Eanm 2018 Techguide Online
Eanm 2018 Techguide Online
CANCER
IMAGING AND
THERAPY
A TECHNOLOGIST’S GUIDE
Introduction 6
Luca Camoni
*Articles were written with the kind support of and in cooperation with the
Foreword
Individualised medicine and tailored treatment solutions are nowadays
unimaginable without diagnostic imaging. The development and
implementation of disease-specific tracers within nuclear medicine has
impacted on patient clinical management and positively affected the
lives of thousands of patients all over the globe.
of the nuclear medicine vision regarding of this book could not have been realised.
prostate cancer, from anatomy to clinical From overseas my gratitude extends to the
tracers, with consideration of both con- Society of Nuclear Medicine and Molecular
ventional nuclear medicine and PET/CT Imaging Technologist Section (SNMMI-TS)
and both fluorine-18 and non-fluorine-18 and I would also like to thank the European
tracers. The role of nuclear medicine with Society of Radiotherapy & Oncology (ES-
respect to external radiotherapy is also TRO) Radiation Therapist (RTT) Committee
discussed in this TG, as are a range of ther- for their valuable contribution.
apeutic and theranostic applications. Like- Lastly, I am very much indebted to the
wise, patient-focussed practice and trans- EANM-TC editorial group, to Rick Mills for
lational medicine chapters are presented. copyediting assistance and to the EANM
I would like to express my gratitude for the Board and Executive Office for their con-
collective effort of all authors who partici- tinuous support on one of the most signif-
pated in this publication. Special thanks are icant and well-received projects to origi-
due to the EANM Technologist, Oncology, nate from our committee.
Radiopharmacy, Dosimetry and Transla-
tional Molecular Imaging & Therapy Com-
mittees involved in this venture, without Pedro Fragoso Costa
whom the truly multidisciplinary nature Chair of the EANM Technologist Committee
Introduction
Prostate cancer is the second most common cancer in men
worldwide. Due to increasing life expectancy and the introduction
of more sensitive diagnostic screening techniques, prostate
cancer is being diagnosed more frequently, with rapidly increasing
incidence and prevalence. It has a wide spectrum of biological
behaviour, ranging from indolent low-risk disease to highly
aggressive castration-resistant prostate cancer.
Nuclear medicine imaging plays a key role and hybrid SPECT/CT. The following two
in this heterogeneous disease as it can chapters provide an overview on pro-
answer key clinical questions at various tocols and the diagnostic value of PET/
phases of the disease, the imaging being CT imaging using fluorine-18 and other
tailored to each phase. Nuclear medicine non-fluorine-18 radioisotopes labelled
has demonstrated efficacy for cancer de- with different molecules. PET/CT is a use-
tection, with an increasing number of po- ful tool for guided radiotherapy planning;
tential targets for imaging and treatment. consequently the sixth chapter describes
The first chapter of this book describes the acquisition and reconstruction proto-
the prostate’s anatomy, physiology and col for the purpose of radiotherapy. One of
pathology. The radiopharmaceuticals that the most recent developments in nuclear
allow study or treatment of prostate cancer medicine is theranostics: the seventh chap-
are discussed in the subsequent chapter. ter reviews the state of the art, describing
Conventional nuclear medicine represents the use of theranostic pairs and quantita-
a cost-effective resource in the manage- tive analysis of tissue and tumour uptake
ment of prostatic disease, and the third in optimisation of patient treatment. The
chapter documents the specific imaging eighth chapter broadens the vision of the
procedures for diagnostic planar imaging field of therapy, adding treatment based
by Lucia Zanoni,
Cristina Nanni and
Stefano Fanti
1
CHAPTER 1
INTRODUCTION
The prostate is a glandular and muscular structure positioned immediately
PAT H O LO GY O F TH E PR O S TATE
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below the neck of the bladder and around the commencement of the
urethra. It is located within the pelvic cavity, below the inferior margin of
the symphysis pubis and above the triangular ligament, anterior to the
rectum. Its base is below the neck of the bladder and is directed upwards,
whereas the apex touches the ligament and is directed downwards. Its
posterior surface is close to the second part of the rectum, whereas its
anterior surface is connected to the pubis by puboprostatic ligaments.
The lateral surfaces are in contact with the levator ani muscles[1].
The prostate consists of two lateral lobes, systemic steroid hormone signals, local
equal in dimension, and a third middle paracrine signalling pathways and cell
lobe, which lies in the central posterior autonomous factors. The prostate is an
region. It is surrounded by a thin, fibrous exocrine gland whose role is part of the
capsule separated by a plexus of veins male reproductive function in mammals.
from the rectovesical fascia. Immediately The mouse has emerged as the most im-
below the capsule, there is muscular tis- portant model system for investigation of
sue, which is also seen around the ure- prostate organogenesis. The first steps in
thra. The prostate derives its arterial sup- prostate development are the male-spe-
ply from the internal pudic, vesical and cific molecular and morphological chang-
haemorrhoidal arteries, while the venous es in the urogenital sinus, the embryonic
drainage starts from the dorsal vein of the precursor of the prostate in males and
penis and terminates into the internal iliac precursor of part of the vagina in females.
vein. The nerve supply of the prostate is Organ determination is mediated by
from the pelvic plexus (inferior hypogas- male-specific gene expression changes in
tric plexus). The intraprostatic portion of the urogenital sinus in response to andro-
the urethra is the most dilatable part of gen signalling. Epithelial budding is the
the canal[2]. first morphological step in prostate de-
velopment, in which cords of undifferen-
tiated epithelial cells from the urogenital
DEVELOPMENT AND sinus epithelium invade the surrounding
PHYSIOLOGY urogenital sinus mesenchyme. Following
Prostate development occurs through a budding, the developing prostatic buds
series of sequential steps dependent on elongate via proliferation at the distal
bud tips. Lumen formation also occurs in stimulating hormone-releasing factor and
PAT H O LO GY O F TH E PR O S TATE
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proximal (adjacent to the urethra) to distal prolactin inhibiting factor) and thus con-
fashion to form prostatic ducts. Prostatic trols the synthesis and release by the pitu-
ducts then undergo multiple rounds of itary of various gonadotropins (luteinising
branching morphogenesis during the de- hormone, follicle stimulating hormone)
velopment process. that influence the production of testoster-
Unlike the prostate in mice, the human one by the testes. The majority of testos-
prostate is not organised into discrete terone production in adult human males
lobes; it also has a different tissue organ- derives from the testes and it plays a cru-
isation, with epithelial ducts surrounded cial role in prostatic growth and physiolo-
by a dense and continuous fibromuscular gy. A further, though minor role is played
stroma. Early molecular studies identified by the adrenal cortex through its steroid
several paracrine signalling pathways as production. Moreover, prolactin produced
playing key roles in prostatic develop- by the adenohypophysis has a direct effect
ment, including components of the trans- on the prostate[6].
forming growth factor beta, fibroblast
growth factor, bone morphogenetic pro-
tein, insulin-like growth factor and sonic ANATOMY
hedgehog pathways. Further early studies McNeal divided the prostate into three ma-
involved transcription factors, including jor areas that are histologically distinct and
the androgen receptor, homeobox genes anatomically separate: the non-glandular
and Nkx3.1. Various differentiated epithe- fibromuscular stroma and two glandular
lial cell types are present within the adult regions called the peripheral and central
prostate (i.e. luminal, basal and relatively zones that contain a complex and histo-
rare neuroendocrine cells). Androgens and logically distinct ductal system (Fig. 1).
androgen receptors are critical for normal The anterior fibromuscular stroma is a
prostate development, and they function band of fibromuscular tissue anterior to
in the normal adult prostate to maintain the transition zone, contiguous with the
organ integrity and the expression of pros- bladder smooth muscle and the skeletal
tate-specific secretory proteins[3–5]. muscle of the sphincter and continuous
A crucial role in the hormonal regulation with the pseudocapsule. It covers the ante-
of the prostate is played by the hypothala- rior and anterolateral surfaces of the gland
mus, which produces releasing factors (lu- and comprises dense irregular connective
teinising hormone releasing factor, follicle tissue with a large amount of smooth mus-
Figure 1
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cle fibres interposed with adjacent skele- ing the ejaculatory ducts. It is most prom-
tal muscle fibres of the urethra. inent at the base of the prostate and has
The central zone is a layer of tissue that a conical shape. Embryologically, it origi-
surrounds the ejaculatory ducts from the nates from the wolffian duct. It accounts
level of the prostatic base down to the ver- for 25% of the total prostate volume but
umontanum. The central zone ducts run almost 40% of the epithelium owing to
predominantly proximally, closely follow- its high epithelial-to-stromal ratio; how-
ever, after the age of 35 years its volume true prostate capsule surrounds the periph-
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decreases gradually. Compared with the eral zone.
peripheral zone, the glands of the central The neurovascular bundles are located
zone are larger and more complex, with postero lateral to the prostate bilaterally
much denser and more compact stroma. and penetrate into the prostate at the apex
Central zone cancers are rare, accounting and base. They consist of cavernous nerves
for 0.5%–2.5% of all prostate cancers and for erectile function, arterial branches of
3%–8% of index tumours, but are usually the inferior vesicle artery and veins. In the
associated with a higher risk. setting of cancer, they provide a route for
The peripheral zone constitutes the re- extraprostatic spread of malignancy[7].
mainder of the gland, surrounding most of The periprostatic venous plexus (also
the central zone and extending inferiorly known as the Santorini venous plexus) is
to partially surround the distal tract of the contiguous to the pseudocapsule of the
urethra. It is a derivative of the urogenital prostate and lies mainly anterior and later-
sinus. Its ducts exit directly laterally from al to the gland. The calibre of the veins var-
the posterolateral recesses of the urethral ies and is usually larger in younger patients
wall. The system consists of ducts and and smaller glands.
acini that are lined with simple columnar The periprostatic lymph nodes are not
epithelium. This area represents the main common, being detected in 4.4% of radi-
site of origin of prostatitis and prostate cal prostatectomy specimens. Most com-
cancer, although not of benign prostatic monly they are located at the base of the
hyperplasia (BPH). It includes the proximal prostate laterally or posterolaterally. Ma-
urethral segment of the prostate, between lignant involvement of the periprostatic
the base of the urinary bladder and the lymph nodes has been documented in
verumontanum (the area where the ejac- 15% of patients who undergo radical pros-
ulatory ducts feed into the urethra). This tatectomy[8].
small region also includes the preprostatic
sphincter, a cylindrical sleeve of smooth
muscle which extends from the base of PRACTICAL INTEGRATED
the bladder to the verumontanum. APPROACH TO PROSTATE
The surgical capsule (pseudocapsule) is a ANATOMY
layer of compressed tissue between the On imaging studies of the prostate, there
hyperplastic transition zone and the sur- is a lack of correlation between the imag-
rounding peripheral zone, whereas the es seen routinely and the lobar or zonal
radiological viewpoint, there are two im- them by cellular origin: epithelial, neu-
portant subdivisions of the prostate, the roendocrine, prostatic stromal, mesen-
peripheral zone and the central gland. chymal, miscellaneous and haematolym-
Using this terminology, the central gland phoid[7, 10].
contains both the central and transition Prostate cancer. Currently prostate can-
zones, which are present in varying pro- cer (PCa) is the second most commonly
portions depending on the degree of BPH. diagnosed cancer in men, accounting for
In young men, the central gland is com- 15% of all cancers diagnosed. The highest
posed mainly of the central zone, where- incidence of PCa diagnosis is in Austra-
as in older men with BPH it is composed lia/New Zealand and Northern America
mainly of the transition zone. The defini- and in Western and Northern Europe. A
tion of the central gland as the combina- family history of the disease is associated
tion of the peri-urethral, central and tran- with an increased incidence of PCa, and
sition zones is somewhat arbitrary but has incidence is also related to racial/ethnic
the clear advantage of corresponding to background. This suggests a genetic pre-
findings on imaging and therefore is the disposition; however, less than 10% of PCa
most useful radiologically. patients have true hereditary disease (de-
fined as three or more affected relatives,
or at least two relatives who have devel-
MAIN PATHOLOGIES oped early-onset PCa). Genetic studies
AFFECTING THE PROSTATE have identified 100 common susceptibil-
A significant overlap can exist in the clini- ity loci and germline mutations in genes
cal history and imaging findings associat- such as BRCA1/2 and HOXB13 that are
ed with prostate disorders; therefore biop- associated with a higher risk of PCa. Fur-
sy is often warranted for final diagnostic thermore, while a wide variety of dietary
confirmation. However, many diseases and environmental factors have also been
also have distinct imaging features which discussed, no effective preventive dietary
can be recognised. or pharmacological interventions are cur-
rently available. The 2009 TNM classifica-
Neoplasms tion for staging of PCa, the EAU risk group
A wide variety of neoplasms occur in the classification and the International Society
prostate, both benign and malignant. The of Urological Pathology (ISUP) 2005 modi-
World Health Organisation’s histological fied Gleason score are the recommended
grading systems for PCa and all three are neous appearance, with areas of central
PAT H O LO GY O F TH E PR O S TATE
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widely used[11]. The key histological fea- necrosis due to the rapid growth. Many
tures of PCa are increased cellular density, sarcomas demonstrate a partial or com-
decreased luminal volume, reduced extra- plete pseudocapsule which separates the
cellular space and neoangiogenesis. tumour from the adjacent compressed
Cystadenoma. Most patients with this periprostatic fat. A rim of fibrosis due to
rare benign tumour initially present with an inflammatory reaction may also be de-
urinary obstruction or a palpable abdom- tected. Rhabdomyosarcoma is the most
inal mass. Aspiration usually yields haem- common type (42%), especially in children
orrhagic fluid and histiocytes but no ma- and adolescents. Embryonal rhabdomyo-
lignant cells. sarcomas are typically large lobulated
Stromal tumour of uncertain malignant masses that often protrude into the blad-
potential (STUMP). STUMPs are rare prolifer- der, whereas the more aggressive alveolar
ative lesions of the prostatic stroma. There form appears more infiltrative and less
are several subtypes with a wide range of well defined. Leiomyosarcoma accounts
biological behaviours and an unpredict- for 25% of sarcomas, mainly in adults, with
able clinical course. The lesions are large, early pulmonary and hepatic metastases.
well circumscribed and hetero geneous Prostate sarcomas are rarely confused with
and may arise from any prostatic zone. It adenocarcinoma, given their large size and
is difficult to differentiate a STUMP from heterogeneous appearance and, in the
a prostate sarcoma, and less aggressive case of rhabdomyosarcoma, their manifes-
forms of STUMP may even mimic BPH tation in a different age group.
nodules. Patients usually undergo surgical Urothelial carcinoma (or transitional cell
resection because of the potential aggres- carcinoma). Urothelial carcinoma origi-
siveness. nates from the prostatic ducts or acini and
Sarcoma. Only 0.1%–0.2% of all primary accounts for 2%–4% of all prostate can-
prostatic neoplasms are accounted for by cers. It usually presents as a synchronous
sarcomas. Most are of mesenchymal or- or metachronous tumour associated with
igin but in rare cases they arise from the urothelial carcinoma of the bladder or ure-
prostatic stroma. Patients often pres ent thra.
with rapid onset of urinary obstruction or Prostatic carcinoid. Along with small
a palpable mass and the prognosis is poor. cell carcinoma, large cell neuroendocrine
Sarcomas generally appear as well-circum- carcinoma and focal neuroendocrine dif-
scribed masses of large size and heteroge- ferentiation in prostate adenocarcinoma,
prostatic carcinoid is one of the four rare eration. Carcinosarcoma is considered one
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bladder; colorectal cancer is the next most acute prostatitis and recurrent infection
PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D
frequent source, but such cases are much may cause chronic bacterial prostatitis,
less frequent. which can also occur in older men without
a prior history but presenting with lower
Benign disorders urinary tract obstruction. Lymphocytes
Benign entities affecting the prostate are are usually detected in chronic prostatitis,
associated with variable clinical manifesta- often accompanied by glandular atrophy.
tions and in some cases are indistinguish- The chronic form tends to be more indo-
able from prostate cancer at standard lent, with lower urinary tract symptoms
imaging. They may even present extra- and no systemic symptoms, unlike in the
prostatic extension and lymphadenopa- acute form. It is important to be aware that
thy, mimicking locally advanced prostate (a) bacterial prostatitis is most commonly
cancer[7, 10]. visualised in the peripheral zone but can
Benign prostatic hyperplasia (BPH). BPH also occur in the transition zone, (b) en-
is a benign proliferation of prostatic epi larged reactive lymph nodes may be pres-
thelial and stromal cells of the transition ent and (c) a clinical history of urinary and/
zone, which form large hyperplastic nod- or sexual symptoms, a fluctuating PSA lev-
ules. These nodules are most commonly el or PSA response to antibiotics can alert
seen in the transition zone but occasional- the practitioner to the fact that the origin
ly can protrude into the peripheral zone or is bacterial and not carcinomatous.
even beyond the prostate as an exophytic Granulomatous prostatitis. The following
pelvic/bladder mass. BPH is exclusively a types of granulomatous prostatitis may oc-
disease of the non-peripheral prostate and cur: idiopathic (the most common type, di-
therefore does not involve the prostate vided into non-specific and non-necrotic),
distal to the verumontanum [12]. infective (specific, non-necrotic or necrot-
Bacterial prostatitis. Both acute and ic), iatrogenic (postsurgical), malacoplakia
chronic cases of bacterial prostatitis are and associated with systemic granuloma-
possible. Acute bacterial prostatitis is un- tous disease. Its hallmark is histiocytoid
common and more likely to occur in young granulomas with central necrotising or
men. It is characterised by an influx of neu- fibrinoid necrosis, surrounded by infiltra-
trophils and originates from intraprostatic tive eosinophils. Infective granulomatous
reflux of urine infected by Escherichia coli, prostatitis can be caused by Mycobacte-
Enterococcus or Proteus or from instrumen- rium tuberculosis or develop after intra-
tation (i.e. prostatic biopsy). Undertreated vesical bacillus Calmette-Guérin therapy
in the peripheral zone, may mimic prostate Calcification. Prostatic calcification may
PAT H O LO GY O F TH E PR O S TATE
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malignancy owing to its complex glan- arise due to precipitation of prostatic se-
dular architecture. It may be caused by cretions or calcification of the corpora
inflammation, radiation, anti-androgens amylacea. Extraprostatic cases are due to
or chronic ischaemia due to local arterio- a phlebolith in the periprostatic venous
sclerosis. plexus. In the context of BPH calcification
Necrosis. Necrosis can occur secondary is more frequent at the junction between
to treated infective prostatitis or focal ther- the transitional and the peripheral zone.
apy of prostate cancer (radiofrequency ab- Haemorrhage. Areas of haemorrhage
lation, cryoablation, high-intensity focused may occur after biopsy, especially in the
ultrasound, irreversible electroporation, peripheral zone. Tumours display a lower
laser ablation). It is characterised by cen- rate of biopsy haemorrhage (2%–10.5%)
tral well-defined coagulative necrosis of than normal tissue owing to the reduction
glands and stroma, with peripheral chronic in the anticoagulant effect of citrate, which
inflammatory cellular infiltrate and atrophy. is produced within the prostate.
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by Martin Behe
2
RADIOPHARMACEUTICALS
CHAPTER 2
INTRODUCTION
This chapter describes the radiopharmaceuticals used for the diagnosis
FO R PR O S TATE CAN CER
CL IN ICAL R AD IO PH AR MACEUTICALS
Prostate cancer is one of the most com- (PSMA) and gastrin-releasing peptide re-
mon cancers. After early detection, pros- ceptor.
tatectomy and/or radiation is the most During the preparation and application
promising therapeutic approach, with of radiopharmaceuticals, the relevant na-
80% of patients remaining free of recur- tional regulations always have to be fol-
rence for 7 years. However, at the time of lowed and it is recommended that the
diagnosis 12% of patients already have rules of current good radiopharmaceutical
metastatic spread to the lymph nodes or practice are taken into consideration[2].
to other organs, and such patients have a
shorter survival time[1]. It is therefore im-
portant to have a tool available that can PET AND SPECT IMAGING
detect metastatic and recurrent lesions at RADIOPHARMACEUTICALS
an early time point and in addition offer
these patients an effective therapeutic op- Sodium [18F]fluoride
tion. Radiotracers play an important role in Sodium [18F]fluoride (Na[18F]F) is a
this situation: they both permit the strat- bone-seeking positron-emitting tracer
ification of prostate cancers and may be which has been used for skeletal imaging
applied therapeutically. Radiotherapeutic since the early 1970s[3]. Although techni-
tracers have long played an important role cal issues limited its use for a long time,
in the palliative treatment of painful bone more routine use has been established
metastases, but in recent years targeted for some years, a trend that has occurred
radiotherapy via proteins overexpressed in conjunction with greater availability of
on the cell membrane has also been used medical cyclotrons and positron emission
successfully in various clinical trials. In the tomography (PET) scanners[3].
case of prostate cancer, the main targets As regards the mechanism of uptake,
are prostate-specific membrane antigen following chemisorption of fluoride ions
Figure 1 Figure 2
Figure 3
FO R PR O S TATE CAN CER
CL IN ICAL R AD IO PH AR MACEUTICALS
PSMA-11, a compound for 68Ga[Ga] labelling[16]. With copyright permission from ACS Publications
Bone is the most common site of me- arm in relation not only to overall surviv-
FO R PR O S TATE CAN CER
CL IN ICAL R AD IO PH AR MACEUTICALS
tastases in patients with advanced pros- al but also to all other secondary efficacy
tate cancer. Such metastases result in end points. Therefore the study was ter-
bone pain, bone fracture and spinal cord minated prior to the predefined endpoint
compression and are associated with a and authorisation of the compound was
higher morbidity and mortality. This ne- placed in a fast track process by the com-
cessitates treatment[20]. The treatment of petent authorities in Europe (EMA) and
bone metastases with [153Sm]Sm-EDTMP USA (FDA). The compound achieved mar-
is basically a palliative treatment for pain ket authorisation in Europe in 2013.
relief; it allows reduction or elimination [223Ra]Ra is a radionuclide with an alpha
of the use of powerful painkillers like opi- decay (E=6.64 MeV) and a half-life of 11.4
ates, which have a major adverse effect on days. The first alpha decay is followed by
quality of life. three other alpha decays and two beta
The radiopharmaceutical is delivered minus decays, ending in stable [207Pb]Pb
as a ready-to-use compound to nucle- (Fig. 5). [223Ra]RaCl2 is delivered as a ready-
ar medicine departments. For palliative for-use solution. Patients receive six cycles
treatment of bone metastases, the inject- every 4 weeks[22].
ed dose of [153Sm]Sm-EDTMP should be 37
MBq/kg. PSMA targeting compounds
The same considerations that apply for
[223Ra]RaCl2 the imaging compounds hold true for
[223Ra]radium chloride is a one of the first therapeutic radiopharmaceuticals target-
alpha-emitting compounds to have been ing PSMA. Various clinical trials are un-
approved for clinical use. Radium is a calci- derway with different radionuclides and
um antagonist and replaces the Ca in hy- small-molecule PSMA inhibitors[23]. The
droxyapatite in bone (see section “Sodium most widely used radionuclide is [177Lu]Lu
[18F]fluoride”)[20, 21]. Therefore the highest in combination with PSMA-617 or PSMA
uptake of [223Ra]radium chloride occurs I&T. [177Lu]Lu is a weak beta minus emitter
in locations with a high bone metabolism with an energy of 0.5 MeV, a mean tissue
caused by metastasis. [223Ra]radium chlo- range of 0.5 mm and a maximum tissue
ride was tested in comparison with a pla- range of 2 mm[24]. The studies to date have
cebo in a phase III study in 921 patients[22]. shown very promising results, with some
The alpha targeted radionuclide therapy sustained responses[23]. The most common
showed a clear benefit over the placebo adverse effects are damage to the salivary
Figure 5
glands, which also express the target, mild 4. Pinkerton TC, Cheng KT, Shaw SM, Wilson GM. Influ-
ence of complex charge and size on the uptake of
haematological toxicology and fatigue.
99mTc-diphosphonates in osteogenic tissue. Int J Ra-
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practice guidelines for bone scintigraphy. Eur J Nucl
Med Mol Imaging 2016;43:1723−1738.
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11. Schmid DT, John H, Zweifel R, Cservenyak T, West- imaging: version 1.0. Eur J Nucl Med Mol Imaging
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Radiology 2005;235:623−628. C, Ezziddin S, Giammarile F, et al. EANM guidelines
12. Troyer JK, Beckett ML, Wright GL Jr. Detection and for radionuclide therapy of bone metastases with
characterization of the prostate-specific mem- beta-emitting radionuclides. Eur J Nucl Med Mol Im-
brane antigen (PSMA) in tissue extracts and body aging 2018;45:846−859.
fluids. Int J Cancer 1995;62:552−558. 20. Shore ND. Radium-223 dichloride for metastatic
13. Silver DA, Pellicer I, Fair WR, Heston WD, Cor- castration-resistant prostate cancer: The urologist‘s
don-Cardo C. Prostate-specific membrane antigen perspective. Urology 2015;85:717−724.
expression in normal and malignant human tis- 21. Poeppel TD, Handkiewicz-Junak D, Andreeff M, Be-
sues. Clin Cancer Res 1997;3:81−85. cherer A, Bockisch A, Fricke E, et al. EANM guideline
14. Sokoloff RL, Norton KC, Gasior CL, Marker KM, Grau- for radionuclide therapy with radium-223 of meta-
er LS. A dual-monoclonal sandwich assay for pros- static castration-resistant prostate cancer. Eur J Nucl
tate-specific membrane antigen: Levels in tissues, Med Mol Imaging 2018;45:824−845.
seminal fluid and urine. Prostate 2000;43:150−157. 22. Parker C, Nilsson S, Heinrich D, Helle SI, O‘Sullivan
15. Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny JM, Fosså SD, et al. Alpha emitter radium-223 and
C. Current status of theranostics in prostate cancer. survival in metastatic prostate cancer. N Engl J Med
Eur J Nucl Med Mol Imaging 2018;45:471−495. 2013;369:213−223.
16. Eder M, Schäfer M, Bauder-Wüst U, Hull W-E, 23. von Eyben FE, Roviello G, Kiljunen T, Uprimny C,
Wängler C, Mier W, et al. 68Ga-complex lipophilic- Virgolini I, Kairemo K, et al. Third-line treatment and
ity and the targeting property of a urea-based 177Lu-PSMA radioligand therapy of metastatic cas-
PSMA inhibitor for PET imaging. Bioconjug Chem tration-resistant prostate cancer: a systematic re-
2012;23:688−697. view. Eur J Nucl Med Mol Imaging 2018;45:496−508.
17. Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut 24. Kratochwil C, Giesel FL, Stefanova M, Benešová M,
M, Zechmann C. [68Ga]Gallium-labelled PSMA Bronzel M, Afshar-Oromieh A, et al. PSMA-targeted
ligand as superior PET tracer for the diagnosis of radionuclide therapy of metastatic castration-re-
prostate cancer: comparison with 18F-FECH. Eur J sistant prostate cancer with 177Lu-labeled PSMA-
Nucl Med Mol Imaging 2012;39:1085−1086. 617. J Nucl Med 2016;57:1170−1176.
18. Fendler WP, Eiber M, Beheshti M, Bomanji J, Ceci F,
3
C AN C E R I MAG IN G
by Wolfgang Römer
CHAPTER 3
INTRODUCTION
In about 30% of patients with prostate cancer, bone metastases are seen.
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
However, only patients with advanced Several studies have proven the high
tumour stages should be examined by sensitivity of planar whole-body bone
this means nowadays. The most recent scintigraphy especially in prostate can-
EAU-ESTRO-SIOG guidelines on prostate cer, since its metastases are typically
cancer recommend metastatic screening osteoblastic, resulting in increased bone
only for patients with high-risk localised metabolism. However, its specificity is
prostate cancer (PSA >20 ng/ml or Glea- limited since it is not only bone metas-
son score >7 or cT2c) or high-risk locally tases that show enhanced tracer uptake.
advanced prostate cancer (any PSA, any Rather, various benign lesions of the
Gleason score, cT3-4 or cN+)[2]. These rec- bone, e.g. degenerative, inflammato-
ommendations are based on a meta-anal- ry and traumatic, are also visualised by
ysis by Abuzallouf et al., who showed that bone scan on the basis of focal tracer en-
in patients with PSA <10 ng/ml the preva- hancement. In the majority of cases, the
lence of bone metastases was only 2.3%[3]. vertebral column and pelvis are affected.
After the treatment of prostate cancer, Especially the differentiation of de-
the probability of a positive bone scan is forming spondylosis and spondylar-
low (<5%) if the PSA level is <7 ng/ml[4]. throsis from metastases is difficult.
Consequently, following treatment, bone On planar scintigraphy, superimpo-
scan is recommended only in patients sition hampers the exact anatomical
with biochemical recurrence (rising PSA localisation of lesions. The addition
values without evidence of tumour re- of single-photon emission comput-
lapse) who have a high PSA (>10 ng/ml) or ed tomography (SPECT) allows better
high PSA kinetics (PSA doubling time <6 distinction of benign from malignant
months) and in patients with new-onset changes due to more exact localisation
bone pain[5]. Guidelines explicitly advise of increased diphosphonate uptake.
against routinely performing bone scintig- However, the specificity of SPECT is also
raphy after treatment of prostate cancer. insufficient for reliable diagnosis[6].
Figure 1A
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
Figure 1B
Figure 1a,b: Bone scintigraphy and SPECT/CT using 99mTc-DPD in a patient with prostate
cancer. a) Planar whole-body bone scan shows enhanced tracer uptake in the left
acetabulum. b) On CT, the focally enhanced bone metabolism correlates with focal sclerosis
in the acetabulum, typical for osteoblastic metastasis in prostate cancer
Figure 2A
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
Figure 2a–c: Bone scintigraphy and SPECT/CT using 99mTc-DPD in a patient with prostate
cancer. a) Planar whole-body bone scan shows two lesions in the seventh and ninth ribs with
increased tracer uptake. Lesions with enhanced bone metabolism in both knees and in the right
cervical spine are typical for osteoarthritis. b) On CT, the focally enhanced bone metabolism
correlates with focal sclerosis in the rib, typical for osteoblastic metastasis in prostate cancer. c)
The findings on low-dose CT from SPECT/CT are confirmed by a diagnostic CT scan
Figure 2B
In 2010 the value of SPECT/CT was stud- for SPECT and 93% and 100% for SPECT/
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
ied by Ndlovu et al.[10] In this study, 48% of CT. The authors reported that SPECT/CT
patients had indeterminate findings when characterised 96% of the equivocal le-
only SPECT images were analysed, com- sions on conventional planar bone scan
pared with 14% when using hybrid imag- and showed that SPECT/CT had a signif-
ing. This study included 42 patients, most icant influence on the clinical manage-
of whom were suffering from breast can- ment of 60.6% of patients compared with
cer (n=22) or prostate cancer (n=8). The planar scintigraphy and 18% compared
additional analysis on a lesion-by-lesion with SPECT.
basis of 189 suspicious lesions found that
indeterminate findings could be reduced Palmedo et al. studied the incremen-
from 31% with SPECT alone to 9% with tal value of SPECT/CT compared with
SPECT/CT. All findings were statistically planar scintigraphy and SPECT alone in
significant. 308 oncological patients with different
Zhao et al. reported the results of tumour entities, 33% of whom had pros-
SPECT/CT in 141 bone lesions in 125 tu- tate cancer[13]. At interpretation of the
mour patients[11]. The sensitivity of SPECT planar scans, 19% of lesions were clas-
and SPECT/CT was 83% and 98%, respec- sified as equivocal, 29% as benign and
tively, and the specificity was 67% and 34% as malignant (in remaining cases no
94%, respectively. The number of indeter- lesions were detected). When reporting
minate findings was reduced from 37 with SPECT scans, the corresponding values
SPECT to five with SPECT/CT. were 20%, 33% and 43%. The addition of
Sharma et al. evaluated 99 patients SPECT/CT resulted in a significant reduc-
who received a bone scan including tion in equivocal reports to only 3.5% of
SPECT/CT owing to different malignant the lesions; 52% of lesions were classified
and non-malignant diagnoses[12]. A total as benign and 36% as malignant. The au-
of 108 vertebral lesions were detected thors found that the specificity and pos-
on planar scans. On planar scintigraphy itive predictive value were significantly
49 lesions were interpreted as indeter- (p<0.01) higher for SPECT/CT compared
minate, compared with 16 on SPECT. with planar whole-body scans and SPECT
However, on SPECT/CT scan, only one alone. On a per-patient basis, the sensi-
remained indeterminate. The calculated tivity, specificity, positive predictive val-
sensitivity and specificity were 100% and ue and negative predictive value were,
36% for planar scintigraphy, 82% and 88% respectively, 97%, 94%, 88% and 97% for
deoxyglucose (FDG) is not useful. There- ificity, PET and PET/CT are of limited use
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
fore, several PET studies on prostate can- due to their restricted availability and high-
cer imaging have been published using er costs. In some countries, PET/CT studies
11
C-acetate and 18F- or 11C-choline. Since will not be reimbursed by the insurance
both tracers do not seek lesions with en- provider. Therefore, bone scanning re-
hanced bone metabolism but rather bind mains the imaging modality of first choice
specifically to the tumour cells, soft tissue to confirm or exclude bone metastases.
metastases can also be detected.
More recently, another tumour-specific
tracer has been introduced. Ligands bind- ACQUISITION PROTOCOL
ing to the prostate-specific membrane In order to confirm or exclude bone me-
antigen (PSMA) have shown high clinical tastases, primarily anterior and posterior
value for detection of local recurrence of planar whole-body scans are acquired
prostate cancer as well as for lymph node between 2 and 4 h after tracer injection. If
staging. In addition, several studies have any remarkable findings are observed on
shown its great value in the detection of these scans, SPECT imaging of the indeter-
bone metastases. Pyka et al. investigated minate areas should be performed. Using
the diagnostic accuracy of bone scanning modern iterative reconstruction algo-
including SPECT and 68Ga-PSMA-PET for rithms, a detailed anatomical correlation of
detection of bone metastases in prostate focally enhanced tracer uptake is possible.
cancer[14]. The sensitivity and specificity of This is especially helpful in the axial skele-
PET were 99% and 100% compared with ton, where differentiation is hampered by
86% and 98% for bone scintigraphy. In superimposition of different anatomical
another study combining PET and SPECT structures. Following the development of
with CT in hybrid scanners, 68Ga-PSMA efficient reconstruction algorithms and
PET/CT outperformed 99mTc-2,3-dicar- fast computer processors, reconstruction
boxypropane-1,1-diphosphonate (DPD) of three-dimensional images can be per-
SPECT/CT, with a sensitivity of 97.7% vs formed within less than 60 s. However, as
69.4% and a specificity of 100% vs 98.3%. already discussed above, SPECT images
As when comparing SPECT and SPECT/CT, alone will often not help to clarify indeter-
in the case of 68Ga-PSMA PET the propor- minate findings with certitude.
tion of equivocal findings was significantly Following the implementation of CT
reduced by CT fusion in PET/CT[15]. In sum- scanners in SPECT cameras, the combi-
mary, despite higher sensitivity and spec- nation of functional and morphological
information regarding a lesion enables the CT software should be able to limit the ex-
REFERENCES
1. Even-Sapir E. Imaging of malignant bone involve- ic, and castration-resistant prostate cancer. Eur Urol
ment by morphologic, scintigraphic, and hybrid mo- 2017;71:630–642.
dalities. J Nucl Med 2005;46:1356–1367. 6. Reinartz P, Schaffeldt J, Sabri O, Zimny M, Nowak B,
2. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch Ostwald E, et al. Benign versus malignant osseous
MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines lesions in the lumbar vertebrae: differentiation by
on Prostate Cancer. Part 1: Screening, diagnosis, means of bone SPET. Eur J Nucl Med 2000;27:721–726.
and local treatment with curative intent. Eur Urol 7. Rybak LD, Rosenthal DI. Radiological imaging for
2017;71:618–629. the diagnosis of bone metastases. Q J Nucl Med
3. Abuzallouf S, Dayes I, Lukka H. Baseline staging of 2001;45:53–64.
newly diagnosed prostate cancer: a summary of the 8. Römer W, Nomayr A, Uder M, Bautz W, Kuwert T.
literature. J Urol 2004;171(6 Pt 1):2122–2127. SPECT-guided CT for evaluating foci of increased bone
4. Beresford MJ, Gillatt D, Benson RJ, Ajithkumar T. A sys- metabolism classified as indeterminate on SPECT in
tematic review of the role of imaging before salvage cancer patients. J Nucl Med 2006;47:1102–1106.
radiotherapy for post-prostatectomy biochemical 9. Helyar V, Mohan HK, Barwick T, Livieratos L, Gnanase-
recurrence. Clin Oncol 2010;22:46–55. garan G, Clarke SE, et al. The added value of multislice
5. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, SPECT/CT in patients with equivocal bony metasta-
Gross T, et al. EAU-ESTRO-SIOG Guidelines on Pros- sis from carcinoma of the prostate. Eur J Nucl Med
tate Cancer. Part II: Treatment of relapsing, metastat- Mol Imaging 2010;37:706–713.
10. Ndlovu X, George R, Ellmann A, Warwick J. Should phy and (68)Ga-PSMA PET for skeletal staging
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E
SPECT-CT replace SPECT for the evaluation of in prostate cancer. Eur J Nucl Med Mol Imaging
equivocal bone scan lesions in patients with 2016;43:2114–2121.
underlying malignancies? Nucl Med Commun 15. Janssen JC, Meissner S, Woythal N, Prasad V, Bren-
2010;31:659–665. ner W, Diederichs G, et al. Comparison of hybrid
11. Zhao Z, Li L, Li F, Zhao L. Single photon emission (68)Ga-PSMA-PET/CT and (99m)Tc-DPD-SPECT/
computed tomography/spiral computed tomog- CT for the detection of bone metastases in pros-
raphy fusion imaging for the diagnosis of bone tate cancer patients: Additional value of morpho-
metastasis in patients with known cancer. Skelet logic information from low dose CT. Eur Radiol
Radiol 2010;39:147–153. 2018;28:610–619.
12. Sharma P, Dhull VS, Reddy RM, Bal C, Thulkar S, Mal- 16. Zacho HD, Manresa JAB, Aleksyniene R, Ejlersen
hotra A, et al. Hybrid SPECT-CT for characterizing JA, Fledelius J, Bertelsen H, et al. Three-minute
isolated vertebral lesions observed by bone scintig- SPECT/CT is sufficient for the assessment of bone
raphy: comparison with planar scintigraphy, SPECT, metastasis as add-on to planar bone scintigraphy:
and CT. Diag Intervent Radiol 2013;19:33–40. prospective head-to-head comparison to 11-min
13. Palmedo H, Marx C, Ebert A, Kreft B, Ko Y, Turler A, SPECT/CT. EJNMMI Res 2017;7:1.
et al. Whole-body SPECT/CT for bone scintigraphy: 17. Horger M, Eschmann SM, Pfannenberg C, Vonthein
diagnostic value and effect on patient manage- R, Besenfelder H, Claussen CD, Bares R. Evaluation
ment in oncological patients. Eur J Nucl Med Mol of combined transmission and emission tomogra-
Imaging 2014;41:59–67. phy for classification of skeletal lesions. AJR Am J
14. Pyka T, Okamoto S, Dahlbender M, Tauber R, Retz Roentgenol 2004;183:655–661.
M, Heck M, et al. Comparison of bone scintigra-
by Daniel Tempesta
and David Gilmore
CHAPTER 4
Positron emission tomography (PET) makes have relatively short half-lives compared
use of gamma ray pairs emitted by specific with the radionuclides used in planar and
radiopharmaceuticals in order to observe SPECT imaging (technetium-99m, indi-
physiological processes in the body. Most um-111 and iodine-123). Due to the short
PET scanners today are hybrid systems with half-lives, PET imaging facilities either
computed tomography (CT) scanners built have their own cyclotron onsite or must
into the same gantry to create a PET/CT be relatively close to a central radiophar-
scanner. The PET data provide information macy with a cyclotron. While most PET
on the physiology of the body while the CT radionuclides are produced in a cyclotron,
serves several purposes, including attenu- two exceptions exist: rubidium-82 and
ation correction of the PET data as well as gallium-68. These two radionuclides are
improved anatomical correlation. produced by generators.
All PET radionuclides have in common Fluorine-18 (18F) is the most commonly
that they emit positrons from their nuclei. used radionuclide in PET imaging today,
The positron emitted will pair with an elec- partly due to its desirable properties. 18F
tron through an annihilation event. The can be substituted for a hydroxyl group
annihilation will then cause a pair of 511- and therefore synthesise many radiophar-
keV photons to be emitted in opposite di- maceuticals. With a physical half-life of 110
rections at nearly 180°. PET scanner design min, 18F can not only be synthesised using
takes advantage of this by using a ring of on-site cyclotrons but also be produced at
detectors, only registering events when central nuclear pharmacies and be trans-
both photons are detected, thereby improv- ported to local imaging facilities. While 18F
ing resolution compared with traditional can be used to synthesise a variety of radio-
planar and SPECT imaging. Multiple rings pharmaceuticals, one in particular, known
of detectors are arranged longitudinally as fluorodeoxyglucose (FDG), has drastical-
along the patient’s body so that sections of ly changed the way in which most cancers
anatomy may be imaged simultaneously, in are diagnosed, staged and restaged.
what are called “bed positions”. The number
of beds per scan depends on the scanner
design and the amount of anatomy imaged. PROSTATE CANCER IMAGING
The majority of positron-emitting ra- WITH PET/CT
dionuclides used in medical imaging Traditional methods of imaging with PET/
(fluorine-18, carbon-11, nitrogen-13 and CT have proven difficult for patients with
prostate cancer. 18F-FDG, the most com- cose. Patients should have nothing to eat
voids immediately before imaging if a Many areas of the body will normally ac-
R AD IO PH AR MACEUTICALS IN PR O S TATE CANCER
PE T/C T PR O CED UR ES WITH FLUO R IN E-18
bladder catheter is not being used in order cumulate 18F-FDG, with the most intense
to reduce activity from urine in close prox- activity noted in the brain, kidneys and
imity to the prostate. The ideal patient bladder. Other organs normally accumu-
position is supine with the arms raised late 18F-FDG to a lesser extent, including
above the head to reduce attenuation the liver, spleen, salivary glands, thyroid
and prevent artefacts over the chest and gland, stomach, bowel, bone marrow and
abdomen. The scout and CT scans can be muscles. Myocardial uptake is quite vari-
performed first, before the PET emission able, and usually depends on the fasting
scan. For the emission scan, the patient state of the patient.
should be scanned in the caudo-crani- As previously mentioned, 18F-FDG PET
al direction, beginning at the pelvis and has traditionally not been used routine-
continuing through the skull base. Data ly in prostate cancer patients due to the
acquisition should be for 2–5 min at each low-metabolic properties of the disease.
bed position, depending on factors such While some studies have shown that PET/
as the age of the scanner and the manu- CT using 18F-FDG can influence the man-
facturer’s recommendations. Sample ac- agement of patients with prostate cancer,
quisition parameters for both the CT and the influence is not as great as in other
the emission PET scan are shown in Tables types of cancer[2]. 18F-FDG PET is typically
1 and 2, respectively. least useful early on in the diagnosis and
Table 1 Table 2
Topogram 35 mA Matrix 256
120 kVp
Zoom 1
1024 mm
Energy peak 511 keV
Slide 5 mm
Acquisition mode 3-dimensional
Rotation time 0.55 s
Scan duration 2–5 min/bed position
Pitch 0.85
Reconstruction Iterations 2, subsets 21
Reconstruction B30s, medium smooth
for AC FOV 780 mm Attenuation correction CT
FWHM 5 mm
Reconstruction B30f, medium smooth,
for Images 5×5 mm, 500 mm FOV Filter Gaussian
Sample CT scan parameters [8]
Sample PET scan parameters [8]
initial staging of prostate cancer. One area Patient preparation includes refraining
that urine excretion and bladder activity results. For example, benign inflammation
R AD IO PH AR MACEUTICALS IN PR O S TATE CANCER
PE T/C T PR O CED UR ES WITH FLUO R IN E-18
are minimal at the time of imaging, allow- may show areas of increased uptake be-
ing for better visualisation of the nearby cause amino acid transporters are over-ex-
prostate or prostate bed in prostatectomy pressed in some types of inflammation.
patients. Some caution should be exercised when
As a general rule, during image inter- interpreting images as other types of can-
pretation large lesions with visual activity cer, in addition to prostate cancer, can
equal to or greater than that of the bone accumulate 18F-fluciclovine. Furthermore,
marrow should be considered suspicious benign prostate hypertrophy in patients
for prostate cancer (Fig. 1). Smaller lesions with primary prostate cancer can also
should be of concern when their visual ac- show increased areas of uptake, potential-
Figure 1
Transaxial PET (left) and PET/CT (right) F-18 fluciclovine images demonstrating
metastatic disease to a lymph node
tivity exceeds that of the blood pool activ- ly leading to false positive results. It may
ity. Similar to the rules for large lesion ma- be difficult to differentiate between be-
lignancy, lymph nodes demonstrating ac- nign prostate pathology and prostate can-
tivity equal to or greater than the activity cer. Therefore, it is recommended that the
of the bone marrow should raise concern patient’s full medical history is reviewed
regarding prostate cancer involvement[4]. when interpreting imaging and in some
Image interpretation requires atten- cases the findings should be confirmed
tion to detail and a full medical history, as histologically[4].
some situations can cause false positive
Figure 2
Fluorine-18 incorporates into the aging. Prostate cancer that has spread to
R AD IO PH AR MACEUTICALS IN PR O S TATE CANCER
PE T/C T PR O CED UR ES WITH FLUO R IN E-18
coupled with the prostate radiotherapy only a few hundred patients have to date
REFERENCES
R AD IO PH AR MACEUTICALS IN PR O S TATE CANCER
PE T/C T PR O CED UR ES WITH FLUO R IN E-18
» Boellaard R, Delgado-Bolton R, Oyen WJG, Giammarile EANM procedure guidelines for bone imaging. Eur J
F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM proce- Nucl Med Mol Imaging 2015;42:1767–1777.
dure guidelines for tumour imaging: version 2.0. EurJ » Hillner BE, Siegel BA, Hanna L, Duan F, Shields AF,
Nucl Med Mol Imaging 2015;42:328–354. Quinn B, et al. Impact of 18F-fluoride PET on intend-
» Jadvar H. FDG PET in prostate cancer. PET Clin ed management of patients with cancers other than
2009;4:155–161. prostate cancer: results from the National Oncologic
» Minamimoto R,Uemura H, Sano F, Terao H, Nagashi- PET Registry. J Nucl Med 2014;55:1054–1061.
ma Y, Yamanaka S, et al. The potential of FDG-PET/CT » Giesel FL, Hadaschik B, Cardinale J, Radtke J, Vinsensia
for detecting prostate cancer in patients with an ele- M, Lehnert W,et al. F-18 labeled PSMA-1007: biodis-
vated serum PSA level. Ann Nucl Med 2011;25:21–7. tribution, radiation dosimetry and histopathological
» Blue Earth Diagnostics, Axumin Prescribing Infor- validation of tumor lesions in prostate cancer pa-
mation, http://www.ema.europa.eu/docs/en_GB/ tients. Eur J Nucl Med Mol Imaging 2017;44:678–688.
document_library/EPAR_-_Product_Information/ » Ross L, York D.Optimisation of PET/CT — acquisition
human/004197/WC500230834.pdf. Accessed on 1 and reconstruction. In: Quality control of nuclear
March 2018. medicine instrumentation and protocol standardiza-
» Beheshti M, Mottaghy FM, Paycha F, Behrendt FF, Van tion. EANM Technologists Guide 2017:85–102.
den Wyngaert T, Fogelman I,et al. 18F-NaF PET/CT:
PROSTAT E
C AN C E R PE T/C T
IMAGI N G BE YO N D
FLUO R I N E -18
T R AC E R S
by Giorgio Testanera
and Giovanna Pepe
CHAPTER 5
INTRODUCTION
Prostate cancer is one of the most commonly diagnosed tumour types.
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
United States data show that in that country (a) around 160,000 new
cases are identified annually, (b) nearly 30,000 men die of the disease
each year and (c) about one in nine men will be diagnosed with prostate
cancer during their lifetime[1]. In the management of prostate cancer, the
methods currently applied for risk stratification, treatment selection and
response prediction, as well as for estimation of prognosis, are considered
suboptimal. Screening for prostate-specific antigen (PSA) is controversial
owing to its low specificity and the risk of overtreatment of cancers that
are not clinically significant. Tissue biopsy samples, on the other hand, can
provide only a small window on the biological characteristics of a cancer,
particularly in cases of widespread disease.
Diagnostic imaging is crucial in the evalu- Molecular imaging techniques are used
ation of patients with suspected metastat- to generate maps of functional and bio-
ic or biochemically recurrent prostate can- chemical activity in target tissues in vivo
cer[2]. The identification and localisation of and may provide non-invasive insights
metastatic disease may significantly alter into tumour biology and diversity on a
the treatment options available to the whole-body scale (Fig. 1).
patient, particularly in the oligometastatic Currently, positron emission tomogra-
setting, as different authors have demon- phy (PET) is one of the most successful
strated oncological benefit of salvage techniques in the diagnostic work-up of
lymph node dissection or radiotherapy prostate cancer, playing an important role
in the setting of low-burden metastatic by addressing several metabolic features.
disease. Furthermore, stereotactic radio- In this chapter, in the spirit of continuity
therapy or metastasectomy in limited/ with EANM and international guidelines
isolated metastatic disease has been prov- on the topic[4, 5], we will cover major clin-
en to be of benefit, with an improvement ical applications of PET/CT techniques
in progression-free survival in patients with non-18F-based tracers, together with
with oligometastatic prostate cancer re- acquisition methods, patient preparation
currence who are treated with high-dose and quality criteria. The aims are to:
stereotactic body radiotherapy (3-year »» Identify the non-18F tracers used in pros-
progression-free survival 99% vs 79% with tate cancer
low dose)[3]. »» Describe patient preparation for each tracer
Figure 1
CT
Bombesin
GRP-R MCT 11C-Acetate
analogues
Endo
some Nucleus
Antibodies AATs
PSMA 11C-Methionine
Overview of molecular imaging strategies currently applied for prostate cancer. AATs, amino
acid transporters; CT, choline transporter; GRP-R, gastrin-releasing peptide receptor; MCT,
monocarboxylate transporter, PSMA, prostate-specific membrane antigen
except, possibly, in aggressive, poorly dif- teristic of prostate cancer cells (phospho-
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
ferentiated tumours. Therefore, different lipids with 11C- or 18F-choline, fatty acids
PET probes have been developed with with 11C-acetate and amino acids with
the aim of enabling better investigation 18
F-fluciclovine) or bone remodelling from
of this neoplastic disease. These tracers osteoblastic osseous metastases (18F-sodi-
can target the metabolic changes charac- um fluoride) or overexpressed cell surface
Scanner A Scanner B
CT protocol
Topogram 50 mA 10 mA
110 kV 120 kV
>1000 mm >1000 mm
Dose modulation parameters 95 mA 400 mA, maximum value
130 kV 140 kV
Slice 3 mm 3.75 mm
CT collimation 6×3 mm 64×3.75 mm
Rotation time 1.0 s 0.5 s
Pitch 1.0 0.984
Reconstruction for attenuation B10s very smooth 4 mm, DFOV AC wide view − DFOV 70 cm
correction 70 cm 2.5 mm
Reconstruction for imaging B31s medium smooth +3 mm Standard wide view
2.5 mm
PET protocol
Scan duration per bed position >2.0 min >1.5 min
Matrix 128 256
Reconstruction Iterations 2; subset 8; OSEM Iterations 3, cut-off 5, subset 24,
TOF+PSF correction
Filter Gaussian Standard axis Z
FWHM 4 mm /
Table 1: Practical example of different parameters used with two different scanners for 11C-choline
imaging (data courtesy of Humanitas Research Hospital, Milan, Italy)
sions in order to help guide further clin- phase 80 s after intravenous injection
ical decisions. of contrast agent (1.5 mL per kilogram
»» When previous PET/CT examinations body weight, maximum 120 mL).
have been performed, images and re- »» PET acquisition should start from the
ports must be available for comparison. mid-thigh and extend to the base of the
»» In pregnant or breast-feeding patients, skull.
specific guidelines must be followed. »» When using 68Ga-PSMA, acquisition
»» The patient should be positioned with should proceed from the lower end
both arms elevated above the head, as of the axial field of view cranially in or-
tolerated by the patient. If PET/CT data der to minimise misalignment for the
are used for radiation therapy planning, urinary bladder, which tends to fill up
the examination should be performed during the course of the examination.
in exactly the same position and em- PET scans are acquired in three-dimen-
ploying the same positioning devices as sional mode with an acquisition time of
in the radiation therapy department. usually 2–4 min per bed position.
»» C T scans should be performed from the »» Overall, PET coverage should be identi-
skull base to the mid-thigh followed by cal to the anatomical CT scan range.
the PET acquisition. CT acquisition pa-
rameters (such as kV, mAs, pitch in helical
CT and dose modulation) should be in CHALLENGES OF WORKING
accordance with institutional protocols. WITH 11C-LABELLED TRACERS
»» If there are focal symptoms or dissemi- The main challenge of working with 11C
nated disease, coverage may be extend- tracers is the reduced half-life of the iso-
ed to include the entire lower extremity tope, only 20.4 min (18F: 110 min). As stat-
and/or the skull. ed above, these tracers are available only
»» When diagnostic contrast-enhanced CT in centres with availability of an on-site
(with intravenous contrast media) needs cyclotron.
to be performed after the PET/CT ex- The operational challenges associated
amination, indications and contraindi- with this situation mean that:
cations must be evaluated by qualified »» All steps in the imaging process must be
personnel[7]. performed without delays.
»» If intravenous CT contrast is used, the »» All professional staff involved in the pro-
suggested protocol consists in a con- cess must be adequately instructed.
Problems Advantages
Table 2: Problems and advantages of working with 11C tracers with a cyclotron on site
»» Patients MUST be adequately instructed deciding whether a scan meets the quality
by PET centre staff. criteria. The sources of artefact on PET/CT
»» Each exam is performed within a short are very similar to those described in the
time, which is sometimes critical for EANM guidelines for 18F-FDG[8], but the dif-
good quality imaging. ferent biodistribution needs to be consid-
Table 2 summarises the problems and ered. These sources include:
advantages of working with 11C tracers »» Patient movement
with a cyclotron on site. The table shows »» Scanner-related factors
that problems that are easy to solve with »» Inappropriate processing
long-lived tracers may cause poor qual- »» Insufficient attenuation correction
ity imaging when using rapidly decaying »» CT artefacts (e.g. respiration)
tracers in a complex procedure such as a »» Recent radiotherapy or chemotherapy
PET/CT scan. Solutions require extra efforts
in terms of internal cooperation and stan-
dardisation of protocols. 11
C-CHOLINE
Prostate cancer cells show increased
phosphocholine levels and elevated turn-
QUALITY CRITERIA AND over of the cell membrane phospholipid,
ARTEFACTS namely phosphatidylcholine[9]. A high-af-
Various potential sources of errors in in- finity transporter system imports choline
terpretation must be considered when into the cell, where it is phosphorylated
by choline kinase in the first step of the ing the examination to confirm that the
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
Figure 2
Figure 3
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
11
C-Choline
11
C-Choline 18
F-Choline
Unremarkable activity in the bladder Significant activity in the bladder 18
F-Choline
Comparison between 18F-choline and 11C-choline PET/CT imaging in the same patient. 18F-choline
shows higher activity in the urinary bladder than 11C-choline, limiting evaluation of the prostatic bed
11
C-Choline PET/CT appears to be a prostate cancer burden in the skeleton;
powerful tool for the restaging of bio- non-sclerotic skeletal metastases can
chemically recurrent prostate cancer, be identified as foci of high uptake, not
particularly for those patients in whom rarely outside the routine field of view
standard imaging (CT, MR imaging and of pelvic MR imaging. It has been clear-
bone scan) has failed to identify the site ly demonstrated that 11C-choline PET/
of recurrence. This subgroup of patients CT has better sensitivity than bone scan.
frequently has one or more lymph node This is attributable to the fact that choline
metastases in the pelvis that are normal accumulates directly in the tumour cells
in size on anatomical imaging but show in the bone marrow, ensuring earlier de-
increased tracer uptake on functional im- tection of lesions, whereas bone-seeking
aging (Fig. 4). radiopharmaceuticals accumulate in the
11
C-Choline PET/CT is an optimal imag- osteoblastic cells, giving an indirect sign
ing modality for the assessment of viable of metastatic disease[14, 15].
Figure 4
11
C-Choline PET/CT in biochemical recurrence. Images show pathological uptake in an iliac
lymph node
11
C-ACETATE by carboxylation reaction of MeMgBr on
a polyethylene Teflon loop ring with 11C-
11
C-Acetate is transported across the cel- CO2, followed by acidic hydrolysis with acid
lular membrane via the monocarboxylate and SCX cartridge and purification on SCX,
transporter and participates in the de novo AG11A8 and C18 SPE cartridges using a com-
synthesis of fatty acids from acetyl-CoA mercially available 11C-tracer synthesiser[17].
and malonyl-CoA through the action of
fatty acid synthase, which is upregulated Specific patient preparation
in prostate cancer[16]. Currently there are no agreed guidelines
The normal prostate usually shows only for 11C-acetate, and a protocol similar to
minor uptake of the tracer while focal inflam- that described for generic 11C tracers and
mation of the prostate can cause increased 11
C-choline is routinely used. There is no
focal tracer accumulation. Automated syn- evidence in the literature regarding specif-
thesis of 11C-acetate has been implemented ic patient preparation.
Figure 5
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
11
C-Choline
11
C-Acetate PET/CT: physiological and pathological findings. Courtesy of G. Karanikas and M. Beheshti
11
C-Acetate 11
C-Choline Ga-PSMA
68
Patient preparation Hydration with, for Hydration with for Hydration with for
Patient position Supine with arms Supine with arms Supine with arms
elevated above the head elevated above the head elevated above the
head.
CT protocol FOV Base of the skull to Base of the skull to Base of the skull to
mid-thigh mid-thigh mid-thigh
PET protocol From mid-thigh to base From mid-thigh to base From mid-thigh to base
of the skull; 1.5–2.5 min of the skull; 1.5–2.5 min of the skull; 3–4 min per
per bed position per bed position bed position
PET reconstruction Attenuation correction Attenuation correction Attenuation correction
from CT data from CT data from CT data
data from prospective multicentre trials in patients with a high suspicion of pros-
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
are not yet available; therefore the criteria tate cancer and previous negative biopsy
for appropriate use of this imaging tech- and in PSMA-directed radiotherapy.
nique mainly derive from the clinical evi- The use of 68Ga-PSMA PET/CT in the pri-
dence available at present. The physiolog- mary staging of high-risk prostate cancer
ical distribution of 68Ga-PSMA is illustrated is increasingly being reported, though it
in Fig. 6. has also been performed in patients with
The current fields of application of this intermediate-risk disease. In a recent ret-
imaging technique are: rospective analysis by Budaus et al.[30] the
»» Staging in primary cancer and in intra- sensitivity and specificity were found to
prostatic tumour be 33.3% and 100%, respectively. Maurer
»» Restaging in biochemically recurrent et al.[31] compared the detection rate of
prostate cancer metastatic lymph nodes on 68Ga-PSMA
Interest is increasing in targeted biopsy PET/CT and conventional imaging (CT and
MRI) in patients prior to radical prostatec-
Figure 6 tomy and pelvic nodal dissection. Sensitiv-
ity and specificity were 65.9% and 98.9%
respectively on a per-patient level for 68Ga-
PSMA-PET/CT, as compared with 44.9%
and 85.4% for conventional imaging.
While its role in primary staging has yet
to be definitively determined, the ben-
efit of 68Ga-PSMA PET/CT in this context
seems to lie especially in the possibility of
early identification of metastatic disease,
particularly in uncommon locations such
as the mesorectum, and as a consequence
it can lead to sensible modification of the
treatment algorithm.
It is to be noted that multiparamet-
ric MRI represents a promising imaging
modality in the diagnosis of primary in-
traprostatic prostate cancers and current
Ga-PSMA PET/CT: physiological distributio
68
data suggest that 68Ga-PSMA PET/MRI may
Figure 7
improve diagnostic yield and localisation CT and choline PET/CT are available in the
in this setting[32]. literature. For example, in a retrospective
A large majority of the evidence sup- analysis by Schwenck and co-workers of
porting the use of 68Ga-PSMA PET/CT has 103 patients with biochemical recurrence
been reported in the setting of biochem- after primary treatment, 68Ga-PSMA PET/
ically recurrent prostate cancer (Figs. 7−9). CT showed a higher detection rate than
In this scenario the evaluation of sensitivity 11
C-choline PET[33]. It is notable that the su-
and specificity is not easily accomplished periority of 68Ga-PSMA PET/CT compared
as a comparative gold standard measure with current imaging modalities appears
does not exist. Histopathology is not al- to be most significant at low PSA levels.
ways feasible and sampling errors may Apart from the EANM/SNMMI guide-
arise due to the small volume of disease lines, it appears that only the European
detectable on 68Ga-PSMA-PET/CT. Howev- Association of Urology makes reference to
er, comparative data on 68Ga-PSMA PET/ 68
Ga-PSMA PET/CT. This not only highlights
Figure 8
BE YO ND FLUO RI NE -18 TRAC E RS
PR O STATE C A NC E R PE T/C T I MAGI NG
68
Ga-PSMA PET/CT in biochemical recurrence. Images show nodal and bone involvement.
again the need for more extensive valida- it is possible to capture by visual analysis
tion of the technique but also reflects the only. Therefore sophisticated computer-
regional variation in availability of 68Ga-PS- ised algorithms have been developed to
MA PET/CT due to varying regulation with accomplish such “high-level” quantitative
respect to the administration of novel ra- studies. Medical images suitable for ra-
diopharmaceuticals. Nonetheless, use of diomics include CT, MR imaging and, of
68
Ga-PSMA PET/CT has been increasingly course, PET/CT.
reported in routine clinical practice in One example is provided by an article
countries where scanning is available[34]. presenting a quantitative radiomics fea-
ture model for performing prostate can-
cer detection using multiparametric MRI
RADIOMICS AND FUTURE (mpMRI). In this study a radiomics feature
PERSPECTIVES model was constructed to detect tumour
Recently radiomics has attracted growing regions within the prostate. The interest-
interest in the field of imaging. It is a con- ing point is that the high-level data de-
cept based on the idea that biomedical rived from this computerised analysis were
images contain more information than designed to fit categories already used by
Figure 9
Comparison between 11C-choline and 68Ga-PSMA PET/CT imaging in the same patient. A suspicious
node seen in the supravesical area on 11C-choline is confirmed on 68Ga-PSMA PET/CT in a patient
with biochemical recurrence and no other pathological findings
between SUVmax and CT radiomic analy- a brand new horizon that may disclose
sis on lymph node density was performed relevant diagnostic information and po-
in several different tumours, including tentially also assist in the development of
prostate cancer. CT density measurements tailored treatments. For example, in the
of lymph nodes correlated with tracer up- future radiomics data might be integrat-
take on PET/CT (the radiopharmaceutical ed into the radiotherapy workflow for the
used for prostate cancer was 68Ga-PSMA, purposes of improved risk stratification,
while for other tumours different tracers radiogenomics, treatment-related toxicity
were applied). The data suggested that prediction, target volume definition, and
this analysis could serve as an additional follow-up.
surrogate parameter for differentiation
between malignant and benign nodes[36]. isclaimer: if not stated differently all im-
D
While few studies are currently available ages are property of Humanitas Research
on the application of radiomics in PET/ Hospital.
REFERENCES
1. Surveillance, Epidemiology, and End Results Pro- 5. Fendler WP, Eiber M, Beheshti M, Bomanji J, Ceci F,
gram. SEER stat fact sheets: prostate cancer—statistics Cho S, et al. 68Ga-PSMA PET/CT: Joint EANM and
at a glance. National Cancer Institute Web site. http:// SNMMI procedure guideline for prostate cancer
seer.cancer.gov/statfacts/html/prost.html. Published imaging: version 1.0. Eur J Nucl Med Mol Imaging
2015. Accessed April 16, 2018. 2017;44:1014−1024.
2. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch 6. Wibmer AG, Burger IA, Sala E, Hricak H, Weber WA, Var-
MG, De Santis M, et al. EAU-ESTRO-SIOG guidelines gas HA. Molecular imaging of prostate cancer. Radio-
on prostate cancer. Part 1: screening, diagnosis, graphics 2016;36:142–159.
and local treatment with curative intent. Eur Urol 7. Antunovic L, Rodari M, Rossi P, Chiti A. Standardization
2017;71:618−629. and quantification in PET/CT imaging: tracers beyond
3. Ost P, Bossi A, Decaestecker K, De Meerleer G, Gianna- FDG. PET Clin 2014;9:259–266.
rini G, Karnes RJ, et al. Metastasis-directed therapy of 8. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile
regional and distant recurrences after curative treat- F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM proce-
ment of prostate cancer: a systematic review of the dure guidelines for tumour imaging: version 2.0. Eur J
literature. Eur Urol 2015;67:852−863. Nucl Med Mol Imaging 2015;42:328–354.
4. EANM. Principles and practice of PET-CT. Part 2. Wien, 9. Ackerstaff E, Glunde K, Bhujwalla ZM. Choline phos-
2012. Available on https://www.eanm.org/con- pholipid metabolism: a target in cancer cells? J Cell
tent-eanm/uploads/2016/12/gl_Principles_and_Prac- Biochem 2003;90:525–533.
tice_of_PET-CT_Part_22.pdf.
10. Farsad M, Schiavina R, Castelluci P, Nanni C, Corti 20. Mena E, Turkbey B, Mani H, Adler S, Valera VA, Bernar-
Ga-PSMA PET/CT imaging in high-risk prostate can- 34. Albisinni S, Artigas C, Aoun F, Biaou I, Grosman J, Gil
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cer patients prior to radical prostatectomy. Eur Urol T, et al. Clinical impact of (68)Ga-prostate-specific
2016;69:393−396. membrane antigen (PSMA) positron emission to-
31. Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, mography/computed tomography (PET/CT) in pa-
Haller B,Weirich G, et al. Diagnostic efficacy of galli- tients with prostate cancer with rising prostate-spe-
um-PSMA positron emission tomography compared cific antigen after treatment with curative intent:
to conventional imaging in lymph node staging of preliminary analysis. BJU Int 2017;120:197−203.
130 consecutive patients with intermediate to high 35. Cameron A, Khalvati F, Haider MA, Wong A. MAPS:
risk prostate cancer. J Urol 2015;195:1436−1443. A quantitative radiomics approach for pros-
32. Perera M, Krishnananthan N, Lindner U, Lawrentschuk tate cancer detection. IEEE Trans Biomed Eng
N. An update on focal therapy for prostate cancer. 2016;63:1145−1156.
Nat Rev Urol 2016;13:641−653. 36. Giesel FL, Schneider F, Kratochwil C, Rath D, Moltz J,
33. Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Holland-Letz T, et al. Correlation between SUVmax
Nikolaou K, et al. Comparison of 68Ga-labelled PSMA- and CT radiomic analysis using lymph node densi-
11 and 11C-choline in the detection of prostate can- ty in PET/CT-based lymph node staging. J Nucl Med
cer metastases by PET/CT. Eur J Nuc Med Mol Imag- 2017;58:282–287.
ing 2017;44:92−101.
6
PE T/C T - GU I D ED
R ADIOT H E R A PY
PL AN N I N G
INTRODUCTION
Prostate cancer is one of the most common cancers in men
PL A NNI NG I N PR O S TATE C A NC E R
PE T/C T- GUI D E D RA D I OTHE RA PY
In the past decade, therapies for prostate disease within the tumour volume. How-
cancer have undergone rapid change ever, experience in the use of 18F-FDG in
and development. In order to fully opti- prostate cancer for the purpose of staging
mise the clinical management of patients has been discouraging owing to the low
with various stages of prostate cancer, glucose metabolism in most prostate can-
improved diagnostic tools are required to cers. Carbon-11/fluorine-18 choline, which
allow accurate characterisation and locali- contains markers of cell membrane and
sation of the disease. metabolism, and prostate-specific mem-
In general, positron emission tomog- brane antigen (PSMA), a cell surface mem-
raphy (PET) based staging has proven to brane glycoprotein, have been suggested
be more accurate than non-PET staging to be promising targets for the diagnosis
owing to the sensitive and quantifiable and treatment of prostate cancer[5, 6].
molecular information that it provides on
the biology and extent of the cancers[4].
The additional metabolic information on PROSTATE CANCER
the primary tumour and lymph nodes has MANAGEMENT
been suggested to be useful in radiother- Several treatment options are available
apy planning. Fluorine-18 fluorodeoxy- for early prostate cancer, including active
glucose (18F-FDG) is the most commonly surveillance, radical prostatectomy, frac-
used radionuclide in clinical PET imaging, tionated external beam radiotherapy and
its uptake being assessed by means of brachytherapy. As yet, no single one of
the semi-quantitative standardised up- these treatment modalities has been prov-
take value (SUV). 18F-FDG accumulates in en to be superior to the others. In optimal
most cancers because of the expression of practice, all suitable options are discussed
both glucose transporters and hexokinase with the patient to facilitate individualised
in tumour cells. Hence, it may be used to treatment based on the patient’s clinical
identify regions of metabolically active scenario and personal preferences.
PL A NNI NG I N PR O S TATE C A NC E R
PE T/C T- GUI D E D RA D I OTHE RA PY
treatment for prostate cancer and is one RADIOTHERAPY PROCESS
of the most important components in
the prostate cancer management chain. Radiotherapy volume delineation and
Radiotherapy administered with cura- planning
tive intent, termed radical radiotherapy, There has been exponential development
involves the delivery of small doses of in radiation delivery techniques, especial-
radiation once a day for several weeks. ly using external beam radiotherapy. The
Each radiotherapy exposure is termed use of intensity-modulated radiotherapy
a fraction. Historically, prostate external (IMRT) and volumetric modulated arc ther-
beam radiotherapy has been given over apy (VMAT) allow individualised, highly
7–9 weeks with a daily fraction size of conformal dose delivery to tumours while
1.8–2 Gy. sparing surrounding normal tissues. These
There is a compelling case for treating advanced techniques enable the delivery
prostate cancer using hypofractionation. of the dose in more than one target vol-
Hypofractionation is the delivery of a ume and have realised the potential of
course of radiotherapy using a smaller dose escalation to the tumour. To exploit
number of fractions with a higher dose the advantage of IMRT/VMAT in creating a
of radiation at each fraction compared steep dose gradient between target vol-
with the conventional 1.8–2 Gy. The hy- umes and normal tissues, it is essential to
pothesis that this approach improves the obtain precise target volume delineations
therapeutic ratio in prostate cancer was and to achieve accurate daily treatment
tested in the conventional versus hypof- delivery with image-guided radiotherapy.
ractionated high-dose intensity-modulat- A successful course of radiotherapy for
ed radiotherapy for prostate cancer (CH- prostate cancer begins with the treatment
HIP) trial in a sample of 3216 patients[7]. planning process. With its excellent spatial
The trial compared schedules of 60 Gy reproducibility, kilovoltage x-ray comput-
in 20 daily fractions and 57 Gy in 19 dai- ed tomography (CT) imaging is the cur-
ly fractions over 4 weeks with a standard rent standard modality for radiotherapy
treatment schedule of 74 Gy in 37 daily planning. CT images can provide electron
fractions over 7.5 weeks. Early data from density information to radiotherapy treat-
the trial suggested that hypofractionated ment planning systems (RTPS) for hetero-
prostate radiotherapy is safe and well tol- geneity-based dose calculations. Howev-
erated. er, sole use of CT for tumour volume delin-
its limited soft tissue contrast, which has to report a treatment using external beam
the potential to give rise to significant in- radiotherapy[9]. ICRU report 62 (a supple-
ter-observer variability when contouring ment to ICRU 50) was developed in 1999
the target volumes. An increased risk of to accommodate the rapid changes in
local relapse due to inaccurate target vol- radiotherapy technologies that had oc-
ume delineation with inadequate imaging curred with the increased use of multimo-
cannot be compensated for by the use of dality imaging, computerised treatment
advanced delivery techniques or dose es- planning, delivery and verification[10].
calation. Multi-parametric magnetic reso- These two reports introduced common
nance imaging (MRI) is consequently of- terminologies for radiotherapy reporting
ten used in combination with CT for pros- and prescribing with the intention of stan-
tate target delineation for radiotherapy. dardising radiotherapy prescribing prac-
As recommended by the Internation- tice internationally. The volumes described
al Atomic Energy Agency (IAEA), PET can in the reports are outlined in Table 1.
also be incorporated into the planning In addition to the target volumes, the
process with CT for more accurate target reports recommended that treatment
volume definition[8]. A radiotherapy plan plans should be prescribed to a stable
can be designed for an individual patient point; this was termed the ICRU reference
to meet various treatment goals using a point. Often the isocentre of the treat-
detailed computer algorithm describing ment is used as the appropriate ICRU ref-
how the radiation dose can be deposited erence point. The treatment plan should
within the patient’s anatomy. be designed so as to fulfil the dose homo-
With the aim of standardising the prac- geneity criteria, such that the dose within
tice of prescribing radiotherapy and de- the planning target volume (PTV) should
signing treatment plans, the International vary by no more than −5% and +7% in re-
Commission on Radiation Units and Mea- lation to the prescribed dose at the ICRU
surements (ICRU) have produced reports reference point.
50, 62 and 83. These reports guide radio- ICRU report 83 was produced in 2010
therapy centres on how they can deliver and referred specifically to the prescrib-
an adequate and reliable dose to the tu- ing, recording and reporting of advanced
mour when treating with fractionated ra- radiotherapy techniques such as IMRT and
diotherapy[9–11]. VMAT[11]. The general principles of the pre-
ICRU report 50 was published in 1993 vious ICRU reports were maintained with-
PL A NNI NG I N PR O S TATE C A NC E R
PE T/C T- GUI D E D RA D I OTHE RA PY
the malignant growth.
For prostate radiotherapy, the GTV can be interpreted as the actual
tumor(s) in the prostate gland. The PET/CT information is useful to
aid in the volume delineation.
Clinical target volume (CTV) The tissue volume that contains a GTV and/or subclinical
microscopic malignant disease, which has to be eliminated.
For radiotherapy to early stage prostate cancer, the CTV often refers
to the whole prostate gland.
Planning target volume (PTV) A geometrical concept, defined to select appropriate beam sizes
and beam arrangements, taking into consideration the net effect of
all the possible geometrical variations and inaccuracies in order to
ensure that the prescribed dose is delivered to the CTV.
Organs at risk (OARs) Normal tissues whose radiation sensitivity may significantly influ-
ence treatment planning and/or prescribed dose.
For prostate radiotherapy, the OARs often refer to the bladder,
rectum and femoral heads.
in the report, which highlighted the need sorbed dose, the near maximum dose and
for consistent dose reporting of PTVs by the VD, which, if exceeded, has a known
reporting of the median absorbed dose, probability of causing complications, e.g.
the near maximum D2% (the highest dose V70Gy for rectum means the volume of rec-
received by at least 2% of the volume) and tum receiving 70 Gy. More consistent re-
the near minimum absorbed doses D98% porting may be achieved by the reporting
(the lowest dose received by at least 98% of the highest dose or lowest dose received
of the volume). In terms of dose prescrib- by at least 1 cc of an OAR, as this is indepen-
ing, it recommended volumetric prescrib- dent of the volume of the region of interest.
ing of the required treatment dose rather With radiotherapy planning, it is clear
than just a single point (e.g. D95, D98 or that the initial images used to develop the
median PTV dose). treatment plan yield a single snapshot of
For organs at risk (OARs), the report rec- the patient concerned, whereas the re-
ommended the reporting of the mean ab- sulting treatment plan has to be designed
cal feasibility of these approaches, which hybrid PET/CT scanner, the PET is assumed
PL A NNI NG I N PR O S TATE C A NC E R
PE T/C T- GUI D E D RA D I OTHE RA PY
provide the foundation for PET/CT-based to be automatically registered with the
dose escalation[14–16]. attenuation CT acquired during the same
In view of the limited temporal and spa- imaging session. First, automatic methods
tial resolution of PET, technical issues such are used to register the attenuation correc-
as hardware calibration, quality assurance, tion CT to the treatment planning CT. The
data post-processing and reconstruc- derived CT-to-CT transformation is then
tion techniques are of major importance applied to the PET, and the registration
when aiming for reliable assessment of a accuracy of PET to treatment planning CT
biologically active area[17]. Accurate patient is thereby improved[18]. Several steps are
positioning and immobilisation are cru- involved in the process of image registra-
cial in radiotherapy treatment. Very often, tion, including image set transfer, storage,
patient positioning for routine diagnostic coordination transformation and voxel in-
PET/CT image acquisition differs from that terpretation. The process is prone to errors,
for the planning CT scan. Hence, it is rec- which can cause serious adverse effects on
ommended that PET/CT data to be used target volume delineation. In accordance
as a basis for radiotherapy planning should with the recommendations of the Amer-
be acquired in the treatment position[18]. ican Association of Physicists in Medicine
Standardisation of these technical require- (AAPM) Task Group 53 Report, it is essential
ments can ensure a more reliable target to implement a quality assurance program
volume delineation using PET/CT images, to review general commissioning tests
leading to a solid basis for PET/CT-based and to ensure that routine procedural
dose escalation treatments. checks are undertaken for verification of
When fusing the biological PET data post-transfer image data integrity, image
with the dedicated planning CT, it is nec- spatial integrity, image orientation and im-
essary to carry out image registration, age registration accuracy[19].
which is a process of determining the op- With the high spatial resolution of IMRT/
timal spatial transformation for mapping VMAT, it is feasible to deliver highly con-
of one image to another. In general, the formal radiotherapy to highly complex
accuracy of image registration depends biological target volumes based on PET
on the quality of images to be registered. information. Accurate verification of pa-
The PET images are usually noisy and con- tient positioning can lead to successful
tain little anatomical information for regis- PET-based dose escalation treatment. Due
tration with CT images. With the use of a to the delivery of an extremely high dose
very small (in the order of millimetres) their practices to keep up to date with
systematic errors in patient positioning new developments, ensuring that these
could cause severe penalties in terms of new techniques are implemented safely
tumour control probability and normal tis- and accurately to the benefit of prostate
sue toxicities [20]. It is important to main- cancer patients.
tain a high quality of geometric accuracy
in radiotherapy treatment with use of the
latest daily IGRT techniques. CONCLUSION
Efficient and successful IGRT implemen- The use of PET/CT with advanced radio-
tation refines the delivery of radiotherapy therapy delivery techniques and IGRT
by using imaging techniques to visualise approaches has the potential to improve
and localise the target volume precisely, in radiotherapy treatment outcomes in pros-
order to allow proper patient reposition- tate cancer patients. The introduction of
ing that will ensure accurate treatment molecular information from PET/CT imag-
and minimisation of the volume of nor- ing into the radiotherapy process is pav-
mal tissue irradiated. The rapid evolution ing the way for personalised medicine for
of radiotherapy technology demands that prostate cancer management.
REFERENCES
PL A NNI NG I N PR O S TATE C A NC E R
PE T/C T- GUI D E D RA D I OTHE RA PY
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7
T HER A N O S T I C S
IN PRO S TAT E
by Sarah M. Schwarzenböck,
Bernd Joachim Krause
and Jens Kurth
CHAPTER 7
INTRODUCTION
The prostate-specific membrane antigen (PSMA) is a transmembrane
THE RA NO S TI C S I N PR O S TATE C A NC E R
PSMA ligands are increasingly being used ity in 46%, 46%, 73% and 80% at PSA levels
for molecular imaging and therapy of of below 0.2, 0.21–0.5, 0.51–1 and 1.1–2 ng/
prostate cancer in the sense of a theranos- mL, respectively[11].
tic approach. 68Ga-PSMA-11 (68Ga-PSMA Besides its diagnostic use, PSMA ligand
HBED-CC), 68Ga-PSMA-617 and 68Ga-PSMA- PET/CT is increasingly being used be-
I&T (being theranostic agents)[2–4] are the fore and during PSMA-based radioligand
most widely used PSMA ligands for PET/ therapy (RLT) of metastasised and castra-
CT imaging for staging of high-risk PC and tion-refractory PC (mCRPC), a stage which
restaging of recurrent PC (for an overview will be reached after some years of an-
see[5]); besides 68Ga-labelled PSMA ligands, drogen deprivation therapy (ADT). In this
18
F-DCFBC, 18F-DCFPyL and 18F-PSMA-1007 scenario, treatment options include tax-
have been introduced for PSMA PET/CT im- ane-based chemotherapies[12], therapeu-
aging[6–8]. In a meta-analysis including 1309 tic substances addressing the androgen
patients, PSMA PET positivity was demon- receptor signalling axis and biosynthesis
strated in 76% [95% confidence interval of androgens (such as enzalutamide and
(CI) 66%–85%] and 40% (95%CI 19%–64%) abiraterone)[13,14] and – in the case of bone
of patients in the detection of recurrence metastases – the bone-seeking alpha
and initial staging, respectively. In patients emitter 223Ra[15]; nevertheless, patients suf-
with biochemical recurrence and PSA val- fering from mCRPC have a poor progno-
ues of 0.2–1, 1–2 and >2 ng/mL, detection sis[16]. Besides the promising use of 131I-la-
rates were 58%, 76% and 95%, respective- belled PSMA targeting therapies[17,18], the
ly[9]. These data are in line with the results of use of 177Lu for PSMA-based radioligand
another recently published meta-analysis therapies (predominantly 177Lu-PSMA
which reported detection rates of 50% for 617[3] and 177Lu-PSMA I&T[4]) has recently
patients with a PSA value of 0.2–0.49 ng/ been demonstrated to be a safe and effec-
mL and 53% for those with a PSA of 0.5– tive therapeutic strategy for the treatment
0.99 ng/mL[10]. These data were confirmed of mCRPC patients[19–21]. This chapter gives
by the results of a retrospective analysis of an overview of the theranostic approach
1007 patients with recurrent prostate can- in prostate cancer, focussing on 68Ga/
cer which demonstrated PSMA PET positiv- 177
Lu–labelled PSMA ligands.
THE RA NO S TI C S I N PR O S TATE C A NC E R
FOR IMAGING, THERAPY AND short-lived radionuclide (with a half-life of
DOSIMETRY 68 min) that decays 89% through positron
In general, the term theranostics describes emission. It also shows favourable chem-
the combination of specific targeted ther- ical properties, so it can easily be labelled
apy based on specific targeted diagnostic with peptides using chelator chemistry.
tests. With respect to molecular imaging Lutetium-177 is also a metal, but it is a me-
and therapy, theranostics means that the dium-energy beta emitter (490 keV) with
same molecular target, which is highly a maximum tissue penetration of about
exclusively expressed by tumour cells, is 2 mm and a relatively long physical half-
used for both diagnosis and therapy. In the life of 6.73 days. The shorter beta range of
first step, patients are identified as possi- lutetium-177 provides better irradiation
ble candidates for therapy by imaging. of small tumours. It also emits low-ener-
This can be done by labelling a molecule gy gamma rays at 208 and 113 keV, which
that binds specifically to a disease-specific allow for in vivo imaging and patient-spe-
molecular target with either a positron or a cific determination of biokinetics. This is
gamma emitter, followed by imaging with the basis for performance of patient-spe-
PET/CT or SPECT/CT. If positive results are cific dosimetry before and during treat-
obtained, in a second step the same or a ment, which offers the opportunity to
very similar molecule can be used for ther- improve the safety and efficacy of target-
apy, now being labelled with a beta parti- ed radionuclide therapies because the
cle-emitting radionuclide (the use of alpha tumour dose can be optimised and the
emitters has also been successfully inves- organ toxicity can be predicted by estima-
tigated in very recent clinical studies[22]). tion of dose to organs at risk.
Finally, response to the therapy can be
assessed with the same diagnostic radio-
pharmaceutical as was used in step one. THERAPY PROCEDURE AND
For the PSMA-targeting theranostic ap- PRACTICAL ASPECTS
proach, the well-known tandem of galli- To date, 177Lu-PSMA has not been ap-
um-68 for diagnosis and lutetium-177 for proved by the U.S. Food and Drug Ad-
therapy is widely used[23–26]. Gallium-68 is ministration and the European Medicines
a metal and one of the first positron-emit- Agency; therefore formal criteria for the
ting radionuclides that have been used for indication of RLT have not been defined.
clinical imaging, such studies dating back According to the recommendations of the
German consensus guideline published cient hydration before, during and after
THE RA NO S TI C S I N PR O S TATE C A NC E R
by an expert panel of the German Asso- the therapy. Pretherapeutic salivary gland
ciation of Nuclear Medicine, 177Lu-PSMA scintigraphy with 99mTc-pertechnetate can
RLT can be offered to mCRPC patients be considered[23]. During therapy-forced
with progressive disease after exhaus- diuresis, ice packs for the salivary glands,
tion of approved therapies. Prerequisites anti-emetic medication and steroid ther-
for 177Lu-PSMA RLT are previous first and apy may be considered depending on
second (or third) line therapies in accor- the patient’s clinical condition[23]. The in-
dance with guidelines and current clinical fluence of continued ADT-based therapy
practice, sufficient organ function and during RLT is still under debate; prelim-
increased PSMA expression[23]; ideally the inary data show that PSMA expression is
indication for RLT should be discussed potentially increased by ADT[28, 29].
and confirmed within an interdisciplinary Dosimetric measurements following
board. 177Lu-PSMA RLT is administered in 177
Lu-PSMA RLT are recommended, as
multiple cycles: according to the German discussed below. The follow-up examina-
consensus guideline, 177Lu-PSMA RLT is tion should include patient history, phys-
repeated at 8-week intervals with 6 GBq ical examination, imaging and laboratory
as a standard activity, being administered measurements at 2- to 4-week intervals.
intravenously as a slow bolus; 4–7 weeks For more details on the recommendations
after the second therapy cycle, restaging regarding use of 177Lu-PSMA RLT, see Fen-
using PSMA ligand PET/CT takes place. dler et al.[23, 30].
Provided that RLT is sufficiently tolerated
and tumour manifestations remain PSMA
positive, further cycles can be considered, INTRA- AND POST-
with a cumulative activity of up to 18 THERAPEUTIC IMAGING AND
GBq[23]. In former studies up to four or six DOSIMETRY
cycles of RLT have been applied without The calculation of doses to tumour le-
salivary toxicities of grade ≥3 or activi- sions and organs at risk requires intra- and
ty-limiting renal toxicity, respectively[24, 27]. post-therapeutic imaging of patients at
Patient preparation should comprise multiple time points during treatment to
evaluation of renal function (potentially extract time-activity curves (TAC) for each
including renal scintigraphy with 99mTc- organ and lesion of interest. The TAC can
MAG3) along with assessment of other be extracted from planar images or SPECT
clinically relevant parameters and suffi- series or a combination of both[31, 32], prop-
er calibration of the gamma camera being for 177Lu-PSMA-targeted therapies[23, 25, 39]
THE RA NO S TI C S I N PR O S TATE C A NC E R
required for both planar and SPECT imag- and the results show rapid blood clear-
ing. SPECT images should be reconstructed ance and activity elimination from the
using iterative algorithms, and corrections body through the renal pathway. Besides
for scatter and attenuation, dead time and uptake in tumour lesions of prostate can-
distant-dependent detector blurring should cer, physiological uptake of PSMA ligands
be used[33]. Considering on the one hand the is also seen in the lacrimal, parotid and
poor health status of many patients suffer- submandibular glands, liver and spleen.
ing from mCRPC and on the other the kinet- The absorbed dose to the kidneys related
ics of 177Lu-PSMA compounds, use of a stan- to 177Lu-PSMA RLT has been reported by
dardised imaging protocol is recommended several authors to be well below the 23 Gy
(four time points at 2, 24, 48 and 72 h post-in- dose-limiting threshold which is associ-
jection)[23]. Preferably, quantitative SPECT/CT ated with a 5% probability of developing
imaging should be performed. However, in severe kidney damage within 5 years[40–42].
some situations multiple SPECT/CT imaging It is currently under debate to what extent
is not possible and/or the axial field of view the limit of 23 Gy, which is derived from ex-
obtained from whole-body imaging is desir- ternal beam radiation therapy, can be used
able. In these cases a combination of whole- for radionuclide therapies, like PSMA-tar-
body imaging and SPECT/CT can be applied geted therapy. However, parotid glands
(so-called 2.5D imaging)[32]. receive higher doses than the kidneys and
Estimations of the doses to organs and the role of the lacrimal and salivary glands
target lesions are generally performed as dose-limiting organs is being discussed
according to the MIRD scheme[34, 35] us- critically[43]. The dose to tumour lesions
ing special software tools[36, 37]. Based on shows a high intra-patient and intra-lesion
the fitted TAC, the integral of the activity variability, mainly related to localisation
over time until infinity can be derived, and biological factors such as receptor
which correlates to the number of decays density, binding affinity, tumour volume
that occur in the specific organ and from and many more.
which the absorbed dose can be calcu- Due to substantial individual variance,
lated. Blood-based and/or imaging-based dosimetry is mandatory for a patient-spe-
methods are used to calculate the dose to cific approach in 177Lu-PSMA-targeted
red bone marrow[38]. therapy: the maximum tolerable dose to
The calculation of organ and lesion dos- organs at risk calculated by an individual-
es forms part of most clinical protocols ised method may be higher in a consider-
able number of patients, allowing for ad- and/or shorter treatment intervals might
THE RA NO S TI C S I N PR O S TATE C A NC E R
Figure 1
177
Lu-PSMA-
Pretherapeutic 617-Therapy Posttherapeutic
68
Ga-PSMA-PET/CT SPECT/CT 68
Ga-PSMA-PET/CT
THE RA NO S TI C S I N PR O S TATE C A NC E R
RESPONSE TO 177LU-PSMA RLT RESPONSE ASSESSMENT OF
Prostate-specific antigen values should be
177
LU-PSMA RLT
obtained after each therapy cycle. Overall, Although response criteria for PSMA li-
the results of available studies on PSMA gand RLT have not yet been established,
ligand RLT in mCRPC patients who have preliminary data show that decline in PSA
received different numbers of therapy cy- values is accompanied by morphological
cles indicate that response to therapy in and/or metabolic changes as assessed by
terms of PSA decline is observed in up to CT (RECIST criteria) and/or 68Ga-PSMA PET/
70%–90% of patients, with a PSA reduction CT (PCWG2 criteria or PERCIST criteria).
of ≥50% in up to 60% [25, 39, 41, 44–50]. These Complete remission, partial remission
results on biochemical response rate and stable disease in 68Ga-PSMA PET/CT-
were confirmed by a German multicentre based therapy response assessment have
study which demonstrated a PSA decline been reported in up to 33%, 80% and 63%
of ≥50% in 45% of patients after all ther- of patients, respectively, with progressive
apy cycles and in 40% after the first ther- disease in up to 36% [25, 39, 44, 46, 51, 52].
apy cycle[24]. Similarly, a recently published Contrast-enhanced CT-based therapy
meta-analysis showed “any PSA decline” in response assessment (according to RECIST
68% of patients and a decline of ≥50% in 1.1) has been reported to reveal partial re-
37%[19]. mission in up to 40% and stable disease in
Stable disease (defined by a change in up to 56% of patients, with progressive dis-
PSA ranging from a decrease of <50% to ease in up to 33%[25, 39, 44, 51]. Morphological
an increase of >25%) has been found in up response assessment has been found to be
to 50% of patients[24, 48]. In the latter study, more reliable in nodal metastases than in
only 23% of patients showed progressive bone metastases owing to better CT de-
disease (with a PSA increase of more than lineation of lymph nodes compared with
25%) during therapy[48]. bone metastases and the difficulties in dif-
Pain relief has been observed in up to 70% ferentiating active bone metastases from
of patients[25, 39, 51, 52], and significant improve- therapy-induced sclerotic bone changes[39].
ment in quality of life in up to 60% of symp- Combined assessment using CT/RECIST
tomatic patients[25, 41]. Karnofsky and East- criteria for soft tissue lesions and 68Ga-PS-
ern Cooperative Oncology Group (ECOG) MA PET/CT/PCWG2 criteria for bone le-
performance status score is improved or sions might be promising[51]. For an image
remains stable in most patients[39, 51, 52] while example of therapy response assessment
worsening is not or seldom observed[39]. using 68Ga-PSMA PET/CT, see Fig. 1.
LU-PSMA RLT
177
dian progression-free survival ranged be-
The most common side effects of RLT are tween 175 days and 13.7 months[39, 41, 50–52].
mild fatigue (for a few days after therapy) In the study by Yadav et al. the median
and mild and in most cases transient xero- overall survival was 16 months[52]; these
stomia[39, 41, 45, 46, 51], which may be reduced results were confirmed by Rahbar et al.,
by a cooling procedure before and after who showed a median overall survival of
therapy administration. 56 weeks[49]. A positive response to RLT, re-
Diffuse bone marrow involvement gardless of the rate of PSA decline, seems
seems be a risk factor for higher grade to be associated with a significantly longer
myelosuppression under treatment, and median overall survival[49, 53].
can be identified pretherapeutically by In a retrospective study, Rahbar et al.
68
Ga-PSMA PET/CT[24, 46]. Grade 3 or 4 hae- showed the estimated median survival
matological toxicities are observed in a of an RLT group to be significantly longer
minority of patients (up to 14%), most of than that of a historical best supportive
whom have previously received chemo- care group[47]. Prospective controlled ran-
therapy or 223Ra therapy[24, 41]. In the major- domised trials are necessary to confirm
ity of studies no acute or long-term side improvement in survival of mCRPC pa-
effects or high-grade haematological or tients who receive RLT compared with
renal toxicities have been observed[25, 27, 39, treated using conventional therapies.
44–48, 50–52]
. For an overview and further de-
tails on the toxicity of PSMA ligand thera-
py, see[20, 21]. CONCLUSION
The role of potential kidney protection 177
Lu-PSMA RLT is a promising safe and
is under discussion. According to the avail- effective treatment option that is already
able data, kidney protection procedures being offered to patients with mCRPC af-
might not be obligatory in patients with ter exhaustion of all approved therapies,
normal kidney function. within clinical trials or under local regu-
lations. In patients with bulky disease, 90Y
may represent an alternative to 177Lu ow-
SURVIVAL DATA OF ing to the higher range of beta particles
LU-PSMA RLT
177
emitted by 90Y. The use of PSMA ligands
Relatively few data are available on the labelled with alpha emitters such as 225Ac
survival of mCRPC patients treated with and 213Bi could in the future be beneficial
THE RA NO S TI C S I N PR O S TATE C A NC E R
row or progressive disease under 177Lu-PS- the GRPR antagonist 68Ga/177Lu-RM2, may
MA RLT[22, 54–56]. Additionally, other novel be promising theranostics for prostate
theranostic agents that address the gas- cancer in the future[57–60].
trin-releasing peptide receptor (GRPR), also
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Nucl Med Mol Imaging 2016;43:42–51. Schäfers M, Essler M, Ahmadzadehfar H, et al. PSMA
41. Kulkarni HR, Singh A, Schuchardt C, Niepsch targeted radioligandtherapy in metastatic castration
K, Sayeg M, Leshch Y, et al. PSMA-based radioligand resistant prostate cancer after chemotherapy,
therapy for metastatic castration-resistant prostate abiraterone and/or enzalutamide. A retrospective
cancer: the Bad Berka experience since 2013. J Nucl analysis of overall survival. Eur J Nucl Med Mol Imaging
Med 2016;57(Suppl 3):97S–104S. 2018;45:12–19.
50. Brauer A, Grubert LS, Roll W, Schrader AJ, Schäfers Bruchertseifer F, Rathke H, Morgenstern A, et al.
M, Bögemann M, Rahbar K. (177)Lu-PSMA-617 Targeted alpha therapy of mCRPC: Dosimetry esti-
THE RA NO S TI C S I N PR O S TATE C A NC E R
radioligand therapy and outcome in patients with mate of (213)bismuth-PSMA-617. Eur J Nucl Med Mol
metastasized castration-resistant prostate cancer. Imaging 2018;45:31–37.
Eur J Nucl Med Mol Imaging 2017;44:1663–1670. 56. Sathekge M, Knoesen O, Meckel M, Modiselle
51. Heck MM, Retz M, D‘Alessandria C, Rauscher M, Vorster M, Marx S. (213)Bi-PSMA-617 targeted
I, Scheidhauer K, Maurer T, et al. Systemic radioligand alpha-radionuclide therapy in metastatic castra-
therapy with (177)Lu labeled prostate specific mem- tion-resistant prostate cancer. Eur J Nucl Med Mol
brane antigen ligand for imaging and therapy in Imaging 2017;44:1099–1100.
patients with metastatic castration resistant prostate 57. Maina T, Nock BA, Kulkarni H, Singh A, Baum RP.
cancer. J Urol 2016;196:382–391. Theranostic prospects of gastrin-releasing peptide
52. Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo receptor-radioantagonists in oncology. PET Clin
RK, Seth A, Bal C. 177Lu-DKFZ-PSMA-617 therapy 2017;12:297–309.
in metastatic castration resistant prostate cancer: 58. Minamimoto R, Hancock S, Schneider B, Chin
safety, efficacy, and quality of life assessment. Eur J FT, Jamali M, Loening A, et al. Pilot comparison of
Nucl Med Mol Imaging 2017;44:81–91. (68)Ga-RM2 PET and (68)Ga-PSMA-11 PET in patients
53. Ahmadzadehfar H, Wegen S, Yordanova A, Fimmers with biochemically recurrent prostate cancer. J Nucl
R, Kürpig S, Eppard E, et al. Overall survival and Med 2016;57:557–562.
response pattern of castration-resistant metastatic 59. Nock BA, Kaloudi A, Lymperis E, Giarika A, Kulkar-
prostate cancer to multiple cycles of radioligand ni HR, Klette I, et al. Theranostic perspectives in
therapy using [(177)Lu]Lu-PSMA-617. Eur J Nucl Med prostate cancer with the gastrin-releasing peptide
Mol Imaging 2017;44:1448–1454. receptor antagonist NeoBOMB1: Preclinical and first
54. Kratochwil C, Bruchertseifer F, Giesel FL, Weis clinical results. J Nucl Med 2017;58:75–80.
M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 60. Dalm SU, Bakker IL, de Blois E, Doeswijk GN, Koni-
for PSMA-targeted alpha-radiation therapy of meta- jnenberg MW, Orlandi F, et al. 68Ga/177Lu-Ne-
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PROSTAT E
C AN C E R
R ADIO N UC L I D E
T HER A PY BA S E D
O N AL P H A
EMIT T E R S
by Mark Konijnenberg
and Domenico Albano
CHAPTER 8
INTRODUCTION
Prostate cancer is one of the most common cancers among men. It is
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
associated with advanced age (it is very uncommon in males <45 years old)
but its pathogenesis is not yet clearly understood. Usually this neoplasm
grows very slowly, but sometimes it spreads to other organs. There are
two main types of metastatic dissemination: local metastasis, with spread
to other organs within the pelvis and usually lymph node involvement,
and distant metastases, when the spread extends beyond the pelvis, to
bone, liver, lung or brain.
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
RADIONUCLIDES AVAILABLE in healthy tissues like salivary glands and
FOR PROSTATE CANCER kidneys (proximal tubules). PSMA target-
THERAPY ing agents labelled with the alpha emit-
The first targeted alpha-particle emitter ters actinium-225 (225Ac) and bismuth-213
therapy to be approved for the treat- (213Bi) have been used on a compassionate
ment of metastatic prostate cancer is ra- use basis in castration-resistant prostate
dium-223 (223Ra) dichloride (Xofigo®)[1]. In cancer patients. The results in disease
the periodic system, radium belongs to reduction are impressive, especially for
the alkaline earth metals (group 2), which 225
Ac-PSMA, which has been shown to be
also include beryllium and calcium. Alka- successful in patients with disease refrac-
line earth metals are known to be calcium tory to lutetium-177 PSMA therapy[3, 4].
mimetic or “bone seekers” and 223Ra is no
exception. It accumulates in bone, with
highest uptake around the interface be- HOW PATIENTS ARE SELECTED
tween bone and metastasis. The same FOR THERAPY
mechanism of uptake occurs with the be- Nuclear medicine therapy for bone me-
ta-particle emitter strontium-89 (89Sr) chlo- tastases is a systemic radionuclide thera-
ride (Metastron®), which is also an alkaline py based on the use of intravenously ad-
earth metal. 223Ra has a great advantage ministered radiopharmaceuticals that are
over 89Sr in that it emits high-LET alpha classified into specific tumour-seeking and
particles; this enables complex DNA dou- bone-seeking agents. Bone-seeking radio-
ble-strand break-induced cell death at a pharmaceuticals are specifically localised
short distance, as the range of the emitted to the sites of active bone reaction and re-
alpha particles is between 40 and 70 μm[2]. modelling (areas with increased osteoblas-
Other agents for alpha-particle emitter tic activity) and deliver focal radiation by
radionuclide therapy for prostate cancer beta emission or alpha particles, targeting
are still at an experimental stage. Most primary metastatic bone lesions. The same
of the compounds under development mechanism is exploited in the diagnosis of
use prostate-specific membrane antigen bone metastases using technetium-99m
(PSMA) targeting agents as carriers to de- phosphonate. Therapeutic bone-seeking
liver the alpha emitter to visceral meta- radiopharmaceuticals can also be divided
static lesions. PSMA is expressed in almost into two principal chemical classes – cat-
all prostate cancers, including soft tissue ionic or calcium analogues (such as phos-
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
PRINCIPLES External beam radiotherapy (EBRT) is only
Radiation induces cell death by produc- applicable for a limited number of bone
ing damage to DNA. This principle has lesions. Radiopharmaceuticals form an im-
been applied with beta-particle emitters portant palliative care option for multifo-
and external beam exposure. In these cal bone metastases and, as already men-
low ionisation density or low-LET radia- tioned, in the case of 223Ra may even offer
tion conditions, less complex sublethal prolongation of survival.
DNA damage will be repaired, especially Technetium-99m methylene diphos-
at the low dose rates encountered with phonate (MDP) bone scan can be used
beta-particle emitters. The high-LET radia- to determine the absorbed dose to bone
tion of the four alpha particles emitted by lesions, offering guidance regarding the
223
Ra creates more complex multiple DNA 223
Ra uptake. A mean absorbed dose of
breaks that are not repairable. The range of 0.7 (0.2–1.9) Gy per treatment cycle of 50
the alpha particles in tissue is 60–100 μm, kBq/kg body weight was reported in nine
whereas the beta particles from samari- patients[7]. With a full therapy consisting
um-153 have a mean range of 1 μm and of six treatment cycles this would result
a maximum range of 3.4 μm. Consequent- in a mean absorbed dose of 4 Gy; taking
ly, when using 223Ra the absorbed dose the enhanced radiobiological effect (RBE)
will be delivered in close proximity to the of alpha particles into account (with an
emission site, which helps to reduce the assumed RBE of 5 for alpha emitters [18]),
absorbed dose in nearby critical organs this would correspond to DRBE=19 Gy. This
such as bone marrow. Small-scale dosim- absorbed dose does not exceed the doses
etry models for metastatic bone lesions in obtained with EBRT and other beta-emit-
the endosteal layer and the bone marrow ting palliative radiopharmaceuticals.
show that even at the highest considered
absorbed dose to bone lesions, i.e. 20 Gy,
more than 40% of the bone marrow will PROSTATE CANCER THERAPY
receive a dose of <2 Gy[5]. Xofigo is the only clinical therapy available
In external beam palliative radiotherapy that is based on 223Ra. 223Ra is obtained
for bone metastases, pain relief is obtained from an actinium-227 generator. Actin-
after a single dose of 8 Gy. More prolonged ium-227 decays via its daughter radio-
pain relief is achieved by the use of frac- nuclide thorium-227 (T1/2=18.7 days) to
tionated dosing schemes, ranging from 20 223
Ra. The six-stage decay of 223Ra to stable
lead-207 occurs via a chain of short-lived in addition, beta and gamma emissions
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
daughter nuclides and is accompanied occur with different energies and emis-
predominantly by alpha emissions (Fig. 1); sion probabilities. 223Ra and its daughter
Figure 1
223
Ra
T½ 11.43 d
5.67 MeV α
219
Rn
T½ 3.96 s
6.75 MeV α
215
Po
T½ 11.78 ms
7.39 MeV α
211
Pb 211
Bi 0.28%
211
Po
0.45 MeV β
T½ 36.1 min T½ 2.14 min 0.17 MeV β T½ 0.516 s
211
Bi 211
Po
0.50 MeV β
T½ 2.14 min T½ 0.516 s
Figure 1: Decay scheme for 223Ra and its progeny, with alpha-particle emissions (downward
arrows with total alpha-particle energy per decay) and beta-particle emissions (sideward arrows
with mean beta-particle energy)
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
211, bismuth-211 and thallium-207, reach with consequently image-degrading ef-
equilibrium after a couple of hours. As a fects in low-energy windows, such as
consequence 223Ra may be considered down-scatter and septal penetration. It is
to be a radionuclide emitting four alpha advisable to perform acquisitions with two
particles per decay with a half-life of 11.43 energy windows centred at 82 keV and
days (Table 1). The fraction of energy emit- 154 keV (20% wide) and a medium-energy
ted from 223Ra and its daughters as alpha general-purpose collimator[8].
particles is 95.3% (energy range of 5–7.5
MeV). Lead-211 and bismuth-211 emit The biokinetics of 223Ra has been stud-
beta particles with mean energies of 0.45 ied extensively for radiation protection
and 0.17 MeV, respectively. 223Ra emits sev- purposes. Based on the biokinetic model
eral gamma- and x-rays, of which the x-rays for 223Ra of ICRP publication 67, organ do-
at 81 keV and 84 keV (with abundances of simetry estimates have been made, with
15.7% and 25.9%/decay) can be used for absorbed dose estimates for the bone
imaging. Additionally at higher energy the endosteum of 3.8 Sv/MBq and for the
gamma-rays at 144 and 154 keV (3.27% and bone marrow of 0.37 Sv/MBq, both with
5.70%/decay) are very suitable for SPECT an RBE=5. This would result in a cumula-
imaging.223Ra and its progeny, however, tive absorbed doses of 16 Gy to the endos-
Nuclide Physical Total alpha energy Abundance per Mean range in Mean range in
half-life (MeV/decay) decay of 223Ra soft tissue cortical bone
(μm) (μm)
Ra
223
11.43 days 5.667 100% 43 28
Rn
219
3.96 s 6.754 100% 57 37
Po
215
1.78 ms 7.386 100% 65 43
Bi
211
2.14 min 6.549 99.724% 54 35
Po
211
0.516 s 7.442 0.276% 66 43
Table 1: Decay properties of 223Ra and its progeny, with total alpha-energy emitted per decay and its
range in soft tissue (density: 1.04 g/cm3) and adult cortical bone (density: 1.92 g/cm3). Alpha-particle
energies from ICRP publication 107 and the ranges in tissue were calculated with the SRIM-2013 code
(available at SRIM.org)
teum and 1.5 Gy to the bone marrow per all patients’ exposures for radiotherapeu-
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
therapy with 4.125 MBq 223Ra. In patients tic purposes, the irradiation of target vol-
with advanced disease these doses might umes shall be individually planned and
be very different[9]. appropriately verified, keeping the ab-
The biodistribution and dosimetry for sorbed doses to non-target tissues as low
223
Ra dichloride have been studied in as reasonably achievable and consistent
phase 1 clinical trials[10, 11]. It was found with the intended radiotherapeutic pur-
that the compound is rapidly cleared from pose of the exposure”. Exact knowledge of
the blood, with less than 1% remaining the absorbed dose-response correlations
at 24 h. Most of the administered activity is essential and a multicentre, observa-
was rapidly taken up into bone (61%±10% tional study regarding lesion dosimetry
of the administered activity at 4 h after has been started in Italy for this purpose[8].
injection). Elimination of 223Ra dichloride
was mainly through the gastrointestinal
tract, and early clearance was seen from DURATION OF RADIONUCLIDE
the small intestine: at 4 h, 40%±19% of the THERAPY
administered activity was in the small in- Therapy with 223Ra is administered in-
testine, but by 72 h all activity had cleared. travenously at a dose of 55 kBq/kg body
Clearance from the large intestine oc- weight. In total, six injections are given
curred at later time points. Urinary excre- at intervals of 4 weeks, resulting in a total
tion was minimal (typically 2%–5%) and of 24 weeks of therapy. Typically 50% of
faecal excretion was found to provide the patients are capable of receiving the full
main route of elimination[10, 11]. six-cycle treatment. Reasons for discontin-
The phase 1 trials with 223Ra revealed a uation of therapy are progressive disease,
maximum tolerable activity of 200 kBq/kg, haematological toxicity, declining health
almost four times the amount that provid- status, and skeletal-related events[13]. Clin-
ed pain relief and survival efficacy in the ical studies are ongoing to compare the
phase 2 and 3 trials. This opens options standard 6×55 kBq/kg with 6×88 kBq/
for the design of more optimal treatment kg and 12×55 kBq/kg, the doses all being
schemes, aimed at increased survival. This given at 4-week intervals[14]. Retreatment
treatment planning approach would also with 6×55 kBq/kg 223Ra was found to be
be more in line with the current European well tolerated, with minimal haematolog-
legislation according to the EC Directive ical toxicity, in a phase 1/2 prospective
2013/59 Euratom[12], which states that ‘‘in study in a highly selected population of
patients with castration-resistant prostate lower than the optimum value at 31 MeV
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
cancer and bone metastases who had un- since at this energy astatine-210 is also
dergone initial 223Ra treatment 6 months formed, which decays to polonium-210:
(median time interval) previously[15]. a pure alpha emitter with a half-life of 138
days which has become infamous after the
poisoning of Alexander Litvinenko.
DEVELOPMENT OF NEW Alpha-emitter therapies are considered
RADIONUCLIDES AND to be the most promising form of radio-
THERAPIES nuclide therapy, as they are capable of
Most new therapies rely on a vector such killing both single cells and small to large
as PSMA-targeting agents that is of proven tumour lesions. The high-LET character of
efficacy in conjunction with a beta emitter the alpha-particle radiation enables it to
or alpha emitter. 225Ac seems to be a favou- be effective in tissues with low oxygen
rite as it can be labelled to the vector by levels, such as the hypoxic core of many
metal chelators such as DOTA. Like 223Ra, tumours. Understandably, the risk of and
it emits four alpha particles per decay by concerns regarding serious toxicity in
itself and through its daughter atoms, all off-target tissue make the development
of which have a shorter half-life than that of these targeted therapies a long-term
of 225Ac (T1/2=10 days). 225Ac is obtained effort and currently most alpha-particle
from a thorium-229 generator (T1/2=7880 therapies are aimed at patients with end-
years), which decays through radium-225 stage disease.
(T1/2=14.8 days) to 225Ac[16]. Another alpha
emitter that is gaining more attention in Disclosure statement: the work of Mark
various preclinical and also some clinical Konijnenberg is being partly supported
studies is astatine-211. Its half-life is much by grants from Advanced Accelerator
shorter (T1/2=7.21 h) and it emits only one Applications.
alpha particle per decay, 41.8% with 5.87
MeV and 58.2% by its daughter poloni-
um-211 (T1/2=0.516 s) with 7.44 MeV[17].
It can be produced through the bis-
muth-209(α,2n) astatine-211 reaction with
a high-energy cyclotron by bombarding
a bismuth target with 30-MeV alpha par-
ticles. The chosen alpha energy is usually
REFERENCES
THE RA PY BA S E D O N A L PHA E M I T TE RS
PR O STATE C A NC E R RA D I O NUC L I D E
1. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan 11. Chittenden SJ, Hindorf C, Parker CC, Lewington VJ,
JM, Fossa SD, et al. Alpha emitter radium-223 and Pratt BE, Johnson B, et al. A phase 1, open-label study
survival in metastatic prostate cancer. N Engl J Med of the biodistribution, pharmacokinetics, and dosim-
2013;369:213–223. etry of 223Ra-dichloride in patients with hormone-re-
2. Poeppel TD, Handkiewicz-Junak D, Andreeff M, Bech- fractory prostate cancer and skeletal metastases. J
erer A, Bockisch A, Fricke E, et al. EANM guideline for Nucl Med 2015;56:1304–1309.
radionuclide therapy with radium-223 of metastatic 12. Council Directive 2013/59/EURATOM of 5 December
castration-resistant prostate cancer. Eur J Nucl Med Mol 2013. Official Journal of the European Union 2014.
Imaging 201845:824–845. Available from: https://ec.europa.eu/energy/sites/
3. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, ener/files/documents/CELEX-32013L0059-EN-TXT.
Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for pdf.
PSMA-targeted alpha-radiation therapy of metastat- 13. Etchebehere EC, Araujo JC, Milton DR, Erwin WD,
ic castration-resistant prostate cancer. J Nucl Med Wendt RE, 3rd, Swanston NM, et al. Skeletal tumor
2016;57:1941–1944. burden on baseline 18F-fluoride PET/CT predicts
4. Kratochwil C, Schmidt K, Afshar-Oromieh A, Bruchert- bone marrow failure after 223Ra therapy. Clin Nucl
seifer F, Rathke H, Morgenstern A, et al. Targeted al- Med 2016;41:268–273.
pha therapy of mCRPC: Dosimetry estimate of (213) 14. NCT02023697. Standard dose versus high dose and
Bismuth-PSMA-617. Eur J Nucl Med Mol Imaging 2018 versus extended standard dose radium-223 dichlo-
Jan;45(1):31–37. ride in castration-resistant prostate cancer meta-
5. Hobbs RF, Song H, Watchman CJ, Bolch WE, Aksnes static to the bone. 5 February 2018. Available from:
AK, Ramdahl T, et al. A bone marrow toxicity model for https://clinicaltrials.gov/ct2/show/NCT02023697. In
(223)Ra alpha-emitter radiopharmaceutical therapy. the meantime the results for this trial were published
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6. Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, et al. dard dose did not lead to extended survival or delay
Palliative radiotherapy for bone metastases: an ASTRO of skeletal events.
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2011;79:965–976. Keizman D, Thellenberg Karlsson C, et al. Re-treat-
7. Pacilio M, Ventroni G, De Vincentis G, Cassano B, Pel- ment with radium-223: first experience from an inter-
legrini R, Di Castro E, et al. Dosimetry of bone metasta- national, open-label, phase I/II study in patients with
ses in targeted radionuclide therapy with alpha-emit- castration-resistant prostate cancer and bone metas-
ting (223)Ra-dichloride. Eur J Nucl Med Mol Imaging tases. Ann Oncol 2017;28:2464–2471.
2016;43:21–33. 16. Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner
8. Pacilio M, Cassano B, Chiesa C, Giancola S, Ferrari M, M, Giesel FL, Haberkorn U, et al. Targeted alpha ther-
Pettinato C, et al. The Italian multicentre dosimetric apy of mCRPC with (225)actinium-PSMA-617: Swim-
study for lesion dosimetry in (223)Ra therapy of bone mer-plot analysis suggests efficacy regarding dura-
metastases: Calibration protocol of gamma cameras tion of tumor control. J Nucl Med 2018;59:795–802.
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9. Lassmann M, Nosske D. Dosimetry of 223Ra-chloride: tatobenzamido)pentyl)ureido)-pentanedioic acid for
dose to normal organs and tissues. Eur J Nucl Med Mol PSMA-targeted alpha-particle radiopharmaceutical
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10. Carrasquillo JA, O’Donoghue JA, Pandit-Taskar N, 18. Sgouros G, Roeske JC, McDevitt MR, Palm S, Allen BJ,
Humm JL, Rathkopf DE, Slovin SF, et al. Phase I phar- Fisher DR, et al. MIRD Pamphlet No. 22 (abridged):
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Med Mol Imaging 2013;40:1384–1393.
T HE
MA N AGE M E N T
O F A PRO STATE
C AN C E R PAT I E N T
by MarieClaire Attard
and Rexhep Durmo
CHAPTER 9
INTRODUCTION
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
uncertain, the burdens associated with the abnormalities (e.g. nodules, asymmetry
There are three types of tumour charac- widely used staging system for prostate
teristic: tumour grade, tumour score and cancer is the American Joint Committee
tumour stage. on Cancer (AJCC) tumour-node-metasta-
sis (TNM) system[11], as shown below.
Tumour grade and score The AJCC staging system for prostate
Tumour aggressiveness can be deter- cancer is based on five key pieces of infor-
mined by the histological results obtained mation:
from the biopsy. The most common tu- »» The extent of the main (primary) tu-
mour grading system is called Gleason mour (T category)
grading. This grading system assigns a »» Whether the cancer has spread to near-
grade to the prostate cancer, from 1, de- by lymph nodes (N category)
noting the least aggressive, to 5, denoting »» Whether the cancer has spread (me-
the most aggressive. The total score is de- tastasised) to other parts of the body
rived by summing the score relating to the (M category)
dominant or most common cell morphol- »» The PSA level at the time of diagnosis
ogy (scored 1–5) and the score relating to »» The grade group (based on the Gleason
the non-dominant cell pattern with the score)
highest grade (scored 1–5) [10]. The high-
er the Gleason score obtained from the T – Primary tumour
biopsy, the more aggressive is the tumour. »» TX Primary tumour cannot be assessed
High-grade cancer refers to tumours with »» T0 No evidence of primary tumour
Gleason scores of 8 to 10 (although it can »» T1 Clinically inapparent tumour that is
also include Gleason 7 tumours)[9]. not palpable
- T1a Tumour incidental histological
Tumour stage finding in 5% or less of tissue resected
The tumour stage refers to the extent of - T1b Tumour incidental histological find-
invasion of surrounding organs by the ing in more than 5% of tissue resected
prostate cancer. Tumours that remain - T1c Tumour identified by needle biop-
confined to the prostate are, of course, sy (e.g. because of elevated PSA level)
more easily treatable that those that have »» T2 Tumour that is palpable and con-
spread to the surrounding tissues. Pros- fined within the prostate
tate cancer that has metastasised to oth- - T2a Tumour involves one half of one
er body organs, such as bone or lymph lobe or less
M – Distant metastasis
»» M0 No distant metastasis
»» M1 Distant metastasis
- M1a Non-regional lymph node(s)
- M1b Bone(s) group[14]. However, there are limitations to
- M1c Other this risk classification. No two patients are
the same and patients’ requests and needs
will depend on their lifestyle, age and tu-
RISK CLASSIFICATIONS mour classification and staging[14].
Patients are usually classified into three Figure 2 shows the classification of pros-
categories (Fig. 1) according to their tate cancer and illustrates some of the
pathological factors and their treatment available management options. A brief ex-
preferences[12, 13], though some authors planation of each imaging technique and
also include a very low and a very high risk treatment is given below.
Figure 2
Prostate Cancer (PC)
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
Radical
Treatment Treatment Palliative prostatectomy not
options options treatment recommended
Brachy- For
localised PC PSMA
therapy
Radium-223
Radiotherapy Radiotherapy dichloride
therapy
Eventual
involvement MRI/ Relief of any
in clinical bone scan complaints
trials
Figure 2: Classification of prostate cancer, illustrating some of the treatment options available in
different risk groups
inability to discriminate between such PSA levels between 10.1 and 19.9 ng/mL
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
cancers and BPH and prostatitis[19, 20]. and 16.2% in patients with PSA levels of
Imaging tracers targeting prostate-spe- 20.0–49.9 ng/mL. It was 6.4% in men with
cific membrane antigen (PSMA) have re- organ-confined cancer and 49.5% in men
cently garnered attention after showing with locally advanced cancers. Detection
promise in the detection of intraprostatic rates were 5.6% and 29.9% for Gleason
cancer on the basis of their good signal- scores of ≤7 and ≥8 respectively[22].
to-noise ratio. 68Ga-PSMA, a urea-based
PSMA inhibitor, via binding to the PSMA Computed tomography/
structure, has the advantage of high sen- magnetic resonance imaging
sitivity for the detection of prostate can- Computed tomography (CT) is useful not
cer independent of PSA level and lesion only for disease staging but also for as-
size[21]. sessment of the anatomy of the patient,
such as lymph nodes. Enlarged lymph
nodes may give an indication regarding
IMAGING FOR DISEASE the presence of metastasis. Visualisation of
STAGING lymph nodes depends on the slice thick-
ness of the scans and on the CT scanner
Technetium-99 bone scan itself. However, a CT scan does not differ-
A conventional technetium-99 bone scan entiate between lymph nodes that are in-
(BS) has been the most widely used meth- flammatory and lymph nodes affected by
od for evaluation of bone metastases of micro-metastases[22].
prostate cancer. A bone scan is relatively Magnetic resonance imaging (MRI) is
well tolerated, readily available and cheap similar in this respect to CT. Studies have
compared with the newer imaging modal- shown that its sensitivity and specificity in
ities. However, the diagnostic yield of BS is the detection of small metastases are low
significantly influenced by the PSA level, because such metastases are usually pres-
the clinical stage and the tumour Gleason ent in small lymph nodes[23].
score and these three factors were found
to be the only independent predictors Nanoparticle magnetic
of BS positivity in a study of 853 patients. resonance imaging
The mean BS positivity rate in 23 differ- One of the latest developments in MRI is
ent series was 2.3% in patients with PSA the introduction of nanoparticles. These
levels <10 ng/mL, 5.3% in patients with nanoparticles can be divided into differ-
group, and once staging has been con- an email address should the patient need
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
Figure 3
MRI
reserved places are kept open for
these patients during the MRI daily list
Figure 4
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
Each patient is assigned a case manager and an oncology nurse. All records are
kept in the hospital system, and through a personal patient folder the patient
can access any information and future appointments. The case manager is
responsible for the patient’s prostate cancer path and should be the person to
contact if the patient has any questions or concerns.
After initial diagnostic steps have been completed, the specialist nurse contacts
the patient to let him know the results. The specialist nurse also informs the
patient whether a biopsy is needed and, if it is, an appointment is planned.
The results of MRI as reported by the radiologist are discussed by the multi-
disciplinary team and the best trajectory for patient management is proposed.
When the biopsy results have been obtained, the case is again discussed and
the treatment options are offered. The specialist nurse once more contacts the
patient to inform him of the result and discuss the next steps.
Figure 4: A further possible patient pathway, from biopsy to receipt of results and discussion
of the next step
bicalutamide, flutamide, and nilutamide. side effects which have been associated
Recently, new anti-androgen agents, such with toxicity, such as cardiac morbidity,
as enzalutamide and abiraterone, have decreased mineral bone density and sex-
been approved for castration-resistant ual dysfunction[28].
prostate cancer. However, there are some
the bone metastases[29]. Correct informa- be considered in patients with BCR after
THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T
tion needs to be delivered to patients be- RP who have a high baseline PSA (>10 ng/
cause they may be wary of alpha radiation. mL) or high PSA kinetics [PSA doubling
time (PSA-DT) <6 months or PSA velocity
Imaging for follow-up >0.5 ng/mL/month] and in patients with
Several studies have reported promising symptoms of bone disease[31].
results in the detection of local recur- Choline PET/CT may change medical
rences using MRI, particularly dynamic management in 18%–48% of patients
contrast-enhanced MRI, with sensitivities with BCR after primary treatment[32–34]. In
and specificities of 76%–90% and 82%– a retrospective two-centre study of 150
100%, respectively. However, the mean patients[34], 14 of the 55 (25.5%) patients
PSA level in these studies was 0.7–1.9 ng/ scheduled for palliative treatment were
mL, which is higher than the 0.5 ng/mL switched to salvage therapy based on
threshold usually used for salvage therapy. choline PET/CT results. Salvage therapy
Two studies evaluated mpMRI in patients induced a complete biochemical re-
with a PSA level <0.5 ng/mL. One found a sponse in 35.7% of these patients at the
sensitivity of only 13% in men with a PSA end of a median follow-up of 18.3 months
level <0.3 ng/mL, while the other reported (range 10–48 months), suggesting that it
a sensitivity of 86% in patients with a PSA continues to miss small-volume metasta-
level <0.4 ng/mL[30]. ses. In patients not considered fit enough
Technetium-99 bone scan historically for curative salvage treatments, choline
is most commonly used for the diagno- PET/CT should be avoided. After RP, the
sis of bone metastases, although it has optimal PSA cut-off level for choline PET/
limited sensitivity. Only 11%–14% of pa- CT analysis seems to be between 1 and
tients with biochemical recurrence (BCR) 2 ng/mL. Choline PET/CT detection rate
after radical prostatectomy (RP) have a was 26% in patients showing PSA <1 ng/
positive CT and a positive scan is rarely mL but rose to 44% in those with PSA
obtained in situations when salvage treat- values between 1 and 2 ng/mL (more-
ment might be considered. In a series of over 37% of this group of patients were
132 men with BCR after RP, the mean PSA oligo-metastatic). It has been suggested
level and PSA velocity associated with a that a PSA-DT <6 months and a PSA ve-
positive CT were 27.4 ng/mL and 1.8 ng/ locity >2 ng/mL/year may also select men
mL/month, respectively. Therefore, bone in whom choline PET/CT could be recom-
scan and abdominopelvic CT should only mended[35].
68
Ga-PSMA PET/CT has shown promising also useful to look up previous examina-
only increases the chances of survival, and de Lauw, specialist nurse, Department of
if the disease is at a later stage, palliative Urology, Radboud University Medical Cen-
care and measures to relieve symptoms ter, Nijmegen, the Netherlands.
will be needed.
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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA and local treatment with curative intent. Eur Urol
Cancer J Clin 2018;68:7−30. 2017;71:618−629.
2. Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, 10. Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR,
Tannock I, et al. Prostate cancer. Lancet 2016;387:70–82. Humphrey PA, et al. The 2014 International Society of
3. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Urological Pathology (ISUP) Consensus Conference
Zappa M, Nelen V, et al. Screening and prostate cancer on Gleason Grading of Prostatic Carcinoma: Defini-
mortality: results of the European Randomised Study tion of grading patterns and proposal for a new grad-
of Screening for Prostate Cancer (ERSPC) at 13 years of ing system. Am J Surg Pathol 2016;40:244−252.
follow-up. Lancet 2014;384:2027–2035. 11. Buyyounouski MK, Choyke PL, McKenney JK, Sartor
4. Andriole GL, Levin DL, Crawford ED, Gelmann EP, Pinsky O, Sandler HM, Amin MB et al. AJCC Cancer Staging
PF, Chia D, et al. Cancer screening in the Prostate, Lung, Manual, 8th edn. New York: Springer; 2017:715.
Colorectal and Ovarian (PLCO) Cancer Screening Trial: 12. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reu-
Findings from the initial screening round of a random- ter VE. WHO Classification of Tumours of the Urinary
ized trial. J Natl Cancer Inst 2005;97:433–438. System and Male Genital Organs-Part B: Prostate and
5. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, bladder tumours. Eur Urol 2016;70:106−119.
Gulati R, et al. Lead time and overdiagnosis in pros- 13. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M,
tate-specific antigen screening: importance of meth- Gross T, et al. EAU-ESTRO-SIOG Guidelines on Prostate
ods and context. J Natl Cancer Inst 2009;101:374–383. Cancer. Part II: Treatment of relapsing, metastatic,
6. Krahn MD, Mahoney JE, Eckman MH, Trachtenberg J, and castration-resistant prostate cancer. Eur Urol
Pauker SG, Detsky AS. Screening for prostate cancer. A 2017;71:630−664.
decision analytic view. JAMA 1994;272:773−780. 14. Morgans AK. Optimization of risk stratification in lo-
7. Bretton PR. Prostate-specific antigen and digital rectal calized prostate cancer. J Clin Oncol 2018;36:528−532.
examination in screening for prostate cancer: a com- 15. Litwin MS, Tan HJ. The diagnosis and treatment of
munity-based study. South Med J 1994;87:720−723. prostate cancer. A review. JAMA 2017;317:2532−2542.
8. Hara R, Jo Y, Fujii T, Kondo N, Yokoyoma T, Miyaji Y, et 16. Padhani AR, Lecouvet FE, Tunariu N, Koh D, de
al. Optimal approach for prostate cancer detection as Keyzer F, Collins DJ, et al. Rational for modernising
initial biopsy: prospective randomized study compar- imaging in advance prostate cancer. Eur Urol Focus
ing transperineal versus transrectal systematic 12-core 2017;3:223−239.
biopsy. Urology 2008;71:191–195. 17. Smeenge M, Barentsz J, Cosgrove D, de la Rosette J, de
9. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch Reijke T, Eggener S et al. Role of transrectal ultrasonog-
MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines raphy (TRUS) in focal therapy of prostate cancer: Report
on Prostate Cancer. Part 1: Screening, diagnosis, from a Consensus Panel. BJU Int 2012;110: 942−948.
18. Fütterer JJ, Briganti A, De Visschere P, Emberton M, Gi- cancer in the era of precision medicine. Cancers (Ba-
FUT UR E
PERSPE C T I V E S
A N D PR E C L I N IC A L
STUD I E S I N
PROSTAT E C A N C E R
by Laura Evangelista
and Federico Caobelli
(on behalf of the Translational
Imaging and Therapy Committee)
CHAPTER 10
INTRODUCTION
Prostate cancer is the most common oncological disease in men worldwide.
STUDI E S I N PR O S TATE C A NC E R
FUTURE PE RS PE C TI V E S A ND PRE C L I NI C A L
Nuclear medicine has provided tools for its management for years, with
bone scans, brachytherapy and pain palliation. However, fluorine-18
fluorodeoxyglucose positron emission tomography (18F-FDG PET) is not
adequate for the detection of prostate cancer, and the development of
alternative tracers is thus required.
countries, regulatory studies are requested uation. The choice of the most appropriate
STUDI E S I N PR O S TATE C A NC E R
FUTURE PE RS PE C TI V E S A ND PRE C L I NI C A L
before a new radiopharmaceutical candi- animal model depends on the characteris-
date may be used in human clinical trials. tics of the molecule to be tested and the
Proof of concept studies of diagnostic/ metabolic pathway affected. For example,
therapeutic efficacy have two potential orthotopic tumour models (tumour in the
effects: same organ in which it occurs clinically)
1. They can rule out ideas that do not and tumour models based on (human)
translate from in vitro to in vivo or, tissue explants are more likely to reflect
conversely, demonstrate that there the clinical tumour pathophysiology than
is hope of successful clinical transla- subcutaneous transplant models using
tion. There are too many unknowns cultured cells (xenografts). Despite this,
to predict that pharmacokinetics, bio- disease models do not necessarily present
distribution, uptake in lesions and in the actual human situation; rather, they
normal tissues, immune system reac- merely allow tracer evaluation in a much
tions and so on will not render useless more advanced setting compared with in
a drug that has shown a good in vitro vitro studies. The diverse disease models
profile of target binding and pharma- available for such studies all artificially rep-
cological effects. In oncology, for in- resent key features of a disease. The choice
stance, a candidate drug, radioactive and pathology of a model may therefore
or not, that shows objective efficacy strongly influence the outcome of a pre-
at doses that do not cause excessive clinical study.
toxicity passes the test. Several considerations need to be taken
2. They can provide a strong argument into account when selecting the appropri-
in favour of, or against, investing in a ate prostate cancer model. First and fore-
new drug. They also help in making most, the model must be representative
the investigational product stronger. of the disease state under examination
The likelihood that preclinical devel- and may serve different purposes. LNCaP
opment and clinical trials will be fund- cells, which are sensitive to androgen
ed strongly depends on the quality of stimulation, show an increased incidence
the proof of concept studies and on of metastasis. LNCaP-LN3 cells result in
advertising their outcomes. smaller prostate tumours but enhanced
Obviously, the means by which the artifi- metastatic propensity[1]. In particular, they
cial model is created will define the degree promote a pattern of regional lymph node
of resemblance with the actual clinical sit- metastases after prostatic implantation,
over, PC-3M variants produce a higher use (i.e. using the minimum number of
incidence of lung metastasis but not animals required to obtain valid results,
lymph node metastasis, suggesting an in- using alternative methods instead of live
creased metastatic propensity to a specific animals where appropriate and avoiding
site rather than all organ sites[1]. The PC3 or minimising discomfort and distress to
model is common but does not express the animals).
PSMA. However, in humans, prostate can- Quite often, handling of animal models
cer, like other solid endocrine cancers, is a requires a diploma, just like handling of ra-
heterogeneous tumour characterised by dioisotopes. Unlike for the clinical situation
different biological pathways, targets and (see below), for preclinical in vivo studies
history of disease, and therefore cannot be approval needs to be obtained for the
represented by a single model. generation of the disease model and the
Furthermore, studies on non-diseased evaluation of the radiopharmaceutical.
animals are as important for translation Radioisotope-based detection tech-
as those on diseased animals: they allow niques such as %ID/g evaluations and pre-
investigation of tracer characteristics such clinical single-photon emission computed
as safety, toxicity, and biodistribution and tomography (SPECT) or PET studies sup-
enable comparison with findings in dis- port the quantitative evaluation of tracers
eased animals. or radiolabelled cells, which is not only key
The performance of in vivo studies in the development of tracers for the field
in, for example, mice, rats, rabbits, dogs, of nuclear medicine but is also routinely
pigs or monkeys, requires approval from of value in drug development. In the in
a local ethics board. Appropriate animal vivo setting, the effect of physiology, en-
care entails compliance with a series of zyme activity, serum binding, biological
conditions that ensure the health and clearance etc. can be determined. Such
well-being of the animals. For example: preclinical in vivo studies may also help to
(1) living conditions must be appropriate, optimise timing and dose. Finally, preclin-
(2) personnel who care for animals or who ical evaluations can be used to assess the
conduct animal studies must be appro- (acute) toxicity of a tracer or radiolabelling
priately qualified and (3) studies involving method. Although not yet conclusive,
animals must be designed and conduct- these preclinical in vivo studies are key in-
ed in accordance with applicable country termediate steps in the process of clinical
and local regulatory guidance and widely translation.
STUDI E S I N PR O S TATE C A NC E R
FUTURE PE RS PE C TI V E S A ND PRE C L I NI C A L
Phase I clinical trials (or “first-in-human have all the requisite certifications. In nu-
studies”) play a crucial role in the radio- clear medicine, since these certified com-
pharmaceutical development process panies generally do not handle radioactive
and are often considered the gateway compounds, toxicity (e.g. determination
between fundamental research and clin- of maximum tolerated dose), pharmaco-
ical medicine. Obviously, the evaluation kinetics and dosimetry studies with the
of new radiopharmaceuticals in humans radioactive drug, as opposed to the parent
requires an ethics statement from local au- unlabelled compound, need to be per-
thorities and informed consent of the pa- formed in academic laboratories.
tient. Within the EU, these rules may vary
between countries or even regions within
a country. Whereas in some countries full RECENT DEVELOPMENTS IN
preclinical and toxicological evaluation is PRECLINICAL STUDIES IN
required in order to obtain ethical approv- PROSTATE CANCER
al for first-in-human studies, in other coun- A careful search of the available literature,
tries some aspects may be omitted. Every using the terms “prostate cancer” AND “nu-
step should be documented. It is manda- clear medicine” as keywords in PubMed,
tory to adhere to good laboratory practice identified 6388 studies published over the
(GLP) and good manufacturing practice past 5 years. Out of these 6388 articles,
(GMP) and to ensure the use of accurate 3697 related to clinical research and 2691
and robust data and standards in order to to preclinical studies (465 in vivo and 2226
guarantee patient safety. in vitro experiments). A detailed discussion
Prerequisites for first-in-human studies of all the in vitro and in vivo studies is be-
are well described in official documents. yond the scope of the present guide. Sum-
They include safety and toxicity studies, marising, it can be stated that different
generally in two animal species, by repeat- receptors, e.g. bombesin, PSMA and uroki-
ed administrations, pharmacokinetic/do- nase-type plasminogen activator receptor
simetry studies and so on. The goal here is (uPar), are currently being actively inves-
exclusively to try and demonstrate that the tigated as potential targets for molecular
first in-human application will be sufficient- imaging and/or radiometabolic therapy.
ly safe, which is clearly not always the case. Different radiopharmaceutical agents
These regulatory studies are not about are now under evaluation for diagnosis,
efficacy. They are generally performed therapy or surgery. The majority of them
Figure 1: Potential targets and useful information for the development of new
radiopharmaceutical agents in prostate cancer
STUDI E S I N PR O S TATE C A NC E R
FUTURE PE RS PE C TI V E S A ND PRE C L I NI C A L
Jan 2017 Cancer Biotherapy 99m
Tc-finasteride In vivo Sprague Dawley Radiochemical
et al. [2] and Radiopharma- rats purity analysis by
ceuticals chromatographic
technique
Ferreira 2017 Biomedicine & Radiolabelled In vivo Swiss mice –
et al. [3] Pharmacotherapy bombesin (xenograft model)
or athymic nu/nu
mice (xenograft
model)
Xu 2017 Bioorganic In-gonadotropin-
111
In vivo Xenograft nude –
et al. [4] & Medicinal releasing hormone mice
Chemistry Letters peptides
Nonnekens 2017 Cancer Biotherapy Bi-PSMA
213
In vitro/ Female nude –
et al. [5] and Radiopharma- in vivo mice
ceuticals
Nock 2017 Journal of Nuclear Radiolabelled In vitro/ Xenograft- Radiochemical
et al. [6] Medicine bombesin in vivo bearing mice purity analysis by
chromatographic
technique
Zhang 2017 Journal of Nuclear 68
Ga-labelled In vitro/ Male athymic Radiochemical
et al. [7] Medicine (gastrin-releasing in vivo NCr-nu/nu mice purity analysis by
peptide antagonist) chromatographic
technique
Sun 2016 Bioconiugate Radiolabelled In vitro/ Xenograft- Radiochemical
et al. [8] Chemistry bombesin in vivo bearing mice purity analysis by
chromatographic
technique
Cheng 2018 Bioconiugate 68
Ga-labelled In vitro/ Xenograft- Radiochemical
et al. [9] Chemistry (gastrin-releasing in vivo bearing mice purity analysis by
peptide agonist chromatographic
and antagonist) technique
Skovgaard 2017 PET Clinics 64
Cu- and 68Ga- NA – –
et al. [10] labelled urokinase-
type plasminogen
activator receptor
agonist
Frigerio et 2017 Oncotarget 123
I-labelled anti- In vitro/ Xenograft- Radiochemical
al. [11] PSMA antibody in vivo bearing mice purity analysis by
fragment ScFvD2B chromatographic
technique
Table 1: Recently published studies of radiolabelled receptor agonists and antagonists that are of
particular interest
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5. Nonnekens J, Chatalic KLS, Molkenboer-Kuenen 10. S kovgaard D, Persson M, Kjaer A. Imaging of prostate
JDM, Beerens CMTE, Bruchertseifer F, Morgenstern cancer using urokinase-type plasminogen activator
A, et al. 213Bi-labeled prostate-specific membrane receptor PET. PET Clin 2017;12:243–255.
antigen-targeting agents induce DNA double-strand 11. Frigerio B, Franssen G, Luison E, Satta A, Seregni
breaks in prostate cancer xenografts. Cancer Biother E, Colombatti M, et al. Full preclinical validation
Radiopharm 2017;32:67–73. of the 123I-labeled anti-PSMA antibody fragment
6. Nock BA, Kaloudi A, Lymperis E, Giarika A, Kulkarni ScFvD2B for prostate cancer imaging. Oncotarget
HR, Klette I, et al. Theranostic perspectives in prostate 2017;8:10919–10930.
DOI: https://doi.org/10.52717/GPJL7081
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Information as per date of printing September 2018.
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