Prostate cancer is the second leading cause of cancer-related death among men in the United States. Traditional diagnostic and staging methods include imaging techniques such as CT, MRI, and bone scanning. However, in recent years, a molecular imaging modality targeting prostate-specific membrane antigen (PSMA) has emerged, attracting attention due to its high affinity and accuracy. PSMA PET has been combined with other modalities such as multiparametric MRI for better diagnostic and prognostic performance. This imaging technique has been studied in different clinical settings and has shown a wide range of disease aggressiveness. In this review, we will delve into the role of PSMA PET in high-risk staging, biochemical recurrence, and castration-resistant prostate cancer. We will focus on the latest advances in the use of PSMA imaging technology and highlight its significant impact and effectiveness in the treatment of prostate cancer. In addition, we will explore the future trends of PSMA PET imaging and its evolving implications in the management of prostate cancer.
Graphical summary
Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer-related death in men. To diagnose, stage, and restage prostate cancer, conventional imaging techniques include CT, MRI, and bone scans. Prostate-specific membrane antigen (PSMA) is a membrane glycoprotein that is abundantly expressed on prostate cancer cells, and its expression is 100-1000 times higher than that of normal prostate cells. Therefore, imaging agents targeting PSMA have been widely used, and they have high affinity and accuracy in the diagnosis, staging, and restaging of prostate cancer. Many different types of PSMA drugs have been studied and developed in the literature, using different radiotracers and imaging modalities (e.g., SPECT and PET). PSMA PET has been used in combination with other imaging modalities such as multiparametric MRI for better diagnostic and prognostic performance. The role of PSMA in different clinical settings has been extensively studied and is of great value in terms of disease aggressiveness. Recently, a multidisciplinary team of healthcare providers and prostate cancer imaging experts developed criteria for the appropriate use of PSMA imaging. According to these criteria, patients with newly diagnosed intermediate-, high-risk, or very high-risk prostate cancer, biochemically recurrent, and castration-resistant prostate cancer (CRPC) had the highest PSMA imaging utilization scores (see Table 1). This review article will focus on the latest advances in the application of PSMA imaging, in particular its effectiveness in the treatment of prostate cancer and how it can significantly change the clinical landscape. By understanding the application and latest advances of PSMA imaging, we can better understand its importance and value in the diagnosis and treatment of prostate cancer.
Radioligands targeting PSMA
Since 1987, PSMA-targeting molecules for prostate cancer have undergone several iterations, and a new generation of PSMA-targeting ligands has finally been developed. These small molecules can more effectively attach to the extracellular domain of the PSMA molecule, enabling more precise targeted therapy. Recently, the FDA approved 68Ga-PSMA-11 and 18F-DCFPyL, two next-generation PSMA-targeting ligands, which are made in small molecule form with a higher tumor-to-background ratio and faster blood clearance. In addition, there are many PSMA-targeted drugs in active clinical trials, such as 18F-PSMA-1007, 68Ga-PSMA-617, 68Ga-PSMA-I&T, and 18F-rhPSMA-7.3, among others. Among them, 18F-rhPSMA-7.3 is a radiohybrid radiotracer with high affinity for PSMA and lower urine excretion, and good results have been achieved in the SPOTLIGHT test.
PSMA scan
The European Association for Nuclear Medicine (EANM) and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) jointly recommend that when performing 68Ga-PSMA-11 surgery, the uptake time should be set to 60 minutes and urinate immediately before imaging to reduce bladder uptake. For patients with BCR with PSA levels below 1 ng/mL, delayed imaging is recommended. To avoid artifacts of residual activity in the collection system, furosemide or over-rehydration can be administered. During the urography phase, the urine collection system can be distinguished from the tumor burden by intravenous contrast and imaging tests. The traditionally recognized absorption time for 18F-PSMA compounds is 60-120 minutes. PSMA has a specific biodistribution in humans, typically seen in the neck, celiac disease, and/or presacral ganglia, which are variants of the normal biodistribution. In addition, PSMA has specific uptake in astrocytes, proximal tubules, small intestine, saliva, and lacrimal glands.
Figure 1
A-D normal 68Ga-PSMA-11 PET biodistribution in whole-body maximal intensity projection (SUV scaled at 0-10), cervical spine (b), celiac disease (c), and presacral (d) ganglion uptake
The effective dose of PSMA PET ligands ranged from 0.0116-0.022 mSv/MBq, and the converted effective dose ranged from 3.4-6.6 mSv. The exact value of this value depends on the type of radioligand used and the dose injected. This value is comparable to that of other PET radiotracers, such as 18F-choline, at an effective dose of 0.01 mSv/MBq [19]. In contrast, the 68Ga-PSMA PET was absorbed by the kidneys and lacrimal glands at the highest dose [19]. On the other hand, the radiation exposure of the CT scan section varies depending on the regimen with an effective dose ranging from 1 to 20 mSv [13].
Comparison of PSMA with other compounds
Biliary PET
Increased turnover and production of phosphatidylcholine in cell membranes is the basis of this radiotracer [20]. Choline is conjugated to 11C or 18F. Studies have shown that although the detection rate in patients with BCR is lower compared with PSMA PET, the results are encouraging, with lower PSA levels leading to more pronounced differences [21,22]. Although the FDA approved the BCR in 2012, the short half-life of 11C limits the availability of this radiotracer in field cyclotron centers. 18F choline has a longer half-life and can be more widely adopted, and this radiotracer has not been adopted in the United States due to regulatory concerns [4].
Fluciclovir PET
Fluciclovir PET targets the amino acid transporter of L-leucine[4]. In early studies of patients with advanced disease, flucyclovir was shown to be at least comparable to PSMA [23,24]. It has been approved by the FDA in 2016 for BCR for prostate cancer. In a recent clinical trial, a head-to-head prospective trial of 50 patients with BCR with low PSA (<2.0 ng/mL) compared fluciclovir to PSMA [25]. The detection rate of PSMA was at least twice as high (56% versus 26%).
Staging of high-risk prostate cancer
The initial staging of prostate cancer is a critical step in determining the most appropriate treatment option, including options such as prostatectomy, radiation therapy with or without regional lymph node therapy, or systemic therapy [4] (Figure 2). Based on criteria such as histologic pattern, PSA level, and clinical stage, risk stratification protocols have been developed to optimize treatment planning [26]. The newly updated guidelines for the Cancer Center Network define a five-tier approach to risk stratification for clinically localized prostate cancer [27]. Imaging is generally not indicated for low- and very low-risk prostate cancer because imaging is unlikely to extend beyond the prostate [2,27].
Figure 2
74 years old, with high-risk prostate cancer. Preoperatively scheduled 68Ga-PSMA-11 PET/CT execution. Single PSMA avid 2 mm right internal iliac chain lymph node (white arrows in panels a and d; SUVmax 4.5), which is not clear on CT (white arrow on panel c). Maximum intensity projection PET A is scaled on a 0-5 SUV
Most studies have reported good specificity and predictive value of PSMA in prostate cancer staging. A prospective, multicenter, single-arm, phase 11 trial conducted by Hope et al. studied 3 patients with high-risk prostate cancer treated with Ga277-PSMA-68 PET prior to prostatectomy. The results showed that 27% of patients had pelvic lymph node metastases, with a sensitivity of 40%, a specificity of 95%, a positive predictive value of 75%, and a negative predictive value of 81%. This study lays the foundation for the new drug application of 68Ga-PSMA-11. Another OSPREY study was a multicenter prospective clinical trial using 18F-DCFPyL that included 252 patients who underwent radical prostatectomy. The median specificity of the study was 97.9%, and the sensitivity for detecting pelvic lymph nodes was 40.3%. The positive predictive value was 86.7% and the negative predictive value was 83.2%. Several studies have compared the performance of PSMA PET with conventional imaging. A multicenter randomized clinical trial involving 302 patients investigated the accuracy of Ga68-PSMA-11 in staging prostate cancer at the time of initial presentation in high-risk patients compared with conventional imaging, with PSMA PET showing higher accuracy (92 percent compared to 65 percent with conventional imaging), sensitivity (85 versus 38 percent). Another study included 160 patients with high-risk prostate cancer who underwent initial staging assessment using F18-DCFPyL. The results of the study showed that 90% of patients with distant metastases were correctly identified, and 48% of them did not have lymphadenopathy on CT. Nearly all patients with evidence of metastases on CT had other sites on F18-DCFPyL. Based on these findings, PSMA PET appears to be superior to conventional imaging for the initial staging of unfavorable intermediate-risk, high-risk, or very high-risk prostate cancer. A meta-analysis evaluating the initial evaluation of prostate cancer (primary and metastatic lymphatic combination) in 257 patients found a sensitivity of 83% and a specificity of 81% for the diagnosis of primary prostate cancer.
Biochemical recurrence
"After successful curative therapy, serum PSA levels gradually drop to their lowest point. However, when it rises above a certain threshold, it means that a biochemical recurrence has occurred. This threshold is typically greater than 2.0 ng/mL above the nadir in radiation therapy and 0.2 ng/mL in two consecutive readings in radical prostatectomy [35,36]. Notably, PSA recurrence after curative therapy is a common occurrence [37], with approximately 50 percent of patients experiencing PSA recurrence within 10 years (Figure 3). "[<>]。
Figure 3
A-B Example of a 75-year-old patient presenting with a local recurrence of slowly elevated PSA after 20 years of prostatectomy. F18-DCFPyL PET/CT showing focal uptake on the operating table on the right side of the anastomosis (white arrows in panels a and b)
Figure 4
Conditioning: A 54-year-old example of a single case of PSMA lymphadenopathy with a recently resected prostate cancer and persistently elevated PSA. F18-DCFPyL PET/CT shows a single focal point of right pelvic PSMA uptake (Panels a and b, SUVmax 4.4), corresponding to a 4 mm lymph node in the lateral wall of the right pelvis (Figure c). Original prostatectomy pathology showed Gleason 4+5 prostate adenocarcinoma in the left prostate leaf, positive for 10/17 core cancer. Uptake of the left pelvis corresponds to ureteral activity. Maximum intensity projection view: SUV with a scale of 0-5
"Early detection of biochemical recurrence (BCR) provides a window of opportunity for effective treatment prior to clinical recurrence through directed radiation therapy and/or surgery. Salvage radiotherapy has been shown to be the most effective treatment after radical prostatectomy and BCR, but routine imaging is often not required and distant lesions may be missed. Therefore, sensitive imaging techniques are essential for the treatment of BCR by being able to detect diseases outside of the expected radiation field for optimal treatment. A recent post-hoc analysis of 270 patients found that PSMA PET imaging changed patient management in 19% of cases. Therefore, a clinical trial by Calais et al. is currently investigating the potential value of PSMA PET imaging in these patient radiation programs. There is substantial evidence to support the use of PSMA PET in BCR. In a recent systematic review and meta-analysis, Pozdnyakov et al. found that PSMA PET changed the treatment plan of 34.3680% of the population, with BCR-free survival of 20.1057% at a median follow-up of 60 patients. Another meta-analysis of 4790 patients found that Ga68-PSMA PET increased the detection rate from 19% at PSA levels below 33.0 ng/mL to 0% at PSA levels below 95.2 ng/mL. The study found that the sensitivity and specificity of lymph node metastasis detection in patients with BCR were high (32% and 52%, respectively), comparable to routine imaging. In a multicenter clinical trial of patients with BCR in prostate cancer patients receiving salvage radiotherapy, PSMA PET was able to predict disease progression over 54 years. PSMA is now included in the American Urology Association's RAY Assessment for Detection of Advanced Recurrence (RADAR III) consensus group, the European Association of Urology) and the NCCN Guidelines for Biochemical Recurrence in Prostate Cancer. "
Castration-resistant prostate cancer and PSMA-targeted therapy for prostate cancer
"When prostate cancer continues to worsen, castration resistance can occur even when low levels of prostate-specific antigen (PSA) are present and treated with androgen deprivation therapy. Differentiating between metastatic and non-metastatic castration-resistant prostate cancer (metastatic anti-prostate cancer, CRPC) is essential to develop appropriate treatment options. PSMA PET imaging is extremely efficient in accurately assessing the extent of disease in both patient groups. In a multicenter retrospective study of 200 patients with CRPC, PSMA PET was able to detect metastatic disease in 55% of patients with a routine imaging diagnosis of M0. Neuroendocrine differentiation is a rare but increasingly aggressive subtype of prostate cancer that is common in advanced CRPC stages. However, recent advances in PSMA-targeted therapy for prostate cancer have demonstrated promise for effective treatment of these types of prostate cancer. There are a variety of life-prolonging treatments for CRPC, including chemotherapy, hormonal therapy, immunotherapy, and radioligand therapy. More recently, a species named 177Lu-PSMA-617 (Pluvicto, 177Lu-vipivotide tetraxetan; Novartis [Basel, Switzerland]/Advanced Accelerator Applications USA, Inc. [Milburn, New Jersey]) received FDA approval based on the results of clinical trials showing the effectiveness of radiopharmaceutical therapy (RPT). The PSMA Imaging Working Group recently updated the AUC to recommend PSMA imaging for the purpose of evaluating eligibility for patients considering PSMA-targeted RPT. A recently published surgical guideline from EANM/SNMMI outlines expert recommendations for patient selection, treatment options, and side effect management. "
Figure 5
a-e 73 years old, castration-resistant metastatic prostate cancer, initially treated with radiotherapy and ADT in 2004 and bone metastases in 2019, treated with chemotherapy and radiotherapy for multiple lesions, initiated with 18Lu-PSMA in view of disease recurrence and elevated PSA after baseline 177F-DCFPyL PET/CT (a). Subsequent post-treatment systemic uptake images (b-e) show a gradual decrease in the visibility of bone lesions, corresponding to interval therapy for bone metastases. During the treatment period, there was also an overall decrease in PSA levels (f). Maximum intensity projection 18F-DCFPyL PET A scaled to 0-10 SUV
Intraprostatic localization and prebiopsy evaluation
Localization of tumors within the prostate facilitates biopsy-targeted, targeted therapy, and may eliminate the need for biopsy in patients with clinically insignificant prostate cancer. For the latter goal, the PRIMARY trial has been conducted [62], which evaluated the potential added value of PSMA PET relative to mpMRI in terms of intraprostate localization and possible elimination of biopsy. A total of 296 patients with suspected prostate cancer were included without MRI or tissue sampling, followed by MRI, biopsy, and PSMA PET imaging. The combination of PSMA + MRI increases the negative predictive value of MRI to 91 versus 72 percent, the sensitivity to 97 versus 83 percent, and the specificity to 40 versus 53 percent [62]. The authors concluded that biopsies could have been avoided in 19% of patients because only 3.1% were at risk in patients with clinically significant prostate cancer. However, the MRI readings in this study were not central readings and were comparable to similar studies with multiple central readings [63]. Therefore, further validation is warranted using larger sample sizes and possibly the inclusion of multivariate risk calculators [64].
Application of PSMA in prostate cancer
Despite the name, PSMA is not specifically expressed on the prostate and is uptaken by many other cancers, including renal cell carcinoma, transitional cell carcinoma, primary brain tumor, thyroid cancer, breast cancer, hepatocellular carcinoma, and lung cancer (Figure 6). 65）[1445]。 Perry et al. retrospectively reviewed 18 patients with prostate cancer with atypical manifestations of 1F-DCFPyL PSMA PET and found that only 2.66 percent of them had non-prostate cancer tumors, and almost all non-prostate cancer tumors had no or low PSMA uptake except renal cell carcinoma [<>].
Figure 6
a-c 74-year-old male, PSA 8.1, Gleason 4+3 prostate cancer. Staging Ga68-PSMA-11 PET findings consistent with T3bN1bMx disease, needle-like 2.6 cm right upper lobe nodule against the background of emphysema, low radiotracer uptake (SUVmax 5.8) (white arrows in Figures a-c). Subsequent FNA is consistent with squamous cell carcinoma of the lung. Increased intraprostatic uptake of known cancer and metastatic pelvic lymph nodes. Several low-level radiotracer uptake lesions without CT in the posterior left sixth rib are associated with the absence of CT or subsequent FDG in favor of benign. Maximum intensity projection SUV grades 0-5
Limitations of PSMA
Although PSMA-targeted imaging is highly effective in detecting tumors expressing PSMA, prostate cancers with neuroendocrine differentiation do not express PSMA due to FOLH1 gene inhibition, and this imaging technique is ineffective [9]. Other molecular imaging targets include fibroblast activating protein (FAP), somatostatin receptor type 2, gaslin-releasing peptide receptor, and FDG as alternative diagnostic tests for these aggressive tumors [9,67,68,69]. However, further research is needed to demonstrate which of these alternatives, if any, are effective for imaging this subtype. Androgen blockers play an important role in improving survival and efficacy and are an integral part of a variety of treatment options for prostate cancer [70]. PSMA expression on prostate cancer cells is severely regulated by treatment that alters androgen receptors [71,72]. This heterogeneity of response has implications for upcoming imaging and therapeutic interventions and varies based on tumor phenotype (hormone sensitivity versus CRPC) and time after treatment [71,72]. In PSMA PET, it can be challenging to determine whether a solitary bone lesion is malignant or benign because it may alter the management of the patient, and false-positive interpretation can cause unnecessary harm to the patient [73]. Isolated rib lesions are common and are caused primarily by benign causes (eg, fractures) or benign causes (eg, fibrodysplasia) (figure 7). In a retrospective study of patients with prostate cancer who had isolated Ga68-PSMA PET rib lesions, the likelihood of malignancy was determined by follow-up imaging, PSA levels, and biopsy [73]. Based on these criteria, only 73 patients had false-negative rib lesions that led to worsening of metastatic disease, and most lesions were classified as benign without the need for follow-up [48]. In a recent study of 18 patients with high-risk primary or recurrent prostate cancer, the results suggest that a 5F-DCFPyL PSMA PET bone lesion with an indeterminate standardized maximum uptake value (SUVmax) of more than 5 and other sites with bone metastases at other sites is more likely to be malignant, while a lesion with an SUVmax of less than 74 and no concurrent suspicious findings is more likely to be benign [<>].
Figure 7
a, PET uptake due to b 68Ga-PSMA-11 fractures, better described on the corresponding CT (c). Both a and b are scaled to 0-5 SUVs.
future
Application of PSMA PET imaging in the metastatic directed therapy of oligometastatic prostate cancer
The use of sensitive prostate-specific antigen (PSA) detection methods and improved PET radiotracers has increased the recognition of "oligometastatic disease", thereby increasing interest in metastasis-directed therapy (MDT) [75,76] (Figure 8). Emerging evidence suggests that localized MDT can delay disease progression, prolong the duration of systemic therapy, and reduce associated toxicities [75]. Several studies have investigated the role of PSMA PET in guiding the treatment of oligometastatic prostate cancer and have shown that PSMA PET improves progression-free survival [77]. One challenge in evaluating the effectiveness of new and more sensitive PSMA-directed oligometastatic disease is that the increased sensitivity of these new techniques compared to traditional imaging results in staged migration, which will limit the use of historical data from previous trials [76].
FIGURE 8
Example of oligometastatic bone disease in a 68-year-old man with a history of prostatectomy presenting with biochemical recurrence and PSA of 1.3 ng/mL. 68 Ga-PSMA-11 PET/CT showing a single focal point of PSMA uptake (white arrows in panels a and b, SUVmax 4), corresponding to small sclerosis foci in the T8 vertebral body (white arrows in panel c). Activity below the bladder corresponds to urine contamination. The maximum intensity projection scale for SUVs is 0-5
Response to CRPC treatment was assessed using 177Lu-PSMA
In addition to its predictive role in determining the degree of response to 177Lu-PSMA treatment and aiding in patient selection, PSMA PET can also be used to assess treatment response [61]. The LuPIN trial investigated the response of 177 patients with castration-resistant prostate cancer (CRPC) to treatment with 617Lu-PSMA-66 and the radiosensitizer NOX37. In this prospective study, 68Ga-PSMA and 18F-FDG PET scans were performed before and after treatment [78]. In this study, quantitative PSMA total tumor volume and PSA progression were identified as the only two independent prognostic variables affecting overall survival [78]. Further studies in a larger patient population will help further evaluate the role of post-treatment PSMA PET as an imaging biomarker.
Reporting framework for PSMA PET
"PROMISE is a unique molecular imaging TNM staging system designed to unify reporting and study design for molecular imaging of prostate cancer. This system classifies local disease into T phases, ranging from miT0 (no local tumor) to miT4 (tumour invasion of structures other than seminal vesicles). Regional lymph node disease is classified into N stages, ranging from miN0 (no regional lymph nodes) to miN2 (involving multiple pelvic lymph node regions). Metastatic disease is divided into M stages, ranging from miM0 (no distant metastases) to miM1 (distant metastases), and further subdivided into diss (disseminated), dmi (diffuse bone marrow involvement), oligometastases (few metastases), and uni (unifocal). PSMA uptake levels are assessed by a unique visual scoring system, with results on a scale of 0, 1, 2, or 3 representing none, low, moderate, or high PSMA expression. PROMISE V2, LAUNCHED IN 2023, INCLUDES AN UPDATED TNM STAGING PROTOCOL AND A PSMA EXPRESSION SCORE REPORT, WHICH ARE NOW INTEGRATED WITH THE PRIMARY SCORE. The PRIMARY score is a 62-point scoring system validated for the detection of clinically significant prostate cancer in patients who have not undergone a biopsy. By PROMISE V62, new recommendations were made for the reporting of sequential studies, lesion distribution, and tumor volume assessment. These new changes facilitate the use of specific PSMA response criteria, such as the PSMA PET Progression Criteria (PPP), which focuses on a single lesion, and the PSMA-PET/CT Response Evaluation Criteria, which focuses primarily on the total tumor volume in patients with extensive disease, and the PSMA-PET/CT Response Evaluation Criteria (RECIP). At the same time, the Prostate-Specific Membrane Antigen Reporter and Data System (PSMA-RADS) is being proposed as a unified and structured reporting system designed to support PSMA-targeted PET studies. PSMA-RADS classifies each lesion and overall scan into categories 1-5. 1 indicates a normal scan or is known to be benign, and 2 indicates a potentially benign lesion for which biopsy results are not available or imaging findings may not be specific. Category 3 includes lesions that are uncertain whether they are prostate cancer or suspected non-prostate malignancy. 4 indicates suspected prostate cancer, while 5 indicates almost certain prostate cancer, with very typical imaging findings. The framework is designed to reflect clinicians' level of confidence in the presence of prostate cancer and to clarify the need for further investigation. "
Conclusion
PSMA PET is a tool with wide application value in the clinical management of prostate cancer. It plays an important role in all aspects of patient care and has shown promising results in the initial staging of prostate cancer, localization of recurrent or persistent disease, and staging prior to PSMA-directed radioligand therapy. At the same time, PSMA PET also has potential applications in guiding prostate biopsy, guiding metastatic targeted therapy, and monitoring systemic and radioligand therapy response. Although the impact of PSMA PET on patient prognosis and management is still being evaluated, its excellent accuracy and added value have been fully highlighted in the staging of prostate cancer. As a result, PSMA PET has been included in clinical guidelines and consensus documents. However, further research and evaluation is needed to fully determine the role of PSMA PET in treatment monitoring and patient prognosis.
Cite this article
Houshmand, S., Lawhn-Heath, C. & Behr, S. PSMA PET imaging in the diagnosis and management of prostate cancer. Abdom Radiol 48, 3610–3623 (2023). https://doi.org/10.1007/s00261-023-04002-z