REVIEW URRENT C OPINION

Rapidly changing landscape of PET/CT imaging in prostate cancer Joshua J. Morigi a,, S. Fanti a, D. Murphy b, and Michael S. Hofman b,

Purpose of review PET/CT imaging in men with prostate cancer (PCa) is rapidly growing as clinicians are becoming aware of its possible fundamental role in the diagnostic flow chart of these patients. As this technology becomes more available worldwide, a considerable number of scientific studies are focusing on specific clinical scenarios and novel PET radiopharmaceuticals that might assist improving early diagnosis and shifting to a truly tailored treatment for PCa. This review focuses on the most recent and important publications in PET/CT imaging of PCa. Recent findings Choline, radiolabelled with either 11-C or 18-F, is now widely used and has shown good performance in detecting sites of disease compared with conventional imaging, especially in biochemical recurrence. However, its sensitivity and specificity when PSA values are low, and especially below 1.0 ng/ml, is insufficient. More recently, a number of new tracers have been proposed for clinical practice. Among them, 68-Ga Prostate-specific membrane antigen have shown so far the most promising results and is replacing choline PET in centres where it is available. It is particularly useful for detecting PCa relapse at low PSA values but may also be useful for staging of patients with intermediate or high risk prostate cancer. 18-F fluorodeoxyglucose PET/CT remains useful for a limited number of patients with PCa and may provide useful prognostic information. Summary PET/CT is a reliable technique in the diagnostic work-up of patients with PCa, particularly in the setting of biochemical recurrence following previous definitive treatment. The landscape of available radiotracers is changing rapidly and includes fluorodeoxyglucose, sodium fluoride, choline, anti-1-amino-3-18Ffluorocyclobutane-1-carboxylic acid, and prostate-specific membrane antigen. Of these, prostate-specific membrane antigen PET/CT appears the most likely to represent a new gold standard with evidence of clinical utility emerging in a variety of scenarios, including staging and biochemical recurrence. Keywords biochemical recurrence, choline, PET/CT, prostate cancer, prostate-specific membrane antigen

INTRODUCTION Accurate imaging is essential for the management of patients with prostate cancer, particularly in those men at higher risk of having metastases, and also in those men suspected of having recurrence following definitive therapy. If detected early, when disease remains localized to the prostate, there is a high disease free survival for patients treated with curative intent therapy. A proportion of patients, however, relapse often detected by rising prostatespecific antigen (PSA) level (biochemical recurrence). At very low levels, conventional imaging, such as computed tomography (CT), MRI, and bone scintigraphy have a low likelihood of detecting recurrent disease. Patients with biochemical recurrence are often treated with curative intent salvage

a Nuclear Medicine Department, Policlinico S.Orsola-Malpighi Hospital and Department of Specialized, Experimental, and Diagnostic Medicine, University of Bologna, Bologna, Italy and bPeter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia

Correspondence to Michael S. Hofman, Centre for Cancer Imaging, Peter MacCallum Cancer Centre and University of Melbourne, Peter MacCallum Cancer Centre, Centre for Cancer Imaging, St Andrew Place, Melbourne, Australia. Tel: +613 9656 1852; fax: +613 8648 6348; e-mail: [email protected] Joshua J. Morigi, Nuclear Medicine Department, Policlinico S. OrsolaMalpighi Hospital, Via Massarenti 9, 40123 Bologna, Italy. Tel: +39 0512143196; e-mail: [email protected]  Joshua J. Morigi and Michael S. Hofman have contributed equally to the writing of this article.

Curr Opin Urol 2016, 26:493–500 DOI:10.1097/MOU.0000000000000309

0963-0643 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.co-urology.com

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Improving diagnosis of prostate cancer

KEY POINTS  PET is rapidly evolving as a potential new gold standard for imaging prostate cancer.  Choline, radiolabelled with either 11-C or 18-F, is superior to conventional imaging and useful in guiding application of radiotherapy in patients with biochemical recurrence.  Sensitivity of choline remains inadequate when PSA values are low, especially below 1.0 ng/ml.  Prostate-specific membrane antigen (PSMA), radiolabeled with 68-Ga, is replacing choline PET in jurisdictions where it is available due to superior sensitivity and higher tumor contrast.

radiotherapy but a significant proportion of patients relapse outside the treatment field. These failures, both with primary and salvage treatments, in part reflect the limited sensitivity and consequent failure of conventional imaging techniques to accurately detect disease. PET is rapidly evolving as a potential new gold standard for imaging prostate cancer. PET has major advantages over conventional nuclear medicine imaging, including higher sensitivity for detecting radioactive substances, superior spatial resolution, quantitative ability, faster imaging, and often lower radiation dose to the patient [1]. All PET devices are now hybrid devices incorporating CT (PET/CT) or MRI (PET/MRI) enabling precise anatomic correlation. In addition to the high tumor-tobackground contrast resulting in higher reporter agreement compared with conventional imaging, a key advantage of PET imaging is the ability to characterize disease phenotype providing prognostic information or predictive biomarkers, thereby potentially enabling better selection of therapy for an individual patient. A variety of PET radiotracers are now available for imaging prostate cancer.

18-F-FDG (FDG) AND NAF Fluorodeoxyglucose (FDG) is widely available and a standard-of-care for oncologic imaging in many malignancies. However, indolent tumors with slow growth have low levels of glycolytic activity, and therefore, its role for imaging early-stage prostate cancer is limited. It is, however, known that high uptake of FDG in PCa may be observed in androgen independent [e.g., castrate- resistant prostate cancer or (CRPC)], more aggressive subtypes [2]. These patients will more often harbor distant metastases and therefore a whole body technique such as 494

www.co-urology.com

PET/CT is very appealing. In particular, high uptake is observed in patients with more aggressive disease (anaplastic or probably related to small cell neuroendocrine differentiation). In a prospective study of 87 patients with CRPC, the intensity of metabolic activity constituted an independent prognostic information on overall survival [3]. As use of other PET radiopharmaceuticals evolve as discussed below, FDG PET may still play a role in disease restaging and characterization. FDG can also be used in addition or in combination with other PET radiotracers. To date, this has been demonstrated with 18-F sodium fluoride (NaF), an osteotropic agent with known sensitivity for osseous metastasis detection and a high impact on management decisions [4]. The combined use of these two PET agents may provide incremental benefits for patients. Preliminary data suggest that FDG might be superior to NaF with regards to response to treatment in metastatic castrate-resistant prostate cancer (mCRPC) patients [5 ]. The use of bone seeking imaging agents is likely to decrease with the accumulating evidence base and availability of more sensitive and specific radiopharmaceuticals, as discussed below. &&

CHOLINE Choline is a precursor of the biosynthesis of phosphatidylcholine, the most common phospholipid in human cell membranes. It has shown increased expression in prostate cancer [6] among others. Choline PET tracers have been marked with either C-11 or F-18. The two compounds have demonstrated similar performances and are therefore considered equally valid. Undoubtedly, Choline-based PET/CT imaging has brought huge benefit to the way men with PCa are managed. On one hand, the use of this family of radiotracers for staging purposes is generally discouraged as sensitivity and specificity values are nonsatisfactory [7,8]. On the other hand, guidelines [9,10] and clinical use have demonstrated the role of choline PET/CT as a powerful tool for detecting biochemical relapse, with a single examination and at an earlier stage than any other imaging [11,12]. Even still, the recommended role of choline-based PET/CT is for patients with PSA above 1.0 ng/ml because of poor accuracy below this level (EAU Guidelines 2016). The main current application is to identify oligometastatic disease that might benefit from targeted therapies. For this purpose it becomes fundamental to accurately select patients to whom molecular imaging will more likely be of benefit. It has been assessed that not only absolute PSA values but PSA doubling time (PSAdt) is a key factor, and that choline PET/CT Volume 26  Number 5  September 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

PET/CT imaging in prostate cancer Morigi et al.

FIGURE 1. 11-C-Choline PET/CT in a patient with Gleason 8 prostate cancer presenting with a rising PSA of 2.6 ng/ml 6 years after primary treatment with radical prostatectomy. Choline PET/CT demonstrates intense uptake of a suspicious left para-vescical nodule (SUVMax ¼ 8), of a left obturator lymph-node (SUVmax ¼ 10) and a para-aortic lymph node (SUVmax ¼ 8.8).

scans at biochemical relapse should be limited to patients presenting with PSA values above 1 and a PSAdt less than 6 months [13]. A recent metanalysis covering both C-11 and F-18 choline tracers [14] reported detection rates higher than 50% for PSA values above 2 ng/ml, with fast PSA kinetics and high Gleason scores (>8) positively related to higher detection rates (see Fig. 1). As it becomes clearer in what clinical scenario choline-guided PET/CT has an edge over conventional imaging, the open issue is the clinical impact of treatment decisions made after choline PET/CT [15 ]. In a recent study conducted on 33 patients after biochemical failure following primary treatment (surgery or radiotherapy), choline PET/CTaltered treatment approach in 55% of them [16]. A positive choline PET/CT also correlated with a shorter progression-free survival in 172 consecutive patients with PC who underwent Choline PET/CT for biochemical recurrence [17]. A positive choline &&

PET/CT after biochemical failure was predictive of the outcome in over 300 hormone-naive PCa patients studied with a mean follow-up of over 7 years. PCa-specific survival was 42.4% in positive choline PET compared with 95.5% in patients with negative choline PET [18]. It is clear that choline PET/CT can influence treatment decisions, in particular, by guiding application of targeted treatments in the radiation-oncology field. Choline-guided radiotherapy planning when biochemical relapse occurs might improve patient outcomes and postpone the beginning of systemic therapy in oligometastatic prostate cancer [19]. In a group of 60 patients with prostate cancer, choline PET/CT would have shifted treatment in 13 cases, either by changing therapeutic targets or by adding a simultaneous integrated boost on PET positive sites [20]. The same group also investigated the predictive role of choline PET/CT on survival outcomes in a population of 68 patients

0963-0643 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.co-urology.com

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

495

Improving diagnosis of prostate cancer

treated with helical tomotherapy for lymph node recurrence. Numerous imaging parameters derived by choline PET/CT such as metabolic tumor volume changes may be useful in emerging treatment strategies [21]. Biochemical response (defined as a drop of PSA value) or metabolic response (defined as reduced or absent uptake at post-treatment choline PET/CT) can be assessed after radiation treatment to establish the accuracy of pretherapy PET scans, and PET/CT guided imaging has recently proven effective in this field [22 ]. Finally, choline PET is being tested as a tool to assess response to systemic treatment. In a cohort of 61 patients with mCRPC investigated with choline PET after first-line docetaxel chemotherapy, 65.5% demonstrated progressive disease. Progressive disease by choline PET was seen in 44% of patients with a PSA response of at least 50% suggesting that PET may be useful to identify patients with radiological progression despite a PSA response [23]. Thirty patients receiving enzalutamide after docetaxel were also monitored by means of choline PET/ CT before and during therapy, showing that baseline SUVmax was an independent prognostic factor for biochemical progression-free survival [24]. Declines in PSA level of at least 50% in 49% of patients were observed in 43 patients studied by means of choline PET/CT after docetaxel and abiraterone [25]. This study is of particular interest as 10% of them presented ‘bone flare, (PSA response but higher uptake of choline in bone lesions within the first few weeks after treatment) that was resolved at further imaging and might constitute a potential pitfall if not taken into account when assessing response to therapy in mCRCP. Further studies specifically addressing this issue are urgently needed. Significantly lower SUVmax for osteoblastic bone lesions in comparison with osteolytic bone lesions has recently been identified [26]. PET imaging may play a role for response assessment following Radium-223 dichloride (Ra-223) for patients with symptomatic advanced bone metastases. Skeletal burden on NaF PET has been shown to represent an independent predictor of overall survival [27].

pendetide (ProstaScint) demonstrated clear superiority [29]. This tracer was also preliminary challenged in different settings [30], including for staging purposes [31] on 26 patients, demonstrating correlations between positive scans and fast PSA kinetics, especially PSAdt. More recently, the group of researchers from Bologna prospectively enrolled 100 patients with BCR comparing choline and FACBC imaging: FACBC demonstrated higher levels of sensitivity (37 vs. 32%) and specificity (67 vs. 40%) [32].

&&

FACBC Anti-1-amino-3–18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC or FACBC), is a newly synthesized L-leucine analogue with favorable dosimetry and biodistribution [28]. Its uptake is mediated via different transport systems, mainly a large-neutral amino acid transport system (e.g., LAT1/4F2hc) and the sodiumdependent alanine-serine-cysteine system. A prospective clinical trial compared FACBC to capromab 496

www.co-urology.com

PROSTATE-SPECIFIC MEMBRANE ANTIGEN PSMA is a cell surface transmembrane glycoprotein which is overexpressed in malignant prostate tissues [33,34]. This has been a target of interest for imaging and therapy for decades but agents such as the radiolabeled antibody ProstaScint failed to provide sufficient incremental utility to be widely adopted [29,35]. More recently, a small molecule peptide that binds with high affinity to the PSMA receptor and radiolabeled to Ga-68 (Ga-68-HBED-PSMA-11) has been rapidly adopted in many centers [36,37]. Ga-68 is produced using a small generator that has a shelf-life of 6–12 months, and the final product can be produced using relatively simple manual methods or automated synthesis units enabling widespread availability. The tumor-to-background contrast with this modality is outstanding and an early study comparing PSMA to choline PET/CT in 37 patients demonstrated significantly greater sensitivity (78 lesions compared to 56, P ¼ 0.04) and superior tumor-to-background contrast in 95% of patients [38 ]. Confident identification of small volume disease less than 10 mm in size is frequently seen with PSMA PET/CT (see Figs. 2–3). The early data in the literature to date are primarily focused on PSMA-PET/CT for localization of prostate cancer in patients with biochemical recurrence. In patients with PSA less than 1–2 ng/ml the positivity rate of PSMA for localizing disease on a patient level is approximately double that of choline PET/CT [38 ,39–46]. For example, in the 1–2 ng/ml range, a detection rate of 93% with PSMA PET/CT [39] compared with 43% for choline PET/CT [47]. The high sensitivity of PSMA PET/CT has reignited interest in using PET for initial staging of patients. It has become evident that in some patients, recurrent disease after primary intervention actually represents failure of accurate staging due to the limited sensitivity of conventional techniques and choline PET/CT. Data using PSMA-PET/ CT for staging of patients with intermediate or high risk prostate cancer are emerging [39,44,48]. These data demonstrate significantly superior sensitivity &

&

Volume 26  Number 5  September 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

PET/CT imaging in prostate cancer Morigi et al.

FIGURE 2. Ga-68-HBED-PSMA-11 PET/CT in a patient with Gleason 8 prostate cancer and rising PSA 2 years after curative intent radical robotic prostatectomy. CT of the chest, abdomen and pelvis and NaF PET/CT demonstrated no evidence of metastatic disease. PSMA PET/CT demonstrated intense uptake in sub-cm para-aortic, retrocrural and a supraclavicular node. These nodes measured as small as 3 mm. A 7 mm supraclavicular node was sampled under ultrasound guidance with histopathology confirm the metastatic prostate adenocarcinoma.

and specificity compared with CT or MRI for identification of locoregional nodal or distant metastatic disease. In the largest series to date of 130 patients, PSMA PET/CT demonstrated a sensitivity and specificity of 66 and 99% compared with 44 and 85% for CT/MRI [39]. Although these clearly demonstrate the utility of PSMA-PET/CT, they are mostly retrospective single center studies, and do not directly compare PSMA-PET/CT to conventional imaging or address important issues such as the impact of this new imaging test on patient management, patient outcomes, or health economics. Recent prospective data on 70 patients with biochemical recurrence, PSA at least 0.05 and less than 1.0, normal CT and no therapy other than prior prostatectomy, has

&

demonstrated clear utility of PSMA PET/CT [49 ]. Overall, 27% had pathologic uptake in the prostate bed, 14% in pelvic nodes, 5% in both, and distant disease in 9%. This conferred a high patient impact with major management change in 29% of patients. Further prospective research is needed to further validate the role of PSMA PET/CT in other scenarios. We will shortly commence a prospective multicenter randomized controlled study in Australia (‘ProPSMA study’) to evaluate the accuracy and impact of PSMA-PET/CT in newly diagnosed high-risk patients. Several newer generation PSMA ligands suitable for PET/CT imaging are also emerging. Fluorinated radiotracers have the advantage of mass production with regional distribution from a central

0963-0643 Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.

www.co-urology.com

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

497

Improving diagnosis of prostate cancer

FIGURE 3. Ga-68-HBED-PSMA-11 PET/CT in a patient with newly diagnosed Gleason 9 prostate cancer. Conventional imaging consistent of computed tomography, bone scintigraphy, and pelvic MRI demonstrated no evidence of disease outside the prostate bed. PSMA PET/CT demonstrates high uptake in the prostate primary, a 3 mm right iliac lymph node and a distant metastasis in the rib.

radiopharmacy due to its cyclotron production and longer half-life. 18-F DCFPyL has recently been described with similar imaging characteristics to Ga-68 PSMA11 [50,51]. In addition, kit-based Ga-68 PSMA ligands that obviate the need for synthesis units have recently been developed [52–54].

STRUGGLING WITH SUPERIOR SENSITIVITY OF PROSTATE-SPECIFIC MEMBRANE ANTIGEN PET/CT With the extraordinary sensitivity and tumor-tobackground contrast visualized with PSMA PET/CT it seems likely to represent a new gold standard for imaging prostate cancer. It is, however, subject to the ‘paradox of the gold standard’ because as the new superior modality, there is no criterion standard against which it can be compared. Although histopathology is frequently cited as the arbiter of truth, it is frequently not possible to biopsy sites of small volume metastases, and biopsy is subject to sampling error and consequent false negative results. 498

www.co-urology.com

Furthermore, the presence of small volume recurrent disease does not always require immediate intervention, and the management decision impact of this superior imaging must therefore be carefully considered. For example, the current interest in an aggressive approach to oligometastaic disease using stereotactic radiotherapy or salvage pelvic lymph node dissection, remains under evaluation and should be considered experimental [55]. Despite the clear advantages of PSMA PET, there is also a small subset (

CT imaging in prostate cancer.

PET/CT imaging in men with prostate cancer (PCa) is rapidly growing as clinicians are becoming aware of its possible fundamental role in the diagnosti...
971KB Sizes 1 Downloads 26 Views