University of Groningen Exploring new molecular imaging concepts of prostate cancer Wondergem, Maurits

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University of Groningen

Exploring new molecular imaging concepts of prostate cancer

Wondergem, Maurits

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PROSTATE CANCER

In Western and Northern Europe, North America, Australia and New Zealand prostate cancer is the most common cancer in men. A lower incidence is reported in other parts of the world, however in recent years the incidence and mortality rate of prostate cancer in some economically developing Asian countries have grown rapidly (1). Incidence of prostate cancer in the Netherlands doubled in two decades, from 4300 per year in 1990 to approximately 10.000 newly diagnosed patients in 2010 (2). In terms of mortality prostate cancer is the third most lethal cancer in man after lung cancer and colorectal cancer with over 2500 deaths in the Netherlands every year since 2010. Both incidence and mortality rate remained more or less stable since 2010.

Except for its high incidence and mortality rate, prostate cancer is also challenging because of its heterogeneous character. This heterogeneity results in a wide spectrum of clinical presentations ranging from patients that are diagnosed with prostate cancer for which they will never need intervention during their life time to patients with rapidly progressive disease, who die within a year after diagnosis (3, 4). For clinicians it is challenging to apply optimal treatment at the right moment to the right patient. Expected profit of treatment options is highly dependent from the stage of the disease. Different tools, including clinical characteristics, biochemical measurements, pathological examinations and medical imaging, are available to get insight in the stage of the disease and help clinicians’ decision-making.

The main tools to diagnose prostate cancer include digital rectal exam, serum concentration of prostate specific antigen (PSA), and transrectal ultrasound guided biopsy (5-8). As for most other cancers, after diagnosis prostate cancer is staged by the TNM-classification, for which the 7th_{edition is currently in use (9) (Table 1). The}

T-status is used to characterize the primary tumour, which may grow locally within the prostate or may directly invade structures and organs in the direct vicinity. In common clinical practice T-status is determined by one or more tools, including: digital rectal exam, needle biopsy and magnetic resonance imaging (MRI) (10). The N-status indicates presence or absence of lymph node metastases in the true pelvis, which are considered loco-regional metastases. Presence of distant lymph node metastases out-side the true pelvis or other metastases are reflected in the M-status. Clinical T-status, serum PSA levels and Gleason score of the primary tumour are used to estimate the risk on presence of local-regional and distant metastases. Patients with Gleason 7 tumours or PSA between 10-20 ng/ml have intermediate risk prostate cancer. Those with cT3 tumours or Gleason ≥8 tumours or PSA ≥20 ng/ml and those with Gleason 7 tumours and PSA between 10-20 ng/ml are considered high risk. All others are considered low risk. High risk may indicate the necessity for further diagnostic tests, including imaging modalities such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), different nuclear medicine imaging techniques including planar scintigraphy or Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET) and hybrid imaging modalities which combine SPECT or PET with CT or MRI (11-16).

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Also pelvic lymphadenectomy may be performed in intermediate and high-risk patients and this surgical approach combines diagnosis and treatment of pelvic lymph node metastases (10).

Table 1. American Joint Committee on Cancer Prostate Cancer Staging, TNM 7th_Edition

Primary Tumour (T) Clinical

TX Primary tumour cannot be assessed T0 No evidence of primary tumour

T1 Clinically inapparent tumour neither palpable nor visible by imaging

T1a Tumour incidental histologic finding in 5% or less of prostate tissue resected (for other

reasons)

T1b Tumour incidental histologic finding in more than 5% of prostate tissue resected T1c Tumour identified by needle biopsy (for example, because of elevated PSA) T2 Tumour confined within prostate

T2a Tumour involves one-half of one-lobe or less

T2b Tumour involves more than one-half of one lobe but not both lobes T2c Tumour involves both lobes

T3 Tumour extends through the prostate capsule

T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s)

T4 Tumour is fixed or invades adjacent structures other than seminal vesicles, such as external

sphincter, rectum, bladder, levator 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(s) Distant Metastasis (M)

MX Distant metastases were not assessed 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

Detection and localisation of metastases is an important aspect in guidance of prostate cancer treatment at different stages of the disease. The presence of advanced metastasis at clinical presentation will withhold the patient from strategies with curative intent, while local, loco-regional or oligometastatic disease may be targeted with aggressive therapies with curative potential. Although most patients diagnosed with prostate cancer in economically developed countries have clinically localised prostate cancer and are treated with treatments with curative intent such as radical prostatectomy or external beam radiation therapy, many of those patients will eventually have biochemical recurrence (10). At this stage imaging modalities, especially PET/CT with different tracers including 11_C-choline,18_{F-fluorocholine or PSMA targeted tracers, are used in present}

clinical practice to indicate the extent of disease. In case of localised, locoregional or limited distant metastases salvage therapeutic options with curative intent, such as salvage radiation therapy or salvage lymphadenectomy, may be indicated (10, 17).

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Table 2. Overview of radiopharmaca studied in this thesis. Chemical name, Molecular formula,

2D-structure and 3D-model

Tracers of bone remodelling Tracers of tumour cells

3D-model legend. White: Hydrogen, black: Carbon, blue: Nitrogen, red: Oxygen, green: Fluorine, purple: Sodium, orange: Phosphorus and dark cyan blue: Technetium.

Subsequently most of them will progress and receive androgen deprivation therapy in a palliative setting (17). Serum PSA and imaging modalities, most commonly bone scintigraphy with 99m_{Tc-phosphonates (BS) or PET/CT with}18_{F-sodiumfluoride (NaF) are}

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castrate levels of testosterone, most patients will progress to develop castrate resistant prostate cancer. At this stage, different systemic agents such as docetaxel, abiraterone, enzalutamide and carbazitaxel and the alpha-emitting radioisotope 223_{Ra may be used}

to prolong life expectancy and treat symptoms of which bone pain is most prevalent

(18-21). Other symptomatic treatments include radioactive bone tracers as 188_Re-HEDP, 153_{Sm-EDTMP or}89_{Sr-strontiumchloride and external radiation therapy. At this stage}

serum PSA and imaging, most commonly imaging of bone metastases, are used for treatment planning and follow-up (22, 23). Progression of disease may result in a switch between available systemic agents or 223_Ra.

Early metastatic disease most commonly comprises haematogenous spread to the skeleton and/or lymphogenic spread to lymph nodes. Therefore diagnosis of prostate cancer metastases is most frequently targeted at detection of bone and/or lymph node metastases (24, 25). In more advanced disease metastases in lungs, liver, pleura and adrenals may be encountered and in rare occasions metastases are found in the brain, breasts, eyes, kidneys, muscles, pancreas, salivary glands and spleen.

This thesis is aimed at nuclear medicine techniques that are useful in detection of prostate cancer lesions. Amongst others those techniques include BS, NaF PET/CT,

11_{C-choline or}18_{F-fluorocholine PET/CT and PET/CT with tracers that target the prostate}

specific membrane antigen (PSMA) which are commonly labelled with 68_{Ga or}18_F

(Table 2).

NUCLEAR MEDICINE IMAGING

In short, nuclear medicine uses non-invasive imaging techniques that can visualize the distribution of radioactive tracers within a living body. A tracer is a molecule or ligand that can be measured and which resembles a molecule that is biologically active in physiological or pathological processes. The administered dosage of a tracer is very low and interference with biological processes in the body does not occur. In nuclear medicine tracers for imaging are labelled with isotopes that either emit gamma-rays (γ-rays) or positrons (β+_{). Gamma-rays can be measured by an Anger gamma camera,}

which provides planar images or SPECT images (26). Positrons are emitted from the nucleus of a radioactive isotope with a certain velocity; first they will lose all their kinetic energy by interactions with their surroundings after which the positron annihilates with a nearby electron. At annihilation the mass of both the positron and electron are transformed into two gamma photons of 511 keV, which will be emitted at almost 180 degrees of each other (27). Those photons may be measured using Anger gamma cameras, however PET-cameras are normally used since those cameras can localise the positron source along a straight line of coincidence. Moreover, the crystals used in these cameras are more appropriate for detection of photons with relatively high energies such as 511 keV (27). The use of PET cameras results in higher photon detection yield,

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which in combination with better localisation of the source of the emitted photons, results in higher quality images as compared to planar scintigraphy or SPECT. Hybrid imaging, which synergises the information of distribution of biologically active tracers from PET or SPECT with anatomical information of CT, has become standard of care for many disorders in oncology, cardiology, orthopaedics and neurology in the past decade (28, 29).

For prostate cancer different nuclear imaging techniques and tracers can be used to assess the extent and localisation of the disease. Depending on the course of the disease and the estimated risk on lymph node or bone metastases, different tracers are used. Some of them only show the secondary process of bone remodelling due to metastatic infiltration in the bone matrix while others show the localisation of tumour cells themselves.

Imaging bone remodelling

From a historical point of view it makes sense to discuss tracers that enable imaging of bone matrix remodelling first. Already in the early 1920s it was recognised that certain radionuclides had the property to accumulate in bone. It was demonstrated that ingested salts by painters of luminous watch dials were concentrated in the bone. Metabolic studies of a wide variety of radionuclides were commenced in the 1930s, including 32_{P orthophosphate,}18_F,45_{Ca and}89_{Sr and}87m_{Sr. Clinical studies indicated}

that bone imaging with 89_{Sr or}87m_{Sr was capable of detecting bone lesions well before}

radiological changes became apparent (30-32). Better results were found with 18_{F in}

the 1960s, due to faster blood clearance and improved skeletal visualisation (33). As a result of the ideal imaging properties of 99m_{Tc for imaging with an Anger gamma-camera,}

which at that time was widely used for other nuclear medicine procedures, and the known effect of phosphonates in the treatment of bone disorders, the search for a bone-seeking tracer was centred on a 99m_{Tc-labelled phosphate complex agent. Many}

bisphosphonates have undergone extensive evaluation and comparison, but because of more rapid blood clearance and higher skeletal affinity 99m_{Tc-methylene diphosphonate}

(99m_{Tc-MDP) and later}99m_{Tc-hydroxymethylene diphosphonate (}99m_{Tc-HDP) became the}

most widely used agents in routine clinical bone scintigraphy (34).

The wide availability and technical improvements of PET/CT cameras after the introduction of 2-deoxy-2-(18_{F)fluoro-D-glucose (FDG) in standard medical imaging from}

the late 1980s and the increased knowledge of the only moderate accuracy of 99m_Tc-MDP

and 99m_{Tc-HDP bone scans resulted in renewed interest in}18_{F, which is a positron emitter,}

as a bone tracer in medical imaging. Improvement of sensitivity was expected due to better image quality of PET techniques including higher spatial resolution, and favourable pharmacokinetics of 18_{F with higher target-to-non-target ratios. Implementation of}

hybrid PET/CT cameras, which enable better anatomical identification of lesions and as a result better discrimination between benign and malignant processes, were expected to improve specificity, but did not reach the market before the turn of the millennium.

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99m_{Tc-diphosphonates}

For decades 99m_{Tc-MDP and}99m_{Tc-HDP have been the most commonly used tracers for}

bone imaging (35). Those tracers consist of 99m_{Tc-diphosphonates complexes (Table 2),}

which are administered intravenously. A substantial degree of those complexes binds to plasma-proteins, increasing in time from around 25% immediately after injection to 50% at 1 hour (36-38). This results in relatively slow bloodpool clearance, slow accumulation in the bone matrix and slow renal excretion. Four hours after injection about 50-60% of the injected amount is accumulated and bound in the bone matrix of the skeleton, 34% is excreted in the urine and only 6% remains in the circulation. Delayed images for detection of bone metastases are commonly acquired from 2 up to 5 hours after intravenous injection, which fits with the half-life of 6.02h of 99m_{Tc emitting one 140.5}

keV gamma ray per decay (35). Typically administered activities usually range between 8 – 10 MBq/kg.

Skeletal uptake of 99m_{Tc-MDP and}99m_{Tc-HDP depends on local blood flow and osteoblastic}

activity but does not reflect the true tumour burden in the bone marrow. Prostate cancer cells in the bone matrix induce a complex biochemically interaction with osteoblasts and osteoclasts resulting in remodelling of the bone matrix and the formation of new hydroxyapatite (39-41). Increased osteoblastic activity results in increased accumulation of 99m_{Tc-MDP and}99m_{Tc-HDP in the vicinity of prostate cancer cells. The nature of the}

actual complex that reacts with bone and the mechanism of uptake into the bone mineral remain unclear. It is postulated that 99m_{Tc-biphosphonate complexes adhere}

to the bone mineral surface of newly formed hydroxyapatite intact or that they may fall apart to allow separate binding of the diphosphonate component and the reduced pertechnetate (42).

Physiologic uptake of 99m_{Tc-MDP and}99m_{Tc-HDP is seen in osseous structures, kidney}

and bladder. A wide spectrum of both malignant and benign lesions may be diagnosed by increased uptake of the tracer. Also soft tissue uptake is seen in a variety of non-osseous disorders including neoplastic, hormonal, inflammatory, ischemic and traumatic entities (43).

18_{F-sodiumfluoride}

NaF is administered intravenously as a solution of the saline sodium fluoride (Na+ 18_F-_{) (Table 2) and only the}18_F-_{ion is the tracer of bone remodelling. However in the}

continuation of this thesis the tracer will be addressed as NaF, as is common in recent medical literature. Rapidly around 30% of the injected NaF is found in erythrocytes due to free diffusion across membranes (44). Almost all NaF is retained in the bone after a single pass of blood (45). The initial distribution of NaF therefore represents blood flow, which varies among different bones (46). NaF is rapidly cleared from the plasma and harboured within bone or excreted by the kidneys. Only 10% of the injected amount is found in the plasma one hour after injection (47). As a result image acquisition of

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the axial skeleton may start about 30-45 minutes after administration, which is ideal concerning the 110 minutes half-life of 18_{F (48). The administered activity for adults}

commonly ranges between 185-370 MBq.

The mechanism of skeletal uptake of NaF is based on ion exchange, probably in the same manner as 99m_{Tc-MDP and}99m_{Tc-HDP is incorporated in the bone matrix.}18_F-_ions

exchange with hydroxyl ions (OH-_{) on the surface of newly formed hydroxyapatite by}

osteoblasts (47, 49, 50). Concentrations of NaF can be up to 10 times higher in areas of bone remodelling, compared with areas of normal bone (33).

Physiologic NaF uptake resembles uptake of 99m_{Tc-MDP and}99m_{Tc-HDP and is found in}

osseous structures, kidney and bladder. Normal physiologic osseous uptake in adults is generally uniform. Mechanisms leading to increased uptake are not limited to neoplastic processes and include any process of bone remodelling (51). As a consequence NaF can visualise the same variety of osseous diseases as 99m_{Tc-MDP and}99m_{Tc-HDP. Non-osseous}

uptake of NaF can be observed in the arterial vasculature, gastrointestinal tract and genitourinary tract. Vascular activity is mainly due to atherosclerotic calcification (52,

53). Lesions containing calcifications such as calcified visceral metastases may show NaF

uptake (54). Occasionally NaF activity is seen in the bowel. The exact uptake mechanism is unclear, however protein losing enteropathy has been suggested as a cause of bowel activity (55).

Imaging tumour cells

Different cellular pathways or characteristics may be upregulated in prostate cancer cells and serve as a target for diagnostic imaging. At present 18_{F-fluorodeoxyglucose (FDG) is}

most commonly used in oncology. The use of glucose is increased in a large number of malignancies as a result of an increased metabolic rate of the tumour cells (56, 57). However the role of FDG for detection of primary disease and metastases in prostate cancer is limited, due to relatively low avidity of prostate tumours for FDG resulting in low sensitivity and due to overlap of FDG uptake intensity with benign entities including benign prostatic hypertrophy and prostatitis (58-60). As a consequence tracers that target other cellular pathways, cellular receptors or transmembrane proteins have been developed, including lipid metabolism, amino acid metabolism, androgen receptor, prostate specific membrane antigen inhibitors/antibodies, cellular proliferation, gastrin releasing peptide receptor expression and gene-mediated imaging (Table 3) (61-71). At present the majority of those tracers have no or limited clinical application and are beyond the scope of this thesis. 11_C-choline,18_{F-fluorocholine and tracers that target}

the prostate specific membrane antigen are becoming integrated in standard clinical practice, and are further introduced in the next paragraphs.

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PET tracer Mechanism

11_C-choline,18_{F-fluorocholine,}11_{C-acetate or}

18_{F-fluoroacetate} Lipid metabolism 18_F-FACBC,11_C-methionine _{Amino acid transport}

18_F-FDHT _{Androgen receptor}

18_F-DCFPyL,18_F-DCFBC,68_{Ga-PSMA-compounds:}

for example 68_{Ga-PSMA-HBED-CC} PSMA inhibitors/antibodies 18_F-FLT,18_F-FMAU _{Cellular proliferation}

18_F-NaF _{Bone remodeling}

68_{Ga-bombesin analogues} _{Gastrin releasing peptide receptor expression} 18_{F-FACBC: anti-1-amino-3-}18_{F-fluorocyclobutane-1-carboxylic acid}

18_{F-FDHT: 16β-}18_{F-fluoro-5α-dihydrotestosterone}

18_{F-DCFPyL: 2-(3-(1-carboxy-5-[(6-[}18_{F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic}

acid

18_{F-DCFBC: N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-}18_{F-fluorobenzyl-L-cysteine} 68_{Ga-PSMA-HBED-CC: Glu-NH-CO-NH-Lys-(Ahx)-[}68_Ga(HBED-CC)]

18_F-FLT:18_{F-3’-deoxy-3’-fluorothymidine}

18_F-FMAU:18_{F-20-fluoro-5-methyl-1-b-D-arabinofuranosyluracil} 18_F-NaF:18_{F-sodiumfluoride}

11_{C-choline and} 18_{F-fluorocholine}

In the 1970s research had been directed to the development of low molecular weight tracers for imaging of biochemically active substrates that play an active role in the biosynthesis of cell constituents, such as proteins, nucleic acids, and lipid derivatives. Choline, a small molecule involved in many cellular functions, was identified as a substrate of interest. Choline homeostasis is altered in different malignancies, probably as a result of increased proliferation of membrane lipids in actively replicating tumours. Increased choline kinase activity and increased choline concentration was found in brain tumours and later on also in other tumours such as lung, colorectal and prostate tumours (72-78).

Radiolabelled choline was first synthesised as 14_{C-choline in the early 1980s, however}

due to unfavourable emission properties, including the 14_{C half-life of approximately}

5730 years, 14_{C-choline was unsuitable for medical imaging (79). As a result}11_C-choline

PET/CT was designed and synthesised for imaging of brain tumours and a few years later 18_{F labelled choline tracers were synthesised, which allowed widespread use}

of choline tracers, also in medical centres without access to a cyclotron facility (Table 2) (80-82).

In prostate cancer choline cellular uptake is a result of both an active transporter-mediated and a passive diffusion-like component (83). The definite mechanism leading to intracellular accumulation and trapping of choline is still unknown. Whether tracer uptake is related to increased synthesis of membrane phosphocholine in tumour cells with high turnover or to cellular proliferation has been investigated, which yielded inconclusive results (84-87).

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The biodistribution of 11_{C- choline and}18_{F-fluorocholine show great resemblance and}

both show a rapid blood clearance and rapid uptake in prostate cancer cells (88). Physiological accumulation is seen in lacrimal glands, salivary glands, liver, spleen, pancreas, small intestine, colon, muscle and bone marrow (89, 90). A larger portion of 18_{F-flurocholine, as compared to}11_{C-choline, is excreted in the urine, which may}

interfere with detection of the primary tumour (81, 82). Increased choline uptake is seen in different malignancies including hepatocellular cancer, lung cancer, breast cancer, lymphomas, brain tumours, melanoma, colon cancer, bladder cancer and multiple myeloma (91). Also benign processes may show increased choline uptake such as a wide variety of infections and inflammations as well as meningioma, benign thyroid nodule, parathyroid adenoma, thymoma, adrenal adenoma, Morbus Paget and posttraumatic bone injury (89, 91, 92).

Prostate specific membrane antigen targeted tracers

Lack of specificity of conventional imaging techniques for prostate cancer has encouraged screening of prostate cancer cells for possible antigens to develop agents capable of specific binding. This resulted in the development of monoclonal antibodies (mAbs) to target PSA and prostatic acid phosphatase (PAP) (93). However, secretion of those antigens preclude cell-associated binding and presence of PSA and PAP in the plasma effectively blocks specific antibody binding at the tumour site. Later PSMA was discovered, which is a 750 amino acid transmembrane protein and a highly specific prostate epithelial cell membrane antigen (94-96). Physiological expression of PSMA is 100-1000 fold less than typical expression in prostate cancer, and expression increases as tumour grade increases with concurrent increase in metastatic sites and castrate refractory prostate cancer (CRPC) (97, 98). Furthermore, PSMA is internalised and endosomally recycled, which increases the deposition of these radiopharmaceuticals into the cell over time (99).

In 2006 111_{In-capromab, a mAb for targeting PSMA, was reported. However this tracer}

has a poor efficacy associated with binding to the intracellular domain of PSMA, which results only in binding to nonviable cells that have damaged cell membranes (100). A few years later mAbs targeting the extracellular domain of PSMA were reported. Due to their relatively large mass these ligands show slow clearance from background and slow target recognition, prohibiting their success as radiopharmaceuticals for imaging, since these are preferably administered and subsequently used for imaging on the same day. Furthermore radiopharmaceuticals require superior safety profiles. mAbs have potential side effects including allergic reactions, which is another disadvantage

(101-103). From the late 2000s small molecule PSMA inhibitors, which are approximately 350

fold smaller than mAbs, have been reported (104-108). Those tracers have rapid target recognition and background clearance and no adverse effects have been reported. Most of these tracers targeting PSMA are glutamate-urea-lysine analogues (109).

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PSMA-tracer kinetics show that, after intravenous injection, the tracer accumulates in prostate cancer cells over time while background activity decreases (110-114). Physiological accumulation of PSMA tracers occurs in lacrimal glands, salivary glands, liver, gall bladder, spleen, small intestine, colon, paravertebral ganglia and coeliac ganglia. Besides prostate cancer increased PSMA expression is demonstrated by other malignant diseases including renal cell carcinoma, adenoid cystic carcinoma of the salivary gland, differentiated thyroid cancer, urothelial cancer, lung cancer, colon cancer, oesophageal cancer and brain tumours (115-120). In some of those malignancies PSMA may be expressed directly at the tumour cell membranes, however in most cases PSMA expression in found in the neovasculature of the tumour. Increased accumulation of PSMA may also be seen in benign entities such as degenerative bone diseases, bone fractures, Morbus Paget, Schwannoma, haemangioma, adrenal adenomas, benign thyroid nodules, sub-acute brain infarction and pleural fluid (121-126).

At the moment, a large variety of PSMA tracers are available for clinical use, most of which are labelled with 68_{Ga. However there is an increasing interest in}18_{F labelled}

PSMA-tracers (Table 2) as a result of favourable physical and imaging characteristics. Positrons emitted by 18_{F decay have lower kinetic energies as compared to those}

emitted by 68_{Ga, which results in higher resolution PET images acquired using}18_F-tracers.

Furthermore the 110-minute half-life of 18_{F compared to 68 minutes for}68_{Ga enables}

imaging at later time points without significant deterioration of image quality or the need for administration of higher dosages.

NUCLEAR MEDICINE IMAGING IN PROSTATE CANCER ACCORDING TO PRESENT

GUIDELINES

Primary staging

According to present guidelines use of nuclear medicine imaging is, at this stage, only recommended for detection of bone metastases and only in cases with significant risk on bone metastases. BS, which has been applied for decades, is indicated at initial staging in a selection of patients with a high pre-test likelihood of having bone metastases. Those include patients with PSA ≥ 20 ng/ml, clinical stage 3 tumour (T3) or Gleason score ≥ 8 according to the Dutch and European guidelines (10, 127). The Dutch guidelines state that NaF, 11_{C-choline or}18_{F-choline PET/CT may substitute BS according to}

local availability.

Biochemical relapse after treatment with curative intent

The Dutch guidelines state that 11_{C-choline PET/CT or}18_{F-fluorocholine PET/CT can be}

used in this patient category provided that there is a reasonable chance on a positive scan which is indicated by a PSA > 5.0 ng/ml or a PSA > 1.0 ng/ml together with a PSA doubling time < 3 months or a Gleason score ≥ 8. 99m_{Tc-phosphonate BS for detection of}

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bone metastases may be indicated in case of a biochemical relapse if the PSA ≥ 20 ng/ ml or in case of bone pain. BS may be substituted by NaF, 11_{C-choline or}18_{F-choline PET/}

CT according to local availability (127).

The European guidelines state that imaging such as 11_{C-choline PET/CT should only be}

performed if therapeutic consequences such as salvage lymphadenectomy or salvage RT to lymph nodes are being considered as a therapeutic option. A PSA doubling time less than 3 months can certainly be regarded as a strong predictor of PET positivity as does a PSA serum level >1.5 ng/ml (17).

Follow-up of metastasised disease

Both Dutch and European guidelines give no recommendations on the use of imaging at this stage of the disease.

AIM AND OUTLINE OF THE THESIS

As described above a lot of new tracers for use in nuclear medicine have been developed in the last decades and some of them found their way into standard clinical practice. Once available for use in patients, insights in clinical aspects including diagnostic accuracy, optimal patient preparation and optimal acquisition parameters, such as acquisition timing after tracer administration, are needed before tracers can be incorporated in standard of care. This thesis aims to elucidate some of these aspects for tracers that recently became available. In the first chapters the scope is mainly fixed at detection of bone metastases, while the remaining chapters are focussed at tracers that enable detection of both bone and soft tissue lesions.

In chapter 2 contemporary literature on the diagnostic accuracy of NaF, 11_{C-choline and} 18_{F-flurocholine PET/CT for detection of bone metastases in prostate cancer patients is}

reviewed systematically using the Oxford Criteria. Available data is pooled and pooled sensitivities and specificities for 11_{C-choline and}18_{F-fluorocholine together and NaF are}

calculated on a per patient and a per lesion basis.

In chapter 3 the diagnostic accuracy and clinical impact of BS with 99m_{Tc-HDP and NaF}

PET/CT is studied in an observational cohort study. Both cohorts consisted of patients primarily staged for high-risk prostate cancer. Additionally, for NaF PET/CT the added value and its impact on management of CT findings, especially detection of enlarged lymph nodes, are analysed.

In chapter 4 the scope is switched to 18_{F-fluorocholine. The kinetics of}18_{F-fluorocholine}

in malignant as well as normal tissues are studied in order to identify imaging characteristics that differentiate malignant from normal lymph nodes and malignant bone lesions from normal bone marrow uptake. The findings are used to optimise timing of acquisition after tracer administration.

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In chapter 5 the impact of fasting for at least 6 hours prior to intravenous 18_{F-fluorocholine}

administration on gastrointestinal uptake and detection of lymph node metastases is investigated.

In chapter 6 we studied whether early dynamic imaging of the prostatic region with

18_{F-fluorocholine PET/CT increased the detection rate of local prostate cancer recurrence}

in patients with a biochemical relapse after radical prostatectomy.

In chapter 7 the scope is switched again to another tracer; the PSMA targeting tracer

18_{F-DCFPyL. Effects of activity kinetics on the detection rate of prostate cancer lesions,}

image quality and biodistribution are studied at 60 and 120 minutes after intravenous administration of the tracer.

In intermezzo 1 a case is reported with high 18_{F-DCFPyL uptake in bilateral adrenal}

adenomas in a patient with rising PSA-serum values while on Luteinizing Hormone-Releasing Hormone agonist therapy.

Future perspectives and conclusions are described in chapter 8.

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