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Eanm 2018 Techguide Online

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Eanm 2018 Techguide Online

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carla.ggm4048
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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PROSTATE

CANCER
IMAGING AND
THERAPY
A TECHNOLOGIST’S GUIDE

Produced with the kind support of


Chapters marked with this symbol are made
available to you as webinar on the EANM
eLearning platform: elearning.eanm.org
TA B LE O F
CO N T E N TS
Foreword 4
Pedro Fragoso Costa

Introduction 6
Luca Camoni

Chapter 1 Anatomy, physiology and pathology of the prostate 9


Lucia Zanoni, Cristina Nanni and Stefano Fanti

Chapter 2 Clinical radiopharmaceuticals for prostate cancer 21


Martin Behe

Chapter 3 Conventional nuclear medicine in prostate cancer imaging 29


Wolfgang Römer

Chapter 4 PET/CT procedures with fluorine-18 41


radiopharmaceuticals in prostate cancer*
Daniel Tempesta and David Gilmore

Chapter 5 Prostate cancer PET-CT imaging beyond F-18 tracers 51


Giorgio Testanera and Giovanna Pepe

Chapter 6 PET/CT-guided radiotherapy planning in prostate cancer 73


Yat Man Tsang and Michelle Leech

Chapter 7 Theranostics in Prostate Cancer 83


Sarah M. Schwarzenböck, Bernd Joachim Krause and Jens Kurth

Chapter 8 Prostate cancer radionuclide therapy based on alpha emitters 95


Mark Konijnenberg and Domenico Albano

Chapter 9 The management of a prostate cancer patient 105


MarieClaire Attard and Rexhep Durmo

Chapter 10 Future perspectives and preclinical studies in prostate cancer 123


Laura Evangelista and Federico Caobelli

*Articles were written with the kind support of and in cooperation with the

EANM TECHNOLGIST’S GUIDE 3


PROSTATE CANCER IMAGING AND THERAPY
FOREWORD

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.

Nuclear medicine technologists are spe- radiopharmacists and dosimetrists whose


cialised professionals who perform or are coordinated effort has culminated in this
involved in a number of procedures, in- guide. Such an ongoing joint effort is the
cluding radiopharmaceutical labelling, pa- reason behind the acknowledged wide
tient management, image reconstruction readership for past editions of A Technolo-
and radiation safety. gist’s Guide (TG) and the extremely positive
The multidisciplinary effort in nuclear response that EANM receives every year
medicine to discover new molecules with concerning this publication.
a significant clinical impact is well known This year’s edition of the TG celebrates a
through the recent research and devel- return to clinical applications, being to-
opments with respect to diagnostic and tally focussed on one pathology in which
therapeutic radiopharmaceuticals for use nuclear medicine is deeply involved. The
in prostate cancer. motivation for the content design of this
As a reference scientific body in Europe, the TG was the desire to explore the multi-
European Association of Nuclear Medicine disciplinary approach to prostate cancer,
(EANM), and its Technologist Committee from preclinical studies with animal mod-
(EANMTC), has had the privilege of gather- els through to established diagnostic and
ing top quality clinical scientists, technolo- therapeutic methodologies. The guide
gists, physicians, physicists, radiochemists, accordingly provides a complete overview

4 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
FOREWORD

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

EANM TECHNOLGIST’S GUIDE 5


PROSTATE CANCER IMAGING AND THERAPY
INTRODUCTION

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

6 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
INTRODUCTION

on alpha-emitting radionuclides. Nuclear fields in preclinical cancer drug research


medicine technologists play an important and development.
part in the multi-professional manage- We hope that this overview of the state
ment of the prostate cancer patient. In of the art of nuclear medicine imaging and
addition to being directly involved in ther- therapy in prostate cancer will provide a
apy through the performance of various valuable resource for all technologists and
roles, they are responsible for other tasks clinical staff involved in this field.
such as patient preparation and imaging The EANM Technologist Committee
processing. The ninth chapter describes would like to thank all the authors who
the clinical pathway of the patient in order have kindly offered their time and exper-
to improve understanding of the technol- tise, which have been fundamental to the
ogist’s tasks. creation of this book.
The recent advances in prostate cancer
specific tracers were significantly support-
ed by the advent of translational medicine. Luca Camoni
With this in mind, the final chapter explains on behalf of the editors
how molecular and non-invasive preclin-
ical imaging become rapidly emerging

EANM TECHNOLGIST’S GUIDE 7


PROSTATE CANCER IMAGING AND THERAPY
A N ATO M Y,
PHYS I O LO G Y
A N D PAT H O LO G Y
O F TH E
PROSTAT E

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
AN ATO MY, PH YS IO LO GY AN D

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

10 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

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
AN ATO MY, PH YS IO LO GY AN D
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-

EANM TECHNOLGIST’S GUIDE 11


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

Figure 1
PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D

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-

12 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

ever, after the age of 35 years its volume true prostate capsule surrounds the periph-

PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D
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

EANM TECHNOLGIST’S GUIDE 13


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

descriptions of prostatic anatomy. From a classification of tumours[9] categorises


PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D

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

14 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

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
AN ATO MY, PH YS IO LO GY AN D
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,

EANM TECHNOLGIST’S GUIDE 15


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

prostatic carcinoid is one of the four rare eration. Carcinosarcoma is considered one
PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D

mani­ festations of neuroendocrine ma- of the most aggressive prostate malignan-


lignancy of the prostate. It demonstrates cies, the mean survival after diagnosis be-
true neuroendocrine differen­tiation with ing only 7 months regardless of the form
classic chromogranin A and synapto- of therapy.
physin immunoreactivity. Patients do not Ductal or endometrioid adenocarcinoma.
present with an elevated prostate-specific Despite the postulated müllerian origins
antigen (PSA) level and the clinical history of the tumour, patients often present with
is fairly indolent. an elevated PSA level. Ductal carcinoma is
Paraganglioma. Paragangliomas are the most com­mon histological variant of
extremely rare extra-adrenal phaeo- prostate carcinoma. In most studies, the
chromocy­ tomas that develop from ex- prognosis of ductal adenocar­cinoma has
tra-adrenal chromaffin cells, from the been observed to be worse than that of
parasympathetic tissue adjacent to and typical acinar adenocarcinoma, a finding
behind the prostate. They are associat- probably related to the higher stage and
ed with several familial syndromes (i.e. grade of the ductal subtype.
multiple endocrine neoplasia IIA and IIB, Mucinous adenocarcinoma. Mucinous
neurofibromatosis 1, von Hippel-Lindau adenocarcinomas account for approxi­
syndrome, Carney complex and familial mately 0.4% of prostatic cancers. Unlike
paraganglioma). Patients with functional typical acinar adenocarcinomas, muci-
tumours often pres­ent the classic triad nous tumours characteristically present
of headache, tachycardia and sweating a proteinaceous fluid content. Originally,
associ­ ated with catecholamine produc- such tumours were thought to be more
tion. aggressive than typical acinar adenocar-
Sarcomatoid carcinoma and carcinosar- cinoma but this hypothesis was finally
coma. These are rare biphasic tumours excluded.
(accounting for less than 0.1% of prostate Metastatic involvement of the prostate
cancers) that show a mixture of sarco- by primary carcinomas of other organs. In-
matous and carcinomatous features, the volvement of the prostate occurs rarely as
latter usually in the form of a high-grade a result of direct extension of tumours in
adenocarcinoma. Differential diagnosis adjacent organs or dissemination of dis-
can be critical but sarcomatoid carcinoma ease involving multiple organs. Bladder
may be supposed on the basis of a lobu- urothelial carcinoma is most commonly
lated tumour with areas of cystic degen- responsible owing to the proximity of the

16 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

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

EANM TECHNOLGIST’S GUIDE 17


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

for bladder cancer. It is characterised by extracellular deposition of amyloid. Pros-


PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D

well-formed granulomas with epithelioid tatic amyloidosis can be interpreted as a


cell and multinucleated giant cell infil- secondary sign of prostate inflammation.
tration with or without central necrosis The identification of localized disease
(caseation). Rarer causative organisms prompts the need for a systemic disease
are Treponema pallidum, viruses (herpes workup.
zoster) and fungi (Cryptococcus, Candida, Prostatic cyst. Various cystic entities may
Aspergillus). Non-necrotic granulomatous be seen within the prostate, all with dif-
prostatitis is highly cellular and may sim- ferent em­bryological origins and clinical
ulate prostate cancer at standard imaging. implications. When a cyst is pear shaped
Malacoplakia is a rare granulomatous in- and is detected in the midline of the pros-
flammatory condition associated with re- tate, it may be either a prostatic utricle
current infection. It predominantly affects cyst or a müllerian duct cyst (as an embry-
the genitourinary tract, particularly the ological remnant of the müllerian duct or
renal collecting system. urogenital sinus), which are virtually indis-
Pyogenic abscess. This is the most com- tinguishable at imaging. Paramedian cysts
mon complication of bacterial prostatitis. are usually ejaculatory duct cysts (that
Patients usually present with fever, dys­uria, arise con­genitally or secondary to duct
pain and fluctuation at digital rectal exam- obstruction), while most lateral cysts are
ination. A complex collec­tion may be seen, retention cysts (from dilatation of glandu-
with increased peripheral vascu­larity. lar acini secondary to small duct obstruc-
Fungal abscess. Prostatic fungal infec- tion) or cystic degeneration of BPH (more
tions are commonly seen only in immuno- common and usually multiple). In the
compromised patients, and in particular in setting of a cystic lesion in the pros­tate, it
the setting of concomitant renal abscess- is important to exclude an abscess, cystic
es. These abscesses are indistinguishable degeneration of a neoplasm and pseudo-
from pyogenic abscesses on the basis of cyst secondary to a neoplasm. If there is
imaging alone and a confirmatory diagno- haemorrhage, internal complexity or a
sis is often made on the basis of the results solid component within the cyst, further
of a urine or aspirate culture. Prolonged workup for malignancy is warranted.
multi-agent systemic antifungal therapy Atrophy. Histological subtypes of at-
is necessary. rophy include simple, sclerotic with cyst
Prostatic amyloidosis. This is a disease of formation and post-atrophic hyperplastic.
uncertain cause that is characterized by Focal atrophy, more frequently occurring

18 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 1

in the peripheral zone, may mimic prostate Calcification. Prostatic calcification may

PAT H O LO GY O F TH E PR O S TATE
AN ATO MY, PH YS IO LO GY AN D
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.

REFERENCES
1.Gray H. Anatomy descriptive and surgical. Male or- 8. 
Villers A1, Steg A, Boccon-Gibod L. Anatomy of
gans of generation. The prostate gland. Pickering Pick the prostate: review of different models. Eur Urol
T, Howden R, eds. New York: Barnes and Noble, 1995. 1991;20:261–268.
2. Coakley FV, Hricak H. Radiologic anatomy of the 9. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Re-
prostate gland: a clinical approach. Radiol Clin North uter VE. The 2016 WHO Classification of Tumours of
Am 2000;38:15–30. the Urinary System and Male Genital Organs – Part B:
3. Powers GL, Marker PC. Recent advances in prostate Prostate and bladder tumours. Eur Urol 2016;70:106–
development and links to prostatic diseases. Wiley 119.
Interdiscip Rev Syst Biol Med 2013;5:243–256. 10. Kitzing YX, Prando A, Varol C, Karczmar GS, Maclean
4. Toivanen R, Shen MM. Prostate organogenesis: tissue F, Oto A. Benign conditions that mimic prostate car-
induction, hormonal regulation and cell type specifi- cinoma: MR imaging features with histopathologic
cation. Development 2017;144:1382–1398. correlation. Radiographics 2016;36:162–175.
5. Hayward SW, Cunha GR. The prostate: development 11. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch
and physiology. Radiol Clin North Am 2000;38:1–14. MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines
6. Sandberg AA. Endocrine control and physiology of on Prostate Cancer. Part 1: Screening, diagnosis,
the prostate. The Prostate. 1980;1:169–184. and local treatment with curative intent. Eur Urol
7. Li Y, Mongan J, Behr SC, Sud S, Coakley FV, Simko J, 2017;71:618–629.
Westphalen AC. Beyond prostate adenocarcinoma: 12. Aaron L, Franco OE, Hayward SW. Review of pros-
Expanding the differential diagnosis in prostate patho- tate anatomy and embryology and the etiology of
logic conditions. Radiographics 2016;36:1055–1075. BPH. Urol Clin North Am 2016;43:279–288.

EANM TECHNOLGIST’S GUIDE 19


PROSTATE CANCER IMAGING AND THERAPY
CLINICAL
FOR PROSTATE
CANCER

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

and treatment of prostate cancers, covering logistics, biochemical


characteristics and mechanism of action. One may distinguish two major
types of radiopharmaceutical according to their mechanism of action:
metabolic radiopharmaceuticals, the accumulation of which reflects the
metabolism at the site of interest, and targeted radiopharmaceuticals,
which target specific proteins overexpressed on prostate cancer cells.

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

22 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 2

onto the surface of hydroxyapatite, they aging. 99mTc labelling of hydroxymethy-

FO R PR O S TATE CAN CER


CL IN ICAL R AD IO PH AR MACEUTICALS
exchange with the hydroxyl (OH−) ions in lene diphosphonate (HMDP, HDP), 3,3-di-
the crystal, forming fluoroapatite[3]: phosphono-1,2-propanodicarboxylic acid
Ca5(PO4)3OH+F− → Ca5(PO4)3F+OH− (DPD) and medronic acid (Fig. 1) can be
performed using a kit preparation. These
The uptake of Na[18F]F, which has a half- tracers show a high stability after prepa-
life (T1/2) of 110 min, reflects the blood flow ration and may be applied for up to 8 h
and the bone metabolism. The tracer can afterwards[4]. The recommended injected
be directly produced using a medical cy- dose in adults is 300–740 MBq[5]. In the first
clotron by purification after irradiation of phase of a bone scan, [99mTc]Tc-diphos-
oxygen-18 labelled water. The maximum phonates show the perfusion status of a
recommended adult dose, delivered by lesion, in the second phase, the blood pool
intravenous injection, is 1.5–3.7 MBq/kg, and in the third (static) phase, the bone
with a maximum injected dose of 370 metabolism. They appear to be actively
MBq for obese patients. In children, 2.2 taken up during bone mineralisation, and

Figure 1 Figure 2

Formula of technetium (99mTc) medronic acid; 11


C[C]-choline and 18F[F]-fluorcholine
exact formula is unknown

MBq/kg is administered, with a minimum consequently most metabolically active


activity of 18.5 MBq and a maximum of 185 lesions in bone are visualised, along with
MBq[3]. The EANM guideline “18F-NaF PET/ bone metastases of various tumours or in-
CT: EANM procedure guidelines for bone flammation[6].
imaging” gives a very good general over-
view[3]. 18
F[F] and 11C[C] labelled choline
Studies in the 1990s showed that cho-
[99mTc]Tc-diphosphonates line kinase expression is associated with
[99mTc]Tc-diphosphonates (T1/2=6 h) are immortality and transformation in cancer
the most widely used radiotracers for cells[7]. Further studies with phospho-
seeking bone metastases with SPECT im- rus-31 magnetic resonance spectroscopy

EANM TECHNOLGIST’S GUIDE 23


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 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

verified this by revealing a high phospha- tical GMP infrastructure on a dedicated


tidylcholine concentration in tumours[8]. module. The 11C[C] compounds can only
This led to the development first of 11C[C] be applied in a nearby PET centre owing
labelled choline[9] and later of 18F[F] deriv- to the short half-life of 11C, whereas 18F-flu-
atives[10] (Fig. 2). The 11C[C] compounds orcholine can be delivered to PET centres
suffer from the fact that 11C has a short without a dedicated radiopharmaceutical
half-life of 20 min, whereas the half-life infrastructure.
of 18F is 110 min. On the other hand, the
18
F[F] labelled compounds have the dis- PSMA targeting compounds
advantage of higher and faster urinary Prostate-specific membrane antigen, or
secretion, which has to be overcome by PSMA, is a type II transmembrane protein
means of early dynamic PET images[11]. which is expressed in different normal tis-
Both 11C[C] and 18F[F] compounds can be sues, including prostate epithelium, the
produced in specialised centres with a small intestine, renal tubules and salivary
medical cyclotron and a radiopharmaceu- glands[12,13]. The protein is 100 to 1000

24 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 2

times overexpressed in prostate cancer RADIOPHARMACEUTICALS FOR

FO R PR O S TATE CAN CER


CL IN ICAL R AD IO PH AR MACEUTICALS
and is associated with tumour aggressive- THERAPEUTIC APPLICATION
ness[14].
The tracers in this field are still under [153Sm]Sm-EDTMP
development and the situation is quite Ethylenediamine tetra(methylene phos-
confusing. Several clinical studies are un- phonic acid) (EDTMP) (Fig. 4) chelated with
derway. The initial tracers were based on [153Sm]Sm is a bone-seeking compound
antibodies radiolabelled with different which can be used for the treatment of
radionuclides for PET and SPECT imag- bone metastases in prostate and other can-
ing[15]. The antibody tracers have in the cers[19]. The mechanism of uptake in bone
meantime been replaced by small-mole- is the same as with the diagnostic biphos-
cule inhibitors of the enzymatic domain. Figure 4
One of the most popular is [68Ga]Ga-PS-
MA-11[16,17] (Fig. 3), but other compounds
based on the same structural features
and radiolabelled with 18F or 99mTc are
under clinical investigation for use with
PET and SPECT imaging. These com-
pounds are discussed in the review by
Virgolini et al.[15].
The [68Ga]Ga compounds are radio-
labelled in a dedicated module. [68Ga]
GaCl3 can be eluted from commercially Structure of EDTMP, an EDTA derivative
available generators. The recommended
injected dose of [68Ga]Ga labelled PSMA
derivatives is 1.8−2.2 MBq/kg[18]. Efforts phonate and is mainly driven by the blood
are underway to establish a kit-based delivery and bone metabolism. [153Sm]Sm is
preparation. [18F]F labelled derivatives a weak beta emitter with a maximum ener-
have to be synthesised in a dedicated ra- gy of 0.81 MeV, a mean energy of 0.23 MeV
diopharmaceutical centre with a medical and a tissue range of 0.6 mm. The gamma
cyclotron for production of the [18F]F and emission with an energy of 103 keV in 30%
modules. The radiolabelling of 99mTc trac- of the decays allows in vivo scintigraphy
ers is performed using a kit-based proce- and/or SPECT control of the distribution of
dure. the compound. The half-life is 46.3 h.

EANM TECHNOLGIST’S GUIDE 25


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 2

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

26 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 2

Figure 5

FO R PR O S TATE CAN CER


CL IN ICAL R AD IO PH AR MACEUTICALS
Decay scheme of [223Ra]Ra

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-
This is still a method under investigation diat Appl Instrum Part B, Nucl Med Biol 1986;13:49−56.
but it is expected that it will enter routine 5. Van den Wyngaert T, Strobel K, Kampen WU, Kuwert
clinical application in the near future. T, van der Bruggen W, Mohan HK, et al. The EANM
practice guidelines for bone scintigraphy. Eur J Nucl
Med Mol Imaging 2016;43:1723−1738.
6. Fogelman I. Skeletal uptake of diphosphonate: A re-
REFERENCES view. Eur J Nucl Med 1980;5:473−476.
1. Institute. NC. Surveillance Epidemiology and End Re- 7. Bhakoo KK, Williams SR, Florian CL, Land H, Noble
sults (SEER) 2018. Available from: https://seer.cancer. MD. Immortalization and transformation are associ-
gov/statfacts/html/prost.html. ated with specific alterations in choline metabolism.
2. Elsinga P, Todde S, Penuelas I, Meyer G, Farstad B, Cancer Res 1996;56:4630−4635.
Faivre-Chauvet A, et al. Guidance on current good 8. Daly PF, Cohen JS. Magnetic resonance spectroscopy
radiopharmacy practice (cGRPP) for the small-scale of tumors and potential in vivo clinical applications:
preparation of radiopharmaceuticals. Eur J Nucl Med A review. Cancer Res 1989;49:770−779.
Mol Imaging 2010;37:1049−1062. 9. Hara T, Kosaka N, Kishi H. PET imaging of pros-
3. Beheshti M, Mottaghy FM, Payche F, Behrendt FFF, tate cancer using carbon-11-choline. J Nucl Med
Van den Wyngaert T, Fogelman I, et al. 18F-NaF PET/ 1998;39:990−995.
CT: EANM procedure guidelines for bone imaging. 10. DeGrado TR, Baldwin SW, Wang S, Orr MD, Liao
Eur J Nucl Med Mol Imaging 2015;42:1767−1777. RP, Friedman HS, et al. Synthesis and evaluation of

EANM TECHNOLGIST’S GUIDE 27


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 2

18F-labeled choline analogs as oncologic PET trac- Cho S, et al. 68Ga-PSMA PET/CT: Joint EANM and
ers. J Nucl Med 2001;42:1805−1814. SNMMI procedure guideline for prostate cancer
FO R PR O S TATE CAN CER
CL IN ICAL R AD IO PH AR MACEUTICALS

11. Schmid DT, John H, Zweifel R, Cservenyak T, West- imaging: version 1.0. Eur J Nucl Med Mol Imaging
era G, Goerres GW, et al. Fluorocholine PET/CT in 2017;44:1014−1024.
patients with prostate cancer: initial experience. 19. Handkiewicz-Junak D, Poeppel TD, Bodei L, Aktolun
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,

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PROSTATE CANCER IMAGING AND THERAPY
CON V E N T I O N AL
N UCL E A R
MEDI C I N E I N
PROSTAT E

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

These are predominantly osteoblastic. Bone scintigraphy with technetium-


99m labelled diphosphonates is cost-effective and widely available and
provides high sensitivity for the detection of bone metastases[1]. For
this reason, bone scintigraphy is recommended by most national and
international guidelines to exclude or confirm such metastases.

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].

30 EANM TECHNOLGIST’S GUIDE


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CHAPTER 3

Up to now, planar radiography has SCIENTIFIC STUDIES ON THE

IN PR O S TATE CAN CER IMAGIN G


CO N VEN TIO N AL N UCLEAR MED ICIN E
been the next step in the diagnostic BENEFIT OF SPECT/CT IN BONE
workup in cases of focally enhanced di- SCINTIGRAPHY
phosphonate uptake. It represents the The first report on the value of SPECT/spi-
least expensive and most widely avail- ral CT in bone scintigraphy was presented
able morphological imaging modality. If in 2006 by the Erlangen study group[8]. In a
planar radiography shows clear-cut signs population of 44 patients with different tu-
of arthrosis or fracture, it is concluded mour entities, a total of 52 lesions detected
that the scintigraphic abnormalities on SPECT images were judged as indeter-
are benign. However, the drawbacks of minate. Of these, 33 (63%) could be cor-
planar radiography in the identifica- related with benign findings on CT. These
tion of lesions, especially in the spine, findings mostly involved osteochondrosis,
are well known. There is clear evidence spondylosis and spondylarthrosis of the
that destruction of more than 50% of spine. Fifteen (29%) lesions could be cor-
trabecular bone is a prerequisite for the related with osteolysis on CT. Only four le-
visibility of metastases on planar x-ray sions (8%) remained indeterminate; these
studies. Thus, if the radiographs are un- lesions were located in the ribs and the
remarkable, further tests, in particular, scapula. In summary, SPECT/CT allowed
magnetic resonance imaging (MRI), are for a definite diagnosis in 92% of lesions
necessary. This may be time consuming located and thus considerably shortened
and may delay therapeutic procedures. the diagnostic process.
Furthermore, waiting for the diagnosis Helyar et al. examined 40 patients with
causes considerable stress to patients. prostate cancer[9]. They detected 50 sus-
picious lesions on planar scans, of which
More than 15 years ago, a hybrid cam- 72% were classified as indeterminate, 18%
era combining a dual-headed SPECT cam- as benign and 10% as malignant. When
era with a low-dose non-diagnostic CT reporting the SPECT scans, 50% of the
scanner became commercially available. lesions were rated as equivocal, 33% as
However, more recently, hybrid cameras benign and 17% as malignant. The addi-
combining SPECT and spiral CT offer the tion of SPECT/CT resulted in a significant
opportunity to perform a diagnostically reduction in the percentage of equivocal
sufficient CT of scintigraphically suspicious reports, to only 8%; 68% of the lesions
lesions in one session. Two clinical exam- were classified as benign and 24% as ma-
ples are shown in Figures 1 and 2. lignant.

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

Figure 1A
IN PR O S TATE CAN CER IMAGIN G
CO N VEN TIO N AL N UCLEAR MED ICIN E

32 EANM TECHNOLGIST’S GUIDE


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Figure 1B

IN PR O S TATE CAN CER IMAGIN G


CO N VEN TIO N AL N UCLEAR MED ICIN E

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

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

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

34 EANM TECHNOLGIST’S GUIDE


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Figure 2B

IN PR O S TATE CAN CER IMAGIN G


CO N VEN TIO N AL N UCLEAR MED ICIN E
Figure 2C

EANM TECHNOLGIST’S GUIDE 35


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

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

36 EANM TECHNOLGIST’S GUIDE


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CHAPTER 3

SPECT/CT compared with 93%, 78%, 59% COMPARISON OF 99MTC-DPD

IN PR O S TATE CAN CER IMAGIN G


CO N VEN TIO N AL N UCLEAR MED ICIN E
and 95% for whole-body bone scan. Fur- SPECT/CT AND PET/CT WITH
thermore, SPECT/CT caused downstaging DIFFERENT TRACERS
in 29.5% of patients with prostate cancer. It is well known that the resolution of
The authors concluded that SPECT/CT positron emission tomography (PET) is
had a significant effect on clinical man- significantly higher than that of SPECT. In
agement because of correct downstag- the last decade, several PET radiotracers
ing or upstaging, better definition of the have been developed that specifically
extent of metastases and a reduction in target cells from prostate cancer. Since
further diagnostic procedures. prostate cancer in most cases exhibits only
Table 1 provides an overview of studies low metabolic activity, imaging with the
discussed in this section. widely available glucose analogue fluoro-

Author, year [ref.] No. of No. of Scanner No. of Tube Indetermi-


patients lesions CT slices current in nate find-
CT (mA) ings after
SPECT/CT
Horger, 2004 [17] 47 104 GE Millennium VG 1 2.5 15%
Hawkeye

Römer, 2006 [8] 44 52 Siemens Symbia T2 2 40 8%

Helyar, 2010 [9] 40 50 Philips Precedence 16 16 100 8%

Ndlovu, 2010 [10] 42 189 GE Infinia Hawkeye 1 2.5 9%

Zhao, 2010 [11] 125 141 Philips Precedence 6 6 140 4%

Sharma, 2013 [12] 99 108 Siemens Symbia T6 6 100 4%

Palmedo, 2014 [13] 308 839 GE Hawkeye 4 Infinia/ 4 2.5–20 3.5%


Siemens Symbia T2

Table 1: Overview of literature concerning the use of SPECT/CT in tumour


patients with indeterminate findings on planar bone scintigraphy

EANM TECHNOLGIST’S GUIDE 37


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

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

38 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

information regarding a lesion enables the CT software should be able to limit the ex-

IN PR O S TATE CAN CER IMAGIN G


CO N VEN TIO N AL N UCLEAR MED ICIN E
definite clarification of indeterminate find- amined area by drawing the boundaries of
ings in one examination. Since the density the CT scan on the SPECT images.
of bone differs extremely from that of the In a recent study, Zacho et al. revealed
surrounding soft tissue, even low-dose CT that in order to establish the status of
using a tube current of around 20 mAs equivocal lesions on planar bone scintig-
enables sufficient imaging of the areas of raphy, a 3-min SPECT/CT is sufficient[16].
interest. Thus, the additional radiation ex- There was no difference in diagnostic ac-
posure due to CT can be limited. Another curacy between standard SPECT/CT last-
approach in order to limit the radiation ex- ing 11 min and ultra-fast SPECT/CT lasting
posure from additional CT in SPECT/CT is 3 min. This may be because the SPECT data
so-called SPECT-guided CT. If there is only indicate the anatomical localisation of the
a single lesion in the field of view of the lesion with enhanced bone metabolism
SPECT scan, the field of view of the CT can and the final diagnosis is primarily derived
be restricted to this area. Modern SPECT/ from the CT information.

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.

EANM TECHNOLGIST’S GUIDE 39


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 3

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-

40 EANM TECHNOLGIST’S GUIDE


PROSTATE CANCER IMAGING AND THERAPY
4
PET/CT PROCEDURES
WITH FLUORINE-18
RADIOPHARMACEUTICALS
IN PROSTATE CANCER

by Daniel Tempesta
and David Gilmore
CHAPTER 4

PET/CT IMAGING oxygen-15) are accelerator produced and


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

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

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CHAPTER 4

prostate cancer. 18F-FDG, the most com- cose. Patients should have nothing to eat

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
monly used radiopharmaceutical in nu- or drink, other than plain water, for at least
clear medicine, is not particularly helpful 4 h before the exam and should attempt
for imaging patients with prostate cancer. to avoid carbohydrates and sugar in their
18
F-FDG has proven to be a very useful tool last meal. Certain medications, especially
in other oncology applications such as those used for the management of diabe-
lymphoma, breast cancer, lung cancer and tes (metformin, insulin, etc.), may alter the
melanoma. In these instances, 18F-FDG biodistribution of the radiopharmaceuti-
will show increased accumulation in tu- cal. The physician of diabetic patients and
mour cells because these types of cancer the radiologist should discuss the best way
exhibit increased glucose metabolism. In to manage each patient’s blood glucose
contrast, prostate cancer usually demon- levels in order to optimise the scan.
strates low metabolic activity, making The patient’s blood glucose should be
18
F-FDG much less useful. Since the devel- taken and a peripheral intravenous line
opment and widespread use of 18F-FDG in should be placed. Patients with blood glu-
oncology, researchers have been looking cose levels exceeding 200 mg/dL should
to develop new radiopharmaceuticals to be rescheduled because excess circulating
evaluate prostate cancer. glucose will compete with the injected
18
F-FDG and uptake in tumour cells will be
reduced. The institutional and manufac-
18
F-FDG turer based activity[1] of 18F-FDG (MBq/kg)
Fluorodeoxyglucose is a glucose analogue should be injected intravenously and the
that diffuses into the cell using glucose patient asked to relax quietly in a chair or
transporters in the cell membrane. Many stretcher for 1 h while the tracer circulates
forms of cancer are characterised by rap- and is taken up into the cells. While not
idly dividing cells with increased metabol- normally employed for oncology patients,
ic demands and an increased number of diuretics and bladder catheters may be
glucose membrane transporters. Because used to help reduce bladder activity of
FDG is not metabolised in the same way the radiopharmaceutical in order to better
as glucose, FDG remains trapped in the cy- visualise the prostate. These techniques
tosol of the cell long enough to allow for should be utilised at the discretion of the
imaging. physician.
Patient preparation for the exam in- Imaging should begin at 60 min post-
volves depriving the body’s cells of glu- injection. It is imperative that the patient

EANM TECHNOLGIST’S GUIDE 43


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 4

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]

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initial staging of prostate cancer. One area Patient preparation includes refraining

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
where 18F-FDG PET may be a valuable from any strenuous exercise for at least
tool is for the staging of advanced pros- 24h before the exam. Other than plain
tate cancer in patients with a high Glea- water, the patient should not eat or drink
son score. Limited studies have shown anything for 4 h prior to the scan.
18
F-FDG PET to be appropriate for detec- The prescribed dose is 370 MBq, inject-
tion of prostate cancer, but only in pa- ed intravenously as a bolus, usually while
tients at more than an intermediate risk[3]. the patient is on the imaging table owing
Because of the previously mentioned lim- to the quick turnaround time between in-
itations, researchers have been seeking to jection and scan. When possible, the pa-
develop new radiopharmaceuticals that tient should be injected in the right arm in
focus on physiological properties other an attempt to prevent a left axillary lymph
than glucose metabolism in order to im- node artefact from occurring. Imaging
age prostate cancer. should begin 3–5 min after radiopharma-
ceutical injection, the time when tumour
uptake is highest. When possible, the pa-
18
F-FLUCICLOVINE (AXUMIN®) tient’s arms should be placed above the
18
F-fluciclovine, produced under the com- head and imaging should start at the mid-
mercial name Axumin® by Blue Earth Di- thigh. Five-minute bed positions are ac-
agnostics Ltd., has recently emerged as a quired over the pelvis, followed by 3-min
promising PET radiopharmaceutical for bed positions through the abdomen and
the detection of recurrent prostate cancer chest. The scan should continue through
in patients with a rising prostate-specific the skull base and takes about 20–30 min
antigen (PSA) level. 18F-fluciclovine, a syn- to complete, depending on the height of
thetic amino acid, is transported into the the patient.
cell membrane by amino acid transport- Normal physiological uptake of 18F-fluci-
ers. Because prostate cancer cells are up- clovine includes the pancreas, liver, spleen
regulated, tumour cells will exhibit greater and kidneys. The pancreas and liver exhib-
tracer accumulation than the normal tis- it the highest uptake, with the pancreas
sues of the body. 18F-fluciclovine may offer receiving the highest radiation dose, at 38
an alternative to carbon-11 choline, which mGy. Mild salivary gland, pituitary gland
requires close proximity to a cyclotron and muscle uptake is normal while the
for imaging owing to the relatively short brain and lungs are generally not visual-
physical half-life of 11C. ised. A major benefit of 18F-fluciclovine is

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 4

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

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CHAPTER 4

Figure 2

However, with the development of PET

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
technology and the great improvement
in resolution from gamma cameras to
PET scanners, 18F-sodium fluoride may
become a better choice for imaging of
skeletal metastases.
The patient should be well hydrated
before the exam to promote soft tissue
tracer clearance, reduce radiation dose to
the patient and reduce bladder activity
that may obscure surrounding bony struc-
tures. The typical adult dose of 18F-sodium
fluoride is 185–370 MBq injected intrave-
nously. The radiopharmaceutical accumu-
lates in the skeleton based on blood flow
and bone remodelling. Since 18F-sodium
fluoride localises in the bones and clears
from the soft tissue faster than 99mTc-based
skeletal agents, imaging may begin 30–45
Anterior and posterior MIP views min after injection when imaging the axial
using F-18 sodium fluoride skeleton. Imaging should begin 90–120
min after injection when imaging the
extremities, but such imaging is not usu-
18
F-SODIUM FLUORIDE ally performed when looking for prostate
18
F-sodium fluoride is a PET radiophar- cancer metastases. The patient should
maceutical that identifies areas of altered void immediately before the scan. If only
osteogenic activity, including those af- imaging of the axial skeleton is requested,
fected by metastatic disease of prostate the patient should be positioned supine
cancer and other types of cancer[5]. Bone with the arms raised above the head. It
scintigraphy using technetium-99m la- may be useful to begin the scan at the pel-
belled radiopharmaceuticals, such as vis, before the bladder fills, and continue
99m
Tc-medronate (MDP), has long been through the skull base. If head-to-toe skel-
a useful tool for identification of met- etal imaging is requested, the arms should
astatic prostate cancer in the bones. be placed down by the side of the body.

EANM TECHNOLGIST’S GUIDE 47


PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 4

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

hydroxyapatite of bones in place of the bones should be identifiable as focal


hydroxyl groups and therefore will ac- areas of increased tracer accumulation.
cumulate in the entire skeleton during Correlation with the CT scan can improve
normal bone turnover. In areas of new specificity and improve confidence in the
bone formation, such as in the case of anatomical localisation of lesions. De-
bones attempting to repair themselves termination of the presence or absence
from prostate cancer metastases, more of skeletal metastases in patients with
binding sites are available for 18F, caus- known prostate cancer can be useful in
ing increased radiopharmaceutical accu- the staging or restaging of disease and in
mulation. In addition, bone tumours tend management planning.The results of a re-
to exhibit increased perfusion, allow- cent study suggested that up to 77% of re-
ing more of the radiopharmaceutical to ferring physicians would not have formu-
be transported to the tumour. For both lated a treatment plan in the absence of
these reasons, prostate cancer metastases availability of 18F-sodium fluoride PET (and
should exhibit increased activity on imag- conventional bone scintigraphy), instead
ing compared with normal tissue around opting for further advanced imaging[6].
the tumours. While 18F-sodium fluoride
imaging is sensitive for the detection of
bone metastases, caution should be ex- PSMA
ercised as benign processes may also ex- RADIOPHARMACEUTICALS
hibit increased accumulation of 18F-sodi- Prostate-specific membrane antigens
um fluoride, and differentiation between (PSMA) are transmembrane proteins found
malignant and benign processes may be in normal prostate tissues as well as other
difficult in certain situations. normal tissues in the body. PSMA is also
Beyond radiopharmaceutical accumu- found in malignant prostate tissue, and
lation in the skeleton, 18F-sodium fluoride PSMA expression correlates with disease
is normally visible in the kidneys, ureters progression, including metastatic disease.
and bladder due to urinary excretion (Fig. Targeting of PSMA is one of the alterna-
2). This can pose challenges when imag- tives to 18F-FDG explored by researchers
ing the bony anatomy around the blad- for detection of prostate cancer. Also,
der and every effort should be made to while 18F-fluciclovine has shown much
keep the patient hydrated and to ensure promise, researchers are looking for a PS-
that they empty their bladder before im- MAligand for theranostic purposes, to be

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 4

coupled with the prostate radiotherapy only a few hundred patients have to date

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
agent lutetium-177 PSMA. The theory is been scanned using 18F-PSMA tracers,
that a PSMA imaging agent will perform compared with the thousands of patients
better than 18F-fluciclovine in predicting scanned with 68Ga-PSMA[7]. Despite the ad-
the distribution of 177Lu. To date, the most ditional research that needs to be done, it
successful PSMA agent has been galli- appears that PSMA radiopharmaceuticals
um-68 PSMA. However, since the develop- may successfully fill a long-term void in
ment of 68Ga-PSMA there has been a desire prostate cancer imaging with PET/CT.
to develop an 18F-based PSMA radiophar-
maceutical owing to the more favourable
imaging characteristics of 18F[7]. CONCLUSION
In comparison with 18F, 68Ga has a short- PET/CT imaging has become standard of
er physical half-life of 68 min, which can care in most oncology cases, especially for
cause logistical problems when attempt- breast cancer, lung cancer and lymphoma.
ing to ship the material from central ra- While 18F-FDG PET has proven successful in
diopharmacies to imaging facilities. In many oncology applications, the biology
addition, 68Ga is produced by a generator of prostate cancer has prevented it from
and can only be eluted a few times per being standard of care for prostate pa-
day, with each elution only producing tients. Researchers have developed new
enough activity for a single patient dose. prostate cancer radiopharmaceuticals,
Because of these elution limitations, the some labelled with 18F and some with other
number of doses that can be produced radionuclides, the most promising being
per day is drastically limited in comparison 18
F-fluciclovine. 18F-sodium fluoride also
with the number of doses that can be pro- remains a useful tool for imaging skeletal
duced with 18F, which is produced in large metastases from prostate cancer. While
amounts by a cyclotron. only a few 18F-based radiopharmaceuticals
Recently, multiple PSMA ligands have are currently being used, researchers are
been developed for labelling with 18F, all of investigating a variety of other options for
which are still being researched. The ben- prostate cancer imaging with PET/CT.
efit of these radiopharmaceuticals is their
specificity for prostate cancer, and normal
distributions have demonstrated very low
urine and bladder activity, something that
is key in prostate cancer imaging. In total,

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 4

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:

50 EANM TECHNOLGIST’S GUIDE


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5
AVA I L A B L E A S W E B I N A R

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

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CHAPTER 5

Figure 1

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PR O STATE C A NC E R PE T/C T I MAGI NG
11C-Coline

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

»» Describe PET/CT protocols tabolites are capable of being incorporated


»» 
Identify the challenges posed by the into cancer cells in a dramatically different
non-18F tracers fashion compared with normal tissues, and
»» Describe the advantages of the non-18F this understanding forms the background
tracers for the development of novel biomarkers
that can be used for imaging purposes.
The most commonly used oncological
PET/CT TRACERS radiopharmaceutical, 18
F-fluorodeoxy-
Cancer cells and healthy tissues show sig- glucose (FDG), which detects increased
nificant differences in the uptake and use of glucose metabolism within malignant tu-
nutrients and constitutional elements. It is mours, has a low sensitivity in detecting
well known that selected radiolabelled me- prostate cancer, severely limiting its use

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CHAPTER 5

except, possibly, in aggressive, poorly dif- teristic of prostate cancer cells (phospho-
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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)

54 EANM TECHNOLGIST’S GUIDE


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proteins [labelled prostate-specific mem- »» Particular attention must be paid to im-

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PR O STATE C A NC E R PE T/C T I MAGI NG
brane antigen (PSMA) ligand][6]. age quality, by calculating radiopharma-
Here we provide an overview of the ceutical activity as a function of patient
tracers routinely available for prostate can- characteristics, scanner type, scanning
cer PET/CT imaging, with the exception of mode and time of acquisition (Table 1).
18
F-labelled radiopharmaceuticals. »» PET and CT parameters for whole-body
acquisition, and reconstruction, must
be set according to the manufacturer’s
PET AND CT PROTOCOLS WITH recommendations and national and in-
NON-18F TRACERS ternational guidelines. These parameters
There are some general aspects that must usually need to be set according to pa-
be considered when carrying out PET/CT tient characteristics and clinical needs.
imaging with tracers other than 18F: However, in order to guarantee a quality
»» National and local rules on radiophar- scan for all patients scheduled in each
maceutical preparation and use must be session, it is also important not to forget
respected by all single centres that per- operational challenges due to the short
form PET studies for clinical or research half-life of the tracer.
purposes. »» The justification principle of radiation
»» Patient preparation should be as homo- protection ought always to be consid-
geneous as possible, to avoid mislead- ered before using any radiation-emitting
ing findings caused by modifications of device or radiopharmaceutical for med-
physiological radiopharmaceutical bio- ical purposes.
distribution. »» Acquisition protocols should be stan-
»» With short half-life tracers, a strict pro- dardised to allow direct comparison
tocol, which includes timing and instru- of PET/CT images acquired in different
ment cross-calibration, is advisable for centres and correct participation in mul-
radiopharmaceutical administration. ticentre clinical research protocols.
»» Administered activity must be adjusted »» Physicians and technologists/radiogra-
to the clinical question addressed by the phers must be aware of the physiologi-
PET/CT study. In Europe, Directive 97/43/ cal tracer distribution and its variants in
EURATOM must be taken into account order to recognise pitfalls that could lead
and recommended national activities for to misinterpretation.
radiopharmaceuticals should not be ex- »» Reporting should be as homogeneous
ceeded for standard procedures. as possible, stressing the most relevant

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clinical findings and specifying conclu- trast-enhanced CT in the portal venous


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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.

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Problems Advantages

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PR O STATE C A NC E R PE T/C T I MAGI NG
»» Shortage of synthesis product »» Easy rescheduling of the synthesis process
»» Quality control not “clearly positive” »» Possibility of staff intervention in the process
»» Patient delay in turning up at the imaging site »» Easy rescheduling of patients
»» Difficulties in injecting the patient »» Rapid tracer decay means that only a short
»» Poor physical, mental and psychological interval is needed between two syntheses
condition of the patient within the same hot cell
»» Insufficient scanners available (e.g. due to a »» Departmental internal coordination without
technical problem) external agents
»» Staff shortage »» Internal agreement on protocols and time
»» Bad patient scheduling scheduling

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

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 5

by choline kinase in the first step of the ing the examination to confirm that the
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PR O STATE C A NC E R PE T/C T I MAGI NG

Kennedy cycle. Key enzymes in choline procedure is appropriate.


metabolism, such as choline kinase, are »» On the day of the examination, the pa-
up-regulated in prostate cancers, and this tient should be asked to fast for at least
is likely the primary reason why prostate 4 h before injection.
cancers concentrate 11C-choline[10]. »» The physician in charge of the patient
Both 11C-choline and 18F-fluorocholine may request the withdrawal of specific
have received much attention over the drugs during prior clinical evaluations.
past several years, particularly in Europe »» Patient height and body weight and the
and Japan, for imaging of men with pros- principal clinical details are recorded, in
tate cancer. 11C-choline has recently been particular:
approved by the Food and Drug Admin- - Tumour type
istration for production and use to detect - PSA value
recurrent prostate cancer at the Mayo - Known tumour localisations
Clinic in Rochester, Minnesota[11]. - Previous therapies (type and time
A major advantage of 11C-choline is its of surgery, chemotherapy, radiation
rapid blood clearance (5 min) and rapid therapy, mono-therapy or others)
uptake within prostate tissue (3–5 min), al- »» Patients should be well hydrated
lowing for early imaging before excretion
of the tracer into the urine. Thus, the pelvis Administered activity
can be viewed before significant excretory The radiopharmaceutical is administered
activity becomes a potential confounder. as a bolus by intravenous injection, fol-
Unfortunately, the 20-min half-life of 11C lowed by flushing of physiological saline
restricts the use of 11C-choline to cen- solution. After the administration, the pa-
tres with an on-site cyclotron. In contrast, tient needs to wait 10 min before the scan
the longer half-life of 18F (110 min) allows starts. Activities of around 350 MBq are
transportation of 18F-fluorocholine to cen- recommended.
tres without a cyclotron, although 18F-cho-
line has a higher urinary excretion than Image interpretation
11
C-choline[12]. Physiologically increased uptake of choline
is noted in the salivary glands, liver, kidney
Specific patient preparation parenchyma and pancreas, with faint up-
»» The indication for use of choline imag- take in the spleen, bone marrow and mus-
ing should be evaluated before schedul- cles; bowel activity is variable (Figs. 2, 3).

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Figure 2

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PR O STATE C A NC E R PE T/C T I MAGI NG
Physiological distribution of 11C-choline

Clinical indications Most groups have not found a signifi-


The principal indication for 11C-choline cant correlation between 11C-choline max-
PET/CT is local disease evaluation. The high imum standardised uptake value (SUVmax)
uptake of choline in prostate cancer seems and PSA levels, Gleason score and disease
to be caused by its active incorporation in stage. SUV is affected by many factors, such
tumour cells for production of phosphati- as patient size and time between tracer in-
dylcholine, a cell membrane constituent, jection and PET/CT scan. It is also possible
to facilitate rapid cell duplication. to calculate the ratio between SUVmax of
Uptake of 11C-choline is similar in pa- the prostate lesion (P) and of the pelvic
tients with benign prostatic diseases and muscles (M), (SUVmax P/M). This may be a
proven prostate cancer; this is the major promising approach, as evidenced by a re-
limitation to use of this tracer for identifica- cent study in which Chen and colleagues
tion of the primary tumour. In addition, the found SUVmax P/M ratio to be significantly
limited spatial resolution of PET/CT needs associated with clinical tumour stage and
to be borne in mind. Gleason score[13].

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Figure 3
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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].

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Figure 4

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PR O STATE C A NC E R PE T/C T I MAGI NG
Lymph node: (Diameter 6mm)
Biomedical failure: LN metastasis

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.

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Figure 5
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11
C-Choline

Case of physiological distribution Case of bone metastasis


18
F-Choline

11
C-Acetate PET/CT: physiological and pathological findings. Courtesy of G. Karanikas and M. Beheshti

Administered activity carcinoma, bladder carcinoma and brain


The radiopharmaceutical is administered tumours; it has also been extensively used
as a bolus by intravenous injection, fol- to evaluate prostate cancer (Fig. 5).
lowed by flushing with physiological sa- With regard to prostate cancer, 11C-ace-
line solution. After the administration, the tate PET has been tested in the detection
patient needs to wait 10−15 min before of the primary tumour and staging (partic-
the scan starts. Activities of 740 MBq are ularly in the evaluation of nodal involve-
recommended[22]. ment and distant metastasis), as well as in
the evaluation of disease relapse. Oyama
Clinical indications and co-workers demonstrated a sensitivi-
11
C-Acetate PET has been applied to mea- ty of 100% in the detection of the primary
sure myocardial oxygen consumption and tumour in a series of 22 patients with his-
to study several different cancers, includ- tologically proven prostate cancer[18]. How-
ing hepatocellular carcinoma, renal cell ever, Kato et al. found that 11C-acetate PET

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cannot reliably distinguish benign pros- Information on the prognostic value

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PR O STATE C A NC E R PE T/C T I MAGI NG
tatic hyperplasia from prostate cancer[19]. of 11C-acetate PET imaging is still limited.
In contrast, Mena et al. demonstrated that Moreover, studies that have systematically
11
C-acetate uptake in tumour is higher than evaluated 11C-acetate as an intermediate
that in normal prostate tissue[20]. Although endpoint biomarker are lacking in the liter-
11
C-acetate PET/CT does not seem to be ature, even if anecdotal evidence suggests
an accurate diagnostic modality for assess- that 11C-acetate imaging may provide such
ment of primary gland-confined prostate information in the context of prostate can-
cancer, it has the potential to guide biopsy cer treatment[25].
in individual clinically suspicious cases with
negative biopsy results[21].
There are few data in the literature on 68
GA-PSMA
the sensitivity of 11C-acetate in assessing Prostate-specific membrane antigen is a
the initial nodal stage in prostate cancer, transmembrane protein primarily present
with a range of results. It has been found in all prostatic tissues. Increased PSMA
that 11C-acetate may be useful for pelvic expression is seen in a variety of malig-
nodal staging and treatment planning in nancies, but most notably in prostate
men with intermediate-risk (T2b–T2c or cancer[26]. Nearly all adenocarcinomas of
Gleason score 7 or PSA 10–20 ng/mL) to the prostate − both primary tumours and
high-risk (T3a or Gleason score 8–10 or metastatic lesions − demonstrate PSMA
PSA >20 ng/mL) prostate cancer[22, 23]. expression. Immunohistochemical stud-
Spick et al. retrospectively compared ies have shown that PSMA expression
conventional bone scan and 11C-ace- increases in de-differentiated, metastatic
tate PET with respect to the detection or hormone-refractory disease and its ex-
of bone metastases. They found the two pression level is a significant prognostica-
imaging techniques to be comparable in tor for disease outcome[27]. Investigators
a patient-based analysis, suggesting that have developed and evaluated, in pre-
11
C-acetate PET can reliably survey bone clinical animal and pilot human studies,
involvement[24]. several radiolabelled ligands using various
11
C-Acetate also appears to be useful in platforms that include antibodies or anti-
the localisation of tumour recurrences in body fragments targeting the intracellular
men with biochemical failure, with a de- (binding to apoptotic or necrotic cells)
tection rate that tends to be positively as- or extracellular (binding to viable cells)
sociated with increasing serum PSA level. motifs of the antigen. These PSMA-based

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tracers include 89Zr-desferrioxamine B Patient height and body weight and


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(DFO)-7E11; 64Cu-labelled aptamers; the principal clinical details are recorded,


and 11C, 18F, 68Ga-, 64Cu- and 86Y-labelled in particular:
low-molecular-weight inhibitors of PSMA, »» Tumour type
including 18F-labelled N-[N-[(S)-1,3-dicar- »» PSA value and Gleason score
boxypropyl] carbamoyl]-4-[18F]fluoroben- »» Known tumour localisations
zyl-L-cysteine and 18F-labelled phospho- »» Previous therapies (type and time of sur-
ramidate peptidomimetics, with some gery, chemotherapy, radiation therapy,
formulations that can also be labelled monotherapy or others)
with radionuclides such as 177Lu or 90Y for »» Relevant symptoms (bone pain, fre-
targeted radioimmunotherapy[28]. quent urination, nocturia, haematuria,
68
Ga-PSMA is currently one of the most dysuria, impotence, erectile dysfunction
successful PET tracers in prostate cancer or painful ejaculation)
due to its clinical specificity and also its »» Previous imaging findings
availability, given that 68Ga is easily ob- »» Relevant co-morbidities
tained from a 68Ge/68Ga generator system. »» Allergies
68
Ga decays with 89% yield by positron »» Renal failure
emission and has a half-life of 67.63 min.
Several low-molecular-weight ligands for Patients should be well hydrated be-
human PSMA, linked with a chelator for fore the injection and during the uptake
68
Ga complexation, are clinically available period. Voiding immediately before imag-
for PET/CT imaging. 68Ga-labelled PSMA ing acquisition is recommended. Despite
ligands were first radiosynthesised and this, in some circumstances, high residual
validated in preclinical models at Johns activity in the urinary system may lead to
Hopkins University[29]. so-called halo artefacts on PET. Activity in
the ureters may lead to false positive find-
Specific patient preparation ings. Furosemide administration (20 mg
The indication for use of 68Ga-PSMA im- i.v., shortly before or after administration
aging should be evaluated before sched- of 68Ga-PSMA) may be especially useful in
uling the examination to confirm that the these situations. Furosemide should not
procedure is appropriate. The physician be administered in patients with medical
in charge of the patient may request the contraindications to furosemide adminis-
withdrawal of specific drugs during prior tration, including allergies (e.g. sulfa aller-
clinical evaluations. gies).

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11
C-Acetate 11
C-Choline Ga-PSMA
68

Patient preparation Hydration with, for Hydration with for Hydration with for

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PR O STATE C A NC E R PE T/C T I MAGI NG
example, oral intake example, oral intake example, oral intake
of 500 mL of water 2 h of 500 mL of water 2 h of 500 mL of water 2 h
prior to acquisition prior to acquisition prior to acquisition
Activity ~
740 MBq ~
350 MBq 1.8–2.2 MBq per
kilogram body weight
Administration Intravenous; flushing Intravenous; flushing Intravenous; flushing
with at least the same with at least the same with at least the same
volume of saline volume of saline volume of saline
Concomitant None None Possibly furosemide
medication (20 mg i.v.)
Uptake time 10−15 min 10 min 60 min (50−100 min)

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

Table 3: Comparison of possible protocols for 11C-acetate, 11C-choline and 68Ga-PSMA

Table 3 provides a comparative over- published data are based on an injected


view of possible protocols for 68Ga-PSMA, activity of approximately 1.8–2.2 MBq per
11
C-acetate and 11C-choline. kilogram of body weight.

Administered activity Clinical applications of


68
Ga-PSMA is injected as an intravenous 68
Ga-PSMA PET/CT
bolus. Currently, the optimal injected ac- As stated in the recently issued EANM/
tivity is still under debate. The majority of SNMMI guidelines on 68Ga-PSMA PET/CT,

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data from prospective multicentre trials in patients with a high suspicion of pros-
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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

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Figure 7

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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 foci of pathological uptake in bones
with no morphological lesions seen on CT, indicating rapidly growing disease

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

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CHAPTER 5

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

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Figure 9

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PR O STATE C A NC E R PE T/C T I MAGI NG

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

radiologists to diagnose prostate cancer − Further validation of the proposed algo-


Morphology, Asymmetry, Physiology and rithm is needed using a larger dataset, but
Size (MAPS) − using biomarkers inspired this represents an interesting application of
by the PI-RADS guidelines for performing the radiomics concept that could also be
structured reporting on prostate MRI[35]. applied to other imaging techniques.

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 5

In a study by Giesel et al. a correlation CT for prostate cancer, this is of course


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

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.

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seer.cancer.gov/statfacts/html/prost.html. Published imaging: version 1.0. Eur J Nucl Med Mol Imaging
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MG, De Santis M, et al. EAU-ESTRO-SIOG guidelines gas HA. Molecular imaging of prostate cancer. Radio-
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4. EANM. Principles and practice of PET-CT. Part 2. Wien, 9. Ackerstaff E, Glunde K, Bhujwalla ZM. Choline phos-
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10. Farsad M, Schiavina R, Castelluci P, Nanni C, Corti 20. Mena E, Turkbey B, Mani H, Adler S, Valera VA, Bernar-

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B, Martorana G, et al. Detection and localization of do M, et al. 11C-acetate PET/CT in localized prostate-
prostate cancer: correlation of (11)C-choline PET/CT cancer: a study with MRI and histopathologic correla-
with histopathologic step section analysis. J Nucl Med tion. J Nucl Med 2012;53:538–545.
2005;46:1642–1649. 21. Karanikas G, Beheshti M. 11C-acetate PET/CT imag-
11. Mitchell CR, Lowe VJ, Rangel LJ, Hung JC, Kwon ing: physiologic uptake, variants, and pitfalls. PET
ED, Karnes RJ. Operational characteristics of 11C-cho- Clin 2014;9:339–344.
line positron emission tomography/computerized 22. Haseebuddin M, Dehdashti F, Siegel BA, Liu J, Roth
tomography for prostate cancer with biochemical re- EB, Nepple KG, et al. 11C-acetate PET/CT before
currence after initial treatment. J Urol 2013;189:1308– radical prostatectomy: nodal staging and treatment
1313. failure prediction. J Nucl Med 2013;54:699–706.
12. Hara T, Kosaka N, Kishi H. PET imaging of pros-  23. Mohsen B, Giorgio T, Rasoul ZS, Werner L, Ali GR, Reza
tate cancer using carbon-11-choline. J Nucl Med DK, Ramin S. Application of 11C-acetate positron
1998;39:990–995. emission tomography (PET) imaging in prostate
13. Chen J, Zhao Y, Li X, Sun P, Wang M, Wang R, Jin X. cancer: systematic review and meta-analysis of the
Imaging primary prostate cancer with 11C-Choline literature. BJU Int 2013;112:1062−1072.
PET/CT: relation to tumour stage, Gleason score and 24. Spick C, Polanec SH, Mitterhauser M, Wadsak W, An-
biomarkers of biologic aggressiveness. Radiol Oncol ner P, Reiterits B, et al. Detection of bone metasta-
2012;46:179–188. ses using 11C-acetate PET in patients with prostate
14. Murphy RC, Kawashima A, Peller PJ. The utility of cancer with biochemical recurrence. Anticancer Res
11C-choline PET/CT for imaging prostate cancer: a 2015;35:6787–6791.
pictorial guide. AJR Am J Roentgenol 2011;196:1390– 25. Yu EY, Muzi M, Hackenbracht JA, Rezvani BB, Link
1398. JM, Montgomery RB, et al. 11C-acetate and 18F-FDG
15. Fuccio C, Castellucci P, Schiavina R, Guidalotti PL, Ga- PET for men with prostate cancer bone metastases:
varuzzi G, Montini GC, et al. Role of (11)C-choline PET/ relative findings and response to therapy. Clin Nucl
CT in the re-staging of prostate cancer patients with Med 2011;36:192–198.
biochemical relapse and negative results at bone 26. Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo
scintigraphy. Eur J Radiol 2012; 81:893–896. C. Prostate-specific membrane antigen expression in
16. Apolo AB, Pandit-Taskar N, Morris MJ. Novel tracers normal and malignant human tissues. Clin Cancer Res
and their development for the imaging of metastatic 1997;3:81–85.
prostate cancer. J Nucl Med 2008;49:2031–2041. 27. Ross JS, Sheehan CE, Fisher HA, Kaufman Jr RP, Kaur
17. Tang X, Tang G, Nie D Fully automated synthesis of P, Gray K, et al. Correlation of primary tumor pros-
C-11-acetate as tumor PET tracer by simple modified tate-specific membrane antigen expression with
solid-phase extraction purification. Appl Radiat Iso- disease recurrence in prostate cancer. Clin Cancer Res
topes 2013;82:81−86. 2003;9:6357–6362.
18. Oyama N, Akino H, Kanamaru H, Suzuki Y, Muramo- 28. Mease RC, Foss CA, Pomper MG. PET imaging in pros-
to S, Yonekura Y, Sadato N, Yamamoto K, Okada K. tate cancer: focus on prostate-specific membrane an-
11C-acetate PET imaging of prostate cancer. J Nucl tigen. Curr Top Med Chem 2013;13:951–962.
Med 2002; 43: 181-6. 29. Banerjee SR, Pullambhatla M, Byun Y, Nimmagadda S,
19. Kato T, Tsukamoto E, Kuge Y, Takei T, Shiga T, Shino- Green G, Fox JJ, et al. 68Ga-labeled inhibitors of pros-
hara N, et al. Accumulation of 11C-acetate in normal tate-specific membrane antigen (PSMA) for imaging
prostate and benign prostatic hyperplasia: compari- prostate cancer. J Med Chem 2010;53:5333–5341.
son with prostate cancer. Eur J Nucl Med Mol Imaging 30. Budaus L, Leyh-Bannurah SR, Salomon G, Michl U,
2002;29:1492–1495. Heinzer H, Huland H, et al. Initial experience of (68)

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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.

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IN PRO S TAT E
C AN C E R

6
PE T/C T - GU I D ED
R ADIOT H E R A PY
PL AN N I N G

by Yat Man Tsang and


Michelle Leech
CHAPTER 6

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

globally and the incidence across Europe is amongst the highest


in the world, with 420,000 new cases reported in 2012[1,2]. The
diagnostic assessment and management of prostate cancer remains
challenging and controversial owing to the disease’s wide spectrum of
histopathological behaviours[3].

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.

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Radiotherapy is an extremely effective EXTERNAL BEAM

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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-

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eation is sometimes inadequate owing to and contained recommendations on how


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PE T/C T- GUI D E D RA D I OTHE RA PY

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-

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Volume name Description


Gross tumour volume (GTV) The gross palpable or visible/demonstrable extent and location of

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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.

Table 1: The various volumes described by ICRU 50/62 [9,10]

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

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in a way that allows adequate delivery of b) correct any patient misalignment by


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

radiation dose to the tumour in multiple changing the relative geometry of


fractions over a period of several weeks. In the treatment machine (couch po-
order to fulfill this requirement, treatment sition) before the treatment is deliv-
margins are added to the initial target at ered.
the treatment planning stage. Different There is a technical component that
margin recipes have been developed to involves the acquisition and registration
allow determination of the margin size of images and a professional component
required in order to ensure that the clin- that involves image review and deci-
ical target volume (CTV) is covered by a sion-making on the extent of patient re-
certain radiation dose. Van Herk presented positioning required. A multidisciplinary
the most commonly used margin recipe approach, particularly with significant in-
from a Monte Carlo study of prostate ra- volvement of radiation therapists, is con-
diotherapy treatments[12]. The margin size sidered essential in the development of an
to ensure that the CTV receives at least effective IGRT protocol.
95% dose in 90% of patients is given as:

Mptv = 2.5 Σ +1.64 (σ – σp) Incorporating PET/CT into radiothera-


py planning
where Σ refers to the systematic variation, With a view to incorporating the informa-
σ to the random variation and σp to the tion from molecular or functional images
penumbra margin. into radiotherapy treatment planning,
Ling et al. introduced the concept of dose
Radiotherapy treatment delivery painting[13]. This approach entails the pre-
To account for the geometrical uncertain- scription of a non-uniform radiation dose
ties, safety margins are applied. Geometri- distribution to the target volume based
cal uncertainties may be reduced by the on the acquired images, with the aim of
implementation of image-guided radio- achieving biological instead of physical
therapy (IGRT). Clinically, IGRT often refers conformity of radiation dose delivery to
to the ability to: the tumour[13]. Subsequently, several in-
a) quantify the variation in position of vestigators proposed further promising
the anatomical target between the new ways to design radiotherapy treat-
planned and initial setup treatment ment in accordance with the radiobiology
images; of tumour cells and illustrated the techni-

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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

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to very small sub-regions of the tumour, radiation therapists continuously advance


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

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.

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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
1. Siegel R, Miller K, Jemal A. Cancer statistics, 2015. CA: A 11. International Commission on Radiation Units and
Cancer Journal for Clinicians 2015;65:5–29. Measurements. Prescribing, recording, and reporting
2. Ferlay J, Soerjomataram I, Ervik M, Forman D, Bray F, photon beam intensity modulated radiation therapy
Dikshit R, et al. GLOBOCAN 2012 v1.0, Cancer Incidence (IMRT). ICRU Report no. 83. Bethesda (MD): Interna-
and Mortality Worldwide: IARC Cancer Base No. 11 tional Commission on Radiation Units and Measure-
[Internet]. Lyon, France: International Agency for Re- ments (ICRU); 2010.
search on Cancer; 2013. Available from: http://globo- 12. Van Herk M, Remeijer P, Rasch C, Lebesque JV. The
can.iarc.fr, accessed 18 March 2018. probability of correct target dosage: dose-population
3. Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark histograms for deriving treatment margins in radio-
JR, Busch C, et al. Radical prostatectomy versus watch- therapy. Int J Radiat Oncol Biol Phys 2000;47:1121–
ful waiting in early prostate cancer. N Engl J Med 1135.
2011;364:1708–1717. 13. Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel
4. Elster A. Recommendations on the use of 18F-FDG S, Koutcher JA. Towards multidimensional radiother-
PET in oncology. Yearbook of Diagnostic Radiology apy (MDCRT): biological imaging and biological con-
2009:163–165. formality. Int J Radiat Oncol Biol Phys 2000;47:551–560.
5. Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann 14. Alber M, Paulsen F, Eschmann SM, Machulla HJ. On
LM. The role of 11C-choline and 18F-fluorocholine pos- biologically conformal boost dose optimization. Phys
itron emission tomography (PET) and PET/CT in pros- Med Biol 2003;48:N31–N35.
tate cancer: a systematic review and meta-analysis. Eur 15. Flynn RT, Barbee DL, Mackie TR, Teraj R. Comparison of
Urol 2013;64:106–117. intensity modulated x-ray therapy and intensity mod-
6. Jadvar H. PSMA PET in prostate cancer. J Nucl Med ulated proton therapy for selective subvolume boost-
2015;56:1131–1132. ing: A phantom study. Phys Med Biol 2007;52:6073–
7. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, 6091.
Bloomfield D, et al. Conventional versus hypofraction- 16. Sovik A, Malinen E, Skogmo HK, Bentzen SM, Bruland
ated high-dose intensity-modulated radiotherapy for OS, Olsen DR. Radiotherapy adapted to spatial and
prostate cancer: 5-year outcomes of the randomised, temporal variability in tumuor hypoxia. Int J Radiat
non-inferiority, phase 3 CHHiP trial. Lancet Oncol Oncol Biol Phys 2007;68:1496–1504.
2016;17:1047–1060. 17. Lee JA. Segmentation of positron emission topog-
8. MacManus M, Nestle U, Rosenzweig K, Carrio I, Messa raphy images: Some recommendations for target
C, Belohlavek O, et al. Use of PET and PET/CT for radia- delineation in radiation oncology. Radiother Oncol
tion therapy planning: IAEA expert report 2006–2007. 2010;96:302–307.
Radiother Oncol 2009;91:85–94. 18. Coffey M, Vaandering A. Patient setup for PET/CT ac-
9. International Commission on Radiation Units and Mea- quisition in radiotherapy planning. Radiother Oncol
surements. Prescribing, recording, and reporting pho- 2010;96:298–301.
ton beam therapy. ICRU report no. 50. Bethesda (MD): 19. Fraass B, Doppke K, Hunt M, Kutcher G, Starkschall
International Commission on Radiation units and Mea- G, Stern R, Van Dyke J. American Association of Phys-
surements (ICRU); 1993. icists in Medicine Radiation Therapy Committee Task
10.  International Commission on Radiation Units and Group 53. Quality assurance for clinical radiotherapy
Measurements. Prescribing, recording and reporting treatment planning. Med Phys 1998;25:1773–1829.
photon beam therapy (supplement to ICRU report 20. Sovik A, Malinen E, Bruland OS, Bentzen SM, Olsen DR.
50). ICRU report no. 62. Bethesda (MD): International Optimization of tumour control probability in hypox-
Commission on Radiation Units and Measurements ic tumours by radiation dose redistribution: A model-
(ICRU); 1999. ling study. Phys Med Biol 2007;52:499–513.

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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

protein which is expressed on the surface of most prostate cancer cells


(expression is 100- to 1000-fold higher compared with normal cells)[1].

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.

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THE THERANOSTIC APPROACH to the early 1960s. It is a generator-eluted,

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

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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-

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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-

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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

ministration of a higher cumulative dose be tested in the future.


to the tumour. Therefore, higher activities

Figure 1
177
Lu-PSMA-
Pretherapeutic 617-Therapy Posttherapeutic
68
Ga-PSMA-PET/CT SPECT/CT 68
Ga-PSMA-PET/CT

os ilium - osseous metastasis

vertebral body - osseous metastasis

Figure 1: Concept of theranostics for treatment of metastasised and castration-refractory prostate


cancer (mCRPC): Quantitative 68Ga-PSMA PET/CT is used to determine PSMA positivity of prostate
cancer manifestations (pretherapeutic PET/CT). Then, targeted therapy is performed using 177Lu-
PSMA, which can be monitored in vivo by imaging with a gamma camera and/or SPECT/CT.
Response to therapy is subsequently assessed, again with quantitative 68Ga-PSMA PET/CT. This image
example relates to an 80-year-old patient with mCRPC (initially pT4cN1cM1, Gleason score of 3). The
patient received hormone ablation therapy and approved systemic therapies (Zytiga®, Taxotere® and
Xtandi®). Due to progressive disease the patient was referred for 177Lu PSMA therapy. Pretherapeutic
68
Ga-PSMA PET/CT showed PSMA-positive nodal and bone metastases (exemplarily shown: osseous
metastases of the right os ilium and a vertebral body). Post-therapeutic 68Ga-PSMA PET/CT after three
cycles of 177Lu-PSMA therapy showed a reduced tumour load, and PSA was significantly decreased

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BIOCHEMICAL AND CLINICAL IMAGE-BASED THERAPY

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.

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SIDE EFFECTS OF RLT. In previous studies the reported me-


THE RA NO S TI C S I N PR O S TATE C A NC E R

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

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in patients with compromised bone mar- overexpressed in prostate cancer, such as

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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32. Ljungberg M, Gleisner KS. Hybrid imaging for 42. Dale R. Use of the linear-quadratic radiobiolog-
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nomenclature. J Nucl Med 2009;50:477–484. response and side effects of repeated radioligand
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37. Kletting P, Schimmel S, Hänscheid H, Luster 46. Kratochwil C, Giesel FL, Stefanova M, Benešová
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EANM Dosimetry Committee. EANM Dosimetry 47. Rahbar K, Bode A, Weckesser M, Avramovic
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39. Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz castration resistant prostate cancer. Clin Nucl Med
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membrane antigen radioligand therapy of meta- 48. Rahbar K, Schmidt M, Heinzel A, Eppard E, Bode
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40. Delker A, Fendler WP, Kratochwil C, Brunegraf metastatic castration-resistant prostate cancer:
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50. Brauer A, Grubert LS, Roll W, Schrader AJ, Schäfers Bruchertseifer F, Rathke H, Morgenstern A, et al.
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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-
static castration-resistant prostate cancer. J Nucl Med oBOMB1, a novel radiolabeled GRPR antagonist
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55. Kratochwil C, Schmidt K, Afshar-Oromieh A, 2017;58:293–299.

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8
AVA I L A B L E A S W E B I N A R

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.

METASTASES IN duction of receptor activator of nuclear


PROSTATE CANCER factor kappa-Β ligand (RANKL), which fur-
Bone is the most frequent site of distant ther drives the immune system and con-
metastatic localisation. Bone lesions usu- trols osteoclast bone regeneration and
ally have an osteoblastic nature, but in remodelling. The result is a vicious cycle
rare cases are osteolytic or mixed. Bone of bone destruction. Therapeutic agents
metastases may be symptomatic and that inhibit osteoclast-mediated bone re-
associated with skeletal events, such as absorption interfere with this process and
fractures, that are responsible for a de- improve outcomes.
creased quality of life and increased mor- The most common symptom from
tality. skeletal metastases is pain. About 75% of
The process by which prostate cancer patients suffer from this and need severe
metastasises to bone involves an interac- pain medication such as opioids. Such
tion between cancer cells, bone matrix skeletal pain is most probably induced by
and cellular elements of the bone. Despite the above-described local bone destruc-
the osteoblastic appearance on radiogra- tion, which may trigger pain receptors
phy, bone metastases from prostate can- within local nerves. Loss of bone strength
cer exhibit an increase in both osteoblast due to the skeletal lesions may lead to
and osteoclast activity. Osteoclast-mediat- bone fractures, including microscopic
ed bone resorption releases factors (such fractures. An inflammatory response is
as tumour growth factors) that promote stimulated by the increased blood flow
cancer cell growth and survival. In turn, to the metastatic lesions, with release of
prostate cancer cells produce proteins cytokines in tumour cells and surrounding
that drive osteoblast and stromal pro- normal cells.

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ALPHA-PARTICLE-EMITTING metastases; however, it is also expressed

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-

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PROSTATE CANCER IMAGING AND THERAPY
CHAPTER 8

phorus-32, strontium-89 and radium-223) The first radiopharmaceuticals to be


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

and anionic or non-calcium analogues used were phosphorus-32, strontium-89,


(such as samarium-153 lexidronam and rhenium-186, rhenium-188 and samari-
rhenium-186 or rhenium-188 etidronate) um-153, but their use is no longer wide-
– with different mechanisms of uptake spread due to their significant side effects,
into bone. especially myelosuppression. These radio-
The choice of radiopharmaceutical is pharmaceuticals are bone-targeting beta
based on the physical characteristics of emitters with a relatively long radiation
the radionuclide in relation to the extent range and significant bone marrow expo-
of metastatic disease, the bone marrow sure.
reserve and the radiopharmaceutical In 2013 the U.S. Food and Drug Admin-
availability in individual countries. Ra- istration (FDA) approved 223Ra as a thera-
diometabolic therapy is inappropriate peutic agent for the treatment of patients
in patients with a life expectancy of less with castration-resistant prostate cancer
than 4 weeks and considering the latency and symptomatic bone metastases in
in onset of the palliative effect, it is more the absence of known visceral metastatic
beneficial in patients with a relatively long disease. The phase 3 ALSYMPCA trial was
life expectancy. The principal side effect stopped early when it became clear after
of bone-seeking radiopharmaceuticals is an interim analysis that the median surviv-
temporary myelosuppression, with com- al in patients treated with 223Ra was signifi-
plete or partial recovery over the following cantly longer than in the placebo group
3 months; thrombocytopenia is common, (14.9 months vs 11.2 months; p<0.001)[1].
neutropenia and anaemia are less com- This result is remarkable, considering that
mon. For this reason, periodic haemato- in most cases the treatment intention is
logical monitoring may be useful. pain palliation.
The EANM guidelines regarding 223Ra
therapy mirror the FDA approval for the
RADIUM-223 THERAPY agent, i.e. they consider it to be indicat-
Generally radionuclide therapy is indicat- ed in patients with castration-resistant
ed for the treatment of bone pain due to prostate cancer, symptomatic bone me-
skeletal metastases and for the treatment tastases, and no known visceral metasta-
of painful skeletal metastases that are in- ses. The presence of not too bulky lymph
adequately treated by analgesics, intoler- node metastases (»3 cm) is not regarded
ant to analgesics and hormone resistant. as an explicit exclusion criterion[2].

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CHAPTER 8

RADIOBIOLOGICAL Gy in 5 fractions to 30 Gy in 10 fractions[6].

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

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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

99.72% 7.44 MeV α


6.57 MeV α

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)

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nuclides radon-219, polonium-215, lead- also emit many high-energy gamma-rays,

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)

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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

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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

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CHAPTER 8

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
Phys Med Biol 2012;57:3207–3222. (4/8/'18): Both the high dose and the extended stan-
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.
evidence-based guideline. Int J Radiat Oncol Biol Phys 15. Sartor O, Heinrich D, Mariados N, Mendez Vidal MJ,
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.
and patient eligibility criteria. Phys Med 2016;32:1731– 17. Kiess AP, Minn I, Vaidyanathan G, Hobbs RF, Josefsson
1737. A, Shen C, et al. (2S)-2-(3-(1-Carboxy-5-(4-211At-as-
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
Imaging 2013;40:207–212. therapy. J Nucl Med 2016;57:1569–1575.
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):
macokinetic and biodistribution study with escalat- radiobiology and dosimetry of alpha-particle
ing doses of (223)Ra-dichloride in men with castra- emitters for targeted radionuclide therapy. J Nucl Med
tion-resistant metastatic prostate cancer. Eur J Nucl 2010;51:311–328.
Med Mol Imaging 2013;40:1384–1393.

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9
AVA I L A B L E A S W E B I N A R

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

A patient is an individual with needs, opinions and expectations, which


may differ from those of another individual of the same age and gender.
Every patient should be treated according to their needs, and any
treatment or procedure should first be discussed with the patient, to
help with decision making. Whether the patient accepts the proposed
treatment or procedure is irrelevant to the responsibility of the clinician to
inform the patient of the possibilities available for treating prostate cancer.

RISK FACTORS pain may be the presenting symptom in


AND SYMPTOMS men with metastatic disease[2].
Since the causes of prostate cancer are
not fully understood, there is currently
no clear prevention strategy. However, a SCREENING AND
number of factors are associated with the EARLY DETECTION
risk of developing the disease, including: Various tests have been developed to
»» Increasing age detect the presence of prostate cancer.
»» A family history of prostate cancer The findings depend on several factors
»» Race (for example, men of Caucasian and behaviours. Screening for prostate
background are more at risk than Asian cancer remains one of the most contro-
men)[1] versial topics in the urological literature.
The two largest trials, the European Ran-
Most patients with clinically localised domized Study of Screening for Prostate
prostate cancer have no symptoms attrib- Cancer (ERSPC) and the prostate arm of
utable to the cancer. Urinary frequency, the Prostate, Lung, Colorectal and Ovarian
urgency, nocturia and hesitancy are com- (PLCO) Cancer Screening, yielded conflict-
monly seen, but are usually related to a ing results. The ERSPC demonstrated a
concomitant benign prostate hyperplasia 20% reduction in prostate cancer-specific
(BPH). Haematuria and haematospermia mortality in men randomised to an invita-
are uncommon presentations of prostate tion to screening compared with controls,
cancer, but their presence in older men whereas the PLCO did not demonstrate
should prompt consideration of the dis- a reduction in mortality. Although the
ease in the differential diagnosis. Bone benefits of prostate cancer screening are

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uncertain, the burdens associated with the abnormalities (e.g. nodules, asymmetry

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


early detection and treatment of prostate or induration) in the posterior and lateral
cancer have been defined. It has been aspects of the prostate gland, where the
estimated that between 23% and 42% majority of cancers arise; however, other
of screen-detected cancers would never areas of the prostate are not reachable by
have been diagnosed in the absence of DRE. Furthermore, most cancers detected
screening[3, 4]. However, the potential for by DRE alone are clinically or pathological-
overdiagnosis, associated overtreatment ly advanced and stage T1 prostate cancers
and adverse treatment effects has led to are non-palpable by definition[6, 7].
neither a clear mandate to screen nor a Although a high PSA and an abnormal
proscription against screening. Most re- DRE may raise the suspicion of prostate
cent guidelines recommend that asymp- cancer, only a biopsy can confirm the pres-
tomatic men who have at least a 10-year ence of cancer cells. With a biopsy, small
life expectancy should have an opportu- cores/samples of prostate tissue are re-
nity to make an informed decision with moved and sent for analysis.
their health care provider about screening
for prostate cancer after they receive infor-
mation about the uncertainties, risks and THE NEWLY DIAGNOSED
potential benefits associated with prostate PROSTATE CANCER PATIENT
cancer screening[5–7, 9, 13]. The diagnosis of prostate cancer can only
The most common tests are analysis be confirmed by the results of histological
of serum prostate-specific antigen (PSA) examination from a prostate biopsy or sur-
levels and direct rectal examination (DRE). gery. Transrectal ultrasound (TRUS)-guided
PSA is a glycoprotein produced by pros- biopsy is currently the standard of care.
tate epithelial cells. While PSA is organ Ten- to 12-core biopsies should be taken,
specific it is not cancer specific, and may bilateral from apex to base, as far posterior
be elevated in BPH, prostatitis and pelvic and lateral as possible from the peripheral
trauma. Furthermore, it does not give any gland. Additional cores should be obtained
indication regarding the nature, location from areas suspicious on DRE or TRUS[8].
or extent of the cancer[3–5]. The biopsy result gives an indication of
A DRE is a rectal examination performed the nature of the tumour and its stage, and
by the physician whereby a gloved finger on this basis the disease is classified as low,
is placed into the rectum to feel the sur- intermediate or high risk[9]; this will be fur-
face of the prostate. It can detect palpable ther explained below.

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TUMOUR CHARACTERISTICS nodes, has a poor prognosis. The most


THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T

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

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- T2b Tumour involves more than half of Low risk

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


one lobe, but not both lobes
- T2c Tumour involves both lobes » Usually a PSA ≤10 ng/mL
» A Gleason score of ≤6
»» T3 Tumour extends through the pros-
» A clinical stage of T1(a,b,c) or T2a
tatic capsule
- T3a Extracapsular extension (unilater- Intermediate risk
al or bilateral) including microscopic
bladder neck involvement » A PSA >10 to 20 ng/mL
- T3b Tumour invades seminal vesicle(s) » A Gleason score of 7
» A clinical stage of T2b
»» T4 Tumour is fixed or invades adjacent
structures other than seminal vesicles:
High risk
external sphincter, rectum, levator
muscles and/or pelvic wall » A PSA >20 ng/mL
» A Gleason score of 8 to 10
N – Regional lymph nodes » A clinical stage of T2c
»» NX Regional lymph nodes cannot be
Figure 1: Patient categorisation according
assessed
to pathological factors and patient
»» N0 No regional lymph node metastasis treatment preferences
»» N1 Regional lymph node metastasis

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.

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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

Low Intermediate High


Risk Risk Risk

Radical
Treatment Treatment Palliative prostatectomy not
options options treatment recommended

Brachy- For
localised PC PSMA
therapy

Follow-up Radical Nano-


(PSA and prostat- particle MRI
DRE) ectomy

Radical Brachy- Choline /


prostat- therapy NaF PET
ectomy

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

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LIFE EXPECTANCY Magnetic resonance imaging

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


The patient’s overall health status is the ma- Nowadays multiparametric MRI (mpMRI)
jor factor when making treatment decisions. is used to assess both morphological and
The younger the patient, the longer the life functional MRI parameters, combining
expectancy; therefore factors such as urinary, methods such as diffusion-weighted im-
sexual and bowel function are very import- aging (DWI), T1-weighted imaging (T1WI),
ant and need to be considered when choos- T2-weighted imaging (T2WI), apparent
ing a therapy[15]. The earlier that prostate can- diffusion coefficient (ADC), dynamic con-
cer is diagnosed, the earlier the treatment trast-enhanced (DCE) imaging and possi-
and thus the better the long-term survival[3]. bly MR spectroscopy in order to improve
the detection and localisation of prostate
cancer. mpMRI has the capability to iden-
IMAGING FOR DISEASE tify and characterise primary prostate can-
DETECTION cer, even occult lesions with persistent PSA
Technological advances in imaging have im- elevation and negative biopsy results. Ad-
proved the detectability and management ditionally, mpMRI is particularly helpful for
of metastases of prostate cancer. An appro- detection of clinically significantly cancer.
priate imaging sequence is necessary to im- Because of its superior diagnostic accura-
prove detection of the disease and thereby cy, mpMRI has the potential to decrease
the standard of care for the patient[16]. unnecessary prostate biopsies[18].

Transrectal ultrasound Positron emission tomography


A TRUS is usually performed to guide biop- Fluorine-18 fluorodeoxyglucose positron
sies rather than to identify the location and emission tomography (PET) is not widely
nature of the cancer[17]. However, TRUS, as used for primary prostate cancer detec-
demonstrated in previous studies, has proved tion or local staging because of limita-
quite good at detecting the presence of a le- tions relating to high bladder activity and
sion, with an overall accuracy of 80%[17]. relatively low tumour uptake. Alternative
Hypoechoic lesions and focal infarcts PET tracers, such as 11C- or 18F-labelled
have been reported to have the same ap- choline and acetate, which are utilised for
pearance as prostate cancer on TRUS, lead- cell membrane synthesis, show increased
ing to false positive results and making radioactive uptake in malignant tumours.
TRUS less specific when used as the only However, these tracers have limited value
imaging modality.[17] in small primary cancers because of their

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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-

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ent groups, including those that are iron 68


Ga-PSMA targeting agents

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


oxide based, usually used for patients The introduction of 68Ga-PSMA targeting
diagnosed with prostate cancer[25]. This agents has increased the accuracy in the
lymphotropic nanoparticle agent (feru- detection of metastases in prostate can-
moxtran-10), also known as Combidex®, cer compared with the sole use of CT and
is mixed with 0.9% w/v saline solution bone scans. 68Ga-PSMA targeting agents
for intravenous administration. The mag- are used in combination with PET/CT.
netic properties of these nanoparticles There is good contrast between tumour
allow them to become magnetised when lesions and normal tissue, and also high
placed in a magnetic field but demagne- specific uptake in PSMA-expressing organs
tised after removal of the magnetic field. and tumours. Unlike nanoparticle MRI,
They have been used as T2-weighted MR 68
Ga-PSMA PET/CT is not lymph node spe-
contrast agents to track and monitor the cific; rather, 68Ga-PSMA PET/CT may show
lymphatic system. The mechanism of ac- metastases in other organs or tissues. A
tion is based on the phagocytosis of the combination of the two modalities is usu-
nanoparticles by the macrophages, with ally used when progressive disease needs
the iron in the macrophages in the lymph to be confirmed or excluded[25].
nodes resulting in a black signal on MRI.
When a lymph node is metastasised, Choline PET
the macrophages cannot infiltrate the Radiolabelled choline PET tracers are at
lymph node and it remains white on the present the best performing tracers wide-
T2-weighted image[24, 25]. ly available for use in patients undergoing
Multimodality PET/MRI is also a possi- prostate cancer imaging. In patients pre-
bility, using the aforementioned nanopar- senting with high-risk or locally advanced
ticles in conjunction with 68Ga-PSMA tar- prostate cancer, imaging to document
geting agents, for example. Nanoparticle potential metastases may be important.
MRI is useful when lymph node metas- At this stage of the disease, choline PET
tases need to be confirmed or excluded. should be considered. However, detec-
Knowledge of the lymph node status tion of micro-metastases with choline PET
determines the treatment and the prog- remains a challeng[19, 20, 25]. The addition of
nosis. From recent studies, it appears that other imaging techniques such as MRI is
nanoparticle MRI has a higher sensitivity useful in determining the metastatic status.
and specificity than conventional CT and Staging of the disease is important to
MRI[23–25]. categorise patients into the appropriate

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CHAPTER 9

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

cluded, treatment can be started. It is of to contact these organisations. Informa-


course important to perform examina- tion regarding prostate cancer and other
tions and imaging as quickly as possible patients’ experiences are also included in
after diagnosis, to prevent progression this logbook.
of the disease. Figures 3 and 4 show two Patients may experience anxiety and
possible patient pathways that may be depression due to their diagnosis or the
implemented. Pathways may differ be- side-effects associated with the treat-
tween countries and also depend on the ment/surgery. It is important for the
availability of personnel and equipment oncology nurse or case manager to rec-
and the guidelines adopted in the individ- ognise this, and to provide help when
ual country. needed.
For low-risk patients, an appointment
with the urologist is planned a week after
the patient receives the results. For inter- TREATMENT OPTIONS
mediate- and high-risk patients, the nec- Most low-risk or very low-risk patients –
essary diagnostic imaging is performed in those with a low Gleason score, low PSA
accordance with decisions made during level and low clinical stage – are managed
the multidisciplinary team meeting. solely by follow-up (watchful waiting).
Information folders may be given to Studies have shown that these patients
the patient, explaining in detail every- have a low risk for clinical progression
thing that he may go through. A space within the first 5–10 years after initial di-
may be included for personal notes by agnosis[26].
the patient that can be raised at the next Follow-up may include periodic DRE
appointment and/or for an appointment with or without PSA testing. A biopsy may
card. Websites with guidelines and ad- also be included, depending on the find-
ditional information may also be shown ings. A follow-up scheme is helpful for a
in the folder. The provision and nature of number of patients, but not all. Treatment
such information folders depends on the is provided with the aim of reducing the
hospital or even the country. For example, likelihood of progression of the cancer
in the Netherlands, the KWF Kanker Bestri- and/or reducing the risk of complications
jding (Dutch Cancer Society) and Prostaat in a cancer that is not likely to progress[27].
Kanker Stichting (PKS) provide the patient In patients who will not benefit from cu-
with a logbook with phone numbers and rative treatment, palliative treatment is of-

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Figure 3

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


Patients meeting the age criteria: 50–75 years

No prostate biopsy performed in the last 2 years

Details are entered into


hospital system and administration

Appointment for PSA and


kidney function blood tests

Planning of an intake appointment


with the specialist nurse
A DRE is performed and a urine sample is collected

MRI
reserved places are kept open for
these patients during the MRI daily list

MRI reported by radiologist

Figure 3: One potential trajectory for a prostate cancer patient

fered. Palliative treatment involves treating Androgen deprivation therapy


the symptoms to alleviate complaints[13]. Androgen deprivation therapy (ADT) is a
For example, in patients with extensive systemic treatment usually given to pa-
metastatic spread, management of the tients with known metastatic prostate
urinary tract or radiotherapy for metastatic cancer. Conventional ADT involved surgi-
lesions in the vertebral column alleviates cal or medical castration and the admin-
complaints of urinary obstruction or pain. istration of anti-androgen agents, such as

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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.

There are two methods of performing the biopsy:


TRUS- or MRI-guided biopsy. The decision on which method to use
depends on the location and size of the tumour in the prostate.

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

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Brachytherapy months for 5 years and annually thereaf-

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


Radioactive seeds are implanted using an ter[21].
ultrasound- or MRI-guided transperineal
approach. Palladium-103 or iodine-125 is Prostatectomy
usually used, with postoperative dosime- Prostatectomy is a surgical procedure
try. Patients who are low or possibly inter- whereby the entire prostate gland is re-
mediate risk usually fall into the category moved. The decision to perform prostatec-
considered suitable for this treatment. tomy depends on the age of the patient,
Prior to any therapy, TRUS is performed to his sexual activity and the tumour charac-
assess the size of the prostate and to de- teristics. The pelvic lymph nodes can also
termine the number of needles and radio- be removed, but this is usually done only
active seeds, the isotope and the isotope in patients who have metastatic lymph
strength required for the procedure. The node involvement. Patients who undergo
radioactive seeds need to be transplanted prostatectomy are usually hospitalised for
properly otherwise the whole effective- 1–3 days and discharged with a urethral
ness of the therapy is reduced[9, 13, 15]. catheter for 1–2 weeks postoperatively,
depending on the country. Patients with
Radiotherapy localised prostate cancer usually benefit
Technological advancements such as from radical prostatectomy. In patients
three-dimensional CT radiotherapy plan- with adjacent organ involvement, pros-
ning have enhanced the specificity of ir- tatectomy is not recommended because
radiation, contributing to dose accuracy there is no guarantee that all the cancer
and reducing radiation to surrounding will be removed, putting the patient at risk
structures. Patients who have a history for recurrence[9, 13].
of inflammatory bowel disease, such as
Crohn’s disease, or have previously under- Radium-223 dichloride
gone pelvic radiotherapy may present a Radium-223 is an alpha emitter that tar-
challenge because of increased complica- gets bone metastases as it accumulates in
tions due to the additional radiotherapy[9, bone analogously to calcium. It is usually
13, 15]
. used in the early stages after diagnosis of
For patients with a Gleason score high- bone metastases, with or without lymph
er than 7 or a PSA level of more than 10 node metastases. In most cases the goal is
ng/mL, post-radiation hormone therapy to improve survival, and a secondary ob-
is recommended, with follow-up every 6 jective may be to alleviate complaints from

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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].

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68
Ga-PSMA PET/CT has shown promising also useful to look up previous examina-

THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T


potential in patients with BCR. Detection tions of this patient as this forms a good
rates of 58% and 76% have been reported basis for comparison and may also be
for PSA ranges of 0.2–1 and 1–2 ng/mL, re- useful in identifying artefacts or suspected
spectively. This suggests that 68Ga-PSMA is artefacts in the acquired images. When the
substantially more sensitive at low PSA lev- patient attends the examination, he may
els than choline PET/CT. Therefore, if local be scared of the result of the scan rather
salvage treatment is planned and 68Ga-PS- than the actual examination, and the tech-
MA PET/CT is available, it should be con- nologist should be prepared to answer
sidered as a valuable assessment option[36]. any technical questions the patient might
A newly developed synthetic amino have and explain which should be direct-
acid analogue PET radiotracer (anti-3-[18F] ed to the clinician, clarifying as much as
FACBC (fluciclovine)] could also be used possible and reassuring the patient. The
to scan patients with recurrent prostate technologist also needs to aware of the
cancer[37]. risks involved in handling patients with ad-
vanced prostate cancer, who may have the
The role of the technologist potential for pathological fractures.
Patients attend imaging at various stages
of their diagnostic and/or treatment path- Conclusion
ways. When an examination is requested, The diagnosis and management of pros-
knowledge of the approximate stage at tate cancer pose different challenges and
which the patient finds himself during concerns for every patient diagnosed with
the clinical pathway may be useful, since the disease. Patients are given a lot of in-
it may give a better indication of what to formation regarding the disease that they
look out for during diagnostic imaging. may find difficult to register and under-
This helps the technologist in providing stand. Appropriate support needs to be
the nuclear medicine physician with a provided for those patients who need bet-
sufficient nuclear medicine examination ter communication and more understand-
having proper image quality to be able to ing than others. The multidisciplinary team
make a correct diagnosis. The risk category is important when discussing the manage-
for the patient is usually indicated on the ment and prognosis of patients because a
requested examination, so that the tech- thorough approach is essential. Different
nologist will have an indication as to why imaging modalities are available to assess
the examination is being performed. It is the staging and progression of the disease.

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Making proper use of what is available Acknowledgements. With thanks to Gijs


THE MA NAGE M E NT O F A PR O S TATE C A N C E R PATI E N T

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
10
AVA I L A B L E A S W E B I N A R

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.

While the introduction of prostate-specif- of animal models, to identify the relevance


ic membrane antigen (PSMA) and choline of animal care in the context of preclini-
has changed the management of the dis- cal imaging and therapy studies, and to
ease, these tracers are not still perfect. Effi- acquaint technologists with the extended
cacy of radiolabelled antibodies (e.g. J591) competences needed as a member of a
has been demonstrated in clinical trials, preclinical team. Moreover, the impact of
but their toxicity is high. Within the ther- nuclear medicine techniques in preclinical
apeutic armamentarium, radium-223 has trials and the problem of the translation
shown efficacy in pain palliation and has from animals to men will be discussed. Fi-
achieved some improvement in survival. nally, some future challenges and oppor-
Nuclear medicine currently offers excit- tunities for prostate cancer management
ing perspectives with the development will be addressed.
of new PET imaging agents and new tar-
geted radionuclide therapies based on
antibody fragments, peptides and PSMA PRECLINICAL IN VIVO STUDIES
inhibitors, which is opening the way to In vitro studies do not do justice to the bio-
true theranostics. Thus, prostate cancer logical complexities that are encountered
is subject to very active translational re- in a living animal (in vivo); consequently, in
search in nuclear medicine and preclinical vivo animal models are required to study,
studies are being performed to obtain for example, tracer pharmacokinetics and
preclinical proof of concept for new ra- actual accumulation in disease models.
diopharmaceuticals, to compare available The principal role of animal studies is the
candidates and to pave the way for clinical advancement of science but obtaining in
developments. vivo proof of concept after in vitro devel-
The present chapter aims to describe opment of drug candidates and before
how such preclinical studies are being full clinical/industrial development is an-
conducted, to provide general knowledge other application of interest. Then, in most

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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,

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with castration-resistant features. More- recognised principles of animal care and


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

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.

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FIRST-IN-HUMAN STUDIES under GLP by specialised companies that

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

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focus on PSMA as the target. Some agents FUTURE CHALLENGES AND


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

are radiolabelled with technetium-99m OPPORTUNITIES


for SPECT images and others with galli- Prostate cancer, like other solid endocrine
um-68 or copper-64 for PET studies or lu- cancers, is heterogeneous, being charac-
tetium-177 for therapeutic purposes. terised by different biological pathways
An intriguing possibility offered by ra- and targets and variations in history of dis-
diolabelled receptor agonists and antag- ease. Each pathway and target can be ad-
onists is to allow for effective theranostics dressed by radiopharmaceutical agents,
due to the intrinsic feasibility of labelling both for diagnosis and for therapy (Fig.
either with beta+ or gamma emitters 1). Therefore, future discoveries should fo-
(such as gallium-68 and indium-111) for cus on the study of new pathways with a
diagnostic purposes or with therapeu- strong potential impact on the manage-
tic, beta-emitting isotopes such as lute- ment and prognosis of patients with pros-
tium-177. Although the in vivo distribu- tate cancer. Furthermore, efforts should
tion can vary depending on the labelling be made to develop tracers able to guide
isotope, this opportunity makes the po- specific treatments and to evaluate their
tential clinical value of molecular imaging efficacy. Moreover, the introduction of
even more promising. The most interest- specific hardware and software would be
ing and recent published studies are listed beneficial to simplify the characterisation
in Table 1. of prostate cancer disease.

BIOLOGY TARGETS SITE OF METASTASIS STAGE OF DISEASE

Proliferation pTEN Prostate gland Local disease


DNA repair K-Ras Lymph nodes Disseminate
Cell cycle control P53 Bones disease

Apoptosis PI3K Liver Hormone


sensitive disease
Invasion and metastasis E-caderin Lung
Castrate resistant
Neoangiogenesis RAF Adenal glands
disease
AR Others
AKT1
others

Figure 1: Potential targets and useful information for the development of new
radiopharmaceutical agents in prostate cancer

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Authors, Year Journal Radiopharma- Phase of Type of animal Quality control


ref ceutical agent study of RA

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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REFERENCES
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

1. Pettaway CA, Pathak S, Greene G, Ramirez E, Wilson cancer with the gastrin-releasing peptide receptor
MR, Killion JJ, Fidler IJ. Selection of highly metastatic antagonist NeoBOMB1: preclinical and first clinical
variants of different human prostatic carcinomas us- results. J Nucl Med 2017;58:75–80.
ing orthotopic implantation in nude mice. Clin Cancer 7. Zhang H, Desai P, Koike Y, Houghton J, Carlin S,
Res 1996;2:1627–1636. Tandon N, et al. Dual-modality imaging of prostate
2. Jan G, Pass ND, Dhawan DK, Chadha VD. Cancer tar- cancer with a fluorescent and radiogallium-labeled
geting potential of 99mTc-finasteride in experimental gastrin-releasing peptide receptor antagonist. J Nucl
model of prostate carcinogenesis. Cancer Biother Med 2017;58:29–35.
Radiopharm 2017;32:39–47. 8. Sun Y, Ma X, Zhang Z, Sun Z, Loft M, Ding B, et al.
3. Ferreira CA, Fuscaldi LL, Townsend DM, Rubello D, A preclinical study on GRPR-targeted 68Ga-probes
Barros ALB. Radiolabeled bombesin derivatives for for PET imaging of prostate cancer. Bioconjug Chem
preclinical oncological imaging. Biomed Pharmacother 2016;27:1857–1864.
2017;87:58–72. 9. Cheng S, Lang L, Wang Z, Jacobson O, Yung B, Zhu
4. Xu J, Feng C, Miao Y. Evaluation of novel 111In-la- G, et al. Positron emission tomography imaging of
beled gonadotropin-releasing hormone peptides for prostate cancer with Ga68-labeled gastrin-releasing
human prostate cancer imaging. Bioorg Med Chem peptide receptor agonist BBN7-14 and antagonist
Lett 2017;27:4647–4651. RM26. Bioconiug Chem 2018;29:410–419.
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.

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DOI: https://doi.org/10.52717/GPJL7081

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Information as per date of printing September 2018.

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