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Diagnostic Applications of Nuclear Medicine: Prostatic Cancer

  • Emilio BombardieriEmail author
  • Maria Grazia Sauta
  • Lucia Setti
  • Roberta Meroni
  • Gianluigi Ciocia
  • Laura Evangelista
Living reference work entry

Abstract

Prostate cancer (PCa) is one of the most common cancers in the male population. Its incidence, mortality, and prevalence are different across different geographical areas, depending on the different approaches adopted for screening, early diagnosis, and availability of treatments. Digital rectal exploration (DRE) and the prostate-specific antigen (PSA) test are the most common clinical practice used for PCa screening.

The choice of treatment should be patient specific and risk adjusted. The therapeutic approaches for patients with PCa include different options: watchful waiting, radical prostatectomy, radiotherapy, hormone therapy, chemotherapy, immunotherapy, and treatment of bone metastases.

Keywords

Prostate cancer Diagnostic imaging Bone scan SPECT/CT PET/CT Biomarkers for prostate cancer 

Glossary

[11C]CHO

[11C]choline

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

[18F]FDHT

16β-[18F]fluoro-5-dihydrotestosterone

18F-CHO

18F-fluoromethylcholine

18F-DCFBC

N-[N-{(S)-1,3-dicarboxypropyl]carbamoyl}4-18F-fluorobenzyl-L-cysteine

18F-DCFPyLis

2-[3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentil}-ureido]-pentanedioic acid

18F-FACBC

Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, or 18F-fluciclovine

18F-NaF

18F-sodium fluoride

3D CRT

Three-dimensional conformal radiotherapy

68Ga-PSMA

Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)]

99mTc-HMDP

99mTc-hydroxymethylene diphosphonate

99mTc-MDP

99mTc-methylene diphosphonate

ACP

American College of Physicians

ACS

American Cancer Society

ADT

Androgen deprivation therapy

AJCC

American Joint Committee on Cancer

ALP

Alkaline phosphatase

AS

Active surveillance

ASCO

American Society of Clinical Oncology

AUA

American Urological Association

BS

Bone scintigraphy

BSI

Bone scan index

CRPC

Castrate-resistant prostate cancer

CT

X-ray computed tomography

CTX

C-terminal telopeptide of type I collagen

CYP17

17-Alpha-monooxygenase, a crucial enzyme for the synthesis of testosterone from non-gonadal sources

DCE MRI

Dynamic contrast-enhanced magnetic resonance imaging

DRE

Digital rectal exploration

DWI

Diffusion-weighted imaging, an MR imaging technique

EBRT

External beam radiation therapy

ED

Effective dose

EMA

European Medicines Agency

ERG

ETS-related gene

ETS

E26 transformation-specific family

FDA

United States Food and Drug Administration

GLUT

Glucose transporter family

GS

Gleason score

HDR

High-dose rate radiotherapy

HIFU

High-intensity focused ultrasound

ICTP

Cross-linked carboxyterminal telopeptide of type I collagen

IGRT

Image-guided radiotherapy

IMRT

Intensity-modulated radiotherapy

LDR

Low-dose rate radiotherapy

LH

Luteinizing hormone

LHRH

Luteinizing hormone-releasing hormone

M

Metastasis status according to the AJCC/UICC TNM staging system

MR

Magnetic resonance

MRI

Magnetic resonance imaging

N

Lymph node status according to the AJCC/UICC TNM staging system

NCCN

National Comprehensive Cancer Network

NCCN

National Comprehensive Cancer Network

NOPR

United States National Oncologic PET Registry

NPV

Negative predictive value

p53

Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)

PCa

Prostate cancer

PERCIST

Positron emission tomography response criteria in solid tumors

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PET/MR

Positron emission tomography/magnetic resonance

PET/MRI

Positron emission tomography/magnetic resonance imaging

PINP

Amino-terminal procollagen propeptide type I

PPV

Positive predictive value

PSA

Prostate-specific antigen

PSA

Prostate-specific antigen

PSMA

Prostate-specific membrane antigen

RANK

Receptor activator of nuclear factor kappa-B

RANKL

Receptor activator of nuclear factor kappa-B ligand, also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF)

RARP

Robot-assisted radical prostatectomy

RECIST

Response evaluation criteria in solid tumors

ROC

Receiver operating characteristic, a statistical analysis to assess the performance of a binary classifier

RT

Radiotherapy

SNMMI

Society of Nuclear Medicine and Molecular Imaging

SPECT

Single photon emission computed tomography

SPECT/CT

Single photon emission computed tomography/computed tomography

SRE

Skeletal related event

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TMPRSS2

Transmembrane protease, serine 2

TNM

AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status) and “M” (distant metastasis status)

TRUS

Transrectal ultrasound

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

USPSTF

United States Preventive Services Task Force

WB

Whole body

WBS

Whole-body scan

Epidemiology

Prostate cancer (PCa) is one of the most common cancers in the male population. Its incidence, mortality, and prevalence are different across the geographical areas, depending on the different approaches adopted for screening, early diagnosis, and availability of treatments. Nearly 900,000 new PCa diagnoses are recorded per year on a global scale or 28.0 per 100,000 persons-year. According to national cancer registers, Australia and New Zealand reported the highest incidence rate, with 104.2 cases per 100,000 persons-year. A high incidence rate is observed also in Northern and West Europe, 73.1 and 93.1 per 100,000 persons-year, respectively. In Northern America, the incidence is similar, with 85.6 cases per persons-year. The lowest incidence rates are observed in Asia, with 7.2 per 100,000 persons-year (particularly in India and in China). The age-adjusted PCa mortality in Europe accounts for 12.00 per 100,000 persons-year, very similar to 9.9 per 100,000 persons-year in Northern America [1, 2].

Incidence and death rates have declined in the last 20 years, most likely as a consequence of decreased application of programs for widespread and “unselected” prostate-specific antigen (PSA) tests which have led to the overdiagnosis of small and localized tumors with a limited likelihood to spread locally or at distance. On the other hand, the increased public awareness for early detection and treatment together with better use of screening programs (i.e., in high-risk patients) has improved PCa mortality [3].

Little is known about the etiology of PCa, although some risk factors can play a role; age, family history, and genetics are the most important of such risk factors [4]. Recent studies demonstrated that also ethnicity, androgen status, diet, and lifestyle are relevant. More than two-thirds of all PCa cases occur in men older than 65 years. In first-degree relatives of affected men, the risk to develop PCa increases to threefold, and PCa tends to develop before the age of 55 [5, 6, 7].

Prostate Cancer Screening

Digital rectal exploration (DRE) and the prostate-specific antigen (PSA) test are the most common clinical practice biomarkers used for PCa screening. PSA is not specific for PCa, as it is elevated in benign prostatic hyperplasia, prostatitis, trauma, and urinary retention. Screening for PCa is a controversial issue. Screening offers the opportunity to find cancers at a more curable stage. On the other hand, the variability of the natural history of PCa should be considered, since some cases show an aggressive progression but many others are indolent and carry little threat about morbidity or mortality. Moreover, transrectal ultrasound (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it has an established role in directing prostatic biopsies.

In the absence of a method to identify patients in whom the disease will have a rapid progression if left without therapy, any screening procedures result in some degree of overtreatment. Guidelines on PCa management have been issued by different scientific organizations: American Cancer Society (ACS), National Comprehensive Cancer Network (NCCN), US Preventive Services Task Force (USPSTF), American Urological Association (AUA), and American College of Physicians (ACP). The NCCN guidelines (revised in 2016) recommend considering the patient’s history (including family history, medications, and any event of prostate disease) and emphasize the importance of physical examination. The clinician should then discuss the risks and benefits to obtain a baseline PSA and consider a baseline DRE to identify high-risk cancers associated with changes in PSA [8]. In asymptomatic patients, the guidelines recommend testing every 2–4 years for men aged 45–75 years with serum PSA values below 1 ng/mL. For men with PSA ranging between 1 and 3 ng/mL, PSA tests should occur at 1- to 2-year intervals. Biopsy should be considered in those men aged 45–75 years with serum PSA >3.0 ng/mL. However, the decision to perform a biopsy should not be based on the PSA cutoff threshold alone, but should be evaluated considering all clinical variables and the patient’s preference.

First Diagnosis

Patients with abnormal DRE or elevated PSA levels should be further evaluated with prostate biopsy. The risk of being diagnosed with PCa increases with increasing PSA values, amounting to 34% for men with PSA values between 3 and 6 ng/mL and from 50% to 70% for those with PSA values >10 ng/mL. In younger subjects (<65 years), the cumulative risk is consistently lower than in older subjects. Patients with a free-to-total PSA ratio of <20% and PSA velocity >0.75 ng/mL/year have a higher risk of PCa and should also undergo prostate biopsy [9, 10].

Transrectal ultrasound (TRUS) imaging is the only imaging procedure to employ in this phase. TRUS-guided core biopsy has become the standard procedure to obtain tissue for histopathological examination. The fact that PCa is often multifocal and heterogeneous makes diagnosis based on a single biopsy difficult, as only a small amount of tissue is obtained with needle biopsy; thus, sampling errors are common. Initial biopsy guided by TRUS detected PCa in only 22–34% of the cases, and repeated biopsy is required in many patients. The likelihood of PCa diagnosis increases with the number of biopsy specimens; currently, at least ten biopsy cores are recommended, and 12–16 are obtained at some centers [11, 12].

Magnetic resonance imaging (MRI) is also important to diagnose PCa and to define its size and location. Cancers in patients with increased PSA and negative transrectal prostate biopsies can be diagnosed on MRI. MRI can specifically detect the anterior and apical tumors, which are usually missed on a TRUS-guided biopsy [13].

Pathology

Histopathological Type and Cancer Growth

Acinar adenocarcinoma is the most common type of PCa, representing over 95% of these cancers. Other rare tumors are basal cell, squamous cell, adeno-squamous carcinoma, and neuroendocrine carcinoma. Adenocarcinoma commonly originates from the peripheral zone of the gland (85%), less frequently from the transitional zone (10–15%), while only 5–10% of cases arise in the central zone [14, 15]. Most cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and non-clonal tumors.

The clinical outcome of PCa is highly variable, since in some patients the tumor grows slowly, while in other patients, it can exhibit a very aggressive behavior with early metastasis and death. This is summarized by the “risk of progression” concept defined by the classes of risk, which can be obtained taking into account the extension (stage TNM), the Gleason score (GS), and PSA levels [16, 17]. PCa follows a multistep course of growth. The first step is known as “carcinoma in situ” when neoplastic cells are confined into a normal gland. Following the initial event, further mutations, including p53, can lead to progression and metastasis. Prostate cells are sensitive to activation of androgen receptors on their surface. Androgens bind to the receptor, an androgen-activated transcription factor that belongs to the steroid nuclear receptor family. The receptor translocates into the nucleus, where it binds to androgen response elements and modulates transcription and cell growth [18]. As the disease progresses from hormone dependent to castration resistance status, this system is altered. Two key changes include upregulation of the androgen receptor, which confers sensitivity to small amounts of androgen, and mutation of the receptor, which results in loss of specificity for androgens [19].

According to their original location in the prostate, locally advanced PCa in the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces is a late event. PCa spreads to bone early, often without significant lymphadenopathy. At present, two predominant theories have been proposed: (1) the mechanic theory and (2) the seed-and-soil theory. Therefore, metastases can be caused by direct spread through the lymphatics and venous spaces into the lower lumbar spine or/and are caused by the presence of tissue factors that allow preferential growth in certain tissues. Lung, liver, and adrenal metastases have also been documented.

TNM Classification

The standard staging system for newly diagnosed PCa is that of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC). This system incorporates the anatomic extent of disease, including the primary tumor (T), regional lymph nodes (N), and distant metastases (M). The TNM staging system is widely used to stage PCa (Tables 1 and 2 ) [20]. Although imaging techniques are only occasionally useful for detecting/diagnosing PCa, they are mostly used for staging once a histological diagnosis is obtained. Usually a combination of the currently available imaging modalities is necessary for defining the most appropriate treatment strategies.
Table 1

AJCC/UICC TNM classification of prostate cancer

Primary tumor (T)

Clinical

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Clinically inapparent tumor neither palpable nor visible by imaging

T1a

Tumor incidental histologic finding in 5% or less of tissue resected

T1b

Tumor incidental histologic finding in more than 5% of tissue resected

T1c

Tumor identified by needle biopsy (e.g., because of elevated PSA)

T2

Tumor confined within prostatea

T2a

Tumor involves one-half of one lobe or less

T2b

Tumor involves more than one-half of one lobe, but not both lobes

T2c

Tumor involves both lobes

T3

Tumor extends through the prostate capsuleb

T3a

Extracapsular extension (unilateral or bilateral) including microscopic bladder neck involvement

T3b

Tumor invades seminal vesicle(s)

T4

Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, elevator muscles, and/or pelvic wall

Pathologic (pT)c

pT2

Organ confined

pT2a

Unilateral, one-half of one side or less

pT2b

Unilateral, involving more than one-half of side, but not both sides

pT2c

Bilateral disease

pT3

Extraprostatic extension

pT3a

Extraprostatic extension or microscopic invasion of bladder neckd

pT3b

Seminal vesicle invasion

pT4

Invasion of rectum, elevator muscles, and/or pelvic wall

Regional lymph nodes (N)

Clinical

NX

Regional lymph nodes were not assessed

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph node

Pathologic

pNX

Regional nodes not sampled

pN0

No positive regional nodes

pN1

Metastasis in regional node(s)

Distant metastasis (M) e

M0

No distant metastasis

M1

Distant metastasis

M1a

Non-regional lymph node(s)

M1b

Bone(s)

M1c

Other site(s) with or without bone disease

aTumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c

bInvasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2

cThere is no pathologic T1 classification

dPositive surgical margin should be indicated by an R1 descriptor (residual microscopic disease)

eWhen more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced

Table 2

AJCC anatomic stage and prognostic groups for prostate cancer. (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC)

Group

T category

N category

M category

PSAa

Gleason scorea

I

T1a–c

N0

M0

<10

≤6

T2a

N0

M0

<10

≤6

T1–2°

N0

M0

X

X

IIA

T1a–c

N0

M0

<20

7

T1a–c

N0

M0

≥10 <20

≤6

T2a

N0

M0

<20

≤7

T2b

N0

M0

<20

≤7

T2b

N0

M0

X

X

IIB

T2c

N0

M0

Any

Any

T1–2

N0

M0

≥ 20

Any

T1–2

N0

M0

Any

≥ 8

III

T3a–b

N0

M0

Any

Any

IV

T4

N0

M0

Any

Any

Any T

N1

M0

Any

Any

Any T

Any N

M1

Any

Any

aWhen either PSA or Gleason is not available, grouping should be determined by T stage and/or whichever of the either PSA or Gleason is available

The 2010 update of this system incorporated the pretreatment serum PSA level and Gleason score/grade to subdivide patients into prognostic categories. This information about prognostic categories is also combined with patient’s age; life expectancy; overall medical condition, including performance status and comorbidities; the presence or absence of symptoms; and patient preferences to make decisions for the optimal treatment for an individual patient.

Histopathological Grade

Gleason score (GS) is recommended as the grading system of choice, because it takes into account the inherent morphologic heterogeneity of PCa, and several studies have clearly established its prognostic value. A primary and a secondary pattern (the range of each is 1–5) are assigned and then summed-up to yield a total score. Scores of 2–10 are possible. It has been reported that high GS is associated with poor prognosis, although the behavior of cancer can be different in accordance with other histopathological variables (i.e., lymphovascular and neurovascular invasions, infiltrated margins, positive lymph nodes).

The majority of newly biopsy-diagnosed PCas are graded GS 6 or above. In a radical prostatectomy, if a tertiary pattern is present, it is commented upon but not reflected in the GS [9]:
  • Gleason X: GS cannot be processed

  • Gleason ≤6: well differentiated (slight anaplasia)

  • Gleason 7: moderately differentiated (moderate anaplasia)

  • Gleason 8–10: poorly differentiated/undifferentiated (marked anaplasia).

Risk Stratification

The initial management of patients with newly diagnosed PCa relies on multidisciplinary evaluation of the patient’s conditions (age, life expectancy, performance status, comorbidities, presence or absence of symptoms, and consensus) and on a pretreatment assessment of the risk of locoregional recurrence or disseminated disease. Important factors in this assessment include clinical staging of the extent of disease (Tables 1 and 2), the pretreatment serum PSA, and GS in the pretreatment biopsy [19, 20, 21].

The categories of risk derived from the abovementioned information are summarized in Table 3. D’Amico’s classification is the most commonly used, validated, and cited risk stratification for PCa.
Table 3

Categories of risk in prostate cancer patients

Very low risk: clinically localized PCa

Disease detected by prostate biopsy based upon serum PSA only, without detectable abnormality on digital rectal examination or imaging

Grade group 1 (Gleason score ≤6), <3 positive cores, no core ≥50% involved

Serum PSA <10 ng/mL

Low risk: clinically localized PCa

No apparent tumor in the prostate (i.e., diagnosis based upon a biopsy only, with no abnormal findings on imaging or palpation) or limited disease in one lobe of the prostate gland

Serum PSA <10 ng/mL and grade group 1 (Gleason score ≤6)

Intermediate risk: clinically localized PCa

Tumor in the prostate involves more than one-half of one lobe of the prostate (T2b), or with bilateral disease (T2c), but without detectable extracapsular extension or seminal vesicle involvement

Patients with T1 or T2a disease are classified as having intermediate-risk disease based upon a serum PSA between 10 and 20 ng/mL or a biopsy grade group 2 or 3 (Gleason score 7)

High risk: clinically localized PCa

Tumor with extracapsular extension (T3a)

Serum PSA >20 ng/mL or a biopsy grade group 4 or 5 (Gleason score of 8–10)

Very high-risk PCa

Tumors with seminal vesicle involvement (T3b), tumor fixation (T4), or invasion of adjacent organs (T4)

Primary Gleason pattern 5 or four or more cores with Gleason score 8–10 (grade groups 4 and 5) are classified as very high risk

Lymph node involvement

Patients with lymph node involvement are classified as having stage IV (metastatic) disease

Disseminated disease

Patients with disseminated metastases (M1) are classified as having stage IV (metastatic disease)

Management Strategies for Prostate Cancer

The choice of treatment should be patient specific and risk adjusted and aims at improving cancer control while reducing the risks of treatment-related complications [8]. The therapeutic approaches for patients with PCa include (1) watchful waiting, (2) radical prostatectomy (with or without lymphadenectomy), (3) radiotherapy, (4) hormonal therapy, (5) chemotherapy, (6) immunotherapy, and (7) treatment of bone metastases. The selection of a treatment should be taken on the basis of a multidisciplinary approach involving all specialists dealing with this pathology (Fig. 1).
Fig. 1

A schematic illustration of treatment management in patients with PCa at different risk categories based on the anticipated years of survival (from NCCN guidelines, version 1.2016)

Active Surveillance and Watchful Waiting

Active surveillance (AS) for patients with PCa consists in postponing the immediate therapy with a definitive treatment that should be started in case of the evidence of a consistent risk of disease progression. AS is an option for the initial management of selected men with localized, well-differentiated PCa thought to be at low risk for progression [22, 23]. This approach is based on the long natural history of PCa, and it is an attempt to balance the risks with the side effects of overtreatment against the possibility of disease progression and a lost opportunity for cure. In 2015, the Cancer Care Ontario organization (CCO) published a Clinical Practice Guideline on Active Surveillance for the Management of Localized Prostate Cancer. The ASCO Endorsement Panel reinforces these recommendations, also adding qualifying statements [24].

The distinction between AS and watchful waiting is important for clinical decision-making. AS, which carries a curative intent and involves regular monitoring with PSA, DRE, and biopsy, is appropriate for patients who have sufficient life expectancy and time to benefit from active treatment when disease progression is detected. For patients with a life expectancy of less than 5 years, watchful waiting (cessation of routine monitoring, with treatment initiated only if symptoms develop) is appropriate and further reduces the issue of overtreatment, including biopsies which carry a small but nonzero risk of infection and hospitalization. For most patients with low-risk (GS≤6) localized PCa, AS is the recommended management strategy. However, since the ASCO Endorsement Panel recognizes that there is non-negligible disease heterogeneity, in selected patients with low-risk PCa, an immediate treatment instead of AS should be chosen, especially in young patients, with high-volume tumor, high GS, and African-American ethnicity, because these patients have a higher likelihood for disease progression during their lifetime.

The NCCN recommendation for follow-up schedule during AS includes PSA no more often than every 6 months unless clinically indicated, DRE no more often than every 12 months unless clinically indicated, and repeated prostate biopsy considered annually to assess for disease progression (biopsy should be repeated within 6 months of diagnosis if initial biopsy was <10 cores or assessment discordant, e.g., palpable tumor contralateral to the side of positive biopsy). A repetition of prostate biopsy is indicated when DRE changes or PSA increases, although neither parameter is very reliable for detecting PCa progression.

Radical Prostatectomy (With or Without Lymphadenectomy)

Radical prostatectomy is usually reserved to patients who are in good health and have tumor confined to the prostate gland (stage I and stage II) [25, 26]. There are two types of radical prostatectomy: retropubic and perineal prostatectomy. The perineal approach requires a separate incision for lymph node dissection. Laparoscopic lymphadenectomy is technically possible and accomplished with reduced morbidity [27]. For small, well-differentiated nodules, the incidence of positive pelvic lymph nodes is less than 20%, and pelvic node dissection may be omitted. With larger, less-differentiated tumors, pelvic lymph node dissection is more important. The value of pelvic lymph node dissection (i.e., open surgical or laparoscopic) in these cases is not therapeutic but spares patients with positive nodes the morbidity of prostatectomy. In some cases, nerve-sparing surgery can be done. However, men with large tumors or tumors that are very close to the nerves may not be eligible for this surgery. This type of surgery may save the nerves that control erection. The advent of robotic prostate surgery offers several advantages over the traditional methods, yielding clinically superior results and reduced risk of complications and allowing a quicker recovery [28, 29]. The use of robot-assisted radical prostatectomy (RARP) for the management of localized PCa has increased dramatically in recent years. RARP is associated with improved perioperative outcomes, such as reduced blood loss and fewer transfusions. However, cancer control after RARP versus retropubic radical prostatectomy is equivalent, with similar incidences of positive surgical margins and comparable early oncological outcomes. RARP appears to provide advantages in recovery of continence, potency, and quality of life compared with retropubic radical prostatectomy [30].

External Beam Radiation Therapy

External beam radiation therapy (EBRT) is a good option as definitive treatment for patients with tumor at early or locally advanced stages and localized within the prostate. The evolution of radiotherapy techniques through three-dimensional conformal radiotherapy (3D CRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) has allowed more accurate and precise treatments and obtained significant improvements in the therapeutic ratio [31, 32]. These modalities make it possible to treat PCa with radical intent and can be an alternative to radical surgery. A critical issue in EBRT of PCa is that the therapeutic effective dose is limited by the dose delivered, since it has been shown that the biochemical disease-free survival increases with increasing radiation dose [33]. Some randomized trials have shown better results with higher doses (>70 Gy). EBRT can be combined also with hormone therapy, in a short or long course, depending on clinical stage [34]. An alternative to EBRT utilizes protons as the radiation source. The advantage of proton therapy is the reduced radiation exposure to normal tissues adjacent to the tumor, while maintaining a therapeutic dose to the lesion.

Suitable candidates for adjuvant radiation therapy are patients with multifocal disease, positive surgical margins, periprostatic tissue invasion (T3-T4), GS>7, or PSA >0.2 ng/mL after radical prostatectomy [35]. Immediate postoperative radiotherapy improves significantly the biochemical recurrence-free survival and local control, but not overall survival. EBRT is also indicated after surgery when increasing PSA levels or diagnostic imaging detects local or distant tumor localization (soft tissues and bone). In the scenario of radiation therapy, intense clinical investigations are ongoing to further optimize treatment of PCa, including dose escalation, moderate and extreme hypo-fractionation, optimal combination between radiotherapy and androgen deprivation therapy, and timing of postoperative RT [36].

Brachytherapy

Brachytherapy (also called seed implantation or interstitial radiation therapy) treats PCa with radiation from inside the prostate gland. There are two types of brachytherapy: (1) low-dose rate therapy (LDR) and (2) high-dose rate therapy (HDR) [37, 38]. Brachytherapy with LDR uses permanent implants of iodine-125 seeds, while HDR uses iridium-192 sources or cesium-137 sources that are removed after irradiation. LDR brachytherapy is safe and efficient and constitutes an alternative to surgery and EBRT, particularly in those patients with a prostate gland of small volume, clinical low risk, GS < 7, and a PSA <10 ng/mL. Recurrence-free survival at 5 years has been reported to range from 71% to 93% with a median follow-up between 36 and 120 months [39]. Differently from LDR, HDR brachytherapy should be performed in the presence of locally advanced PCa, often delivered as a boost in combination with EBRT.

High-Intensity Focused Ultrasound Therapy and Cryotherapy

High-intensity focused ultrasound (HIFU) therapy and cryotherapy, two sophisticated options for local treatment of PCa, can be performed both as primary treatment and as salvage treatment, after unsuccessful surgery or radiotherapy [40, 41]. At present, the diffusion of these techniques is limited. Therefore, despite some encouraging results, the overall clinical experience is limited to a few centers and data should be confirmed on larger series of patients. However, the clinical value of these techniques has a definite role, since both HIFU and cryotherapy can achieve precise ablation of small lesions (focal therapy) by treating a partial volume of the prostate gland.

Hormone Therapy

The growth of PCa cells is sustained by testosterone [42]. This is the reason why the treatment of PCa is based on suppression of this hormone [43]. This effect can be obtained by orchiectomy or by administering luteinizing hormone-releasing hormone (LHRH) agonists (leuprolide, goserelin, and buserelin) or LHRH antagonists (degarelix) that block LH production in the pituitary gland, thus inhibiting the synthesis of testosterone [44, 45, 46]. This strategy is called androgen deprivation therapy (ADT). LHRH agonists are indicated in the different phases of the disease and can be used alone or in combination with other drugs, in association with radiotherapy or after surgery. ADT has clinical and prognostic importance as adjuvant treatment after radical prostatectomy, if lymph nodes are positive for metastasis. For the treatment of extraprostatic cancer, ADT can be combined with EBRT, since clinical evidences demonstrated superiority of the combined treatment versus the single treatment. ADT should be considered as the first-choice therapy in patients with metastatic disease, with involvement of distant organs other than prostate gland and locoregional lymph node (e.g., bone, lung, or distant lymph nodes).

Another important type of hormone therapy is based on the use of antiandrogens (bicalutamide, flutamide, and cyproterone acetate), compounds that compete directly with circulating androgens for binding sites on their receptors within the prostate cells, thus promoting apoptosis and inhibiting PCa growth [47, 48]. Cyproterone acetate additionally blocks gonadotropin release by the pituitary, thus contributing to reduce the testosterone plasma levels. These drugs are administered as monotherapy or in combination with LHRH agonists.

Two new drugs have recently been made available in the armamentarium for hormone therapy: abiraterone acetate and enzalutamide, with different mechanisms of action. Abiraterone acetate is a potent inhibitor of the enzyme 17-alpha-monooxygenase (CYP17), which is essential for the synthesis of testosterone from nongonadal sources [49]. The inhibition of CYP17 (normally expressed in testicular, adrenal, and prostate tumor tissues) translates into reduced testosterone synthesis from cholesterol. Enzalutamide is a new generation antiandrogen with a higher affinity for the ligand binding the androgen receptor than the first-generation agents, such as bicalutamide [50]. This agent acts at three different steps: (1) it inhibits androgen binding to androgen receptors, (2) it inhibits androgen receptors from entering into the nucleus, and (3) it inhibits androgen receptors from binding to DNA.

Chemotherapy

Docetaxel belongs to the taxane family (anti-mitochondrial agents) and its use is mainly indicated in patients with metastatic PCa resistant to ADT. Docetaxel plus prednisone showed to be significantly superior to mitoxantrone in patients defined as castrate-resistant prostate cancer (CRPC) for all endpoints of efficacy, including overall survival [51, 52]. CRPC patients develop progression of disease (e.g., biochemical relapse or progression of metastases) in spite of low levels of circulating testosterone (<50 ng/dL). Another agent named cabazitaxel, a new semisynthetic analogue of docetaxel, has been shown to be effective in metastatic CRPC patients, with significant survival benefit versus mitoxantrone [53].

Immunotherapy

Recently, some interesting results have been obtained with vaccines, such as GVAX, PROSTVAC-VF, and sipuleucel-T [54, 55, 56], and with novel anti-immune checkpoint inhibitors like ipilimumab [57, 58, 59]. Sipuleucel-T, approved by the FDA and EMA, is a dendritic vaccine obtained by isolating dendritic cells from patients, priming cells in vitro with prostate-specific acid phosphatase through a fusion protein and reinfusion of the activated cells in the patient. Ipilimumab is a fully human antibody that binds to the inhibitory cytotoxic T lymphocyte antigen 4 (CTLA-4), thereby enhancing antitumor immunity. The results achieved in PCa are so far of a very preliminary nature.

Treatment of Skeletal Metastases

Bone-modifying agents can modulate the activity of osteoclasts, osteoblasts, and osteocytes. Several bisphosphonates (e.g., zoledronic acid) and an inhibitor of the RANK/RANKL pathway (denosumab) have been approved for the treatment of bone metastases in solid tumors with the goal to reduce skeletal-related events [60]. Denosumab has been shown to have superior activity over zoledronic acid in delaying and preventing skeletal-related events in patients with skeletal metastases from metastatic CRPC. Overall, some clinical evidence supports the introduction of zoledronic acid in the treatment of hormone-sensitive metastatic PCa [61]. None of these agents, however, has induced an improvement in overall survival.

As a calcium analogue, the alpha emitter radium-223 ion (administered in the form of a chloride salt) is selectively taken up in osteoblastic areas, where it conveys high radiation energy within a short penetration range, thus resulting in irreparable DNA damage. Results of the ALSYMPCA trial indicate that, when used for the treatment of bone metastases, this radiopharmaceutical leads to an advantage in survival for metastatic CRPC patients who presented with symptoms [62, 63]. In addition to significant reduction in bone pain and better quality of life versus placebo, treatment with 223Ra-dichloride caused a 30% reduction in the risk of death versus placebo and reduction of new skeletal related events (SRE) both in post-docetaxel and in chemo-naïve patients [64].

In the new therapeutic scenario for metastatic CRPC, the appropriate algorithm for use of the available drugs is still an area of open discussion. Abiraterone acetate and enzalutamide demonstrated significantly increased overall survival and progression-free survival in the post- and pre-docetaxel setting in patients with bone metastases, respectively. Moreover, a significant impact on the incidence and severity on bone-related adverse events was observed in patients receiving enzalutamide [50]. Also EBRT represents an effective palliative treatment for control of pain in patients with localized skeletal metastases. EBRT achieves significant clinical results in 60–80% of patients, with more than 50% of patients obtaining complete pain relief at the treated site [65, 66, 67].

For initial treatment of CRPC patients with skeletal metastases, NCCN Clinical Practice Guidelines recommend abiraterone, enzalutamide, and docetaxel (for rapidly progressing patients), radium-223 (for patients with bone metastases and no visceral metastases), or participation in clinical trials. Nevertheless, no consensus exists on the sequence of therapies to be employed alone or in combination after failure of initial therapy or first-line docetaxel. All agents plus cabazitaxel and salvage chemotherapy are options for second-line therapy. Figure 2 shows some examples of treatment strategies in PCa.
Fig. 2

Possible treatment strategies in different phases of PCa

Biochemical and Diagnostic Modalities

Laboratory Tests

PSA is recognized as the first-choice tumor marker for PCa, since it has an absolute prostate specificity and is expressed by the majority of prostate cancers [50]. However, several nonneoplastic conditions of the prostate gland are associated with increased PSA levels; therefore, it has a lack of tumor specificity [68], which is the major drawback of PSA as a circulating marker for PCa. A number of patients with PCa have serum PSA levels below the cutoff of 4 ng/mL, even if about 15% of men with PSA below this threshold will have a biopsy-proven PCa. The probability of having a PCa rises as the PSA levels rise; the highest values correspond to the highest probability to have a PCa. Subjects with PSA levels ranging from 4 to 10 ng/mL have a 25% chance of having PCa (one out of four patients); when PSA concentrations are >10 ng/mL, the chance of having PCa is over 50–60%. Patients with a free-to-total PSA ratio <20% and PSA velocity >0.75 ng/mL per year have a higher risk of PCa. Different approaches were adopted in the past to optimize the sensitivity of the PSA test, for instance, by changing the cutoff threshold, variously elaborating on the PSA test (PSA density, PSA velocity), and investigating PSA isoforms (i.e., free PSA, conjugated PSA, pro-PSA). Novel biomarkers have also been explored, belonging to various molecular families (i.e., PCA-3, TMPRSS2-ERG gene fusions) [69, 70].

At variance with the use of PSA for the initial diagnosis, PSA is to be considered a strictly cancer-specific marker in patients in whom PCa has already been diagnosed and/or after primary treatments. In patients radically treated with curative intent, prostate tissue would not be represented anymore in the body, since it was fully removed by surgery or destroyed by radiotherapy. Then PSA should become undetectable in the serum after radical prostatectomy or should keep very low levels after radiotherapy. In these conditions, any significant and/or progressive increase of PSA values has to be considered cancer specific, particularly when the increase is constant over time. All patients with residual or relapsing PCa exhibit PSA changes, which therefore represent a clear biochemical sign of cancer presence [70, 71, 72]. There are two main characteristics of PSA as tumor marker: (a) a high proportion of prostate cancers produce PSA; (b) PSA is exclusively synthesized by prostatic tissue and this avoids any other analytical confounding noise that might mask PSA. Therefore, PSA is useful for monitoring patients radically treated, because the false-positive results are extremely rare in these conditions and any small increase of PSA may be considered to indicate cancer relapse.

Bony metastases are very frequents in PCa patients and are associated by high focal bone turnover with increased activity of osteolysis and/or osteogenesis. Markers of bone turnover might therefore be ideal to monitor progression of osteolytic or osteoblastic metastasis and/or to evaluate response to treatment. At present, bone alkaline phosphatase (bALP), total alkaline phosphatase (tALP), and amino-terminal procollagen propeptide type I (PINP) are considered as standard markers of bone formation, while cross-linked C-terminal telopeptide of type I collagen (CTX) and cross-linked C-terminal telopeptide of type I collagen (ICTP) are utilized as markers of bone resorption [73, 74, 75]. The results from several studies conclude that in cancer patients with skeletal metastases, serum or urinary levels of bone turnover markers may be increased for various concomitant causes, in addition to skeletal metastases (e.g., age, vitamin D deficiency, and adjuvant hormone therapy). This makes it impossible to distinguish the contribution of the different components that determine high levels of bone markers; therefore, markers of bone turnover should not be considered as diagnostic tools for skeletal metastasis. Instead, markers of bone turnover can be considered as indicators of prognosis and parameters of progression. Some clinical investigations demonstrated a positive association between high levels of these markers and presence or progression of skeletal metastases from PCa [76, 77]. The highest diagnostic accuracy was described for b-ALP (72% sensitivity, 88% specificity), and the greatest diagnostic specificity was reported for PINP (92%). According to other reports, both baseline and on-study elevations in bone marker levels were associated with increased risks of SRE, disease progression and death [78, 79, 80]. In conclusion, clinical evidences confirm that all markers of bone turnover at present can be considered as parameters of prognosis or of response to therapy, but they have a very poor diagnostic value.

Radiological Imaging

Transrectal ultrasonography is used to look at the prostate when a patient has PSA abnormalities (e.g., high/increased levels, or altered free-to-total ratio, and/or high PSA velocity) or has abnormal DRE findings. TRUS has become the standard procedure to obtain material for histopathological examination [81]. Since early studies indicated that TRUS-guided single-spot biopsies detected PCa only in 22–34% of the cases, the current procedure is based on multiple sampling [14, 15]. The likelihood of PCa diagnosis increases with the number of biopsy specimens, and at least ten biopsy cores are recommended; 12–16 samples are obtained in some centers [17, 18]. Besides this recommendation, some US abnormalities do not correspond to a cancer lesion; therefore, the procedure can be affected by both false-negative and false-positive results. Attempts to improve its accuracy are based on the use of color Doppler, power US, and 3-D US. Moreover, TRUS can be used also to measure the size of the prostate gland, which can help in determining the PSA density, or can represent also a guide during some forms of treatment such as brachytherapy [82, 83].

CT scan has no value when the cancer is likely to be confined to the gland. Therefore, CT cannot be used for studying the prostate gland itself. However, CT can be helpful when spread to lymph nodes and adjacent structures is suspected (see Fig. 3), and for restaging patients. The role of CT scan in the current clinical routine consists in studying bone and soft tissues of the entire body, since it is the most available and reliable radiological whole-body method to detect and monitor lymph node, visceral, and skeletal metastases [84].
Fig. 3

CT images suggesting primary prostate cancer (upper left panel), pelvic lymph node involvement (lower left panel) in a 78-year-old patient with newly diagnosed PCa, before any treatment. Bone window CT images show bone metastases in the pelvis (upper and lower right panels)

Magnetic resonance imaging (MRI) has recently emerged as the modality of choice for the detection of PCa after an inconclusive biopsy, for local staging, and for seminal vesicle evaluation. T2-weigted MRI sequences allow a precise definition of the local anatomy (see Fig. 4). The use of functional MRI sequences (namely, dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and MRI spectroscopy) enables more accurate examinations [85, 86]. MRI associated with a systematic biopsy determines a better cancer detection also in patients with previous standard US-guided negative biopsies and elevated serum PSA [87, 88]. Although the bone itself does not have an MR signal, skeletal metastases are visualized by MRI through the detection of early changes in bone marrow that precede bone reaction to tumor invasion. MRI could represent an imaging technique of choice for detection and follow-up of bone metastases [89, 91]. New whole-body (WB) protocols have been adopted, and ad hoc WB-DWI sequences were developed to explore with multiparametric projections (MPR) areas that are difficult to analyze on standard anatomical imaging. In very few centers, WB hybrid PET/MRI scanners have been introduced, for simultaneous acquisition and exact anatomical coregistration of PET and MRI. A limitation of this modality is that such sophisticated approaches are available in a limited number of specialized centers and these examinations are time-consuming, require specific expertise, and have an intrinsic high cost.
Fig. 4

MRI images obtained in a patient with PCa. A focal hypointense tumor focus in the right apical region of the prostate gland is shown in different sequences

Nuclear Medicine Modalities

Nuclear medicine modalities can be classified according to the physical characteristics of the tracers (based on γ-emitting or β+-emitting radionuclides), the type of detection (planar scintigraphy, SPECT, SPECT/CT, PET/CT,), the mechanism of accumulation of the agents (targeting bone or targeting cancer cells), and their availability in the clinical practice (already approved or experimental).

The choice of the best imaging strategy depends on several factors, such as availability and costs. Planar imaging and SPECT with bone targeting agents are the most commonly employed techniques, both for their availability and for economic reasons. PET/CT represents the more sophisticated technique that can be used with different radiotracers, both for bone and for cancer imaging.

Radiopharmaceuticals for PCa can be divided into two main groups: (1) targeting bone (99mTc-labeled diphosphonates and 18F-fluoride) and (2) targeting cancer cells ([11C]choline, 18F-choline, [18F]FDG, 68Ga-PMSA-ligand, 18F-FACBC, etc.).

99mTc-Biphosphonates Bone Scan, SPECT, and SPECT/CT

The commonest radiopharmaceuticals used to visualize bone metastases belong to the bisphosphonates family labeled with 99mTc, such as 99mTc-hydroxymetilendiphosphonic acid (99mTc-HMDP), 99mTc-methylene diphosphonate (99mTc-MDP), and 99mTc-3,3-diphosphono-1,2-propanedicarboxylic acid (99mTc-MDP) [90, 91, 92]. 99mTc-MDP accumulates in the mineral component of bone: nearly two-thirds in the hydroxyapatite crystals and one-third in calcium phosphate. Its uptake is related to the osteoblastic activity, blood flow, and extraction efficiency. The vast majority of skeletal metastases from PCa are osteoblastic, lesions that can easily be depicted on a whole-body scan. Bone scintigraphy (BS) is the cornerstone of nuclear medicine for the assessment of the skeleton, particularly in oncology. The conventional whole-body scan (WBS) is recommended in the most important guidelines for PCa, because it is widely available, has low costs and high sensitivity, and is able to detect bone metastases several months before they are revealed by planar x-ray. In fact, more than 40% of trabecular bone has to be destroyed before the lesion becomes detectable by conventional x-ray [92, 93]. It is well known that the highest sensitivity of BS for PCa metastases is achieved in presence of osteoblastic lesions. BS can efficiently image both the osteoblastic and the mixed lesions, while the detection of osteolytic lesions is less efficient due to reduced calcium deposit and consequent poor uptake of the radiolabeled phosphonates. Another important notion to keep in mind is that BS cannot detect cancer invasion in the bone marrow per se, unless an osteoblastic reaction is activated.

The diagnostic sensitivity of BS in PCa patients varies from 75% to 95%; its specificity is relatively lower (from 60% to 75%), because metabolic bone reactions can also occur in benign conditions such as arthrosis, inflammation, and trauma [93, 94, 95]. The high variability reported across the clinical studies depends on differences between patient populations and pretest probability of bone metastases.

When is BS indicated in PCa patients? In asymptomatic newly diagnosed patients, we have to consider the class of risk described above, in order to keep to a minimum the use of diagnostic investigations, especially in patients with a very low probability of having bone metastases. PSA levels represent the most common parameter to evaluate the probability of having bone metastases. Several retrospective studies indicate that PSA levels <20 ng/mL can exclude with a high probability the presence of bone metastases at BS, with a negative predictive value closed to 99% [96]. Conversely, WBS should be performed in PCa patients at high risk or very high risk (PSA >20 ng/mL or GS>8) (NCCN recommendations). In patients with intermediate risk, BS should be considered only in presence of clinical conditions suspected for bone metastases. In these patients, calculation of the pretest probability would be useful; several statistical approaches that produce complex nomograms are now available [97, 98, 99, 100, 101].

In patients with PCa after primary treatment (surgery or radiotherapy), the indications for bone imaging occur in two different situations: (a) symptomatic patients or biochemical recurrence (increase in PSA levels) and (b) patients under treatment, for monitoring response to therapy. In the first case, the physician faces the clinical problem to detect a possible cancer relapse with or without bone involvement, often driven by the appearance of clinical and/or biochemical symptoms based on the trend of rising PSA [102, 103, 104, 105, 106, 107] (see Fig. 5). There are established cutoff values for PSA doubling time and PSA velocity (doubling time less than 2–3 months and velocity >5 ng/mL per year) suggesting the presence of bone metastases. Moreover, BS is often indicated to solve equivocal/nondiagnostic findings at radiological imaging.
Fig. 5

Restaging BS in patients with biochemical PCA recurrence. (Left) A 65-year-old patient with a nonsurgical treated PCa with PSA 1,015 ng/mL, showing intensely increased tracer uptake in virtually all the skeletal segment (“super scan”). (Right) A 68-year-old patient with recurrent PCa, in whom the BS shows many areas of focally increased tracer uptake throughout several skeletal segments

In the second case, the goal is to describe changes in radiopharmaceutical uptake (i.e., intensity, size, or number) as an index to assess response to therapy. The use of BS to evaluate the response of bone metastases to therapy has recently been extensively discussed by Evangelista et al. reporting various important critical issues, such as timing of the scan, the possibility of false-positive results due to the flare phenomenon (a marked increase in multifocal skeletal tracer uptake as a result of a change in therapy within 2-3 months of the bone scan) the criteria of interpretation at different times during and after therapy, and other factors [108]. Of course, the flare phenomenon is the most important factor to consider; in spite of some existing standard criteria to carry out a correct interpretation of bone uptake, at present it still constitutes a limitation that affects the value of BS in assessing the response to therapy [46, 109, 110, 111]. It can be concluded that, in patients with bone metastases, WBS is more reliable for defining tumor progression than for measuring the changes of response to therapy.

A bone scan index (BSI) has been developed to quantitate the load of bone metastases from PCa. This index is calculated by considering the average weight of bones derived from a reference man and the fractional contribution of each bone expressed as a percentage of the entire skeleton [112]. Therefore, BSI represents the percentage of the skeletal mass occupied by metastases, and this value indicates the extent of bone involvement. BSI was demonstrated to represent a reproducible prognostic tool and can be used both for stratifying patients in treatment protocols and for assessing treatment response [113, 114]. Since calculation of the BSI is a very laborious and time-consuming procedure, various automated computer-assisted methods were developed, resulting in a clear improvement of accuracy and feasibility [115]. Significant correlation has been described between BSI and overall survival. However, BSI has not entered in the diagnostic routine and the general opinion is that BSI would be mainly adopted for clinical trials [116, 117].

SPECT can improve on the limited specificity of planar BS, as it enables better definition of particular skeletal areas, such as the spine, pelvis, hip, and knee. SPECT was shown to improve the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of conventional BS up to 92%, 91%, 94%, 82%, and 90%, respectively, over planar imaging [118, 119, 120]. In particular, hybrid SPECT/CT , by integrating the anatomical information from CT with the metabolic-functional information from SPECT, results in better interpretation of bone areas with increased tracer uptake, thus making it easier to distinguish benign from malignant lesions [121]. Several clinical studies on scintigraphically equivocal lesions, the majority localized in the spine, demonstrated that SPECT/CT significantly improves the assessment of skeletal metastases from PCa [122, 123, 124]. Sharma et al. [125] showed that among 49 indeterminate lesions on planar BS, 96% were correctly classified with SPECT/CT and the patient management was changed in 61% [127]. Palmedo et al. compared SPECT/CT to 99mTc-HMDP BS and 99mTc-HMDP stand-alone SPECT in a series on PCa patients and found that SPECT/CT significantly improved specificity (94% versus 78%) and PPV (88% versus 59%) [126]. Although SPECT/CT has the advantage, over conventional BS, to allow a more detailed study of a limited region of the skeleton, its use in treatment monitoring is hampered by the hardware which prevents the WB acquisition in a reasonable time frame. In this regard, attempts have been undertaken to develop particular WB SPECT protocols enabling to image the entire body [127]. However, in spite of some particular multi-FOV methods reliable for the analysis of the WB scan, these modalities are not currently adopted in the clinical routine, due to their long acquisition time, limited compliance. Moreover, they do not solve the main drawback of conventional BS, which maintains a low diagnostic specificity and the inability to visualize the osteolytic lesions.

18F- Fluoride PET/CT

18F-Sodium fluoride (18F-NaF) PET/CT detects skeletal metastatic disease by a mechanism of similar to that of 99mTc-HMDP. Clinical indications are the same as for 99mTc-HMDP WBS, including the detection of primary and secondary bone tumors, the evaluation of equivocal findings at radiological imaging, and the assessment of response to therapy [127, 128]. The clinical imaging protocol has been described by Segall et al. in the procedure guidelines published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) [129]. The recommended activity of 18F-NaF is 1.5–3.7 MBq/kg (40–100 μCi/kg) up to a maximum of 370 MBq for oncologic imaging. Due to the lower injected activity and the physical decay characteristics, the total absorbed dose for 18F-NaF PET is similar to that of the 99mTc-MDP BS [130, 131]. The kinetics of 18F-NaF is characterized by a rapid plasma clearance and a high uptake in skeletal metastases with an especially favorable target-to-background ratio. Imaging quality of 18F-NaF PET/CT is better than with 99mTc-MDP, with superior spatial resolution (4–5 mm versus 10–15 mm); imaging with 18F-NaF is acquired earlier than with 99mTc-MDP (0.5–1 h versus approx. 3 h).

The overall diagnostic sensitivity of 18F-NaF PET/CT is higher than that of conventional BS (Fig. 6). In a study by Even-Sapir et al. on 23 patients, patient-based sensitivity was 100% for 18F-NaF PET/CT and 70% for BS, with 100% and 57% specificity, respectively. This advantage was reported also on a lesion-based analysis. Furthermore, the authors observed that PET/CT has significantly better sensitivity and specificity than SPECT/CT imaging [128]. A review article by Langsteger et al. on 22 patients with PCa found sensitivity, specificity, and accuracy values of 91%, 83%, and 88%, respectively, for skeletal metastases [132]. This superior sensitivity was reported also in other studies with 18F-NaF PET/CT [133, 134, 135, 136]. For example, Poulsen et al. described the superiority of 18F-NaF PET/CT over conventional BS by studying 50 patients bearing 526 metastatic bone lesions from PCa; 18F-NaF PET/CT had sensitivity, specificity, accuracy, and positive and negative predictive values of 93% versus 51%, 54% versus 82%, 81% versus 61%, 82% versus 86%, and 78% versus 43%, respectively [138].
Fig. 6

Mismatch between 18F-fluoride PET/CT and BS in a 76-year-old patient with a significant increase in PSA (from 2 to 38 ng/mL) after radiotherapy. 18F-fluoride PET/CT shows multiple sites of uptake in the skeleton, while the bone scan is negative

Evangelista et al. confirmed that 18F-NaF PET/CT has the highest weighted sensitivity (range of 81–100%) among the nuclear medicine modalities for the evaluation of bone metastases from PCa [108]. An important advantage of 18F-NaF PET/CT is the ability to image both blastic and lytic skeletal metastatic lesions [137]. Despite the good performance of 18F-NaF PET in detecting bone metastases (mainly in sensitivity), the interpretation of focal uptakes should be careful because of the increased number of false-positive results (which lowers specificity). A more accurate interpretation of the focal skeletal uptake can be achieved by semiquantitative evaluation of uptake with the standardized uptake value (SUV) [143]. This approach has been employed by different authors, in particular for lesions located in the spine, demonstrating that SUV evaluation can play a role in better discriminating metastases from degenerative lesions [130, 138, 144, 145]. A large-cohort study based on data from the American National Oncologic PET Registry (NOPR) was carried out with the aim to elucidate the clinical impact of 18F-NaF PET/CT on the management of patients. Results from 2,839 PET/CT scans performed in patients with different neoplastic diseases (68% prostate, 17% breast, 6% lung, 8% others) were evaluated. It was found that 18F-NaF PET/CT induced changes of strategy in 40% of the cases [140]. Early diagnosis of cancer progression and early detection of metastatic lesions can lead to different successful treatments capable of altering prognosis. The prognostic impact of 18F-NaF PET/CT was recently assessed by Apolo et al. in patients with bone metastases from PCa. A significant correlation was found between overall survival and modifications of SUV (besides the number of sites of skeletal uptake in the baseline PET scan) [137]. 18F-NaF PET/CT was used in patients with bone metastases from PCa for evaluating the response to therapy and resulted in better performance than BS [139]. However, similar to conventional WBS, also the 18F-NaF PET/CT findings can be affected by a “flare phenomenon” [141, 142].

There are sufficient data to demonstrate that PET/CT offers several advantages over conventional BS. However, PET/CT scanners are still less available than gamma cameras and the test is more expensive. 99mTc- MDP is easily and widely available, while the production of 18F requires a cyclotron. Again, a conclusive and complete cost-effectiveness study on the clinical use 18F-NaF PET/CT supported by a statistically significant number of tests is not available; for all these reasons, this modality is not still established worldwide in the current clinical practice.

[11C]Choline and 18F-Choline PET/CT

PET/CT with either [11C]choline or 18F-choline visualizes PCa using a metabolic tracer involved in phospholipid and in membrane metabolism, with the rationale that PCa is characterized by an upregulated choline transport, phosphorylation, and membrane metabolism. Choline (CHO) is phosphorylated to phosphoryl choline by the enzyme choline kinase; in this chemical form, it is trapped within the cancer cell [146, 147]. The radioisotopes used for labeling CHO are 11C (half-life 20.4 min) or 18F (half-life 109.7 min), to produce the imaging agents [11C]CHO and 18F-CHO, respectively.

Unfortunately, 18F-CHO has a high urinary excretion, which may interfere with evaluation of tracer uptake in the prostate. On the other hand, [11C]CHO has the disadvantage of a short physical half-life, thus making the [11C]CHO PET scan feasible only in centers with an on-site cyclotron. An analog of [11C]choline labeled with 18F, 18F-CHO can be distributed and utilized in centers without cyclotron facilities. Moreover, the emission energy of 18F allows better detection with PET than 11C [148, 149]. Nevertheless, [11C]CHO and 18F-CHO exhibit many similar characteristics, and for this reason, they are currently an established imaging modality to evaluate patients with PCa. [11C]CHO is available in the USA with FDA approval (September 2012), while 18F-CHO is available for routine clinical use in Europe. [11C]CHO PET/CT imaging protocols are based on the i.v. bolus injection of 370–740 MBq. The effective dose (ED) is estimated to be approx. 0.3 Sv and the dose critical organ is the liver. The PET/CT scan starts 3–5 min after tracer injection and images are acquired for a total of 10–20 min with 2–5 min per bed position, depending on the PET camera. Similarly to 18F-CHO, fasting is not strictly necessary, although many studies suggest to fast at least 4–6 h before PET scanning. For 18F-CHO PET/CT imaging, patients receive an i.v bolus injection of 4.07 MBq/kg, whole-body imaging starting 60–90 min after tracer administration (see Fig. 7). Occasionally, for prostate bed evaluation, early static or dynamic pelvic images may be obtained 2 min after tracer administration [150, 151, 152].
Fig. 7

18F-choline PET/CT for the detection of lymph node metastases in a 65-year-old patient with high-risk PCa. Radical prostatectomy was performed in 2011 (pT3bN1; GS = 9). The patient started Enantone in 2013 for disease progression in bone (a, c). Because of further increase in PSA level (36 ng/mL), the patient underwent PET/CT with 18F-choline (b, d) that showed disease progression in the bone and lung

Evangelista et al. analyzed the diagnostic effectiveness of radiolabeled choline PET/CT in different phases of patient management: in primary cancer localization, preoperative staging, and restaging and for the evaluation of therapy response [153]. The data suggest that the use of choline PET imaging for primary cancer detection in the preoperative phase is not supported by sufficiently convincing elements nor by a consistent number of observations. The region of the prostate gland can be successfully imaged by alternative radiological imaging modalities (US, MRI, CT), while preoperative evaluation of lymph node involvement with [11C]CHO and 18F-CHO PET/CT gave controversial results [154]. In a previous meta-analysis, Evangelista et al. had reported 49.2% pooled sensitivity with 95% pooled specificity for radiolabeled choline PET/CT in the detection of metastatic lymph node disease before a curative treatment. However, wide heterogeneity (between 22.7% and 78.4%) was reported across the studies [155]. Data from other studies showed sensitivity ranging from 33% to 45%, but confirmed high specificities when including larger patients’ cohorts [156, 157]. The variability in the detection rate of lymph node metastasis was related to different biases, such as nonhomogeneity of GS, stage of disease, and other clinical factors. Therefore, despite good specificity, the current guidelines do not recommend choline PET imaging for lymph node staging of patients with primary PCa.

On the basis of clinical experience, the use of radiolabeled choline PET/CT in newly diagnosed patients should be limited to the detection of early osseous metastatic disease in high-risk patients [158]. When evaluating the value of 18F-CHO PET/CT in the initial staging of 210 patients, Poulsen et al. found that a high focal bone uptake, consistent with bone metastasis, was seen in 18 patients. On the other hand, 18F-CHO PET/CT has demonstrated some limitations in detecting densely sclerotic malignant lesions [159], since they are generally characterized by low metabolic activity.

At present, the best indication for [11C]CHO or 18F-CHO PET/CT consists in detecting PCa recurrence in patients already treated, but with biochemical recurrence (Fig. 8).
Fig. 8

Patient with increasing PSA after radical prostatectomy. This 72-year-old man had a high PSA level (36 ng/mL) at the time of initial diagnosis and underwent 18F-choline PET/CT for staging. The MIP image (a) and coronal PET/CT images at two different depths demonstrate diffusion of the disease in the prostate (b) and in lymph nodes (c)

Krause et al. demonstrated a linear correlation between PSA values and the detection rates of recurrences at radiolabeled choline PET/CT; this rate reached 75% in patients with PSA >3 ng/mL [160]. In patients with PSA values <1 ng/mL, recurrences were detected in approximately one out of three patients. The precise localization of the site of recurrence (local recurrence, recurrence as lymph node metastases, or systemic recurrence) is crucial for the choice of the subsequent treatment, as it directly influences personalized therapy. Graziani et al. published a retrospective analysis of 9,632 choline PET/CT scans performed for restaging in an academic center between 2007 and 2015. The inclusion criteria were radical prostatectomy, available levels of PSA, and proven biochemical relapse (PSA >0.2 ng/mL after radical prostatectomy or PSA >2 ng/mL above the nadir after primary EBRT with rising PSA levels); 3,203 patients matched the inclusion criteria and 4,426 scans were considered [161]. Overall, 52.8% of the [11C]CHO PET/CT scans were positive. In patients with PSA levels between 1 and 2 ng/mL, 995 scans were performed and the positive rate was 44.7% with an incidence of distant findings of 19.2% and an incidence of oligometastatic disease of 37.7% These findings confirm the feasibility of [11C]CHO PET/CT for detecting the site of metastatic disease in patients with confirmed biochemical recurrence.

Beheshti et al. investigated the 18F-CHO PET/CT value for detecting bone metastases in patients with biochemical recurrence of disease and found that 18F-CHO PET/CT had 79% sensitivity, 97% specificity, and 84% accuracy. The use of 18F-CHO PET/CT for discovering skeletal metastases in general yields a detection rate lower than conventional BS, but with greater specificity. The interpretation of focal uptakes with 18F-CHO PET/CT leads to fewer false-positive and indeterminate findings and reduces the number of indeterminate lesions [162, 163, 164, 165, 166]. Beheshti et al. compared the diagnostic performance of 18F-CHO and 18F-fluoride PET/CT in 38 patients with biopsy-proven PCa for the detection of bone metastases. The authors found 81% sensitivity, 93% specificity, and 86% accuracy 18F-fluoride, while the corresponding values were 74%, 99%, and 85%, respectively, for 18F-CHO. In addition 18F-CHO induced a change in the management in 2 out of 38 patients, due to the early detection of bone marrow metastases (bone invasion by cancer, before involvement of cortical bone) [134]. In a similar series of patients, Picchio et al. observed that [11C]CHO PET/CT had lower sensitivity but higher specificity than BS in the detection of bone metastases in PCa patients with biochemical progression. The ranges of sensitivity, specificity, PPV, NPV, and accuracy for [11C]CHO PET/CT were 89–89%, 98–100%, 96–100%, 94–96%, and 95–96%, respectively. For conventional bone scintigraphy, the corresponding values were 70–100%, 75–100%, 68–100%, 86–100%, and 83–90%. [11C]CHO PET/CT and bone scan achieved a diagnostic concordance in 55 of 78 (71%) cases. This means that, in some selected cases, the combination of [11C]CHO PET/CT with bone scan can provide additional useful information [164] (Fig. 9).
Fig. 9

Mismatch between BS and 18F-choline PET/CT findings. (Left) The bone scan shows a single focus of uptake in the fourth left rib. (Right) 18F-choline PET/CT confirms focal uptake in the fourth left rib but also in the right hemibody of T4

Sometimes patients with a single bone metastasis visualized by BS undergo [11C]CHO PET/CT in order to obtain additional information about the extent of disease, both in bone and in other organs. In fact, some authors reported that PET/CT is able to depict multiple bone metastases and may provide images of bone lesions in up to 15% of patients with biochemical relapse after radical prostatectomy [167]. A recent article by Ceci et al. including 304 bone lesions from PCa found some differences in terms of SUV and PSA kinetics at [11C]CHO PET/CT among osteoblastic lesions, osteolytic lesions, and bone marrow involvement. Osteoblastic lesions showed lower values of SUVmax, while osteolytic lesions had higher values. This interesting approach can represent an important proposal for classifying skeletal involvement [168] and may be of interest in terms of treatment choice and patient management.

Evaluation of response to treatment is a very critical issue, since in the clinical practice, this evaluation has a strategic role. The use of morphological and functional imaging criteria (e.g., with CT, PET, MRI) for assessing response to therapy is already well established, but its application and interpretation are, at present, still a matter of discussion (Fig. 10).
Fig. 10

Evaluation of response to therapy with 18F-choline PET/CT. A 73-year-old with PCa shows progressively increasing PSA level during androgen deprivation therapy (bicalutamide). For this reason, therapy was switched to Enantone, then again to abiraterone acetate for further increasing serum PSA. The serial 18F-choline PET/CT scans show a significant reduction in 18F-choline uptake in the lymph nodes, after the start of treatments, particularly with abiraterone acetate

Radiolabeled CHO PET/CT has been proposed as biomarker for response evaluation in PCa patients, and the PERCIST criteria (PET response criteria in solid tumors) might be applied to this purpose. Furthermore, quantitative parameters such as the metabolically active tumor volume and SUV derivatives are under study, and some preliminary confirmations were obtained as prognostic parameters (related to overall survival) or as tool for assessing the efficacy of treatments [169, 170, 171].

68Ga-PSMA-Ligand PET/CT and PSMA Derivates

The prostate-specific membrane antigen (PSMA) is a cell surface membrane-bound enzyme highly expressed in prostate carcinoma cells versus benign prostatic tissue. The localization of the catalytic site of PSMA in the extracellular domain allowed for the development of small specific inhibitors that are internalized after ligand binding [172, 173].

PSMA ligands have been labeled with different radionuclides enabling the use for PET imaging (89Zr, 68Ga, and 18F 18F), for single-photon scintigraphy (111In, 99mTc), or for therapy (177Lu, 90Y) [174]. 111In-capromab pendetide (a monoclonal agent against the intracellular epitope of PSMA) has been approved for clinical use to visualize PSMA expression by the FDA in 1996, with the trade name of 111In-ProstaScint [175]. The use of this radiopharmaceutical has then been progressively abandoned in clinical practice, since the antibody cannot bind the intracellular domain of PSMA of intact cells, but only PSMA exposed in either apoptotic or dead cells. Therefore, the diagnostic performances of this immunoscintigraphic modality, in spite of some acceptable results, are not comparable with those that can be obtained with the most recent radiopharmaceuticals and novel PET/CT modalities for PCa assessment. Alternative monoclonal preparation probes targeting the extracellular domain of PSMA are under study, and a new 99mTc-labeled radiopharmaceuticals are being developed [176]. The 68Ga-PSMA ligand represents the most promising agent for the evaluation of patients with early biochemical recurrence of disease. Many studies have been published comparing the diagnostic performances of radiolabeled choline PET/CT with those of 68Ga-PSMA PET/CT.

Preliminary studies demonstrated that PET/CT with the 68Ga-PSMA ligand (Glu-NH-CO-NH-Lys-(Ahx)-68Ga(HBED-CC)), an inhibitor of the extracellular portion of PSMA molecule, resulted in significantly higher accuracy for the detection of early recurrence compared to 18F-choline PET/CT [177]. These investigations also reported a higher tumor-to-background ratio for 68Ga-PSMA PET/CT for the detection of suspected PCa metastases versus 18F-choline PET/CT; moreover, highly promising performances were reported also at very low PSA levels.

Conversely, few data are available about the use of 68Ga-PSMA PET/CT for the primary diagnosis of PCa. Fendler at al. recently evaluated the accuracy of this modality to localize cancer in the prostate and surrounding tissue at initial diagnosis. 68Ga-PSMA PET/CT was able to detect invasion of the seminal vesicles and the extracapsular tumor spread [178]. The combined use of 68Ga-PSMA PET with multiparametric MRI can enable targeted fusion biopsies, especially in patients with a negative biopsy. At present, these preliminary experiences are too limited [179].

Interesting results were reported by Maurer et al. regarding primary staging of PCa patients. In a retrospective analysis on 130 consecutive patients with intermediate- and high-risk PCa who had radical prostatectomy with lymph node dissection, 68Ga-PSMA PET/CT showed a 65.9% sensitivity and 98.9% specificity [180]. Conversely, Budaus et al. evaluated 30 PCa patients who underwent radical prostatectomy and lymph node dissection, using a preoperative 68Ga-PSMA PET/CT for the identification of lymph node involvement, reporting overall sensitivity, specificity, PPV, and NPV of 68Ga-PSMA PET/CT for the detection of lymph node metastasis of 33.3%, 100%, 100%, and 62.9%, respectively. Moreover, per site analysis revealed values of 27.3%, 100%, 100%, and 52.9% [181]. 68Ga-PSMA PET/CT is able to detect visceral and skeletal lesions not visible by other modalities [182]. In recurrent disease, Afshar-Oromieh et al. studied 319 patients with PCa [177]. In this series, despite the nonhomogeneous features of the patients’ population (mean PSA 161 ng/mL, median PSA 4.59 ng/mL, 28 patients not treated with radical therapies), 68Ga-PSMA PET/CT showed an overall detection rate of 82.8%. A detection rate of 50% was observed for serum PSA values <0.5 ng/mL and of 58% for PSA values ranging from 0.5 to 1 ng/mL. Interestingly, the detection rate was not influenced by the Gleason score or by ADT (Fig. 11).
Fig. 11

A 59-year-old patient with PCa showing a slight increase in serum PSA level (0.6 ng/mL) after radical prostatectomy. The 68Ga-PSMA PET/MRI shows significant tracer uptake in a right internal iliac lymph node (Images supplied by courtesy of Thomas A. Hope, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA)

In a cohort of 248 recurrent patients with median PSA of 1.99 ng/mL, Eiber et al. reported an overall positivity of 89.5% for 68Ga-PSMA PET/CT [183]. Verburg et al. evaluated with 68Ga-PSMA PET/CT the extent of disease in 151 patients with recurrent PCa. The imaging results were correlated to PSA levels, PSA doubling time, and GS [184]. In this study, the presence of recurrent lesions was correlated with absolute PSA levels and PSA kinetic. The detection rate resulted in 30% of GS values of less than 8 and 32% for values between 8 and 10. This finding confirms other data suggesting that PSMA overexpression is not directly related to GS and that fast PSA kinetics are more likely to be associated with a positive PSMA scan.

A critical review was recently published by Perera et al. [185]. Sixteen articles involving 1,308 patients were analyzed. 68Ga-PSMA PET was positive in 40% of patients for primary staging and in 76% for biochemical recurrences. Positive 68Ga-PSMA PET scans for biochemical recurrences increased with the pre-PET PSA value. For the PSA categories 0–0.2, 0.2–1, 1–2, and >2 ng/mL, the rates of positive scans were 42%, 58%, 76%, and 95%, respectively. A shorter PSA doubling time increased the PET/CT positivity. The conclusions indicate a favorable sensitivity and specificity profile, compared to choline-based imaging techniques, particularly in case of low PSA levels. New emerging indications for 68Ga-PSMA PET/CT are in the management of radiotherapy [186].

At present, the most widely applied indication for 68Ga-PSMA PET/CT is the detection of recurrent disease and restaging of treated patients. This modality seems to increase the rate of detection, even with serum PSA values <0.5 ng/mL [187]. Despite these promising findings, the results obtained up to now with 68Ga-PSMA PET/CT have not been extensively validated with either histology (biopsy of the areas of uptakes) or with lesion-directed imaging techniques characterized by high specificity. Furthermore, the overall clinical experience is still limited and derived from retrospective series and mostly from German institutions. For these reasons, further prospective studies and larger series of patients should be investigated in order to confirm the promising results.

A number of alternative radiopharmaceuticals to 68Ga-labeled PSMA are being explored, and the most interesting radiopharmaceuticals under development today are PSMA-based fluorinated compounds. The advantages of 18F over 68Ga are mainly based on the wider availability of the tracer without problems in production and distribution and better quality of imaging because of the favorable emission energy of 18F for PET imaging. Two radiopharmaceuticals at present raise the interest of the nuclear medicine community: 18F-DCFBC (N-[N-{(S)-1,3-dicarboxypropyl]carbamoyl} 4-18F-fluorobenzyl-L-cysteine]) and 18F-DCFPyLis (2-[3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentil}-ureido]-pentanedioic acid). Both 18F-DCFBC and 18F-DCFPyLis exhibit favorable parameters in terms of radiation dosimetry, and biodistribution [188, 189]. Preliminary data in a limited series of patients suggest advantages of both tracers versus the current imaging modalities; however, these data require further confirmation in large-scale clinical trials [190, 191].

18F-FACBC PET/CT

The anti 1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC or 18F-fluciclovine) is a synthetic L-leucine analogue characterized by an excellent uptake in PCa cell lines [192]. The uptake is mediated through three L large-neutral amino acid sodium-independent systems, involving transporters related to proliferation and angiogenesis [193, 194]. 18F-FACBC was initially evaluated in PCa patients with recurrence after radical treatment. This radiopharmaceutical has recently obtained FDA approval (May 2016).

Biodistribution and radiation dosimetry studies of 18F-FACBC in healthy volunteers demonstrated that the organs with the highest initial uptake are the liver, red bone marrow, lung, and pancreas. Bone marrow demonstrates moderate and heterogeneous uptake, similarly as skeletal muscles [195, 196, 197]. A retrospective analysis by Kairemo et al. evaluated the role of 18F-FACBC PET/CT in 26 patients with treated PCa related to PSA concentrations, PSA doubling time, and correlative images [198]. 18F-FACBC PET/CT scans found 58 lesions: 12 (20.7%) were due to local relapse in the prostate bed and seminal vesicles, 9 (15.5%) were located in regional lymph nodes, 10 (17.2%) in distant lymph nodes, and 26 (44.8%) in the skeleton. The mean serum PSA level in 18F-FACBC-positive patients was higher than in the negative patients (9.5 versus 1.9 ng/mL), and PSA doubling time was shorter in patients with metabolically active uptake.

Turkbey et al. carried out a study in 21 patients with localized PCa, benign prostate hyperplasia, and normal prostate, who underwent dynamic and static abdominopelvic 18F-FACBC PET/CT and multiparametric MRI before robotic-assisted prostatectomy [198]. SUVs of 18F-FACBC PET/CT were compared with the MR findings and histopathologic analysis was carried out. Sector-based comparison with histopathologic analysis revealed 67% sensitivity and 66% specificity for 18F-FACBC PET/CT versus 73% and 79% for T2-weighted MRI. The sensitivity of combined PET and multiparametric MRI to localize tumors was 90%. The uptake of 18F-FACBC was higher in intraprostatic tumor foci than in normal tissue; however, 18F-FACBC uptake is similar in cancer as in benign prostate hyperplasia. Therefore, even though 18F-FACBC turned out not to be specific for PCa, the combined use of PET/CT and MRI can enable a more accurate localization of cancer [199].

A retrospective analysis was performed in 53 patients with suspected recurrent prostate carcinoma and negative BS who underwent 18F-FACBC PET/CT and diagnostic CT within 90 days. 18F-FACBC PET/CT and CT were positive in 41 (77.4%) and 10 (18.9%) patients, respectively. Positive rates were higher for 18F-FACBC PET/CT than for CT, at all ranges of PSA concentration, PSA doubling time, and GS. 18F-fluciclovine PET/CT had diagnostic performance superior to those of CT, both for detecting lesions in the prostate bed and for imaging metastases in extraprostatic regions. For 51 patients with a follow-up adequate enough to correctly evaluate the diagnostic performances in the prostate bed, the sensitivity, specificity, accuracy, PPV, and NPV were 88.6%, 56.3%, 78.4%, 81.6%, and 69.2% for 18F-FACBC PET/CT and 11.4%, 87.5%, 35.3%, 66.7%, and 31.1% for CT, respectively. In 41 patients evaluated for lesions in extraprostatic regions, the corresponding values for 18F-FACBC PET/CT were 46.2%, 100%, 65.9%, 100%, and 51.7%, respectively, versus 11.5%, 100%, 43.9%, 100%, and 39% for CT, respectively [200].

A prospective clinical trial was published by Shuster et al. who compared 18F-FACBC PET/CT with 111In-ProstaScint in 93 PCa patients with recurrent PCa [201]. 18F-FACBC PET/CT was positive in 77 (82.8%) patients, including 49 (63.6%) in the prostate/bed only, 24 (31.2%) in the prostate/bed and in extraprostatic regions, and 4 (5.2%) only in extraprostatic regions. In 70 of 93 patients with a definitive consensus on extraprostatic disease, 18F-FACBC demonstrated 55% sensitivity, 96.7% specificity, 72.9% accuracy, 95.7% PPV, and 61.7% NPV, figures significantly higher than with 111In-ProstaScint scintigraphy.

In spite of very limited data published in the literature 18F-FACBC has shown some favorable characteristics in comparison with CHO-PET/CT in terms of acquisition protocol, biodistribution, and image quality [199]. The very low excretion of this radiopharmaceutical in the urinary tract improves the detection of small lesions in the pelvis and namely in the prostatic region. The very rapid uptake in prostate cells and its very fast blood clearance allows the acquisition of images 4–5 min after the injection. The first study comparing 18F-FACBC with [11C]CHO PET/CT has been published by Nanni et al. who conclude that the detection rate with 18F-FACBC PET/CT is better than with [11C]CHO PET/CT, regardless of the PSA levels [202]. Therefore, this radiopharmaceutical may be useful for the primary diagnosis, staging and for restaging patients after treatment. Further studies are needed to confirm these preliminary results.

[18F]FDG PET/CT

[18F]FDG is a biomarker of the expression of glucose transporters (mainly GLUT-1) and hexokinase enzymatic activity in tissues [203]. GLUT-1 is overexpressed in poorly differentiated PCa cell lines [204]. The expression of GLUT-1 is modulated by androgens [205]; however, such enhanced expression occurs not only in PCa but also in benign prostatic hyperplasia. Furthermore, a strong correlation exists between GLUT-1 expression and GS [206, 207, 208].

Nevertheless, [18F]FDG PET is not recommended for the diagnosis and staging of organ-confined PCa, nor for the detection of locally recurrent disease, because of the overlap of the intense activity accumulated in the urinary bladder on tumor uptake. Furthermore, [18F]FDG is not a cancer-specific molecular probe and the tracer localizes in areas of wound healing, and inflammatory conditions [207, 208, 209]. However, [18F]FDG uptake in PCa increases in advanced clinical disease high PSA levels, and elevated GS [210].

There is limited experience on the detection of lymph node metastases by [18F]FDG PET/CT in patients with biochemical recurrence after potentially curative therapy [211, 212]. Chang et al. evaluated the performance of [18F]FDG PET in 24 patients with rising serum PSA levels after treatment for PCa and who had negative findings on bone scan and equivocal CT results [213]. For the detection of metastatic pelvic lymph nodes, [18F]FDG PET/CT showed 75% sensitivity, 100% specificity, 83.3% accuracy, 100% PPV, and 67.7% NPV. Schoder et al. reported that [18F]FDG uptake was higher in patients with treatment failure and was associated with higher PSA levels [214]. Moreover, using ROC analysis, the authors found that the best compromise between the optimal sensitivity and specificity would be reached for a PSA concentration of 2.4 ng/mL (80% and 70% respectively) and a PSA velocity of 1.3 ng/mL per year (71% and 77%, respectively). Since [18F]FDG uptake is associated with metabolic activity, [18F]FDG PET/CT can be useful for to assess tumor response to treatment. In a preclinical study, Zhang et al. evaluated immunodeficient mice harboring prostate tumor cell line CWR22 xenografts, by performing [18F]FDG microPET to assess [18F]FDG uptake before, during, and after treatment with a proteasome inhibitor (bortezomib). The reduction observed in [18F]FDG uptake was more reliable than the reduction in tumor volume as a parameter of response to therapy [215].

Zukotynski et al. performed [18F]FDG PET/CT, 18F-NaF PET/CT, and standard 99mTc-MDP bone scintigraphy in nine patients with CRPC before and after 8 weeks of therapy with abiraterone and cabozantinib [216]. They found that the intensity of uptake of 18F-NaF PET/CT in bone lesions did not predict response to treatment, while [18F]FDG PET/CT enabled to stratify patients into three groups (widespread cancer [18F]FDG-avid versus oligometastatic [18F]FDG-avid versus non-[18F]FDG-avid metastases). This approach could drive the choice of a tailored appropriate treatment. Another recent investigation showed that [18F]FDG PET could be useful for assessing response to treatment with a mTOR inhibitor, everolimus, in combination with docetaxel [217]. Yu et al. compared [11C]acetate and [18F]FDG PET/CT for assessing treatment response to androgen deprivation therapy in eight patients with >3 PCa metastases on bone scintigraphy [218]. A lesion-by-lesion analysis of [18F]FDG PET was performed by Morris et al. in 17 patients with progressive metastatic PCa with 134 skeletal lesions [219]. Ninety-five lesions (71%) were detected on both the [18F]FDG PET and the bone scans, 31 lesions (23%) were only seen on the bone scan, and 8 lesions (6%) were seen only on [18F]FDG PET scan. All metabolically active lesions on the [18F]FDG PET were noted to be active on the follow-up bone scans (thus suggesting true-positive findings on PET). The authors concluded that the added value of [18F]FDG is to identify metabolically active lesions from those scintigraphically quiescent. The extent and the intensity of [18F]FDG uptake in metastatic lesions may also provide prognostic information. In fact, a >33% increase in the average SUVmax of metastatic lesions or the appearance of new lesions assigned patients to different groups: patients in progression versus patients with stable disease.

The prognostic value of bone scan and [18F]FDG PET/CT was evaluated also by Meirelles et al. in a prospective trial in 43 men with metastatic CRPC [220]. This study demonstrated that the overall survival was inversely correlated with SUVmax obtained from the skeletal uptake. In patients with a median survival of 14.4 months SUVmax was >6.10, while it was ≤6.10 in patients with a median survival of 32.8 months. Although the BSI was also prognostic, in the multivariate analysis only SUVmax of [18F]FDG uptake resulted an independent factor as a predictor of survival.

Vargas et al. evaluated 38 patients with metastatic CRPC who underwent CT, [18F]FDG PET and 18F-16β-fluoro-5-dihydrotestosterone (18F-FDHT) PET/CT [221]. The number of lesions seen on CT, [18F]FDG, and 18F-FDHT PET was significantly associated with overall survival. However, in this trial, the association between tracer uptake and survival was demonstrated only with 18F-FDHT, while it was not seen with the intensity of [18F]FDG uptake.

On the contrary, a positive relationship was found by Jadvar et al. who showed in a multivariate analysis, after considering several confounding factors (such as age, PSA and serum AP levels, use of pain medication, prior chemotherapy, and GS at diagnosis) that the sum of SUVmax of up to 25 metabolically active lesions (lymph nodes, bone, and soft tissue metastases) was statistically significant as a predictor of overall survival [222].

The current clinical experience with [18F]FDG PET/CT suggests this radiopharmaceutical has less to offer for clinical management compared to more specific radiopharmaceuticals targeting PCa, although the intensity of [18F]FDG uptake in lesions might be an independent predictor of overall survival [223].

Clinical Considerations

PCa is evolving both in terms of development of new therapeutic options and in terms of better definition of strategies for cancer cure and/or management. For this reason, a general overview of the available modalities of imaging in the different steps of PCa can be useful, as summarized in Table 4.
Table 4

Pros and cons of diagnostic imaging modalities and their current applications for PCa in clinical practice

 

Pros

Cons

Current clinical indications

TRUS

1. Wide availability

1. Sensitivity is limited by the high number of isoechoic tumors originating in the peripheral zone

1. To guide prostate biopsies

2. Possibility to perform biopsy

2. Reduced sensitivity in detecting transition zone tumors

2. To deliver local treatments such as brachytherapy

3. No radiations

3. Inability to detect the anterior portion of the gland

3. To monitor cryotherapy treatment

CT

1. Wide availability

1. High radiation dose

1. Initial staging (for lymph node disease)

2. Allows assessment of fine bone details and characterization of smaller lesions

2. Not used for systematic bone screening

2. Recurrence of disease

3. Allows detection of lymph node and visceral metastases

3. Not useful for assessing response to therapy

3. Evaluation of response to therapy (RECIST criteria v. 1.1)

MRI

1. Good availability

1. Bone metastases outside vertebral spine or pelvic bones are not detected (in case of spinal MRI)

1. Active surveillance

2. Earlier detection of tumor foci

2. Advanced diagnostic techniques only available in diagnostic imaging centers of excellence

2. Initial staging (for primary tumor and locoregional lymph node involvement)

3. Better diagnostic performance in detection and characterization of bone lesions

3. Longer duration of examination, higher costs

3. Recurrence of disease (particularly in prostatic fossa)

4. Highest diagnostic performance in detection and characterization of bone lesions

5. Allows detection of lymph node and visceral metastases

6. Possible role of DWI in assessment of response to therapy

BS

1. Low cost

1. Low sensitivity for osteolytic lesions

1. Initial staging of disease (bone involvement)

2. Wide availability

2. Does not detect bone marrow disease

2. Recurrence of disease (high PSA levels)

3. Detection of bone metastases several months before they are revealed by planar x-ray

3. Poor sensitivity for osteolytic lesions without bone remodeling

3. Assessment of response to therapy

4. Low specificity (false-positive findings in case of degenerative changes, inflammatory processes, trauma, mechanical stress, and Paget’s disease)

5. Necessity of bone reactive changes to achieve the optimal sensitivity

6. Flare phenomenon due to some systemic treatments (also 223Ra)

SPECT

1. Improves the sensitivity of planar images

1. Limited field of view

1. See BS

2. No improvement in terms of specificity over planar images

2. Not standardized

3. As bone scan (see above)

SPECT/CT

1. Improved sensitivity over planar images

1. Whole-body imaging with this modality is not currently standard practice

1. See BS

2. Improved specificity over planar images

2. Resource implications of increased cost, specialist equipment, and specialist manpower hours

2. Not standardized

3. Increased radiation dose than BS (from 3 to 5 mSv)

4. As bone scan (see above)

18 F-fluoride PET/CT

1. The extraction of fluoride from the blood is rapid. The first-pass extraction is 100% vs. 64% for diphosphonates

1. Very sensitive to minimal degenerative changes

1. Restaging of disease (as an alternative to BS)

2. Superior image quality and therefore high diagnostic accuracy

2. High costs

2. Assessment of response to therapy (in some clinical trials and as an alternative to BS)

3. Rapid acquisition protocol (after 15 or 60 min from the injection)

3. Clinical impact when used to monitor treatment response is uncertain

4. As for 99mTc-diphosphonate is able to identify high bone turnover and remodeling

4. Flare phenomenon due to some systemic treatments (also 223Ra)

5. Quantitative and automatic semiquantitative analyses of uptake in the lesions

[ 18 F]FDG PET/CT

1. Can detect bone metastases at early stage of disease (bone marrow involvement)

1. Sclerotic metastases can be missed due to the relatively small amount of viable tumor tissue

1. Restaging of disease in patients with undifferentiated tumors (GS>8)

2. In case of osteolytic lesion and in presence of aggressive prostatic cancer, tracer accumulation is higher for an increase in the glycolytic rate

2. [18F]FDG uptake is limited in moderately or well-differentiated prostate cancer

3. Lack of FDG uptake in the osteoblastic lesion can be associated with the present of quiescent cells

3. Higher costs and increased radiation dose versus BS (from 3 to 5–7 mSv)

4. Superior image quality and therefore high diagnostic accuracy

5. Prognostic information

6. Quantitative and automatic semiquantitative analyses of uptake in the lesions

[ 11 C]/ 18 F- CHO PET/CT

1. More specific for prostate cancer

1. Flare phenomena reported during the administration of abiraterone acetate and GCSF

1. Restaging of disease (based on PSA levels and PSA kinetic)

2. Able to identify three patterns of bone disease (bone marrow involvement, osteoblastic lesions, no active tumor)

2. [11C]CHO is not available in centers without an on-site cyclotron

2. Assessment of f response to therapy

3. No uptake in chronic degenerative bone disease

3. High costs and increased radiation dose versus BS (from 3 to 5–7 mSv)

4. Quantitative and automatic semiquantitative analysis of uptake in the lesions

68 Ga-PSMA-ligand PET/CT

1. More specific for prostate cancer

1. PSMA expression is apparently differentially regulated by androgens

1. Restaging of disease (based on PSA levels and PSA kinetic)

2. High detection rate, in the recurrence setting, for low PSA level

2. It is still considered an experimental imaging agent

3. Able to detect all sites of prostate cancer recurrences (lymph nodes, bone, visceral sites)

3. High costs and increased radiation dose versus BS (from 3 to 5–7 mSv)

4. No uptake in chronic degenerative bone disease

4. High costs for the production of the radiotracer

5. Quantitative and automatic semiquantitative analyses of uptake in the lesions

18 F-FACBC PET/CT

1. More specific for prostate cancer

1. High uptake in the muscles

1. Restaging of disease (based on PSA levels and PSA kinetic)

2. Higher detection rate, in the recurrence setting, than [11C]CHO

2. It is still considered an experimental imaging agent

3. It is able to detect all sites of prostate cancer recurrences (lymph nodes, bone, and visceral sites)

3. High costs and increased radiation dose versus BS (from 3 to 5–7 mSv)

4. No uptake in chronic degenerative bone disease

5. Quantitative and automatic semiquantitative analysis of uptake in the lesions

Based on the overall considerations reported in this chapter and on the current strategy of treatment for PCa patients, in closing this chapter, the author proposes a flow chart including a reasonable approach for the management of PCa patients, according to the state of the art of general knowledge on the diagnostic and therapeutic armamentarium currently available. (Fig. 12).
Fig. 12

A suggested diagnostic flow chart for patients with PCa. TRUS transrectal ultrasonography, MRI magnetic resonance imaging, CT computed tomography, BS bone scintigraphy, PSMA 68Ga-PSMA-ligand PET/CT

Notes

Aknowledgments

The authors are grateful to Dr. Thomas A. Hope, Department of Radiology and Biomedical Imaging, University of California (USA), for his scientific contribution and to Ms. Annaluisa De Simone Sorrentin for her kind editorial assistance.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Emilio Bombardieri
    • 1
    • 2
    Email author
  • Maria Grazia Sauta
    • 3
  • Lucia Setti
    • 2
  • Roberta Meroni
    • 4
  • Gianluigi Ciocia
    • 2
    • 5
  • Laura Evangelista
    • 6
  1. 1.Department of Nucleare MedicineHumanitas Gavazzeni HospitalBergamoItaly
  2. 2.Nuclear Medicine Unit“Humanitas Gavazzeni” HospitalBergamoItaly
  3. 3.Oncology Unit“Humanitas Gavazzeni” HospitalBergamoItaly
  4. 4.Radiology Unit“Humanitas Gavazzeni” HospitalBergamoItaly
  5. 5.Radiotherapy Unit“Humanitas Gavazzeni” HospitalBergamoItaly
  6. 6.Nuclear Medicine and Molecular Imaging UnitVeneto Institute of Oncology IOV - IRCCSPaduaItaly

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