1. health and fitness
2. disease
3. cancer

Screening and active surveillance in prostate
cancer: prognostic and short-term outcomes
of active surveillance and quality of life
aspects
Hanna Vasarainen
Department of Urology
Helsinki University Central Hospital
Faculty of Medicine
Helsinki University, Finland
Academic Dissertation
To be publicly discussed, with the permission of the Faculty of Medicine of
the University of Helsinki, for public examination in lecture hall 2 of Meilahti
University Hospital, on May 23rd 2014, at 12 o’clock.
Helsinki 2014
Supervised by:
Docent Antti Rannikko, M.D., Ph.D.
University of Helsinki
Reviewed by:
Docent Jukka Häkkinen, M.D., Ph.D.
University of Tampere
Docent Markku Vaarala, M.D., Ph.D.
University of Oulu
Discussed with:
Docent Peter Boström, M.D., Ph.D.
University of Turku
ISBN (paperback)
978-952-10-9929-8
ISBN (PDF)
978-952-10-9930-4
Helsinki 2014
Unigrafia, Helsinki
2 To My Family
3 CONTENTS
1. ABBREVIATIONS ................................................................................... 7
2. LIST OF ORIGINAL PUBLICATIONS ..................................................... 9
3. ABSTRACT ........................................................................................... 10
4. INTRODUCTION.................................................................................... 12
5. REVIEW OF LITERATURE ................................................................... 14
5.1 The Prostate ............................................................................................... 14
5.2 Epidemiology .............................................................................................. 15
5.3 Risk factors................................................................................................. 17
5.4 Classification .............................................................................................. 17
5.4.1 Histology .............................................................................................. 17
5.4.2 Grading, Gleason score ....................................................................... 18
5.4.3 Staging, TNM classification .................................................................. 19
5.5 Diagnosis.................................................................................................... 20
5.5.1 Prostate-specific antigen and other markers ....................................... 20
5.5.2 Digital rectal examination ..................................................................... 21
5.5.3 Transrectal ultrasound and prostate biopsies ...................................... 21
5.5.4 Imaging ................................................................................................ 22
5.6 Prostate cancer screening.......................................................................... 23
5.6.1 QOL aspects related to the PSA screening process ............................ 24
5.7 Treatment options with curative intent........................................................ 25
5.7.1 Radical prostatectomy ......................................................................... 25
5.7.2 External beam radiation therapy .......................................................... 26
5.7.3 Brachytherapy ...................................................................................... 26
5.7.4 Focal therapies .................................................................................... 27
5.8 Hormonal therapy ....................................................................................... 27
5.9 Active surveillance...................................................................................... 28
5.9.1 Rationale for active surveillance .......................................................... 28
5.9.2 Watchful waiting versus active surveillance ......................................... 29
5.9.3 Definition of clinically insignificant prostate cancer .............................. 29
5.9.4 Patient selection for active surveillance ............................................... 30
5.9.5 Monitoring and triggers for intervention ............................................... 31
5.9.6 Outcomes of active surveillance studies .............................................. 32
5.9.6.1 Treatment free-survival, PC-specific mortality and overall mortality 32
5.9.6.2 Outcomes from deferred treatment ................................................. 32
5.9.6.3 Rebiopsy outcomes ......................................................................... 33
5.9.7 Psychological and QOL aspects .......................................................... 34
5.9.8 Imaging ................................................................................................ 35
5.9.9 Biomarkers ........................................................................................... 35
5.9.10 The role of 5-Alpha Reductase Inhibitors ............................................. 36
6. AIMS OF THE STUDY ........................................................................... 37
7. MATERIALS AND METHODS .............................................................. 38
7.1 Study populations ....................................................................................... 38
7.1.1 The Finnish arm of the ERSPC trial (study III) ..................................... 38
7.1.2 The PRIAS study (studies I, II, IV and V) ............................................. 38
7.2 Study protocols and study design .............................................................. 39
7.2.1 Study III the Finnish arm of the ERSPC trial ........................................ 39
7.2.2 Studies I, II, IV and V protocol ............................................................. 39
4 7.2.3
7.2.4
7.2.5
7.2.6
7.2.7
PRIAS internet website ........................................................................ 41
RAND 36 – Item Health Survey (II, III) ................................................. 41
MRI (IV) ................................................................................................ 42
Statistics ............................................................................................... 43
Ethics ................................................................................................... 43
8. RESULTS .............................................................................................. 44
8.1
8.2
8.3
8.4
8.5
The short-term outcomes of the first 500 PRIAS patients (study I) ............ 44
Short-term HRQL effects of AS (study II) ................................................... 47
Short-term HRQL effects of PC screening (study III) ................................. 49
DW-MRI after a year of AS and before rebiopsy (study IV) ....................... 51
Free/total PSA ratios in patients on AS (study V)....................................... 54
9. DISCUSSION ......................................................................................... 58
9.1 Short-term outcomes of the PRIAS study (study I) .................................... 58
9.2 QOL during the continuum of PC: the effect of the screening process and AS
(studies II and III) ......................................................................................... 59
9.2.1 Short-term effects of PC screening on HRQL (study III) ...................... 60
9.2.2 Short-term changes in HRQL during AS (study II) ............................... 61
9.2.3 Challenges in measuring QOL (studies II and III) ................................ 63
9.3 Possible diagnostic and prognostic tools for AS (studies IV and V) ........... 64
9.3.1 DW-MRI in AS (study IV) ..................................................................... 64
9.3.2 %fPSA ratio as a prognostic tool on AS (study V) ............................... 66
9.4 Future perspectives .................................................................................... 67
10.
SUMMARY AND CONCLUSIONS ...................................................... 69
11.
ACKNOWLEDGEMENTS ................................................................... 71
12.
REFERENCES .................................................................................... 73
13.
APPENDICES .................................................................................... 102
The FinnProstate XI co-ordinators and Trial Centers ........................................ 102
Rand-36 health-related quality of life questionnaire .......................................... 103
IPSS questionnaire............................................................................................ 107
IIEF-5 questionnaire .......................................................................................... 109
14.
ORIGINAL PUBLICATIONS ............................................................. 110
5 6 1.
ABBREVIATIONS
ADC
5-ARI
AS
ATFS
AUA
BPH
BT
CaPSURE
CSAP
cT
CT
cTNM
DCE-MRI
3D-CRT
DRE
DW-MRI
EAU
EBRT
ER
ERSPC
%fPSA
FPXI
HDR-BT
HGPIN
HIFU
HRQL
IGRT
IIEF-5
IMRT
IPSS
ISUP
LDR-BT
LHRH
MRI
mRNA
MRSI
PASS
PC
PCA3
PCPT
Apparent diffusion coefficient
5-alpha reductase inhibitor
Active surveillance
Active treatment-free survival
The American Urological Association
Benign prostatic hyperplasia
Brachytherapy
The Cancer of the Prostate Strategic Urological Research Endeavor
Cryosurgical ablation of the prostate
Clinical T –class
Computed tomography
Clinical Tumor-Node-Metastasis-stage
Dynamic contrast-enhanced magnetic resonance imaging
Three-dimensional conformal radiation therapy
Digital rectal examination
Diffusion-weighted magnetic resonance imaging
The European Association of Urology
External beam radiation therapy
Emotional role
The European Randomized Study of Screening for Prostate Cancer
Free/total PSA ratio
The FinnProstate Study XI
High-dose rate brachytherapy
High-grade prostatic intraepithelial neoplasia
High-intensity focused ultrasound
Health-related quality of life
Image-guided radiotherapy
The International Index of Erectile Function
Intensity-modulated external-beam radiotherapy
The International Prostate Symptom Score
International Society of Urological Pathology
Low-dose rate brachytherapy
Luteinizing hormone-releasing hormone
Magnetic resonance imaging
Messenger ribonucleic acid
Magnetic resonance spectroscopy imaging
The Prostate Active Surveillance Study
Prostate cancer
Prostate cancer antigen 3
The Prostate Cancer Prevention Trial
7 PET
PIVOT
PLCO
PR
PRIAS
ProtecT
PSA
PSAD
PSADT
PSAV
pTNM
QALY
QOL
RARP
REDEEM
REDUCE
RP
SEER
SPCG-4
STUMP
TNM-stage
TRUS
TURP
WHO
WW
Positron emission tomography
The Prostate Cancer Intervention Versus Observation Trial
The Prostate, Lung, Colorectal and Ovarian cancer screening trial
Physical role
The Prostate Cancer Research International: Active Surveillance
Study
The Prostate testing for cancer and Treatment trial
Prostate-specific antigen
PSA density
PSA doubling time
PSA velocity
Pathological Tumor-Node-Metastasis-stage
Quality-adjusted life year
Quality of life
Robot-assisted radical prostatectomy
The Reduction by Dutasteride of Clinical Progression Events in
Expectant Management trial
The Reduction by Dutasteride of Prostate Cancer Events trial
Radical prostatectomy
Surveillance, Epidemiology, and End Results program
The Scandinavian Prostate Cancer Group Study Number 4
Stromal tumour of uncertain malignant potential
Tumor-Node-Metastasis-stage
Transrectal ultrasound
Transurethral resection of prostate
World Health Organization
Watchful waiting
8 2.
LIST OF ORIGINAL PUBLICATIONS
This dissertation is based on the following original publications, which are
referred to in the text by their Roman numerals:
I.
Roderick C.N. van den Bergh, Hanna Vasarainen, Henk G. Van der Poel,
Jenneke J. Vis-Maters, John B. Rietbergen, Tom Pickles, Erik B. Cornel,
Riccardo Valdagni, Joris J. Jaspars, John van der Hoeven, Frederic Staerman,
Eric H.G.M. Oomens, Antti Rannikko, Stijn Roemeling, Ewout W.
Steyerberg, Monique J. Roobol, Fritz H. Schröder and Chris H. Bangma:
Short-term outcomes of the prospective multicentre ‘Prostate Cancer
Research International: Active Surveillance study’. BJU Int 2009; 105:956962.
II.
Hanna Vasarainen, Utku Lokman, Mirja Ruutu, Kimmo Taari and Antti
Rannikko: Prostate cancer active surveillance and health-related quality of
life: results of the Finnish arm of the prospective trial. BJU Int 2011;
109:1614-1619.
III.
Hanna Vasarainen, Hanna Malmi, Liisa Määttänen, Mirja Ruutu, Teuvo
Tammela, Kimmo Taari, Antti Rannikko and Anssi Auvinen: Effects of
prostate cancer screening on health-related quality of life: Results of the
Finnish arm of the European randomized screening trial (ERSPC). Acta
Oncol 2013; 52:1615-21.
IV.
Hanna Vasarainen, Kanerva Lahdensuo, Ritja Savolainen, Mirja Ruutu,
Kimmo Taari and Antti Rannikko: Diffusion-weighted magnetic resonance
imaging in prostate cancer patients on active surveillance one year after
diagnosis and before repeat biopsy. Scand J Urol 2013; 47:456-61.
V.
Hanna Vasarainen, Jolanda Salman, Heidi Salminen, Riccardo Valdagni,
Tom Pickles, Chris Bangma, Monique Roobol and Antti Rannikko:
Predicting adverse rebiopsy findings, deferred treatment and radical
prostatectomy findings with %fPSA in men on a prospective active
surveillance program (PRIAS). Submitted.
9 3.
ABSTRACT
Prostate cancer (PC) is a significant health problem worldwide. It is the second most
frequently diagnosed cancer and the sixth leading cause of cancer death among men.
The wide use of prostate-specific antigen (PSA) has led to increased detection of
PCs in its early stages. Active surveillance (AS) has emerged as an alternative
management option to that of immediate radical treatments of these potentially
overdiagnosed PCs. The aim of AS is to avoid or at least delay the side effects of
immediate treatments.
The objective of this study was to evaluate the feasibility of AS as a
management option for low-risk PC and determine how AS affects the quality of life
(QOL) of low-risk PC patients. The more specific aims of the present study were to
evaluate the short-term outcomes of the prospective AS cohort, analyse the effects of
AS on the QOL during screening and AS overall, assess the respective roles of
diffusion-weighted magnetic resonance imaging (DW-MRI) and a free/total PSA
ratio as diagnostic and prognostic tools in AS.
The PRIAS (Prostate cancer Research International: Active Surveillance)
study is an international prospective AS trial that originates from the European
Randomized Study of Screening for Prostate Cancer (ERSPC). ERSPC is a
multicenter, population-based and randomized screening trial that is being conducted
in eight European countries. In study I, the outcomes of the 500 first PRIAS patients
were analysed, the main outcome parameter was active treatment-free survival.
Secondary endpoints included reasons for discontinuing AS, findings in the standard
1-year rebiopsies, and outcomes after radical prostatectomy. For the health-related
quality of life (HRQL) analyses, the Finnish version of the RAND 36-Item Health
Survey was used in both QOL studies. In addition, participants also received IPSS
and IIEF-5 questionnaires in study II to analyse possible voiding symptoms and
erectile function. In study III, RAND-36 QOL questionnaires were delivered to a
total of more than 2000 screening participants of the Finnish arm of the ERSPC trial
in five phases of the first screening round. In study IV, 80 men who had enrolled in
the Finnish arm of the PRIAS study underwent DW-MRI before standard 1-year
rebiopsy. In study V, the global PRIAS study cohort was used with the initial free
PSA value available in 939 patients to assess the role of free/total PSA ratio
(%fPSA) as a prognostic tool in AS.
Strict AS criteria of the PRIAS protocol resulted in a quarter of the patients
stopping surveillance within two years after PC diagnosis. The main reason for
discontinuation was adverse findings in the standard 1-year rebiopsy. Biopsy results
were independent of the PSA-doubling time (PSADT). AS did not provoke major
short-term QOL changes as assessed by standardized questionnaires and none of the
patients on AS discontinued due to anxiety or distress. The HRQL of study patients
was even better than that for the general age-stratified Finnish male population.
Moreover, the PC screening did not have substantial effects on the short-term QOL
of participants. This study population also had similar or slightly higher HRQL
scores compared to the reference values obtained from the age-stratified general
Finnish male population. DW-MRI, as interpreted in a routine clinical setting and
performed in this study, could not predict treatment change or adverse rebiopsy or
radical prostatectomy findings. PCs were small and rather well-differentiated,
making it challenging to visualize these tumours using MRI. Free/total PSA ratio
10 (%fPSA) at diagnosis could not predict outcomes of AS, although median %fPSA
values were significantly lower in patients with treatment change after one year of
surveillance. However, %fPSA kinetics may predict future treatments.
AS is a feasible management option for patients with low-risk PC. Shortterm analyses revealed that a quarter of men discontinue AS, mainly because of
reclassification of PC in standard rebiopsy, which highlights the importance of
accurate diagnostics. Neither screening nor AS seemed to provoke short-term
disturbances in QOL in the PC continuum. Small low-grade PCs are a challenge for
non-spezialized radiologists to visualize accurately by DW-MRI. Change of %fPSA
over time may have a value as a prognostic tool in AS.
11 4.
INTRODUCTION
Prostate cancer (PC) is currently the most common malignancy in males in Finland
and other Western countries (Jemal et al. 2011; Pukkala and Rautalahti 2013). The
number of new cases reported has increased dramatically in recent years, which is
mainly due to active and widespread use of prostate-specific antigen (PSA) in the
diagnosis of PC. It has been estimated that up to half of all PCs, detected by PSA
testing are clinically insignificant, which indicates that even if PC was not
diagnosed, these tumours would not cause any symptoms during the men’s lifetimes
(Draisma et al. 2003). The detection of clinically insignificant cancers leads to
substantial overdiagnosis of PCs and overtreatment of patients. Overtreated patients
are unnecessarily exposed to the side effects of radical treatments that provide no
survival benefit but which may have an unfavourable effect on quality of life (QOL).
Active surveillance (AS) has emerged as an alternative strategy for managing these
potentially overdiagnosed PCs. The idea of AS is to initially withhold radical
treatments (i.e. surgery or radiation therapy), but reserve the opportunity for deferred
treatment with curative intent in the case of disease progression or reclassification
during follow-up.
AS takes advantage of the long natural history of PC and the good prognosis
associated with localized low-grade disease. AS strategy is based on defined triggers
to detect and predict higher risk PC in patients during follow-up. Currently
diagnostic PSA, Gleason score at prostate biopsy and Tumor-Node-Metastasis-stage
(TNM-stage) have been widely studied and they have established their position as
significant prognostic factors for PC. During follow-up, patients are closely
monitored using tools such as PSA, clinical examinations such as digital rectal
examination (DRE) and prostate rebiopsies, and when any signs of disease
progression occur, deferred radical treatment is given (Parker et al. 2004).
Hitherto, data related to AS are scarce and outcome of long-term follow-up is
lacking. In addition, prospective and randomized trials, in which AS is compared
with immediate radical treatment have not been published. The present research
project investigates the feasibility of AS as a management option for low-risk PC
within the framework of the PRIAS (Prostate cancer Research International: Active
Surveillance) study (van den Bergh et al. 2007). The PRIAS- trial is an international
prospective AS- trial that originates from the European Randomized Study of
Screening for Prostate Cancer (ERSPC) (Schröder et al. 2003). The PRIAS study
was initiated in 2006 in the Erasmus University Medical Center in the Netherlands
and it is still ongoing. PRIAS is currently the largest prospective AS study in
existence. The study design of this prospective cohort study does not include
randomization, since the differences in survival benefits between immediate radical
treatments and AS would probably appear minor and a large patient cohort in
addition to long follow-up would be needed, thus making such a study difficult to
conduct.
The objectives for study of this thesis were to investigate the feasibility of
AS as an expectant management strategy for low-risk PC and to analyse outcomes of
follow-up on short-term after PC diagnosis. The specific aim was also to analyse the
QOL during the screening and the subsequent AS after the diagnosis of low-risk PC.
One of the main challenges to using the AS approach is to find those cancers that
12 progress and offer these patients a curative treatment in time. A substantial part of
this thesis was to clarify the role of magnetic-resonance imaging (MRI) and
free/total PSA ratio (%fPSA) as possible additional prognostic tools for AS.
13 5.
REVIEW OF LITERATURE
5.1
The Prostate
The prostate is a walnut-sized exocrine gland and a part of the male reproductive
system. It is located in the pelvis, just below the bladder, anterior to the rectum and
it surrounds the proximal urethra. The prostate can be divided into central, peripheral
and transition zones (Fig.1). The transition zone is the common area for benign
prostatic hyperplasia and a peripheral zone for PC. Approximately two thirds of the
prostate consist of glandular tissue and one third of fibromuscular tissue. The main
function of this gland is the excretion of fluid that forms one-fifth the volume of the
semen ejaculate. This prostatic fluid helps to carry and nourish the sperm. The
smooth muscles of the prostate have an essential role in controlling the flow of
semen during ejaculation. PC is a malignant disease of the prostate, but several
benign conditions, such as benign prostatic hyperplasia and prostatitis commonly
and coincidently occur in the prostate (Campbell-Walsh Urology 2007).
CROSS SECTION
Urethra
Central Zone
Ejaculatory ducts
Seminal vesicles
Fibromuscular stroma
SAGITAL VIEW
Peripheral Zone
Proximal urethra
Transition Zone
Distal urethra
Ejaculatory ducts
Figure 1. The prostate gland divided into zones.
14 5.2
Epidemiology
Prostate cancer (PC) is a significant health problem worldwide. PC is the second
most frequently diagnosed cancer and the sixth leading cause of cancer death among
men worldwide with an estimated 903 500 new diagnoses and 258 400 deaths in
2008, this represents 14% of all new cancer cases and 6% of all cancer deaths in
males (Jemal et al. 2011). The incidence rates of PC vary by more than 25-fold
worldwide. Elderly men are more often affected by PC, which makes the disease a
considerable health problem in developed countries. Thus, the highest estimated PC
incidence rates (age standardized rate per 100 000, in 2008) are observed in the
highest resourced areas of the world, in North America (85.6), Australia/New
Zealand (104.2), Western Europe (93.1), Northern Europe (73.1), and the lowest in
South-Central Asia (4.1). 72% of the PC cases and 53% of the PC deaths occur in
developed countries (all regions of Europe, North America, Australia/New Zealand,
and Japan), which have <20% of the world population (Center et al. 2012).
However, the highest estimated PC mortality rates are seen elsewhere, primarily in
the Islands of the Caribbean (26.3/100 000), and in Southern Africa (19.3/100 000).
The lowest mortality rates are found in Eastern Asia (2.5/100 000) (Ferlay et al.
2010).
Between the mid-1980s and early 1990s, after the introduction of the PSA test,
PC incidence rates increased in many high-income countries (Potosky et al. 1995;
Etzioni et al. 2002; Baade et al. 2009; Bray et al. 2010). Although there is still no
clear declining incidence trends in sight, most of the registries in developed
countries have shown signs of a stabilization (Center et al. 2012). In contrast to the
increasing incidence of PC, the PC mortality rates have decreased in many highincome areas (North America, Oceania, Northern and Western Europe)(Center et al.
2012). In the United States this decrease has been particularly noticeable and over
the last decade the mortality rates have decreased by as much as 4.3% (9.9/100 000)
in 2008 (Jemal et al. 2010). There are several reasons for the declining mortality
rates, but the main factors are early and increased detection rates of PC, in
combination with advances and changes in treatments (Collin et al. 2008; Etzioni et
al. 2008).
In Finland, PC has been the most common cancer diagnosed among males since
1993 with 4715 new diagnoses (31.4% of all new cancer cases) in 2011 (Fig.2a)
(Pukkala and Rautalahti 2013). Since the middle of the 1980s PC has been the
second leading cause of cancer death with 882 deaths attributed to PC (14.4% of all
cancer deaths) in 2011 (Fig.2b) (Pukkala and Rautalahti 2013). The incidence of PC
has remained stable in Finland during the most recent years, but mortality has
decreased by 3.1% per year since 2000 (Center et al. 2012).
15 (a)
(b)
Figure 2. Cancer incidence (a) and mortality trends (b) including PC (with prediction) among Finnish males
(Finnish Cancer registry) (Pukkala and Rautalahti 2013) (Copyright permission 7.1.2014).
16 5.3
Risk factors
At present, three well-established risk factors for developing clinical PC have been
identified. First, older age is a significant risk factor. In post-mortem studies a
microscopic foci of PC was found in 15-29% of men aged 30-40 years. By the age of
70, a histological PC was identified in 60% of men and this rose to 80% who had
some form of PC by the age of 80 (Sakr et al. 1993; Sakr et al. 1994). Second,
ethnicity is a well-established risk factor for PC. For example, in the United States
African Americans have a higher PC incidence rate than the white population. The
results from Surveillance, Epidemiology, and End Results (SEER) program showed,
that age-adjusted PC incidence between 2002 and 2006 for the white population was
153.0/100 000 as compared to 239.8/100 000 for the African American population
(Horner et al. 2009). Third, heredity is also an established risk factor for PC. Men
with an affected first-line relative (i.e. father or brother) have at least a doubled risk
for PC (Steinberg et al. 1990). If two or more first-line relatives have this disease,
the risk increases approximately 5 to 11 -fold (Bratt 2002; Hemminki 2012; Jansson
et al. 2012). It has been estimated that in about 9% of men with PC, the disease has a
true hereditary background with a strong genetic component. The definition of
‘hereditary PC’ includes the criteria that three or more relatives are affected or at
least two relatives have early-onset PC before 55 years of age (Hemminki 2012).
There also exists a wide range of additional and exogenous factors, such as alcohol
and food consumption, chronic inflammation, pattern of sexual behaviour, ultraviolet
radiation exposure, that may be potential risk factors for PC, but have not produced
definitive evidence of the association (Gronberg 2003; Schmid et al. 2007).
5.4
Classification
5.4.1 Histology
Prostatic adenocarcinoma is the most common malignancy in the prostate and it
comprises over 90% of cases (Bostwick 1989). Although the majority of PCs are
typical acinar adenocarcinomas, between 5-10% can be considered as variants
(Grignon 2004; Mazzucchelli et al. 2008), i.e. mucinous adenocarcinoma, ductal
adenocarcinoma and intraductal carcinoma. There are also several other primary and
secondary tumours that may involve the prostate, but they are rare. Other primary
tumour types, from the epithelial origin, are small cell carcinoma, basal cell
carcinoma, urothelial carcinoma and mucin-producing urothelial type
adenocarcinoma. Tumour types of mesenchymal origin are prostatic stromal tumours
of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (Osunkoya
2012). Other variants of prostatic adenocarcinoma include pseudohyperplastic
adenocarcinoma, adenosquamous carcinoma, atrophic adenocarcinoma, foamy gland
adenocarcinoma, adenocarcinoma with carcinoid-like morphology, adenocarcinoma
with Paneth-like neuroendocrine differentiation, adenocarcinoma with sarcomatoid
differentiation, signet ring cell adenocarcinoma and adenocarcinoma with
neuroendocrine differentiation. Neuroendocrine differentiation in PC tumour has
17 been reported to follow androgen deprivation therapy and it has been hypothesized
to be involved in the progression to castrate-resistant and metastatic PC (Alberti
2010). The treatment of unusual variants of PCs may be challenging as some of
these subtypes can behave aggressively and do not respond to conventional
therapies, such as hormonal therapy (Osunkoya 2012).
The most common secondary malignancy that involves the prostate through
direct extension is that of the urinary bladder. In radical cystoprostatectomy series
the incidence of prostatic involvement with urothelial carcinoma of the bladder is
reported to be 12-48% (Schellhammer et al. 1977; Revelo et al. 2004). From other
sites, the metastases to the prostate typically arise from the lung, gastrointestinal
tract, kidney, skin, testicle or endocine organs. The incidence of secondary tumours
in the prostate is 0.1-6.0% (Johnson et al. 1974; Zein et al. 1985; Bates et al. 2002).
High-grade prostatic intraepithelial neoplasia (HGPIN) is presumed to be a
premalignant lesion for PC. This is based on its common presence adjacent to PCs.
HGPIN is defined as architecturally benign prostatic ducts and acini lined by
atypical or dysplastic epithelial cells. In the prostate biopsy the expected incidence
of HGPIN is 5-8% and the median risk for PC following HGPIN on needle biopsy is
estimated to be 24% (Epstein et al. 2006).
5.4.2 Grading, Gleason score
The current standard for histological grading of prostatic adenocarcinoma is based
on the Gleason score system (Gleason 1966). It replaced the previously widely used
World Health Organisation (WHO) differentiation grading system that is still
generally used for grading other malignant tumors. The Gleason grading system is
based on the pattern of tumour growth, not just single nuclei or cells. The Gleason
grade ranges from 1 (the least aggressive) to 5 (the most aggressive). The Gleason
score that consists of two summed grade patterns, ranges from 2-10. The Gleason
grading system was updated by the International Society of Urologic Pathology
(ISUP) consensus conference held in 2005. According to the current standard for
Gleason grading, the most extensive and the highest grade should be incorporated
into Gleason score in prostate biopsy, not the two most common patterns as in the
earlier version (Epstein et al. 2005). In radical prostatectomy (RP) specimens the
most and the second most common Gleason grade should be reported in addition to
the presence and proportion of the tertiary grade (Epstein et al. 2005). Two wellknown problems related to the Gleason grading are the tendency for upgrading from
prostate biopsy to the RP specimen and interobserver variability (Iczkowski and
Lucia 2011).
The Gleason score is currently the most important prognostic factor for PC
(Epstein 2010). A variety of different nomograms and prediction models have been
created to be able to predict more accurately the status and prognosis of disease. In
case of PC, Kattan nomograms and Partin tables can be considered the most
commonly known nomograms and with PSA value, clinical stage and Gleason score
of the tumour, it is possible to predict the presence of an indolent cancer (Kattan et
al. 2003) or draw up the risk classification of the progression of PC (Partin et al.
2001).
18 5.4.3 Staging, TNM classification
The extent of PC is commonly classified by the TNM -staging system. Table 1
presents the 2009 TNM classification (Sobin et al. 2009). Clinical TNM (cTNM)
stage is estimated at the time of diagnosis and pathological TNM (pTNM) stage can
be issued only after surgical treatment as tissue samples are required for pTNM
staging. The definition of clinical T stage is currently based on DRE and transrectal
ultrasound (TRUS). Positron emission tomography/computed tomography
(PET/CT), MRI and novel TRUS techniques are not routine practice in PC staging
(Turkbey et al. 2009). Accurate staging is essential for prognosis assessment. In
addition, treatment selection differs for localized (T1-T2N0M0), locally advanced
(T3-4, NX-N0, MX-M0) and metastasized (T1-4, N1 or M1) PCs.
Table 1. TNM classification of PC (version 2009) (Sobin et al. 2009).
T - Primary tumor
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Clinically inapparent tumor not palpable or visible by imaging
T2
T3
T4
T1a
Tumor incidental histologic finding in 5% or less of resected tissue
T1b
Tumor incidental histologic finding in more than 5% of resected tissue
T1c
Tumor identified by needle biopsy
Tumor confined within the prostate
T2a
Tumor involves one-half of one lobe or less
T2b
Tumor involves more than one-half of one lobe but not both lobes
T2c
Tumor involves both lobes
Tumor extends through the prostatic capsule
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumor invading seminal vesicle(s)
Tumor is fixed or invades adjacent structures other than seminal vesicles
(e.g., external sphincter, levator muscles, rectum, and/or pelvic wall)
N – Regional lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M – Distant metastasis
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
M1a
Non-regional lymph node(s)
M1b
Bone(s)
M1c
Other site(s) with or without bone disease
19 5.5
Diagnosis
The most commonly used modalities in the diagnostics of PC are a measurement of
serum PSA, DRE, and TRUS -guided biopsies (Heidenreich et al. 2013).
5.5.1 Prostate-specific antigen and other markers
PSA was characterized in 1970s (Ablin et al. 1970; Wang et al. 1979) and after mid1980s it became available for clinical use as an important tumour marker and
potential screening tool for the detection of PC (Stamey et al. 1987; Catalona et al.
1991). PSA is a kallikrein-like serine protease that liquefies semen and is secreted by
the epithelial cells of the prostate. A higher level of PSA indicates a higher risk for
PC (Schröder et al. 2008). PSA is an organ-specific and not a cancer-specific tumour
marker, also other conditions such as benign prostatic hyperplasia (BPH), prostatitis,
ejaculation, urinary retention, prostate biopsy, and transurethral resection of prostate
(TURP) may elevate the levels of serum PSA at least temporarily (Dalton 1989;
Brawn et al. 1991; Neal et al. 1992; Yuan et al. 1992; Oesterling et al. 1993b; Nadler
et al. 1995; Herschman et al. 1997; McNeill and Hargreave 2000).
Although PSA concentration is a continuous variable, a cut-off point of 4
ng/ml was originally considered to be the upper limit for a normal PSA value
(specificity 59% and sensitivity 79%) (Catalona et al. 1991). Currently, a PSA value
of 3 or 3.1 microg/l should be considered for World Health Organization (WHO)calibrated assays in order to have the same sensitivity/specificity (Stephan et al.
2009). The positive predictive value of PSA values for PC > 4.0 ng/ml has been
estimated to be 32% (Catalona et al. 1994). The results from the Prostate Cancer
Prevention Trial (PCPT), suggest a cut-off point of 4.0 ng/ml, whereby up to 15% of
PCs may be left undetected. Notably, 15% of these PCs were graded as Gleason 7 or
higher (Thompson et al. 2004). Age-adjusted reference values have been proposed
instead of a single PSA cut-off value. These age-adjusted values take into account
the increase in PSA due to BPH with advancing age (Oesterling et al. 1993a).
The percentage of free PSA (%fPSA) in serum is calculated as the free to
total PSA ratio, which has been shown to improve the specificity of PSA testing in
PC detection conditions and low free PSA percentage is associated with a higher risk
of PC (Catalona et al. 1995; Luderer et al. 1995; Chen et al. 1996; Elgamal et al.
1996; Partin et al. 1996; Van Cangh et al. 1996; Catalona et al. 1998). Generally, the
free to total PSA ratio has been considered an especially useful marker in patients
with a total PSA concentration range between 2.1-10 ng/ml (Kobori et al. 2008). A
number of derivatives of serum PSA value, such as PSA density (PSAD) (Benson et
al. 1992), PSA doubling time (PSADT) (Schmid et al. 1993) and PSA velocity
(PSAV) (Carter et al. 1992) have been considered to improve the diagnostic
accuracy of PSA testing and to enhance early detection of PC. Previous prospective
studies indicate that the use of these in everyday clinical practice has not been
demonstrated to be superior compared to the use of serum total PSA value alone
(O'Brien et al. 2009; Vickers et al. 2009; Heidenreich et al. 2013).
Messenger RNA (mRNA) of the PC antigen 3 (PCA3) gene is found to be
overexpressed in >95% of primary PC cells (Bussemakers et al. 1999). PCA3 is
therefore used as a biomarker and is measured in urine sediment after prostatic
massage. It has been suggested to be marker independent of the serum PSA level,
20 prior prostate biopsy or prostate volume (Deras et al. 2008). PCA3 has shown
potential as an adjunct marker in PC diagnostics, but due to its lack of sensitivity it
cannot replace the PSA test in clinical practice and its value as a first-line diagnostic
test is indefinitely limited (Roobol 2011). The PCA3 score may be combined with
the serum PSA value and other clinical risk factors into a nomogram, that may be
used in decision-making concerning biopsy/rebiopsy (Auprich et al. 2011).
5.5.2 Digital rectal examination
Before the PSA era, DRE was practically the main method for detection of PC
(Gerber et al. 1993; Kavasmaa et al. 2013). Approximately every fifth PC (18%) is
detected by a suspicious DRE finding alone, regardless of the PSA value (Carvalhal
et al. 1999). DRE is not very specific, since only 40-50% of cases with abnormal
DRE findings have PC on biopsy (Philip et al. 2005). The risk of PC is higher in
cases of an abnormal DRE finding, and especially when combined with an increased
serum PSA value (Carvalhal et al. 1999; Gosselaar et al. 2008a). An abnormal DRE
finding is also associated with high-grade PCs (Okotie et al. 2007).
5.5.3 Transrectal ultrasound and prostate biopsies
TRUS is the most common imaging method to examine the prostate. Abnormal areas
in TRUS have been associated with PC (Dahnert et al. 1986; Lee et al. 1986;
Gosselaar et al. 2008b). The classic finding of PC on gray-scale ultrasound is
described as a hypoechoic lesion, but cancer foci may also be visualized as being
isoechoic or even hyperechoic (Muldoon and Resnick 1989; Flanigan et al. 1994;
Tzai et al. 1995). It has been estimated that over 40% of PC lesions are isoechoic and
approximately 5% appear as hyperechoic (Ellis and Brawer 1994). Sensitivity and
specificity for conventional gray-scale TRUS are 39-75% and 40-82%, respectively
(Heijmink et al. 2011). Standard TRUS technique has a limited role in detecting or
staging early PC (Onur et al. 2004), because of particularly low accuracy (52-62%)
(Heijmink et al. 2011). Many PCs are not visible on standard TRUS and the positive
predictive value of hypoechoid lesions is only in the 25-30% range (Rifkin et al.
1990). Colour Doppler scanning combined with TRUS can improve the detection of
PC (Rifkin et al. 1993). Some new ultrasound techniques have also been developed
to improve the detection of PC. These innovative techniques, such as ultrasound with
contrast agents, 3-D and 4-D sonography and elastography have shown promising
results compared with standard TRUS in PC diagnosis (Balaji et al. 2002; Halpern et
al. 2005; Miyanaga et al. 2006; Yi et al. 2006; Abul et al. 2007).
TRUS-guided prostate biopsy is the standard method for histopathological
diagnosis of PC (Hara et al. 2008; Takenaka et al. 2008). The basic sextant biopsy
protocol was introduced in the late 1980s to enhance the accuracy of PC diagnosis
(Hodge et al. 1989). The PC detection rates can be improved by increasing the
number of targeted regions and biopsy cores (Eskew et al. 1997; Babaian et al. 2000;
21 Ravery et al. 2000; Emiliozzi et al. 2004; Eskicorapci et al. 2004). Moreover, the
extended biopsy scheme with 12 biopsy cores has replaced the sextant biopsy
protocol. Despite increasing the number of cores, the risk of adverse events (i.e.
bleeding, infection, voiding dysfunction, pain) is not increased (Eichler et al. 2006).
A 12-core systematic prostate biopsy scheme, that includes apical and far-lateral
core sampling in a template distribution, has been shown to be a compromise
between maximal detection of PCs, whilst avoiding rebiopsies and it provides
sufficient information about the disease (Bjurlin et al. 2013). Taking more than 12
biopsy cores does not seem to increase the benefit substantially (Eichler et al. 2006),
but in selected cases it may be reasonable to increase the number of biopsy cores.
Typically, saturation biopsies (i.e. template with ≥20 and transition zone included)
are considered, when prostate biopsies are repeatedly negative, but when there is still
a high suspicion of PC (Scattoni et al. 2010). In selected cases saturation biopsy can
be performed with transperineal approach to improve the detection of PC (Moran et
al. 2006).
5.5.4 Imaging
CT and MRI have generally been considered to have a limited role in detecting and
staging PC. Despite high specificity (>80%), CT has low sensitivity (<30%) in the
local staging of PC (Tarcan et al. 1996; Yu and Hricak 2000) and a minor role in
terms of detection and staging PC (Platt et al. 1987; Hricak et al. 2007). The MRI
allows a functional assessment with modalities such as diffusion-weighted MRI
(DWI-MRI), magnetic resonance spectroscopy imaging (MRSI), dynamic contrastenhanced MRI (DCE-MRI) and these MRI techniques can be used for the detection
and staging of PC (Ravizzini et al. 2009). The sensitivity and specificity of PC
detection and local staging with MRI vary considerably with the population and the
technique used (Turkbey et al. 2009). Indefinitely, PET scanning does not play a
significant role in the detection or localization of PC due to its invasive nature, high
costs and availability of other imaging modalities such as MRI (Heijmink et al.
2011). However, if TRUS-guided biopsies and MRI are negative, PET scanning can
be used and it may provide additional advantages especially when combined with
other imaging modalities, such as MRI (Heijmink et al. 2011). CT and MRI are
currently the main imaging modalities commonly used for staging nodal PC,
although they have similar, equally low sensitivity for evaluation of lymph node
metastases (Hovels et al. 2008). Radionuclide bone scan (scintigraphy) after a
technetium-99m injection is the current standard method for investigating potential
bone metastasis in high-risk PC patients. The guidelines of The European
Association of Urology (EAU) have recommended bone scanning in those cases of
poorly differentiated PC (Gleason score >7) and locally advanced disease (≥cT3),
irrespective of the serum PSA level. For patients with a PSA value <20 ng/ml bone
scanning is recommended in the presence of symptoms or poorly differentiated
tumour (Heidenreich et al. 2008). Despite the high sensitivity of scintigraphy, it
suffers from a lack of specificity, and therefore other imaging modalities, such as
18
F-choline PET/CT are under active evaluation (Even-Sapir et al. 2004; Jadvar
2013).
22 5.6
Prostate cancer screening
The objective of PC screening is to reduce overall and PC-specific mortality and to
improve men´s QOL by preventing locally advanced and metastatic disease (Baum
2013). Elevated PSA is the most important diagnostic tool of PC in early detection
programmes although other diagnostic measures, such as DRE have been used.
Currently, there is no general consensus about recommended population-based
screening for all men to detect early PCs (Ilic et al. 2011).
Two major randomized controlled studies are ongoing that evaluate
population-based PC screening. The European Randomized Study of Screening for
Prostate Cancer (ERSPC) (Schröder et al. 2003; Schröder et al. 2009) and the
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (Andriole et
al. 2009) have the capacity to evaluate better the efficacy of PC screening. Both
ERSPC and PLCO trials were initiated in the early 1990´s. ERSPC is a multicenter
trial conducted in eight European countries. In practice, ERSPC consists of several
smaller screening trials each of which has its own criteria for the age of participants,
screening intervals, threshold for a positive screening result and type of recruitment.
In general, the ERSPC trial included a total of 162 243 men aged 55-69 years and
they were randomized to the PSA screening group (offered PSA measurement about
once every 4 years) or to unscreened control group (Schröder et al. 2009). The
PLCO was initiated in the USA and has more congruent criteria. The PLCO
randomized 76 693 men to receive annual screening with PSA and DRE or standard
care as the control (Andriole et al. 2009). The main end-point of these two major
studies is PC-specific mortality, but in addition, QOL and cost-effectiveness are also
analyzed.
Both ERSPC and PLCO reported their interim data in 2009. The ERSPC trial
showed a significant reduction of 20% in PC mortality in the screening group after a
median follow-up of nine years (Schröder et al. 2009). After adjustment for
contamination (i.e. control group participants who sought opportunistic PSA
screening) and noncompliance (i.e. men in the screening group who did not
participate in the screening), the mortality reduction was shown to be up to 31%
(Roobol et al. 2009). The cumulative incidence of PC was 8.2% in the screening
group and 4.8% in the control group. The results showed the absolute risk difference
to be 0.71 death per 1000 men, that is 1410 men would have to be screened and 48
additional PC cases would have to be treated to prevent one death from PC
(Schröder et al. 2009). Moreover, the updated analysis after a median follow-up of
11 years showed a decrease in both of these numbers; based on recent results, 1055
would have to be screened and 37 treated to prevent one PC death. The relative risk
reduction for PC-specific death was shown to be 21% in favour of PC screening
(Schröder et al. 2012).
The Swedish part of the ERSPC, the Göteborg screening trial, published the
mortality results separately (Hugosson et al. 2010). This trial was initiated in 1994 as
an independent study, but joined the ERSPC soon after. With a follow-up of 14
years, the study detected a mortality reduction of 44% in the screening arm,
accompanied by a significant risk of over-diagnosis. The differences compared to the
ERSPC and also the probable reasons for different results are longer follow-up,
younger age at screening, shorter screening interval (2 years) and lower PSA
threshold (3.0 ng/ml).
23 The PLCO trial did not find a PC mortality benefit in the screening arm. This result
has been explained by contamination of the control arm. The contamination was
extensive in the control arm since over a third of participants had undergone PSA
testing and DRE within the first year of the study and half of the participants had
PSA testing during the trial (Andriole et al. 2009).
The results of the ERSPC and the PLCO trials, as evaluated by the major
urological societies indicated that widespread population-based mass screening for
PC is not recommended at present. The EAU recommends early detection of PC (i.e.
opportunistic screening) in well-informed men instead of mass screening. A baseline
PSA level should be determined at the age of 40 and screening intervals should be
adapted to this baseline PSA serum concentration thereafter. An interval of 8 years
might be appropriate for screening in men with baseline levels of ≤ 1 ng/ml. PSA
testing is not recommended in men > 75 years as early detection of PC would not
have any impact clinically (Heidenreich et al. 2013). The American Urological
Association (AUA) do not recommend PSA screening for the following categories:
men < 40 years, men 40-54 years of age at average risk, men > 70 years of age or
life expectancy less than 10-15 years. They recommend shared decision making for
men 55-69 years of age and a screening interval of ≥ 2 years (Carter et al. 2013).
5.6.1 QOL aspects related to the PSA screening process
PC screening has been shown to reduce PC-related mortality and the rate of
advanced disease. Reduction in mortality from PC is the primary endpoint in the
screening trials, but QOL is also a major aspect, and often expressed as quality-oflife adjusted gain in life years (QALYs). The problem of overdiagnosis related to
screening has already been emphasized (Djulbegovic et al. 2010; Ilic et al. 2011).
However, more confirmed data from randomized trials is needed as reports about the
benefits and harmful effects of PSA screening have varied widely and are rather
inconsistent (Ilic et al. 2007; Crawford and Abrahamsson 2008). Recently, data from
the ERSPC trial concluded that the benefit of PSA screening was diminished by the
loss of QALYs owing to post diagnosis long-term effects. Before more general
recommendations regarding PSA screening can be made, data from longer-term
follow-up, data on long-term effects of PC treatments, and AS data on QOL are also
needed (Heijnsdijk et al. 2012).
Previous studies have shown that PSA screening participants do not
experience any significant increases in anxiety levels, even with an abnormal PSA
result (Essink-Bot et al. 1998; Brindle et al. 2006). The screening process does not
seem to affect substantially the health status of individuals in the short-term; the
exception to this is the short-lasting side effects of having a prostate biopsy (EssinkBot et al. 1998). In addition, only men who have a tendency to anxiety have
experienced higher levels of anxiety and distress during the screening process
(Essink-Bot et al. 1998). In general, men seem to cope well through the PSA
screening process, although a minority of participants experience distress at the time
of prostate biopsy, which is not entirely resolved even by a negative screening result
(Macefield et al. 2010). Screening for disease does not appear to have long-term
negative emotional impact on participants (Collins et al. 2011) and the screening
process itself has only little if any effect on participant´s psychological health
(Awsare et al. 2008; Macefield et al. 2010).
24 5.7
Treatment options with curative intent
At present there are various treatment options available for PC, depending on the
clinical stage of the disease. The options for localized PC with curative intent are
AS, radical prostatectomy (RP), external beam radiotherapy (EBRT), brachytherapy
(BT) and focal therapy. AS is hereafter discussed in the review as a separate entity.
Currently the lack of randomized controlled trials makes the comparison of
treatment modalities difficult.
5.7.1 Radical prostatectomy
RP is a surgical procedure to remove the prostate gland. Open retropubic RP has
been the most commonly used technique, but recently robot-assisted radical
prostatectomy (RARP) has become a commonly used option for open surgery
(Novara et al. 2012b). Patients with a life expectancy of over 10 years and local
disease are generally considered suitable, and the goal for RP is the eradication of
PC while saving urinary continence and potency if possible (Bianco et al. 2005).
Data from the Cancer of the Prostate Strategic Urological Research Endeavor
(CaPSURE) database has showed that RP is at present the most common treatment
in men with localized PC and approximately half of these patients undergo RP
procedure in the US (Cooperberg et al. 2010). A carefully selected patient population
with high-risk and more advanced PC (PSA>20 ng/ml with clinical stage T3 and/or
Gleason score 8-10 in biopsy) may also benefit from RP (Spahn et al. 2010; Gontero
et al. 2011).
Two prospective randomized trials reported a PC-specific survival benefit
from RP compared with watchful waiting (WW). The Scandinavian Prostate Cancer
Group Study Number 4 (SPCG-4) reported that compared to WW a reduction in the
rate of death from PC, and at 15 years the absolute risk reduction was 6.1%
following randomization to RP (Holmberg et al. 2012). The subanalysis of this study
clarified, that individual prediction of benefit of RP varies widely depending on age
and PC characteristics. The absolute 10-year PC mortality reduction in the RP group
was 4.5% for low-risk versus 17.2% for high-risk patients, in men at 65 years of age
(Vickers et al. 2012). The other randomized trial, the Prostate Cancer Intervention
Versus Observation Trial (PIVOT) showed a benefit attributable to RP in men < 65
years of age, but only in those who had only an intermediate or high risk of PC
progression (Wilt et al. 2012).
It would be more acceptable to treat all PC patients when radical treatment
did not cause any side effects or decrease QOL. Nevertheless, each treatment
modality for localized PC has side effects, even in the long-term after treatment
(Sanda et al. 2008; Litwin et al. 1995; Mols et al. 2009). The improvement in
surgical techniques including the introduction of RARP, have resulted in advantages
in postoperative recovery and functional outcomes (Novara et al. 2012b; Novara et
al. 2012a; Ficarra et al. 2012a; Ficarra et al. 2012b). However, urinary incontinence
and erectile dysfunction remain significant parts of the side effect profile of RP. The
rates of urinary incontinence and erectile dysfunction after surgery vary widely
between published reports. Approximately 8% of men that have undergone RP, have
persisting urinary incontinence a year after the operation (Murphy et al. 1994).
25 Nerve-sparing techniques can be considered in a patient with organ-confined disease
and reported potency rates after bilateral nervesparing RP varied between 31 and
86% (Dubbelman et al. 2006).
5.7.2 External beam radiation therapy
EBRT is one of the primary treatment modalities for patients with localized or
locally advanced PC. It is also commonly used in cases that suggest a greater
likelihood of non-organ-confined disease. Radiotherapy continues to be an important
and valid alternative to surgery as a radical treatment for PC. In EBRT, radiation is
delivered to the prostate gland via an external energy source. Three-dimensional
conformal radiation therapy (3D-CRT) has been the gold standard for EBRT in
many countries, and if possible, intensity-modulated external-beam radiotherapy
(IMRT), with or without image-guided radiotherapy (IGRT), is currently
recommended (Bauman et al. 2012; Heidenreich et al. 2013). IMRT is an optimized
form of 3D-CRT and by using implanted fiducial markers in the gland it enhances
the ability to escalate radiation dosage without additional toxicity. To optimize
outcomes of EBRT, a dose of ≥74 Gy is recommended for treating low-risk PC
(Kupelian et al. 2005). For intermediate- and high-risk PC a dose escalation from 76
to 81 Gy has been shown to have a significant positive impact on 5-year progressionfree survival (Kupelian et al. 2008; Krauss et al. 2011). One possibility for treatment
of intermediate- or high-risk PC, is the combination of EBRT with low- or high-dose
brachytherapy. Androgen-deprivation therapy is also recommended to be combined
with EBRT to improve overall survival in patients with high-risk localized PC
(D'Amico et al. 2008; Jones et al. 2011). The risk for side effects of EBRT increases
with dose-escalation and patients are informed about potential later gastrointestinal
or genitourinary toxicity, and possible adverse effects of EBRT on erectile function.
The most typical side effects related to radiation therapy include gastrointestinal
symptoms such as rectal bleeding and proctitis and genitourinary symptoms such as
urgency, haematuria and incontinence (Budaus et al. 2012; Mohammed et al. 2012;
Schmid et al. 2012). According to retrospective surveys, the effects of radiotherapy
on erectile function are reported to be less than those of RP (Fowler et al. 1996). One
of the long-term effects and risks related to radiotherapy is the development of
radiation induced secondary malignancy, such as rectal or bladder cancer (Murray et
al. 2013)
5.7.3 Brachytherapy
BT refers to the treatment of PC using ionizing radiation that is delivered via
radioactive seeds placed in the prostate gland. The low-dose rate brachytherapy
(LDR-BT) approach is transperineal and done under TRUS guidance. In LDR-BT,
permanent low-energy radioactive implants, i.e. iodine-125 or palladium-103, are
inserted into the prostate. LDR-BT is indicated in patients with low-risk PC (Ash et
al. 2000). The updated consensus guidelines for LDR-BT in patient selection,
optimal technique and follow-up, were recently published (Davis et al. 2012). In
high-dose rate brachytherapy (HDR-BT) iridium-192 high-radiation source is
26 implanted temporarily into the gland. HDR-BT can be used in combination with
EBRT for more aggressive and advanced PC tumours. The analyses of a BT series
demonstrated good results for the oncological outcome (Sylvester et al. 2011; Morris
et al. 2013). The main side effect profile of BT includes a risk of urinary retention
(1.5-22%), incontinence (0-19%) and a risk for post-implantation transurethral
resection of the prostate (required in up to 8.7% of cases) (Budaus et al. 2012).
Erectile dysfunction develops in about 40% of men 3-5 years after BT (Heidenreich
et al. 2013).
5.7.4 Focal therapies
The number of smaller PCs detected at an earlier stage, has increased during the past
two decades due to the screening. Focal treatment, such as cryosurgical ablation of
the prostate (CSAP) and high-intensity focused ultrasound (HIFU) therapy, has
emerged as a treatment option in men with clinically localized small focus PC and
for whome RP is not indicated (Babaian et al. 2008; Crouzet et al. 2010; Warmuth et
al. 2010). Although recent studies have shown promising results (Donnelly et al.
2010), the long-term efficacy data are still lacking (Heidenreich et al. 2013). Known
complications related to CSAP include acute urinary retention, erectile dysfunction
(45-100%), urethral sloughing (0-6%), incontinence (2-4%), and fistula formation
(<1%). Potential complications after HIFU are erectile dysfunction (13-53%),
incontinence (1-15%), urethral stricture (4-14%), urinary retention (1-9%) and
rectourethral fistulae (0-3%)(Nguyen and Jones 2011).
5.8
Hormonal therapy
Hormonal therapy is mainly used in patients with locally advanced or metastasized
PC, in postponing clinical progression and reducing symptoms. The principle behind
endocrine therapy is to eliminate androgens (by chemical or surgical castration) or
androgen action (antiandrogens) and hence achieve an inhibitory effect on PC cells.
When prostate cells are deprived of androgenic stimulation they undergo apoptosis.
The elimination of androgens can be achieved by suppressing the secretion of
testicular androgens, i.e. surgical castration or with chemical castration by using
luteinising hormone-releasing hormone (LHRH) agonists, with or without
antiandrogens. In recent years LHRH antagonists have also become available for
chemical castration. Immediate androgen deprivation therapy compared with
deferred therapy initiated at the time symptomatic progression occurs, gives a
modest improvement in overall survival, but not in disease-specific survival, except
in patients with aggressive PC (Studer et al. 2013). Data of SPCG-7/SFUO-3 trials
suggest that when androgen deprivation therapy in combination with radiotherapy is
compared with endocrine treatment alone, it halves the 10-year PC-specific mortality
and decreases overall mortality in men with locally advanced disease or high-risk
local PC (Widmark et al. 2009). Hormonal treatment can also be used as a
neoadjuvant or adjuvant therapy. In cases of locally advanced PC, for which
27 immediate androgen suppression with LHRH agonists given during and for three
years after EBRT, improved disease-free and overall survival (Bolla et al. 2002).
There are many side effects related to hormonal therapy. Castration is
associated with hot flushes, loss of energy, loss of libido, loss of potency,
osteoporosis, weight gain, nausea, vomiting and mood swings. Patients on long-term
conventional androgen deprivation therapy may also have a higher risk of
cardiovascular disease (Bourke et al. 2012). The main side effects associated with
antiandrogens are gynecomastia and breast pain (Iversen et al. 2010).
5.9
Active surveillance
5.9.1 Rationale for active surveillance
Over the last two decades, the proportion of low-risk PCs in which earlier detection
did not change the prognosis, has increased (Welch and Black 2010). This
phenomenon is described by the term overdiagnosis. The most significant evidence
for PC overdiagnosis comes from randomized screening trials. PSA-based PC
screening has led to the overdiagnosis of indolent tumours in up to 50% of cases
(Draisma et al. 2003). AS has emerged as an alternative strategy for managing these
potentially overdiagnosed PCs. The objective of this strategy is to avoid, or postpone
the treatment of PC, and thereby diminish the possible adverse effects of radical
treatments (Parker 2004). Radical treatment of all men with low-risk PC, would
cause a considerable amount of unnecessary side effects, such as incontinence and
impotence (Pardo et al. 2010) that have adverse effects on QOL (Sanda et al. 2008).
The specific approach of AS is to initially withhold radical treatments (i.e. surgery or
radiation therapy), but reserve the opportunity to deferred treatment with curative
intent in the case of disease progression or reclassification observed during followup. During AS, patients are intensively monitored using such tools as repetitive PSA
measurements, clinical examination including DRE and prostate biopsies.
The basis for using the AS strategy is the substantial evidence and knowledge
of the long natural history of PC. Post-mortem studies have shown that the
prevalence of indolent PCs is high in aging men; in about 50% of men in their fifties
harbour histological evidence of PC and the rate increases with age (Sakr et al.
1994). Such tumours are not likely to progress or their growth potential is so slow
that these patients are likely to die of other causes than PC. Widespread PSA-based
screening and extended-pattern biopsy schemes have led to an increasing trend in
overdiagnosis (Draisma et al. 2003; Welch and Black 2010).
A Gleason score of 6 for PC has been seen as a part of the aging process
(Sakr et al. 1994). A Gleason score of 6 PC has been shown not to have the
characteristic hallmarks of many other cancers, which are: apoptosis resistance,
sustained angiogenesis, local tissue invasion/metastasis, unlimited replicative
potential, insensitivity to antigrowth signals and self-sufficiency to growth signals
(Guo et al. 1997; Skacel et al. 2001; Padar et al. 2003; Pasquali et al. 2006; True et
al. 2006; Susaki and Nakayama 2007; Mucci et al. 2009; Hanahan and Weinberg
2011; Ross et al. 2011; Bismar et al. 2012; Fleischmann et al. 2012). The 20-year
outcomes following conservative management, based on the Albertsen WW cohort
before the PSA testing era, reported a mortality rate of 22% for Gleason score of 5 or
28 6 PC (Albertsen et al. 2005b). However, ERSPC data indicate that screen-detected
PCs are diagnosed approximately 10 years earlier (Schröder et al. 2010). The
Gleason grading system was changed in 2005 (Epstein et al. 2005), which resulted in
the relative upgrading of the disease; it has been estimated that one-third of patients
(with a Gleason score 6 PC) in the Albertsen study would be upgraded according to
the current grading system (Albertsen et al. 2005a). Of importance is that, the
grading of the tumours in the WW series is based on biopsy rather than surgical
staging, which is known to underestimate the proportion of higher grade PCs. A
study of 12 000 men with pathologically confirmed Gleason score 6 PC after RP,
found that 0.2% progressed to the metastatic phase during the 20-year follow-up, but
after the re-analysis the same individuals of this group upgraded to Gleason 4 pattern
(Eggener et al. 2011). Similar results were reported for a RP series of 14 000 men
with a Gleason score 6 cancer of which only 22 had lymph node metastases and
these PCs upgraded into Gleason score ≥7 after re-analysis (Ross et al. 2012). It
could be concluded that the prevailing current thinkings suggest Gleason score 6
cancer to be only a risk factor for clinically significant PC rather than a cancer with
metastatic potential itself.
5.9.2 Watchful waiting versus active surveillance
AS emerged from the experience of WW. The term ‘watchful waiting’ is used to
describe the conservative approach to management of PC. The rationale for this
observational strategy is the finding that PCs often progress slowly and are
diagnosed in elderly men with high incidence of comorbidity. WW aims to avoid or
at least delay treatment and the related side effects, and thus helps maintain the
QOL. When treatment is required, it is palliative only. By contrast, patients on AS
should be initially fit for radical treatment. The AS strategy aims to diagnose
clinically significant disease and if it occurs during follow-up, offer deferred radical
treatment with curative intent only when needed. Hence, avoidance of unnecessary
morbidity from overtreating PCs is a desired objective. This observational strategy
was first described in 2002 (Choo et al. 2002).
5.9.3 Definition of clinically insignificant prostate cancer
The aggressiveness of PC is partly defined by its pathological characteristics, i.e.
pathological stage, differentiation grade and tumour volume. The terms ‘indolent’
and ‘clinically insignificant’ have been widely used for low-risk asymptomatic PCs.
These terms are often used interchangeably. However, the term ‘insignificant’ takes
the clinical aspect more into account, whereas the term ‘indolent’ refers to the
pathological features (Ploussard et al. 2011b). Frequently used criteria for indolent
PC include pathological stage T2, absence of Gleason pattern 4/5 and tumour
volume less than 0.5ml in a RP specimen (Epstein et al. 1994). The tumour volume
threshold of <0.5 ml is based on only a modest series of cystoprostatectomies taken
before PSA testing era ensured (Stamey et al. 1993). Recent ERSPC trial data
suggest a cancer volume of 1.3 ml as a cut-off point for indolent Gleason score 6
(stage ≤T2) PC (Wolters et al. 2011).
29 Clinical criteria that combines clinical and biopsy findings were based on
histological data. Currently, the definition for low-risk PC as described by D’Amico
is the most widely accepted: i.e. a PSA of less than 10 ng/ml, Gleason score of 6 or
less, and nonpalpable tumour or palpable in less than half of one lobe of the prostate
(i.e. T1c or T2a) (D'Amico et al. 1995). A more strict definition (Epstein criteria)
distinguishes the very low-risk PC into separate category, as defined as a PSAD of
<0.15 ≤50% PC involvement of any biopsy core, and maximum of two positive
biopsy cores (Epstein 2011), the other low-risk PCs fulfill the D’Amico criteria.
Various nomograms have also been developed to assess the probability of indolent
or low-risk PC (Bangma et al. 2009).
5.9.4 Patient selection for active surveillance
The most effective AS programme would reliably be able to recognize the patients
with the more aggressive disease and the need for active treatment early after
diagnosis. Although there exists no randomized trials that compare selection criteria
for AS, several prospective AS series have provided a feasible basis for indentifying
appropriate patients using this management strategy (Dall'Era et al. 2008; van As et
al. 2008; Klotz et al. 2010b; Soloway et al. 2010; Adamy et al. 2011; Tosoian et al.
2011; Bul et al. 2013b). Patients who are considered candidates for AS should be fit
for radical treatment, thus comorbidities and age are essential issues in the AS
decision-making process. Eventually, treatment decision for patients with localized
early stage PC should take into account several things such as age, comorbidities,
personal preferences, estimation of the aggressiveness of the PC and potential
benefits and risks of radical treatments (Smith 2011). Although the specific inclusion
criteria for AS vary by institution and there is also a wide range of criteria, the
majority of criteria are similar and offer a common basis for patient selection. These
include low clinical stage (T1-T2), low PSA (<10-15 ng/ml), well-differentiated PC
(Gleason score< 7 in most series) and small volume tumour in the biopsy. The
inclusion criteria of largest prospective AS trials are listed in Table 2.
Table 2. Inclusion criteria of largest AS studies.
Institution
PSA
Clinical Gleason
stage
score
PC positive Single core
biopsy cores positivity
Other
PRIAS
(van den Bergh et al. 2007)
≤ 10
T1-T2
≤ 3+3
≤2
NR
PSAD < 0.2
University of Toronto
(Klotz et al. 2010b)
≤ 10
T1c
≤ 3+3*
NR
NR
-
University of Miami
(Soloway et al. 2010)
≤ 10
≤ T2a
≤ 3+3
≤2
≤ 20%
-
UCSF
(Dall'Era et al. 2008)
≤ 10
≤ T2a
≤ 3+3
≤ 33%
NR
-
Johns Hopkins
(Tosoian et al. 2011)
-
T1c
≤ 3+3
≤2
≤ 50%
PSAD ≤ 0.15
Royal Marsden Hospital
(van As et al. 2008)
≤ 15
≤ T2a
≤ 3+4
≤ 50%
NR
-
MSKCC
(Adamy et al. 2011)
≤ 10
≤ T2a
≤ 3+3
≤3
≤ 50%
-
* Until 2000 for men over 70: GS≤3+4, PSA≤15
MSKCC = Memorial Sloan Kettering Cancer Center; NR=not recorded; PSAD=PSA-density; UCSF = University of California, San Francisco
30 Most of the AS protocols accept only patients with a Gleason score of 6 PC and the
presence of Gleason pattern 4 is considered a contraindication for AS. However,
previous studies have shown promising results, and suggest that a small amount of
Gleason pattern of 4 might still be categorized as indolent disease and these patients
should also be considered as candidates for AS, since the progression rates have not
differed significantly from Gleason score 6 PCs (Choo et al. 2002; Cooperberg et al.
2011b; Bul et al. 2012b). This approach may be more applicable in older patients
(over >65 years) or in men with short life expectancy and comorbidities (Klotz
2013).
5.9.5 Monitoring and triggers for intervention
The aim of intensive monitoring during AS is to identify those patients with
biologically aggressive PC missed initially or PCs that have developed during
surveillance, but which are still at a curable stage. Each AS protocol has its own
follow-up strategy and there is no preferable way of monitoring. Contemporary AS
protocols monitor potential progression by means of PSA testing, clinical
examination by DRE and by prostate biopsy. Monitoring includes repetitive
measurements of serum PSA (e.g. at 3-month intervals) and based on these
measurements the PSADT or PSAV values can be calculated. A rebiopsy is
performed at one year of surveillance and in most AS protocols biopsy are repeated
at least every 3 to 4 years. The common triggers for intervention (Table 3) include
Gleason progression to ≥7 or higher tumour volume in prostate rebiopsy, short
PSADT (a cut-off value ranging between ≤2 and ≤4 years), increasing PSA velocity,
changes on serial imaging or patient’s request mainly due to increased anxiety.
Table 3. Triggers for intervention in AS series.
Institution
PRIAS
(van den Bergh et al. 2007)
Triggers for intervention
PSADT<3 years; GS≥7; >2 positive cores
University of Toronto
(Klotz et al. 2010b)
PSADT≤3 years; T stage progression; GS upgrade
University of Miami
(Soloway et al. 2010)
GS ≥7; increase of positive cores, increase of core involvement
UCSF
(Dall'Era et al. 2008)
GS≥7; PSAV>0.75ng/ml per year
Johns Hopkins
(Tosoian et al. 2011)
GS≥7; >2 positive cores; >50% core involvement
Royal Marsden Hospital
(van As et al. 2008)
Primary GS≥4; PSAV>1ng/ml per year; >50% core involvement
MSKCC
(Adamy et al. 2011)
PSA≥10; GS≥7; >3 positive cores; >50% core involvement
GS=Gleason score; PSADT=PSA doubling time; PSAV=PSA velocity
MSKCC = Memorial Sloan Kettering Cancer Center; UCSF = University of California, San Francisco
Changes of serum PSA value over time seem to be a trigger for treatment less often
than upgrading the classifications or Gleason scores in rebiopsies (Dall'Era et al.
2008). PSADT is a trigger for active treatment in about 10-20% of cases (Bul et al.
31 2012c) and a short PSADT (i.e. ≤3 years) has been shown to be associated with
adverse rebiopsy findings (Bul et al. 2012a). However, some recent studies have
questioned the association between PSA kinetics and reclassification or adverse
rebiopsy results in the short-term (Ross et al. 2010; Whitson et al. 2011), and
therefore PSA kinetics are often combined with information from DRE and biopsy.
In addition to being an invasive procedure with potential morbidity, prostate biopsy
often underestimates the grade and stage of the disease (Stav et al. 2007). This
creates the need for the development of novel biomarkers and imaging technology,
such as MRI, to improve AS.
5.9.6 Outcomes of active surveillance studies
5.9.6.1 Treatment free-survival, PC-specific mortality and overall
mortality
Despite the varying inclusion criteria of AS studies, PC-specific and overall
mortality rates are low in the short-term (Table 4). The longest median follow-up
(6.8 years) of AS was reported for the Toronto cohort, in which the 5- and 10-year
PC-specific survival rates were 99.7% and 97.2%, respectively (Klotz et al. 2010b).
This patient cohort includes men with low-risk and intermediate-risk (30%) PCs.
Men > 70 years had PSA values of up to 15 ng/ml and Gleason scores ≤ (3+4). The
median age of patients in this AS series was relatively high (70.3 years), which
probably explains the high all-cause mortality rate (overall survival 78.6%). AS
study by Johns Hopkins University reported results with no PC deaths or metastatic
cases, after a median follow-up of 2.7 years (Tosoian et al. 2011). In this study the
patients fulfilled strict criteria for very low-risk PC, i.e. the Epstein criteria. A
retrospective study from the ERSPC, on 988 participants and a median follow-up of
3.91 years, reported 10-year PC-specific survival of 100% (van den Bergh et al.
2009b). The prospective PRIAS AS study reported a treatment-free survival of
77.3% after 2 years, a median follow-up of 1.6 years and PC-specific survival of
100% (Bul et al. 2013b).
5.9.6.2 Outcomes from deferred treatment
As PC progress or is reclassified beyond the initial inclusion criteria, deferred radical
treatment is often recommended. The results from PRIAS data showed, that patients
who discontinued AS due to protocol deviations, 14% had a Gleason score of ≥4+3
and 19% extracapsular extension (Bul et al. 2012c). This is in concordance with
previous studies. Several previous studies have examined RP series that compared
deferred to immediate treatments and no significant differences were observed in
pathological outcome or in biochemical recurrence rates (Warlick et al. 2006; van
den Bergh et al. 2010b; Holmstrom et al. 2010; Dall'Era et al. 2011). Furthermore, a
nationwide cohort study in the United States showed similar rates for PC mortality in
men with low-risk PC who chose deferred treatment on AS and those who were
treated immediately (Shappley et al. 2009). The majority of AS patients, about 2/3
remain treatment free, and metastatic cases and PC mortality are shown to be rare in
32 prospective AS trials (van As et al. 2008; Dall'Era et al. 2008; Klotz et al. 2010a
Tosoian et al. 2011). However, the longest AS cohort study from Toronto reported a
biochemical recurrence rate of 50% in radically treated men, which represented 13%
of the total patient cohort (Klotz et al. 2010b).
Table 4. Summary of survival results of AS series.
Institution
Size of
cohort
ATFS
(%)
OS
(%)
CSS
(%)
2494
Median Median
follow-up age
(months) (years)
19
65
PRIAS
(Bul et al. 2013b)
76
97.1
100
University of Toronto
(Klotz et al. 2010b)
453
82
70
70
78.6
97.2
University of Miami
(Soloway et al. 2010)
230
32
64
86
100
100
UCSF
(Dall'Era et al. 2008)
321
47
64
54
97
100
Johns Hopkins
(Tosoian et al. 2011)
769
32
66
54
98
100
Royal Marsden Hospital
(van As et al. 2008)
326
22
67
73
98
100
MSKCC
(Adamy et al. 2011)
238
22
64
-
-
-
ATFS = active treatment-free survival; OS = overall survival; CSS = cancer-specific survival
MSKCC = Memorial Sloan Kettering Cancer Center; UCSF = University of California, San Francisco
5.9.6.3 Rebiopsy outcomes
Most of the AS trials include prostate rebiopsy as a part of surveillance strategy.
This is based on the assumption that the Gleason grade is a significant predictor for
PC prognosis. The data from radical prostatectomy specimen showed that
preoperative clinical undergrading is common, it is estimated to be 20-30% with a
standard 12-biopsy core system (Conti et al. 2009; Smaldone et al. 2010; Suardi et
al. 2010). In most cases, Gleason classification upgrading is likely to be due to the
more accurate resampling than true disease progression (Porten et al. 2011). The
results from the PRIAS study indicated the risk of reclassification towards higher
risk of PC in 21.5% of men in 1-year rebiopsies (Bul et al. 2012a). Higher PSAD
and number of positive biopsy cores at diagnosis (2 versus 1) were predictive of a
higher grade and a higher volume PC at rebiopsy. Several other studies have
reported reclassification rates between 13-55% (Venkitaraman et al. 2007; Ng et al.
2009; Ross et al. 2010; Tseng et al. 2010; Adamy et al. 2011; Isharwal et al. 2011;
San Francisco et al. 2011; Whitson et al. 2011). In many of these studies PSAD has
also shown to be a significant baseline predictor for reclassification in rebiopsy
(Venkitaraman et al. 2007; Ng et al. 2009; San Francisco et al. 2011).
33 5.9.7 Psychological and QOL aspects
The principal aim of AS is to avoid or delay side effects of radical treatment, but one
concern is the possible psychological burden on the patient caused by the knowledge
of having an untreated cancer. Men with low-risk PC may experience anxiety during
AS and this may have negative effects on their QOL (Bacon et al. 2001; Galbraith et
al. 2001; Litwin et al. 2002). Men on a surveillance-like strategy may be unsettled
due to a perception of danger and this may negatively influence their QOL (Wallace
2003). However, recent studies showed that patients with low-risk PC and on AS, do
not seem to have higher anxiety or distress levels in the short-term. During a ninemonth period, anxiety and distress levels remained relatively low, but those patients
with a more neurotic personality and lower physical health scores reported higher
anxiety and distress levels (van den Bergh et al. 2009a; van den Bergh et al. 2010a).
Previous studies also suggest that AS is not significantly associated with
psychological distress when compared to immediately treated patients who received
radiotherapy with or without hormonal therapy (Burnet et al. 2007). Patients on AS
have been shown to have comparable generic- and disease-specific health-related
quality of life (HRQL) dimensions compared to patients treated with EBRT. Patients
on AS had fewer problems with bowel function than patients who had received
radiation therapy. Patients treated by radiation therapy also reported significantly
more problems with erectile function. HRQL of patients on surveillance was
comparable to age- and sex- matched normative population up to 10 years after
diagnosis (Thong et al. 2010). Surveillance, unlike immediate treatment, was
associated with QOL benefits as a long-term decrease in the risk of urinary
incontinence and impotence. QOL outcomes were not worse in patients who had
delayed treatment after initial surveillance compared to those who had immediate
treatment (Kasperzyk et al. 2011). AS has also been reported to have the highest
quality-adjusted life expectancy, when compared with radiation therapy,
brachytherapy or radical prostatectomy (Hayes et al. 2010). Serial prostate rebiopsies
may have an adverse effect on erectile function, but no significant effect on lower
urinary tract symptoms has been observed (Fujita et al. 2009).
The majority of the patients seem to be satisfied with the choice of
surveillance and only a limited number of men were reported to be afraid of PC
progression (Latini et al. 2007). Communication, education and peer-support groups
can be beneficial to ease anxiety concerning AS (Pickles et al. 2007).
Discontinuation of AS and a change to deferred radical therapy are not often due to
anxiety or distress (Cooperberg et al. 2011a). The patients who have chosen
expectant management (WW) as their treatment option, have similar or even better
HRQL scores compared to men without PC at the beginning of the surveillance, but
many of HRQL domains are affected by increasing age and scores decrease over
time (Arredondo et al. 2008). Longer follow-up is needed to be able to assess the
long-term psychological and QOL effects of AS. Ongoing studies, such as the
Prostate testing for cancer and Treatment (ProtecT) study that randomize treatments
of patients with low-risk PC, may offer more information about QOL effects of AS
(Lane et al. 2010).
34 5.9.8 Imaging
The role of imaging in AS patients is currently under extensive investigation. MRI
seems to be the most promising imaging modality. Since the early 1980s, MRI has
been used to evaluate the anatomy of the prostate and PC disease (Steyn and Smith
1982). The utility of MRI is its accurate representation of soft tissue anatomy, high
spatial resolution, and the possibility for functional measurements to be taken, e.g.
spectroscopy. These advantages have led to the active evaluation of the role of MRI
in the diagnosis and staging of PC (Lindner et al. 2010). T2-weighted MRI was
initially used for tumour localization, but benign conditions (i.e. prostatitis,
haemorrhage) were found to have a similar appearance. T2-weighted MRI has a
varying sensitivity (46-96%) and a low specificity (54-82%) in tumour localisation
(Wefer et al. 2000; Engelbrecht et al. 2002; Kirkham et al. 2006). Hence, other MRI
modalities were developed namely: diffusion weighted MRI (DW-MRI), which
measures the diffusion of water molecules in tissue; dynamic contrast-enhanced MRI
(DCE-MRI), which utilizes the microvascular properties of tissue and MR
spectroscopy (MRSI), which measures metabolite levels (creatine, choline, citrane,
polyamides) in tissue. The multiparametric approach i.e. combinations of these
modalities (T2 weighted imaging combined DW-MRI and/or DCE-MRI and/or
MRSI) accurately rules out clinically important lesions, and has negatively
predictive values for high grade PCs (Villers et al. 2006; Delongchamps et al. 2011;
Somford et al. 2013). A large cancer lesion under MRI in a patient with PC has a
high predictive value for clinically significant disease (Futterer et al. 2009; Villeirs
et al. 2011). A study reported that multiparametric MRI also has a significant
correlation with Gleason score, but significant overlap between different grades still
existed (Hambrock et al. 2011).
Multiparametric MRI has been used to target biopsies at suspicious lesions.
Previous results report PC detection rates of 41% with (median 4 cores) MRI guided
targeted biopsy in men with previous negative TRUS-guided 12-core random
biopsies (Hoeks et al. 2012). The majority of cancers detected (87%) were clinically
significant. Multiparametric MRI in combination with MRI guided biopsy may thus
have a role in risk classification at diagnosis and during follow-up in AS patients.
The role of MRI in AS has not yet been fully determined, although it has been
shown to aid in the detection of the anteriorly located tumours (Lawrentschuk et al.
2010). Guidelines have been developed for prostate MRI including imaging
acquisition protocols and a structurized reporting system to improve the reproducible
and reliability of MR images with standardised methods and technologies (Barentsz
et al. 2012; Moore et al. 2013). Accurate interpretation of MRI is challenging and
requires experience that can result in significant interobserver variability
(Mussurakis et al. 1996). MR imaging is not assumed to replace the histological
verification of PC, but to help decrease the frequency of rebiopsy and biopsy-related
morbidity in patients on AS (Turkbey et al. 2011b; Turkbey et al. 2012).
5.9.9 Biomarkers
Potential serum and urine biomarkers for PC have been intensively studied in basic
research laboratories for the past decade. Future novel biomarkers may make it
possible to improve the risk rating of PC at an early stage. Unfortunately, no
35 clinically relevant markers have been validated as relevant prognostic factors in AS
as yet. Isoforms of PSA, such as combination of free PSA and -2ProPSA (Isharwal
et al. 2011) are under evaluation. Prostate cancer antigen 3 (PCA3) was initially
promising, as it was shown to be associated with PC volume (Ploussard et al.
2011a). However, results about its accuracy in predicting stage and grade of PC were
contradictory (Roobol 2011). The PCA3 marker has also been studied in an AS
cohort, but no association was found with biopsy progression after a short follow-up
(Tosoian et al. 2010). Further evaluation is needed to clarify the role of PCA3 in AS.
5.9.10 The role of 5-Alpha Reductase Inhibitors
Two randomized, placebo-controlled trials, The Prostate Cancer Prevention Trial
(PCPT) (Thompson et al. 2003) and The Reduction by Dutasteride of Prostate
Cancer Events trial (REDUCE) (Andriole et al. 2010) found an approximately 25%
reduction in overall PC incidence in men taking 5-alpha reductase inhibitors (5ARI). These results suggest that men on AS may benefit from using 5-ARI, but these
two studies also reported a 0.5% increase in high-risk PC in 5-ARI users. A
retrospective study on 5-ARI use in men on AS found, that men with low-risk PC,
who were using 5-ARI had a favourable prognosis compared to those without 5-ARI
medication (Finelli et al. 2011). A prospective study, The Reduction by Dutasteride
of Clinical Progression Events in Expectant Management trial (REDEEM),
randomized men on AS between dutasteride and placebo. The results showed a
reduced risk of PC progression in 5-ARI users and no increase in high-grade PC
after 3 years (Fleshner et al. 2012). This study suggests that men on AS may benefit
from the use of 5-ARI in reducing the risk of reclassification on rebiopsy.
36 6.
AIMS OF THE STUDY
Active surveillance is an alternative option for immediate radical treatments in
patients with low-risk PC. The aim of this initial expectant management strategy is
to avoid or postpone the risk of side effects from radical treatment. The overall
objective of the present study was to evaluate the feasibility of AS as a management
option for low-risk PC and further analyse the QOL issues during the continuum of
the PC disease.
The specific aims of the study were:
I.
to evaluate the short-term outcomes of the prospective international PRIAS
study (study I).
II.
to analyse the effects of AS on the HRQL and urinary and erectile function
(study II).
III.
to observe the short-term effects of various phases of PC screening on HRQL
(study III).
IV.
to assess the role of DW-MRI interpreted in a routine clinical setting, as a
diagnostic and prognostic tool in AS (study IV).
V.
to evaluate the utility of a free/total PSA ratio as a prognostic tool in AS
(study V).
37 7.
MATERIALS AND METHODS
PRIAS is an international prospective trial that originates from the ERSPC. In this
dissertation the data from the PRIAS study is used in two articles (I, V), and the data
from the Finnish arm of the PRIAS study is used in two articles (II, IV). The data
from the Finnish arm of ERSPC is used in one article (III).
7.1
Study populations
7.1.1 The Finnish arm of the ERSPC trial (study III)
ERSPC is a multicenter, population-based and randomized PC screening trial that
commenced in the early 1990´s and is conducted in eight European countries. In the
first screening round (1996-1999) in Finland, 80 144 men were identified from the
population registry and randomized into screening (31 866) or into the control arm
(48 278). The men were born between 1929-1944 and were living in the Helsinki or
Tampere metropolitan areas. Men who had emigrated, or deceased prior to the
screening invitation, and with previous PC diagnosis (identified from the Finnish
Cancer Registry) were excluded. A PSA blood sample was drawn from 20 793
participants (30 190 invited, response 69%).
7.1.2 The PRIAS study (studies I, II, IV and V)
In 2006 the PRIAS study was initiated in the Erasmus University Medical Center in
the Netherlands and between December 2006 and July 2008 the first 500
international patients were included in the PRIAS trial (I). The PRIAS study is still
ongoing and the number of participating countries and centres has also increased
(Figure 3). In Finland, the PRIAS commenced in Helsinki University Central
Hospital and since 2007, the PRIAS study expanded under the name of the national
FinnProstate Study XI (FPXI) into eight other clinics in Finland. Between December
2006 and May 2009, the first 124 patients had been included in the study; 80 of these
participants had been followed for at least a year by May 2009 (II). Between
February 2009 and May 2011, 80 of Finnish PRIAS patients underwent DW-MRI in
Helsinki University Central Hospital (IV). Men were included between December
2006 and October 2013 from the international PRIAS data, a free PSA value was
determined in 939 patients at the study enrolment (V). The RP data used in the
analysis was available from the Finnish arm of the PRIAS study (V).
38 Canada
3%
Spain Sweden
3%
3%
Australia
2%
Norway
1%
France
4%
Germany
6%
Netherlands
44 %
Japan
9%
Finland
10 %
italy
15 %
Figure 3. Distribution of PRIAS patients (n= 3744) inclusions (largest medical centers included, i.e. > 8 study
participants) per country (at 29 October, 2013).
7.2
Study protocols and study design
7.2.1 Study III the Finnish arm of the ERSPC trial
Men were invited for a blood test to determine their serum PSA concentration in the
screening arm. Men with PSA 3.0-3.9 ng/ml were referred to DRE, and since 1998 a
determination of the free/total PSA ratio was used as an ancillary test in these
screening participants. Men with a PSA value over 4 ng/ml were referred to a full
clinical examination, whereas DRE was used as an ancillary standalone test for men
with marginally elevated PSA values. Men with a PSA ≥ 4 ng/ml or a suspicious
finding in DRE or free/total PSA ratio < 0.16 were referred for diagnostic
examination i.e. TRUS with prostate biopsy. In the screening arm, men received a
re-invitation to the second and third screening rounds that were arranged four and
eight years after the first round. The men were invited for the latter rounds,
regardless of previous participation or non-response to screening.
7.2.2 Studies I, II, IV and V protocol
The protocols for studies I, II, IV and V are based on the PRIAS study. The PRIAS
inclusion criteria are histologically confirmed adenocarcinoma of the prostate with a
PSA level ≤ 10 ng/ml, clinical T –class (cT) ≤ 2, a Gleason score ≤ 6, a maximum of
two positive biopsies and PSA density < 0.2 ng/ml. A patient should be fit for
39 curative treatment and have no history of previous PC treatments to be considered a
candidate for the PRIAS study. The patients in studies I, II, IV and V were
intensively monitored during AS. PSA was measured every 3 months and DRE
every 6 months during the first two years after diagnosis. Thereafter, PSA was
measured every 6 months and DRE was performed annually. Prostate rebiopsies
were standard and were taken 1, 4 and 7 years after enrolment in the study. If
PSADT was between 3 to 10 years, annual rebiopsies were advised. The criteria for
discontinuation of surveillance and deferred active treatment were PSADT less than
3 years, cancer in more than two rebiopsy cores or Gleason score higher than 6. If
PSA exceeded over 20 ng/ml, a bonescan was recommended (Fig.4).
!
!
!
!
ACTIVE SURVEILLANCE
END OF ACTIVE
SURVEILLANCE
Yes
PSA <20ng/mL
Yes
cT <T3
Yes
No
Bone metastases?
No
No
DEFINITIVE TREATMENT
Yes
PSADT >3yr
No
No
Yes
Rebiopsy indicated by
protocol?
Rebiopsy:
maximum of 2 positive cores
with carcinoma and Gleason
score 3+3
Yes
No
PSADT >10yr
No
Yes
CONTINUE ACTIVE
SURVEILLANCE
Yes
!
Figure 4. Studies I, II, IV and V based on the PRIAS protocol.
A prostate volume-dependent number of random biopsies was also advised, but not
obligatory. The recommendation for the number of biopsies was: prostate volume <
40 ml 8 biopsies, 40-60 ml 10 biopsies, > 60 ml 12 biopsies (Vashi et al. 1998). In
Finland, 12 TRUS-guided random biopsies were routinely taken. The measurement
of free PSA was not mandatory according to the study protocol, but many of the
participating centres had incorporated free PSA measurement into the study visit
plan (V).
40 In the analysis of the first 500 PRIAS patients (I), the main outcome parameter was
active treatment-free survival. Secondary endpoints included reasons for
discontinuation of AS, findings in the standard 1-year rebiopsies, and outcomes after
RP. Distributions of PSADT, DRE findings and preliminary survival were also
analysed.
7.2.3 PRIAS internet website
The PRIAS trial has its own website that can be found at www.prias-project.org. The
site offers general information about AS of PC and the PRIAS study itself and is
available to the public. The web-based tool within the website is used for the
inclusion and follow-up of study participants. After logging in using a personal
account, physicians have access and can include new patients and search for followup details of their own study participants. PSADT is calculated automatically and the
site also generates a graph presenting the patient´s PSA values over time. The
PRIAS website provides automatic individualized recommendations, such as
whether continuation of AS is indicated according to the protocol or not. The
Erasmus University Medical Center in Rotterdam is the co-ordinating study centre
that maintains the PRIAS website.
7.2.4 RAND 36 – Item Health Survey (II, III)
The Finnish version of RAND 36-Item Health Survey (Hays et al. 1993) was used in
two studies (II, III) to analyse HRQL. The RAND-36 questionnaire is validated and
had good reproducibility in the Finnish population (i.e. Cronbach´s α 0.80-0.94).
Age-stratified reference values were also available, which made the comparison with
the general population possible (Aalto et al. 1999). The RAND-36 questionnaire
included 36 items that were further divided into eight subscales: physical
functioning, bodily pain, general health perceptions, mental health, role limitations
due to physical and emotional problems, social function and vitality. Each of the
eight subscales was scored from 0 to 100 and a higher score indicated better HRQL.
The PRIAS protocol does not require the use of any particular standard
quality of life-survey. In Helsinki University Hospital, the RAND-36 questionnaire
was chosen to evaluate effects of AS on participants’ general QOL and to allow
comparisons across different treatments and diseases. QOL is monitored at the study
inclusion and in surveillance at 3, 5, and 7 years. One year QOL questionnaire was
answered by the patients before the first rebiopsy. At the same time, points relating
to voiding symptoms and erectile function were also evaluated using the wellvalidated and standardized IPSS and IIEF-5 questionnaires (II).
The quantification of the impact of the screening process on HRQL was
achieved when RAND-36 questionnaires were delivered to the screening participants
at each of the five phases of the first screening round: 500 at invitation, 500 after a
PSA test, 500 after the PSA result, 314 after DRE (before information of its result,
but aware of the PSA value); and >300 after TRUS and biopsy (before information
of its result, but aware of the PSA value)(Fig.5). Additional copies of questionnaires
were made and delivered without keeping track of the exact numbers in one
department. Consequently, the exact number of delivered questionnaires after TRUS
41 and biopsy is not available. Participants were different in each of the five phases and
were asked to fill in RAND-36 questionnaires. Information on sociodemographic
and behavioural factors was also collected at invitation, attendance and partly at PSA
result phases, but was not ancillary to either the screening test by DRE or the
diagnostic examination (TRUS/biopsy) phases. The questionnaires were delivered
with the invitation letter, which also included information about the study and PC in
general (III).
80 456
identified from the
Finnish population
registry
312
excluded (prostate
cancer, emigration,
death)
80 144
randomized
31 866
screening arm
48 278
control arm
30 190
invited at 1st
screening round
Phase 1)
invitation (293/500)
Phase 2)
screening (386/500)
20 793
participants with PSA
blood sample drawn
1826
PSA ≥ 4 ng/ml
1071
PSA 3.0-3.9 ng/ml
17 896
PSA< 3 ng/ml
!
Phase 5)
TRUS and biopsy
(319)
Phase 3)
PSA result
(271/500)
Phase 4)
DRE (217/314)
Figure 5. Flow chart of the recruitment of study (III) participants
7.2.5 MRI (IV)
!
MRI is not a mandatory part of the PRIAS protocol, but in Helsinki University
Central Horpital, DW-MRI was incorporated into the follow-up protocol and
patients had the opportunity to have DW-MRI after a year of AS, before the first
rebiopsy (IV). MRI was performed with 3T T2-W MRI (Philips Medical Systems)
with using a body-array coil. Echo-planar DW-MRI images (with b-values 0 s/mm2,
42 300 s/mm2, 600 s/mm2) were obtained transverse to the prostate parallel to the
corresponding set of T2-W images. The analysis of T2-W MRI images was
quantitative and for the analyses the prostate was divided into seven regions (right
apex, middle, basis, left apex, middle, basis and anterior part). Low T2 signals in the
peripheral zone and in the central area were considered suspicious for malignant
lesion. T1 images were also analysed to rule out benign processes (e.g. prostate
hyperplasia or haemmorrhage) and to ensure that high signal areas did not exist in
the same locations. DW-MRI images and apparent diffusion coefficient (ADC) maps
were compared with each other and the appearance of the lesion in bright contrast in
DW-MRI and low signal intensity on ADC, was considered suspicious for
malignancy. MRI images were interpreted by two genitourinary radiologists and
results were made available, as a written report, to the clinicians at the patient´s first
rebiopsy follow-up visit.
7.2.6 Statistics
The Statistical Package for the Social Sciences (SPSS) was used for data analyses.
The cut-off level of statistical significance was set at p=0.05 in all tests. Values are
expressed as median and range, unless stated otherwise.
The differences in means of the RAND-36 questionnaire scores were
analysed using the paired/non-paired t-test, or when non-parametric by the MannWhitney U-test, depending on the groups and distribution of the data. A ‘half SD
rule’ was used to interpret the QOL data, i.e. a change in QOL variables more than
0.5 SD was considered clinically significant (Norman et al. 2003). Correlation
analysis and Pearson chi-squared test clarified the associations between patients´
characteristics and HRQL variables. Binary and ordinal logistic regression analyses
further interpreted the associations between HRQL variables and assumed HRQL
predicting factors (II, III). Spearman´s rank coefficient correlation analysis and
Pearson chi-squared test were used to assess the associations between clinical
variables/rebiopsy findings and DW-MRI results. Logistic regression was used to
analyse assumed predictors of deferred radical treatment (IV) and to explore
potential predictors of adverse rebiopsy findings (I, V). Active treatment-free
survival was assessed using the logrank test and graphically displayed by the
Kaplan-Meier survivorship method (I, V). Time to treatment change and association
of patients’ baseline characteristics and adverse RP findings were analysed using the
Cox regression (V). Hazard ratios were estimated together with the associated 95%
confidence interval and p-values (V).
7.2.7 Ethics
The Ethics Committees of Helsinki University Central Hospital and Tampere
University Hospital approved The Finnish Prostate Cancer Screening Trial protocol.
The PRIAS study protocol was approved by The Ethics Committee of Helsinki
University Central Hospital in 2006. In other PRIAS centers (I, V), the study
protocol was approved by the respective ethics committees in each participating
country. 43 8.
RESULTS
8.1 The short-term outcomes of the first 500 PRIAS
patients (study I)
Table 5 shows the baseline characteristics of the first 500 patients in the PRIAS
study (I). At the time of analysis the median follow-up was 1.02 years. The 2-year
active treatment-free survival (ATFS) rate was 73%. Figure 6 presents the total
ATFS and also stratifies the reasons for discontinuing AS. A considerable drop in
the survival curve was observed for all reasons, at biopsy and also at PSADT at 1
year of follow-up.
Table 5. The characteristics of study patients (study I).
Variable
At diagnosis
Median (25-75 percentiles)
66.0 (60.7-70.4)
5.3 (3.9-6.7)
0.12 (0.09-0.16)
42.6 (35.0-56.0)
Age, year
PSA, ng/ml
PSAD, ng/ml/cc
Prostate volume, cm3
DRE
T1c
79.2%
T2a
19.2%
T2b
1.2%
T2c
0.4%
Positive biopsy cores
1 core
68.6%
2 cores
31.4%
Gleason score
=6
95.0%
<6
5.0%
PSA = prostate-specific antigen; PSAD = prostate-specific antigen density; DRE = digital rectal examination
Figure 6. ATFS for discontinuing in AS (total and stratified for reason).
44 At the time of analysis 82/500 (16%) men had already discontinued AS; 83%
(68/82) due to protocol-based reasons and 17% (14/82) because of anxiety and/or by
request. The reasons for the discontinuations in protocol were adverse rebiopsy
findings (Gleason score >6 and/or >2 PC positive rebiopsy cores) for 43% (29/68),
PSADT for 37% (25/68) and for both reasons combined 19% (13/68). Table 6 lists
the specific reasons for discontinuation of AS and the active treatments chosen.
Table 6. Reasons for discontinuation of AS (n=82) and deferred active treatments (study I).
Reason for active treatment
Deferred active treatment
RP
RT
BT
Unknown/other
Total
PSADT (only)
7
4
12
2
25
Number of positive cores at
rebiopsy and Gleason score
5
5
1
1
12
Number of positive cores at
rebiopsy
6
1
5
-
12
Gleason score at rebiopsy
2
-
3
-
5
PSADT, number of positive
cores at rebiopsy and
rebiopsy Gleason score
1
-
-
-
1
PSADT, number of positive
cores at rebiopsy
4
2
-
1
7
PSADT and rebiopsy
Gleason score
1
2
1
1
5
T stage (only)
Psychological
-
-
-
1
1*
Anxiety
4
3
-
1
8
Request to discontinue on AS
-
2
1
1
4
Unknown
1
-
1
-
2
Protocol-based
Other
Total
31
19
24
8
*MRI was performed, revealing clinical stage T3a
BT= brachytherapy; PSADT = prostate-specific antigen doubling time
RP= radical prostatectomy; RT= external beam radiation therapy;
82
In total, 261/500 (52%) of study patients had standard rebiopsy and biopsies were
taken a median of 1.02 (25-75 percentiles: 1.0-1.1) years after PC diagnosis. In the
rebiopsy the median number of biopsy cores was 10 (25-75 percentiles: 8-12). No
cancer was found in 34% (90/261), favourable result (i.e. Gleason score ≤6, ≤2
positive biopsy cores) in 44% (114/261) and unfavourable result (i.e. Gleason score
>6 and/or >2 positive biopsy cores) in 22% (57/261). Rebiopsy results in relation to
PSADT at the time of biopsy are shown in Table 7. PSADT was not available in
14/261 (5%) patients. When PSADT was compared in patients with favourable and
45 unfavourable biopsy results, the difference between the groups was not statistically
significant (p=0.411). The univariate analysis revealed that only variable predicting
unfavorable rebiopsy findings was the number of PC positive biopsy cores at
diagnostic biopsy (two versus one). 17% (32/183) of men with one PC positive
biopsy at diagnosis also had unfavourable rebiopsy findings and 32% (25/78) of men
with two positive biopsy cores (p=0.014). Age, prostate volume, PSA, PSADT,
clinical stage, time to rebiopsy and number of diagnostic/rebiopsy cores had no
significant association with unfavourable rebiopsy findings.
Table 7. Rebiopsy findings after 1 year of AS in relation to PSADT at the time of biopsy (n=261) (study I).
Rebiopsy
Findings
Favourable (n=194)
No 1-2 positive Total
PC cores and
Gleason 6
Unfavourable (n=53)
>2
≤2
>2
Total
positive positive biopsy
cores,
cores,
cores,
Gleason Gleason Gleason
≤6
>6
>6
Total
0-3 years
24/
(28%)
30/
(28%)
54/
(28%)
7/
(24%)
5/
(50%)
3/
(21%)
15/
(28%)
69/
(28%)
3-10 years
18/
(21%)
30/
(28%)
48/
(25%)
12/
(41%)
1/
(10%)
5/
(36%)
18/
(34%)
66/
(27%)
>10 years
7/
(8%)
8/
(7%)
15/
(8%)
1/
(3%)
2/
(20%)
0/
(0%)
3/
(6%)
18/
(7%)
Negative
37/
(43%)
40/
(37%)
77/
(40%)
9/
(31%)
2/
(20%)
6/
(43%)
17/
(33%)
94/
(39%)
Unknown
4
6
10
3
0
1
4
14
32/
(12%)
10/
(4%)
15/
(6%)
57/
(22%)
261/
(100%)
PSADT
Total
90/
114/
204/
(34%)
(44%)
(78%)
PSADT = prostate-specific antigen doubling time
Of the 27 men who underwent RP, 24 (89%) results were available. Patients
underwent RP a median of 1.0 (25-75 percentile: 0.5-1.1) year after PC diagnosis
and the study enrolment. The reasons for surgical treatment were: PSADT <3 years
only (6/27), adverse rebiopsy findings only (10/27), combination of these two
protocol-based reasons for discontinuation (6/27) and other reasons (5/27). In all
four cases of T3 tumors, in rebiopsy more than two PC positive cores were found
and in three of these Gleason scores were also upgraded >6. In 50% (12/24) of RP
specimens Gleason scores were upgraded; in the rebiopsies of 11 men taken
previously, unfavorable biopsy characteristics were found in all of them. No
significant association could be observed between adverse RP findings (Gleason >6
or T3) and PRIAS inclusion variables or PSADT.
The present data do not allow for a mortality analysis. During follow-up, no
one died of PC. Two patients died due to other reasons and in one patient PC lymph
node metastases were detected.
46 8.2
Short-term HRQL effects of AS (study II)
In study II, of the enrolled 124 Finnish PRIAS patients (in the area of Helsinki
University Central Hospital), 105/124 (85%) had completed and returned the
baseline RAND-36 questionnaire and 19/124 (15%) had not responded by the time
of analysis. 80 patients had been followed for at least a year and 75 of these (94%)
had completed the questionnaires at the study inclusion and after one year of followup. The response rates for IPSS and IIEF-5 questionnaires were 80% (60/75) and
56% (42/75), respectively. The patient characteristics of the study group (75 men
with baseline and follow-up questionnaires available) and the non-respondent group
(19) are shown in Table 8. The only significant difference between the groups was in
the educational backround; the respondents had a significantly higher level of
education (p=0.02).
Table 8. Characteristics of study patients and non-respondents (study II).
Variable
Study group (N=75)
N(%)/ median(range)
Non-respondents (N=19)
N(%)/ median(range)
p value
(Unless noted otherwise)
(Unless noted otherwise)
Age at diagnosis, years
(median, 25th-75th percentiles)
Initial PSA, ng/ml
64 (60-69)
64 (60-69)
0.9
5.1(2.0-10.0)
5.0 (1.4-9.3)
0.7
Initial free PSA, ng/ml
0.7 (0.0-2.8)
0.7 (0.2-1.8)
0.9
Clinical stage T1 at diagnosis
75 (100)
19 (100)
One positive biopsy at diagnosis
53 (71)
12 (63)
0.5
Two positive biopsies at diagnosis
22 (29)
7 (37)
0.5
Higher education (college/university)
23 (50)
1 (10)
0.02
Married/living with a partner
51 (67)
13 (68)
0.7
After one year of AS, no significant differences in mental (mental health, physical
role, social function, vitality) or in physical health dimensions (bodily pain, general
health, physical function, physical role) were observed (Table 9). Slightly inferior
results were noted in two domains of eight HRQL subgroups, but the differences
were not statistically significant: bodily pain (p=0.149) and physical function
(p=0.608) decreased during AS. After follow-up the scores of three HRQL domains,
i.e. social function, emotional and physical role, were slightly better than at the study
enrolment. The only statistically significant improvement was observed for physical
role (p=0.010), but the change was not clinically significant (<0.5 SD). The
correlation and regression analyses revealed that the assumed HRQL predicting
factors (i.e. age, diagnostic PSA, PSA change during follow-up at any time point)
did not correlate or associate with any of the eight HRQL domains at the study
enrolment or during AS. Compared to the reference values obtained from the general
Finnish male population (aged 55-64 and 65-74), mean HRQL scores among men on
AS were significantly better in all eight subgroups of RAND-36 (p<0.05) at
diagnosis and after follow-up (Figures 7 & 8).
47 During AS follow-up, total IPSS score increased slightly (mean 7.9 vs 9.2, p
=0.121). In total IIEF-5 score, significant change was not observed (mean 18.8 vs
19.5, p=0.583).
Table 9. Mean (SD) HRQL in AS patients, measured by RAND-36 questionnaire (study II).
RAND-36 questionnaire score
General health
Physical function
Mental health
Social function
Vitality
Body pain
Role physical
Role emotional
Baseline,
at the study inclusion
mean (SD)
65 (15.2)
91 (13.6)
81 (14.9)
91 (14.4)
76 (15.7)
90 (15.6)
81 (34.2)
82 (32.6)
After a year of AS
mean (SD)
p value
65 (16.3)
90 (12.9)
81 (14.1)
93 (14.0)
76 (16.0)
87 (18.7)
89 (25.7)
88 (29.0)
0.780
0.608
0.696
0.279
0.582
0.149
0.010*
0.052
Score
* p <0.05 statistically significant cut-off
100
80
60
40
20
0
Inclusion
Follow up
Standard score
PF PR ER VT MH SF BP GH
Figure 7. RAND-36 scores in men aged 55-64 (study II).
(PF, physical function; PR, physical role; ER, emotional role; VT, vitality; MH, mental health; SF, social function; BP,
body pain; GH, general health)
100
Score
80
Inclusion
60
Follow up
40
Standard score
20
0
PF
PR
ER
VT
MH
SF
BP
GH
Figure 8. RAND-36 scores in men aged 65-74 (study II).
(PF, physical function; PR, physical role; ER, emotional role; VT, vitality; MH, mental health; SF, social function; BP,
body pain; GH, general health)
48 8.3
Short-term HRQL effects of PC screening (study III)
During the first screening round, the RAND-36 questionnaire was delivered to a
total of more than 2000 participants in five discrete phases. At the invitation phase
293/500 men (59%, 4 excluded due to incompletely filled questionnaires) responded,
at screening 386/500 men (77%, 9 exclusions), at PSA result 271/500 men (54%, 12
exclusions) and at DRE 217/314 men (69%, 6 exclusions). The exact number of
questionnaires delivered after the diagnostic examination phase (i.e. TRUS and
biopsy) is not known, because additional copies of the questionnaires were made and
delivered without keeping track of the actual numbers at one participating
department. In total 319 responders were evaluated for this screening phase. In the
RAND-36 questionnaires, the item ‘non-response rate’ was 0.5-1.5% at each of
different screening phases. A range of 8.8-12.5% of screening participants did not
respond to one or more questions.
The range of mean ages of the participants for the different phases was 60-63
years (Table 10). Information on sociodemographic and behavioral factors was
collected at phases 1 to 3 (i.e. invitation, PSA blood test and partly at PSA result
group), but not at the DRE and TRUS/biopsy phases. No significant differences were
noted between the screening participants in the sociodemographic and behavioral
factors at different screening phases (Table 11).
Table 10. Mean ages of questionnaire respondents at different phases of the PC screening process (study III).
Screening phase
1) Invitation
Mean age, years (SD)
60.2 (4.6)
2) PSA blood test
3) PSA result
4) Digital rectal examination
5) TRUS and biopsy
60.7 (4.4)
60.8 (4.5)
62.3 (4.3)
62.8 (4.3)
The highest HRQL response scores of the RAND-36 questionnaire (medians of 90100) were related to the emotional role, physical role, physical function and social
function. The lowest scores of RAND-36 were consistently found for general health
(median 65) at each screening phase and followed by energy/fatigue. No major or
systematic changes in HRQL could be detected during the screening process (Table
12). However, a decrease was observed in the emotional role subscale (p=0.005) at
the ancillary screening test (DRE) phase and a minor but statistically significant
decrease was found in social function after receiving the PSA result (p=0.035). After
diagnostic examination (TRUS/biopsy) the pain HRQL score was higher than after
DRE (p=0.003).
HRQL scores were higher in patients with abnormal PSA values (PSA ≥3)
than those with normal PSA values (PSA <3), which was unexpected. No significant
differences were found between these groups when general health and mental
dimensions were compared.
The ordinal regression analysis showed results that were largely
unremarkable. Significant associations (p<0.01) between age and poorer physical
function were detected. In contrast, physical exercise with better physical function,
49 energy and general health, improved energy and mental health, and also education
with physical function and physical role were reported. At DRE phase an unexpected
association between a higher serum PSA level and better general health scores was
observed among other findings of borderline significance.
Table 11. Socio-demographic and lifestyle factors among study participants (study III).
Employment
Full/Part time employed
Unemployed
Retired
Not known
Position
White collar
Blue collar
Retired
Not known
Smoking
No
Yes
Not known
Marital status
Unmarried
Married/Cohabitation
Divorced
Widow
Education level
Elementary/Secondary school
Secondary school graduate
Vocational school/institute
College
University
Not known
Exercise ≥ ½ hours (leisure time)
Not at all
Occasionally
Regularly once a week/ less frequently
Regularly twice a week
At least 3 times a week
Not known
*NA = Not available
Invitation
N (%)
PSA blood test
N (%)
PSA result
N (%)
Pearson
Chi-Square
(p value)
131 (45)
25 (9)
104 (36)
33 (11)
141 (37)
52 (13)
141 (37)
52 (13)
105 (39)
26 (10)
107 (39)
33 (12)
p=0.173
84 (29)
73 (25)
116 (40)
20 (6)
90 (23)
104 (27)
178 (46)
14 (4)
75 (28)
62 (23)
121 (45)
13 (5)
p=0.508
183 (63)
107 (37)
1
242 (63)
142 (37)
2
175 (65)
96 (35)
p=0.556
15 (5)
240 (82)
30 (10)
8 (3)
25 (7)
317 (82)
29 (8)
15 (4)
*NA
p=0.457
118 (41)
3 (1)
75 (26)
7 (2)
56 (19)
34 (11)
152 (39)
7 (2)
107 (28)
12 (3)
66 (17)
42 (11)
*NA
p=0.681
7 (2)
72 (25)
40 (14)
48 (16)
121 (42)
3 (1)
10 (3)
80 (21)
35 (9)
71 (18)
183 (47)
7 (2)
*NA
p=0.298
The comparison of HRQL scores to the reference values (for the subscales) of
general Finnish age-stratified male population (aged 60-64), showed no significant
differences; HRQL was similar or slightly better among screening participants
(Figure 9).
50 Table 12. HRQL as RAND-36 scores (median, 25th–75th percentiles) at five screening phases (study III).
RAND-36
subgroup
*
Invitation
PSA blood
test
PSA result
Digital rectal
examination
General health
Phase 1
65 (50-75)
Phase 2
65 (50-75)
Phase 3
65 (50-75)
Phase 4
65 (45-75)
Transrectal
ultrasound and
biopsy
Phase 5
65 (50-75)
Physical function
90 (80-95)
90 (80-100)
90 (80-95)
90 (80-95)
90 (80-95)
Mental health
84 (69-92)
84 (72-92)
80 (72-92)
84 (72-92)
84 (68-82)
Social function
100 (75-100)
100(75-100)
95 (75-100) *
100 (75-100)
100(75-100)
Energy/Fatigue
70 (55-85)
75 (60-85)
75 (60-85)
75 (60-85)
75 (60-85)
Pain
90 (68-100)
90 (68-100)
90 (68-100)
80 (68-100)
90 (78-100) ***
Physical role
100 (75-100)
100(75-100)
100 (75-100)
100 (75-100)
100(75-100)
Emotional role
100 (67-100)
100(67-100)
100 (67-100)
94 (67-100) **
100(67-100)
p = 0.035; 3 vs. 2; ** p = 0.005; 4 vs. 3; *** p = 0.003; 5 vs. 4
100
90
80
70
60
50
40
30
20
10
0
Invitation
After PSA-blood test
After PSA-test result
After digital rectal
examination
After transrectal
ultrasound and biopsy
Age-stratified (60-64)
general male population
Figure 9. RAND-36 results at testing compared with age-stratified (60-64) of the general Finnish male
population (study III).
8.4 DW-MRI after a year of AS and before rebiopsy
(study IV)
80 PRIAS patients in Helsinki University Central Hospital underwent DW-MRI
after one year of follow-up but before the first rebiopsy. The characteristics of the
study patients are shown in Table 13.
51 Table 13. Characteristics of study patients (study IV).
Variable
Study patients (n=80)
Age at diagnosis (years), median (range)
64 (50-77)
PSA at diagnosis (ng/ml), median (range)
5.7 (1.4-10.0)
Free PSA at diagnosis (ng/ml), median (range)
0.9 (0.0-2.8)
Prostate volume (cc), median (range)
44.2 (16-100)
Clinical stage T1 at diagnosis (%)
80 (100)
One positive biopsy core at diagnosis (%)
56 (70)
Two positive biopsy cores at diagnosis (%)
24 (30)
Gleason score 3+3=6 (%)
78 (97.5)
PC length at diagnostic biopsy, mm (mean % of total biopsy length)
2.1 (1.2)
Rebiopsy
No cancer (%)
Gleason score 6 (%)
Gleason score 7 (%)
Gleason score 9 (%)
No repeat biopsy
30 (38.5)
37 (47.4)
10 (12.8)
1 (1.3)
2*
PC length at rebiopsy, mm (mean % of total biopsy length)
* One patient could not undergo rebiopsy due receiving an antithrombotic medication
and one patient refused rebiopsy
PC = prostate cancer; PSA = prostate-specific antigen
5.0 (2.6)
40/80 patients (50%) had a lesion suspicious for malignancy in T2-weighted MRI
and 30 (75%) of these 40 patients also had a suspicious lesion on their ADC maps,
generated from DW-MRI sequences. Neither the malignant suspicious lesion in MRI
(i.e. MRI positivity) nor the tumour ADC revealed any significant correlations with
clinical variables, such as age, PSA at diagnosis, free PSA, prostate volume,
percentage of PC at diagnostic biopsy, PSA at discontinuation of AS or PSADT
(Table 14). No significant associations were detected between MRI
positivity/tumour appearance in ADC maps and diagnostic biopsy (number of PC
positive cores, Gleason score), rebiopsy findings (number of PC positive cores,
Gleason score) or discontinuation of AS (Table 15). Similarly, no significant
associations were found in a separate analysis of the patient group (n=23) with
adverse findings in rebiopsy (Gleason score >6 and/or number of PC positive cores
>2) or discontinuation of AS.
Table 14. Spearman´s correlations between clinical variables and tumour appearance on MRI / ADC maps (study
IV).
Study
population
(N=80)
Age
Prostate
volume
PSA at
dg
% of PC at
diagnostic
biopsy
MRI
r
0.103
0.106
0.106
p value
0.361
0.351
0.349
ADC
r
0.072
0.034
-0.018
p value
0.525
0.768
0.875
r =correlation coefficient; ADC = apparent diffusion coefficient
PSA-DT
PSA at
discontinuation
-0.222
0.069
-0.056
0.411
0.080
0.560
-0.219
0.073
-0.037
0.745
0.015
0.898
52 Table 15. Chi-squared analysis between clinical variables and MRI / ADC maps (study IV).
Study
population
(N=80)
Gleason score
at diagnostic
biopsy
Cancer positive
cores at
diagnostic
biopsy
Gleason score
at rebiopsy
Cancer
positive cores
at rebiopsy
Discontinue on
AS
MRI
r
0.000
0.109
-0.006
0.098
p value
1.000
0.329
0.530
0.739
ADC
r
-0.041
-0.169
-0.055
-0.089
p value
0.712
0.131
0.447
0.887
r =correlation coefficient; ADC = apparent diffusion coefficient; AS = active surveillance
-0.028
0.805
0.021
0.848
Rebiopsy results were available for 78 (98%) of the study patients, including
information on cancer length and location in biopsy cores. 30/78 (38.5%) patients
had no cancer on the first rebiopsy. The only significant association for tumour
location emerged between right middle lobe in MRI and right base on rebiopsy
(p=0.004) (Table 16).
Table 16. Associations between MRI and carcinoma location in rebiopsy (Pearson chi-squared test) (study IV).
Rebiopsy
apex dx
mid dx
basis dx
0.430
0.004
apex sin
mid sin
basis sin
0.059
0.545
MRI
apex dx
mid dx
basis dx
apex sin
0.307
0.977
0.584
mid sin
basis sin
0.409
dx = right; sin = left
By the time of the analysis 23 patients had already discontinued AS; 19 of these
were due to reclassification/progression in the first rebiopsy (Gleason score >6
and/or number of PC positive cores >2) and the remaining 4 were because of
biochemical progression, i.e. PSADT<3 years. None of the patients discontinued AS
due to MRI results or anxiety.
The only predicting variable for active treatment was higher PSA at
discontinuation (p=0.002). Appearance of tumour suspicion (Table 17) on T2-W
MRI (p=0.273) or on ADC maps (p=0.691) could not predict treatment change
according to the logistic regression analysis (Table 17). The PPV and NPV for MRI
findings in predicting treatment change were 30% and 73%, and for ADC maps 30%
and 72%.
Table 17. Logistic regression analysis of overall treatment changes (study IV).
Variable
p-value
OR (95% Cl)
Age
0.057
0.9 (0.73-1.01)
PSA at diagnosis
0.371
0.8 (0.41-1.40)
PSA density
0.921
1.0 (0.99-1.01)
% of PC at diagnostic biopsy
0.199
1.8 (0.74-4.28)
PSADT
0.921
1.0 (0.99-1.01)
PSA at stopping AS
0.002
1.8 (1.23-2.59)
MRI/T2
0.273
3.4 (0.38-30.73)
ADC
0.691
0.6 (0.07-5.86)
ADC = apparent diffusion coefficient; OR = odds ratio; PSA = prostate-specific antigen
53 Results of RP specimen were available from 22 patients. All PCs in specimens were
small (median cancer surface 5%; range 1-25%) and prostate confined (<pT3). Four
patients had a Gleason score of 6, 12 patients Gleason scores of (3+4) and six
patients Gleason score of (4+3) for PC. Of 22 operated patients, 50% (11) had a
lesion suggestive of malignancy as indicated by DW-MRI and in eight patients the
lesion also appeared malignant in the ADC map. No significant association was
noted between cancer location in RP specimen and MRI.
8.5
Free/total PSA ratios in patients on AS (study V)
The diagnostic %fPSA value data of 939 PRIAS patients were obtained. Table 18
presents the characteristics of the study cohort. By the time of the analysis 438 men
had been on AS for at least a year and these men provided data for the 12 months
follow-up %fPSA measurements.
By the time of analysis 656/939 (69.9%) patients of study cohort were still on
AS, because 283/939 (30.1%) had discontinued. Of these 283, 181 (64.0%) had
discontinued AS for protocol-based reasons and 102 (36.0%) for non-protocol based
reasons such as anxiety. The median surveillance was 17.2 (range 0.7-82.7) months.
The median follow-up period until discontinuation (for all reasons) was 14.7 months
(range 0.7-82.7) and for protocol-based discontinuation 14.9 (range 4.0-54.8)
months. Of the discontinued patients, 153 (54.1%) had undergone RP (i.e. robotassisted laparoscopic or open retropubic), 32 (11.3%) had EBRT, 40 (14.1%) BT
and one (0.4%) patient underwent HIFU. 19 (6.7%) patients had changed AS to WW
and in 38 (13.4%) patients another kind of management option was chosen or
information about treatment was not available.
Table 18. Characteristics of the study patients (study V).
Variable
Age, yr, median (25-75p)
All patients (n=939) No treatment (n=758) Active treatment (n=181)
64.9 (60.0-69.6)
65.2 (60.1-69.8)
64.4 (60.4-68.3)
p value
0.290
Prostate vol, cm3, median (25-75p) 44.0 (34.9-54.0)
44.0 (35.0-55.0)
43.7 (33.5-52.0)
0.176
PSA, ng/mL, median (25-75p)
5.6 (4.5-7.0)
5.6 (4.5-6.8)
5.8 (4.8-7.3)
0.063
%fPSA, median (25-75p)
14.5 (9.7-18.8)
14.7 (10.1-19.7)
13.5 (8.6-18.6)
0.068
PSAD, ng/mL/g, median (25-75p)
0.13 (0.10-0.16)
0.13 (0.10-0.16)
0.14 (0.11-0.17)
0.001*
Clinical stage, no (%)
T1c
T2a-c
863 (91.9)
76 (8.1)
699 (92.2)
59 (7.8)
164 (90.6)
17 (9.4)
Biopsy cores median, no (25-75p)
12 (10-12)
12 (10-12)
12 (10-12)
0.451
0.004*
Positive biopsy, no (%)
1
649 (69.1)
534 (70.4)
115 (63.5)
2
282 (30.0)
216 (28.5)
66 (36.5)
NA
8 (0.9)
8 (1.1)
*Significant result (p<0.05)
th
25-75p = 25-75 percentile
PSA = prostate-specific antigen; fPSA% = free/total PSA ratio (%); PSAD = prostate-specific antigen density
0.050
54 First rebiopsy results were available for 595 of the study patients. PC reclassification
occurred in 144 (24.2%). The predicting variables for adverse first rebiopsy findings
(i.e. Gleason score >6 and/or >2 PC positive biopsy cores) were the number of
cancer positive cores (one versus two) at the diagnostic biopsy (p=0.000) and age at
diagnosis (p=0.002) (Table 19).
Table 19. Association of baseline characteristics with rebiopsy progression (study V).
Baseline characteristics
1-year rebiopsy (n=595)
OR (95% Cl)
p value
Age at dg
1.1 (1.02-1.09)
0.002*
PSA
0.96 (0.74-1.25)
0.79
%fPSA
1.0 (0.99-1.04)
0.41
PSAD
1.1 (0.95-1.22)
0.26
Clinical stage
T1c
T2
ref.
1.62 (0.81-3.24)
Total Bx cores
0.98 (0.88-1.08)
Positive Bx cores
1
2
ref.
2.06 (1.38-3.09)
0.17
0.64
0.000*
*Significant result (p<0.05)
PSA = prostate-specific antigen; fPSA% = free/total PSA ratio (%); PSAD = prostate-specific antigen density; OR = odds ratio;
CI = confidence interval
In a multivariate analysis, baseline %fPSA could not predict the probability of
treatment change, although after a year of AS the difference in median %fPSA
values between those men still on AS compared to those who had discontinued was
statistically significant (p=0.031) (Table 20). The probability of discontinuing AS
was significantly lower in men with a baseline of %fPSA ≥15 and a positive %fPSA
velocity compared to men with a baseline of %fPSA <15 and a negative %fPSA
velocity (p=0.001)(Fig.10).
Table 20. Baseline %fPSA and after 12 months of AS, stratified into subgroups on the basis of treatment change
(study V).
AS
continue/
discontinue
(n=438)
%fPSA at dg, median (25-75p)
AS continued
(n=324)
AS discontinued due to protocolbased reasons (n=114)
p value
14.4 (8.9-18.5)
13.0 (8.7-17.9)
0.602
%fPSA after 12 months,
median (25-75p)
16.6 (10.7-20.9)
13.1 (10.0-18.5)
0.031*
*Significant result (p<0.05)
dg = diagnosis;
25-75p = 25th and 75th percentiles
55 Figure 10. Treatment-free survival of study patients stratified into subgroups based on %fPSA characteristics
(study V).
1) %fPSA ≥15 and %fPSA velocity positive
2) %fPSA ≥15 and %fSA velocity negative
3) %fPSA <15 and %fPSA velocity positive
4) %fPSA <15 and %fPSA velocity negative
Statistical differences between groups: p <0.05; 1 vs. 4
p ≥0.05; all other comparisons
Cox regression analysis demonstrated an association between PSAD and treatment
change, as well as an association between the number of PC positive cores at the
diagnostic biopsy and treatment change due to protocol-based reasons (Table 21).
Cox regression analysis also revealed that PSAD was the only baseline variable
predictive for unfavourable RP findings (T3 and/or Gleason score of >6) (Table 22).
Table 21. Association of baseline characteristics with treatment change (protocol-based) over time (study V).
Baseline characteristics
p value
Age at dg
Treatment change
(n=181)
HR (95% Cl)
1.0 (0.97-1.02)
PSA
1.0 (0.94-1.14)
0.48
%fPSA
0.99 (0.88-1.20)
0.74
PSAD
1.1 (1.01-1.11)
0.013*
Clinical stage
T1c
T2
ref.
1.3 (0.74-2.18)
Total Bx cores
1.0 (0.92-1.08)
0.81
0.39
0.92
Positive Bx cores
0.019*
1
ref.
2
1.5 (1.07-2.01)
*Significant result (p<0.05)
PSA = prostate-specific antigen; fPSA% = free/total PSA ratio (%); PSAD = prostate-specific antigen density;
HR = hazard ratio
56 Table 22. Association of baseline characteristics and PSA-DT with unfavourable radical prostatectomy findings
(Cox regression) (study V).
Baseline characteristics and
PSA-DT
Radical prostatectomy
(n=53)
HR (95% Cl)
p value
Age at diagnosis
1.0 (0.97-1.01)
0.43
PSA
0.9 (0.74-1.06)
0.18
%fPSA
1.0 (0.98-1.06)
0.43
PSAD
3.5 (1.14-5.09)
0.028*
Clinical stage
T1c
T2
ref.
0.76 (0.21-2.73)
Total biopsy cores
1.1 (0.72-1.68)
Positive biopsy cores
1
2
ref.
1.1 (0.63-2.12)
0.67
0.84
0.20
PSADT
0.41
Negative or >10 yrs ref.
3 to 10 yrs
1.0 (0.48-2.11)
<3 yrs
0.6 (0.25-1.43)
*Significant result (p<0.05)
HR = hazard ratio; PSA = prostate-specific antigen; fPSA% = free/total PSA ratio (%); PSAD = prostate-specific
antigen density; PSADT = PSA doubling time
57 9.
DISCUSSION
9.1
Short-term outcomes of the PRIAS study (study I)
AS has been proposed to alleviate the problem of overdiagnosis and overtreatment of
low-risk PCs. Special interest in AS was shown when the ERSPC data on decreasing
mortality were published (Schröder et al. 2009; Schröder et al. 2012) in tandem with
the notion of overdiagnosis.
The study I presents interim data from the largest prospective AS cohort,
with a good protocol compliance, based on the first 500 PRIAS study inclusions.
The main outcome parameter was ATFS. The results showed that one out of every
four patients following a strict surveillance protocol discontinued AS, the ATFS
value was 73% after 2 years. In the majority of cases, AS was discontinued for
protocol-based reasons (83%). Adverse rebiopsy findings were an important reason
for discontinuation of AS, since every fifth patient had adverse characteristics in the
standard 1-year rebiopsy. PSADT, which was calculated after a year of surveillance,
was not significantly associated with favourable or unfavourable rebiopsy outcomes.
The short-term results of this prospective study are valuable in assessing the utility
of this AS protocol in men with early PC.
Recently published results from more mature PRIAS data demonstrated a
slightly higher ATFS rate of approximately 77% at two years (Bul et al. 2013b). In
general, results of this study are in accordance with the other AS studies, which have
reported ATFS rates between 67-86% (van As et al. 2008; Dall'Era et al. 2008; Klotz
et al. 2010b; Soloway et al. 2010; Tosoian et al. 2011), though this depends on
patient selection and median follow-up periods. During AS, approximately every
third PC will be reclassified and such patients have higher risk for disease
progression. The proportion of men discontinuing surveillance, mainly depends on
how stringent the inclusion criteria for AS are and how rapidly the clinician is
willing to initiate active treatment. The more stringent criteria for AS, i.e. biopsies
with only one or two positive cores with minimal PC will be, the more likely to
comprise a cohort that remain untreated. Based on the interim results of PRIAS trial
(I) and other AS studies, it seems obvious, that a considerable number of patients
discontinue AS during follow-up and this emphasizes the importance of accurate
staging and grading at diagnosis. If patient selection could be improved, perhaps AS
follow-up strategies could be simplified. Avoiding or delaying radical treatments is a
fundamental goal of AS. Therefore, the switching to deferred active treatment during
surveillance when reclassification or progression of disease occurs, is a relevant part
of this strategy.
In most cases tumour upgrading is probably caused by undersampling at
diagnostic biopsy, thus subsequently leading to tumour reclassification at rebiopsy
(Bul et al. 2012a), although true biological progression of PC may also occur. 22%
of our patients had adverse rebiopsy findings in the 1-year rebiopsy. Results for
PRIAS data with longer follow-up and larger patient cohort are similar, as 27% of
men experienced PC reclassification at rebiopsy during surveillance. Other studies
have reported reclassification rates between 18-55% of cases (Al Otaibi et al. 2008;
Ross et al. 2010; Adamy et al. 2011; Isharwal et al. 2011; Kotb et al. 2011). In our
analysis the number of positive biopsy cores at diagnostic biopsy was the only
parameter that showed a positive association to unfavourable rebiopsy result. The
58 most recent analyses from PRIAS data have demonstrated, that the strongest
predictor for reclassification is PSAD, in addition to the number of positive biopsy
cores (Bul et al. 2012a; Bul et al. 2013b). One of the main aims of AS studies is an
attempt to find those factors that could predict and identify higher risk PCs in AS
cohorts. With more precise predictors and patient selection it would be possible to
reduce the number of patients who undergo reclassification of PC and treatment
change. At present, MRI and novel biomarkers such as isoforms of PSA are under
very active research in their potential roles as tools in AS protocols.
The number of RP specimens in the present study (I) is too low to draw any
definite conclusions. However, the results of our cohort of deferred RPs are in line
with those of previously published studies that have evaluated RP outcomes of men
who would have been eligible for AS (Conti et al. 2009; Kane et al. 2010; Thaxton et
al. 2010; Drouin et al. 2012;). The rate of tumour upgrading in these studies varied
between 21-36%, positive surgical margin rates ranged between 14-35% and the
extracapsular extension rates were between 5-19%. One of the main issues related to
the AS is the concern of ‘missing the window’ of curability. In comparison to
immediately treated patients, it would be logical that larger PCs and more
extracapsular extension could appear in RP specimens after surveillance. Patients
were directed for deferred active treatment mainly because of increasing PSA values
or because of an upgrading at rebiopsy. This would make the patient cohort more
selected than those in a retrospective series, which evaluate RP outcomes of patients
who would otherwise have been eligible for AS. Several studies have already
evaluated the oncological outcomes of the RP series compared to immediate
treatment in men with low-risk PC and in most series no significant differences
between outcomes have been observed (Warlick et al. 2006; van den Bergh et al.
2010b; Holmstrom et al. 2010; Dall'Era et al. 2011; Bul et al. 2012c). Recently, RP
outcomes from the more mature PRIAS data have been published. Those authors
found that in the majority of cases pathology results of deferred RPs had organconfined PC and favourable Gleason gradings.
The strengths of this study (I) are its prospective nature and the large patient
cohort. The PRIAS study has already included more patients than any other
prospective AS trial. This study also has robust protocol compliance with PRIAS
and adherence, which is probably due to web-based inclusion and follow-up. The
limitations of this study are the lack of a randomized control group, which received
immediate radical treatment after PC diagnosis and a short follow-up period. Based
on the current analysis, I conclude that no new indications could be found that would
tighten the existing PRIAS criteria and thereby improve the safety of the AS
strategy. Moreover, the data of study I emphasizes the importance of prostate
rebiopsy during AS.
9.2 QOL during the continuum of PC: the effect of the
screening process and AS (studies II and III)
Studies II and III both show that short-term changes in health-related QOL appear
non-substantial during the screening process or during AS, as measured by the
RAND-36 instrument. In addition, both studies show that the mean HRQL scores are
comparable to those of the general Finnish population; in patients on AS perhaps
59 even better. This is likely a consequence of selecting those patients for AS who,
according to a treating clinician, can psychologically cope with it.
9.2.1 Short-term effects of PC screening on HRQL (study III)
Although reduction in mortality from PC is the principal endpoint in the screening
trials, the effects on QOL are also important. Some concern has been raised about
the possible negative effects on psychological health and QOL that relate to
screening process. Our results suggest that population-based PC screening does not
seem to provoke major effects on participants’ short-term HRQL, as assessed by the
structured and validated RAND-36 instrument (III). The minor differences in HRQL
observed between the five phases of PC screening were not significant. The changes
in HRQL seem to have been temporary as they occurred only at one time point and
did not persist throughout the screening process. Our results are supported by the
outcomes of previous studies that concluded PC screening has only little if any
impact on the psychological health of the participants (Brindle et al. 2006; Awsare et
al. 2008). Negative emotional impacts may araise, but these do not seem to persist in
the long-term (Collins et al. 2011). Increased cancer-related anxiety in the short-term
has been reported, but again, no severe or long-term effects were observed (Wardle
et al. 1993). One exception may be those screening participants who have preexisting anxiety, as they also tend to remain anxious (Essink-Bot et al. 1998). In
concordance with our results, the Rotterdam section of the ERSPC trial also reported
minor effects of PC screening on QOL or health-status in the short-term. An
exception were short-lasting side effects that were related to the prostate biopsy
(Essink-Bot et al. 1998). This is logical, since TRUS-guided prostate biopsy has
been associated with discomfort, anxiety and substantial pain in a proportion of men
(Peyromaure et al. 2002), even to the extent, that some men refused rebiopsy. TRUS
and biopsy could be considered as a threshold for screening participants as they are
the most invasive part of PC screening process. However, only a minority of men
experience elevated distress levels at the time of prostate biopsy or after receiving
negative results (Macefield et al. 2010). Similarly, a higher serum PSA value, older
age or a PC positive family history did not predict anxiety in men during a testing
process for PC (Macefield et al. 2009). Even men with false-positive screening
results have been reported to view their screening experience as positive (Essink-Bot
et al. 2003). In contrast, a later study revealed that a proportion of men with a benign
prostate biopsy result were concerned about PC (Katz et al. 2007). Overall it seems
that the most significant adverse psychological and QOL effects occur mainly after
PC diagnosis during the period of different treatments or surveillance strategies.
Overall, only a few statistically significant differences were observed
between different phases of the screening process in this study. The emotional-role
subscale score decreased following DRE, but it is unclear, if this is the effect of the
examination itself or if it relates to the awareness of further diagnostic examinations.
Study participants were aware of their abnormal screening results, but at the time
their HRQLs were evaluated, they were not aware of the findings of the current
screening phase. Therefore, these screening phases were thought to be the most
stressful, but surprisingly HRQL scores turned out to be better in men with an
abnormal screening finding (PSA≥3), compared to participants with normal PSA
value. One explanation for this can be, that men with an abnormal PSA result felt
60 relieved by the fact that they were being further examined by the clinician. The
ordinal regression analysis indicated that a higher PSA was associated with a better
HRQL except at the DRE phase. However, some studies have shown, that men with
an elevated PSA value are not able to assess the risk for false-negative or falsepositive results, or risk for PC, as both over- and underestimations are common
(Frosch et al. 2001; Chan et al. 2003; Katz et al. 2007).
Studying five different cohorts at different phases of screening instead of a
longitudinal cohort moving along each of five phases may be considered as a
shortcoming of this study. However, this study design was originally chosen to avoid
bias arising from loss during follow-up, which would likely have occurred, if the
same study group had been asked to fill in the same questionnaire for up to four
times at consecutive phases of the screening process. In addition, a large number of
participants would have been needed, to ensure that a sufficient cohort of study
participants would have been available in the final phase, due to incomplete
participation and the relatively low number of men that would be referred and have
to undergo prostate biopsy. A potential bias could also have resulted from
participants responding to the questions in the same way out of habit. Our study
design may increase sampling error, but we found no indication of such as judged by
the sociodemographic and lifestyle factors of three study samples. A potential bias
that should be taken into account when interpreting our study results, is the lack of
comparisons between groups of respondents and non-respondents.
9.2.2 Short-term changes in HRQL during AS (study II)
Some concern has been raised about AS causing a psychological burden on patients
as they live with untreated PC. Our results (II) contradict this and show that men
with low-risk PC manage AS well, i.e. AS does not seem to provoke adverse HRQL
changes in the short-term. The only statistically significant finding was the
improvement in physical role functioning, but that change was not considered to be
clinically significant (II). In our study cohort, none of the patients discontinued AS
due to non-protocol based reasons such as anxiety or distress. In the majority of men,
the reason for discontinuation was reclassification of PC in the first prostate rebiopsy
a year after follow-up. These results are in line with the findings of recent studies
showing that QOL is relatively good in most men on AS, with low levels of anxiety
and distress, and good psychological and physical wellbeing (van den Bergh et al.
2009a; van den Bergh et al. 2010a).
Psychological factors, such as increased anxiety or distress, may lead to
discontinuation of AS. In the public mind the term ‘cancer’ is generally conflated
with a dreaded disease, and a diagnosis of cancer is strongly associated with a
distressing experience. The diagnosis of PC is also likely to cause many
psychosocial responses in patients and their family members. Men who consider
low-risk cancer as a dreaded and life-threatening disease, are probably more suitable
candidates for immediate curative treatment, as a conservative management option
such as AS may be difficult for them to accept thus causing more anxiety, distress
and perhaps reduces their general QOL. Awareness of the untreated cancer may also
cause undue anxiety during follow-up, resulting in discontinuation of surveillance in
the absence of objective signs of disease reclassification or progression. Some
studies have reported nonmedical reasons to be a significant factor, which
61 contributes to discontinuing AS (Choo et al. 2002). In our study cohort of 500
patients (I), only a minority (17%) of men stopped AS due to psychological factors
(i.e. increased anxiety/distress) or on request. In a recent update of the PRIAS trial,
the proportion of patients who switched from AS to deferred treatment because of
anxiety was 9% (Bul et al. 2013b). Interestingly, none of the patients in the Finnish
arm of the trial discontinued AS due to anxiety (II). It is remarkable that these
studies are nonrandomized and participants comprise a highly self-selected cohort.
This may explain to large extent the low impact of AS on HRQL (II). After PC
diagnosis, patients are comprehensively informed about the different treatment
options in the discussions with a clinician and with a specialized PC nurse. Our
patients (II) also completed their first HRQL questionnaire only after choosing AS as
their treatment option and thus they were already aware of the good prognosis of
their disease. This may have further alleviated the anxiety and psychological stress.
After discussions with the treating urologist and in the opinion of that urologist’s,
only patients considered able to be able to cope well mentally with the idea of
‘possibly insignificant PC’ and ‘living with untreated PC’, were actually offered AS
as their primary treatment choice, making the study cohort highly selected. Thus, it
may be possible that only those patients with favourable psychological
characteristics and who are likely to adhere to study protocol are eventually
included. Perhaps as a result of the multidisciplinary teamwork (a clinician and a PC
nurse) described in this study and the highly selected group of patients, none of the
patients in our cohort discontinued due to anxiety (II).
When properly selecting patients for AS, it is important for a clinician to be
aware of the possible risk of psychological morbidity in men during AS, as
psychological symptoms may influence patient’s likelihood to discontinue
surveillance. The personality of the patients and their behavioural characteristics
should be considered within a broader perspective, because these may have a
considerable effect on the psychological burden in the long-term (Blank and Bellizzi
2006). On some occasions, uncertainty and awareness of the existence of an
untreated cancer may become too much for a patient to bear, leading to immediate
radical treatment instead of AS, to prevent continuing or increasing concerns about
the disease (Patel et al. 2004). The Dutch PRIAS investigators reported that during a
nine-month period of AS, anxiety and distress levels remain relatively low, but
patients with a more neurotic personality and lower physical health scores had higher
anxiety and distress levels (van den Bergh et al. 2009a; van den Bergh et al. 2010a).
Impaired mental health has also shown to be a predictive factor for poor QOL in
men on AS (Bellardita et al. 2013).
Although AS as a management option for low-risk PC is gaining popularity
currently, only a limited proportion of men who were suitable for this strategy
eventually choose AS (10-57%) (Cooperberg et al. 2007; Miocinovic et al. 2011).
The main reason for choosing AS, is the wish to delay the possible physical side
effects of radical treatments (van Vugt et al. 2012). However, uncertainty related to
untreated PC and the fear of cancer progression are the main reasons to abandon AS
as an option (Steginga et al. 2008; Xu et al. 2011). Experiences of friends and family
members have a significant influence on a patient when he is considering the choice
of treatment options (Xu et al. 2011). Demographic factors and the extent of
knowledge about PC may infuence and also contribute to the treatment choice (van
den Bergh et al. 2012). The clinician has a key role in the choice made as the
patients are strongly influenced by their treating clinicians with regard to selecting
62 the treatment (Davison and Goldenberg 2011; Xu et al. 2011). A previous study
suggested that men diagnosed with low-risk PC should obtain improved support and
patients and their partners should be more involved in the decision-making process
(Steginga et al. 2008). The active participation of the patient in the treatment
decision may have a positive effect on that patient´s sense of control. A common
phenomenon is that patients have difficulties in decision-making and thus decisionrelated distress may persist over time. Cancer-specific psychological distress (such
as fear of recurrence, but not overall anxiety) appears to be related to elevations of
PSA levels; and this distress also influences treatment pathways. Decision support
interventions are known to be acceptable to men, they improve patients’ knowledge
and may reduce decision- and cancer-related distress (Steginga et al. 2008). Every
person is unique and there is a wide variation in the amount of psychological care
and support an individual needs (Lintz et al. 2003). It is probable that the importance
of multidisciplinary teams will be emphasized in supporting men during AS, such as
when guiding how to cope with higher levels of anxiety and distress. Increased
education, communication and peer-support groups may also alleviate and improve
the sense of patient’s control of the situation during AS (Pickles et al. 2007).
The results of study II indicate that AS does not seem to provoke significant
short-term QOL disturbances in respect of urinary or erectile function, as assessed
by the standardized IPSS and IIEF-5 questionnaires. A minor, but statistically
nonsignificant, increase was noted in the IPSS total score. Urinary, sexual and bowel
function scores have been shown to decrease due to aging alone during WW and the
same is expected to occur during AS (Arredondo et al. 2008). Side effects of radical
treatments may improve even for a long time after treatment, whereas urinary, bowel
and sexual functions may worsen during AS. A previous retrospective study has
demonstrated the preferable side effect profile of AS (urinary, bowel or sexual
function scores) compared with the side effects of radical treatments (Thong et al.
2010). However, prospective and randomized trials with longer follow-up are needed
to clarify the true longitudinal changes associated with AS.
The strengths of study II are its prospective nature and the use of
standardized, validated questionnaires. Its limitations include the lack of
randomization and a highly selected patient cohort. A longer follow-up period is
needed to have longitudinal evidence regarding to HRQL in patients on AS. The
effects of different treatments for low-risk PC on HRQL should also be compared
more comprehensively in randomized trials, such as the ProtecT study (Lane et al.
2010).
9.2.3 Challenges in measuring QOL (studies II and III)
In both of the QOL studies (II and III), the same generic HRQL intrument, RAND36 was used. This questionnaire is extensively validated and has been used earlier. A
challenge in measuring HRQL is in its multidimensional nature, which includes
physical, mental and social components. Generic, domain- or disease-specific
questionnaires can be used for QOL studies. The advantage of using generic
questionnaires, such as RAND-36, is the possibility for comparison across diseases,
disease stages, treatments and between individuals with and without the condition. A
drawback of generic questionnaires is the lack of sensitivity and specificity for the
detection of minor subtle changes in a person´s mental or physical health, which are
63 induced by inter alia PC screening or the AS protocol. Baseline psychological
factors can continue to be predictive of anxiety and distress long after the screening
process and during AS. These psychological phenomena may not be measurable by
using only general HRQL questionnaires. In addition, measuring generic HRQL is
merely an indirect way of studying possible coincidental emotional reactions that
have arisen during screening process or during AS. In this study, we did not have
information on the men's personality traits such as their predisposition to anxiety, or
their coping strategies. In order to detect possible subtle changes in men´s
psychological function during the screening process or in AS, more sensitive
measures that focus on specific symptoms such as anxiety or distress might be useful
(Avery et al. 2008; Macefield et al. 2010). In addition, another challenge to QOL
based-studies is the timing of when the questionnaires were given as it has been
observed that QOL can vary rather rapidly, even while waiting for a PSA result
(Dale et al. 2005).
9.3 Possible diagnostic and prognostic tools for AS
(studies IV and V)
9.3.1 DW-MRI in AS (study IV)
One objective of study IV was to evaluate, if DW-MRI interpreted in a routine
clinical setting by a general uroradiologist, could be used as a diagnostic or
prognostic tool in AS. A specific aim of the study was to clarify, whether DW-MRI
findings would correlate with rebiopsy findings and whether treatment change could
be predicted. Study data revealed only a poor correlation between tumour location
on MRI and prostate biopsies, and also tumour appearance on MRI could not predict
either treatment change or rebiopsy findings.
DW-MRI has been shown to be more sensitive and specific in detecting
malignant tumours than conventional T2-W MRI (Kim et al. 2007; Afaq et al. 2011;
Miao et al. 2007). DW-MRI also offers additional information and value in the form
of ADC maps (Vargas et al. 2011). Only a few studies have shown MRI and ADC
mapping to be a valuable tool in PC imaging on AS. One of those studies showed
that ADC values for both benign and cancerous tissue decreased over time in men
with PC progression in AS, whereas the changes in ADC values were not significant
in non-progressors (Morgan et al. 2011). Other studies showed that tumour ADC
values can be potentially differentiated between high-risk and low-risk PC (deSouza
et al. 2008) and predicted deferred radical treatment (van As et al. 2009).
Multiparametric MRI i.e. the combination of different MRI modalities (T2 weighted
imaging combined DW-MRI and/or DCE-MRI and/or MR spectroscopy) may
further improve the performance of MRI (Turkbey et al. 2011a). The usefulness of
MRI in patients on AS is currently under active research, and some studies have
already supported the incorporation of MRI into surveillance protocols (van As et al.
2009; Fradet et al. 2010; Vargas et al. 2011; Margel et al. 2012).
Results of the present MRI-study (IV) showed a poor correlation between
biopsy and MRI findings, especially in the apex. One explanation for this result may
be, that the biopsies themselves correlated poorly with the respective RP specimen
64 (Gregori et al. 2001; Mayes et al. 2011). Moreover, most of the study patients in our
PRIAS AS programme (IV) were likely to have a minimal low-grade PC. We found
that one out of three patients had no cancer on rebiopsy and the majority of men with
cancer on rebiopsy had small Gleason score 6 PC foci. This finding is in line with
the results of previous studies, which found that low-grade PCs are a challenge to
visualize on MRI (Vargas et al. 2011; Guzzo et al. 2012). Although encouraging
results have been published for the use of MRI during AS (van As et al. 2009; Fradet
et al. 2010; Vargas et al. 2011; Margel et al. 2012), some studies have failed to show
such a benefit (Cabrera et al. 2008; Ploussard et al. 2011c; Shukla-Dave et al. 2012).
Clearly, our results are hampered by the fact that MRIs were evaluated by a general
radiologist, instead of uroradiologist with a special expertise in interpreting prostate
MRI findings. It has been shown that the experience of radiologists has a significant
influence on diagnostic accuracy in interpreting MR images. The number of false
reports is dependent on the observer and the rate of misinterpretations has been
found to be significantly higher in a less experienced group of radiologists (Krampla
et al. 2009). In the present study (IV), the small number of RPs was such that the
correlation analysis between MRI and RP findings lacked statistical-power.
Guidelines have recently been introduced for prostate MRI imaging
including a structured reporting protocol (Barentsz et al. 2012), to improve the
reproducibility and reliability of MRI. The published guidelines indicate, that the
current minimal requirements for DW-MRI are b-values of 0, 100, and 800-1000
s/mm2 (Barentsz et al. 2012). When study (IV) was originally designed, no standard
technique for performing prostate DW-MRI existed, nor was there any
recommendation for a structured reporting protocol. The b-values used (300-600
s/mm2) in study (IV) may not have been optimal, as clearly higher b-values are
currently recommended for PC detection (Hoeks et al. 2011). It may be that the
tumours are probably not visible with b-values under 600 s/mm2 (Afaq et al. 2011).
Another limitation of this study is the use of qualitative (rated as either positive or
negative) instead of quantitative analysis. Dichotomizing continuous variable (ADCvalues) may have resulted in a loss of power of the analysis, despite the fact that
currently there is no consensus of the cut-off ADC values for malignant findings for
the prostate (Kim et al. 2007; Gibbs et al. 2009; Woodfield et al. 2010; Vargas et al.
2011). Patients in our study had MRI only after one year of follow-up, but not at the
diagnosis. This can cause some bias in the assessment of MRI as changes during
surveillance cannot be analysed. However, the rationale to conduct MRI before
standard 1-year rebiopsy was based on the fact that transrectal prostate biopsy may
miss a considerable number of tumors, especially tumours that are located apically.
Another aim of the study was to rule out these tumours during AS (Vis et al. 2000;
Mazal et al. 2001; Iremashvili et al. 2012). In addition, multiparametric MRI was not
available in our institution at the time and this may also have contributed to the
results (Turkbey et al. 2011a). Multiparametric imaging in PC diagnosis would also
require a specially trained uroradiologist to interpret the MRI images. Such
uroradiologists will probably not be available in many small-volume centres. The
absence of endorectal coil and the use of a pelvic coil instead, may be considered as
a relative shortcoming of the study, although no consensus exists about the use of
coil type (Dickinson et al. 2011).
The strengths of this study are the use of modern imaging technology (3T
MRI), timing of the rebiopsies and the prospective nature of the study. A recent
65 European consensus meeting concluded that 3T MRI is an optimal imaging
technique (Dickinson et al. 2011) for PC.
The present study (IV) results indicate that DW-MRI as performed here, did
not provide any additional prognostic benefit or reliable information to guide the
treatment of PC patients on AS. Further evaluations by a well-trained uroradiologists
are essential to assess whether multiparametric MRI prostate imaging will add
sufficiently to prognostic tools to justify its routine use in a clinical setting.
9.3.2 %fPSA ratio as a prognostic tool on AS (study V)
Although AS is a widely accepted management option for PC, more accurate staging
and grading at an early stage of PC could further increase the acceptance and uptake
of this strategy. Although there are a lot of expectations for the utility of MRI as a
tool in AS programs, novel biomarkers are also needed and they are under ongoing
urologic research. In the present study (V) we aimed at evaluating if free/total
%fPSA could serve as a prognostic tool in the AS protocol. The specific aim of the
study V was to address, whether a %fPSA evaluation at diagnosis and during followup would associate with rebiopsy or RP findings or whether the discontinuation of
AS could be predicted. Although median %fPSA values were statistically
significantly different between those men still on AS compared to those who had
discontinued, the results showed no clinically relevant associations of diagnostic
%fPSA to guide clinical practice. However, the probability of continuing AS was the
highest in men with favourable %fPSA characteristics at diagnosis and also during
surveillance.
The %fPSA as a marker in predicting the probability of PC diagnosis is
widely evaluated (Partin et al. 1996; Catalona et al. 1998). The association between a
low %fPSA and a clinically significant PC has been demonstrated (Nam et al. 2007),
in addition to the association between a low %fPSA and a higher grade PC with
aggressive characteristics (Southwick et al. 1999; Catalona et al. 2000). Only a few
studies have clarified the role of %fPSA as a prognostic tool in the AS setting. In
contrast to our results, a few previous studies demonstrated that %fPSA may predict
adverse histology in rebiopsy (Selvadurai et al. 2013) and the time to deferred
radical treatment (van As et al. 2008; Selvadurai et al. 2013) in men with low-risk
PC on AS. In contrast to the PRIAS protocol used in studies (I, II, IV and V), the
other patient cohorts also included higher risk cancers, i.e. Gleason score 7 (3+4),
which is likely to increase the statistical power of the analyses for the end-points
used. The PRIAS patient population represents a rather homogenous cohort, as only
minimal findings of low-risk PC and maximum Gleason score of 6 are accepted
criteria. In addition, the definitions for adverse rebiopsy findings and also %fPSA
cut-off used at follow-up, were all different making it difficult to compare the results
between studies. Only the 1-year rebiopsy results were predominantly used for the
analysis in our study due to the limited number of patients available with both
%fPSA and first rebiopsy results. It is probable that first rebiopsies after the year of
surveillance are likely to have a high preponderance of misclassification of PC at
diagnosis instead of true cancer progression. Longer follow-up is, therefore, needed
to further assess the role of diagnostic %fPSA in this PRIAS patient cohort. The
multivariate analysis indicated that baseline characteristics that were associated with
66 treatment change due to protocol-based reasons, were PSAD and the number of PC
positive cores at diagnostic biopsy (study V). This is in line with results from other
AS cohorts (Kotb et al. 2011; San Francisco et al. 2011) and with the data from a
recent PRIAS analysis (Bul et al. 2013b), which also support the validity of the
present analysis.
Although baseline %fPSA could not predict the treatment change, the median
%fPSA value after one year of surveillance was significantly higher in men
continuing AS compared to men who discontinued AS due to protocol-based
reasons. The difference was particularly significant when %fPSA and %fPSAvelocity were used as a joined categorical variable in the analysis. The probability to
continue AS was highest in those patients with a favourable %fPSA at diagnosis and
during surveillance, i.e. an initial %fPSA of over 15 and a positive %fPSA velocity.
At present, the literature on the utility of %fPSA-velocity as a prognostic tool in AS
strategies is scarce. Although the role of PSA-kinetics in general is still unclear and
its utility in AS strategy has raised some doubts (Iremashvili et al. 2013), to our
knowledge %fPSA-velocity has not been studied as a predictor of AS outcomes
before. It may be that longitudinal biomarker measurements have a better predictive
accuracy than a single baseline value in AS programmes (Ng et al. 2009) and serial
measurements over time may provide the potential to characterize the tumour more
accurately than on the basis of a single baseline measurement. Interestingly, recently
published data suggests that PSA-velocity risk count is independently associated
with adverse histology in rebiopsy in an AS cohort (Patel et al. 2013). The
multivariate analysis of our study (V) determined that the baseline variables
predictive of adverse histology in rebiopsy were the number of PC positive cores at
diagnostic biopsy and age. Reclassification of disease was more likely to occur in
men with two cancer positive cores at diagnostic biopsy compared to men who had
only one positive biopsy core. This finding concords with those data of the recent
PRIAS interim study (Bul et al. 2013b), and also with the results from other AS
series (van As et al. 2008; Dall'Era et al. 2008; Klotz et al. 2010b; Tosoian et al.
2011).
Study (V) data could not show any association between %fPSA and RP
findings and the only predicting variable identified by the multivariate analysis was
PSAD, which has also been demonstrated previously (Vellekoop et al. 2014). In
contrast to study V data, few previous studies have shown the association between
low %fPSA values and significant upgrading of low-grade PC after RP (Visapaa et
al. 2010). However, the capability of %fPSA in predicting higher stage PC in RP
(Southwick et al. 1999; Elabbady and Khedr 2006) and also further adverse
pathology following surgery have been reported (Steuber et al. 2007). The small
number of RPs done in our series is insufficient to provide the statistical power
needed for meaningful analysis and therefore results of study V do not allow
drawing of definite conclusions. Furthermore, a larger AS cohort and longer followup time is needed to clarify this issue more precisely.
9.4
Future perspectives
Several prospective AS studies have been initiated within the past decade to increase
our knowledge on AS as a management option for low-risk PC. Unfortunately,
follow-up periods in the majority of AS cohorts are still too short and longer follow-
67 up is needed to evaluate proper long-term outcomes and resolve the optimal
eligibility criteria, the follow-up protocol and any triggers for intervention in AS. At
present, the PRIAS study is the largest prospective AS trial. However, a lack of
randomization must be considered as a study weakness. There are a few challenges
in AS study design regarding the randomization, as the patient cohort needed would
be very large and would need to have a long follow-up time. It is also probable that
eventually the differences in survival benefits of radical treatments appear minor
(Bill-Axelson et al. 2008). In the near future, the results from a randomized ProtecTtrial are awaited. That study aims to evaluate the differences between radical
treatments and AS in low-risk PC, and hopefully it will clarify the assessment of
mortality and morbidity associated with AS and radical treatment approaches (Lane
et al. 2010).
Unless there is a new strategy to prevent the overdiagnosis of low-risk PCs
implemented, AS is likely to remain as a major management option for insignificant
PC. The rationale for the AS strategy is obvious, but there are still challenges to
resolve, e.g. how to distinguish reliably insignificant PCs from aggressive PCs, so
that the curability of the disease is not missed due to misclassification or true
progression or a combination of both. A more accurate staging and grading of PC is
thus needed and research on new biomarkers and imaging techniques, such as
multiparametric MRI, is essential and will hopefully improve the usefulness of AS in
routine clinical practice. Targeted biopsies that use MRI have raised interest in focal
ablation. Treating the dominant PC lesion instead of the whole prostate gland may
result in sufficient PC control while avoiding the side effects of radical treatments
(Hou et al. 2009).
Retrospective studies with longer follow-up have provided evidence that AS
is a safe management option in men with low-risk PC (Bul et al. 2012b; Godtman et
al. 2013), but prospective longitudinal series with longer follow-up are warranted to
validate the accuracy of this interpretation. Currently the inclusion criteria,
surveillance protocols and the triggers for intervention vary between AS trials.
Therefore, detailed reporting of the data from these trials is essential as they mature,
which is the aim of the ongoing PRIAS study. A global AS database with data from
all the major AS series is currently under consideration to overcome inherent
challenges in randomized trials on low-risk prostate cancer. Creation of biobanks,
e.g. the Prostate Active Surveillance Study (PASS), will allow research on the
genetic and molecular profile of low-risk PC and changes of these characteristics
during AS (Newcomb et al. 2010). Patients on AS also represent a cohort that
enables reseach on secondary prevention strategies (Parsons et al. 2009). Finally,
QOL is a subject for further analysis and requires long-term data to clarify the
possible long-term effects of AS on anxiety, distress and QOL in general. The
importance of options and capabilities of multidisciplinary teams in supporting men
during AS especially needs further evaluation.
68 10. SUMMARY AND CONCLUSIONS
The objectives of the present study were to analyse the feasibility of AS strategy and
outcomes in the short-term after PC diagnosis. The QOL of men during the first
steps of the continuum of PC disease, i.e. during the screening and AS was also
studied. The utility of DW-MRI and free/total PSA ratio, as additional prognostic
tools in AS were investigated.
The following conclusions of the five studies can be drawn:
I.
AS appears to be a feasible strategy to avoid overtreatment in the shortterm in selected men diagnosed with low-risk PC. Active monitoring and
applying strict criteria of the PRIAS protocol in study I resulted in a
quarter of the patients discontinuing surveillance after two years. The
main reason for stopping AS was the adverse findings in the standard 1year rebiopsy and biopsy results, and were independent of the PSADT.
The present short-term analysis, indicated the mortality outcomes remain
unknown, but the PRIAS-based protocol used in study I seems not to
have comprised curability.
II.
The standardized QOL questionnaires revealed that AS does not seem to
cause short-term QOL disturbances, when the questionnaires were
administered to patients after entering AS and who were receiving
specialized support for their management choice. During the short
follow-up none of the study patients discontinued due to anxiety or
distress. The HRQL of patients on AS was significantly better than for
the general age-stratified Finnish male population.
III.
HRQL effects of PC screening, as carried out in the Finnish arm of the
ERSPC study and assessed by standardized HRQL-questionnaire, appear
minor and transient in the short-term. The screened participants were also
found to be comparable to the general population as HRQL scores were
similar to those of the age-stratified general Finnish male population.
IV.
DW-MRI data, as interpreted in a routine clinical setting and performed
in study IV, did not provide additional prognostic benefit in comparison
with the PSA measurement or with prostate rebiopsies. Localized lowgrade PC is challenging to visualize by DW-MRI and it should be further
studied. It remains to be seen, if the multiparametric approach of prostate
MRI and well-trained uroradiologists will add sufficiently to pre-existing
prognostic tools of AS and induce the routine use of MRI in a clinical
setting.
V.
Diagnostic %fPSA alone could not provide any detectable additional
prognostic benefit when compared to other predictors already used in AS
protocols, such as PSA-kinetics. However, %fPSA coupled to %fPSA-
69 velocity during AS may aid in predicting the probability for
discontinuation of AS due to protocol-based reasons and future treatment
change.
70 11. ACKNOWLEDGEMENTS
The present study was carried out at the Department of Urology of the Helsinki
University Central Hospital. I wish to express my sincere gratitude to a number of
people who made this work possible:
I wish to express my utmost and sincere gratitude to my supervisor Docent Antti
Rannikko, M.D., Ph.D. for proposing the topic of this study and for affording me the
opportunity for scientific work in the PRIAS study. His advice, guidance and
experience were essential during the study and completing this thesis.
I want to honour the memory of Professor Mirja Ruutu, M.D., Ph.D. I am deeply
grateful to her for her valuable expertise, enthusiastic support and encouragement in
the beginning of and during this study. Her charisma, expertise and attitude to both
science and urology made her a role model for us younger urologists.
I wish to express my gratitude to Professor Anssi Auvinen, M.D., Ph.D., Professor
Monique Roobol, Ph.D. and Professor Kimmo Taari, M.D., Ph.D. for their valuable
guidance, advice and support in drafting the original manuscripts.
I want to thank Docent Mika Matikainen, M.D., Ph.D., the Chief of the Department
of Urology in Helsinki University Central Hospital, and Eero Wuokko, M.D., the
former Chief of the Department of Urology in Helsinki University Hospital for
providing me with the facilities for this research work and thesis.
I want to thank all PRIAS co-researchers and all co-authors; it has been a pleasure to
collaborate with you. Especially, I want to thank Kanerva Lahdensuo M.D., and
Utku Lokman M.D. for warm collaboration and scientific brainstorming during this
study.
I am grateful to our PRIAS study nurses Seija Björklund, Anja Laukka and Pirjo
Lehtolainen for their invaluable assistance during this study. Without their
contribution to PRIAS study, it would not have been possible to accomplish this
work.
I wish to acknowledge all the international PRIAS co-researchers, and all the
urologists and nurses in Finnprostate XI trial centers.
I want to express my gratitude to Docent Jukka Häkkinen, M.D., Ph.D. and Docent
Markku Vaarala, M.D., Ph.D, the official reviewers, for their valuable criticism and
constructive review of the manuscript. Their advice produced a significant
improvement in the manuscript.
I acknowledge Alisdair Mclean, Ph.D., for revising the English of this thesis.
I want to thank Raino Terho, M.D., the Chief of the Department of Surgery in
Savonlinna Central Hospital, for introducing me this supreme specialty, Urology.
His enthusiasm and expertise in urology influenced the choice of my future career.
71 I wish to thank my colleagues and the other staff in the Urological Clinic for the
support and the positive attitude to my work.
I want to thank my relatives and friends for their encouragement during this study.
Especially, I express my warmest thanks to my mother Ritva and father Jukka, for
their everlasting love and support, and for making me become who I am. And my
brother Olli, I want to thank you for all the help and encouragement during this
study.
Finally, I want to give my deepest love to my family. Markku, I thank you for the
patience, love and understanding during these many years. I am grateful for your
everlasting support. And Martta, you are the joy of my life.
This study has been financially supported by the Biomedicum Helsinki Foundation,
the Finnish Cancer Society and the Finnish Urological Association.
Helsinki, May 2014
Hanna Vasarainen
72 12.
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101 13. APPENDICES
The FinnProstate XI Co-ordinators and Trial Centers
Etelä- Pohjanmaa Central Hospital, Seinäjoki: Markku Leskinen
Etelä-Savo Central Hospital, Mikkeli: Niilo Hendolin, Tapani Liukkonen
Helsinki University Hospital: Antti Rannikko
Kuopio University Hospital: Sirpa Aaltomaa
Kuusankoski District Hospital: Markku Multanen, Markku Onali
Oulu University Hospital: Pekka Hellström, Erkki Ollikkala
Päijät-Häme Central Hospital, Lahti: Taina Isotalo
Tampere University Hospital: Andres Kotsar, Teuvo Tammela
102 Rand-36 health-related quality of life questionnaire
103 104 105 106 IPSS questionnaire
1. Kuinka usein teillä on ollut tunne, että rakko ei ole tyhjentynyt täysin virtsaamisen
jälkeen?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
2. Kuinka usein teidän on täytynyt virtsata uudelleen ennen kuin edellisestä
virtsaamisesta on kulunut kaksi tuntia?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
3. Kuinka usein olette huomannut, että virtsasuihku on katkeillut virtsaamisen aikana?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
4. Kuinka usein teillä on ollut vaikeuksia pidättää virtsaa virtsaamistarpeen ilmaannuttua?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
107 5. Kuinka usein olette huomannut, että virtsasuihku on heikentynyt?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
6. Kuinka usein olette joutunut ponnistelemaan saadaksenne virtsaamisen käyntiin?
Ei koskaan
Noin joka 5. kerta
Noin joka 3. kerta
Noin joka 2. kerta
Noin kahtena kertana kolmesta
Melkein aina
7. Kuinka monta kertaa yön aikana olette tavallisimmin joutunut nousemaan virtsalle
mentyänne illalla nukkumaan ja ennen kuin nousitte aamulla ylös?
En kertaakaan
Kerran
2 kertaa
3 kertaa
4 kertaa
5 kertaa tai useammin
108 IIEF-5 questionnaire
Sukupuolielämän häiriöiden kyselykaavake miehille (IIEF-5)
Tämä kyselykaavake on suunniteltu helpottamaan Sinun ja lääkärisi
välistä keskustelua erektiohäiriösi selvittelyssä ja hoidon suunnittelussa.
Valitse ja ympyröi kunkin kysymyksen vastausvaihtoehdoista se, joka
parhaiten kuvaa Sinun tilannettasi viimeisen 6 kuukauden aikana.
Valitse jokaiseen kysymykseen ainoastaan yksi vastaus!
Viimeisen 6 kuukauden aikana:
2. Kun Teillä oli seksuaalisen kiihottumisen aikana erektioita,
kuinka usein ne olivat tarpeeksi kovia yhdyntään?
0 = Ei seksuaalista toimintaa
1 = Ei koskaan tai ei juuri koskaan
2 = Muutaman kerran (harvemmin kuin joka toisella kerralla)
3 = Joskus (noin joka toisella kerralla)
4 = Useimmiten (useammin kuin joka toisella kerralla)
5 = Melkein aina tai aina
3. Kuinka usein pystyitte yhdynnässä ylläpitämään erektion sisään
työntymisen jälkeen?
0 = En yrittänyt yhdyntää
1 = En koskaan tai en juuri koskaan
2 = Muutaman kerran (harvemmin kuin joka toisella kerralla)
3 = Joskus (noin joka toisella kerralla)
4 = Useimmiten (useammin kuin joka toisella kerralla)
5 = Melkein aina tai aina
4. Kuinka vaikeaa Teidän oli säilyttää erektionne yhdynnän
loppuun saakka?
0 = En yrittänyt yhdyntää
1 = Äärimmäisen vaikeaa
2 = Hyvin vaikeaa
3 = Vaikeaa
4 = Hieman vaikeaa
5 = Ei lainkaan vaikeaa
5. Kun yrititte sukupuoliyhdyntää, kuinka usein saitte siitä tyydytystä?
0 = En yrittänyt yhdyntää
1 = En koskaan tai en juuri koskaan
2 = Muutaman kerran (harvemmin kuin joka toisella kerralla)
3 = Joskus (noin joka toisella kerralla)
4 = Useimmiten (useammin kuin joka toisella kerralla)
5 = Melkein aina tai aina
Sexual Health Inventory for Men - IIEF-5, suomennos FinnImpo-tutkimusryhmä
1. Millaiseksi arvioitte luottamuksenne siihen, että voitte saavuttaa
erektion ja säilyttää sen yhdynnän ajan
1 = Hyvin vähäiseksi
2 = Vähäiseksi
3 = Kohtalaiseksi
4 = Suureksi
5 = Hyvin suureksi
Yhteispistemäärä:
Alle 22 pistettä viittaa erektiohäiriön olemassaoloon. Keskustelkaa
tilanteesta lääkärinne kanssa, jos haluatte hoitoa erektiohäiriön
hoitamiseksi.
Nimi __________________________________________________________
Sosiaaliturvatunnus ______________________________________________
Päivämäärä _____________________________________________________
109 14. ORIGINAL PUBLICATIONS
110