Prostate Cancer Imaging and Therapy

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 TABLE OF CONTENTS

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

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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

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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 supported 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 preclinical imaging become rapidly emerging

EANM TECHNOLGIST’S GUIDE 7 PROSTATE CANCER IMAGING AND THERAPY

ANATOMY, PHYSIOLOGY AND PATHOLOGY OF THE PROSTATE

by Lucia Zanoni, Cristina Nanni and Stefano Fanti 1 CHAPTER 1

INTRODUCTION PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND The prostate is a glandular and muscular structure positioned immediately 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 development, 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

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bud tips. Lumen formation also occurs in stimulating hormone-releasing factor and PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND 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 protein, 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-

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Figure 1 PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND

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-

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ever, after the age of 35 years its volume true prostate capsule surrounds the periph- PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND 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 posterolateral 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

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PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND descriptions of prostatic anatomy. From a classification of tumours[9] categorises 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 (defined 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 currently 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

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grading systems for PCa and all three are neous appearance, with areas of central PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND 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 heterogeneous 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 present 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,

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PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND prostatic carcinoid is one of the four rare eration. Carcinosarcoma is considered one manifestations 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 chromocytomas 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, associated 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

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bladder; colorectal cancer is the next most acute prostatitis and recurrent infection PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND 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

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PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND for bladder cancer. It is characterised by extracellular deposition of amyloid. Pros- 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 infection) 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

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in the peripheral zone, may mimic prostate Calcification. Prostatic calcification may PATHOLOGY OF THE PROSTATE ANATOMY, PHYSIOLOGY AND malignancy owing to its complex glan- arise due to precipitation of prostatic se- dular architecture. It may be caused by cretions or calcification of the corpora inflammation, radiation, anti-androgens amylacea. Extraprostatic cases are due to or chronic ischaemia due to local arterio- a phlebolith in the periprostatic venous sclerosis. plexus. In the context of BPH calcification Necrosis. Necrosis can occur secondary is more frequent at the junction between to treated infective prostatitis or focal ther- the transitional and the peripheral zone. apy of prostate cancer (radiofrequency ab- Haemorrhage. Areas of haemorrhage lation, cryoablation, high-intensity focused may occur after biopsy, especially in the ultrasound, irreversible electroporation, peripheral zone. Tumours display a lower laser ablation). It is characterised by cen- rate of biopsy haemorrhage (2%–10.5%) tral well-defined coagulative necrosis of than normal tissue owing to the reduction glands and stroma, with peripheral chronic in the anticoagulant effect of citrate, which inflammatory cellular infiltrate and atrophy. is produced within the prostate.

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EANM TECHNOLGIST’S GUIDE 19 PROSTATE CANCER IMAGING AND THERAPY

CLINICAL RADIOPHARMACEUTICALS FOR PROSTATE CANCER by Martin Behe 2 CHAPTER 2

INTRODUCTION FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS This chapter describes the radiopharmaceuticals used for the diagnosis 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 important 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

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onto the surface of hydroxyapatite, they aging. 99mTc labelling of hydroxymethy- FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS 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; 11C[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 overview[3]. 18F[F] and 11C[C] labelled choline Studies in the 1990s showed that cho- [99mTc]Tc-diphosphonates line kinase expression is associated with 99m [ Tc]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

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Figure 3 FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS

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 that11 C 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 18F[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

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times overexpressed in prostate cancer RADIOPHARMACEUTICALS FOR FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS 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 compounds are discussed in the review by Virgolini et al.[15]. The [68Ga]Ga compounds are radiolabelled in a dedicated module. [68Ga] Structure of EDTMP, an EDTA derivative GaCl3 can be eluted from commercially 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.

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FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS Bone is the most common site of me- arm in relation not only to overall surviv- 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 223 [ Ra]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

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Figure 5 FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS

Decay scheme of [223Ra]Ra

glands, which also express the target, mild 4. Pinkerton TC, Cheng KT, Shaw SM, Wilson GM. Influ- haematological toxicology and fatigue. ence of complex charge and size on the uptake of 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

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18F-labeled choline analogs as oncologic PET trac- Cho S, et al. 68Ga-PSMA PET/CT: Joint EANM and

FOR PROSTATE CANCER CLINICAL RADIOPHARMACEUTICALS ers. J Nucl Med 2001;42:1805−1814. SNMMI procedure guideline for prostate cancer 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,

28 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CONVENTIONAL NUCLEAR MEDICINE IN PROSTATE CANCER IMAGING by Wolfgang Römer 3 CHAPTER 3

INTRODUCTION IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE In about 30% of patients with prostate cancer, bone metastases are seen. 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].

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Up to now, planar radiography has SCIENTIFIC STUDIES ON THE IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE 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 suspicious 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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Figure 1A IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE

32 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 3

Figure 1B IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE

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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Figure 2A IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE

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

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Figure 2B IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE

Figure 2C

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IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE In 2010 the value of SPECT/CT was stud- for SPECT and 93% and 100% for SPECT/ 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

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99M IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE SPECT/CT compared with 93%, 78%, 59% COMPARISON OF TC-DPD 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

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IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE deoxyglucose (FDG) is not useful. There- ificity, PET and PET/CT are of limited use 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 11C-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

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information regarding a lesion enables the CT software should be able to limit the ex- IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE 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.

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IN PROSTATE CANCER IMAGING CONVENTIONAL NUCLEAR MEDICINE 10. Ndlovu X, George R, Ellmann A, Warwick J. Should phy and (68)Ga-PSMA PET for skeletal staging 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 PET/CT PROCEDURES WITH FLUORINE-18 RADIOPHARMACEUTICALS IN PROSTATE CANCER

by Daniel Tempesta and David Gilmore4 CHAPTER 4

RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-18 PET/CT IMAGING oxygen-15) are accelerator produced and 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

42 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 4

prostate cancer. 18F-FDG, the most com- cose. Patients should have nothing to eat RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-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 18F-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 18F-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 18F-FDG and uptake in tumour cells will be reduced. The institutional and manufac- 18F-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

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RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-18 voids immediately before imaging if a Many areas of the body will normally ac- 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 RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-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. 18F-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 radiopharmaceutical injection, the time when tumour uptake is highest. When possible, the pa- 18F-FLUCICLOVINE (AXUMIN®) tient’s arms should be placed above the 18F-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 of18 F-fluciclovine is

EANM TECHNOLGIST’S GUIDE 45 PROSTATE CANCER IMAGING AND THERAPY CHAPTER 4

RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-18 that urine excretion and bladder activity results. For example, benign inflammation are minimal at the time of imaging, allow- may show areas of increased uptake being 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

46 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 4

Figure 2

However, with the development of PET RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-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 structures. The typical adult dose of 18F-sodium fluoride is 185–370 MBq injected intravenously. The radiopharmaceutical accumulates 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- 18F-SODIUM FLUORIDE ally performed when looking for prostate 18F-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 99mTc-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.

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RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-18 Fluorine-18 incorporates into the aging. Prostate cancer that has spread to 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

48 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 4

coupled with the prostate radiotherapy only a few hundred patients have to date RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-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 radiopharmaceutical 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 18F-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,

EANM TECHNOLGIST’S GUIDE 49 PROSTATE CANCER IMAGING AND THERAPY CHAPTER 4

RADIOPHARMACEUTICALS IN PROSTATE CANCER PROCEDURES PET/CT WITH FLUORINE-18 REFERENCES

» 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 PROSTATE CANCER IMAGING AND THERAPY AVAILABLE AS WEBINAR

PROSTATE CANCER PET/CT IMAGING BEYOND FLUORINE-18 TRACERS

by Giorgio Testanera and Giovanna Pepe5 CHAPTER 5

INTRODUCTION BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT Prostate cancer is one of the most commonly diagnosed tumour types. 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

52 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 5

Figure 1 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

11C-Coline

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, 18F-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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT except, possibly, in aggressive, poorly dif- teristic of prostate cancer cells (phospho- 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 18F-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 for11 C-choline imaging (data courtesy of Humanitas Research Hospital, Milan, Italy)

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proteins [labelled prostate-specific mem- »» Particular attention must be paid to im- FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT 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). 18F-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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT clinical findings and specifying conclu- trast-enhanced CT in the portal venous 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. »» CT 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 parameters (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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT »» 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 standardisation of protocols. 11C-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 infinity transporter system imports choline terpretation must be considered when into the cell, where it is phosphorylated

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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT by choline kinase in the first step of the ing the examination to confirm that the 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-choline has a higher urinary excretion than Image interpretation 11C-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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

11C-Choline

11C-Choline 18F-Choline Unremarkable activity in the bladder Significant activity in the bladder 18F-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

11C-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 11C-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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

Lymph node: (Diameter 6mm) Biomedical failure: LN metastasis

11C-Choline PET/CT in biochemical recurrence. Images show pathological uptake in an iliac lymph node

11C-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 11C-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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

11C-Choline

Case of physiological distribution Case of bone metastasis18F-Choline

11C-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- 11C-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 FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT 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 11C-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- 11C-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 68GA-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- 11C-acetate PET can reliably survey bone clinical animal and pilot human studies, involvement[24]. several radiolabelled ligands using various 11C-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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT tracers include 89Zr-desferrioxamine B Patient height and body weight and (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, 68Ga-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 68Ga 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 68Ga 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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11C-Acetate 11C-Choline 68Ga-PSMA

Patient preparation Hydration with, for Hydration with for Hydration with for FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT 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 11C-acetate and 11C-choline. kilogram of body weight.

Administered activity Clinical applications of 68Ga-PSMA is injected as an intravenous 68Ga-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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT data from prospective multicentre trials in patients with a high suspicion of pros- 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 benefit of68 Ga-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 multiparametric MRI represents a promising imaging modality in the diagnosis of primary intraprostatic prostate cancers and current 68Ga-PSMA PET/CT: physiological distributio data suggest that 68Ga-PSMA PET/MRI may

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Figure 7 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

68Ga-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 11C-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/ 68Ga-PSMA PET/CT. This not only highlights

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Figure 8 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

68Ga-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 radiopharmaceuticals. Nonetheless, use of diomics include CT, MR imaging and, of 68Ga-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 feature model for performing prostate cancer 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 BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT

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 on68 Ga-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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT In a study by Giesel et al. a correlation CT for prostate cancer, this is of course 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]. Disclaimer: if not stated differently all im- While few studies are currently available ages are property of Humanitas Research on the application of radiomics in PET/ Hospital.

REFERENCES

1. Surveillance, Epidemiology, and End Results Pro- 5. Fendler WP, Eiber M, Beheshti M, Bomanji J, Ceci F, gram. SEER stat fact sheets: prostate cancer—statistics Cho S, et al. 68Ga-PSMA PET/CT: Joint EANM and at a glance. National Cancer Institute Web site. http:// SNMMI procedure guideline for prostate cancer seer.cancer.gov/statfacts/html/prost.html. Published imaging: version 1.0. Eur J Nucl Med Mol Imaging 2015. Accessed April 16, 2018. 2017;44:1014−1024. 2. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch 6. Wibmer AG, Burger IA, Sala E, Hricak H, Weber WA, Var- MG, De Santis M, et al. EAU-ESTRO-SIOG guidelines gas HA. Molecular imaging of prostate cancer. Radio- on prostate cancer. Part 1: screening, diagnosis, graphics 2016;36:142–159. and local treatment with curative intent. Eur Urol 7. Antunovic L, Rodari M, Rossi P, Chiti A. Standardization 2017;71:618−629. and quantification in PET/CT imaging: tracers beyond 3. Ost P, Bossi A, Decaestecker K, De Meerleer G, Gianna- FDG. PET Clin 2014;9:259–266. rini G, Karnes RJ, et al. Metastasis-directed therapy of 8. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile regional and distant recurrences after curative treat- F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM proce- ment of prostate cancer: a systematic review of the dure guidelines for tumour imaging: version 2.0. Eur J literature. Eur Urol 2015;67:852−863. Nucl Med Mol Imaging 2015;42:328–354. 4. EANM. Principles and practice of PET-CT. Part 2. Wien, 9. Ackerstaff E, Glunde K, Bhujwalla ZM. Choline phos- 2012. Available on https://www.eanm.org/con- pholipid metabolism: a target in cancer cells? J Cell tent-eanm/uploads/2016/12/gl_Principles_and_Prac- Biochem 2003;90:525–533. tice_of_PET-CT_Part_22.pdf.

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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- FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT 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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BEYOND FLUORINE-18BEYOND TRACERS PROSTATE IMAGING CANCER PET/CT Ga-PSMA PET/CT imaging in high-risk prostate can- 34. Albisinni S, Artigas C, Aoun F, Biaou I, Grosman J, Gil 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.

72 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY PET/CT-GUIDED RADIOTHERAPY PLANNING IN PROSTATE CANCER

by Yat Man Tsang and Michelle Leech 6 CHAPTER 6

INTRODUCTION PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED Prostate cancer is one of the most common cancers in men 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 PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED 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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PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED eation is sometimes inadequate owing to and contained recommendations on how 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 PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED 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 influence 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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PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED in a way that allows adequate delivery of b) correct any patient misalignment by 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 radiotherapy 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 PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED 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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PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED to very small sub-regions of the tumour, radiation therapists continuously advance 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 PLANNING IN PROSTATE CANCER RADIOTHERAPYPET/CT-GUIDED

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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THERANOSTICS IN PROSTATE CANCER

by Sarah M. Schwarzenböck, Bernd Joachim Krause and Jens Kurth 7 CHAPTER 7

INTRODUCTION THERANOSTICS IN PROSTATE CANCER The prostate-specific membrane antigen (PSMA) is a transmembrane 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 18F-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- 177Lu–labelled PSMA ligands.

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THE THERANOSTIC APPROACH to the early 1960s. It is a generator-eluted, THERANOSTICS IN PROSTATE CANCER 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 radiopharmaceutical 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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THERANOSTICS IN PROSTATE CANCER German consensus guideline published cient hydration before, during and after 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 177Lu-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] THERANOSTICS IN PROSTATE CANCER 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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THERANOSTICS IN PROSTATE CANCER able number of patients, allowing for ad- and/or shorter treatment intervals might ministration of a higher cumulative dose be tested in the future. to the tumour. Therefore, higher activities

Figure 1 177Lu-PSMA- Pretherapeutic 617-Therapy Posttherapeutic 68Ga-PSMA-PET/CT SPECT/CT 68Ga-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 68Ga-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 THERANOSTICS IN PROSTATE CANCER RESPONSE TO 177LU-PSMA RLT RESPONSE ASSESSMENT OF 177 Prostate-specific antigen values should be 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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THERANOSTICS IN PROSTATE CANCER SIDE EFFECTS OF RLT. In previous studies the reported me- 177LU-PSMA RLT 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. 68Ga-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 details on the toxicity of PSMA ligand therapy, see[20, 21]. CONCLUSION The role of potential kidney protection 177Lu-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 regulations. In patients with bulky disease, 90Y may represent an alternative to 177Lu ow- SURVIVAL DATA OF ing to the higher range of beta particles 177LU-PSMA RLT 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 THERANOSTICS IN PROSTATE CANCER 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-

patient-specific dosimetry in radionuclide therapy. ical model for quantifying kidney response in THERANOSTICS IN PROSTATE CANCER Diagnostics (Basel) 2015;5:296–317. targeted radiotherapy. Cancer Biother Radiopharm 33. Dewaraja YK, Frey EC, Sgouros G, Brill AB, Roberson 2004;19:363–370. P, Zanzonico PB, Ljungberg M. MIRD pamphlet No. 43. Hohberg M, Eschner W, Schmidt M, Dietlein M, Kobe 23: Quantitative SPECT for patient-specific 3-dimen- C, Fischer T, et al. Lacrimal glands may represent sional dosimetry in internal radionuclide therapy. J organs at risk for radionuclide therapy of prostate Nucl Med 2012;53:1310–1325. cancer with [(177)Lu]DKFZ-PSMA-617. Mol Imaging 34. Bolch WE, Eckerman KF, Sgouros G, Thomas SR. Biol 2016;18:437–445. MIRD pamphlet No. 21: a generalized schema for 44. Ahmadzadehfar H, Eppard E, Kürpig S, Fimmers radiopharmaceutical dosimetry -- standardization of R, Yordanova A, Schlenkhoff CD, et al. Therapeutic nomenclature. J Nucl Med 2009;50:477–484. response and side effects of repeated radioligand 35. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays therapy with 177Lu-PSMA-DKFZ-617 of castrate-re- MT, Koral KF, et al. MIRD pamphlet no. 16: Techniques sistant metastatic prostate cancer. Oncotarget for quantitative radiopharmaceutical biodistribution 2016;7:12477–12488. data acquisition and analysis for use in human radia- 45. Ahmadzadehfar H, Rahbar K, Kürpig S, Bögemann tion dose estimates. J Nucl Med 1999;40:37S–61S. M, Claesener M, Eppard E, et al. Early side effects 36. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the and first results of radioligand therapy with (177) second-generation personal computer software for Lu-DKFZ-617 PSMA of castrate-resistant metastatic internal dose assessment in nuclear medicine. J Nucl prostate cancer: a two-centre study. EJNMMI Res Med 2005;46:1023–1027. 2015;5:114. 37. Kletting P, Schimmel S, Hänscheid H, Luster 46. Kratochwil C, Giesel FL, Stefanova M, Benešová M, Fernández M, Nosske D, et al. The NUKDOS M, Bronzel M, Afshar-Oromieh A, et al. PSMA-targeted software for treatment planning in molecular radio- radionuclide therapy of metastatic castration-resis- therapy. Z Med Phys 2015;25(3):264–274. tant prostate cancer with 177Lu-labeled PSMA-617. J 38. Hindorf C, Glatting G, Chiesa C, Linden O, Flux G, Nucl Med 2016;57:1170–1176. EANM Dosimetry Committee. EANM Dosimetry 47. Rahbar K, Bode A, Weckesser M, Avramovic Committee guidelines for bone marrow and N, Claesener M, Stegger L, Bögemann M. Radioli- whole-body dosimetry. Eur J Nucl Med Mol Imaging gand therapy with 177Lu-PSMA-617 as a novel 2010;37:1238–1250. therapeutic option in patients with metastatic 39. Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz castration resistant prostate cancer. Clin Nucl Med M, Wiessalla S, et al. 177Lu-labeled prostate-specific 2016;41:522–528. membrane antigen radioligand therapy of meta- 48. Rahbar K, Schmidt M, Heinzel A, Eppard E, Bode static castration-resistant prostate cancer: safety and A, Yordanova A, et al. Response and tolerability of efficacy. J Nucl Med 2016;57:1006–1013. a single dose of 177Lu-PSMA-617 in patients with 40. Delker A, Fendler WP, Kratochwil C, Brunegraf metastatic castration-resistant prostate cancer: A, Gosewisch A, Gildehaus FJ, et al. Dosimetry for A multicenter retrospective analysis. J Nucl Med (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical 2016;7:1334–1338. for the treatment of metastatic prostate cancer. Eur J 49. Rahbar K, Boegemann M, Yordanova A, Eveslage M, Nucl Med Mol Imaging 2016;43:42–51. Schäfers M, Essler M, Ahmadzadehfar H, et al. PSMA 41. Kulkarni HR, Singh A, Schuchardt C, Niepsch targeted radioligandtherapy in metastatic castration K, Sayeg M, Leshch Y, et al. PSMA-based radioligand resistant prostate cancer after chemotherapy, therapy for metastatic castration-resistant prostate abiraterone and/or enzalutamide. A retrospective cancer: the Bad Berka experience since 2013. J Nucl analysis of overall survival. Eur J Nucl Med Mol Imaging Med 2016;57(Suppl 3):97S–104S. 2018;45:12–19.

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50. Brauer A, Grubert LS, Roll W, Schrader AJ, Schäfers Bruchertseifer F, Rathke H, Morgenstern A, et al.

THERANOSTICS IN PROSTATE CANCER M, Bögemann M, Rahbar K. (177)Lu-PSMA-617 Targeted alpha therapy of mCRPC: Dosimetry esti- 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 2016;57:1941–1944. for theranostic use in oncology. J Nucl Med 55. Kratochwil C, Schmidt K, Afshar-Oromieh A, 2017;58:293–299.

94 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY AVAILABLE AS WEBINAR

PROSTATE CANCER RADIONUCLIDE THERAPY BASED ON ALPHA EMITTERS

by Mark Konijnenberg and Domenico Albano8 CHAPTER 8

INTRODUCTION THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE Prostate cancer is one of the most common cancers among men. It is 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 THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE 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 225Ac-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 meta-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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THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE phorus-32, strontium-89 and radium-223) The first radiopharmaceuticals to be 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 indicated 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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RADIOBIOLOGICAL Gy in 5 fractions to 30 Gy in 10 fractions[6]. THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE 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 223Ra creates more complex multiple DNA 223Ra 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 223Ra. The six-stage decay of 223Ra to stable

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THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE lead-207 occurs via a chain of short-lived in addition, beta and gamma emissions 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

223Ra T½ 11.43 d

5.67 MeV α

219Rn T½ 3.96 s

6.75 MeV α

215Po T½ 11.78 ms

7.39 MeV α

211Pb 211Bi 211Po 0.45 MeV β 0.28% T½ 36.1 min T½ 2.14 min 0.17 MeV β T½ 0.516 s

99.72% 6.57 MeV α 7.44 MeV α

211Bi 211Po 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, THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE 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)

223Ra 11.43 days 5.667 100% 43 28

219Rn 3.96 s 6.754 100% 57 37

215Po 1.78 ms 7.386 100% 65 43

211Bi 2.14 min 6.549 99.724% 54 35

211Po 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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THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE teum and 1.5 Gy to the bone marrow per all patients’ exposures for radiotherapeu- 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 223Ra 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 intestine, 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 THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE 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 225 225 of Ac (T1/2=10 days). Ac 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. 225 [16] (T1/2=14.8 days) to Ac . 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- [17] um-211 (T1/2=0.516 s) with 7.44 MeV . It can be produced through the bismuth-209(α,2n) astatine-211 reaction with a high-energy cyclotron by bombarding a bismuth target with 30-MeV alpha particles. The chosen alpha energy is usually

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REFERENCES THERAPY BASED ON ALPHA EMITTERS PROSTATE CANCER RADIONUCLIDE 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.

104 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY AVAILABLE AS WEBINAR

THE MANAGEMENT OF A PROSTATE CANCER PATIENT

by MarieClaire Attard and Rexhep Durmo9 CHAPTER 9

THE MANAGEMENT OF A PROSTATE CANCER PATIENT INTRODUCTION 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 MANAGEMENT OF A PROSTATE CANCER PATIENT 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 information 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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THE MANAGEMENT OF A PROSTATE CANCER PATIENT TUMOUR CHARACTERISTICS nodes, has a poor prognosis. The most 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-metastasis (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) tumour 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 higher 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

108 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY CHAPTER 9 THE MANAGEMENT OF A PROSTATE CANCER PATIENT - T2b Tumour involves more than half of Low risk 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 »» T4 Tumour is fixed or invades adjacent » A clinical stage of T2b 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 MANAGEMENT OF A PROSTATE CANCER PATIENT

Low Intermediate High Risk Risk Risk

Treatment Treatment Radical Palliative prostatectomy not options options treatment recommended

Brachy- For therapy localised PC PSMA

Follow-up Radical Nano- (PSA and prostat- particle MRI DRE) ectomy

Radical prostat- Brachy- Choline / ectomy therapy NaF PET

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 MANAGEMENT OF A PROSTATE CANCER PATIENT 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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THE MANAGEMENT OF A PROSTATE CANCER PATIENT inability to discriminate between such PSA levels between 10.1 and 19.9 ng/mL 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 68Ga-PSMA targeting agents THE MANAGEMENT OF A PROSTATE CANCER PATIENT 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 68Ga-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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THE MANAGEMENT OF A PROSTATE CANCER PATIENT group, and once staging has been con- an email address should the patient need cluded, treatment can be started. It is of to contact these organisations. Informa- course important to perform examination 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 MANAGEMENT OF A PROSTATE CANCER PATIENT

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 MANAGEMENT OF A PROSTATE CANCER PATIENT

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 multidisciplinary 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 MANAGEMENT OF A PROSTATE CANCER PATIENT 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 MANAGEMENT OF A PROSTATE CANCER PATIENT the bone metastases[29]. Correct informa- be considered in patients with BCR after 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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68Ga-PSMA PET/CT has shown promising also useful to look up previous examina- THE MANAGEMENT OF A PROSTATE CANCER PATIENT 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 advanced 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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THE MANAGEMENT OF A PROSTATE CANCER PATIENT Making proper use of what is available Acknowledgements. With thanks to Gijs 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.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA and local treatment with curative intent. Eur Urol Cancer J Clin 2018;68:7−30. 2017;71:618−629. 2. Attard G, Parker C, Eeles RA, Schröder F, Tomlins SA, 10. Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Tannock I, et al. Prostate cancer. Lancet 2016;387:70–82. Humphrey PA, et al. The 2014 International Society of 3. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Urological Pathology (ISUP) Consensus Conference Zappa M, Nelen V, et al. Screening and prostate cancer on Gleason Grading of Prostatic Carcinoma: Defini- mortality: results of the European Randomised Study tion of grading patterns and proposal for a new grad- of Screening for Prostate Cancer (ERSPC) at 13 years of ing system. Am J Surg Pathol 2016;40:244−252. follow-up. Lancet 2014;384:2027–2035. 11. Buyyounouski MK, Choyke PL, McKenney JK, Sartor 4. Andriole GL, Levin DL, Crawford ED, Gelmann EP, Pinsky O, Sandler HM, Amin MB et al. AJCC Cancer Staging PF, Chia D, et al. Cancer screening in the Prostate, Lung, Manual, 8th edn. New York: Springer; 2017:715. Colorectal and Ovarian (PLCO) Cancer Screening Trial: 12. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reu- Findings from the initial screening round of a random- ter VE. WHO Classification of Tumours of the Urinary ized trial. J Natl Cancer Inst 2005;97:433–438. System and Male Genital Organs-Part B: Prostate and 5. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, bladder tumours. Eur Urol 2016;70:106−119. Gulati R, et al. Lead time and overdiagnosis in pros- 13. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, tate-specific antigen screening: importance of meth- Gross T, et al. EAU-ESTRO-SIOG Guidelines on Prostate ods and context. J Natl Cancer Inst 2009;101:374–383. Cancer. Part II: Treatment of relapsing, metastatic, 6. Krahn MD, Mahoney JE, Eckman MH, Trachtenberg J, and castration-resistant prostate cancer. Eur Urol Pauker SG, Detsky AS. Screening for prostate cancer. A 2017;71:630−664. decision analytic view. JAMA 1994;272:773−780. 14. Morgans AK. Optimization of risk stratification in lo- 7. Bretton PR. Prostate-specific antigen and digital rectal calized prostate cancer. J Clin Oncol 2018;36:528−532. examination in screening for prostate cancer: a com- 15. Litwin MS, Tan HJ. The diagnosis and treatment of munity-based study. South Med J 1994;87:720−723. prostate cancer. A review. JAMA 2017;317:2532−2542. 8. Hara R, Jo Y, Fujii T, Kondo N, Yokoyoma T, Miyaji Y, et 16. Padhani AR, Lecouvet FE, Tunariu N, Koh D, de al. Optimal approach for prostate cancer detection as Keyzer F, Collins DJ, et al. Rational for modernising initial biopsy: prospective randomized study compar- imaging in advance prostate cancer. Eur Urol Focus ing transperineal versus transrectal systematic 12-core 2017;3:223−239. biopsy. Urology 2008;71:191–195. 17. Smeenge M, Barentsz J, Cosgrove D, de la Rosette J, de 9. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch Reijke T, Eggener S et al. Role of transrectal ultrasonog- MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines raphy (TRUS) in focal therapy of prostate cancer: Report on Prostate Cancer. Part 1: Screening, diagnosis, from a Consensus Panel. BJU Int 2012;110: 942−948.

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18. Fütterer JJ, Briganti A, De Visschere P, Emberton M, Gi- cancer in the era of precision medicine. Cancers (Ba- THE MANAGEMENT OF A PROSTATE CANCER PATIENT annarini G, Kirkham A, et al. Can clinically significant sel) 2018;10(2). prostate cancer be detected with multiparametric 29. Parker C, Heidenreich A, Nilsson S, Shore N. Current magnetic resonance imaging? A systematic review approaches to incorporation of radium-223 in clinical of the literature. Eur Urol 2015;68:1045. practice. Prostate Cancer Prostatic Dis 2018;21:37−47. 19. Evangelista L, Zattoni F, Guttilla A, Saladini G, Zattoni F, 30. Mertan FV, Greer MD, Borofsky S, Kabakus IM, Me- Colletti PM, et al. Choline PET or PET/CT and biochem- rino MJ, Wood BJ, et al. Multiparametric magnetic ical relapse of prostate cancer: a systematic review resonance imaging of recurrent prostate cancer. Top and meta-analysis. Clin Nucl Med 2013;38:305–314. Magn Reson Imaging 2016;25:139−147. 20. Brogsitter C, Zöphel K, Kotzerke J. 18F-Choline, 31. Kane CJ, Amling CL, Johnstone PA, Pak N, Lance RS, 11C-choline and 11C-acetate PET/CT: comparative Thrasher JB, et al. Limited value of bone scintigra- analysis for imaging prostate cancer patients. Eur J phy and computed tomography in assessing bio- Nucl Med Mol Imaging 2013;40 Suppl 1:S18−S27. chemical failure after radical prostatectomy. Urology 21. Ceci F, Castellucci P, Fanti S. Current application and 2003;61:607−611. future perspectives of PSMA PET imaging in prostate 32. Mitchell CR, Lowe VJ, Rangel LJ, Hung JC, Kwon cancer. Q J Nucl Med Mol Imaging. March 2018. doi: ED, Karnes RJ. Operational characteristics of (11) 10.23736/S1824-4785.18.03059-5 [Epub ahead of print]. c-choline positron emission tomography/compu- 22. Abuzallouf S, Dayes I, Lukka H. Baseline staging of terized tomography for prostate cancer with bio- newly diagnosed prostate cancer: a summary of the chemical recurrence after initial treatment. J Urol literature. J Urol 2004;171:2122−2127. 2013;189:1308−1313. 23. Fortuin AS, Smeenk RJ, Meijer HJM, Witjes AJ, Bar- 33. Soyka JD, Muster MA, Schmid DT, Seifert B, Schick U, entsz JO. Lymphotropic nanoparticle-enhanced MRI Miralbell R, et al. Clinical impact of 18F-choline PET/ in prostate cancer: Value and therapeutic potential. CT in patients with recurrent prostate cancer. Eur J Curr Urol Rep 2014;15:389. Nucl Med Mol Imaging 2012;39:936. 24. Kilcoyne A, Harisinghani MG, Mahmood U. Pros- 34. Ceci F, Herrmann K, Castellucci P, Graziani T, Bluemel tate cancer imaging and therapy: Potential C, Schiavina R, et al. Impact of 11C-choline PET/CT on role of nanoparticles. J Nucl Med 2016;57(Suppl clinical decision making in recurrent prostate cancer: 3):105S−110S. results from a retrospective two-centre trial. Eur J Nucl 25. Schwenck J, Rempp H, Reischl G, Kruck S, Stenzl A, Med Mol Imaging 2014;41:2222. Nikolaou K, et al. Comparison of 68Ga-labelled PSMA- 35. Colombié M, Campion L, Bailly C, Rusu D, Rousseau 11 and 11C-choline in the detection of prostate can- T, Mathieu C, et al. Prognostic value of metabolic pa- cer metastases by PET/CT. Eur J Nucl Med Mol Imaging rameters and clinical impact of (18)F-fluorocholine 2017;44:92−101. PET/ CT in biochemical recurrent prostate cancer. Eur 26. Hamdy FC, Donovan JL, Lane AL, Mason M, Metcalfe J Nucl Med Mol Imaging 2015;42:1784–1793. C, Holding P, et al. 10-Year outcomes after monitor- 36. Afshar-Oromieh A, Zechmann CM, Malcher A, Eder ing, surgery, or radiotherapy for localized prostate M, Eisenhut M, Linhart HG, et al. Comparison of PET cancer. N Engl J Med 2016;375:1415−1424. imaging with a (68)Ga-labelled PSMA ligand and 27. Raldow AC, Zhang D, Chen MH, Braccioforte MH, (18)F-choline-based PET/CT for the diagnosis of re- Moran BJ, D’Amico A. V. Risk group and death from current prostate cancer. Eur J Nucl Med Mol Imaging prostate cancer: Implications for active surveillance 2014;41:11−20. in men with favorable intermediate-risk prostate can- 37. Odewole OA, Tade FI, Nieh PT, Savir-Baruch B, Jani AB, cer. JAMA Oncol 2015;1:334. Master VA, et al. Recurrent prostate cancer detection 28. Fujimura T, Takayama K, Takahashi S, Inoue S. Estro- with anti-3-[(18)F]FACBC PET/CT: comparison with gen and androgen blockade for advanced prostate CT. Eur J Nucl Med Mol Imaging 2016;43:1773−1783.

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FUTURE PERSPECTIVES AND PRECLINICAL STUDIES IN PROSTATE CANCER

by Laura Evangelista and Federico Caobelli (on behalf of the Translational 10Imaging and Therapy Committee) CHAPTER 10

INTRODUCTION STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES Prostate cancer is the most common oncological disease in men worldwide. 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 targeted 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 STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES 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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STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES with castration-resistant features. More- recognised principles of animal care and 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 STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES 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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STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES focus on PSMA as the target. Some agents FUTURE CHALLENGES AND 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 STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES Jan 2017 Cancer Biotherapy 99mTc-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 111In-gonadotropin- In vivo Xenograft nude – et al. [4] & Medicinal releasing hormone mice Chemistry Letters peptides Nonnekens 2017 Cancer Biotherapy 213Bi-PSMA 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 68Ga-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 68Ga-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 64Cu- and 68Ga- NA – – et al. [10] labelled urokinase- type plasminogen activator receptor agonist Frigerio et 2017 Oncotarget 123I-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

EANM TECHNOLGIST’S GUIDE 129 PROSTATE CANCER IMAGING AND THERAPY CHAPTER 10

STUDIES IN PROSTATE CANCER AND PRECLINICALFUTURE PERSPECTIVES REFERENCES

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130 EANM TECHNOLGIST’S GUIDE PROSTATE CANCER IMAGING AND THERAPY IMPRINT

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