lesions biopsied by mpMRI are not necessarily the same lesions as those discovered by random TRUS biopsy. For instance, Salami et al. [10] evaluated the performance of mpMRI in predicting PCa on repeat biopsy, and compared the cancer detection rate of MRI/TRUS fusion-guided biopsy with standard 12-core systemic biopsy in 140 men with at least one previous negative biopsy. The fusion biopsy was more likely to detect clinically significant PCa when compared with the 12-core modality (47.9 vs. 30.7%) and among the cancers missed by 12 core, 20.9% were clinically significant [10]. Several other groups recently reported on the utility of mpMRI in noninvasive detection of PCa [11–13]. &
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Historically, mpMRI has been used for staging PCa, specifically for identifying extracapsular extension (ECE). However, its value has been debated because it cannot reliably detect microscopic ECE, which is often predicted from clinical nomograms. Gupta et al. [14] compared mpMRI with Partin tables in predicting ECE after radical prostatectomy. They reported sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI in detecting organ-confined disease as 81.6, 86.4, 91.2, and 73.1%, respectively. The ability of mpMRI to detect ECE was somewhat lower with a sensitivity, specificity, PPV, and NPV of 77.8, 83.4, 66.7, and 89.7%, respectively. The AUC values of Partin tables and mpMRI for correct staging were 0.62 and 0.82, respectively [14], indicating a clear advantage for mpMRI. Recently, there have been developments in the acquisition of mpMRI. For improving DW-MRI, a popular topic is the use of high b-value DW-MRI. Wetter et al. [15] quantitatively evaluated five different b values and they reported that contrast ratios calculated from signal intensities of diffusionweighted images (DWI) for tumor vs. normal tissue were highest at b values of 1500 and 2000 s/mm2, respectively, and differed significantly from contrast ratios at b values of 800 and 1000 s/mm2, respectively [15]. Tamada et al. [16] investigated tumor conspicuity and the discrimination potential for tumor aggressiveness on DW-MRI with high b values, and reported that b values of 2000 s/mm2 were more useful than values of 1000 s/mm2. It may not always be possible to obtain adequate high b value. DW-MRI may depend on equipment used; therefore, several groups have evaluated (calculated) high b-value DW-MRI derived from the lower b values used in conventional DW-MRI. Grant et al. [17] compared calculated high b-value DW-MRI derived from conventional low b-value DW-MRI using different diffusion decay models (intravoxel incoherent motion and diffusion kurtosis) and found them comparable to acquired high b-value DW-MRI. Calculated high b-value DWI obtained using the intravoxel incoherent motion model had the same lesion visibility as that of acquired DWI. However, the image quality of calculated high b-value DWI relative to corresponding acquired DWI decreases with increasing b value [17]. High b-value DW-MRI has become a component of the prostate imaging reporting and data system (PIRADS) evaluation criteria but there is debate regarding how high the b value should be. The value of DCE-MRI as one of the parameters of mpMRI has been called into question in recent years. As mentioned earlier, biparametric MRI performed very well without DCE-MRI. It is clear that Volume 27 Number 3 May 2015
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Advances in imaging modalities in prostate cancer Bouchelouche et al.
DCE-MRI does have value but only in a minority of patients. Quantitative features of DCE-MRI have been investigated as a means of better understanding tumor biology. Van Niekerk et al. [18], for instance, correlated pharmacokinetic parameters derived from DCE-MRI with histopathologic microvascular and lymphatic parameters. They reported moderate correlations between the parameter Kep (reverse rate constant) and tumor/normal microvessel density and perimeter ratios. They also stated that interpatient variations in microvascularity were large, making it difficult to create cutoff values [18]. Thus, the debate continues over whether DCE-MRI is needed. The final component of mpMRI, MRSI, displays the chemical composition of the prostate through specific metabolites, such as citrate, choline, and creatine. MRSI improves specificity, tumor detection rates, and tumor volume estimates; on the other hand, MRSI requires considerable expertise, long acquisition times, and specialized equipment. It is currently being used in academic centers. A relatively new spectroscopic technique is hyperpolarized 13C-pyruvate magnetic resonance, which can be used to study metabolic reprogramming by tumors. Hyperpolarization using dynamic nuclear polarization is a technique used to increase the spectroscopic signal 10–50 000-fold compared with conventional MRI. This increased sensitivity has enabled the study of metabolic pathways in vitro and in vivo [19]. Nelson et al. [20 ] reported the first-in-man study on the safety and feasibility of hyperpolarized [1-13C]pyruvate for noninvasively characterizing alterations in PCa metabolism. The promising results confirmed the safety of the agent and showed elevated [1-13C] lactate/[1-13C]pyruvate in regions of biopsy-proven PCa that would be expected to exhibit the ‘Warburg effect’ [20 ]. In 2012, the European Society of Urogenital Radiology published the PIRADS as part of its prostate MR guidelines [21]. PIRADS includes a 5-point score assigned to identify each lesion suggestive of cancer for each individual sequence of mpMRI. In addition, each lesion is assigned an overall score between 1 and 5 that is used to determine which lesions should be biopsied. Although high PIRADS score lesions have been reported to indicate suspicious lesions in need of biopsy, the interobserver agreement of PIRADS is only in the moderate range [22–25]. Recently, the American College of Radiology and the European Society of Urogenital Radiology prostate committee have been working in collaboration to release a revised version of PIRADS to further simplify standardized acquisition and reporting of mpMRI. &
Imaging methods in the progression of prostate cancer
Detection
Staging
Recurrence
Metastases
TRUS mpMRI PET
FIGURE 1. Relative uses of the imaging modalities discussed in the review. TRUS, transrectal ultrasound.
In conclusion, mpMRI is a powerful tool mostly used in the detection of PCa. The role of mpMRI has shifted from local staging toward lesion detection and biopsy guidance; however, it continues to also have a role in detecting recurrence, and its role in monitoring metastatic disease continues to evolve (Fig. 1). Several research efforts are directed toward improving image acquisition and there is a global effort to improve the standardization of image acquisition and interpretation. Thus, great progress is being made in prostate MRI.
PET PET is reserved for staging of high-risk PCa, biochemical recurrence, or metastatic disease. PET is not being used in the detection of PCa. Several tracers have been tested in clinical studies and some of these are promising. Another step further in improving PET imaging is PET/MRI, and recently the first clinical studies in PCa using PET/MRI have been published. In the following section, we focus on advancement in PET/CT and PET/MRI in PCa during the past year.
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F-Fluorodeoxyglucose
PET with 18F-fluorodeoxyglucose (FDG) plays an important role in many cancers, but is not very useful in the early stages of PCa because of low-level metabolism resulting in low uptake of FDG. Furthermore, there is overlap of FDG uptake in normal, benign, and malignant tissues. Abnormal incidental prostate uptake on FDG PET/CT performed in non-PCa patients is common. Two studies reported that incidental FDG uptake in the prostate occurred in approximately 2% of the scans done in men for other reasons [26,27]. The incidental FDG uptake was due to PCa (15–20%) or benign lesions (80–85%). When focal FDG uptake in the peripheral zone of the prostate is detected, further clinical evaluation with PSA may be warranted [26].
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Choline Radiolabeled choline, 11C-choline and 18F-fluorocholine (FCH), have been widely used for a variety of PCa imaging applications [28–30]. A recent metaanalysis included 47 choline PET/CT studies with a total of 3167 patients [31]. The pooled sensitivity of choline PET/CT for pelvic lymph node metastases was 62% and the pooled specificity was 92%. Choline PET/CT led to a change in treatment in 41% of patients. Choline was found to be useful in PCa with biochemical recurrence with PSA between 1.0 and 50 ng/ml. Another recent meta-analysis focused on PSA kinetics and detection rate of choline PET/CT [32]. The pooled detection rate increased to 65% when PSA doubling time was 6 months or less and to 71 and 77% when PSA velocity was higher than 1 or higher than 2 ng/ml/year, respectively. During the last year, several studies have been published with choline PET/CT describing optimization of technique [33–40], and staging [41–45], restaging [46–54], radiation treatment planning [55 ,56], and evaluation of treatment response [57]. Furthermore, two studies reported a prognostic value of choline PET/CT [58,59 ]. Kitajima et al. [54] compared mpMR to choline PET/CT for detection of recurrent PCa, and found mpMRI with ERC superior for the detection of local recurrence, but choline was superior for pelvic lymph node metastases, and both were equally very good for pelvic bone metastases. In order to further improve imaging of PCa, choline PET/MRI has been used [53,60 ,61,62]. Wetter et al. [60 ] compared the FCH PET/MRI with FCH PET/CT in PCa. All lesions visible on PET/CT were also seen on PET/MRI, and the quality of the PET images was comparable in both the groups. Both maximum standardized uptake value (SUVmax) and SUVmean were significantly lower in PET/MRI than in PET/CT. The difference is likely caused by different techniques of attenuation correction. FCH PET/MRI is a promising technique, but the exact clinical role of PET/MRI in PCa remains to be elucidated further. &
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node involvement is low [65]. Buchegger et al. [66] prospectively compared acetate PET/CT and FCH PET/CT in patients with biochemical relapse. Overall, acetate and FCH showed excellent concordance, on both a per-lesion and a per-patient basis, suggesting that both tracers perform equally for recurrent PCa staging.
Fluoride PCa has a predilection to metastasize to bone. Traditionally, whole-body bone scintigraphy (WBS) with 99m-Tc methylene diphosphonate has been used for the detection of bone metastases in PCa. However, 18F-fluoride (NaF) PET/CT is superior to both WBS and single-photon emission computed tomography (SPECT)/CT [67,68]. FCH PET/CT is also used for detection of bone metastases in PCa [69–71]. The uptake mechanisms of the two PET tracers are different, that is, NaF uptake reflects the local bone osteoblastic reaction to tumor, whereas FCH uptake reflects metabolic activity within the tumor cells. Recently, Poulsen et al. [72] prospectively compared NaF and FCH PET/CT with WBS using MRI as the reference standard. Sensitivity, specificity, PPV and NPV, and accuracy were as follows: WBS: 51, 82, 86, 43, and 61%; NaF-PET/ CT: 93, 54, 82, 78, and 81%; and FCH PET/CT: 85, 91, 95, 75, and 87%, respectively. The study confirmed previous results that both FCH PET/CT and NaF-PET/CT are superior to WBS with regard to sensitivity for bone metastases [68]. Furthermore, FCH PET/CT was demonstrated to be superior to NaF-PET/CT in specificity [72]. However, the specificity of NaF in this study is lower than previously reported by others [68,69]. A recent meta-analysis also found that FCH PET/CT is superior to WBS and SPECT/CT [71]. It still remains unresolved as to which PET tracer is the best for detection of bone metastases in PCa.
Prostate-specific membrane antigen Acetate 11
C-acetate PET/CT has been used both for staging and restaging of PCa [30]. Similar to FDG and choline, there can be overlap among the uptake levels in PCa, benign prostatic hyperplasia (BPH), and normal prostate gland [63]. A recent meta-analysis of acetate PET imaging found that for primary tumor detection, pooled sensitivity was 75.1% and specificity was 75.8%. For detection of recurrent PCa, pooled sensitivity was 64% and specificity was 93% [64]. Studies comparing acetate and choline PET/CT were reported to be comparable. Similar to choline, the ability to detect microscopic lymph 228
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Prostate-specific membrane antigen (PSMA) is an excellent target for radionuclide imaging and therapy of PCa. PSMA is mainly expressed in the prostate, highly expressed at all stages of cancer, upregulated in androgen-insensitive or metastatic disease, expressed on the cell surface as an integral membrane protein and not released into the circulation, and internalized after antibody binding (receptor-mediated endocytosis) [73]. Recently, methods have been developed to label PSMA ligands with 68Ga, 99mTc, and radioiodine enabling their use for PET or SPECT imaging and therapy [73–76]. Afshar-Oromieh et al. [77 ] compared FCH PET/CT &
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and 68Ga-PSMA PET/CT in patients (n ¼ 37) with biochemical relapse of PCa [77 ]. A total of 78 lesions were detected using PSMA and 56 lesions were detected using choline. The difference was significant. All lesions detected by choline were also seen by PSMA. Especially at lower PSA levels, PSMA detected more PCa lesions when compared with FCH. Furthermore, metastatic lesions in lymph nodes frequently presented with higher contrast when compared with choline. This may contribute to the higher detection rate with PSMA PET/CT. Larger clinical studies are needed to confirm these findings and define sensitivity and specificity. Furthermore, Afshar-Oromieh et al. [78] compared PET/CT and PET/MRI using 68Ga-labeled PSMA ligand for the diagnosis of recurrent PCa. PSMA PET/MRI was able to detect recurrent PCa accurately and with less radiation exposure compared with PET/CT. Furthermore, unclear findings on PET/CT could be clarified by PET/MRI. However, scatter correction was challenging, and reduced PET signal (‘halo’), at least around the urinary bladder, can cause false-negative results. Moreover, SUVs determined using PET/CT and PET/MR need to be carefully compared when using the PSMA ligand. &
1-amino-3-fluorine 18-fluorocyclobutane-1carboxylic acid Anti 18F-1-amino-3-fluorine 18-fluorocyclobutane1-carboxylic acid (FACBC) PET/CT has been used in the assessment of primary and metastatic PCa [79–83]. Accurate depiction of the location of dominant tumors may enable improved management of PCa. Turkbey et al. [84 ] characterized the uptake of FACBC in patients (n ¼ 21) with localized PCa, BPH, and normal prostate tissue. FACBC PET/CT depicted higher uptake in patients with PCa than in those with normal prostate tissue; however, uptake overlapped with BPH nodules. Sector-based comparison with histopathological analysis of all tumors revealed sensitivity and specificity of 67 and 66%, respectively, for FACBC PET/CT, and 73 and 79%, respectively, for T2-weighted MRI. FACBC PET/CT and mpMRI were used to localize dominant tumors (sensitivity of 90% for both). Combined FACBC and MRI demonstrated PPV of 82% for tumor localization, which was significantly higher than with either modality alone. FACBC and T2-weighted MRI enabled more accurate localization of PCa than either modality alone [84 ]. Schuster et al. [85] compared FACBC PET/CT with ProstaScint (Cytogen Corporation, Princeton, New Jersey, USA) (111In– capromab pendetide, antibody to PSMA) SPECT/CT to detect recurrent PCa. Better diagnostic performance was noted for FACBC than for ProstaScint.
Compared with choline, preliminary results indicate that the detection rate of FACBC may be higher [86–88]. Nanni et al. [86] demonstrated that the detection rate of FACBC PET/CT was greater than choline PET/CT, with approximately 20% additional patients and approximately 60% additional lesions detected.
CONCLUSION In conclusion, several PET tracers for imaging of PCa have been tested in clinical trials, and most of the PET/CT studies reported have used radiolabeled choline. New tracers like 68Ga-PSMA and 18F-FACBC are demonstrating promising results. Preliminary results indicate that PET/MRI may be superior to PET/CT for detecting recurrent disease but larger clinical trials are needed to further evaluate the role of PET/MRI. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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Incidental prostate 18F-FDG uptake without calcification indicates the possibility of prostate cancer. Oncol Rep 2014; 31:1517–1522. 28. Bouchelouche K, Turkbey B, Choyke P, Capala J. Imaging prostate cancer: an update on positron emission tomography and magnetic resonance imaging. Curr Urol Rep 2010; 11:180–190. 29. Brogsitter C, Zophel K, Kotzerke J. 18F-Choline, 11C-choline and 11Cacetate PET/CT: comparative analysis for imaging prostate cancer patients. Eur J Nucl Med Mol Imaging 2013; 40 (Suppl 1):S18–S27. 30. Cho SY, Szabo Z. Molecular imaging of urogenital diseases. Semin Nucl Med 2014; 44:93–109. 31. von Eyben FE, Kairemo K. Meta-analysis of (11)C-choline and (18)F-choline PET/CT for management of patients with prostate cancer. Nucl Med Commun 2014; 35:221–230. 32. Treglia G, Ceriani L, Sadeghi R, et al. Relationship between prostate-specific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab Med 2014; 52:725–733. 33. Calabria F, Chiaravalloti A, Schillaci O. (18)F-choline PET/CT pitfalls in image interpretation: an update on 300 examined patients with prostate cancer. Clin Nucl Med 2014; 39:122–130. 34. Chondrogiannis S, Marzola MC, Ferretti A, et al. Is the detection rate of 18Fcholine PET/CT influenced by androgen-deprivation therapy? Eur J Nucl Med Mol Imaging 2014; 41:1293–1300. 35. Garcia JR, Cuberas G, Riera E, et al. Dual-phase 11C-choline PET/computed tomography in the early evaluation of prostate cancer recurrence. Nucl Med Commun 2015; 36:8–15.
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36. Grosu AL, Weirich G, Wendl C, et al. (11)C-Choline PET/pathology image coregistration in primary localized prostate cancer. Eur J Nucl Med Mol Imaging 2014; 41:2242–2248. 37. Rischke HC, Beck T, Vach W, et al. Furosemide diminishes (1)(8)F-fluoroethylcholine uptake in prostate cancer in vivo. Eur J Nucl Med Mol Imaging 2014; 41:2074–2082. 38. Palumbo B, Sivolella S, Palumbo I, et al. Influence of hormonal therapy in prostate cancer patients undergoing 18Fluoromethylcholine PET/CT: a retrospective study. Q J Nucl Med Mol Imaging 2014. [Epub ahead of print] 39. Fabbri C, Galassi R, Moretti A, et al. Radiation dosimetry of 18F-fluorocholine PET/CT studies in prostate cancer patients. Phys Med 2014; 30:346– 351. 40. Chondrogiannis S, Marzola MC, Grassetto G, et al. New acquisition protocol of 18F-choline PET/CT in prostate cancer patients: review of the literature about methodology and proposal of standardization. Biomed Res Int 2014; 2014:1–10. 41. Garcia JR, Jorcano S, Soler M, et al. 11C-Choline PET/CT in the primary diagnosis of prostate cancer: impact on treatment planning. Q J Nucl Med Mol Imaging 2014. [Epub ahead of print] 42. Heck MM, Souvatzoglou M, Retz M, et al. Prospective comparison of computed tomography, diffusion-weighted magnetic resonance imaging and [11C]choline positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer patients. Eur J Nucl Med Mol Imaging 2014; 41:694–701. 43. Vag T, Heck MM, Beer AJ, et al. Preoperative lymph node staging in patients with primary prostate cancer: comparison and correlation of quantitative imaging parameters in diffusion-weighted imaging and 11C-choline PET/ CT. Eur Radiol 2014; 24:1821–1826. 44. Kjolhede H, Ahlgren G, Almquist H, et al. 18F-fluorocholine PET/CT compared with extended pelvic lymph node dissection in high-risk prostate cancer. World J Urol 2014; 32:965–970. 45. Hodolic M, Michaud L, Huchet V, et al. Consequence of the introduction of routine FCH PET/CT imaging for patients with prostate cancer: a dual centre survey. Radiol Oncol 2014; 48:20–28. 46. Ceci F, Castellucci P, Graziani T, et al. 11C-choline PET/CT detects the site of relapse in the majority of prostate cancer patients showing biochemical recurrence after EBRT. Eur J Nucl Med Mol Imaging 2014; 41:878–886. 47. Ceci F, Herrmann K, Castellucci P, et al. Impact of (11)C-choline PET/CT on clinical decision making in recurrent prostate cancer: results from a retrospective two-centre trial. Eur J Nucl Med Mol Imaging 2014; 41:2222–2231. 48. Gacci M, Cai T, Siena G, et al. Prostate-specific antigen kinetics parameters are predictive of positron emission tomography features worsening in patients with biochemical relapse after prostate cancer treatment with radical intent: results from a longitudinal cohort study. Scand J Urol 2014; 48:259– 267. 49. Karnes RJ, Murphy CR, Bergstralh EJ, et al. Salvage lymph node dissection for prostate cancer nodal recurrence detected by C-choline positron emission tomography/computed tomography. J Urol 2015; 193:111–116. 50. Rodado-Marina S, Coronado-Poggio M, Garcia-Vicente AM, et al. Clinical utility of F-fluorocholine PET-CT in biochemical relapse of prostate cancer after radical treatment. Results of a multicentre study. BJU Int 2014. [Epub ahead of print] 51. Osmonov DK, Heimann D, Janssen I, et al. Sensitivity and specificity of PET/ CT regarding the detection of lymph node metastases in prostate cancer recurrence. SpringerPlus 2014; 3:340. 52. Castellucci P, Ceci F, Graziani T, et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-choline PET/CT scan before salvage radiation therapy? J Nucl Med 2014; 55:1424–1429. 53. Piccardo A, Paparo F, Picazzo R, et al. Value of fused 18F-choline-PET/MRI to evaluate prostate cancer relapse in patients showing biochemical recurrence after EBRT: preliminary results. Biomed Res Int 2014; 2014:103718. 54. Kitajima K, Murphy RC, Nathan MA, et al. Detection of recurrent prostate cancer after radical prostatectomy: comparison of 11C-choline PET/CT with pelvic multiparametric MR imaging with endorectal coil. J Nucl Med 2014; 55:223–232. 55. Picchio M, Berardi G, Fodor A, et al. (11)C-Choline PET/CT as a guide to & radiation treatment planning of lymph-node relapses in prostate cancer patients. Eur J Nucl Med Mol Imaging 2014; 41:1270–1279. Choline PET/CT for radiation treatment planning of biochemical relapse of PCa. 56. Jereczek-Fossa BA, Rodari M, Bonora M, et al. [11C]choline PET/CT impacts treatment decision making in patients with prostate cancer referred for radiotherapy. Clin Genitourin Cancer 2014; 12:155–159. 57. Challapalli A, Barwick T, Tomasi G, et al. Exploring the potential of [11C]choline-PET/CT as a novel imaging biomarker for predicting early treatment response in prostate cancer. Nucl Med Commun 2014; 35:20–29. 58. Kwee SA, Lim J, Watanabe A, et al. Prognosis related to metastatic burden measured by 18F-fluorocholine PET/CT in castration-resistant prostate cancer. J Nucl Med 2014; 55:905–910. 59. Giovacchini G, Picchio M, Garcia-Parra R, et al. 11C-choline PET/CT predicts & prostate cancer-specific survival in patients with biochemical failure during androgen-deprivation therapy. J Nucl Med 2014; 55:233–241. Choline PET/CT may add important prognostic information by predicting PCaspecific survival.
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Advances in imaging modalities in prostate cancer Bouchelouche et al. 60. Wetter A, Lipponer C, Nensa F, et al. Evaluation of the PET component of simultaneous [(18)F]choline PET/MRI in prostate cancer: comparison with [(18)F]choline PET/CT. Eur J Nucl Med Mol Imaging 2014; 41:79–88. Important study for comparison of PET image quality of PET/CT and PET/MRI using 18F-choline. 61. Wetter A, Lipponer C, Nensa F, et al. Quantitative evaluation of bone metastases from prostate cancer with simultaneous [18F] choline PET/ MRI: combined SUV and ADC analysis. Ann Nucl Med 2014; 28:405–410. 62. Wetter A, Lipponer C, Nensa F, et al. Simultaneous 18F choline positron emission tomography/magnetic resonance imaging of the prostate: initial results. Invest Radiol 2013; 48:256–262. 63. Mena E, Turkbey B, Mani H, et al. 11C-Acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation. J Nucl Med 2012; 53:538–545. 64. Mohsen B, Giorgio T, Rasoul ZS, et al. Application of C-11-acetate positronemission tomography (PET) imaging in prostate cancer: systematic review and meta-analysis of the literature. BJU Int 2013; 112:1062–1072. 65. Schumacher MC, Radecka E, Hellstrom M, et al. [(11)C]Acetate positron emission tomography-computed tomography imaging of prostate cancer lymph-node metastases correlated with histopathological findings after extended lymphadenectomy. Scand J Urol 2015; 49:35–42. 66. Buchegger F, Garibotto V, Zilli T, et al. First imaging results of an intraindividual comparison of (11)C-acetate and (18)F-fluorocholine PET/CT in patients with prostate cancer at early biochemical first or second relapse after prostatectomy or radiotherapy. Eur J Nucl Med Mol Imaging 2014; 41:68–78. 67. Tateishi U, Morita S, Taguri M, et al. A meta-analysis of (18)F-fluoride positron emission tomography for assessment of metastatic bone tumor. Ann Nucl Med 2010; 24:523–531. 68. Even-Sapir E, Metser U, Mishani E, et al. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multifield-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006; 47:287–297. 69. Langsteger W, Balogova S, Huchet V, et al. Fluorocholine (18F) and sodium fluoride (18F) PET/CT in the detection of prostate cancer: prospective comparison of diagnostic performance determined by masked reading. Q J Nucl Med Mol Imaging 2011; 55:448–457. 70. Balogova S, Zakoun JB, Michaud L, et al. Whole-body 18F-fluorocholine (FCH) PET/CT and MRI of the spine for monitoring patients with castrationresistant prostate cancer metastatic to bone: a pilot study. Clin Nucl Med 2014; 39:951–959. 71. Shen G, Deng H, Hu S, Jia Z. Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis. Skeletal Radiol 2014; 43:1503–1513. 72. Poulsen MH, Petersen H, Hoilund-Carlsen PF, et al. Spine metastases in prostate cancer: comparison of technetium-99m-MDP whole-body bone scintigraphy, [(18) F]choline positron emission tomography (PET)/computed tomography (CT) and [(18) F]NaF PET/CT. BJU Int 2014; 114:818–823. 73. Bouchelouche K, Choyke PL, Capala J. Prostate specific membrane antigen: a target for imaging and therapy with radionuclides. Discov Med 2010; 9:55– 61. 74. Eder M, Eisenhut M, Babich J, Haberkorn U. PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging 2013; 40:819–823. 75. Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2013; 40:486–495.
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76. Zechmann CM, Afshar-Oromieh A, Armor T, et al. Radiation dosimetry and first therapy results with a (124)I/(131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging 2014; 41:1280–1292. 77. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET & imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/ CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2014; 41:11–20. Study for comparison of PET/CT and PET/MRI with 68Ga-labeled PSMA ligand for the diagnosis of recurrent PCa. 78. Afshar-Oromieh A, Haberkorn U, Schlemmer HP, et al. Comparison of PET/ CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagnosis of recurrent prostate cancer: initial experience. Eur J Nucl Med Mol Imaging 2014; 41:887–897. 79. Schuster DM, Votaw JR, Nieh PT, et al. Initial experience with the radiotracer anti1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med 2007; 48:56–63. 80. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/ CT and 111In-capromab pendetide SPECT/CT. Radiology 2011; 259:852– 861. 81. Sorensen J, Owenius R, Lax M, Johansson S. Regional distribution and kinetics of [18F]fluciclovine (anti[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nucl Med Mol Imaging 2013; 40:394–402. 82. Schuster DM, Taleghani PA, Nieh PT, et al. Characterization of primary prostate carcinoma by anti1-amino-2-[(18)F]-fluorocyclobutane-1-carboxylic acid (anti3-[(18)F] FACBC) uptake. Am J Nucl Med Mol Imaging 2013; 3:85– 96. 83. Kairemo K, Rasulova N, Partanen K, Joensuu T. Preliminary clinical experience of trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti(18)FFACBC) PET/CT imaging in prostate cancer patients. Biomed Res Int 2014; 2014:305182. 84. Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F & FACBC PET/CT: comparison with MR imaging and histopathologic analysis. Radiology 2014; 270:849–856. The first study for comparison of 18F-FACBC PET/CT with MRI and histology for detection of localized PCa. 85. Schuster DM, Nieh PT, Jani AB, et al. Anti3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol 2014; 191:1446–1453. 86. Nanni C, Schiavina R, Brunocilla E, et al. 18F-FACBC compared with 11C-choline PET/CT in patients with biochemical relapse after radical prostatectomy: a prospective study in 28 patients. Clin Genitourin Cancer 2014; 12:106–110. 87. Brunocilla E, Schiavina R, Nanni C, et al. First case of 18F-FACBC PET/CTguided salvage radiotherapy for local relapse after radical prostatectomy with negative 11C-choline PET/CT and multiparametric MRI: new imaging techniques may improve patient selection. Arch Ital Urol Androl 2014; 86:239– 240. 88. Schiavina R, Concetti S, Brunocilla E, et al. First case of 18F-FACBC PET/ CT-guided salvage retroperitoneal lymph node dissection for disease relapse after radical prostatectomy for prostate cancer and negative 11C-choline PET/CT: new imaging techniques may expand pioneering approaches. Urol Int 2014; 92:242–245.
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Advances in imaging modalities in prostate cancer Kirsten Bouchelouche a, Baris Turkbey b, and Peter L. Choyke b
Purpose of review Imaging plays an important role in the clinical management of prostate cancer (PCa). Thus, much effort has gone into improving imaging modalities in PCa. This review focuses on the recent advancements in transrectal ultrasound, MRI and PET during the past year. Recent findings Contrast-enhanced transrectal ultrasound with microbubbles may be useful in PCa, but needs further evaluation before more widespread use. Multiparametric MRI has emerged as a valuable tool to assist clinical management of PCa, and great progress has been made in the past year. Several radionuclides for PET/computed tomography have been tested in clinical trials; most of the studies have used radiolabeled choline. However, new PET tracers such as 18F-1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid and 68Ga-labeled prostate-specific membrane antigen ligands are demonstrating promising results. PET/MRI may further improve imaging in PCa, but this imaging modality needs to be evaluated further. Summary Several advances in the imaging of PCa have been made during the past year. In particular, important clinical developments have been reported in multiparametric MRI, PET/computed tomography, and PET/MRI. The continuing development of imaging techniques in PCa has the potential to optimize treatment of PCa. However, the optimal imaging strategies for each of the major clinical scenarios in PCa have not yet been identified. Keywords MRI, PET/CT, PET/MRI, prostate cancer, transrectal ultrasound
INTRODUCTION Prostate cancer (PCa) is the most frequently diagnosed cancer in men [1]. Appropriate imaging of PCa is a crucial component of detection, staging, restaging, and therapy. Thus, it is important at primary diagnosis, at follow-up and recurrence, and in the presence of metastases to obtain accurate assessment of the disease in order to provide the best treatment strategies. For the purpose of this review, we consider the following major clinical scenarios: PCa detection and diagnosis, staging of PCa, detection of recurrent disease, and detection and monitoring of metastatic disease. The purpose of this review is to highlight the most important developments in transrectal ultrasound (TRUS), multiparametric MRI (mpMRI), and PET reported in the past year.
TRANSRECTAL ULTRASOUND TRUS is the most commonly used imaging technique for the prostate. The primary role of TRUS is in guiding biopsies of the prostate gland. TRUS has www.co-oncology.com
limited ability in detecting PCa; thus, these biopsies are considered ‘blind’ or ‘random’ because they are not targeted to a specific abnormality. Recently, contrast-enhanced TRUS (CE-TRUS) using gas-filled microbubbles has been reported to provide higher sensitivity for tumor detection than conventional unenhanced TRUS. Cornelis et al. [2] retrospectively evaluated the diagnostic accuracy of real-time CE-TRUS-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA). These patients (n ¼ 178) had previously negative TRUS-guided biopsies, but positive MRI findings.
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Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark and bMolecular Imaging Program, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA Correspondence to Kirsten Bouchelouche, Chief Physician, MD, DMSc, Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, Aarhus DK-8200, Denmark. Tel: +45 20 29 19 03; e-mail: [email protected] Curr Opin Oncol 2015, 27:224–231 DOI:10.1097/CCO.0000000000000174 Volume 27 Number 3 May 2015
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Advances in imaging modalities in prostate cancer Bouchelouche et al.
KEY POINTS Imaging plays an increasingly important role in the clinical management of PCa, and research has focused on new and more accurate imaging modalities. Contrast-enhanced TRUS with microbubbles may be useful in PCa, but needs further evaluation before more widespread use. Significant progress has been made in improving image acquisition and interpretation of mpMRI, and the role of mpMRI is shifting from local staging toward lesion detection and biopsy guidance. Several PET tracers (predominantly choline) have been tested in PCa, and new PET tracers such as 18F-FACBC and 68Ga-PSMA are demonstrating promising results in recurrent and metastatic PCa. PET/MRI may improve PCa imaging but the exact clinical role of PET/MRI remains to be elucidated.
CE-TRUS-targeted biopsies (TBx) were performed in regions that were suspicious for cancer by MRI, followed by 12-core random TRUS-guided biopsies. TBx had a positive overall detection rate of 30.9%, whereas the overall detection was only 6.9% with the 12-core TRUS-guided biopsies [2]. Nontargeted ultrasound microbubbles were studied by Uemura et al. [3] who performed targeted prostate biopsies with microbubbles in 71 patients. Although there was a significant difference in cancer detection rate by TBx between two cohorts with PSA less than 10 ng/ml (22.9%) and PSA of at least 10 ng/ml (52.2%), the added value of CE-TRUS was relatively small [3]. Thus, the literature in CE-TRUS appears promising but somewhat contradictory. Confirmation of the role of CE-TRUS awaits more widespread use, but this will require off-label use of the microbubble agent. Furthermore, the transient nature of the enhancement, lack of expertise with this method, operator dependence, and a tradition in most ultrasound departments for not using intravenous contrast agents have inhibited progress in this field.
MULTIPARAMETRIC MRI MpMRI combines both anatomical and functional pulse sequences consisting of T1-weighted MRI, T2weighted MRI, diffusion-weighted MRI (DW-MRI), dynamic contrast-enhanced MRI (DCE MRI), and, in some cases, magnetic resonance (MR) spectroscopy imaging (MRSI). MRI is particularly useful in identifying clinically significant lesions that are missed on routine TRUS biopsy, but fails to detect most
small low-grade cancers that likely do not warrant treatment. As a result, there is a shift toward use of mpMRI for guiding biopsy. Salami et al. [4] compared the performance of the Prostate Cancer Prevention Trial risk calculator for high-grade PCa with MRI for detecting PCa. The area under the receiver-operating characteristic curve for Prostate Cancer Prevention Trial risk calculator for high grade in detecting high-grade PCa was 0.676, for MRI was 0.769, and for mpMRI was 0.812, respectively [4]. Therefore, mpMRI appears to predict clinically significant PCa with higher accuracy than standard clinical nomograms. Once the decision to perform a biopsy is made, various methods for combining MRI and TRUS have been proposed. Jambor et al. [5] evaluated the diagnostic accuracy of mpMRI and mpMRI-targeted TRUS-guided biopsy using ‘cognitive fusion’. In ‘cognitive fusion’, the operator performs a TRUS biopsy based on the estimated location on the corresponding MRI. This method relies on substantial experience in reconciling the location of an abnormality on TRUS with the abnormality seen more clearly on MRI. The sensitivity, specificity, accuracy, and area under the curve (AUC) values for MRdirected biopsy in the detection of clinically relevant PCa on a sextant basis were 72, 89, 85%, and 0.81, respectively [5], which conforms with the most recent studies using state-of-the-art equipment. A limitation of this study is that ‘cognitive fusion’ is quite operator dependent. It is also currently not clear whether MRI can be improved to increase sensitivity to approximately 90% and replace 12-core random biopsies. Although mpMRI is considered an advance in the diagnosis of PCa, concerns have been raised about its costs. Thus, methods that might reduce the cost while maintaining efficacy are of interest. Rais-Bahrami et al. [6] determined the diagnostic yield of biparametric (T2-weighted and diffusionweighted) MRI for PCa detection compared with digital rectal exploration and PSA-based screening. Biparametric MRI reduced costs by shortening scan time and avoiding costs associated with contrast media. The AUC for cancer detection for biparametric MRI, PSA, and PSA density were 0.80, 0.66, and 0.74, respectively, which is comparable to mpMRI [6]. Another means of reducing costs and discomfort would be to eliminate the use of the endorectal coil (ERC). Turkbey et al. [7] performed a study in which patients had mpMRI with and without ERC in the same session and then underwent radical prostatectomy. Overall sensitivity of the ERC mpMRI and non-ERC mpMRI were 0.76 and 0.45, respectively. Among the 20 index cancers, ERC mpMRI was able to detect 85%, whereas non-ERC mpMRI detected
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75% of the cancers [7]. Thus, the majority of the extra tumors detected by ERC mpMRI were low grade and probably not clinically significant. These results are encouraging; however, they warrant further prospective randomized studies. Another method of reducing costs is to be more patient selective. Shakir et al. [8 ] performed a study in 1003 patients who underwent mpMRI, TRUS, and MRI/TRUS-guided biopsies. Targeted biopsy led to significantly more upgrading to clinically significant disease compared with 12-core biopsy. However, this difference only became significant when the PSA was more than 5.4 ng/ml in which 90% of the upgrading by targeted biopsy was captured. Therefore, MRI was only of significant benefit in 64% of the patients who underwent mpMRI and subsequent MRI/TRUS fusion biopsy. Conversely, 36% of patients with lower PSA did not benefit from mpMRI; therefore, this procedure could be avoided in such patients [8 ]. Larger trials are needed to confirm these outcomes; however, it is evident that mpMRI might not be needed in every patient, therefore lowering costs. Thus, the combination of increased selectivity of mpMRI candidates, shorter examination times, and eliminating the ERC may lower the cost of mpMRI. The promising results with mpMRI have led to its increased use for biopsy planning and targeting. Many groups have reported equivalent or superior tumor detection rates for mpMRI-guided biopsies compared with random TRUS-guided biopsies. Quentin et al. [9] performed a prospective study in 132 biopsy naı¨ve men with increased PSA more than >4 ng/dl. TRUS and in-bore MRI-guided biopsies provided the same 53.1% overall tumor detection rate, including 79.4 and 85.3%, respectively, for significant PCa. However, in-bore MRI-guided biopsy achieved these results with significantly fewer cores and revealed a higher percentage of cancer involvement per biopsy core [9]. This study confirms a clear advantage of mpMRI-guided biopsies. However, the lesions biopsied by mpMRI are not necessarily the same lesions as those discovered by random TRUS biopsy. For instance, Salami et al. [10] evaluated the performance of mpMRI in predicting PCa on repeat biopsy, and compared the cancer detection rate of MRI/TRUS fusion-guided biopsy with standard 12-core systemic biopsy in 140 men with at least one previous negative biopsy. The fusion biopsy was more likely to detect clinically significant PCa when compared with the 12-core modality (47.9 vs. 30.7%) and among the cancers missed by 12 core, 20.9% were clinically significant [10]. Several other groups recently reported on the utility of mpMRI in noninvasive detection of PCa [11–13]. &
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Historically, mpMRI has been used for staging PCa, specifically for identifying extracapsular extension (ECE). However, its value has been debated because it cannot reliably detect microscopic ECE, which is often predicted from clinical nomograms. Gupta et al. [14] compared mpMRI with Partin tables in predicting ECE after radical prostatectomy. They reported sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI in detecting organ-confined disease as 81.6, 86.4, 91.2, and 73.1%, respectively. The ability of mpMRI to detect ECE was somewhat lower with a sensitivity, specificity, PPV, and NPV of 77.8, 83.4, 66.7, and 89.7%, respectively. The AUC values of Partin tables and mpMRI for correct staging were 0.62 and 0.82, respectively [14], indicating a clear advantage for mpMRI. Recently, there have been developments in the acquisition of mpMRI. For improving DW-MRI, a popular topic is the use of high b-value DW-MRI. Wetter et al. [15] quantitatively evaluated five different b values and they reported that contrast ratios calculated from signal intensities of diffusionweighted images (DWI) for tumor vs. normal tissue were highest at b values of 1500 and 2000 s/mm2, respectively, and differed significantly from contrast ratios at b values of 800 and 1000 s/mm2, respectively [15]. Tamada et al. [16] investigated tumor conspicuity and the discrimination potential for tumor aggressiveness on DW-MRI with high b values, and reported that b values of 2000 s/mm2 were more useful than values of 1000 s/mm2. It may not always be possible to obtain adequate high b value. DW-MRI may depend on equipment used; therefore, several groups have evaluated (calculated) high b-value DW-MRI derived from the lower b values used in conventional DW-MRI. Grant et al. [17] compared calculated high b-value DW-MRI derived from conventional low b-value DW-MRI using different diffusion decay models (intravoxel incoherent motion and diffusion kurtosis) and found them comparable to acquired high b-value DW-MRI. Calculated high b-value DWI obtained using the intravoxel incoherent motion model had the same lesion visibility as that of acquired DWI. However, the image quality of calculated high b-value DWI relative to corresponding acquired DWI decreases with increasing b value [17]. High b-value DW-MRI has become a component of the prostate imaging reporting and data system (PIRADS) evaluation criteria but there is debate regarding how high the b value should be. The value of DCE-MRI as one of the parameters of mpMRI has been called into question in recent years. As mentioned earlier, biparametric MRI performed very well without DCE-MRI. It is clear that Volume 27 Number 3 May 2015
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DCE-MRI does have value but only in a minority of patients. Quantitative features of DCE-MRI have been investigated as a means of better understanding tumor biology. Van Niekerk et al. [18], for instance, correlated pharmacokinetic parameters derived from DCE-MRI with histopathologic microvascular and lymphatic parameters. They reported moderate correlations between the parameter Kep (reverse rate constant) and tumor/normal microvessel density and perimeter ratios. They also stated that interpatient variations in microvascularity were large, making it difficult to create cutoff values [18]. Thus, the debate continues over whether DCE-MRI is needed. The final component of mpMRI, MRSI, displays the chemical composition of the prostate through specific metabolites, such as citrate, choline, and creatine. MRSI improves specificity, tumor detection rates, and tumor volume estimates; on the other hand, MRSI requires considerable expertise, long acquisition times, and specialized equipment. It is currently being used in academic centers. A relatively new spectroscopic technique is hyperpolarized 13C-pyruvate magnetic resonance, which can be used to study metabolic reprogramming by tumors. Hyperpolarization using dynamic nuclear polarization is a technique used to increase the spectroscopic signal 10–50 000-fold compared with conventional MRI. This increased sensitivity has enabled the study of metabolic pathways in vitro and in vivo [19]. Nelson et al. [20 ] reported the first-in-man study on the safety and feasibility of hyperpolarized [1-13C]pyruvate for noninvasively characterizing alterations in PCa metabolism. The promising results confirmed the safety of the agent and showed elevated [1-13C] lactate/[1-13C]pyruvate in regions of biopsy-proven PCa that would be expected to exhibit the ‘Warburg effect’ [20 ]. In 2012, the European Society of Urogenital Radiology published the PIRADS as part of its prostate MR guidelines [21]. PIRADS includes a 5-point score assigned to identify each lesion suggestive of cancer for each individual sequence of mpMRI. In addition, each lesion is assigned an overall score between 1 and 5 that is used to determine which lesions should be biopsied. Although high PIRADS score lesions have been reported to indicate suspicious lesions in need of biopsy, the interobserver agreement of PIRADS is only in the moderate range [22–25]. Recently, the American College of Radiology and the European Society of Urogenital Radiology prostate committee have been working in collaboration to release a revised version of PIRADS to further simplify standardized acquisition and reporting of mpMRI. &
Imaging methods in the progression of prostate cancer
Detection
Staging
Recurrence
Metastases
TRUS mpMRI PET
FIGURE 1. Relative uses of the imaging modalities discussed in the review. TRUS, transrectal ultrasound.
In conclusion, mpMRI is a powerful tool mostly used in the detection of PCa. The role of mpMRI has shifted from local staging toward lesion detection and biopsy guidance; however, it continues to also have a role in detecting recurrence, and its role in monitoring metastatic disease continues to evolve (Fig. 1). Several research efforts are directed toward improving image acquisition and there is a global effort to improve the standardization of image acquisition and interpretation. Thus, great progress is being made in prostate MRI.
PET PET is reserved for staging of high-risk PCa, biochemical recurrence, or metastatic disease. PET is not being used in the detection of PCa. Several tracers have been tested in clinical studies and some of these are promising. Another step further in improving PET imaging is PET/MRI, and recently the first clinical studies in PCa using PET/MRI have been published. In the following section, we focus on advancement in PET/CT and PET/MRI in PCa during the past year.
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F-Fluorodeoxyglucose
PET with 18F-fluorodeoxyglucose (FDG) plays an important role in many cancers, but is not very useful in the early stages of PCa because of low-level metabolism resulting in low uptake of FDG. Furthermore, there is overlap of FDG uptake in normal, benign, and malignant tissues. Abnormal incidental prostate uptake on FDG PET/CT performed in non-PCa patients is common. Two studies reported that incidental FDG uptake in the prostate occurred in approximately 2% of the scans done in men for other reasons [26,27]. The incidental FDG uptake was due to PCa (15–20%) or benign lesions (80–85%). When focal FDG uptake in the peripheral zone of the prostate is detected, further clinical evaluation with PSA may be warranted [26].
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Choline Radiolabeled choline, 11C-choline and 18F-fluorocholine (FCH), have been widely used for a variety of PCa imaging applications [28–30]. A recent metaanalysis included 47 choline PET/CT studies with a total of 3167 patients [31]. The pooled sensitivity of choline PET/CT for pelvic lymph node metastases was 62% and the pooled specificity was 92%. Choline PET/CT led to a change in treatment in 41% of patients. Choline was found to be useful in PCa with biochemical recurrence with PSA between 1.0 and 50 ng/ml. Another recent meta-analysis focused on PSA kinetics and detection rate of choline PET/CT [32]. The pooled detection rate increased to 65% when PSA doubling time was 6 months or less and to 71 and 77% when PSA velocity was higher than 1 or higher than 2 ng/ml/year, respectively. During the last year, several studies have been published with choline PET/CT describing optimization of technique [33–40], and staging [41–45], restaging [46–54], radiation treatment planning [55 ,56], and evaluation of treatment response [57]. Furthermore, two studies reported a prognostic value of choline PET/CT [58,59 ]. Kitajima et al. [54] compared mpMR to choline PET/CT for detection of recurrent PCa, and found mpMRI with ERC superior for the detection of local recurrence, but choline was superior for pelvic lymph node metastases, and both were equally very good for pelvic bone metastases. In order to further improve imaging of PCa, choline PET/MRI has been used [53,60 ,61,62]. Wetter et al. [60 ] compared the FCH PET/MRI with FCH PET/CT in PCa. All lesions visible on PET/CT were also seen on PET/MRI, and the quality of the PET images was comparable in both the groups. Both maximum standardized uptake value (SUVmax) and SUVmean were significantly lower in PET/MRI than in PET/CT. The difference is likely caused by different techniques of attenuation correction. FCH PET/MRI is a promising technique, but the exact clinical role of PET/MRI in PCa remains to be elucidated further. &
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node involvement is low [65]. Buchegger et al. [66] prospectively compared acetate PET/CT and FCH PET/CT in patients with biochemical relapse. Overall, acetate and FCH showed excellent concordance, on both a per-lesion and a per-patient basis, suggesting that both tracers perform equally for recurrent PCa staging.
Fluoride PCa has a predilection to metastasize to bone. Traditionally, whole-body bone scintigraphy (WBS) with 99m-Tc methylene diphosphonate has been used for the detection of bone metastases in PCa. However, 18F-fluoride (NaF) PET/CT is superior to both WBS and single-photon emission computed tomography (SPECT)/CT [67,68]. FCH PET/CT is also used for detection of bone metastases in PCa [69–71]. The uptake mechanisms of the two PET tracers are different, that is, NaF uptake reflects the local bone osteoblastic reaction to tumor, whereas FCH uptake reflects metabolic activity within the tumor cells. Recently, Poulsen et al. [72] prospectively compared NaF and FCH PET/CT with WBS using MRI as the reference standard. Sensitivity, specificity, PPV and NPV, and accuracy were as follows: WBS: 51, 82, 86, 43, and 61%; NaF-PET/ CT: 93, 54, 82, 78, and 81%; and FCH PET/CT: 85, 91, 95, 75, and 87%, respectively. The study confirmed previous results that both FCH PET/CT and NaF-PET/CT are superior to WBS with regard to sensitivity for bone metastases [68]. Furthermore, FCH PET/CT was demonstrated to be superior to NaF-PET/CT in specificity [72]. However, the specificity of NaF in this study is lower than previously reported by others [68,69]. A recent meta-analysis also found that FCH PET/CT is superior to WBS and SPECT/CT [71]. It still remains unresolved as to which PET tracer is the best for detection of bone metastases in PCa.
Prostate-specific membrane antigen Acetate 11
C-acetate PET/CT has been used both for staging and restaging of PCa [30]. Similar to FDG and choline, there can be overlap among the uptake levels in PCa, benign prostatic hyperplasia (BPH), and normal prostate gland [63]. A recent meta-analysis of acetate PET imaging found that for primary tumor detection, pooled sensitivity was 75.1% and specificity was 75.8%. For detection of recurrent PCa, pooled sensitivity was 64% and specificity was 93% [64]. Studies comparing acetate and choline PET/CT were reported to be comparable. Similar to choline, the ability to detect microscopic lymph 228
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Prostate-specific membrane antigen (PSMA) is an excellent target for radionuclide imaging and therapy of PCa. PSMA is mainly expressed in the prostate, highly expressed at all stages of cancer, upregulated in androgen-insensitive or metastatic disease, expressed on the cell surface as an integral membrane protein and not released into the circulation, and internalized after antibody binding (receptor-mediated endocytosis) [73]. Recently, methods have been developed to label PSMA ligands with 68Ga, 99mTc, and radioiodine enabling their use for PET or SPECT imaging and therapy [73–76]. Afshar-Oromieh et al. [77 ] compared FCH PET/CT &
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Advances in imaging modalities in prostate cancer Bouchelouche et al.
and 68Ga-PSMA PET/CT in patients (n ¼ 37) with biochemical relapse of PCa [77 ]. A total of 78 lesions were detected using PSMA and 56 lesions were detected using choline. The difference was significant. All lesions detected by choline were also seen by PSMA. Especially at lower PSA levels, PSMA detected more PCa lesions when compared with FCH. Furthermore, metastatic lesions in lymph nodes frequently presented with higher contrast when compared with choline. This may contribute to the higher detection rate with PSMA PET/CT. Larger clinical studies are needed to confirm these findings and define sensitivity and specificity. Furthermore, Afshar-Oromieh et al. [78] compared PET/CT and PET/MRI using 68Ga-labeled PSMA ligand for the diagnosis of recurrent PCa. PSMA PET/MRI was able to detect recurrent PCa accurately and with less radiation exposure compared with PET/CT. Furthermore, unclear findings on PET/CT could be clarified by PET/MRI. However, scatter correction was challenging, and reduced PET signal (‘halo’), at least around the urinary bladder, can cause false-negative results. Moreover, SUVs determined using PET/CT and PET/MR need to be carefully compared when using the PSMA ligand. &
1-amino-3-fluorine 18-fluorocyclobutane-1carboxylic acid Anti 18F-1-amino-3-fluorine 18-fluorocyclobutane1-carboxylic acid (FACBC) PET/CT has been used in the assessment of primary and metastatic PCa [79–83]. Accurate depiction of the location of dominant tumors may enable improved management of PCa. Turkbey et al. [84 ] characterized the uptake of FACBC in patients (n ¼ 21) with localized PCa, BPH, and normal prostate tissue. FACBC PET/CT depicted higher uptake in patients with PCa than in those with normal prostate tissue; however, uptake overlapped with BPH nodules. Sector-based comparison with histopathological analysis of all tumors revealed sensitivity and specificity of 67 and 66%, respectively, for FACBC PET/CT, and 73 and 79%, respectively, for T2-weighted MRI. FACBC PET/CT and mpMRI were used to localize dominant tumors (sensitivity of 90% for both). Combined FACBC and MRI demonstrated PPV of 82% for tumor localization, which was significantly higher than with either modality alone. FACBC and T2-weighted MRI enabled more accurate localization of PCa than either modality alone [84 ]. Schuster et al. [85] compared FACBC PET/CT with ProstaScint (Cytogen Corporation, Princeton, New Jersey, USA) (111In– capromab pendetide, antibody to PSMA) SPECT/CT to detect recurrent PCa. Better diagnostic performance was noted for FACBC than for ProstaScint.
Compared with choline, preliminary results indicate that the detection rate of FACBC may be higher [86–88]. Nanni et al. [86] demonstrated that the detection rate of FACBC PET/CT was greater than choline PET/CT, with approximately 20% additional patients and approximately 60% additional lesions detected.
CONCLUSION In conclusion, several PET tracers for imaging of PCa have been tested in clinical trials, and most of the PET/CT studies reported have used radiolabeled choline. New tracers like 68Ga-PSMA and 18F-FACBC are demonstrating promising results. Preliminary results indicate that PET/MRI may be superior to PET/CT for detecting recurrent disease but larger clinical trials are needed to further evaluate the role of PET/MRI. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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