The incidence and mortality of prostate cancer rank first among all cancers, accounting for 1/10 of all cancer deaths in the United States (1). After receiving effective treatment such as surgery and radiotherapy, 2/5 of patients with prostate cancer experience a detectable rise in the serum prostate-specific antigen (PSA) level in the next 10 years from the first treatment, which includes local recurrence and metastatic disease (2, 3). With the increased management of hormone therapy, nearly all patients eventually develop castration-resistant prostate cancer (CRPC), which is the main cause of disease-related death (4, 5). Some CRPC patients would progress into a rare pathological subtype called neuroendocrine prostate cancer (NEPC). The resistance to treatment is caused by following the mechanisms as TP53 mutation, AR amplification, or mutations or RB1 loss. For the difficulty in early diagnosis and prediction of prognosis, PSA monitoring along with radiologic evaluations is standard for tumor burden assessment. Multiple imaging techniques are used for diagnosis or staging, assessment of treatment, and prognosis prediction including Magnetic Resonance Imaging (MRI), Computed Tomography (CT), ultrasound, Single-Photon Emission Computed Tomography (SPECT), and PET/CT. Guidelines recommend MRI or CT for staging, detecting lymph node metastases, and local recurrence. Besides traditional anatomic imaging, nuclear imaging-based PET/CT is a rapidly developing field for compensating the limitation of whole-body evaluation and precise prognosis prediction. The most commonly used tracer is ¹⁸F-fluorodeoxyglucose (FDG), and the newer tracer ⁶⁸Ga-prostate-specific membrane antigen (PSMA) also provides good detection. ¹⁸F-FDG PET/CT is shown to be a useful prognostic tool in selected patients with advanced disease (6–8). Intraprostatic uptake of ¹⁸F-FDG imaged by PET/CT suggests that aggressive behavior and castration resistance with increased glucose uptake (9, 10). In addition, ¹⁸F-FDG PET/CT has played a significant role in many kinds of cancer for a long time. ¹⁸F-FDG PET/CT is widely used in lymphoma, breast cancer, lung cancer, esophageal cancer, colorectal cancer, and many other cancers (11); it performs well in diagnosis, staging, prediction of recurrence, and prognosis prediction of the above diseases.

This article mainly summarizes the former research of the mechanism and usage of ¹⁸F-FDG and ⁶⁸Ga-PSMA PET/CT in prostate cancer. We compare the pros and cons of ¹⁸F-FDG and ⁶⁸Ga-PSMA in localized prostate cancer. We then focus on exploring the potential of ¹⁸F-FDG PET/CT in aggressive and progressive prostate cancer. In addition, in order to maintain a comprehensive review, we also briefly summarized the clinical use of choline PET in prostate cancer.

PET/CT is a non-invasive examination for diagnosis, and many radiotracers are widely used in different malignant tumors. PET-based radiotracers, ¹⁸F-FDG, is the most commonly used radiotracer for oncologic imaging and is based on the increased glucose metabolism in malignant tumors (12, 13). FDG, a glucose analog, is transported into the cell through GLUTs and then phosphorylated by hexokinases to FDG-6-phosphate which then is stored within the cells. Malignant cancers convert to an increased rate of glycolysis at an advanced stage named Warburg effects in the transformation process (14, 15). Androgens enhance glucose metabolism by modulating glycolytic-related genes (16). Furthermore, Glucose uptake and metabolism rely on the transporter GLUT family and hexokinase which are involved in tumor progression and overall survival (17–20). Compared with normal epithelial cells, cancer cells enhancee glycolysis, showing higher SUVmax in PET/CT. The expression of GLUT1 correlated with disease progression, and tumor cells enhance glycolysis with the elevation of GLUT1 (19). A significant association was found between GLUT1 expression levels and SUVmax level (p = 0.005), lymph node status (p = 0.05), volume of cancer (p = 0.01), CRPC disease progression (p = 0.02), and metastases development (p = 0.04). Prostate cancer upgrades the expression of hexokinase2 when progressing to CRPC. Several studies have proven that Pten/p53 deficient mice elevated levels of hexokinase2 and its binding to mitochondrial enhanced enzyme activities (21, 22). ¹⁸F-FDG is used as an auxiliary method to analyze glucose metabolism in prostate cancer cells and find new targets and methods for the diagnosis and treatment of prostate cancer.

The new tracer PSMA in prostate cancer is a transmembrane protein with a 707-amino-acid extracellular portion located in the apical prostate cell surrounding ducts. In the physiological statue, PSMA shows accumulation in the salivary gland, the liver, the spleen, the small bowel, and the urinary tract. In normal prostate, PSMA localizes in the cytoplasm and apical side of the epithelium surrounding prostatic ducts. Dysplastic or neoplastic transformation transfers PSMA from the apical membrane to the luminal surface of the ducts, and this has been detected by PET/CT (23). PSMA has become the standard method for diagnosing and staging prostate cancer. Several meta-analyses concluded ⁶⁸Ga-PSMA PET/CT improved detection of localized prostate cancer and metastases (24, 25).

¹⁸F-FDG PET/CT acts as a detection tool to detect metastases during the observation period but has low sensitivity in localized prostate cancer. At present, many viewpoints believed that for localized prostate cancer, compared with observation, active radical prostatectomy or external-beam radiotherapy didn’t have much effect on the mortality of patients but it could control the progression of some prostate cancer (26, 27). Although the current data showed that the detection of ¹⁸F-FDG PET/CT had some limitations, there were still some studies suggesting the value of ¹⁸F-FDG PET/CT. Serendipitous high focal ¹⁸F-FDG uptake in the prostate gland in several case reports suggested that this imaging tool was useful for specific types of tumors (5, 28–30). In an investigation among 47,109 men who underwent ¹⁸F-FDG PET in a 10-year period, 1,335 (2.83%) showed incidental prostatic ¹⁸F-FDG uptake, and 99 of these men underwent prostate biopsy (31). Prostate cancer occurred in 1 of 26 patients (3.8%) with serum PSA<2.5 ng/mL, compared with 40 of 67 patients (59.7%) with serum PSA≥2.5 ng/mL. It revealed that patients with high ¹⁸F-FDG uptake in the prostate should be further evaluated by the measurement of serum PSA and prostate biopsy. Despite the low sensitivity, ¹⁸F-FDG could predict therapy effects for patients who exhibiting high absorption of ¹⁸F-FDG in tumor lesions. We looked at a patient who was primarily diagnosed with prostate cancer with oligometastatic lesions, and he was sensitive to androgen deprivation therapy ( Figure 1 ). With the continuous decrease of PSA level, the FDG accumulation decreased in the prostate and right ischium. New tracers, ⁶⁸Ga-PSMA and ¹¹C-choline, have higher sensitivities in localized prostate cancer. In primary prostate cancer, the sensitivity of PSMA was 40–95%, which correlated with the levels of serum PSA. When PSA was over 2ng/mL, the sensitivity elevated to 95% (24). A meta-analysis including nine studies and a total of 547 patients with primary prostate cancer found the sensitivity of PSMA ranging from 67–97% (32). This study pointed out that PSMA had higher sensitivity and specificity in detecting primary prostate cancer compared with conventional imaging examinations. Similarly, the sensitivities of ¹¹C- and ¹⁸F-choline in the diagnosis of primary prostate cancer were 66–86.5%, and the specificities were 43–81%. However, some studies showed that choline PET could not distinguish between benign and malignant tumors, or between inflammatory and malignant tissue in microcarcinomas and small tumors (33–41). Besides, choline PET/CT has a limited role in staging and is only beneficial in the detection of distant metastases such as bone metastases (33).

There is the consensus that CT/MRI is preferred for detecting primary prostate cancer. PET/CT is not particularly satisfactory because of the lower or similar sensitivity and being less convenient and commercial in clinical practice. ¹⁸F-FDG, ⁶⁸Ga-PSMA, and ¹¹C-choline have relatively low sensitivity when PSA is lower than 2ng/mL and increase the sensitivity when PSA is over 2ng/mL. Patients whose PSA is over 2ng/mL are often required for biopsy to diagnose. For primary prostate cancer, PET/CT may act as an auxiliary method to evaluate the tumor burden and metastases.

After initial treatment as radical prostatectomy or androgen deprivation therapy (ADT), the disease progresses into metastasis, recurrence, or resistance to treatment. ¹⁸F-FDG PET/CT has been used as a commonly used means to observe the effects of treatment and surveillance together with CT, MRI, PSMA, and bone scan (42).

It is widely accepted that ⁶⁸Ga-PSMA PET/CT has more considerable accuracy in diagnosis and staging in primary prostate cancer than ¹⁸F-FDG (63). In a study focusing on the sensitivity of ⁶⁸Ga-PSMA in evaluating biochemical recurrence, the total positive predictive values of the prostate, pelvic lymph nodes, extra-pelvic lymph nodes, bones, and distant organs were 28%, 38%, 13%, 22%, and 5%, respectively (64). Multiple studies have revealed that PSMA needs to improve sensitivity but has high specificity for detection of nodal metastases in intermediate-to-high-risk prostate cancer.

Plenty of studies have shown ⁶⁸Ga-PSMA PET/CT had advantages in evaluating local recurrence or distance metastases but in CRPC PSMA had some limitations. A prospective single-arm clinical trial focused on accuracy in localizing recurrent prostate cancer. The data showed 75% of recurrent prostate cancer were positive and detection rates increased with PSA: 38% for <0.5 ng/mL, 57% for 0.5 to <1.0 ng/mL, 84% for 1.0 to <2.0 ng/mL, 86% for 2.0 to <5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173, P <.001) (65). This study demonstrated PSMA had high sensitivity in recurrent prostate cancer while it also showed PSMA might neglect tumor lesions for patients with low PSA. There are still some missed lesions because of the negative PSMA. A 61-year-old mCPRC patient had widespread metastases ( Figure 2 ). ⁶⁸Ga-PSMA showed negative in suspicious lesions in the liver while ¹⁸F-FDG exhibited high enhancement. This case demonstrated for some mCRPC patients FDG still had a role in risk stratification and recognizing metastatic lesions. A prospective trial included 37 patients which underwent both FDG and PSMA PET/CT (66). Of all 114 lesions, 81 were PSMA+FDG+, and 33 were PSMA-FDG+. PSMA-FDG+ lesions had a poor prognosis and resistance to castration. PSMA was a more sensitive and specific agent in prostate cancer, but in castration-resistant lesions, the sensitivity would reduce and mean more malignant lesions (67–69). Several case reports observed heterogeneity results that relied on pathological and clinical grading of prostate cancer. Some castration-resistant cancers showed PSMA negative and neuroendocrine tumors showed FDG and DOTATATE positive (68–70).

In the detection of primary and metastatic prostate cancer, the overall sensitivity and specificity of ⁶⁸Ga-PSMA PET/CT are significantly higher than ¹⁸F-FDG PET/CT, but this does not mean that PSMA PET/CT has an excellent performance in all types of prostate cancer and all clinical environments, on the contrary, ¹⁸F-FDG plays a crucial role in CRPC and NEPC. For patients with negative ⁶⁸Ga-PSMA, ¹⁸F-FDG has a diagnostic value correlated with PSA and the Gleason score (71). With the continuous improvement of the status of ⁶⁸Ga-PSMA in the detection of prostate cancer, the auxiliary role of ¹⁸F-FDG should not be underestimated. The combination of ⁶⁸Ga-PSMA and ¹⁸F-FDG may be more beneficial to the treatment and prognosis of patients.

PET/CT has an important role in initial diagnosis, staging, and recurrence surveillance in a variety of cancers. The conventional tracer ¹⁸F-FDG was efficient for detecting lesions that maintained high glucose metabolism both in the primary tumor and metastases. Several clinical guidelines, like myeloma and lymphoma, recommended ¹⁸F-FDG PET/CT in diagnosis (72, 73). In solid tumors, ¹⁸F-FDG showed its high sensitivity for detecting metastases (74).

Prostate cancer is characterized by slow development and low glucose metabolism. In the 2020 prostate cancer NCCN guideline, CT/MRI is the priority when it comes to identifying primary lesions and evaluating the tumor volume. Conventional molecular imaging as ¹⁸F-FDG PET/CT should not be used routinely for staging in primary prostate cancer. In guidelines, new tracers such as ¹¹C-choline can be used to detect small volume disease in soft tissues and bone. ⁶⁸Ga-PSMA PET/CT is under several clinical trials and shows its advantages in both specificity and sensitivity in detecting lesions, but it requires more prospective clinical trials (75). Recent research focused on a group with prostate cancer, which was suitable for ⁶⁸Ga-PSMA, and data prompts its appliance in primary prostate cancer to generally evaluate tumor burden and metastases.

Aggressive prostate cancer, however, transforms into higher glucose metabolism and makes it possible for ¹⁸F-FDG PET/CT to detect tumors. In high-risk prostate cancer, ¹⁸F-FDG still has limitations on low sensitivity while ¹⁸F-FDG is competitive to ⁶⁸Ga-PSMA in recurrence or CRPC. Both ¹⁸F-FDG and ⁶⁸Ga-PSMA are predictors of prognosis and therapeutic effect. ⁶⁸Ga-PSMA PET/CT is the mainstream of nuclear imaging in CRPC and mCRPC. The high sensitivity and specificity make it promising in treatment management. While partial patients are PSMA negative, which increases the difficulty in disease surveillance. Some characters may be found such as low serum PSA level, special pathological subtype, or different molecular mechanisms. Several clinical trials revealed ¹⁸F-FDG could effectively detect metastases after ADT. Tumors in CRPC and mCRPC generally elevate glucose metabolism, and FDG can localize the recurrence and metastases, which are negative in PSMA. Although ⁶⁸Ga-PSMA is effective in evaluating recurrence, and ¹⁸F-FDG PET/CT can compensate for the shortage and effectively verify the tumor lesions in CRPC.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

KS and BL wrote the first manuscript. KS and BL contributed equally as first authors. YJ, LC, and XZ read, reviewed, edited, and wrote sections related to their areas of expertise. WX and QW read, reviewed, edited throughout the whole writing process, and signed off on the final paper. All authors contributed to the article and approved the submitted version.

We are grateful for funding provided by the National Natural Science Foundation of China (No 81702542, 81972578, 82072847, and 81772742); Science and Technology Commission of Shanghai Municipality (19XD1402300); Shanghai Municipal Health Commission (2019LJ11); Shanghai Jiao Tong University Medical Engineering Cross Fund (YG2019GD02).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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