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New aspects of molecular imaging in prostate cancer
Methods xxx (2017) xxx–xxx
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New aspects of molecular imaging in prostate cancer Francesco Ceci a,b,⇑, Paolo Castellucci c, Juliano J. Cerci d, Stefano Fanti c a
Department of Surgical Sciences, University of Bologna, Italy Department of Molecular and Medical Pharmacology, University of California Los Angeles, USA c Nuclear Medicine Unit, S.Orsola-Malpighi Hospital, University of Bologna, Italy d Quanta Diagnóstico e Terapia, Diagnostic and Therapy Clinic, Curitiba, Brazil b
a r t i c l e
i n f o
Article history: Received 26 April 2017 Received in revised form 12 June 2017 Accepted 10 July 2017 Available online xxxx Keywords: PSMA PET/CT 68 Ga-PSMA 177Lu-PSMA 18 F-FACBC: 68 Ga-RM2: prostate cancer Biochemical recurrence Metastases directed therapy Theranostics PSMA-I&T
a b s t r a c t Nowadays several new imaging modalities are available for investigating prostate cancer (PCa) such as magnet resonance imaging (MRI) in the form of whole body MRI and pelvic multiparametric MRI and positron emission tomography (PET) using choline as radiotracers. Nevertheless, these modalities proved sub-optimal accuracy for detecting PCa metastases, particularly in the recurrence setting. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been recently developed for PET imaging. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallopeptidase over-expressed in PCa cells. It has been shown that PSMA based imaging offers higher tumor detection rate compared to choline PET/CT and radiological conventional imaging, especially at very low PSA levels during biochemical recurrence. In addition PSMA, as theranostics agent, allows both radiolabeling with diagnostic (e.g. 68 Ga, 18 F) or therapeutic nuclides (e.g. 177Lu, 225Ac). Initial results show that PSMA-targeted radioligand therapy can potentially delay disease progression in metastatic castrate-resistant PCa. Despite still investigational, the bombesin-based radiotracers and antagonist of gastrin releasingpeptide receptor (GRP) (RM2) and anti1-amino-3-18 Ffluorocyclobutane-1-carboxylic acid (18 FFACBC) are emerging as possible alternatives for investigating PCa. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68 Ga-PSMA11, 18 F-FACBC, 68 Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy. Ó 2017 Elsevier Inc. All rights reserved.
1. Introduction Prostate cancer (PCa) is the most common cancer and the third most common cause of cancer death in men [1]. At present, depending on the clinical stage, imaging of PCa can be indicated for primarydiagnosis, staging and detection of biochemical recurrent (BCR) disease as well as therapy response. Conventional imaging modalities, including ultrasound (US), bone scintigraphy (BS) and computed tomography (CT) are used to detect primary and metastatic PCa for staging and risk stratification. Despite significant efforts, these modalities do not contribute essentially to ⇑ Corresponding author at: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Ahmanson Translational Imaging Division, 10833 Le Conte Ave., 200 Medical Plaza, Los Angeles, CA 90095-7370, USA. E-mail address: [email protected] (F. Ceci).
patient management as much as imaging performed in patients with other common cancers [2]. Magnetic resonance imaging (MRI), especially innovative methods such as diffusion-weighted MRI (DWI-MRI) or dynamic contrast-enhanced MRI (DCE-MRI) allowing functional assessment of the disease, are growingly important for imaging of PCa [3]. Nevertheless, these techniques do not allow tumor-specific imaging and cannot be applied throughout the whole body. Functional imaging with positron emission tomography (PET) shows molecular function and metabolic activity information in a single-step whole body examination [4]. Over the last decade, PET/CT (with 11 C-choline or 18 Fcholine) proved its role for investigating PCa [5]. Particularly, choline PET/CT proved to be a better diagnostic tool for restaging PCa patients presenting BCR, as compared with radiological imaging [6]. Furthermore, choline PET/CT demonstrated its usefulness for
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staging high-risk PCa, with high PSA levels and Gleason Scores (GS), before the primary treatment [7]. However, choline based PET imaging presents several limitations both for staging the disease (lack of accuracy for detecting lymph-node involvement) and for restaging in case of BCR (lack of accuracy in case of PSA < 2 ng/mL). As a consequence functional metabolic imaging still holds a sub-optimal performance for investigating PCa [6]. Several efforts have been made over the last years to develop new probes able to provide better performances when compared with the choline-PET/CT [8]. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been developed recently for PET imaging [9]. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallo-peptidase physiologically expressed in several tissues. Although the function of GCPII in prostate remains unclear, it is well-known that this protein is over expressed in PCa [10]. The first investigations reported a higher tumor to background ratio for 68 Ga-PSMA PET/CT for the detection of suspected PCa metastases when compared with choline PET/CT [11] and very promising performances also at very low PSA levels. In addition, other recently developed PSMA-inhibitors (PSMA I&T, PSMA-617, PSMA-1007) can be used as theranostics agents allowing radio-labeling with diagnostic (e.g. 68 Ga, 18 F) or therapeutic nuclides (e.g. 177Lu, 225Ac). In recent years an investigational amino acidic PET compound, anti1-amino-318 Ffluorocyclobutane-1-carboxylic acid (18 F-FACBC), a synthetic L-leucine
analogue, was developed and tested in PCa patients with BCR after radical treatment. This radiotracer that actually falls within the category of metabolic radiotracers has been recently approved in the US, by the Food and Drug Association (FDA), as alternative metabolic radiopharmaceuticals for investigating PCa patients with biochemical recurrence [12]. Finally, Bombesinbased radiotracers and antagonists of gastrin-releasing peptide (GRPr) receptor, labeled with 68 Ga (68 Ga-RM2), are also of interest [13,14] and a recently PSMA-GRPr PET hybrid tracer developed (tested on murine samples) [15] suggests that this field is ever evolving towards new and hopefully more accurate diagnostic tools. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68 Ga-PSMA-11, 18 F-FACBC, 68 Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy.
2. New molecular probes in prostate cacncer: PSMA PET/CT imaging The prostate-specific membrane antigen (PSMA) is a type II transmembrane protein that was first detected on the human PCa cell line LNCaP [16]. Its expression and localization in the normal human prostate is associated with the cytoplasm and apical side of the epithelium surrounding prostatic ducts but not basal epithelium, neuroendocrine or stromal cells [17]. In malignant tissue, PSMA is involved in angiogenesis, as increased PSMA expression was found in the stroma adjacent to neovasculature of solid tumors [18]. Due to its selective overexpression in 90–100% of PCa lesions [19], PSMA is a reliable tissue marker for PCa and is considered an ideal target for tumor specific imaging and therapy [20]. Several studies showed that PSMA expression levels increase according to the stage and grade of the tumor as well as aneuploidy
and biochemical recurrence thus potentially allowing PSMAimaging to account for prognosis [21]. Recently, a large number of urea-based PSMA ligands labeled with 68 Ga have been presented, including PSMA HBED-CC (PSMA-11), PSMA I&T [22] and PSMA-617. More recently, 18 F-labeled compound with hepatobiliar excretion (PSMA-1007) attracted the most attention [23]. According to preliminary data, PSMA-1007 seems to be the most promising tracer showing a comparable accuracy to 68 Ga-PSMA11, but its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68 Ga-labeled PSMA tracers. Furthermore, 18 FPSMA-1007 can be produced in large amounts per batch in PET radiopharmacies with an onsite cyclotron, reducing the demand for multiple tracer syntheses per day and enabling transfer to satellite centers. Preliminary data suggest reduced urinary excretion and high tumor to background ratios contribute to exceptional sensitivities including for tiny tumor deposits in the body. 2.1. Staging In patients eligible to curative primary therapy, the decision to proceed with a further staging work-up is guided by which treatment options are available, taking into account the patient’s preference and co-morbidity. Several imaging modalities have been proposed to assess the extension of the intraprostatic lesion before radical prostatectomy (RP). In predominantly Gleason pattern 4, multiparametric MRI (mp-MRI) provided the most valuable performance with best values both for sensitivity and specificity. Thus, the use of mp-MRI is recommended by the European Association of Urology (EAU) guidelines in intermediate and high-risk PCa before primary treatment [3,24]. The use of choline PET/CT in the pre-operative setting has not been recommended by the EAU, both for intermediate and high-risk patients. Despite EAU guidelines still consider PSMA based PET imaging an investigational procedure, very promising results have been recently presented, both for detecting the intraprostatic lesion and for the assessment of lymph-node metastases (LNM). Fendler et al. [25] evaluated the accuracy of PET/CT with 68 GaPSMA-11 to localize cancer in the prostate and surrounding tissue at initial diagnosis in cohort of 21 patients. It was assessed a sensitivity of 67%, a specificity of 92%, an accuracy of 72%, a PPV of 97% and a NPV of 42%. Histopathology positive segments (100/126; 79%) demonstrated a significantly higher mean SUVmax than histopathology-negative segments. However, despite better values for specificity and PPV if compared to choline PET/CT, the sensitivity still remain sub-optimal. Thus, it was recently proposed the combination of PSMA based PET with MRI to improve the performance of both methodologies. Zamboglou et al. [26] demonstrated that the hybridization of the two techniques performed even better in terms of sensitivity (82%) and specificity (89%). Eiber et al. confirmed these results [27]: authors compared the diagnostic performance of simultaneous 68 Ga-PSMA PET/MRI for the localization of primary PCa with mpMRI and PET alone in a cohort of 53 patients. Simultaneous PET/MRI statistically outperformed mpMRI and PET imaging alone for a precise localization of PCa. The hybrid diagnostic procedure detected correctly the lesion in the 98% of cases with a sensitivity of 76% and a specificity of 98% (MRI alone 43%, 98%; PET alone 58%, 82%). Moreover, according to the data available in literature so far, it seems reasonable to assume that PSMA PET/MRI is able to distinguish with good accuracy between intraprostatic PCa lesion and BPH [25,27]. The individual risk of finding LNM can be estimated using externally validated with preoperative nomograms according to D’Amico criteria [28]. A risk of nodal metastases > 5% is an indication to perform an extended nodal dissection (ePLND). As a consequence, the role of imaging is crucial in the work-up of high-risk
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and locally advanced PCa patients. According to EAU guidelines [3], MRI sensitivity for detecting LNM is low or similar to that of choline PET/CT. Despite the role of PSMA PET/CT currently remains investigational, its efficacy for detecting LNM was tested, as reported in some studies recently published in literature. The first results presented by Budäus et al. [29] in a cohort of 30 patients, revealed a poor sensitivity for PSMA PET/CT for identifying LNM: the sensitivity assessed in the per-patient analysis was 33,3%, while the sensitivity assessed in the per-side analysis was 27,3%. Conversely, authors assessed an optimal specificity and positive predictive value (PPV), both resulted to be 100% in the perpatient and in the per-side analysis. Nevertheless, this study presented several limitations including the retrospective design of the study, the low incidence of LNM in the enrolled population (53 LNM in 608 lymph node removed; 8,7%) and the criteria used to defined LNM in PET/CT scan. In the study presented by Maurer et al. [30] the diagnostic performance of PSMA PET/CT for assessing the presence of LNM before RP was tested in a cohort of 130 patients. On patient based analysis the sensitivity, specificity and accuracy of PSMA PET were 65.9%, 98.9% and 88.5%, and those of morphological imaging were 43.9%, 85.4% and 72.3%, respectively. Of 734 dissected lymph node templates 117 (15.9%) showed metastases. On per-side based analysis the sensitivity, specificity and accuracy of PSMA PET were 68.3%, 99.1% and 95.2%, and those of morphological imaging were 27.3%, 97.1% and 87.6%, respectively. These results were confirmed by van Leeuwen et al. [31]: authors assess the accuracy of PSMA PET/CT for lymph node staging in a cohort of 30 intermediate and high-risk PCa patients. The 37% of patients presented LNMs: in total, 180 LN fields were analyzed and 26 LNMs were identified in the histological analysis. Patient analysis showed that PSMA PET/CT had a sensitivity of 64%, specificity was 95%, the PPV was 88%, and the NPV was 82%. In the LN region-based analysis, the sensitivity was 56%, specificity was 98%, PPV was 90% and NPV was 94%, while the reported mean size of missed LNMs was 2.7 mm. According to the preliminary results published in literature, PSMA PET imaging showed a promising accuracy to stage PCa prior to curative treatment, both for defying the intraprostatic lesion and to evaluate the burden of the disease evaluating the presence of LNM. In this context, the presence of PET hybrid tomograph with MRI seems to increase the sensitivity of this new promising imaging procedure in the staging work-up. Furthermore, as whole body imaging procedure PSMA PET is a crucial tool for the detection of bone metastases. Despite no dedicated studies are at the moment available in literature, PSMA PET showed very high accuracy and optimal TBR for detecting bone lesions. As a consequence, PSMA PET scan should be considered before primary therapy in those patient with a very high risk of distant lesions. In this context, patient presenting bone metastases can be addressed to hormonal therapy or to palliative radiotherapy, according to PET results. 2.2. Recurrence setting The main application of PET imaging in PCa remain the restaging of the disease, with the detection of the site(s) of relapse in case of BCR as the main purpose. PET imaging could help physicians by addressing patients to the most tailored salvage therapies (e.g. salvage radiotherapy or salvage lymph-node dissection), as main clinical advantage in case of BCR. Choline-PET/CT still holds relatively low sensitivity, especially in patients with low PSA levels at the time of imaging [5]. Unfortunately, to obtain the best chance of cure in case of BCR, the optimal timing for salvage therapies would be when the PSA level is low, which reflect a still limited cancer burden [32]. The first investigations reported better accuracy for PSMA PET/CT for detecting suspected PCa metastases when com-
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pared with choline PET/CT [33] and very promising performances also at very low PSA levels [34]. In particular, in one of the largest patient-series published so far, Eiber et al. [34] reported about the performance of PSMA PET/CT in a population of 248 recurrent PCa with BCR (median PSA 1,99 ng/mL). The authors observed a promising overall positivity rate of 89.5% for 68 Ga-PSMA PET/CT. More in detail, the authors observed a considerably high positivity rate with low PSA levels with positivity rate of 93.0% (67 of 72) for a PSA value between 1 and 2 ng/mL, 72.7% (24 of 33) between 0.5 and 1 ng/mL, and 57.9% (11 of 19) for a PSA value between 0.2 and 0.5 ng/m. Later, Ceci and colleagues [35] investigated the role of PSMA PET/CT for restaging PCa patients and evaluated which clinical and pathologic features were associated with PET/CT positivity rate. In a cohort of 70 patients (median PSA 1.7 ng/mL), it was described a positivity rate of 74.2%. A PSA level of 0.83 ng/mL and a PSAdt of 6.5 months were found to be valuable cut-off values for predicting with high probability a positive or negative scan result. Moreover, PSA at the time of the scan and PSAdt were associated with an increased probability of a positive PSMA PET/CT result. Recently, the clinical impact of PSMA PET/CT on the management of patients with BCR after treatment with curative intent was investigated [36]. In a cohort of 131 consecutive PCa patients (median PSA 2.2 ng/mL) with an overall detection rate of 75% for PET/CT, it was demonstrated an impact on subsequent management in 99/131 patients (76%). The main modifications included continuing surveillance, hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment. According to the data present in literature, this novel approach proved its promising performance for investigating PCa, confirming the importance of this imaging modality for the precise individualization of the site of recurrence. Pfister D et al. [37] compared the usefulness of PSMA PET/CT vs choline PET/CT as diagnostic tool to guide salvage lymph-node dissection. They reported better sensitivity and specificity for PSMA (86,9%; 93,1%) compared to choline (71,2%; 86,9%) in the detection of LNM using histology as standard of reference. These results are consistent with data presented by Rauscher et al. [38]: authors evaluated the accuracy of PSMA PET/CT compared with morphologic imaging for the assessment of LNM in patients with BCR, using histopathology as standard of reference. They observed that PSMA was much more accurate to guide salvage lymph-node dissection than conventional morphological imaging with CT and/or MRI. In detail they observed, for the assessment of LNM, a sensitivity of 77.9% and specificity of 97.3% for PSMA vs. a sensitivity of 26.9% and specificity of 99.1% for conventional morphologic imaging. Later, the same group proposed the use of 111In-PSMA-I&T for radioguided salvage surgery (111In-PSMA-RGS) in recurrent PCa, using comparison of intra-operative gamma probe measurements with histopathological results of dissected specimens [39]. 31 recurrent patients with positive pelvic or retroperitoneal LNs in 68 Ga-PSMA PET/CT were included in the analysis. All patients were injected with 111In-PSMA-I&T before salvage lymph-node dissection and metastatic PCa lesions were tracked during surgery using a gamma probe. In 30/31 patients, 111In-PSMA-RGS allowed intra-operative identification of metastatic lesions. The ex-vivo measurements with gamma probe correlated excellently with histology, resulting in a sensitivity of 92.3%, specificity of 93.5%, accuracy of 93.1 &, PPV of 88.9% and NPV of 95.6%. Concluding, metastases directed therapy performed with curative intent and in accordance with this highly accurate imaging procedure could impact on patient management. In addition, the assessment of those parameters more likely to relate to a positive scan may lead to a better patient selection with an improvement in sensitivity, thus decreasing the number of false negative findings. This would help in optimizing the use of lesion-targeted approach in PCa recurrent disease.
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2.3. Therapy management and theranostics approach In addition to the substantially higher detection rates during BCR reported for PSMA based imaging compared to other diagnostic procedures, this tracer can also serve as a theranostics agent for treating metastatic castrate-resistant PCa (mCRPC). This theranostic concept has been highly successful in the context of somatostatin receptor imaging and therapy. Several studies reported promising results for response rates and a favorable safety profile after radioligand therapy (RLT) with 177Lu-PSMA-617 in patients with mCRPC [40–42]. Recently, the German Society of Nuclear Medicine published a retrospective multicenter analysis: twelve therapy centers retrospectively collected and pooled data on safety and efficacy of 177Lu-PSMA-617 RLT [43]. All patients were recruited on the basis of a positive 68 Ga-PSMA-11 PET. 248 therapy cycles were performed in 145 patients and an average dose of 5.9 GBq of 177Lu-PSMA-617 was administered (range, 2–8 GBq). Nineteen patients died during the observation period. Grade 3–4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. This multicenter analysis demonstrated favorable safety and efficacy of 177Lu-PSMA-617 RLT in a large number of mCRPC patients. 177Lu-PSMA-617 RLT might exceed the performance of other third-line systemic therapies reported in the literature. However, prospective phase II/III trials are currently in preparation, to evaluate the potential of this new targeted radioligand therapy especially with regards to improved patient survival. In this context, PSMA based PET imaging can play a crucial role as a gatekeeper in the management of metastatic advanced patients. mCRPC patients who present bone lesions only in the PSMA scan could addressed to 223Ra, while patients presenting visceral metastases with or without bone metastases could be considered as ideal candidates for PSMA based RLT. Finally, PSMA PET could be considered as a valuable tool to assess the response to treatment after RLT.
3. New molecular probes in prostate cacncer: GRPr and FACBC PET/CT 3.1. GRPr based PET imaging GRPr proteins are highly overexpressed in several human tumors, including prostate cancer [44], and GRPr has been detected in 63–100% of human prostate cancer tissue [45,46] Because synthetic bombesin receptor antagonist that targets GRPr (RM2) and PSMA target different biologic processes, understanding how these two tracers behave in patients with biochemically recurrent prostate cancer is critical to finding the best management options for this clinical scenario. Recently, Minamimoto [14] et al. in a small cohort of seven patients compared the biodistribution of 68 GaRM2 and 68 Ga-PSMA in patients with biochemically recurrent prostate cancer and to compare uptake of 68 Ga-PSMA outside the expected physiologic biodistribution with that of 68 Ga-RM2 in the same patients. Authors reported that the 68 Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between 68 Ga-PSMA and 68 GaRM2. However, 68 Ga-PSMA localized in a lymph node and seminal vesicle in a patient with no abnormal 68 Ga-RM2 uptake. Abdom-
inal periaortic lymph nodes were more easily visualized by 68 GaRM2 in two patients because of lack of interference by radioactivity in the small intestine. Authors concluded that, according to the preliminary results presented, 68 Ga-RM2 PET/CT could represent an alternative to 68-PSMA PET/CT for investigating PCa patients. Later, Wieser et al. [13] explore the value of GRPr-PET using the 68 Ga-labeled GRPr antagonist RM2 in a selected population of PCa patients with BCR and a negative or inconclusive 18 Fcholine PET/CT. 68 Ga-RM2-PET/CT showed at least one region with focal pathological uptake in 10/16 patients (62.5%). Seven of ten positive 68 Ga-RM2scans were positively confirmed by surgical resection and histology of the lesions (n = 2), by response to sitedirected therapies (n = 2) or by further imaging (n = 3). However, in literature are described the characteristic of only 37 men with PCa recurrence investigated with various radiolabeled GRPr ligands PET/CT. For this reason, no consideration can be drawn at this stage about the feasibility of this imaging procedure for investigating PCa in the clinical routine. Furthermore, it is not be proven that all PCa cellular subtypes present the overexpression of GRPr. Thus, at the moment, the use of radiolabeled GRPr ligands should be reserved to investigational purposes only.
3.2. FACBC based PET imaging Amino acid transport is upregulated in several tumors because of increased amino acid use for energy requirements and protein synthesis. Therefore, the molecular imaging of amino acid activity is an attractive target, especially in situations in which 18 F-FDG PET has limitations, such as PCa. The most comprehensive work to date with a synthetic amino acid PET radiotracer for prostate cancer imaging has been conducted with anti-1-amino-3-18 Ffluorocyclobutane-1-carboxylic acid (18 F-FACBC) [12]. In clinical practice, 18 F-FACBC proved to be most useful in patients with biochemical failure and suspected recurrent disease. In a recently completed prospective study [47] authors compared the accuracy of 18 F-FACBC and 11 C-choline PET/CT in patients radically treated for PCa presenting with BCR. A final report from this trial for 89 patients for whom the reference standard of clinical follow-up for at least 1 y was available provided a complete description of diagnostic performance. In this analysis, choline and 18 Ffluciclovine had sensitivities of 32% and 37%, specificities of 40% and 67%, accuracies of 32% and 38%, PPVs of 90% and 97%, and negative predictive values of 3% and 4%, respectively. These results demonstrated the 18 F-FACBC is a reliable biomarker for investigating PCa. However, this prospective trial provided a slightly better performance of 18 F-FACBC if compared to 11 C-choline PET/CT. Authors concluded that main benefit for using 18 FACBC PET/CT is related to practical and technical advantages of 18 F-FACBC over 11 C-choline. These included more favorable biodistribution, with lower background activity in the abdomen and pelvis and a longer half-life. Recently, a retrospective multi-site analysis has been published in a cohort of 596 recurrent PCa patients [48]. With a mean PSA values of 5.3 ng/mL in the overall population (range 0,05– 82 ng/mL) authors reported a detection rate for 18 F-FACBC PET/ CT of 67.7% (403 of 595). At the region level the detection rate was 38.7% (232 of 599) in the prostate/bed and 32.6% (194 of 596) in the pelvic lymph nodes. Metastatic involvement outside the pelvis was detected in 26.2% of patient scans (155 of 591), including skeletal sites in 9% (55 of 610) of cases. Overall, the subject level detection rate was 41.4% (53 of 128 patients) in the lowest quartile of PSA (0.79 ng/mL or less). Authors concluded that 18 F-FACBC is well-tolerated radiopharmaceuticals and able to detect local and distant PCa recurrence across a wide range of PSA values. Nevertheless, considering the few data available in literature about this radiotracer for investigating PCa, the real
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usefulness of 18 F-FACBC based imaging in the clinical practice should be to be assessed in further studies. 4. Conclusion PET/CT imaging represents, at the moment, one of the most useful diagnostic procedures for investigating PCa. Nowadays, several novel radiotracers are available in the market, with PSMA base PET imaging that already proved to be superior if compared to choline base PET imaging and conventional radiological imaging. Moreover, the theranostics approach of this radiotracer represents a very attractive treatment opportunity in metastatic patients. However, further prospective trials are needed in order to confirm these promising results. References [1] R.L. Siegel, K.D. Miller, A. Jemal, et al., Cancer statistics, CA Cancer J. Clin. 2015 (65) (2015) 5–29. [2] T.K. Choueiri, R. Dreicer, A. Paciorek, et al., A model that predicts the probability of positive imaging in prostate cancer cases with biochemical failure after initial definitive local therapy, J. Urol. 179 (2008) 906–910 [discussion: 10]. [3] Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol. 2016. pii: S0302-2838(16)30470-5. [4] M.E. Phelps, Inaugural article: positron emissiont omography provides molecular imaging of biological processes, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 9226–9233. [5] P. Castellucci, F. Ceci, T. Graziani, et al., Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11 C-Choline PET/CT scan before salvage radiation therapy?, J Nucl. Med. 55 (2014) 1424–1429. [6] F. Ceci, P. Castellucci, P. Mapelli, et al., Evaluation of prostate cancer with 11Ccholine PET/CT for treatment planning, response assessment, and prognosis, J. Nucl. Med. 57 (2016) 49S–54S. [7] L. Evangelista, A. Guttilla, F. Zattoni, P.C. Muzzio, Utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a systematic literature review and meta-analysis, Eur. Urol. 63 (2013) 1040–1048. [8] A. Afshar-Oromieh, A. Malcher, M. Eder, et al., PET imaging with a [68 Ga]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 40 (4) (2013) 486–495. [9] A. Ghosh, W.D. Heston, Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer, J. Cell. Biochem. 91 (2004) 528– 539. [10] C. Barinka, C. Rojas, B. Slusher, et al., Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer, Curr. Med. Chem. 19 (2012) 856–870. [11] A. Afshar-Oromieh, C.M. Zechmann, A. Malcher, 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 41 (2014) 11–20. [12] D.M. Schuster, C. Nanni, S. Fanti, Evaluation of prostate cancer with radiolabeled amino acid analogs, J. Nucl. Med. 57 (Suppl. 3) (2016) 61S–66S. [13] Wieser G, Popp I, Christian Rischke H, et al. Diagnosis of recurrent prostate cancer with PET/CT imaging using the gastrin-releasing peptide receptor antagonist (68)Ga-RM2: preliminary results in patients with negative or inconclusive [(18)F]Fluoroethylcholine-PET/CT. Eur. J. Nucl. Med. Mol. Imaging 2017. doi: 10.1007/s00259-017-3702-8. [Epub ahead of print]. [14] R. Minamimoto, S. Hancock, B. Schneider, et al., Pilot Comparison of 68Ga-RM2 PET and 68Ga-PSMA-11 PET in Patients with Biochemically Recurrent Prostate Cancer, J. Nucl. Med. 57 (4) (2016) 557–562. [15] C. Liolios, M. Schäfer, U. Haberkorn, M. Eder, K. Kopka, Novel Bispecific PSMA/ GRPr Targeting Radioligands with Optimized Pharmacokinetics for Improved PET Imaging of Prostate Cancer, Bioconjug. Chem. 27 (3) (2016) 737–751. [16] R.S. Israeli, C.T. Powell, W.R. Fair, W.D. Heston, Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen, Cancer Res. 53 (1993) 227–230. [17] A.M. DeMarzo, W.G. Nelson, W.B. Isaacs, J.I. Epstein, Pathological and molecular aspects of prostate cancer, Lancet Lond. Engl. 361 (2003) 955– 964, http://dx.doi.org/10.1016/S0140-6736(03)12779-1. [18] D.A. Silver, I. Pellicer, W.R. Fair, W.D. Heston, C. Cordon-Cardo, Prostatespecific membrane antigen expression in normal and malignant human tissues, Clin. Cancer Res. 3 (1997) 81–85. [19] S. Minner, C. Wittmer, M. Graefen, G. Salomon, T. Steuber, A. Haese, et al., High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer, Prostate 71 (2011) 281–288, http://dx.doi.org/ 10.1002/pros.21241.
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Larcher, F. Abdollah, et al., Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores, Eur. Urol. 61 (2012) 480–487. [29] L. Budäus, S.R. Leyh-Bannurah, G. Salomon, et al., Initial Experience of (68)GaPSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy, Eur. Urol. 69 (3) (2016) 393–396, http://dx.doi.org/10.1016/j. eururo.2015.06.010. [30] T. Maurer, J.E. Gschwend, I. Rauscher, et al., Diagnostic Efficacy of (68)GalliumPSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer, J. Urol. 195 (5) (2016) 1436–1443, http://dx.doi.org/10.1016/j. juro.2015.12.025. [31] P.J. Van Leeuwen, L. Emmett, B. 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New aspects of molecular imaging in prostate cancer Francesco Ceci a,b,⇑, Paolo Castellucci c, Juliano J. Cerci d, Stefano Fanti c a
Department of Surgical Sciences, University of Bologna, Italy Department of Molecular and Medical Pharmacology, University of California Los Angeles, USA c Nuclear Medicine Unit, S.Orsola-Malpighi Hospital, University of Bologna, Italy d Quanta Diagnóstico e Terapia, Diagnostic and Therapy Clinic, Curitiba, Brazil b
a r t i c l e
i n f o
Article history: Received 26 April 2017 Received in revised form 12 June 2017 Accepted 10 July 2017 Available online xxxx Keywords: PSMA PET/CT 68 Ga-PSMA 177Lu-PSMA 18 F-FACBC: 68 Ga-RM2: prostate cancer Biochemical recurrence Metastases directed therapy Theranostics PSMA-I&T
a b s t r a c t Nowadays several new imaging modalities are available for investigating prostate cancer (PCa) such as magnet resonance imaging (MRI) in the form of whole body MRI and pelvic multiparametric MRI and positron emission tomography (PET) using choline as radiotracers. Nevertheless, these modalities proved sub-optimal accuracy for detecting PCa metastases, particularly in the recurrence setting. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been recently developed for PET imaging. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallopeptidase over-expressed in PCa cells. It has been shown that PSMA based imaging offers higher tumor detection rate compared to choline PET/CT and radiological conventional imaging, especially at very low PSA levels during biochemical recurrence. In addition PSMA, as theranostics agent, allows both radiolabeling with diagnostic (e.g. 68 Ga, 18 F) or therapeutic nuclides (e.g. 177Lu, 225Ac). Initial results show that PSMA-targeted radioligand therapy can potentially delay disease progression in metastatic castrate-resistant PCa. Despite still investigational, the bombesin-based radiotracers and antagonist of gastrin releasingpeptide receptor (GRP) (RM2) and anti1-amino-3-18 Ffluorocyclobutane-1-carboxylic acid (18 FFACBC) are emerging as possible alternatives for investigating PCa. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68 Ga-PSMA11, 18 F-FACBC, 68 Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy. Ó 2017 Elsevier Inc. All rights reserved.
1. Introduction Prostate cancer (PCa) is the most common cancer and the third most common cause of cancer death in men [1]. At present, depending on the clinical stage, imaging of PCa can be indicated for primarydiagnosis, staging and detection of biochemical recurrent (BCR) disease as well as therapy response. Conventional imaging modalities, including ultrasound (US), bone scintigraphy (BS) and computed tomography (CT) are used to detect primary and metastatic PCa for staging and risk stratification. Despite significant efforts, these modalities do not contribute essentially to ⇑ Corresponding author at: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Ahmanson Translational Imaging Division, 10833 Le Conte Ave., 200 Medical Plaza, Los Angeles, CA 90095-7370, USA. E-mail address: [email protected] (F. Ceci).
patient management as much as imaging performed in patients with other common cancers [2]. Magnetic resonance imaging (MRI), especially innovative methods such as diffusion-weighted MRI (DWI-MRI) or dynamic contrast-enhanced MRI (DCE-MRI) allowing functional assessment of the disease, are growingly important for imaging of PCa [3]. Nevertheless, these techniques do not allow tumor-specific imaging and cannot be applied throughout the whole body. Functional imaging with positron emission tomography (PET) shows molecular function and metabolic activity information in a single-step whole body examination [4]. Over the last decade, PET/CT (with 11 C-choline or 18 Fcholine) proved its role for investigating PCa [5]. Particularly, choline PET/CT proved to be a better diagnostic tool for restaging PCa patients presenting BCR, as compared with radiological imaging [6]. Furthermore, choline PET/CT demonstrated its usefulness for
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staging high-risk PCa, with high PSA levels and Gleason Scores (GS), before the primary treatment [7]. However, choline based PET imaging presents several limitations both for staging the disease (lack of accuracy for detecting lymph-node involvement) and for restaging in case of BCR (lack of accuracy in case of PSA < 2 ng/mL). As a consequence functional metabolic imaging still holds a sub-optimal performance for investigating PCa [6]. Several efforts have been made over the last years to develop new probes able to provide better performances when compared with the choline-PET/CT [8]. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been developed recently for PET imaging [9]. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallo-peptidase physiologically expressed in several tissues. Although the function of GCPII in prostate remains unclear, it is well-known that this protein is over expressed in PCa [10]. The first investigations reported a higher tumor to background ratio for 68 Ga-PSMA PET/CT for the detection of suspected PCa metastases when compared with choline PET/CT [11] and very promising performances also at very low PSA levels. In addition, other recently developed PSMA-inhibitors (PSMA I&T, PSMA-617, PSMA-1007) can be used as theranostics agents allowing radio-labeling with diagnostic (e.g. 68 Ga, 18 F) or therapeutic nuclides (e.g. 177Lu, 225Ac). In recent years an investigational amino acidic PET compound, anti1-amino-318 Ffluorocyclobutane-1-carboxylic acid (18 F-FACBC), a synthetic L-leucine
analogue, was developed and tested in PCa patients with BCR after radical treatment. This radiotracer that actually falls within the category of metabolic radiotracers has been recently approved in the US, by the Food and Drug Association (FDA), as alternative metabolic radiopharmaceuticals for investigating PCa patients with biochemical recurrence [12]. Finally, Bombesinbased radiotracers and antagonists of gastrin-releasing peptide (GRPr) receptor, labeled with 68 Ga (68 Ga-RM2), are also of interest [13,14] and a recently PSMA-GRPr PET hybrid tracer developed (tested on murine samples) [15] suggests that this field is ever evolving towards new and hopefully more accurate diagnostic tools. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68 Ga-PSMA-11, 18 F-FACBC, 68 Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy.
2. New molecular probes in prostate cacncer: PSMA PET/CT imaging The prostate-specific membrane antigen (PSMA) is a type II transmembrane protein that was first detected on the human PCa cell line LNCaP [16]. Its expression and localization in the normal human prostate is associated with the cytoplasm and apical side of the epithelium surrounding prostatic ducts but not basal epithelium, neuroendocrine or stromal cells [17]. In malignant tissue, PSMA is involved in angiogenesis, as increased PSMA expression was found in the stroma adjacent to neovasculature of solid tumors [18]. Due to its selective overexpression in 90–100% of PCa lesions [19], PSMA is a reliable tissue marker for PCa and is considered an ideal target for tumor specific imaging and therapy [20]. Several studies showed that PSMA expression levels increase according to the stage and grade of the tumor as well as aneuploidy
and biochemical recurrence thus potentially allowing PSMAimaging to account for prognosis [21]. Recently, a large number of urea-based PSMA ligands labeled with 68 Ga have been presented, including PSMA HBED-CC (PSMA-11), PSMA I&T [22] and PSMA-617. More recently, 18 F-labeled compound with hepatobiliar excretion (PSMA-1007) attracted the most attention [23]. According to preliminary data, PSMA-1007 seems to be the most promising tracer showing a comparable accuracy to 68 Ga-PSMA11, but its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68 Ga-labeled PSMA tracers. Furthermore, 18 FPSMA-1007 can be produced in large amounts per batch in PET radiopharmacies with an onsite cyclotron, reducing the demand for multiple tracer syntheses per day and enabling transfer to satellite centers. Preliminary data suggest reduced urinary excretion and high tumor to background ratios contribute to exceptional sensitivities including for tiny tumor deposits in the body. 2.1. Staging In patients eligible to curative primary therapy, the decision to proceed with a further staging work-up is guided by which treatment options are available, taking into account the patient’s preference and co-morbidity. Several imaging modalities have been proposed to assess the extension of the intraprostatic lesion before radical prostatectomy (RP). In predominantly Gleason pattern 4, multiparametric MRI (mp-MRI) provided the most valuable performance with best values both for sensitivity and specificity. Thus, the use of mp-MRI is recommended by the European Association of Urology (EAU) guidelines in intermediate and high-risk PCa before primary treatment [3,24]. The use of choline PET/CT in the pre-operative setting has not been recommended by the EAU, both for intermediate and high-risk patients. Despite EAU guidelines still consider PSMA based PET imaging an investigational procedure, very promising results have been recently presented, both for detecting the intraprostatic lesion and for the assessment of lymph-node metastases (LNM). Fendler et al. [25] evaluated the accuracy of PET/CT with 68 GaPSMA-11 to localize cancer in the prostate and surrounding tissue at initial diagnosis in cohort of 21 patients. It was assessed a sensitivity of 67%, a specificity of 92%, an accuracy of 72%, a PPV of 97% and a NPV of 42%. Histopathology positive segments (100/126; 79%) demonstrated a significantly higher mean SUVmax than histopathology-negative segments. However, despite better values for specificity and PPV if compared to choline PET/CT, the sensitivity still remain sub-optimal. Thus, it was recently proposed the combination of PSMA based PET with MRI to improve the performance of both methodologies. Zamboglou et al. [26] demonstrated that the hybridization of the two techniques performed even better in terms of sensitivity (82%) and specificity (89%). Eiber et al. confirmed these results [27]: authors compared the diagnostic performance of simultaneous 68 Ga-PSMA PET/MRI for the localization of primary PCa with mpMRI and PET alone in a cohort of 53 patients. Simultaneous PET/MRI statistically outperformed mpMRI and PET imaging alone for a precise localization of PCa. The hybrid diagnostic procedure detected correctly the lesion in the 98% of cases with a sensitivity of 76% and a specificity of 98% (MRI alone 43%, 98%; PET alone 58%, 82%). Moreover, according to the data available in literature so far, it seems reasonable to assume that PSMA PET/MRI is able to distinguish with good accuracy between intraprostatic PCa lesion and BPH [25,27]. The individual risk of finding LNM can be estimated using externally validated with preoperative nomograms according to D’Amico criteria [28]. A risk of nodal metastases > 5% is an indication to perform an extended nodal dissection (ePLND). As a consequence, the role of imaging is crucial in the work-up of high-risk
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and locally advanced PCa patients. According to EAU guidelines [3], MRI sensitivity for detecting LNM is low or similar to that of choline PET/CT. Despite the role of PSMA PET/CT currently remains investigational, its efficacy for detecting LNM was tested, as reported in some studies recently published in literature. The first results presented by Budäus et al. [29] in a cohort of 30 patients, revealed a poor sensitivity for PSMA PET/CT for identifying LNM: the sensitivity assessed in the per-patient analysis was 33,3%, while the sensitivity assessed in the per-side analysis was 27,3%. Conversely, authors assessed an optimal specificity and positive predictive value (PPV), both resulted to be 100% in the perpatient and in the per-side analysis. Nevertheless, this study presented several limitations including the retrospective design of the study, the low incidence of LNM in the enrolled population (53 LNM in 608 lymph node removed; 8,7%) and the criteria used to defined LNM in PET/CT scan. In the study presented by Maurer et al. [30] the diagnostic performance of PSMA PET/CT for assessing the presence of LNM before RP was tested in a cohort of 130 patients. On patient based analysis the sensitivity, specificity and accuracy of PSMA PET were 65.9%, 98.9% and 88.5%, and those of morphological imaging were 43.9%, 85.4% and 72.3%, respectively. Of 734 dissected lymph node templates 117 (15.9%) showed metastases. On per-side based analysis the sensitivity, specificity and accuracy of PSMA PET were 68.3%, 99.1% and 95.2%, and those of morphological imaging were 27.3%, 97.1% and 87.6%, respectively. These results were confirmed by van Leeuwen et al. [31]: authors assess the accuracy of PSMA PET/CT for lymph node staging in a cohort of 30 intermediate and high-risk PCa patients. The 37% of patients presented LNMs: in total, 180 LN fields were analyzed and 26 LNMs were identified in the histological analysis. Patient analysis showed that PSMA PET/CT had a sensitivity of 64%, specificity was 95%, the PPV was 88%, and the NPV was 82%. In the LN region-based analysis, the sensitivity was 56%, specificity was 98%, PPV was 90% and NPV was 94%, while the reported mean size of missed LNMs was 2.7 mm. According to the preliminary results published in literature, PSMA PET imaging showed a promising accuracy to stage PCa prior to curative treatment, both for defying the intraprostatic lesion and to evaluate the burden of the disease evaluating the presence of LNM. In this context, the presence of PET hybrid tomograph with MRI seems to increase the sensitivity of this new promising imaging procedure in the staging work-up. Furthermore, as whole body imaging procedure PSMA PET is a crucial tool for the detection of bone metastases. Despite no dedicated studies are at the moment available in literature, PSMA PET showed very high accuracy and optimal TBR for detecting bone lesions. As a consequence, PSMA PET scan should be considered before primary therapy in those patient with a very high risk of distant lesions. In this context, patient presenting bone metastases can be addressed to hormonal therapy or to palliative radiotherapy, according to PET results. 2.2. Recurrence setting The main application of PET imaging in PCa remain the restaging of the disease, with the detection of the site(s) of relapse in case of BCR as the main purpose. PET imaging could help physicians by addressing patients to the most tailored salvage therapies (e.g. salvage radiotherapy or salvage lymph-node dissection), as main clinical advantage in case of BCR. Choline-PET/CT still holds relatively low sensitivity, especially in patients with low PSA levels at the time of imaging [5]. Unfortunately, to obtain the best chance of cure in case of BCR, the optimal timing for salvage therapies would be when the PSA level is low, which reflect a still limited cancer burden [32]. The first investigations reported better accuracy for PSMA PET/CT for detecting suspected PCa metastases when com-
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pared with choline PET/CT [33] and very promising performances also at very low PSA levels [34]. In particular, in one of the largest patient-series published so far, Eiber et al. [34] reported about the performance of PSMA PET/CT in a population of 248 recurrent PCa with BCR (median PSA 1,99 ng/mL). The authors observed a promising overall positivity rate of 89.5% for 68 Ga-PSMA PET/CT. More in detail, the authors observed a considerably high positivity rate with low PSA levels with positivity rate of 93.0% (67 of 72) for a PSA value between 1 and 2 ng/mL, 72.7% (24 of 33) between 0.5 and 1 ng/mL, and 57.9% (11 of 19) for a PSA value between 0.2 and 0.5 ng/m. Later, Ceci and colleagues [35] investigated the role of PSMA PET/CT for restaging PCa patients and evaluated which clinical and pathologic features were associated with PET/CT positivity rate. In a cohort of 70 patients (median PSA 1.7 ng/mL), it was described a positivity rate of 74.2%. A PSA level of 0.83 ng/mL and a PSAdt of 6.5 months were found to be valuable cut-off values for predicting with high probability a positive or negative scan result. Moreover, PSA at the time of the scan and PSAdt were associated with an increased probability of a positive PSMA PET/CT result. Recently, the clinical impact of PSMA PET/CT on the management of patients with BCR after treatment with curative intent was investigated [36]. In a cohort of 131 consecutive PCa patients (median PSA 2.2 ng/mL) with an overall detection rate of 75% for PET/CT, it was demonstrated an impact on subsequent management in 99/131 patients (76%). The main modifications included continuing surveillance, hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment. According to the data present in literature, this novel approach proved its promising performance for investigating PCa, confirming the importance of this imaging modality for the precise individualization of the site of recurrence. Pfister D et al. [37] compared the usefulness of PSMA PET/CT vs choline PET/CT as diagnostic tool to guide salvage lymph-node dissection. They reported better sensitivity and specificity for PSMA (86,9%; 93,1%) compared to choline (71,2%; 86,9%) in the detection of LNM using histology as standard of reference. These results are consistent with data presented by Rauscher et al. [38]: authors evaluated the accuracy of PSMA PET/CT compared with morphologic imaging for the assessment of LNM in patients with BCR, using histopathology as standard of reference. They observed that PSMA was much more accurate to guide salvage lymph-node dissection than conventional morphological imaging with CT and/or MRI. In detail they observed, for the assessment of LNM, a sensitivity of 77.9% and specificity of 97.3% for PSMA vs. a sensitivity of 26.9% and specificity of 99.1% for conventional morphologic imaging. Later, the same group proposed the use of 111In-PSMA-I&T for radioguided salvage surgery (111In-PSMA-RGS) in recurrent PCa, using comparison of intra-operative gamma probe measurements with histopathological results of dissected specimens [39]. 31 recurrent patients with positive pelvic or retroperitoneal LNs in 68 Ga-PSMA PET/CT were included in the analysis. All patients were injected with 111In-PSMA-I&T before salvage lymph-node dissection and metastatic PCa lesions were tracked during surgery using a gamma probe. In 30/31 patients, 111In-PSMA-RGS allowed intra-operative identification of metastatic lesions. The ex-vivo measurements with gamma probe correlated excellently with histology, resulting in a sensitivity of 92.3%, specificity of 93.5%, accuracy of 93.1 &, PPV of 88.9% and NPV of 95.6%. Concluding, metastases directed therapy performed with curative intent and in accordance with this highly accurate imaging procedure could impact on patient management. In addition, the assessment of those parameters more likely to relate to a positive scan may lead to a better patient selection with an improvement in sensitivity, thus decreasing the number of false negative findings. This would help in optimizing the use of lesion-targeted approach in PCa recurrent disease.
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2.3. Therapy management and theranostics approach In addition to the substantially higher detection rates during BCR reported for PSMA based imaging compared to other diagnostic procedures, this tracer can also serve as a theranostics agent for treating metastatic castrate-resistant PCa (mCRPC). This theranostic concept has been highly successful in the context of somatostatin receptor imaging and therapy. Several studies reported promising results for response rates and a favorable safety profile after radioligand therapy (RLT) with 177Lu-PSMA-617 in patients with mCRPC [40–42]. Recently, the German Society of Nuclear Medicine published a retrospective multicenter analysis: twelve therapy centers retrospectively collected and pooled data on safety and efficacy of 177Lu-PSMA-617 RLT [43]. All patients were recruited on the basis of a positive 68 Ga-PSMA-11 PET. 248 therapy cycles were performed in 145 patients and an average dose of 5.9 GBq of 177Lu-PSMA-617 was administered (range, 2–8 GBq). Nineteen patients died during the observation period. Grade 3–4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. This multicenter analysis demonstrated favorable safety and efficacy of 177Lu-PSMA-617 RLT in a large number of mCRPC patients. 177Lu-PSMA-617 RLT might exceed the performance of other third-line systemic therapies reported in the literature. However, prospective phase II/III trials are currently in preparation, to evaluate the potential of this new targeted radioligand therapy especially with regards to improved patient survival. In this context, PSMA based PET imaging can play a crucial role as a gatekeeper in the management of metastatic advanced patients. mCRPC patients who present bone lesions only in the PSMA scan could addressed to 223Ra, while patients presenting visceral metastases with or without bone metastases could be considered as ideal candidates for PSMA based RLT. Finally, PSMA PET could be considered as a valuable tool to assess the response to treatment after RLT.
3. New molecular probes in prostate cacncer: GRPr and FACBC PET/CT 3.1. GRPr based PET imaging GRPr proteins are highly overexpressed in several human tumors, including prostate cancer [44], and GRPr has been detected in 63–100% of human prostate cancer tissue [45,46] Because synthetic bombesin receptor antagonist that targets GRPr (RM2) and PSMA target different biologic processes, understanding how these two tracers behave in patients with biochemically recurrent prostate cancer is critical to finding the best management options for this clinical scenario. Recently, Minamimoto [14] et al. in a small cohort of seven patients compared the biodistribution of 68 GaRM2 and 68 Ga-PSMA in patients with biochemically recurrent prostate cancer and to compare uptake of 68 Ga-PSMA outside the expected physiologic biodistribution with that of 68 Ga-RM2 in the same patients. Authors reported that the 68 Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between 68 Ga-PSMA and 68 GaRM2. However, 68 Ga-PSMA localized in a lymph node and seminal vesicle in a patient with no abnormal 68 Ga-RM2 uptake. Abdom-
inal periaortic lymph nodes were more easily visualized by 68 GaRM2 in two patients because of lack of interference by radioactivity in the small intestine. Authors concluded that, according to the preliminary results presented, 68 Ga-RM2 PET/CT could represent an alternative to 68-PSMA PET/CT for investigating PCa patients. Later, Wieser et al. [13] explore the value of GRPr-PET using the 68 Ga-labeled GRPr antagonist RM2 in a selected population of PCa patients with BCR and a negative or inconclusive 18 Fcholine PET/CT. 68 Ga-RM2-PET/CT showed at least one region with focal pathological uptake in 10/16 patients (62.5%). Seven of ten positive 68 Ga-RM2scans were positively confirmed by surgical resection and histology of the lesions (n = 2), by response to sitedirected therapies (n = 2) or by further imaging (n = 3). However, in literature are described the characteristic of only 37 men with PCa recurrence investigated with various radiolabeled GRPr ligands PET/CT. For this reason, no consideration can be drawn at this stage about the feasibility of this imaging procedure for investigating PCa in the clinical routine. Furthermore, it is not be proven that all PCa cellular subtypes present the overexpression of GRPr. Thus, at the moment, the use of radiolabeled GRPr ligands should be reserved to investigational purposes only.
3.2. FACBC based PET imaging Amino acid transport is upregulated in several tumors because of increased amino acid use for energy requirements and protein synthesis. Therefore, the molecular imaging of amino acid activity is an attractive target, especially in situations in which 18 F-FDG PET has limitations, such as PCa. The most comprehensive work to date with a synthetic amino acid PET radiotracer for prostate cancer imaging has been conducted with anti-1-amino-3-18 Ffluorocyclobutane-1-carboxylic acid (18 F-FACBC) [12]. In clinical practice, 18 F-FACBC proved to be most useful in patients with biochemical failure and suspected recurrent disease. In a recently completed prospective study [47] authors compared the accuracy of 18 F-FACBC and 11 C-choline PET/CT in patients radically treated for PCa presenting with BCR. A final report from this trial for 89 patients for whom the reference standard of clinical follow-up for at least 1 y was available provided a complete description of diagnostic performance. In this analysis, choline and 18 Ffluciclovine had sensitivities of 32% and 37%, specificities of 40% and 67%, accuracies of 32% and 38%, PPVs of 90% and 97%, and negative predictive values of 3% and 4%, respectively. These results demonstrated the 18 F-FACBC is a reliable biomarker for investigating PCa. However, this prospective trial provided a slightly better performance of 18 F-FACBC if compared to 11 C-choline PET/CT. Authors concluded that main benefit for using 18 FACBC PET/CT is related to practical and technical advantages of 18 F-FACBC over 11 C-choline. These included more favorable biodistribution, with lower background activity in the abdomen and pelvis and a longer half-life. Recently, a retrospective multi-site analysis has been published in a cohort of 596 recurrent PCa patients [48]. With a mean PSA values of 5.3 ng/mL in the overall population (range 0,05– 82 ng/mL) authors reported a detection rate for 18 F-FACBC PET/ CT of 67.7% (403 of 595). At the region level the detection rate was 38.7% (232 of 599) in the prostate/bed and 32.6% (194 of 596) in the pelvic lymph nodes. Metastatic involvement outside the pelvis was detected in 26.2% of patient scans (155 of 591), including skeletal sites in 9% (55 of 610) of cases. Overall, the subject level detection rate was 41.4% (53 of 128 patients) in the lowest quartile of PSA (0.79 ng/mL or less). Authors concluded that 18 F-FACBC is well-tolerated radiopharmaceuticals and able to detect local and distant PCa recurrence across a wide range of PSA values. Nevertheless, considering the few data available in literature about this radiotracer for investigating PCa, the real
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