PSMA PET in prostate cancer – a step towards personalized medicine

Abstract

Purpose of review

Increasing attention is being given to personalized medicine in oncology, where therapies are tailored to the particular characteristics of the individual cancer patient. In recent years, there has been greater focus on PSMA in prostate cancer (PCa) as a target for imaging and therapy with radionuclides. This review highlights the recent advancements in PSMA PET in PCa during the past year.

Recent findings

Several reports on PSMA PET/CT in PCa patients are demonstrating promising results, especially for detection of biochemical recurrence. ¹⁸F-PSMA PET/CT may be superior to ⁶⁸Ga-PSMA PET/CT. The detection rate of PSMA PET is influenced by PSA level. PSMA PET/CT may have a higher detection rate than choline PET/CT. Only a few reports have been published on PSMA PET/MRI, and this modality remains to be elucidated further.

Conclusion

Molecular imaging with PSMA PET is paving the way for personalized medicine in PCa. However, large prospective clinical studies are needed to further evaluate the role of PSMA PET/CT and PET/MRI in the clinical workflow of PCa. PSMA is an excellent target for imaging and therapy with radionuclides, and the “image and treat” strategy has the potential to become a milestone in the management of PCa patients.

INTRODUCTION

Prostate cancer (PCa), the most common cancer in men, is the second leading cause of cancer deaths among men[1]. The clinical management of PCa is challenging due to the variable clinical and pathologic behavior of the disease. Thus, the treatment of PCa should be optimized and specific to each patient in order to improve their outcomes. Much attention is being given to the development of precision medicine in oncology, where pharmaceutical therapies are tailored to the particular characteristics of the individual cancer patient. Precision medicine requires accurate characterization and location of the cancer. In recent years, there has been increasing focus on prostate-specific membrane antigen (PSMA) as a target for both imaging and therapy[2]. PSMA is a type II integral membrane glycoprotein (100–120 kDa), with an intracellular component, a transmembrane component, and a large extracellular domain[3,4]. PSMA is highly expressed by all PCa, and its expression increases with tumor aggressiveness, metastatic disease and disease recurrence[2,5]. Despite its name, PSMA is also expressed in several healthy tissues such as the salivary glands, proximal renal tubules, epididymis, ovary, the luminal side of the ileum-jejunum, and astrocytes in CNS, while normal prostatic tissue expresses little PSMA in the apical epithelium of secretory ducts[6–7,••8]. Furthermore, PSMA is expressed in the neovasculature of other tumors, including bladder, pancreas, lung, and kidney cancers, but not in normal vasculature[7,9]. Therefore, PSMA represents an excellent target for both imaging and therapy of PCa[2,••8]. During the last two decades, many efforts have been undertaken to develop high affinity PSMA ligands for both imaging and therapy [2,••8]. This “image and treat” strategy has the potential to become a milestone in the management of PCa patients[10–12]. The purpose of this review is to highlight the most important developments of PSMA PET imaging reported in the past year.

PSMA PET ligands

The first widely used PSMA imaging agent in PCa was ProstaScintTM (EUSA Pharma), an ¹¹¹In-labeled version of the monoclonal antibody 7E11 that targets PSMA. However, this PSMA agent targets only the internal domain of PSMA and therefore is only accessible to its antigen target in dying and dead cells where the membrane is permeable. Furthermore, the PSMA radiotracer is technically demanding to administer, with only moderate clinical diagnostic performance[4]. The recently developed antibody-based PSMA PET radiotracers primarily target the extracellular domain of the PSMA (hence also detecting viable cells) and include ⁶⁴Cu- and ⁸⁹Zr- labeled PSMA antibodies and antibody fragments and ⁶⁴Cu-labeled aptamers[3]. More recently, small molecule high affinity PSMA antagonists have been developed that are labeled with ⁶⁸Ga-, ¹⁸F-, ¹¹C-, ⁶⁴Cu -, and ⁸⁶Y [3]. One of these ligands, ⁶⁸Ga (HBED-CC), also known as PSMA-11, has up to now been the most clinically used PSMA PET radiotracer in PCa patients. This agent has a strong binding affinity to PSMA, and is efficiently internalized into PCa cells[13,14]. A human biodistribution study (n=37) of ⁶⁸Ga (HBED-CC) PET/CT reported no adverse events[15]. Within healthy organs, kidneys and salivary glands show the highest radiotracer uptake, while lacrimal glands, liver, spleen and bowel show relatively moderate uptake[15]. Intense radiotracer uptake in the urinary bladder is due to excretion of the radiotracer through the kidneys. Excellent contrast on the images is seen 1 h post injection (p.i.) even at low PSA levels. Kabasakal et al. compared ⁶⁸Ga-PSMA PET images obtained at 5 min p.i and 60 min p.i. and found no difference in the number of lesions detected[16]. However, SUVmax for primary tumors, LN and bone metastases were significantly higher on late images, while on early images prostatic evaluation was easier because of lack of urinary tracer activity within the bladder. Thus, early imaging may be useful for the evaluation of lesions close to the bladder. Biphasic imaging may help in discriminating benign from malignant lesions since ⁶⁸Ga-PSMA uptake increases over time in PC cells via internalization of the PSMA protein. Recently, modifications of PSMA-11 have resulted in a novel small molecule PSMA-ligand, PSMA-617, with a significantly higher binding affinity to PSMA and also highly efficient internalization into PCa cells[18]. Like ⁶⁸Ga (HBED-CC), kidneys and salivary glands show the highest ⁶⁸Ga-PSMA-617 uptake, whereas lacrimal glands, spleen, liver and bowel show relative moderate uptake[•19]. PSMA-617 can be labeled with ⁶⁸Ga, ¹¹¹In, ¹⁷⁷Lu, and ⁹⁰Y, and therefore may potentially be used for imaging as well as for therapy[•19]. In the past few years, ¹⁷⁷Lu-PSMA-617 has been used for treating metastatic PCa at several centers[20–22].

PSMA ligands may also be labeled with ¹⁸F for PSMA PET imaging. Unlike generator-produced ⁶⁸Ga, a cyclotron is needed for production of ¹⁸F -PSMA agents. However, like ¹⁸F-FDG, ¹⁸F-PSMA agents may be centrally produced and distributed to multiple institutions due to its longer half-life of 110 min. Moreover, ¹⁸F imaging results in improved spatial resolution and more accurate quantitation due to shorter positron range and higher positron yield of ¹⁸F versus ⁶⁸Ga[23]. N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]- 4-fluorobenzyl-L-cysteine (DCFBC) is a first generation low-molecular-weight, urea-based inhibitor of PSMA which binds to PCa cells with high PSMA expression in preclinical studies[24] The basic structure is the same as the ⁶⁸Ga-based agents with the exception that the latter have a chelate attached for binding the radiometal. The estimated ¹⁸F-DCFBC mean effective radiation dose to patients is comparable to that of ¹⁸F-FDG[24]. A new second-generation ¹⁸F-PSMA–agent (¹⁸F-DCFPyL) demonstrates higher affinity and faster clearance resulting in higher tumor to background ratio, which may produce better detection of lower-grade or smaller-sized PCa compared with ¹⁸F-DCFBC[•25]. Dietlein et al compared ¹⁸F-DCFPyl PET/CT and ⁶⁸Ga-PSMA(HBED-CC) PET/CT in patients with biochemically relapsed PCa (n=14)[••26]. All suspicious lesions identified by ⁶⁸Ga-PSMA-HBED-CC were also detected with ¹⁸F-DCFPyL. In 3 patients, additional lesions were observed using ¹⁸F-DCFPyL PET/CT. The mean SUV_max in the concordant ¹⁸F-DCFPyL PSMA lesions was significantly higher as compared to ⁶⁸Ga-PSMA-HBED-CC (14.5 vs. 12.2, p=0.028, n=15). Thus, ¹⁸F-DCFPyL represents a highly promising alternative to ⁶⁸Ga-PSMA-HBED-CC for PET imaging in PCa.

More recently, a different PSMA agent, EuK-Subkff-68Ga-DOTAGA (⁶⁸Ga-PSMA I&T), was developed, which also can be labeled with ¹⁷⁷Lu for therapy[•27]. A favorable dosimetry of ⁶⁸Ga-PSMA I&T has been reported, and organ doses (kidneys) are comparable to or lower than those from ¹⁸F-FDG[28]. PSMA I&T may also be labeled with ¹¹¹In for SPECT imaging, and has been used for radio-guided surgery in a case report[29].

PSMA PET/CT in primary staging

Accurate staging of PCa is of high importance for treatment decisions and patient management[30]. Treatment strategies are dictated by the presence or absence of metastases. Prostate cancer most often spreads to lymph nodes (LNs) and bone, and highest PSMA expression has been demonstrated in adenocarcinoma of the prostate and LN metastases, while a lower expression of PSMA is seen in bone metastases[31,32]. In the prostate, magnetic resonance imaging (MRI) is widely used for characterization of malignant tumors. Rowe et al prospectively compared ¹⁸F- DCFBC PET/CT and MRI for detection and characterization of primary PCa in men (n=13) undergoing surgery with histology[••33]. MRI was more sensitive than ¹⁸F-DCFBC PET for detection of malignancy in the prostate on a per-segment (sensitivities of 0.17 and 0.39 for PET and MRI, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MRI, respectively). However, ¹⁸F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 for PET and 0.89 for MRI, for corresponding sensitivity). PSMA-PET may be used as PET/CT in combination with MRI or as hybrid PET/MR. Recently, the initial experience with ⁶⁸Ga-PSMA PET/MRI was reported as promising for tumor delineation in the prostate[34], and ⁶⁸Ga-PSMA PET may have a role for gross tumor volume delineation in radiation treatment planning of primary PCa[35]. PET/MRI has the potential to identify clinically significant PCa, to guide biopsies, and for planning of focal therapy, but further studies are needed to establish the role of PET/MRI in PCa. Given the cost of PET/CT, it is unlikely that PSMA PET/CT or PET/MRI will displace MRI as a method for detecting prostate cancer and guiding biopsies and focal therapies.

Lymph node metastases represent a significant adverse prognostic factor in PCa and can be associated with systemic metastases[36]. The gold standard for diagnosing LN metastases in locally advanced PCa is extended pelvic lymph node dissection (PLND)[30]. Hijazi et al evaluated PLND for nodal oligometastatic PCa detected by ⁶⁸Ga-PSMA PET/CT in 35 patients (23 biochemical recurrence; 12 primary staging)[37]. Malignant lesions were detected in 91.4 % (32/35). In the study, PLND was performed in 17 men with oligometastatic disease. Diagnostic accuracies per nodal lesion (213 removed nodes) were: sensitivity, 94%; specificity, 99%; positive predictive value (PPV), 89%; and negative predictive value (NPV), 99.5%. Similar high sensitivity (88.1%) of ⁶⁸Ga-PSMA PET/CT for LN metastases was demonstrated in another study[••38]. In contrast, lower detection rate for LN disease has also been reported[39]. Thus, prospective clinical trials in large cohorts are needed to evaluate the role of PSMA-PET/CT in primary N-staging of PCa. In a small pilot study, ⁶⁸Ga-PSMA(HBED-CC) was used for radio-guided surgery of metastatic LNs in PCa[40]. Recently, ⁶⁸Ga-PSMA PET/MRI and ⁶⁸Ga-PSMA PET/CT were retrospectively compared in 26 patients, who underwent ⁶⁸Ga-PSMA PET/CT_{low dose} (1 h p.i.) followed by ⁶⁸Ga-PSMA PET/MRI (3 h p.i.)[•41]. The overall discordance in PET positive findings was low, and the agreement between PET/CT and PET/MRI was high. The SUVs of pathological lesions were influenced by the time of acquisition, as previously reported[42]. It was demonstrated that SUVs of LNs were significantly higher on PET/MRI 3 h p.i. than on PET/CT 1 h p.i.; however, there were no significant differences between the bone lesions SUVs[•41].

Conventional imaging modalities (CIM), like bone scan and CT, have limited sensitivity and specificity for detection of metastatic PCa. Rowe et al investigated prospectively ¹⁸F-DCFBC for detection of metastatic disease in PCa[43]. ¹⁸F-DCFBC PSMA PET/CT was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both hormone-naïve (n=9) and castration-resistant cancer (n=8). DCFBC detection of LN, bone lesions and visceral lesions was superior to CIM. Fluoride PET/CT is a common agent for detection of bone metastases, and a recent case report indicates that PSMA PET/CT may be superior to fluoride PET/CT in PCa, although this may be contingent on whether the patient is on androgen ablation therapy (ADT) [44]. Some PCa patients have suspicious lesions in the lungs, but SUV analysis of ⁶⁸Ga-PSMA PET cannot discriminate reliably between lung metastases and primary lung cancer as the neovasculature could be positive in the latter[45].

PSMA PET/CT in recurrence

One of the important clinical issues in the management of PCa is early detection of recurrent disease. An accurate diagnostic modality with high sensitivity and specificity is necessary to select the optimal treatment strategy, i.e., surgery, external radiation or systemic therapy. Recently, PSMA PET/CT has demonstrated promising results in patients with biochemical recurrence of PCa. Afshar-Oromieh et al retrospectively analyzed the diagnostic value of ⁶⁸Ga-PSMA PET/CT in a large cohort (n=319) of PCa patients with biochemical recurrence[••38]. A lesion-based analysis demonstrated sensitivity, specificity, NPV and PPV of 76.6 %, 100 %, 91.4 % and 100 %, respectively. On a patient-based analysis the sensitivity was 88.1 %. In the study, tumor detection was positively associated with log PSA level but not with PSA doubling time (PSAdt). However, not all lesions were histologically confirmed. The effect of PSA levels and kinetics on PSMA PET/CT detection rate have also been investigated in other studies[46,••47,••48]. In a study by Ceci et al, ⁶⁸Ga-PSMA PET/CT was positive in 74.2% of patients (52/70) with a mean PSA of 3.5 ng/mL[46]. A positive scan was demonstrated in 85 % of patients (17/20) with PSA <2 ng/ mL and PSAdt <6.5 months, and in 18.7% of patients (3/16) with PSA <2 ng/mL and PSAdt ≥6.5 months. In patients with PSA <2 ng/mL PSMA PET/CT was positive in 59% of patients (23/39), which is in agreement with the study by Afshar-Oromieh et al that reported a detection rate of 61.1 % in 90 patients with PSA <2 ng/mL[••38]. By contrast, PSAdt was associated with positive ⁶⁸Ga-PSMA PET/CT in the study by Ceci et al. In a retrospective study (n=248), Eiber el al demonstrated pathological scans in 89.5% (222/248) of the patients (median PSA 1.99 ng/mL) with biochemical recurrence[••47]. The detection rates were 96.8%, 93.0%, 72.7%, and 57.9% for PSA levels of ≥2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL, respectively. Again, limited pathologic validation is available. Interestingly, the detection rate of 58% in patients with a PSA level <0.5ng/mL may have the most important clinical impact since European guidelines[30] define a PSA value <0.5ng/mL as the upper limit for salvage radiation therapy. Detection rates increased with a higher PSA velocity (81.8%, 82.4%, 92.1%, and 100% among patients with <1, 1 to <2, 2 to <5, and ≥5 ng/mL/y PSA velocities, respectively). However, no significant association could be found for PSAdt in this study.

PSMA expression may be inversely regulated by the androgen receptor. Preclinical studies have shown PSMA expression to be down regulated by androgen therapy and up regulated by ADT[49,50]. One study reported a strong and significant association between a positive PET result and ADT[••38]. In contrast, other studies reported no significant difference in detection efficacy regarding ADT[46,••47]. The effect of ADT on the PSMA PET results is not fully understood and needs to be elucidated further in clinical trials.

The pelvic LNs are a common site of recurrent PCa after surgery or radiation. However, modalities like CT and MRI are non-specific and are not considered reliable enough for routine N-staging[51,52]. Giesel et al retrospectively evaluated the volume and size of LNs identified by ⁶⁸Ga-PSMA PET/CT in 21 patients with biochemical relapse[53]. A total of 49 PET positive LNs were identified, and ⁶⁸Ga-PSMA PET/CT detected LN recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. Sterzing et al retrospectively analyzed the impact of PSMA PET/CT on changes in staging and radiotherapy management in 57 PCa patients (15 primary staging, 42 recurrence after radical prostatectomy)[54]. PET/CT and CT were performed in all patients. The TNM staging was changed in 50.8% (29/57) after PSMA PET/CT, and resulted in a different radiotherapeutic management strategy compared to the plan based on conventional CT imaging. Another study also reported on the impact of PSMA PET/CT on the clinical management of biochemical recurrence[55].

The most commonly used clinical PET agent for patients with biochemical recurrence in the past 10 years has been choline, either labeled with ¹⁸F or ¹¹C[56]. Morigi et al compared prospectively ¹⁸F-choline PET/CT with ⁶⁸Ga-PSMA PET/CT in 38 patients with biochemical recurrence[••48]. When PSA was below 0.5 ng/mL, the detection rate was 50% for ⁶⁸Ga-PSMA versus 12.5% for ¹⁸F-choline. When PSA was 0.5–2.0 ng/mL, the detection rate was 69% for ⁶⁸Ga-PSMA versus 31% for ¹⁸F-choline, and when PSA was above 2.0, the detection rate was 86% for ⁶⁸Ga-PSMA versus 57% for ¹⁸F-choline. On lesion-based analysis, ⁶⁸Ga-PSMA detected more lesions than ¹⁸F-choline (59 vs. 29, P<0.001). Furthermore, the tumor-to-background ratio in positive scans was higher for ⁶⁸Ga-PSMA than for ¹⁸F-choline, and may allow identification of even very small lesions. The major limitation of this study, as with many of the other PSMA studies, is that confirmation with histopathology was obtained in only 24 patients. The superior sensitivity of ⁶⁸Ga-PSMA PET/CT, as compared with ¹⁸F-choline PET/CT, has also been reported in a recent retrospective study of 37 patients with biochemical recurrence[57]. In this study, PSMA PET/CT detected PCa lesions with improved contrast when compared to standard ¹⁸F-choline PET/CT, especially at low PSA levels.

SUMMARY

Much focus has been on PSMA as a target for imaging and therapy with radionuclides in PCa. In the past year, several PSMA PET/CT studies are beginning to demonstrate promising results, and PSMA PET/CT is now in clinical use at an increasing number of institutions. Only a limited number of reports have been published on PSMA PET/MRI. Large prospective clinical studies are needed to further evaluate the role of PSMA PET/CT and PET/MRI in the clinical management of PCa. Furthermore, PSMA has the potential to be an excellent therapeutic target in PCa patients. Thus, molecular imaging with PSMA PET is paving the way for personalized medicine in PCa.

KEY POINTS.

• ⁶⁸Ga PSMA PET/CT is demonstrating promising results in prostate cancer patients, especially for detection of biochemical recurrence after primary treatment.

• Second generation ¹⁸F-PSMA PET/CT may be superior to ⁶⁸Ga-PSMA PET/CT.

• PSMA PET/CT may have a higher detection rate than choline PET/CT.

• The role of PSMA PET/MRI remains to be elucidated further, especially for guiding biopsies and delivery of focal therapy.

• “Image and treat” strategy is possible with PSMA ligands labeled with radioisotopes for imaging and therapy, and PSMA molecular imaging is paving the way for personalized medicine in prostate cancer.