PET/CT had a number of potential roles in prostate cancer management strategies, and each of these will be considered in turn:

  1. 1.

    Diagnosis

  2. 2.

    Staging at diagnosis

  3. 3.

    Restaging at relapse

  4. 4.

    Monitoring treatment response

  5. 5.

    Prognostication

  6. 6.

    Radiotherapy planning

A wide range of PET radiopharmaceuticals have been developed, each selectively targeting specific cellular functions or structures. The most commonly used tracer in clinical oncological PET imaging is 18F-FDG which behaves as a glucose analogue, accumulating in cells with greater glycolysis. However, 18F-FDG PET has never achieved widespread use in prostatic malignancies because of a limited sensitivity of only 75% for staging disease at diagnosis and 26% for detecting recurrent disease [1]. The high urinary excretion of 18F-FDG can obscure the view of the prostate.

Choline tracers (commonly labeled with 11C- or 18F-) have received growing interest for prostate cancer and within the UK are gaining increasing clinical utility (Figs. 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, and 5.8). Choline is an essential component of cell-membrane phospholipid synthesis. Tumours, including prostate cancer, have an increased requirement for cell membrane synthesis, and it has been shown that prostate cancer cells have an increased intracellular transport of choline and increased choline metabolism [2], confirmed by MRI spectroscopy [3]. PSMA PET tracers are gaining increasing acceptance in prostate cancer imaging and will probably replace choline tracers in most applications (see Chap. 6).

Fig. 5.1
figure 1

A normal 18F-choline PET scan (MIP image). Physiological uptake of choline is present in the salivary glands, liver, spleen, kidneys, bowel and bladder with low-grade normal bone marrow activity

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Fig. 5.2
figure 2figure 2

(a) 11C-choline (i) coronal PET and (ii) transaxial PET and fused PET/CT in the pelvis, (b) 18F-choline (i) coronal PET and (ii) transaxial PET and fused PET/CT in the pelvis. 11C-choline and 18F-choline PET/CT studies performed at an interval of 5 months in a 65-year-old male with rising PSA after previous prostatectomy for prostate cancer. Both tracers show a metabolically active 8 mm left external iliac lymph node (arrow), appearing more prominent on the later 18F-choline scan, in keeping with nodal disease recurrence. In addition, in both studies there is low-grade mediastinal/hilar and inguinal nodal uptake in keeping with nonspecific reactive changes. Note slight differences in biodistribution between the two tracers. There is less urinary excretion and muscle activity with 11C-choline

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Fig. 5.3
figure 3

A patient with a new diagnosis of prostate cancer. The 18F-choline scan shows abnormal uptake in the primary cancer in the right side of the prostate gland (a). This corresponds with an area of low signal of the T2-weighted (b) and restricted diffusion on the ADC (c) MRI scans

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Fig. 5.4
figure 4

A patient who presented with prostate cancer and a PSA of 300 ng/ml. The 18F-choline PET/CT shows abnormal uptake in the prostate gland, lymph nodes and skeletal metastases. MIP (a), pelvic axial fused images (b), prostate (c), pelvic nodes (d), iliac nodes and bone metastases

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Fig. 5.5
figure 5

A patient previously treated with brachytherapy subsequently was found to have a rising PSA. The 18F-choline scan showed recurrent disease within the prostate gland but no areas of nodal or distant metastatic disease

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Fig. 5.6
figure 6

18F-choline axial CT, PET and fused PET/CT images of a 72-year-old man previously treated with brachytherapy for prostate cancer with a subsequent rising PSA. The images demonstrate focal activity in the seminal vesicle on the left (arrow) indicating recurrent disease

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Fig. 5.7
figure 7

A patient with a rising PSA 1 year after a radical prostatectomy. The 18F-choline PET/CT scan shows small volume recurrent nodal disease in the left side of the pelvis on the MIP image (a) and axial fused image (b)

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Fig. 5.8
figure 8

18F-choline PET/MRI scan with axial pelvic images, T2 (top left), PET (top right), ADC map (bottom left), b900 image (bottom right). A 68-year-old man with previous prostatectomy for prostate cancer and subsequent rising PSA. The images demonstrate a left presacral nodal recurrence (arrows) with high 18F-choline activity, low ADC and high signal on the b900 diffusion-weighted image

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Acetate is a substrate for numerous cellular processes, including the anabolic pathway leading to fatty acid synthesis. Radiolabelled acetate tracers have demonstrated utility in imaging prostate cancer, including in patients with lower PSA levels, but such tracers are neither cancer nor prostate specific.

There is increasing interest in more prostate-specific tracers, including prostate-specific membrane antigen (PSMA)-targeted imaging tracers, and those targeting androgen receptors (Figs. 5.9, 5.10, and 5.11). PSMA are type II transmembrane proteins, overexpressed in prostate cancer [4].

Fig. 5.9
figure 9

68Ga-PSMA PET/CT. (a) Axial fused PET/CT and CT images through the pelvis and (b) PET MIP and sagittal CT and fused PET/CT images. A man with recently diagnosed adenocarcinoma prostate adenocarcinoma (Gleason score: 4 + 4). There is an intensely 68Ga-PSMA avid lesion involving the left anterior and posterior peripheral zones of the prostate gland. (b) There are no other 68Ga-PSMA avid lesions in the rest of the body. Physiological 68Ga-PSMA distribution with physiological uptake in the lacrimal, salivary glands, liver, bowel loops, kidneys and urinary bladder

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Fig. 5.10
figure 10figure 10

68Ga-PSMA PET/CT. (a) PET MIP, (b) axial (top) and coronal (bottom) fused PET/CT and CT through the prostate gland, (c) axial PET/CT and CT images through the pelvis and (d) axial PET/CT and CT images (bone windows) through the pelvis. A man with a diagnosis of Gleason 5 + 4 prostate cancer. The images demonstrate a primary prostate cancer in the right peripheral zone (a, b), right external and internal iliac nodes (c) and right iliac and sacral bone metastases (d)

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Fig. 5.11
figure 11

68Ga-PSMA PET/CT. (a) axial PET/CT and CT through the prostate gland and seminal vesicles and (b) same images after treatment with hormone therapy. The baseline images (a) show primary cancer in the peripheral and central zones as well as the right seminal vesicle. After hormone therapy (b) there is a marked reduction in activity at all sites of disease

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Other tracers have shown potential utility for prostate cancer imaging, including markers of amino acid transport (e.g. the leucine analogue, anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, 18F-FACBC), cellular proliferation (e.g. 18F-fluorothymidine (FLT)), hypoxia (18F-fluoromisonidazole) and angiogenesis (RGD-based tracers). Such tracers have a potential role in prostate cancer management.

5.1 Diagnosis of Prostate Malignancies

The current diagnostic tools of serum prostate-specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasound scan (TRUS)-guided biopsies to provide pre-surgical tumor grading of prostate cancer are only accurate in around 69% of patients [5].

Most prostate malignancies show increased uptake of choline-PET tracers. However, uptake in benign prostate hypertrophy has been shown, and some report an inability of these tracers to differentiate between benign and malignant prostate tissue [6]. A sensitivity of up to 90% and specificity of 86% have been reported for the detection of localized prostate malignancy [7] with choline PET/CT, but the accuracy is lower for smaller tumors.

There is not enough evidence currently to support the use of choline-PET/CT, or other tracers, for screening patients for malignancy. There may be a role for guiding biopsies in patients who have repeated negative prostate biopsies despite a high clinical suspicion [8] but this remains an area of research interest at present.

5.2 Staging of Prostate Malignancies

Given the uncertainty of the accuracy of choline-PET in differentiating benign from malignant tissue, the value of this technique for T-staging prostate tumors is limited. The spatial resolution of clinical PET/CT scanners in widespread use is insufficient to accurately assess the prostate capsule for evidence of involvement or breach. The development of PET/MRI may show T-staging benefits, as suggested in a 15-patient feasibility study using 18F-choline PET/MRI [9] (Figs. 5.3 and 5.8).

Identifying involved lymph nodes at diagnosis (N-staging) has significant clinical significance, but has been difficult to achieve accurately with all imaging modalities, including MRI. Contractor et al. showed that 11C-choline PET/CT was more sensitive than MRI for nodal staging (p = 0.007), detecting more sub-centimeter involved nodes [10]. Whilst choline-PET/CT has demonstrated good specificity, the sensitivity is relatively low and is dependent on the size of the involved lymph node and the PSA levels. De Jong et al. reported sensitivity/specificity values of 80%/96%, respectively, but the mean PSA for the 67 patients studied was over 100 ng/ml. In contrast, Beheshti et al. reviewed 130 patients with a mean PSA of 27 ng/ml (suggesting earlier disease and/or less disease burden) and reported a sensitivity of only 45% for nodal analysis, but a specificity of 96% [8]; the sensitivity increased to 66% if only nodes larger than 5 mm were considered. Other studies have demonstrated similar values of sensitivities and specificities [10,11,12].

The diagnosis of distant metastatic disease has important treatment implications; metastatic prostate cancer is incurable, and therefore invasive and morbid treatment to the primary disease is unlikely to be appropriate. Prostate cancer most frequently spreads to the bone causing typically sclerotic deposits. The current most common imaging method for screening for metastatic bone disease is with standard scintigraphy using technetium-labeled diphosphonates which are incorporated into the bone matrix of metastatic deposits secondary to the excess osteoblastic activity. 18F-fluoride, as a PET tracer, has a similar mechanism of uptake, but offers potential benefits from the resolution of PET/CT imaging, offering quantification potential and providing tomographic information as routine (Fig. 5.12). Faster clearance also allows imaging as early as 1 h post-injection. Choline PET/CT has been compared with standard bone scintigraphy in prostate cancer patients; Picchio et al. reported a sensitivity for identifying bone metastases of 89% for 11C-choline PET/CT and 100% for bone scintigraphy, but the specificity was much greater for 11C-choline PET/CT at 98 vs. 75% for bone scintigraphy [13]. Similar results have been reported by other groups [14]. This advantage of choline as a tracer is likely because there is little increased uptake in chronic degenerative lesions, unlike with standard 99mTc bone scintigraphy. Beheshti et al. reported that in one study, 18F-choline PET/CT identified early bone marrow involvement that was not visible on CT alone [8]. No evidence currently demonstrates the superiority of choline PET/CT compared with standard staging techniques for the identification of bone metastases from prostate cancer, but it may have value in certain individual cases for problem solving (Fig. 5.4).

Fig. 5.12
figure 12

A 18F-fluoride PET/CT scan (a) MIP image and (b) axial fused image at the level of the lower thoracic spine showing multiple bone metastases. This is the same patient as in Fig. 5.4

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5.3 Restaging at Disease Recurrence

Imaging needs to identify sites of disease relapse, in particular whether this relapse is local to the prostate, within local or distant lymph nodes or distant metastatic spread. This has important treatment implications; a confined local recurrence might still be cured with salvage treatment. It is not uncommon for prostate cancer patients to have disease recurrence suspected by serial serum PSA rises. TRUS-guided biopsy only detects local recurrence in about 25–54% of these patients and is particularly poor when PSA values are low [15, 16]. CT has only a low diagnostic accuracy for localizing recurrent disease [17].

Most studies of PET tracers in prostate cancer have examined patients at the time of disease relapse (Figs. 5.5– 5.8). A recent meta-analysis of 19 studies (1555 patients) examining choline-PET and PET/CT imaging at the time of disease recurrence concludes a pooled diagnostic sensitivity of 85.6% (95%CI = 60.6–100%) and specificity of 92.6% (36.4–100%), comprising a nodal sensitivity of 100% (90.5–100%) and specificity of 81.8% (48.2–97.7%), and a prostatic fossa sensitivity of 75.4% (66.9–82.6%) and specificity of 82% (68.6–91.4%) [18]. The sensitivity of 18F-choline PET imaging is proportional to the PSA level and the initial Gleason grade of the disease [12, 14, 19,20,21,22,23,24,25]. Husarik et al. reported that the sensitivity of choline PET/CT was 70% with a PSA ≤2 ng/ml at the time of the scan, compared with 86% when PSA >2 ng/ml [12]. Another group showed a sensitivity of only 20% with PSA ≤1 ng/ml, 44% for PSA 1-5 ng/ml and 82% when PSA >5 ng/ml [24].

Other tracers have shown utility in this clinical setting. There is a suggestion that acetate tracers might have a role in identifying sites of disease recurrence in patients with lower PSA levels, with acetate being a substrate of oxidation in the TCA cycle to produce energy in early prostate cancer deposits [26]. Labeled ligands for the androgen receptor (e.g. 18F-FDHT) may help demonstrate the role of the androgen receptor in patients with relapsed androgen-resistant disease [26].

A statistically significant higher detection rate was shown using a 68Ga-labelled PSMA ligand tracer compared with 18F-choline PET/CT, with a higher lesion SUVmax and greater tumor-to-background ratio [27]. There is also growing evidence to support the potential utility of 18F-FACBC, a leucine analogue, for detecting recurrent disease with improved sensitivity compared to 11C-choline PET/CT [28].

5.4 Assessing Treatment Response

No evidence yet demonstrates superiority of using choline-PET/CT over standard clinical measures of response to treatment, although it is suggested that such functional imaging may have significant advantages, particularly in detecting responses sooner than currently achievable following the PCWG2 guidelines [29]; this is currently under evaluation. Work in mouse models has highlighted this potential of 11C-choline and 18F-FLT PET imaging for detecting responses to docetaxel chemotherapy [30, 31]. Androgen receptor-targeted tracers might have utility in the development of targeted therapeutics and the subsequent treatment monitoring.

5.5 Prognostication

It has been reported that a negative 11C-choline PET/CT scan at relapse correlates with a higher disease-specific survival and lower treatment rate [32], and conversely a positive scan predicted a worse freedom-from-recurrence survival [33].

5.6 Radiotherapy Planning

There is increasing interest in using functional imaging to define radiotherapy target volumes; for prostate cancer this ties in with the uncertainty of how to best approach patients with pelvic lymph node involvement. Pinkawa et al. have demonstrated the feasibility of using 18F-choline PET/CT to allow dose escalation using a simultaneous integrated boost during radical radiotherapy [34], although the long-term survival data from such an approach is awaited. Vees et al. combined 99mTc-Nanocoll prostatic sentinel lymph node detection using SPECT/CT with 18F-choline PET/CT in 20 men with high-risk prostate cancer; 40% of patients had nodal involvement outside the standard pelvic radiotherapy target volume, highlighting that this approach may allow for tailoring of the radiotherapy treatment volume [35].

Conclusion

There has been a rapid development of new PET tracers in line with technological advances, but also in line with a greater knowledge of tumor biology and involved metabolic processes with resultant advantages and few disadvantages compared to conventional imaging (Table 5.1). The translation of the novel tracers into widespread clinical utility has not been as rapid and is dependent on the access to suitable facilities. Choline PET imaging is increasingly being accessed in the UK, particularly at the time of PSA progression, but also at diagnosis to evaluate the nodal status. PSMA tracers are showing incremental value and are likely to be used more widely (see Chap. 6). The role of functional imaging in early and accurate detection of a therapeutic response remains an important aim and is currently being investigated. PET imaging could have further roles in targeting radiotherapy treatment and in targeted-drug development. It is likely that PET imaging will become an integral part of prostate management paradigms in the near future.

Table 5.1 Advantages and disadvantages of PET in prostate cancer imaging
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Key Points

  • PET/CT had a number of potential roles in prostate cancer management strategies.

  • A wide range of PET radiopharmaceuticals have been developed, each selectively targeting specific cellular functions or structures.

  • Choline tracers (commonly labeled with 11C- or 18F-) have received growing interest for prostate cancer and within the UK are gaining increasing clinical utility.

  • There is increasing interest in more prostate-specific tracers, including prostate-specific membrane antigen (PSMA)-targeted imaging tracers and those targeting androgen receptors.

  • PSMA are type II transmembrane proteins, overexpressed in prostate cancer.

  • Most prostate malignancies show increased uptake of choline-PET tracers. However, uptake in benign prostate hypertrophy has been shown, and some report an inability of these tracers to differentiate between benign and malignant prostate tissue.

  • Given the uncertainty of the accuracy of choline-PET in differentiating benign from malignant tissue, the value of this technique for T-staging prostate tumors is limited.

  • 11C-choline PET/CT is more sensitive than MRI for nodal staging, detecting more sub-centimeter involved nodes.

  • No evidence yet demonstrates superiority of using choline-PET/CT over standard clinical measures of response to treatment.

  • A negative 11C-choline PET/CT scan at relapse correlates with a higher disease-specific survival and lower treatment rate, and conversely a positive scan predicted a worse freedom-from-recurrence survival.