The Value of 3 Tesla Magnetic ResonanceImaging for the Detection and Aggressiveness

Assessment of Prostate Cancer

- From Theory to Practice -

THOMAS HAMBROCK

SIEMENS

The Value of 3 Tesla Magnetic Resonance Imaging for the Detection and Aggressivenes

Assessment of Prostate Cancer

From Theory to Practice

THOMAS HAMBROCK

1

The studies presented in this thesis were carried out at the Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, This project was supported by the Queen Wilhelmina Fund from the Dutch Cancer Society.

Nov 2012

Copyright Thomas Hambrock

Publisher:

ISBN:

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.

978-90-9027256-6

Nov 2012

Copyright Thomas Hambrock

Publisher: Drukkerij Efficint Nijmegen

ISBN: 978-90-902756-6

The Value of 3 Tesla Magnetic Resonance Imaging for the Detection and Aggressivenes

Assessment of Prostate Cancer

From Theory to Practice

PROEFSCHRIFT

TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE RADBOUD UNIVERSITEIT NIJMEGEN OP GEZAG VAN DE RECTOR MAGNIFICUS, PROF.

MR. S.C.J.J. KORTMANN, VOLGENS BESLUIT VAN HET COLLEGE VAN DECANEN IN HET OPENBAAR TE VERDEDIGEN OP DINSDAG 4 DECEMBER

2012 OM 13:30 UUR PRECIES

DOOR

THOMAS HAMBROCK

GEBOREN OP 1 SEPTEMBER 1978 TE PRETORIA, ZUID-AFRIKA

3

PROMOTOR : Prof. dr. J.O. Barentsz

COPROMOTOREN : Dr. ir. H.J. Huisman

Dr. ir. T.W.J. Scheenen

Dr. C.A. Hulsbergen-van de Kaa

MANUSCRIPTCOMMISIE : Prof. dr. J. van Krieken

Dr. E. van Lin

Prof. dr. A. Villers (University of Lille)

4

PROMOTOR : Prof. dr. J.O. Barentsz

COPROMOTOREN : Dr. ir. H.J. Huisman

Dr. ir. T.W.J. Scheenen

Dr. C.A. Hulsbergen-van de Kaa

MANUSCRIPTCOMMISIE : Prof. dr. J. van Krieken

Dr. E. van Lin

Prof. dr. G. Villeirs (University of Gent)

Dedicated to my grandfather . . . . . .

HERMANN AUGUST HAMBROCK * 8. MAY 1907 -

Who died at the young age of 63 years due to metastatic prostate cancer.

5

,WLVIXWLOHWRSRQGHURQWKHPHDQLQJRIOLIH Sir Bertrand Russels (1872-1970)

6

Table of Contents

PART ONE - INTRODUCTION AND BACKGROUND

Chapter 1 . . . . 11 28

Introduction.

Chapter 2 . . . . 29 59

Background to functional MR imaging.

PART TWO - DETECTION OF PRIMARY AND RECURRENT PROSTATE CANCER -

Chapter 3 . . . . 61 82

32-Channel 3T MR guided biopsies of prostate tumor suspicious regions identified on multi-

modality 3T MR imaging : Technique and feasibility. Invest Radiol 2009[HAMBROCK T,

FTTERER JJ, HUISMAN HJ et al.]{Impact factor 4.7}

Chapter 4 . . . . 83 100

MRI guided prostate biopsies in men with repetitive negative biopsies and elevated PSA.

J Urol 2010 [HAMBROCK T, SOMFORD DM, HOEKS C et al.]{Impact factor 3.9}

Chapter 5 . . . . 101 114

MR guided prostate biopsies of DCE-MR imaging suspicious tumor regions for the diagnosis

of prostate cancer following radiotherapy. Invest Radiol 2010 [YAKAR D; HAMBROCK T,

HUISMAN HJ et al.] {Impact factor 4.7}

Chapter 6 . . . . 115 140

Multiparametric MR imaging for detection and localization of low vs. high-grade transition

zone prostate cancer. Radiology Accepted [HOEKS C, HAMBROCK T, YAKAR D et al.]

{Impact factor 6.1}

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Table of Contents

PART THREE - ASSESSMENT OF PROSTATE CANCER AGGRESSIVENESS -

Chapter 7 . . . . 142 -165

The Relation of Apparent Diffusion Coefficient and prostate cancer Gleason grade in

Peripheral Zone. Radiology 2011 [HAMBROCK T, SOMFORD DM, HUISMAN HJ et al.]

{Impact factor 6.1}

Chapter 8 . . . . 166 182

Initial experience with identifying high-grade prostate cancer using diffusion-weighted MR

imaging in patie -guided biopsy. Invest

Radiol2012[HAMBROCK T, SOMFORD DM, OORT I et al.]{Impact factor 4.7}

Chapter 9 . . . . 183 199

In vivo assessment of prostate cancer aggressiveness using three-dimensional proton MR

spectroscopy at 3T with the combined endorectal coil and pelvic phased array coil. Eur

Urol 2011[KOBUS T, HAMBROCK T, HULSBERGEN C et al.] {Impact factor 8.8}

Chapter 10 . . . . 200 219

Prospective Assessment of Prostate Cancer Aggressiveness using 3 Tesla diffusion weighted

MR imaging guided biopsies versus a systematic 10-Core transrectal ultrasound prostate

biopsy cohort Eur Urol 2012 [HAMBROCK T, HOEKS C, HULSBERGEN C et al.] {Impact

factor 8.8}

PART 4 CALIBRATION/COMPUTER ASSISTED DIAGNOSIS OF PROSTATE CANCER -

Chapter 11 . . . . 221 236

The effect of inter-patient normal peripheral zone apparent diffusion coefficient variation

on the prediction of prostate cancer aggressiveness. (Radiology Accepted) [LITJENS G,

HAMBROCK T, BARENTSZ JO et al.]{Impact factor 6.1}

Chapter 12 . . . . 238 259

Computer-aided diagnosis of prostate cancer using multiparametric 3T MR imaging: Effect

on observer performance. Radiology Accepted[HAMBROCK T, VOS P, BARENTSZ JO et

al.] {Impact factor 6.1}

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Table of Contents

PART THREE - ASSESSMENT OF PROSTATE CANCER AGGRESSIVENESS -

Chapter 7 . . . . 142 -164

The Relation of Apparent Diffusion Coefficient and prostate cancer Gleason grade in

Peripheral Zone. Radiology 2011 [HAMBROCK T, SOMFORD DM, HUISMAN HJ et al.]

{Impact factor 6.1}

Chapter 8 . . . . 165 182

Initial experience with identifying high-grade prostate cancer using diffusion-weighted MR

imaging in patie -guided biopsy. Invest

Radiol2012[HAMBROCK T, SOMFORD DM, OORT I et al.]{Impact factor 4.7}

Chapter 9 . . . . 183 199

In vivo assessment of prostate cancer aggressiveness using three-dimensional proton MR

spectroscopy at 3T with the combined endorectal coil and pelvic phased array coil. Eur

Urol 2011[KOBUS T, HAMBROCK T, HULSBERGEN C et al.] {Impact factor 8.8}

Chapter 10 . . . . 200 220

Prospective Assessment of Prostate Cancer Aggressiveness using 3 Tesla diffusion weighted

MR imaging guided biopsies versus a systematic 10-Core transrectal ultrasound prostate

biopsy cohort Eur Urol 2012 [HAMBROCK T, HOEKS C, HULSBERGEN C et al.] {Impact

factor 8.8}

PART 4 CALIBRATION/COMPUTER ASSISTED DIAGNOSIS OF PROSTATE CANCER -

Chapter 11 . . . . 221 236

The effect of inter-patient normal peripheral zone apparent diffusion coefficient variation

on the prediction of prostate cancer aggressiveness. (Radiology Accepted) [LITJENS G,

HAMBROCK T, BARENTSZ JO et al.]{Impact factor 6.1}

Chapter 12 . . . . 238 259

Computer-aided diagnosis of prostate cancer using multiparametric 3T MR imaging: Effect

on observer performance. Radiology Accepted[HAMBROCK T, VOS P, BARENTSZ JO et

al.] {Impact factor 6.1}

Table of Contents

PART 5 - DISCUSSION, CONCLUSIONS AND FUTURE PERSPECTIVES -

Chapter 13 . . . . 261 292

Discussion, conclusions and future perspectives

Chapter 14 . . . . 293 308

English summary - Nederlandse samenvatting

PART SIX POSTLUDE

A. List of Publications . . . . 310 314

B. List of Presentations Scientific Paper Presentations . . . . 315 316

C. List of Presentations Presentations on Invitation . . . . 317 317

D. List of Awards . . . . 318 318

E. Curriculum Vitae . . . . 319 319

F. Dankwoord . . . . 320 322

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PART SIX POSTLUDE

A. List of Publications . . . . 311 315

B. List of Presentations Scientific Paper Presentations . . . . 316 317

C. List of Presentations Presentations on Invitation . . . . 318 318

D. List of Awards . . . . 319 319

E. Curriculum Vitae . . . . 320 320

F. Dankwoord . . . . 321 323

PART ONE

INTRODUCTION AND BACKGROUND

CHAPTER 1

Introduction

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CHAPTER 1CHAPTER 1

Introduction 1

GENERAL INTRODUCTION

March 2011, the Netherlands:

[UROLOGIST] : Mr. v. R, your PSA levels have now continuously been rising over the last 8

years from 3 ng/ml to 50 ng/ml. You have severe allergies to multiple antibiotics. So I think

prostate biopsies are no option.

[PATIENT MR. v. R]: How can we exclude prostate cancer then?

[UROLOGIST]: Apart from biopsies, which we cannot perform in your case, there is no

alternative.

[PATIENT MR. v. R]: I have heard that MRI can be used for prostate cancer detection.

[UROLOGIST]: Nonsense, you cannot see prostate cancer on MRI!

This is a true conversation which has taken place in a first world country at the beginning of the

year 2011. The patient mentioned above, was the second last patient (prior to writing this

introduction) the author of this book had scanned using multi-parametric MRI for the evaluation

of prostate cancer. After patient persistence, a biopsy was performed under special antibiotic

coverage. The final diagnosis on biopsy: prostate cancer in all 10 biopsy cores left and right,

Gleason Score 4+3=7. Following MR imaging, extracapsular extension with neurovascular

bundle infiltration and seminal vesicle invasion was diagnosed. In addition, the presence of

metastatic lymph nodes was also established. Radiological stage T3B N1 M0 disease. Treatment

with intent to cure: unlikely.

The author can only stand in awe and disbelief when such hesitancy, ignorance and lack of

knowledge in the year 2011 is still present in a first world country. A change has to be brought

about. Not a mere change, but more importantly A PARADIGM SHIFT.

There is probably no single word in human history which has caused so much fear, suffering,

and inner turmoil both on the side of the patient as well as the side of relatives and friends as the

word: CANCER. Celsus (28 BC - 50 AC), a Roman doctor, translated the Greek word "carcinos"

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into the word "cancer", a Latin word meaning crab or crayfish as a symbol of being eaten and

torn apart by a crab (cancer). The fear this word arose has elicited the greatest battle fought on

earth, the battle of the inner mind. The author subjectively is of the opinion that in the 21st

century, cancer has become more of a mental burden to humans than a physical one, without

downplaying the severe physical suffering of millions of patients who die to this conglomerate of

diseases or suffer severe morbidity thereof.

The cover page of Section One Introduction and Background, reveals the scene from Leonardo

da Vincis (1452-1519) lost painting, The Battle of Anghiari (1505), believed to be still hidden

beneath later frescoes in the Hall of Five Hundred in the Palazzo Vecchio, Florence, Italy. The

current picture is a painting of the original made by the famous Flemish painter Peter Paul

Rubens (1577-1640) and this copy can still be appreciated in the Louvre, Paris, France. To the

author, this painting is the perfect reflection on the current state of the diagnosis and

management of prostate cancer. It is a state of war, blood, tears, swords and horses and sounds

of thunder. Truly a state of chaos!

It is therefore the humble vision of the author that this current thesis may provide a stepping

stone to bring about A PARADIGM SHIFT in the Prostate World of Warcraft. This thesis is not

THE paradigm shift, but merely the beginning of a stone that has become dislodged, one that in

combination with many new scientific insights will bring about this future shift. It is inherent to

human nature to resist an alteration of ones chosen path, especially if one had trod that path for

so many years. As the medical community gains more scientific evidence, and as the plight of the

patient is increasingly recognized, a more peaceful path can be taken along the long journey of

prostate cancer. There will be a different way of thinking and a different way of doing.The

author agrees with the Joker from the movie Batman, who said: I like to rattle cages. If cages

are rattled and people are stirred by the content of this thesis and awakenings happen, then it

has fulfilled its purpose already. May this hold true for radiologists, oncologists, urologists,

radiotherapists and patients alike!

It is exceptional in modern days for new discoveries, inventions or advances in science to be

labeled to the sole genius of a single persons work. For all scientific facts that we unravel and

discover in current year and age, the author humbly and whole heartedly is obliged to agree with

Bernard of Chatres ( 1124) who said:

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"Nos esse quasi nanos, gigantium humeris insidentes, ut possimus plura eis et remotiora videre, non

utique proprii visus acumine, aut eminentia corporis, sed quia in altum subvenimur et extollimur

magnitudine gigantea"

We are like dwarfs on the shoulders of giants, so that we can see more than they, and things at a

great distance, not by virtue of any sharpness of sight on our part, or any physical distinction, but

because we are carried high and

Cedalion standing on the shoulders of the giant Orion, by Nicolas Poussin, 1658

In the current chain of inventions and groundbreaking discoveries, as well as the small

improvements which have lead to some of the MR imaging advances in prostate cancer as

outlined in this thesis, the author can merely acknowledge that we and our work are dwarfs on

the shoulders of giants. Many giants have been before us lifting us high to see what we currently

see. It is important in this thesis to mention a few of the hundreds of giants: Conrad Rntgen

(1845-1923) the discoverer of Rntgen rays and therefore the father of the most exciting field in

medicine: Radiology; Rudolf Virchow (1821-1902) whose pioneering work in the field of

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histopathology has introduced the gold standard of all our work the father of Histopathology.

Furthermore the ingenious work of Max Planck (1858-1947), regarded as the father of

Quantumphysics which underlies the crucial fundamentals of magnetic resonance imaging and

with which Walther Gerlach (1889-1979) later discovered the spin quantification in a magnetic

field, thereby serving as the beginning point of MRI. The ground breaking and fundamental

work on prostate cancer pathology and assessment, later referred to as the Gleason Scoring

system cannot be omitted by mentioning the giant: Donald F. Gleason (1920-2008).

In memory of these and many other Giants who paved the way of science..

Conrad Rntgen Max Planck Rudolf Virchow

Walther Gerlach Donald Gleason

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INTRODUCTION TO PROSTATE CANCER

Why is the prostate so important? This little organ which serves a crucial role in the

reproductive capabilities of the human species. However, for other reasons it has much greater

importance. The greatest importance is the effect that this organ has on the mind of the man

(agreeing that the external male sexual organs probably have a larger impact). It is rumored

that the sexual wellbeing of a woman is directly related to the wellbeing of the male prostate.

Most articles dealing with prostate cancer (PCa) all start with mentioning the prevalence and

mortality and the great burden prostate cancer has on society. Especially the notion that 1 in 6

men will develop prostate cancer is enough the let the war trumpets sound for the Battle of

Anghiari. A second disturbing phrase is so often mentioned in combination with PCa: Surely sir,

you are more likely to die with prostate cancer than from it. While this is true for a large

proportion of patients, this undoubtedly adds to the turmoil, chaos and bewilderment mostly on

the side of the patient. It is almost unfathomable that such a minute organ as the prostate has

become galactic in size (regarding the amount of literature on it and for some patients, this

organ, even in the benign state, can become truly gigantic). It is therefore purposeless and futile

to give a full introduction on this topic. To vaguely unravel the chaos of the Battle of Anghiari,

the author wishes to mention a few epidemiological, statistical and pathological points,

especially to introduce the unacquainted reader with some background to assist in reading this

thesis. More details especially on the anatomy and pathology of prostate cancers will become

evident in later chapters.

Indeed, PCa has become the most widely diagnosed cancer in males with 29% of all cancer

diagnoses being prostate cancer. Equally, in females, breast cancer has become the mostly

diagnosed malignancy, representing 29% of all cancers being diagnosed. For both, the absolute

mortality figures are only surpassed by lung cancer. These figures are surely shocking as regard

to the absolute numbers, being slightly over 240 000 diagnosed new cases for prostate and

220 000 breast cancers in the U.S.A. (1) and around 10 000 prostate cancers diagnosed in the

Netherlands in 2010. According to the American cancer statistics of 2012, around 12% of men

diagnosed with PCa succumb from their prostate cancer compared to 17% for females with

breast cancer. Therefore, a considerable difference exists in being diagnosed with PCa and

eventually dying from it. It is however important to consider the fact that patients currently

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dying from PCa are more often elderly men who have missed the earlier screening and

effective therapy now offered to younger patients. Therefore the likelihood of dying from

prostate cancer when one is currently (in the year 2012) diagnosed with the disease, is expected

to be much lower. About 3.5% of all male deaths are from PCa, making the lifetime risk that a

man will succumb of this disease about 1 in 28. This compares to the lifetime risk of dying in a

car accident, about 1 in 4 000 or in an airline accident about 1 in 100 000 (2).

Figure 1. Cancer Statistics 2012 in U.SA. from Siegel et al.(1)

Prostate cancer has been known as a disease of elderly men. It is therefore not surprising that

2/3 of all PCa deaths occur in men > 75 years. Although ~ 1 in 7 (14%) of men die from PCa,

only 1 in 20 (5%) of these deaths are premature (the author acknowledges that this might be

arbitrarily in the modern age), occurring in men younger < 75 years. Diagnosis is rare before

age 50, but after this age incidence increases exponentially and the rate of increase is faster than

seen in other malignancies.

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Figure 2. Worldwide incidence and mortality of prostate cancer. (3;4)

Yet, many publications advocated that at least 50% of currently diagnosed prostate cancer are

indolent or insignificant, comprising small (< 0.5 cc) tumours with only well differentiated

components (Gleason grade 3 or less) that apparently wont lead to death or morbidity. From a

statistical point of view, this is true. There is a great advocacy that men diagnosed with such

cancers should be left alone and sent home. The author wishes to make a bold and provocative

statement that this is not true. Every cancer begins with one cell, then two then four . until it

has reached great size and metastasizes. Additionally, it appears that most humans are not born

with cancers or with an increased likelihood of genetic mutation. These occur most often de

novo during their life time. Even if there are hereditary components, a two-hit sequence is often

needed for eventual manifestation of disease. From postmortem examination, the true

prevalence of prostate cancer in all ages is at the least to say, catastrophic. The author

contemplates that he himself (at the age of 33 years) has a likelihood of around 25% of

harboring PCa as these sentences are written. Yet this toothless lion sometimes grows teeth

and sometimes not. Sometimes it sleeps in its den and sometimes it comes out to feed. When

and why, we dont know. At least, not yet!

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Figure 3. Prevalence of PCa in Autopsy of white American males. Delongchamps et al.(3)

There is no current evidence (and this is also very difficult to prove) to show that aggressive

prostate cancers (that eventually lead to morbidity and mortality), start their life as aggressive

(meaning Gleason grade 4/5) small tumours. The vast majority of aggressive tumours have well

differentiated components as well. Would an aggressive proliferating cell suddenly turn benign?

The contrary is rather the case. Therefore, a substantial number of tumours begin as well

differentiated good little cancers the wolf in sheepskin. For reasons unknown, some of these

tumours (probably undergoing additional mutations under carcinogenic or other influences)

undergo further dedifferentiation into tumours that cause eventual clinical problems.

It is the burden of the scientific community to unravel which tumours have the potential to cause

problems in the future from those who dont. Probably this is not possible at all, as visiting the

Oracle of Delphi is not an option anymore and future additional mutations cannot be predicted.

They happen when they happen. Therefore the author undoubtedly is of the opinion that these

good little cancers should not be diagnosed at all (in their sheepskin phase) and only the

tumours with potential asocial behavior identified early and treated, BUT that all patients should

be offered a reliable method to follow them through life to identify when good tumours show

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aggressive dedifferentiation and further treatment is necessary. This thesis presents some

important concepts that will lift the veil of what is possible, both now, and in the future.

Nearly every aspect of PCa generates controversies for both doctors and patients. While dietary

fat of animal origin has repeatedly been associated with the risk of developing and dying of

prostate cancer, there is no clear evidence yet that dietary alterations or supplementation of

micronutrients can prevent or modify the course of this disease. Similarly, diagnosis and staging

are also controversial. While the introduction of the serum Prostate Specific Antigen (PSA) has

dramatically changed the rate of PCa diagnosis and altered the stage at diagnosis, it has often

been criticized for its lack of specificity resulting in over performing random prostate biopsies

and leading to over detection of innocuous cancers. Despite this, its role in the current and

future diagnosis of prostate cancer remains.

Unfortunately many (especially older, for some reason, mostly German) physicians rely and

swear on their own fingers capabilities to feel and therefore diagnose prostate cancers with a

high certainty. Needless to say, only a small proportion of the prostate gland can be felt by

digital rectal examination (DRE). DRE is unfortunately too often used to stage prostate cancer

and to make decisions regarding preservation (albeit not) of the neurovascular bundles during

radical prostatectomy. The overall sensitivity for the digital rectal examination is only 37% (5).

The author is of the opinion that the digital rectal examination should rather be placed in the

spiritual, more theological realm. One definitely needs a divine finger to rely on (Fig. 4), when

dealing with prostate cancer. As Prof. Barentsz always says, Our fingers have no eyes but we have

MRIs! The fallen Finger of God in South-West Africa (fallen 1988) (Fig. 5) serves as an

understatement of the current role of DRE in prostate cancer diagnosis and management. Of

course, the exception is the case, where tumours are only initially identified using DRE. It

however still has some role to play in the subjective experience, both by patient and physician,

that a thorough examination was performed.

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Figure 4. The Divine finger (needed to be good in cancer detection and staging) by

Michelangelo, Cistine chapel, 1511. Figure 5. in Namibia, fallen down

in 1988.

PCa is often (not always) detected by multiple, systematic but actually random, transrectal

needle biopsies of the prostate, rather than targeted biopsy of a palpable nodule or a lesion

visible by imaging. There is no other solid organ in which blinded biopsies are performed to

make a diagnosis. Both patient and clinicians alike would vehemently resist the possibility that

for example breast cancer should be diagnosed by performing 20 odd blind biopsies of the

breast on each side, hoping to have struck the tumour nodule hiding in the abundance of fat and

glandular tissue. This however was and is still the case with prostate cancer. Different biopsy

schemes have been advocated to strike gold more often.

Figure 6. Prostate biopsy schemes and cancer detection rates as advocated by Presti (6)

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Once detected, the size, location and extent of the lesion, as well as its grade, are difficult to

determine with precision. It is commonly known that biopsy results underestimate the extent

and grade of the cancer. Unfortunately many clinicians still lack confidence in imaging, despite

substantial progress being made in the field of MRI. Clinicians recommendation for treatment,

therefore, arises from a profound sense of uncertainty about the precise nature of the cancer

they are treating. After diagnosis, treatment decisions are hampered by further difficulties in

accurately staging the disease. In this atmosphere it is no wonder that treatment decisions are

so difficult for patient and their physicians. For the patient who chooses active rather than

deferred therapy, which treatment is best: radical prostatectomy, external beam irradiation,

brachytherapy or some combination? Not only do the treatments differ in timing of onset and

degree of side effects, but the likelihood of cancer control. The number of complications and

side effects depend as much on the specific technique employed as well as the expertise of the

treating physician on the method of therapy chosen.

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AIM OF THESIS

Figure 7. PCa

Undoubtedly a substantial number of factors play a role in the chaotic nature of the Battle of

Anghiari. The author started his thesis with the confident hope of trying to unravel this battle

with one overriding consideration:

, identify the clinical problem, then identify why there is a problem, then find a solution to

solve this problem.

The author was fortunate to have been able to build on the important foundations of MR imaging

of the prostate, laid down by the valuable research done in Nijmegen by his PhD predecessors.

Only with this foundation, is the continuous work and developments highlighted in this thesis

possible.

Problems faced by Clinicians:

1. Patients with an elevated/elevating PSA value but persistent negative TRUS

biopsies, are of considerable concern. Does he have cancer or not? Should further

TRUS biopsies be performed or not?

2. If MRI is accurate in identifying a tumour location, what effective method is there

to reliably obtain histological proof of this location?

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3. After radiation therapy for PCa, diagnosing local recurrence vs. metastatic disease

when the PSA starts rising again, is challenging.

4. Pretreatment identification of prostate cancer aggressiveness is crucial for

management and prognostication. The current methods to determine this are

inaccurate. What in vivo methods are available to reliably predict PCa nature?

5. When a patient is diagnosed with PCa Gleason Score 3+3=6 on biopsy, is there a

method available to reliably aid in differentiating those patients where biopsies

represent an undergrading (and therefore need more radical therapy) from those

where it is a correct prediction (and therefore may be managed more

conservatively)?

6. Transrectal ultrasound guided biopsies only reflect the true aggressiveness i.e.

Gleason grade in about 60% of patients. Are there any methods to improve the

tumour aggressiveness representativeness in biopsy samples on which further

management decisions can be based?

Problems faced by Radiologists:

7. No prostate looks alike. In particular the transition zone is a radiologically chaotic

region. What multi-parametric MR imaging features and techniques are available

8. What is normal? In one sue looks different from

tissue in a different

quantitative measurements and our assessment of what is malignant?

9. It is often mentioned that prostate multi-parametric MR imaging should be left to

the experts. The prostate is too complex, too many imaging modalities are needed

and tumours are very heterogeneous. Is there any help for the non-expert?

THE AIM of this thesis therefore is to target these specific problems faced by doctors and

patients and develop and validate methods in order to provide solutions for them.

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OUTLINE OF THESIS

In contrast to PhD theses in other non-medical fields, the fragmented nature of writing a thesis

in a medical science is based on the fact that a number of chapters should be based on peer

reviewed articles. Therefore each chapter has a similar repetitive composition being outlined in

an introduction, materials and methods, results, discussion and conclusions. Many chapters

start of with a similar introduction and to the unacquainted, this might appear cumbersome and

excessively repetitive. This is unfortunately a drawback of medical PhD theses. Yet, each

chapter can be read as a small thesis in itself, with a sufficient overview to provide the reader

with insight into the clinical question addressed in that chapter. Most chapters therefore will be

read and understood separately instead of seeing the complete picture. Many pictures, diagrams

and images are provided throughout the thesis. Radiologists are undoubtedly visually

stimulated creatures who are notoriously easily bored by great amounts of text.

This thesis is spread in 6 principal parts. PART ONE includes Chapter 1 and 2 which provide an

Introduction and Background to this thesis. PART TWO deals with the detection of primary

and recurrent prostate cancer and includes Chapter 3-6. PART THREE consists of the

assessment of PCa aggressiveness and includes Chapter 7-10. PART FOUR deals with

computerized calibration of normal peripheral zone tissue for increased accuracy in

assessment of aggressiveness and this is presented in Chapter 11. Chapter 12 deals with

computer aided diagnosis. PART FIVE is the finale, dealing with a discussion, conclusion and

future perspective, being outlined in Chapter 13. An English and Dutch summary is given in

Chapter 14. PART SIX is the usual postlude including a list of publications, presentations and

prizes, words of gratitude and ending with a short curriculum vitae.

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PART ONE INTRODUCTION and BACKGROUND

Chapter 1 provides the non acquainted reader with a broad introduction in the interesting field

of prostate cancer demographics, diagnostics and sets the basis for the problem-solution

orientated approach as is presented in this thesis.

Chapter 2 provides an introduction and basis of understanding for the advanced functional MR

imaging modalities that are tested and validated in this thesis. These modalities consist of

Dynamic Contrast Enhanced MRI (DCE-MRI) and Diffusion Weighted Imaging (DWI) with the

derived Apparent Diffusion Coefficient (ADC) maps.

PART TWO DETECTION of PRIMARY and RECURRENT PROSTATE CANCER

Chapter 3 describes the feasibility and method of using an MR compatible transrectal biopsy

device within a 3 Tesla MRI scanner, to obtain biopsies of tumour suspicious regions on multi-

parametric MR imaging.

Chapter 4 goes further and determines the value of MR guided biopsies on the yield of prostate

cancer in men with elevated PSA > 4 ng/ml and more than two prior negative TRUS guided

biopsy sessions. Furthermore, it also determines the location of tumours not found by

conventional biopsy techniques and the significance of the detected tumours.

Chapter 5 determines if DCE-MRI can be a useful technique to detect local recurrence of PCa

following external beam radiotherapy. Furthermore it evaluates if the MR guided biopsy

procedure is a useful technique for providing definite histological proof thereof.

Chapter 6 deals with transition zone cancers and evaluates the role of the individual anatomical

and functional MR imaging modalities to detect and localize low- vs. high-grade tumours.

PART THREE ASSESMENT OF PROSTATE CANCER AGGRESIVENESS

Chapter 7 evaluates the relationship between ADC values of tumour in the peripheral zone and

aggressiveness of prostate cancer and establishes a basis for a further study which prospectively

determines the Gleason grades prior to treatment.

Chapter 8 reports on the initial experience with identifying PCa undergrading using DWI

derived ADC values in patients wiTRUS-guided biopsy.

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Chapter 9 determines the potential value of 1H-MRSI in the assessment of prostate cancer

aggressiveness.

Chapter 10 evaluates the value of using DWI combined with MR guided biopsies to

prospectively improve the pretreatment prediction of true prostate cancer aggressiveness.

These findings are then compared to the conventional 10-core TRUS biopsy scheme.

PART FOUR COMPUTER AIDED DIAGNOSIS OF PROSTATE CANCER

Chapter 11 builds on the findings reported in Chapter 7. The substantial variation in normal

peripheral zone ADC values is used for calibration. Re-assessment is done for this this mixed

model incorporating both normal peripheral zone as well as tumour ADC values for

improvement in tumour aggressiveness differentiation.

Chapter 12 shows the development of a computer aided diagnosis (CAD) technique using both

quantitative pharmacokinetic parameters derived from DCE-MRI combined with quantitative

ADC values from DWI to differentiate tumour from benign tissue (but with tumour suspicious

characteristics) with a high diagnostic accuracy. This CAD system is then tested on multiple

less-experienced and experienced readers in evaluation of prostate MRI and determines if the

less-experience reader can be aided to improve his/her assessment of prostate tumours.

PART FIVE - DISCUSSION, CONCLUSION, FUTURE PERSPECTIVES

Chapter 12 provides a detailed discussion, conclusion and considers the future perspectives.

Chapter 13 an English and Dutch Summary

PART SIX THE POSTLUDE

List of Publications

List of Presentations both Scientific and Invited

Awards

27

Introduction 1

Introduction 1

REFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J.Clin. 2012 Jan;62(1):10-29.

2. Scardino PT, Kelman J.K. Dr. Peter Scardino's Prostate Book. New York, Avery Press: 2005.

3. Delongchamps NB, Singh A, Haas GP. The role of prevalence in the diagnosis of prostate cancer. Cancer Control 2006 Jul;13(3):158-68.

4. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J.Clin. 2005 Mar;55(2):74-108.

5. Schroder FH, van der MP, Beemsterboer P, Kruger AB, Hoedemaeker R, Rietbergen J, Kranse R. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. J.Natl.Cancer Inst. 1998 Dec 2;90(23):1817-23.

6. Presti JC, Jr., O'Dowd GJ, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. J.Urol. 2003 Jan;169(1):125-9.

28

Introduction 1

Introduction 1

REFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J.Clin. 2012 Jan;62(1):10-29.

2. Scardino PT, Kelman J.K. Dr. Peter Scardino's Prostate Book. New York, Avery Press: 2005.

3. Delongchamps NB, Singh A, Haas GP. The role of prevalence in the diagnosis of prostate cancer. Cancer Control 2006 Jul;13(3):158-68.

4. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J.Clin. 2005 Mar;55(2):74-108.

5. Schroder FH, van der MP, Beemsterboer P, Kruger AB, Hoedemaeker R, Rietbergen J, Kranse R. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. J.Natl.Cancer Inst. 1998 Dec 2;90(23):1817-23.

6. Presti JC, Jr., O'Dowd GJ, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. J.Urol. 2003 Jan;169(1):125-9.

28

Introduction 1

CHAPTER 2

Background to Functional MR Imaging of the Prostate

T. Hambrock; C. Hoeks, R. Somford et al.

/HRQDUGRGD9LQFL6NHWFKRIDKRUVHO

CHAPTER 2CHAPTER 2

Background to Functional MRI of the Prostate 2

The content of this chapter is principally based on three publications:

Dynamic contrast enhanced MR imaging in the diagnosis and management of prostate

cancer; Categorical Course in Diagnostic Radiology: Genitourinary Radiology 2006.

Hambrock T, Padhani A, Tofts P et al.

Diffusion and perfusion MR imaging of the prostate; Magnetic Resonance Imaging Clinics

of North America 2008. Somford R, Ftterer J, Hambrock T.

Prostate Cancer: Multiparametric MR imaging for Detection, Localization and Staging;

Radiology 2011. Hoeks C, Barentsz J, Hambrock T et al.

INTRODUCTION

The development of clinical utilization of MRI, culminating from multiple important

breakthroughs in quantum mechanics, is according to the author one of the most ingenious

developments of the 20th century. The basic principals underlying magnetic resonance imaging

are extremely complex (and extremely interesting) and it is definitely beyond the scope of this

thesis to provide a thorough introduction to physical principals underlying it. However, the

principals underlying more recent developments in functional MR imaging modalities incl.

Diffusion Weighted Imaging (DWI) and Dynamic Contrast Enhanced Imaging (DCE) will be

explained in more detail as these were the most important techniques evaluated in this thesis.

Additionally, a brief overview is given of the pathophysiological processes which underlie

imaging of the prostate. For a more detailed understanding of the physics underlying MRI, the

reader is referred to: MRI in Practice by Catherine Westbrook (1).

BASIC PRINCIPALS OF MAGNETIC RESONANCE IMAGING

Certain atoms are characterized by their tendency to align their axis of magnetic moment to an

external magnetic field. This happens because of their inherent angular moment or spin, as they

contain positively charged protons, that is, they possess electrical charge. The laws of

electromagnetic induction (as described originally by Faraday) refer to three individual forces

30

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

motion, magnetism and charge. The law of Faraday states that if two of these forces are present,

then the third is automatically induced. Atoms that have the properties of aligning along a

magnetic field are amenable to MR imaging. The most important one is hydrogen (1H), partially

because of its profound abundance in living matter, but also because of its large gyromagnetic

ratio. Certain isotopes of particular nuclei including carbon (13C), phosphorus (31P) and fluorine

(19F) are also amenable to MR imaging.

Figure 1. Random positioning of hydrogen atoms in the absence of a magnetic field (left)

and alignment against/with the main magnetic field (depending on their energy) (right).

When hydrogen atoms are aligned within the external magnetic field, a precession occurs

around the field with a specific frequency (for a 3T magnet this is 127 MHz). If an external

radiofrequency pulse is applied at this exact frequency, low energy hydrogen atoms aligned with

the magnetic field (y-axis) are flipped over causing a change in the net magnetization moment.

The net magnetization is now in the transverse plane (x-axis). After the RF pulse, the net

magnetization slowly returns to the y-axis. Recovery of longitudinal magnetization (y-axis) is

caused by nuclei giving up their energy to the surrounding environment. The rate of recovery is

an exponential process with a recovery time constant called the T1 time. This is the time it takes

63% of the longitudinal magnetization to recover. T2 decay of transverse magnetization is

caused by nuclei exchanging energy with neighboring nuclei. The rate of loss of coherent

transverse magnetization is also an exponential process, with the T2 relaxation time of a tissue,

the time it takes for 63% of the transverse magnetization to be lost. Using a receiver coil placed

31

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Background to Functional MRI of the Prostate 2

over the patient this change in magnetization after the RF pulse can be measured. The T1 and

T2 time for different tissues and molecules differs

between tissues on MR imaging.

Figure 2. Schematic presentation of the sequence of events in an MRI scanner. After the

RF pulse on the hydrogen atoms, placed in a magnetic field, spin magnetization is flipped

into the transverse direction.

A clinical 1.5T MRI scanner T1-w image of the prostate T2-w image of the prostate

The T1-weighted (T1-w) and T2-weighted (T2-w) images are considered anatomical images and

the functional MR imaging modalities considered hereafter are DCE-MRI and DWI-MRI with the

exception of MR spectroscopic imaging, not included in this chapter.

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Background to Functional MRI of the Prostate 2

A. DYNAMIC CONTRAST ENHANCED MRI

Pathophysiological basis - Angiogenesis and the prostate

For a prostate tumour, one critical factor that affects development, growth, invasiveness, and

progression into the metastatic form is the ability of the tumour to generate new blood vessels.

Angiogenesis, which we define as the sprouting of new capillaries from existing blood vessels,

and vasculogenesis, the de novo generation of new blood vessels, are the two primary methods of

vascular expansion by which nutrient supply to tumour tissue is adjusted to match physiologic

needs. Angiogenesis is an essential component of several normal physiologic processes,

including menstrual cycle changes in the ovaries and uterus, organ regeneration, wound healing,

and the spontaneous growth of collateral vessels in response to ischemia (2). Pathologic

angiogenesis is an integral part of a number of disease states, including rheumatoid disease, age-

related macular degeneration, proliferative retinopathy, and psoriasis, as well as being critical

for the growth and metastasis of malignant tumours (3).

A number of different mechanisms are involved, including vessel sprouting and bridge

formation. These processes depend on the migration and proliferation of endothelial cells.

Circulating endothelial progenitor cells derived from bone marrow are also recruited to sites of

active angiogenesis by tumour-derived growth factors such as vascular endothelial growth

factor (VEGF) (4). Tumour growth larger than 12 mm in diameter in solid tissues cannot occur

without vascular support (5). Tumour neovascularization often lags behind tumour growth,

leaving areas of low oxygen tension (hypoxia). The decrease in oxygen tension stimulates

further angiogenesis through various signaling pathways by the production of numerous

transcriptional factors, the most important being hypoxia-inducible factors (HIFs), especially

HIF-1 and HIF-2 (6). In the presence of hypoxia, HIF-1 binds to HIF-1 at the HIF response

elements (HREs); this is made possible because HIF-1 does not undergo hydroxylation and

subsequent degradation. Many of the genes activated by the HIF-HRE complex are beneficial to

tumour survival, including those involved in angiogenesis (VEGF), glucose metabolism (glucose

transporter 1), proliferation (insulin-like growth factor 2), and pH regulation (carbonic

anhydrase 9) (7) (Fig 1). Mediation of the physiologic and pathologic stimulation that causes a

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Background to Functional MRI of the Prostate 2

change in cellular phenotype is enacted by a variety of pro-angiogenic factors, which include the

following: (a) VEGF, the most prominent of the angiogenic stimulators; (b) thymidine

phosphorylase, also known as platelet-derived endothelial growth factor; (c) matrix

metalloproteinases (MMPs), a multifarious family of proteolytic enzymes involved in the

breakdown of extracellular matrix; (d) carbonic anhydrase 9, an enzyme that catalyzes the rapid

conversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions; and

(e) cyclooxygenase-2, a key enzyme in the prostaglandin biosynthesis pathway that converts

arachidonic acid to prostaglandin (7).

Figure 1. Cascade of gene activations with HIF, after hypoxic stimulation. Cascade results

in eventual angiogenesis to overcome the hypoxia. CA-9 = carbonic anhydrase 9, COX-2 =

cyclooxygenase-2, GLUT-1 = glucose transporter 1.

The importance of angiogenesis in prostate cancer is well established. Angiogenesis is an

integral part of benign prostatic hyperplasia, is associated with prostatic intraepithelial

neoplasia, and is a key factor in the growth and metastasis of prostate cancer (Fig 2). The results

of some studies have demonstrated a direct correlation of angiogenesis with Gleason score,

tumour stage, progression, metastasis, and survival (8,9). Angiogenesis is not directly associated

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

with serum PSA levels, which might reflect the ability of PSA to convert plasminogen to

angiostatin-like fragments, possibly contributing to the slow growth of prostate tumours.

Expression of angiogenic cytokines in prostate cancer might be induced as a response to hypoxic

stress or by hormonal stimulation but can also result from activation of oncogenes. The

angiogenic process in prostate cancer is highly dependent on VEGF. VEGF is produced in

abundance by the prostatic secretory epithelium of normal, hyperplastic, and tumour-containing

prostate glands. With respect to the vasculature, it is clear that VEGF is required for vascular

homeostasis in benign prostatic hyperplasia, and the overproduction of VEGF maintains a high

fraction of immature vessels (those without investing pericytes and/or smooth muscle cells) in

prostate cancers (10,11). In the prostate, production of VEGF requires continual stimulation by

androgens, and at androgen withdrawal, VEGF expression is down-regulated, and tumours

undergo vascular regression before tumour cell death (12). VEGF has a positive association with

microvessel density, tumour stage and grade, and disease-specific survival in patients with

prostate cancer (13). As noted earlier in this section, HIF-1 is a key mechanism for VEGF

regulation, and it is known that HIF-1 is up-regulated in the majority of prostate tumour tissues

and that its expression is induced in prostate cancer in situ (14).

Figure 2. Growth and metastasis of tumour with hypoxia-induced angiogenesis, mediated

by VEGF.

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Background to Functional MRI of the Prostate 2

Role of DCE-MRI in visualizing angiogenesis in the prostate

A number of distinguishing features are characteristic of malignant vasculature, many of which

are amenable to study with dynamic contrast agentenhanced MR imaging methods. These

features include (a) spatial heterogeneity and chaotic structure: little hierarchy of vascular

structures is observed, with abrupt changes in diameter and blind-ending vessels, particularly

within the centers of tumours; and few structurally complete arteries or veins are found with

sinusoidal capillary plexuses prevailing; the remodeling of the vasculature seen in inflammation

or wound healing is largely missing; (b) poorly formed fragile vessels with high permeability to

macromolecules because of the presence of large endothelial cell gaps or fenestrae, incomplete

basement membrane, and relative lack of pericytes or smooth muscle association with

endothelial cells; (c) arteriovenous shunting, high vascular tortuosity, and vasodilatation; (d)

intermittent or unstable blood flow (with acutely collapsing vessels and areas of spontaneous

hemorrhage; and (e) extreme heterogeneity of vascular density, with areas of low vascular

density mixed with regions of high angiogenic activity. These features are distinct from the

organized regular structure and normal blood flow seen in mature vessels. Angiogenic vessels

are also leaky, a feature that aids extracellular matrix signaling and metabolism, as well as

contributing to tumour cell invasion and metastasis (10). These tumour-induced vascular and

structural abnormalities result in functional impairments that are important to dynamic

contrast-enhanced MR imaging observations, including the following:

1. The interstitial pressure is increased because of an increased vascular permeability and

poor lymphatic drainage. As a result, the interstitial space is enlarged (by as much as five

times), allowing low-molecular weight contrast agents to accumulate. The higher interstitial

pressure also leads to compression of vessels and thus increased vascular resistance and

regional areas of acute perfusion-related hypoxia.

2. The transcapillary permeability increases, allowing a more rapid exchange of low-

molecular-weight contrast agents. As a consequence, contrast agents are more easily able to

access the interstitial extracellular space and flow out when plasma levels drop. This can be

observed as an increase in MR signal intensity followed by a subsequent decrease.

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

3. The total vascular cross-sectional area may increase and can be combined with arterio-

venous shunts. This gives rise to increased blood flow overall. The global increase in flow in

cancers causes the bolus of contrast agent to arrive just a little earlier than it does in

surrounding normal tissue. In the prostate, differences in arrival time between normal and

abnormal tissue are short (differences of only 1 second have been observed). It is important

to remember that all of these functional changes do not necessarily occur homogeneously

throughout the tumour but most often are heterogeneously distributed, and they need not

coincide spatially. Thus, areas of increased interstitial volume may occur separately (at

different locations) from areas of increased permeability.

Fast T1-weighted dynamic contrast-enhanced MR imaging for monitoring the uptake of an

intravascular contrast agent has proved itself to be a powerful technique for studying the

characteristics of the microvasculature of prostate tumours and normal prostatic tissues. The

essence of fast prostate T1- weighted dynamic contrast-enhanced MR imaging lies in the

differences in microvascular characteristics that have been observed between normal and

malignant prostatic tissues. Differences in the enhancement pattern observed in the prostate are

due to three physiologic processes in the microvasculature:

a) perfusion, or blood flow; the higher the perfusion, the quicker the contrast agent will be

available for diffusion into the extravascular extracellular space;

b) capillary permeability; the higher the permeability and the greater the microvessel

surface area, the faster the transfer of contrast agent to the extravascular extracellular

space and the greater the rate of T1-weighted enhancement; and

c) cellular density; the higher the cellular density outside the vasculature, the less free

interstitial fluid is available for relaxivity changes induced by the gadolinium-based

contrast agent (i.e., reduced extravascular extracellular space).

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

Permeability, or leakiness, of capillaries refers to the ability of molecules to pass through

interendothelial fenestrae and junctions into the interstitial compartment. Note that most

normal tissues are leaky to micromolecules (the exception being the brain because of the blood-

brain barrier), but macromolecular permeability is specific for tumours; that is, high

permeability of the vasculature is a characteristic of pathologic blood vessels in inflamed tissues

and tumours. It is because both benign and malignant tissues are leaky to low-molecular-weight

contrast agents that simple pre- and post-contrast images are usually ineffective in detecting the

intraprostatic location of prostate cancer; only minimal differences between benign tissue and

prostate cancer are seenunlike the case in the brain, which, as stated previously, has an

intrinsic low vascular permeability. Imaging performed for a few minutes after administration of

contrast agent has been described as a way to detect breast lesions (19); however, in the

prostate, nearly all tissues tend to enhance similarly on these images (20). It is for these reasons

that dynamic sequences acquired at high temporal resolution by exploiting differences in

perfusion are currently the only way of differentiating prostatic tissues.

Principals underlying DCE-MRI

Dynamic contrast-enhanced MR imaging with the routinely available low-molecular-weight

gadolinium chelates enables noninvasive imaging of tissue functional vascular features. The

three essential aspects of dynamic contrast-enhanced MR imaging include:

a) Fast dynamic imaging, referring to the temporal (time) component in imaging; complete

coverage of the anatomic area with a fast T1-weighted sequence is required before and

after the bolus injection of a lowmolecular-weight contrast agent;

b) Contrast agent administration, that is, intravenous administration of a low-molecular-

weight, usually gadolinium-based contrast agent; increases in signal intensity are seen

on the dynamically acquired T1-weighted MR images; and

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

c) Quantification of signal intensity changes, that is, semiquantitative and quantitative

estimation of signal intensity changes to determine the kinetic parameters of the

contrast agent.

Depending on the technique used, data can be obtained reflecting the tissue perfusion (blood

flow, blood volume, and mean transit time), the microvessel permeabilitysurface area product,

and the extracellular leakage space. Insights into these physiologic processes can be obtained by

the evaluation of kinetic enhancement curves or by the application of complex compartmental

modeling techniques. In addition to the signal intensity increases observed with T1-weighted

MR sequences, it is possible to observe the effects of the contrast agent while still confined to the

early vascular phase. While in the vascular space, concentrated contrast agent produces focal

magnetic field inhomogeneities that result in a decrease in the signal intensity of the

surrounding tissues (T2* effect). Thus, MR sequences can be designed to be:

a) Sensitive to the vascular phase of contrast agent delivery (the so-called T2*-weighted or

susceptibility-based methods), which reflect tissue perfusion and blood volume; or

b) Sensitive to the presence of contrast agent in the extravascular space (also termed T1-

weighted or relaxivity-based methods) and reflecting the perfused microvessel area and

permeability, as well as the extravascular extracellular leakage space.

The choice of the dynamic contrast-enhanced MR imaging sequences and parameters to be used

will depend on the required anatomic coverage, the acquisition times, the susceptibility to

artifacts resulting from magnetic field variations, and the need for quantification (10).

Analysis of the tissue signal intensity or the uptake of gadolinium-based contrast agent can be

done semiquantitatively (eg, with the onset time, the maximum enhancement, or the time to

peak) or with more complicated but quantitative pharmacokinetic modeling approaches. The

latter methods quantify enhancement with parameters like the transfer constant (Ktrans), the

volume of interstitial extravascular extracellular space (Ve), and the rate constant (kep) (15). The

quantification of kinetic parameters has the advantages of being biologically meaningful, helping

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

to establish objective criteria for classifying tissues, and being able to be used to objectively

assess the response to therapy (9,16).

A relationship exists between the uptake rate for gadolinium-based contrast agent and the

surface area of perfused microvessels. Histopathologic examination can only show microvessel

density and does not provide information with regard to the functionality (perfusion) of the

microvessels. It is important to note that implanted tumour xenograft data show that there is a

discrepancy between perfused and visible microvessels at histologic examination. The perfusion

of microvessels shows a variation from 20% to 85% at any given time (17,18). Dynamic MR

imaging can therefore provide additional information on tumour neovascularity as well as the

perfused fraction of vessels. Two aspects of dynamic MR imaging are of extra importance:

contrast agents and microvasculature of the prostate. These two will be discussed in the

following sections.

Contrast Agents

A number of different groups of contrast agents could be used for assessment of the angiogenic

status in tumours. These groups include (a) low-molecularweight agents (30 000 Da) designed for prolonged intravascular retention

(macromolecular contrast agents or blood pool agents), such as gadofosveset trisodium, which

itself is of low molecular weight but binds rapidly to plasma albumin and so effectively behaves

like a macromolecular contrast agent; however, there is a small fraction that remains unbound,

particularly in the first 1 minute after contrast agent administration; and (d) agents intended to

accumulate at sites of concentrated angiogenesisnanoparticulate gadoliniumcontaining

liposomes. In the United States, for dynamic contrast-enhanced MR imaging, only low-

molecular-weight gadolinium chelate contrast agents are currently approved. They shorten the

longitudinal (spin lattice) T1 relaxation of protons, resulting in increased signal intensity on T1-

weighted MR images. The increase in signal intensity is dependent on the native T1 relaxation of

tissue, the dose of the contrast agent, the imaging sequence and parameters used, and the gain

and scaling factors of the MR imaging equipment. These agents are unable to cross cell

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

membranes and thus will stay in the intravascular extracellular space (blood plasma) or the

extravascular extracellular space (interstitial fluid space). Note that although gadolinium

chelates affect protons in their immediate vicinity, proton diffusion occurs sufficiently quickly

for their sphere of influence to extend to the intracellular compartment. Thus, although

gadolinium chelates cannot enter intact cells, they can and do affect the proton relaxation in

cells. In Europe, a wider range of agents has recently become available: superparamagnetic iron

oxide agents like ferumoxides, which might be used in dynamic susceptibility-weighted MR

imaging, as well as the first clinically available blood pool contrast agent, gadofosveset

trisodium. The exact role of these contrast agents in oncologic imaging still needs to be defined.

Figure 3 shows a work-flow diagram for the technique of DCE-MR imaging.

Figure 3. Work-flow diagram to show the technique of DCE-MR imaging, from intravenous

(IV) administration of contrast agent to the generation of colored images.

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Background to Functional MRI of the Prostate 2

Contrast Agent Administration

For optimal qualitative and quantitative estimation of dynamic contrast agentrelated changes

in prostatic tissue, controlled administration of a bolus of contrast agent into a peripheral vein is

required. Manual administration can result in distorted enhancement characteristics. To

minimize this problem, automatic power injectors should be used with fixed administration

rates (usually 2.5 mL/sec although a higher rate of. 4-5 ml/sec seems more advantageous). After

injection of the bolus of gadolinium-based contrast agent, a normal saline flush is also needed to

clear the line and to chase the injected bolus of contrast agent into the central circulation.

Dynamic Sequences

T1-weighted sequences.The T1-weighted signal intensity increase in tissue (Fig. 4) is

dependent on the baseline T1 value. In general, quantification is improved by estimating

changes in the T1 relaxation rate at each time point during the dynamic acquisition. T1-weighted

sequences, usually of gradient-echo or saturation-recovery/inversion-recovery snapshot types,

are used for data acquisition. High spatial resolution to cover the whole prostate can only be

achieved by compromising the temporal resolution and vice versa.

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

Figure 4. Graphs of signal intensity versus time for a T1-weighted dynamic contrast-

enhanced MR imaging acquisition. Different semiquantitative parameters are calculated

from the graph after curve-fitting algorithms have been applied.

As a result, two types of schemes having different temporal resolutions are used when

performing dynamic contrast-enhanced MR imaging of the prostate: a) slow sequences

(temporal resolution, approximately 30 seconds) with high spatial resolution; these in general

have high sensitivity and low specificity; and b) Fast sequences (imaging techniques with

temporal resolution of 14 seconds) with lower spatial resolution; these have low sensitivity

and high specificity.

The optimal temporal resolution and spatial resolution still need to be established to achieve the

highest sensitivity and specificity, and this will depend on the clinical question. To date, most

researchers have used strategies of high temporal resolution, but it seems that cancer might be

accurately depicted, at least in the peripheral zone, by using slower sequences (21). The great

advantage of higher temporal resolution, compared with low temporal resolution, is the ability

to accurately quantify enhancement parameters and gain valuable pharmacokinetic information.

Although most studies emphasize high temporal resolution at the expense of spatial resolution,

lower spatial resolution may not depict critical features needed for optimal staging (e.g., minimal

capsular penetration). Despite this, studies with high temporal resolution have shown that

43

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

dynamic contrast-enhanced MR imaging can improve the staging capabilities of less-experienced

radiologists (22).

Figure 5. Graphs of signal intensity versus time showing the difference between fast (left)

and slow (right) acquisition methods.

Data Processing

T1-weighted sequence data.From the raw data acquired with the T1-weighted sequence, a

pixel-by pixel analysis of signal intensity changes is made. Signal enhancement seen on T1-

weighted dynamic contrast-enhanced MR images can be assessed in two ways:

a) Semiquantitative analysis of signal intensity changes and

b) Quantitative analysis of contrast agent concentration (change in relaxivity) by using

pharmacokinetic modeling techniques.

Semiquantitative parameters describe signal intensity changes by using a number of descriptors.

These parameters include curve shape, onset time (t 0 = time from injection or appearance in an

44

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

artery to the arrival of contrast agent in the tissue of interest), gradient of the slope of

enhancement curves, maximum signal intensity, area under the signal intensity curve at a fixed

time point (usually 6090 seconds after onset time), and washout gradient (late washout). These

parameters have the advantage of being relatively straightforward for calculation, but they are

limited by the fact that they are not biologically meaningful, may not accurately reflect contrast

agent concentration in tissues, and can be influenced by the imaging equipments settings

(including gain and scaling factors). These factors limit the usefulness of semiquantitative

parameters and make between-patient and between-system comparisons difficult.

Quantitative techniques use pharmacokinetic modeling, which is usually applied to changes in

the contrast agent concentrations in tissue. Signal intensity changes observed during dynamic

acquisition are used to estimate contrast agent concentration in vivo (23). Concentration-time

curves are then mathematically fitted by using one of a number of recognized pharmacokinetic

models, and quantitative kinetic parameters are derived. Examples of modeling parameters

include the volume transfer constant of the contrast agent (Ktrans [formally called the

permeabilitysurface area product per unit volume of tissue], measured in units per minute), the

interstitial fluid space as a percentage of unit volume of tissue (Ve), and the rate constant (kep,

measured in units per minute). These standard parameters are related mathematically (24): kep

= Ktrans/Ve (1). Quantitative parameters are more complicated to derive than those derived

semiquantitatively, which deters their use. However, commercially available software is

beginning to appear, and if contrast agent concentration can be measured accurately and if the

type, volume, and method of administration of contrast agent are consistent, then it is possible

to directly compare pharmacokinetic parameters acquired serially in a given patient and in

different patients imaged at the same or different imaging sites (25). Uncertainties exist with

regard to the reliability of kinetic parameter estimates derived from the application of contrast

agent kinetic models to T1-weighted dynamic contrast-enhanced MR imaging data. These

uncertainties derive from assumptions implicit in kinetic models and those assumptions made

for the measurement of the contrast agent concentration in tissue. The vascular input function

used in the calculations also affects the reliability of the data obtained; robust methods for

measuring arterial input function for routine dynamic contrast-enhanced MR imaging studies

are currently emerging but are still not widely available (2628).

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

Figure 6. Body compartments accessed by low-molecular-weight contrast agents. IV =

intravenous.

Quantitative Dynamic Contrast-enhanced Parameters

1. Extravascular Extracellular Space Volume (Ve)

The volume of extravascular extracellular space (Ve) is defined as:

where [Cgd]plateau_prostate is the prostate gadolinium concentration at plateau of peak

enhancement (i.e., the signal amplitude at which the exponential curve levels off), and

[Cgd]plateau_ref_tissue is the gadolinium concentration at plateau of peak enhancement in the

reference tissue used for calibration purposes. Ve refers to the space into which gadolinium

can leak from a capillary and has the benefit of specifically excluding the vascular space.

There may be regions (such as fibrous tissue) that are in the extravascular extracellular space

and yet are inaccessible to gadolinium-based contrast agents. Alternatives terms would

therefore be leakage space or distribution space. This is a theoretical parameter, though; and

in practice, in leaky tumours the contribution of plasma contrast agent and interstitial

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Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

contrast agent cannot be discriminated. Thus, Ve in practice measures the total extravascular

extracellular volume and therefore, 1 - Ve represents the cellular fraction.

2. Rate Constant (kep)

The rate constant (kep) is defined as:

where ttpprostate is the time to peak enhancement in the prostate, and ttpref_tissue is the time to

peak enhancement in the reference tissue. The rate constant kep is formally the diffusion rate

constant between the extravascular extracellular space and blood plasma. Both the volume

transfer constant and the rate constant have the same units (units per minute). kep Is always

greater than the transfer constant Ktrans. For a range of typical extravascular extracellular

space fractional volumes seen in tumours (Ve = 20%50%), kep is two to five times higher

than Ktrans. The kep is the exponential decay constant for tissue concentration that would result

if the arterial concentration could be (a) instantaneously raised from zero to a constant value

or (b) dropped to zero. The kep is also the mean residence time for contrast agent in the

extravascular extracellular space after a bolus arterial input (24).

3. Volume Transfer Constant (Ktrans)

The volume transfer constant Ktrans is defined as follows:

47

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

Ktrans has several physiologic interpretations, depending on the balance between capillary

permeability and blood flow in the tissue of interest. In high-permeability situations, where

diffusion through the interendothelial fenestrae is limited by flow, Ktrans is equal to the blood

plasma flow per unit volume of tissue. In the other limiting case of low permeability, where

contrast agent diffusion is limited by permeability, Ktrans is equal to the permeabilitysurface

area product of the capillary vessel walls, per unit volume of tissue (24).

Limitations of the DCE-MERI technique

It should be evident that dynamic contrast-enhanced MR imaging combined with high-spatial

resolution T2-weighted imaging and Diffusion weighted imaging will remain the mainstay of

prostate cancer MR imaging for the foreseeable future. However, the limitations of dynamic

contrast-enhanced MR imaging should be borne in mind. The transition zone, often replaced by

benign prostatic hyperplasia, can be highly vascularized and show rapid and high levels of

enhancement. As noted previously, discriminating normal transition zone and benign prostatic

hyperplasia from tumours within the same region is often challenging. Pathologic but

nonmalignant lesions within the prostate can often also mimic tumour on dynamic contrast-

enhanced MR images. The most common of these lesions are high-grade prostatic intraepithelial

neoplasia and prostatitis; the underlying reasons for the overlap with tumour lies in the fact that

these lesions also incite angiogenic responses in tissues. Administration of a contrast agent is an

invasive procedure with additional costs and potential side effects. For quantitative dynamic

contrast-enhanced MR imaging to be widely applied in clinical practice, it is necessary to

develop standardized robust analytic approaches for the measurement of enhancement. This

includes the need for commercial equipment manufacturers to provide robust methods for

rapidly measuring time-varying change in T1 relaxation rates, incorporation of arterial input

function into kinetic modeling processes (or other reliable methods that substitute for arterial

input function measurement), and robust analytic software that allows input from the different

MR imagers (17). Finally, interpretation requires a certain level of experience because no

quantitative parameter is able to be used to reliably separate tumour from benign tissues. In

conclusion, dynamic contrast-enhanced MR imaging has established itself as a valuable imaging

tool with a wide variety of applications for patients with prostate cancer.

48

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

Figure 7. Dynamic contrast-enhanced MR imaging in localization of prostate cancer. (a)

Histologic determination of tumour areas. (b) T2-weighted MR image. Arrows indicate

tumour. (ce) Semiquantitative parameters. (c) Wash-in rate. (d) Late washout. (e)

Relative enhancement. Quantitative parameters: (f-h). (f) Rate constant (kep). (g) Leakage

space (Ve). (h) Volume transfer constant (Ktrans). (i) Graph of signal intensity versus time

shows the difference between enhancement characteristics of tumour and normal

peripheral zone (PZ).

49

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

B. DIFFUSION WEIGHTED IMAGING (DWI)

Pathophysiological basis and the role of DWI in depicting prostatic tissue

Water molecules exhibit random motion in tissue, related to temperature (Brownian effect)(29).

The intra- and extracellular movement of molecules in tissue is largely restricted by membranes

forming barriers to diffusion., The more barriers water molecules meet in a certain time interval,

the smaller the mean movement (diffusion) distance (32). The degree of restriction to water

diffusion in biological tissue is inversely correlated to tissue cellularity and the integrity of cell

membranes. Free motion of water molecules is more restricted in tissues with a high cellular

density. DWI can quantify this water motion in an indirect manner (30,31). The DWI pulse

sequence labels hydrogen nuclei in space, of which most is water molecules at any moment, and

determines the length of the path that water molecules travel over a short period of time

(labeling time in the order of 50 ms). DWI estimates the mean distance traveled by all hydrogen

nuclei in every voxel of imaged tissue. The greater this mean distance the higher the apparent

mobility of the water molecules in the tissue. In the clinical setting, diffusion-weighted

sequences are sensitized to detect diffusion distances ranging from 1 to 20 m predominantly

measuring microcapillary water movement (5% of total volume of voxel), intracellular and

extracellular space diffusion. From the DWI images quantitative values can be calculated, called

the apparent diffusion coefficients (ADC) with high values indicating free water movement and

low ADC values indicating restrictions to free movement.

DWI was initially used for the early detection of cerebral ischemia (36). The evolution of DWI

characteristics in cerebral ischemia over time has classically been attributed to the extracellular

to intracellular distribution of hydrogen nuclei caused by different types of edema (37). It has

been postulated that extracellular water molecules have a much higher range of mobility,

because they are not bound within membranes or by other cellular structures (38,39). When

this is translated to prostate tissue, which is predominantly glandular tissue, the predominant

contribution of the extracellular component is from tubular structures and their fluid content,

whereas the intracellular component is determined by the epithelial and stromal cells.

50

Background to Functional MRI of the Prostate 2

Background to Functional MRI of the Prostate 2

A prerequisite for the correct interpretation of diffusion and ADC images relies on good

knowledge of the diffusion characteristics of the different anatomic zones of the prostate and of

benign prostatic conditions compared with prostate cancer (40). The normal prostatic gland is

rich in tubular structures. This allows for abundant self-diffusion of water molecules within

these structure and provides high ADC values. In most cases, the peripheral zone can be easily

discriminated from the transition zone on DWI, because it displays relatively higher ADC values

(41-43). The exact background of this phenomenon remains unclear, because the exact ratio of

extracellular to intracellular components for the different anatomic zones of the prostate has not

yet been described. Moreover, exchange of water over membranes can obscure a fully

compartmentalized interpretation of the diffusion characteristics. The transition zone by

microscopic observation consists of more compact smooth muscle and sparser glandular

elements than the peripheral zone, leading to a lower extracellular to intracellular fluid ratio

(44). Furthermore, an age-related increase of T2 signal intensity of the peripheral zone

compared with the transition zone has also been demonstrated (45) and an age-related increase

in ADC values in both transition zone and peripheral zone has been seen (46), which are most

likely caused by atrophy in the prostate leading to reduced cell volume and enlarged glandular

ducts. Benign prostatic hyperplasia (BPH) gives rise to nodular adenomas in the transition zone

and with time these compress the central zone to form a pseudocapsule, consequently occupying

the complete transition zone. The peripheral zone is usually not affected by BPH and retains its

own histologic characteristics. BPH is defined by hyperplasia of all cells that constitute the

transition zone, with glandular, muscular, and fibrous compartments involved in various

degrees within a patient and between patients. This nodular hyperplasia gives rise to

inhomogeneous diffusion patterns and because tubular structures often remain in place, the

increased cellular density of hyperplasia, which is far less predominant than in prostate

carcinoma, might explain the observed reduction in ADC levels of the transition zone on DWI.

However since BPH has inhomogeneous diffusion characteristics, not only reduction in ADC but

also increases in ADCs have also been described (46).

Prostatitis almost uniquely originates in the peripheral zone. With respect to MR imaging,

chronic prostatitis is of far more importance than the acute prostatit