Document 22199

I dedicate this book to my family and my parents, who left us very early.
Their absence has left me and my sisters in great grief.
List of Papers
This thesis is based on the following papers, which are referred to in the text
by their Roman numerals.
I
Sandblom G, Ladjevardi S, Garrmo H, Varenhorst E. The Impact of
Prostate-specific Antigen Level at Diagnosis on the Relative Survival of
28,531 Men With Localized Carcinoma of the Prostate.
II Ladjevardi S, Berglund A, Sandblom G, Varenhorst E. Tumour grade,
Treatment, and Relative Survival in a population-based cohort of Potentially Curable Prostate Cancer.
III Ladjevardi S, Berglund A, Bratt O, Widmark A, Varenhorst E, Sandblom G. Treatment with curative intent, and survival in men with highrisk prostate cancer. A population-based study of 11,380 men with serum PSA 20-100 ng/ml.
IV Ladjevardi S, Wies J, Sörensen J, Häggman M, Tolf A, Jorulf H. Imaging of the prostate to indicate the areas for targeted biopsy
Reprints were made with permission from the respective publishers
Contents
Introduction...................................................................................................11
Background ..............................................................................................11
Aetiology..................................................................................................12
Incidence ..................................................................................................13
Normal anatomy and histology of the prostate ........................................16
Neuraoanatomy ........................................................................................17
Histology of prostate cancer and the Gleason Score ................................18
Symptoms.................................................................................................20
Prostate-specific antigen PSA ..................................................................20
Diagnosis..................................................................................................20
Staging......................................................................................................21
Imaging ....................................................................................................22
Management .............................................................................................23
Management of localised PCa..................................................................24
Expectancy ...............................................................................................25
Management of locally advanced PCa .....................................................26
Management of generalised PCa .........................................................27
Quality of life ...........................................................................................27
Randomised studies..................................................................................28
Register Studies........................................................................................29
Population-based study design ............................................................29
Aims of this thesis.........................................................................................30
Material and methods....................................................................................31
Studies I-III ..............................................................................................31
The Swedish Cancer Register..............................................................31
National Prostate Cancer Register (NPCR) of Sweden .......................31
The Swedish Cause of Death Register.................................................32
Study IV ...................................................................................................32
Statistical analysis ....................................................................................33
Study I..................................................................................................33
Study II ................................................................................................33
Study III...............................................................................................33
Study IV...............................................................................................34
Ethical considerations ..............................................................................34
Results...........................................................................................................35
Study I ......................................................................................................35
Study II ................................................................................................40
Study III...............................................................................................45
Study IV...............................................................................................48
Discussion .....................................................................................................51
Study I ......................................................................................................51
Study II.....................................................................................................52
Study III ...................................................................................................54
Study IV ...................................................................................................57
General discussion ........................................................................................59
Conclusion ....................................................................................................62
Swedish summary (Sammanfattning på svenska).........................................63
Slutsatser ..................................................................................................65
Recent Development and Future Perspectives..............................................67
Acknowledgements.......................................................................................70
Referens: .......................................................................................................72
Abbreviations
ADT
ADC
AS
CCI
CI
CNB
DRE
DW
GS
HR
LPR
MRI
MRSI
NA
NNT
NPCR
NPR
PCa
PET
PSA
RP
RS
RT
SCDR
SCR
SPCG-4
TNM
TRUS
WW
Androgen deprivation therapy
Apparent diffusion coefficient
Active surveillance
Charlson Co-morbidity Index
Confidence intervals
Core needle biopsy
Digital rectal examination
Diffusion-weighted
Gleason Score
Hazard Ratio
Laparoscopic radical prostatectomy
Magnetic resonance imaging
Magnetic resonance spectroscopic imaging
Not applicable
Number of men needed to treat
National Prostate Cancer Register
National population Register
Prostate cancer
Positron Emission Tomography
Prostate specific antigen
Radical prostatectomy
Relative survival
Radiation therapy
The Swedish Cause of Death Register
The Swedish Cancer register
Scandinavian Prostate Cancer Group Study Nr 4
Tumour Node Metastasis
Transrectal ultrasonography
Watchful waiting
Introduction
The aim of the present thesis was to investigate the potential benefit of curative treatment compared with conservative treatment for men with the aggressive prostate cancer. The first study reports the concern required for men
with prostate-specific antigen in the lowest range. In the second study relative survival in a large, unselected, population-based cohort of men with
potentially curable prostate cancer is assessed. In third study focuses on
treatment modalities in relation to cause-specific mortality in a large unselected population-based cohort of men with prostate cancer and serum prostate-specific antigen levels between 20 and 100 ng/ml. The fourth study explores the effectiveness of Magnetic Resonance imaging and Positron Emission Tomography imaging techniques in planning the prostate biopsy.
Background
The prostate was first described by the Venetian anatomist Niccolò Massa in
1536, and illustrated by the Flemish anatomist Andreas Vesalius in 1538.
Prostate cancer (hereafter referred to as ´PCa´), however, was not identified
until 1853. PCa was initially considered a rare disease, probably because of
shorter lifespan and poorer detection methods in the 19th century.
At the beginning of 19th century, George Langstaff described PCa for the
first time in the UK [1]. Towards the end of the 19th century Von
Recklinghausen observed that the primary prostatic focus was often small
and insignificant in comparison to the numerous and often far advanced bone
metastases [2], which led to PCa being considered a disease with the
potential to metastasise to the skeleton.
PCa is the most common malignancy among males in the western World.
It accounted for almost 36% of cancer diagnoses among men in Sweden in
2009 [3]. With its high incidence and the development of new and technically advanced forms of management, PCa has also become a substantial
financial burden for society [4]. The total cost of PCa in Sweden increased
from 20 million euros in 1991 to 65 million euros in 2002 [5]. A high proportion of these costs are incurred during the first year after diagnosis; in
2006, this amounted to between 106.7 and 179.0 million euros (€) in the
European countries where these data are available (Italy, Spain, UK, France,
11
and Germany). In the USA, the total estimated expenditure on PCa was
9.862 billion US dollars ($) in 2006. The mean annual cost per patient in the
USA was $10,612 in the initial phase after diagnosis, $2134 for continuing
care and $33,691 in the last year of life [6]. In the late stages of PCa, patients
require a considerable amount of hospital care and palliative treatment [7, 8].
Depending on the choice of treatment, side-effects such as incontinence, loss
of libido and potency, osteoporosis and anemia may occur.
Aetiology
PCa has no clearly defined aetiology and a varying natural history [9, 10].
There are several risk factors known, but the exact causes are incompletely
described. Ages together with geographical, racial and hereditary factors are
known risk factors, and the disease is regarded to be a result of multifactorial
influences. Hereditary factors have the potential to increase the risk 2-3-fold
[11]. Approximately 10–20% of patients with PCa have a positive family
history which increases the lifetime risk of the disease for a given individual
2–11 fold [12, 13].
The typical way of living in the western World, including high intake of
dietary fat, seems to be important. The Western diet contains high amounts
of animal products and processed foods, which results in a high intake of
saturated fats and refined carbohydrates. In general there is an abundance of
calorie-rich products, whereas certain essential nutrients are lacking. In
contrast, in East Asian countries, e.g. Japan and China, where PCa incidence
is lower, the traditional diet is mainly vegetarian and minimally processed or
refined. The Asian diet includes relatively small amounts of animal products,
but is still likely to contain greater amounts of certain essential nutrients.
Recently an association was shown, in a large population-based study on
Swedish men [14], between phytoestrogens and a lower incidence of PCa. A
high intake of food items rich in phytoestrogens (flaxseed, sunflower seeds,
berries, peanuts, beans and soy) was associated with a decreased over-all risk
for PCa. After multivariate adjustment, risk for PCa was 26% lower in the
highest compared to the lowest quartile of estimated intake and applied to
both advanced and localised PCa. The intake of phytoestrogens is higher in
China and Japan than in the West and could partly explain the lower
incidence of PCa in East Asian countries.
Subsequent generations of populations migrating from low to high
prevalence regions have shown an increased incidence [15]. Physical activity
is important in the primary prevention of several cancer types, including the
colon and breast [16, 17]. However, PCa, there is no epidemiological evidence for a protective effect of physical activity. If there is a hypothetical
risk reduction, it is very small [18, 19]. Most epidemiologic studies suggest
that alcohol consumption is not involved in the development of PCa. Com12
pared to non-drinkers, there was no difference in risk for PCa among drinkers of any amount of any type of alcohol, adjusting for age and intake of
other types of alcohol [19, 20]. As regards urothelial neoplasms, smoking is
a crucial factor in carcinogenesis. The role of smoking in PCa, however, is
still controversial, though large epidemiological studies have shown that
smoking is associated with higher risk for developing and dying of PCa [21,
22].
Incidence
Rates of PCa vary widely across the world. PCa is the second most common
cancer and the sixth leading cause of cancer death in males, accounting for
14% (903,500) of all new cancer cases and 6% (258,400) of all cancer deaths
in the world in males in 2008. Age-adjusted incidence rates vary more than
25-fold worldwide, with the highest rates recorded in the developed countries, in particular Western Europe, and North America (Figure1), largely
because of widespread prostate-specific antigen (PSA) testing. In contrast,
males of African descent in the Caribbean region have the highest PCa mortality rates in the world, perhaps due to genetic susceptibility [23, 24]. Time
trends in incidence rates in countries with widespread PSA testing such as
the United States, Australia, Canada, and the Nordic countries have also
followed similar patterns [25, 26]. Rates rose rapidly in the early 1990s, soon
after the introduction of PSA testing, followed by a sharp decline due to a
diminished pool of prevalent cases. In other high-income countries with a
low and gradual increase in the prevalence of PSA testing, such as Japan and
the United Kingdom, rates continue to climb slightly [26].
13
Figure 1 Age- Standardised Prostate Cancer Incidence and Mortality Rates by
World Area. Source: GLOBOCAN 2008
Death rates for PCa have been decreasing slowly in many developed countries, including Australia, Canada, the United Kingdom, the United States,
Italy, and Norway. It is not known whether this is due to earlier diagnosis
(PSA testing), improved treatment, or a combination of these or other factors
[26-28].
The age-standardised incidence of PCa in the world ranges from
2,84/100,000 in Tianjin, China [29] to 240/100,000 in USA [30]. In China
the incidence of PCa showed 3 incremental stages during the 24-year period
at an annual average of 4.02% [29].
The low incidence rate of PCa in the Far East may be largely attributed to
low level of PSA testing. It is likely that PSA screening also contributes
14
significantly to the differences in PCa mortality rates [31]. In contrast to the
low incidence of PCa in Eastern Asia, PCa has the highest incidence rate of
the five most common malignancies in Asian Americans [31].
In Iran there are no population-based data available for cancer. In Tehran,
a city that comprises almost 10% of the Iranian population, the over-all agestandardised rate (ASR) (adjusted to the world population structure) was
163.0 per 100,000 males in 2008. The most frequently reported malignancies
in males were stomach cancer (ASR 19.8), followed by PCa (ASR 15.6)
[32].
In Sweden PCa is the most common malignancy among men. The agestandardised PCa incidence increased to 236/100 000 in 2004, and the
greatest increase was seen for low-risk PCa [33, 34]. The total incidence of
PCa cases increased from 5,946 in 1997 to 10,317 in 2009. A downward
trend in incidence was noticed from 2004 until 2009. In 2009, this trend was
broken, and since then it has been increasing [35].
PCa is the second leading cause of cancer death in U.S. after lung cancer,
and the third in Europe after lung and colorectal cancer [30, 36]. In Sweden,
on the other hand, the mortality rate for PCa has been stable since 1970 with
2424 deaths in 2009 (figure 2). In 2007, 5.6% of 44,025 over-all male deaths
were due to PCa. More than 80% of the present Swedish male population
today will have developed PCa by the age of 80. Already 1977, an autopsy
study showed that invasive (“latent”) cancer is present in 27% of 30-40 yearold men and that the incidence increases to more than 60% in men in their
eighties [37, 38]. The high prevalence of latent PCa seen in previous studies
may, however, have decreased due to widespread screening.
PCa mortality rates are lower than they were before the era of PSA
testing, though the lifetime risk of dying from PCa has remained around 3%
[39].
Age-standardized rates (W) over time
Incidence
Age-standardized rates (W) over time
Incidence
150
150
100
100
50
50
0
0
1960
1970
NORDCAN
1980
1990
2000
1960
1970 1980
1990
2000
NORDCAN
Figure 2. Age- Standardised incidence and mortality from prostate cancer per
100 000 men in Sweden, 1970-2009. NORDCAN (mortality), www.ancr.nu.
15
Normal anatomy and histology of the prostate
The base of the prostate is at the bladder neck and the apex at the urogenital
diaphragm. The Denonvillers’ fascia (DVF), a thin, layer of connective
tissue, separates the prostate and the seminal vesicles from the rectum
(figure 3).
Figure 3. Sagittal view of the rectum, bladder, Denonvillier’s fascia, and the prostate.
The peripheral zone comprises all the prostatic glandular tissue at the apex
as well as of the tissue located posteriorly near the capsule, representing 70%
of the gland. In this zone carcinoma, chronic prostatitis and post
inflammatory atrophy are relatively more common than in the other zones.
The central zone which represents 25% of the gland, is cone-shaped, with
the apex of the cone at the confluence of the ejaculatory ducts and the
prostatic urethra at the verumontanum. The transition zone comprises 10 %
of the gland and consists of two equal portions of glandular tissue lateral to
the urethra in the midgland. This portion of the prostate is involved in the
development of the age-related benign prostatic hyperplasia (BPH) and less
16
commonly, adenocarcinoma. Some cancers arise in the transitional zone and
are the ones mostly detected incidentally at TUR-P.
Figure 4. Relationships
The prostatic capsule is composed of fibrous tissue surrounding the gland.
The seminal vesicles are located cranially to the base of the prostate (Figure
4). They join with the vas deferentes on each side to form the ejaculatory
ducts [40].
Neuraoanatomy
The prostate is richly innervated. Two neurovascular bundles are located
postero-laterally adjacent to the gland and form the superior and inferior
pedicles on each side. The prostate receives both parasympathetic and sympathetic innervations, the former from the hypogastric and pelvic nerves, and
the latter from a peripheral hypogastric ganglion (Figure 5). These nerves are
crucial for penile erection [41].
17
Figure 5. Nerves Surrounding the Prostate Gland
Histology of prostate cancer and the Gleason Score
Prostatic intra-epthelial neoplasia (PIN) has been postulated to be the main
precursor of invasive carcinoma of the prostate. The term PIN was
introduced by Bostwick [42, 43]. The criteria for subdivision into three
grades were established by McNeal [43].
The Gleason Score (GS) describes the histologic appearance of PCa under
low magnification (architectural as opposed to cytologic grading). The Gleason scoring system is composed of a scale 1 to 5 (Figure 6).
18
Figure 6.. The Gleason grading system. The Primary Gleason pattern has to be
greater than 50% of the total pattern seen (i.e. the pattern of the majority of the
cancer observed). The Secondary Gleason pattern has to be less than 50%, but at
least 5%, of the pattern of the total cancer observed. The sum of the primary and
secondary Gleason patterns is known as the Gleason Score or Sum (i.e. primary
pattern + secondary pattern = GS; i.e. 4+3 or 3+4 = GS 7).
Well-differentiated PCa patterns (Gleason grades 1 or 2) are characterised by
proliferation of microacinar structures lined by prostatic luminal cells without an accompanying basal cell layer. Gleason pattern 5 is the highest grade
and implies a solid pattern with central necrosis or infiltrating individual
cells. As PCa is usually heterogeneous with two or more patterns in a given
cancer, Gleason incorporated both a primary (most prevalent) and a secondary (next most prevalent) pattern into the system. The primary pattern grade
is added to the secondary pattern grade to determine the GS. Consequently,
the GS ranges from 2 (1+1) up to 10 (5+5) [40].
19
Symptoms
The most common symptoms raising suspicion of PCa are related to local
growth, i.e. voiding problems. Sometimes pain from the back or the skeleton
may be first symptom that brings the patient to the doctor. Digital rectal examination (DRE) may confirm this suspicion and until recently has remained
the gold standard in the staging of primary tumours.
Prostate-specific antigen PSA
PSA was described in 1979 by Wang and co-workers [44], and in 1987
Stamey et al. showed that PSA performed better as a serum marker for PCa
than prostatic acid phosphatase [45].
PSA has been used as a biologic marker for PCa for more than two
decades [46]. The benefits of systematic PSA-based PCa screening,
however, is an ongoing debate that has yet to be concluded, as illustrated by
the results of two large prospective trials: the European Randomised Study
of Screening for Prostate Cancer (ERSPC) and the American Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial (PLCO) [47].
PCa mortality rates are lower than they were before the era of PSA testing, though the lifetime risk of dying from PCa has remained around 3%
One controversy is the PSA cut-off value to be used for screening. Catalona
et al. suggested a PSA cut-off value 2.5 ng/ml for PCa screening [48]. However, the optimal range of normal PSA values has yet to be defined. It has
been shown that PSA values are quite broadly distributed within a population. In 1993, Oesterling et al. developed age-specific relevance ranges for
white men [49]. Using the age-specific range for PSA can decrease the biopsy rate in older patients, and reveal more potentially curable cancers in
younger men [50]. Ethnic background may also influence the reference
range. Healthy black men have higher PSA values than white men of similar
age [51]. Meanwhile, some studies have shown that Asian men have much
lower PSA values than whites and blacks of similar age [52-54]. The cut-off
serum PSA value 4.0 ng/ml, derived from the white population, is well accepted in Europe and North America.
Diagnosis
Since the early 1990’s PSA has become widely used together with DRE for
detecting prostate tumours.
Fine-needle aspiration biopsy via the rectum with cytologic assessment
used to be a commonly used method in Sweden for confirming the diagnosis.
In the last 2 decades histopathologic assessment of core needle biopsy
20
obtained under ultrasound guidance has gradually replaced fine-needle
aspiration. A disadvantage of core needle biopsy is the greater risk for
complications such as infection, rectal bleeding and haematuria [55, 56].
Core needle biopsy provides tissue specimens sufficient for histopathology
and estimation of GS. The diagnosis of latent PCa may be made at autopsy.
Staging
In the early 1950s, the TNM (Tumour- Node-Metastasis) system to classify
PCa stage was developed [57]. The TNM classification system is presented
in Table 1.
Table 1.Tumour Node Metastasis (TNM) classification of prostate cancer, 7th ed.
2009, International Union against Cancer (UICC)
21
As mentioned above, DRE is still the gold standard in the staging of the primary tumour. DRE often underestimates tumour extension; a positive correlation between DRE and pathological tumour stage was found in less than
50% of cases [58]. The sensitivity and specificity of DRE equals at least
transrectal ultrasonography (TRUS) and is clearly superior to CT scanning
[59]. Furthermore, in a large multi-institutional study, TRUS was no more
accurate at predicting organ-confined disease than was DRE [60]. Only 60%
of tumours have an echogenicity that makes them visible with TRUS. A
combination of DRE and TRUS can detect T3a PCa more accurately than
either method alone [61]. TRUS is not able to determine tumour extension
with sufficient accuracy to be recommended for routine use in staging.
About 60% of pT3 tumours will not be detected pre-operatively by TRUS
[62].
Stage distribution at the time of detection of PCa varies widely [63, 64],
probably for the same reasons as variations in incidence. Increased detection
rate results in stage migration and a larger proportion of localised tumours.
However, comparisons of stage distribution between different populations of
men with PCa are biased because of differences in staging technique [65].
Any stage may, per se, include patients with large differences in tumour
burden. Local tumour growth as estimated by DRE is highly dependent on
the observer [66]. The diagnosis of regional and distant metastases may be
biased, since the decision to perform a bone scan or pelvic lymph node exploration depends on circumstances that are involved in the decision to treat.
The development and improvement of staging systems is a complex procedure and today, clinical subspecialities focus on the improvement of staging
systems for neoplastic disease so as to more precisely predict each patient’s
prognosis.
Imaging
During the last decade, a continuous rise in the detection of PCa has led to
increased use of systematic TRUS-guided biopsy in which the prostate is
sampled in the same stereotypical fashion for all patients, regardless of tumour location, and has resulted in a high rate of false-negative findings [67].
CT scan is of limited value in the detection and staging of PCa since it lacks
sufficient sensitivity.
The development of new Magnetic Resonance Imaging (MRI) techniques
has improved staging and detection of PCa over the last decade. MRI, has
the potential to address this by providing more accurate tumour localisation,
enabling image-guided targeted biopsy [68], and facilitating optimal management planning. This may prove to be especially useful with the emergence of novel and potentially less morbid targeted therapies. Recently,
22
Shukla-Dave et al. developed nomogram models to predict the presence of
insignificant PCa in patients with clinically low-risk disease, based on a
combination of clinical variables and findings from MRI or combined
MRI/MR spectroscopic imaging (MRSI) [69, 70]. MRSI can be performed
in the same examination as MRI using commercially available software. It
provides information about metabolic activity in the prostate and has been
shown to increase the accuracy of MRI in PCa detection, staging, and tumour volume estimation [71-73].
T2-weighted MRI, has traditionally been used for morphologic PCa imaging.
However, it is limited by its low specificity, particularly in the central gland.
Even in the peripheral zone, benign conditions such as prostatitis, benign
prostatic hyperplasia, and scarring, can appear to be hypointense on T2weighted MRI scans, thus mimicking cancer. To overcome this, additional
techniques, such as MRSI, dynamic contrast-enhanced MRI, and diffusionweighted (DW) MRI, have been used to increase specificity with improved
results [74, 75]. Suspect areas for PCa have an increased choline/citrate ratio
on MRSI, increased early contrast uptake and washout on dynamic contrastenhanced MRI, and a hypointense appearance indicative of decreased
Brownian motion of water on apparent diffusion coefficient (ADC) maps
derived from DW MRI. However, implementing these sequences requires
more time, greater signal/noise ratios, and greater field strength magnets [76,
77].
Management
The choice of treatment depends on the patient’s age at diagnosis, the stage
and aggressiveness of the tumour, the potential side-effects of the treatment,
patient co-morbidity, and the patient’s personal preferences.
The first treatment of PCa was surgery aimed at relieving urinary
obstruction. Radical prostatectomy (RP) was described by Billroth in the mid
19th century [78]. Removal of the entire gland (radical perineal
prostatectomy) was first performed in 1904 by Hugh H. Young at Johns
Hopkins Hospital [79].
Radiation therapy (RT) for PCa was first developed in the early 20th century and initially consisted of intra-prostatic radium implants. Bagshaw is
credited with developing external beam radiation in 1956. This became more
popular as stronger radiation sources were developed [80]. Brachytherapy
with implanted seeds was first described in 1952 [81].
Androgen-deprivation therapy (ADT) is achieved by either medical or
surgical intervention [82]. It has been standard care for patients with metastatic disease. ADT has been shown in several studies to reduce morbidity
23
associated with metastatic disease such as spinal cord compression, urethral
obstruction and bone pain [83].
Patients with progressive disease despite castration testosterone levels are
candidates for cytotoxic chemotherapy. More recent studies have
demonstrated a 2-3 month survival and quality-of-life benefit in patients
treated with docetaxel and prednisolone [84, 85].
Management of localised PCa
Optimal treatment for men with localised PCa is one of the most
controversial aspects of PCa:
Radical prostatectomy (RP)
The treatment of men with localised PCa has undergone rapid development
in recent years. Nevertheless, the favourable prognosis of these tumours
even if left untreated has made the management of men with localised PCa a
controversial issue not least due to the effects of treatment on the patient’s
quality of life. It has been shown that RP may improve over-all survival if
the tumour is detected at an early stage [86]. The potentially favourable outcome following RP should, however, be considered in the context of the risk
of over-treatment of men with slowly progressing tumours that do not benefit from aggressive treatment. The number of men needed to treat (NNT) in
order to avoid one PCa death in SPCG-4 was estimated to be 16 [86]. In
another NNT analysis of men with favourable risk PCa, it was estimated that
approximately 73 patients would require radical treatment for each PCa
death averted [87]. Similar results were also found in a study based on tumours detected in the European Randomised Study of Screening for PCa
[88].
One of the most important side-effects of RP is impotence and
incontinence. In 1982 the nerve-sparing technique which decreases the
frequency of impotence was introduced [89]. In the late 1990´s laparoscopic
radical prostatectomy (LPR) was introduced [90, 91] and shortly after the
robot-assisted laparoscopic (RARP) technique was introduced by Binder [92,
93]. Initial problems with incontinence have been reduced by improvement
in techniques [94].
Enthusiasm regarding the development of these new techniques, should
not, however, lead to neglect of the risk of over-treatment. A recently
published population-based nationwide study showed that men with
localised low-risk PCa put on surveillance have a low risk for dying of PCa
over a 10-year period [95]. Careful selection of men undergoing treatment
with curative intent is thus required.
24
Radiotherapy (RT)
The aim of RT, as with RP, is complete cure of localised tumours. RT represents an alternative to surgery since this approach may provide excellent
results in patients carefully selected for the procedure [96, 97]. In the absence of randomised controlled trials comparing the outcomes of RT and RP,
these two approaches should be considered equal alternatives. RT is, however, by tradition offered to those somewhat older and with more concomitant disease. Several attempts have been made to compare the outcome of the
two treatments, but a major methodological obstacle has been that the treatment groups may have had an uneven distribution of tumour burden [98100].
RT can either be delivered as external X-ray beams generated by a linear
accelerator [101], i.e. external beam RT, or implantation of radioactive seeds
directly into the tumour, i.e. interstitial brachytherapy. In contrast to
external-beam RT, interstitial brachytherapy does not lead to radiation
passing through superficial tissues on it’s way to the internal target. In
interstitial brachytherapy most radiation is released close to seed location.
Externalbeam radiotherapy and interstitial brachytherapy can be applied
alone or in combination taking advantage of both methods.
Men with small tumours confined to the prostate, undergoing external
beam RT, have been shown to have virtually the same survival as the agematched general male population, whereas survival was poorer for those
with large tumours or pelvic lymph node metastases [102, 103].
RT, however, is not without side-effects. Even if the mortality and risk for
complications are not the same as after RP, the risk for adverse events
should not be neglected; the main problem being toxic effects on the rectum
and bladder. Impotence is also common [104, 105], as well as late toxicity
and other serious adverse events [106, 107].
External beam RT is usually considered most appropriate for men with
intermediate- or high-risk features [99, 108], providing long-term disease
control in most men with PCa [109].
Expectancy
Watchful Waiting (WW)
Men with well- or moderately-differentiated tumours without a very long life
expectancy may be candidates for the approach termed “Watchful Waiting”.
WW implies that the patient is followed regularly. When symptoms of progressive disease occur, palliative hormonal therapy is initiated. Obstructive
symptoms may be relieved by transurethral resection (TURP). Several studies have shown that the the survival rate of older patients with localised tu-
25
mours managed with WW is essentially the same as in an age-matched
population [95, 110, 111].
Active surveillance (AS)
The cumulative risk of being diagnosed with PCa in developed countries is
7.8% and a 0.9% cumulative risk of dying from prostate cancer by the age of
75. Important aspects of PSA screening include the risk of overdiagnosis and
overtreatment of patients with localised, low malignant tumours. The idea of
AS is to delay the decision to treat and to offer curative treatment to patients
with progression of the disease. Curative treatment is given when the tumour
progresses, but before it is beyond cure. This is totally different to WW. For
this reason, patients who are offered AS are generally younger than patients
managed with WW. Once AS has been decided upon, the patients are closely
monitored with repeated PSA and prostate biopsy. When there are signs of
progression, the patient is offered treatment. The uncertainty surrounding the
relative beneficial and harmful effects of different treatment strategies for
PCa make radical treatment of men with low-risk PCa questionable. A good
candidate for AS is a patient with a PSA< 10 ng/ml, GS < 7 and T1c-T2a.
Almost 50% of newly diagnosed PCa patients fall into this category [87].
Management of locally advanced PCa
According to D'Amico's criteria, locally advanced PCa is defined either by
extracapsular extension (T3 or T4), by a high Gleason Score (> 7), a PSA
higher than 20 ng/ml, or pelvic lymph node involvement [99].
The widespread use of PSA testing has led to a significant migration in
stage and grade of PCa, with more than 90% of men in the current era being
diagnosed with clinically localised disease [112]. Despite this trend towards
lower-risk PCa, 20-35% of patients with newly diagnosed PCa are still classified as high-risk, with a PSA > 20 ng/mL, Gleason Score > 8, or an advanced clinical stage as criteria [113]. The treatment of men with locally
advanced PCa remains controversial due to the lack of conclusive wellcontrolled or randomised studies comparing outcomes of conservative management, RT, and RP. Men with locally advanced PCa are often not considered for treatment with curative intent for fear of early relapse. As a result
these men usually receive non-curative therapy, particularly hormone therapy. There are, however, two randomised controlled trials on men with highrisk PCa that have shown longer over-all survival rates in those treated with
RT combined with hormonal treatment, than in those on hormonal treatment
alone [114, 115]. In recent years, there has been a tendency towards more
active treatment of these patients [34].
26
Management of generalised PCa
When PCa is generalised, cure is no longer possible. At this stage of the
disease, androgen deprivation hormonal therapy may delay progression and
provide symptomatic relief [82, 116-119]. This treatment, known as ADT, is
considered to be first-line therapy. Most men show a response to ADT as
manifested by a drop in PSA and/or symptomatic improvement. Ultimately,
all patients on ADT eventually fail even on this treatment, with the reemergence of castration-resistant tumours. These tumours may still be susceptible to secondary hormonal therapies that block androgen receptors and
decrease the adrenal production of androgens. Combined androgen blockade
with GnRH analogues and anti-androgens has at best a modest survival advantage over GnRH analogue monotherapy in some meta-analyses [120,
121].
With progression, chemotherapy may also be considered [84, 85]. At this
point, there are treatment options aimed at controlling local symptoms, e.g.
deviation of the upper urinary tract with nephrostomy catheters or pigtail
catheter insertion in the case of symptomatic supravesical obstruction. There
are also palliative measures for anaemia, nausea and pain. Palliative RT also
has its place during this phase of the disease.
There are some serious side-effects associated with ADT. It is of great
importance that the well-known metabolic side-effects, e.g osteoporosis,
fatigue, weight gain, hormonal hot flashes and mental effects are adequately
treated [122, 123]. In addition, there are studies that have shown an increase
in mortality from cardiovascular disease and a 2-fold increased risk for
thromboembolic disease [124, 125].
Quality of life
Since the discovery of PCa, focus has mainly concentrated on prolonging
survival. As new PCa treatment options lead to improved survival, the
quality of life of men who are affected by the disease should also be
considered. The main side-effects of RP, despite the fact that there have been
improvements in surgical technique, are impotence and incontinence. The
same side effect may also be seen following RT, as well as problems from
the rectum such as bleeding and diarrhea [104, 105]. These side-effects
affect the quality of life significantly, and must therefore be minimised in
order to provide patients with not only longer survival, but also a better
quality of life. Men with metastatic disease may suffer from bone pain and
obstruction of the urinary tract which also reduce the quality of life
significantly.
Many studies have shown how quality-of-life changes following various
treatment options. Johansson et al. compared quality-of-life between men
27
who were included in the SPCG-4 randomised trial where half the group was
treated with RP and the other half with WW [126]. This study showed that
patients who underwent RP had more problems with urinary incontinence
and loss of libido, and they were under constant psychological stress.
However, men in the WW group had more problems with voiding. It was
also shown that erectile dysfunction was regarded as the most negative effect
on their quality of life. Men with erectile dysfunction reported significantly
greater stress related to this dysfunction than did men in the WW group.
In another study comparing health-related quality-of-life between RP and
brachytherapy-treated men, it was demonstrated that men treated with
brachytherapy scored lower in urinary and sexual symptoms compared to
men who underwent RP [127].
Men who received ADT showed more depression compared to controls
[126]. They also showed poorer body image perception, poorer quality of
life and lower sleep quality [128].
It is important to be aware of pain in PCa patients so as to provide them
with adequate analgesia. Many cancer patients fear pain, and if well
managed their quality of life can be greatly improved. Several studies have
shown that physicians generally underestimate pain in cancer patients and do
not prescribe adequate pain relief for these patients [129, 130].
Randomised studies
Unbiased data are fundamental for all evidence-based medicine. Randomised
controlled clinical trials are usually considered the gold standard for
assessing treatment outcome. Two randomised controlled studies comparing
RP and WW have been published [86, 131]. The first was considered
inconclusive due to the fact that the sample size was too small, the staging
incomplete and the distribution of poorly differentiated tumours uneven.
There are also two randomised controlled trial comparing RT plus endocrine
treatment in one arm and endocrine treatment alone in the other [114, 132].
The results of these studies showed survival benefit for RT plus endocrine
treatment. There are also randomised controlled trials which compare RP to
RT [133, 134]. The first publication was in 1982, showing a higher
progression-free survival for men undergoing RP. However, this study has
been criticised because some patients did not receive the treatment they were
assigned to and the results in the patients treated with radiation were less
favourable than those reported at most centres. Expectant management as an
alternative to immediate hormonal treatment for men with PCa has been
established since the first VACURG (The Veterans Administration Cooperative Urological Research Group) randomised clinical trial was
published in 1967 [135]. When first presented, no difference in survival was
28
seen between the groups. However, a re-analysis of the same data showed a
slight overall survival advantage with immediate hormonal treatment [136].
There is also another large European randomised controlled trial (ERSPC)
which was initiated in the early 1990s to evaluate the effect of PSA
screening on death rate from PCa [47]. The result of this study is the subject
of an ongoing debate on the benefits and disadvantages of PSA screening.
Register Studies
Population-based study design
High-risk PCa represents a therapeutic challenge. The role of curative
treatment in patients with very high PSA values is under discussion.
Consecutive case series at one or several units over a defined period may
provide data on treatment outcome. However, this approach gives a
convenience sample, which may result in selection bias due to confounding
factors that lead the patients to the units involved. Meta-analysis, the pooling
of data from several studies, may provide information based on different
centres and large numbers of cases. The outcome from population-based
studies covering all patients in a geographically defined area have an even
higher external validity as they include patients treated in all clinical
settings, not just those in selected medical centres.
Several reports based on population-based registers have been published,
contributing considerably to our knowledge about the influence of genetic
factors on incidence [11], the association between diagnostic activity and
incidence of PCa [63, 137-139], prognostic factors [140, 141], treatment
outcome [138], survival after conservative management [110, 111] and the
effect of screening on survival [64, 142]. One of the most extensive
population-based tumour registers is the Surveillance, Epidemiology and
End Result Program (SEER) of the National Cancer Institute in the United
States, covering nine geographic areas and 10% of the US population [39,
143]. It provides data collected from all hospitals in the areas covered, but
may miss treatment given on an outpatient basis (e.g radiotherapy, androgen
deprivation therapy, and expectant management). The National Cancer Data
Base (NCDB) is a hospital-based register and a resource when studying
patterns of patient care and treatment outcome, with reports from over 1000
hospitals in the United States [144]. However, the NCDB represents a
convenience sample of data rather than a population-based register since
hospital participation is voluntary. Although not population-based,
CaPSURE is a large observational database with detailed registration,
including medical history, tumour stage, laboratory findings, diagnosis,
treatment and health-related quality-of-life [145].
29
Aims of this thesis
The over-all aim of the entire study was to compare the benefits of curative
treatment compared to conservative treatment in men with PCa without
distant metastases. The specific aims were:
I
to evaluate the predictive value of prostate-specific antigen in a
population-based cohort in Sweden, and also to investigate the relative
survival of patients who are considered plausible candidates for
treatment with curative intent
II to evaluate the relative survival in a large, unselected population-based
cohort of men with potentially curable prostate cancer
III to evaluate the association between curative treatment and causespecific mortality, and over-all as well as relative survival in men
diagnosed with prostate cancer with a serum level of prostate-specific
antigen between 20 and100 ng/ml
IV to create a model for imaging of the prostate to increase the safety of
guided Core Needle Biopsy in men with suspect prostate cancer thereby
improving staging
30
Material and methods
The cohorts in the first three studies were prospectively assembled in a
population-based register (the National Prostate Cancer Register). Study IV
is a clinical study on patients included between 2010 and 2011.
Studies I-III
The Swedish Cancer Register
Since 1958 all newly diagnosed cancers have been recorded in the Swedish
Cancer Register (SCR). SCR contains basic data on all solid malignant
tumours, including: personal identity number (unique for every Swedish
resident); date of diagnosis and basis of diagnosis; municipality and county
of residence of the patient at diagnosis; the type and the site of each new
tumour; but not tumour grade, stage or treatment [146]. The Swedish
National Board of Health and Welfare requires all physicians to report all
new cases of cancer. Pathologists and cytologists separately report cases
with a cancer diagnosis. Thus, for the majority of cases the SCRis notified
by both clinical and pathology departments. The over-all capture rates has
been estimated to be 96, 3% for all tumours. The capture rates are highest for
subjects 70 years or younger [147].
National Prostate Cancer Register (NPCR) of Sweden
Using the National Cancer Register as a basic source, regional prostate
cancer registers were started in the south-east region 1987 and in the
northern health-care region 1992. These registers serve as extensions of the
National Cancer Register, with additional data on the patient’s tumour and
treatment included. In 1996 these two regional prostate cancer registers were
merged to form the Swedish National Prostate Cancer Register that from
1996 also included the south and Uppsala/Örebro regions, from 1997 the
west region and from 1998 the Stockholm region, thereby covering the
whole of Sweden [34]. Approximately 97% of all incident PCa cases in the
Swedish Cancer Register are registered in the NPCR of Sweden. The register
contains information on diagnosing unit, date of diagnosis, cause of
diagnosis (screening or tumour symptoms), tumour grade, tumour stage
31
according to the TNM classification, serum PSA level at diagnosis and
primary treatment either performed or planned up to six months after
diagnosis [146]. Until 2007, treatment coded “expectancy” included both
active surveillance and watchful waiting. Since 2007 information on prostate
size, amount and total length of core biopsies and length of cancer in the
cores have also been registered, as well as the handling of the nerves in RP.
The Swedish Cause of Death Register (SCDR)
The first efforts to introduce a nationwide register for Swedish population
statistics were made in 1749 when clergymen were given the responsibility
of registering the cause of death. The Swedish Cause of Death Register
(SCDR) as it appears today was started in 1961. It contains data on personal
identity number, date of death, underlying cause of death, municipality and
county of residence of the person at the time of death [148]. Registration of
date of death and underlying cause of death is mandatory- The validity of the
cause of death registered in the SCDR has been demonstrated to be high. Of
all deaths attributed to PCa among men diagnosed with localised disease,
88% were attributed to prostate cancer in a re-examination of medical
records [149].
Study IV
Men at our Urology department with a high PSA level or with clinically
suspected PCa were included. The inclusion criteria were men up to the age
of 75 years with PSA level between 3 and 20 ng/ml or suspected tumour on
DRE and who were considered potential candidates for radical treatment.
Altogether 45 men were included between 2010 and 2011. Men with cardiac
or other electronic implant and who reported claustrophobia, were excluded
since an MRI was required for the study protocol. The study was approved
by the Ethics Committee of Uppsala University No 2009/191. Informed
consent was obtained.
All men initially underwent guided Core Needle Biopsy (CNB), with10
cores being biopsied according to a standardised map. Of these 45 men, 24
presented with PCa and GS between 5 and 10. One patient with PCa did not
fulfil the study criteria, and 21 patients had a normal CNB. Ten of the 23
patients with PCa had LRP, 2 RT, and 11 patients AS due to the small
amount and highly differentiated cancer in core biopsy material.
All patients with verified PCa and assigned for prostatectomy underwent
examination with PET/CT ¹¹C Acetate but only 8 patients were examined
with MRSI and 6 patients with MRI Diffusion ADC due to technical
problems with the MRI apparatus.
32
Statistical analysis
Study I
In Study I, relative survival (RS) was estimated by dividing the observed
survival for men in each age strata with expected survival of the Swedish
male population in that age group. Stratification for PSA level and tumour
differentiation (GS 2–6, GS 7, and GS 8–10) was performed. If GS was
missing, then patients were categorised according to cytology grading, with
highly differentiated tumours allocated to the GS 2 - 6 group, moderately
differentiated tumours to the GS 7 group, and poorly differentiated to the GS
8 - 10 group. A Poisson regression analysis was performed using observed
death as response and expected death rate as offset. Expected and observed
numbers of survivors were calculated with stratification for PSA level and
tumour differentiation. The regression model was based on PSA as linear
splines with breakpoint at a PSA of 4 ng/mL and with tumour differentiation
as category variable. An equivalent Poisson regression analysis with
stratification for PSA level and treatment was also performed.
Study II
Study II was also performed with relative outcome as primary endpoint. RS
was calculated by dividing the observed survival of the study group with the
expected survival in the Swedish male population of corresponding age.
Stratification for treatment and tumour differentiation was performed. In a
separate multivariate analysis, the ratio between observed survival and
expected death rate was tested using GS and treatment (conservative or with
curative intent) as covariates. We also tested whether there was an
interaction between GS and treatment.
Study III
In Study III, probability of PCa death using Kaplan-Meier estimates was
calculated. Cox regression with relative risks expressed as hazard ratios
(HR) and 95% confidence intervals (CI) were calculated to assess prostate
cancer-specific mortality in relation to treatment, adjusted for age at diagnosis, calendar period, serum PSA, co-morbidity, T-stage and GS. The Charlson Co-morbidity Index (CCI) was used to assess the burden of concomitant
disease for each PCa patient and has been shown in a study based on NPCR
to have an impact on management and survival [150]. The Charlson score
takes into account the presence of 19 diseases that are considered to be associated with early mortality. A Charlson sum calculated according to the
number of morbidities that affect an individual. For each illness, a number of
points allocated to the sum of these points give an overall score. This sum
33
can be used in connection with the patient's age as a Charlson score to calculate a probability of survival (table 2).
Table 2. Charlson co-morbidities and their respective point scores
Points
Morbidity
1
MI
CCF
PVD
COPD
DM (without end-organ damage)
Cerebrovascular disease
Dementia
Ulcers
Connective tissue disease
Mild liver disease
2
3
Hemiplegia
Moderate–severe liver disease
Moderate–severe
CRF
DM (with end-organ damage)
Malignancy
Leukaemia
Lymphoma
6
Metastatic solid tumour
AIDS
Abbreviations: MI, myocardial infarction; CCF, congestive cardiac failure; PVD, peripheral
vascular disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; CRF,
chronic renal failure
Study IV
The prostate was divided into 10 zones (Figure 16) according to our routine
CNB scheme: apex, middle zone (medial and lateral), and base (medial and
lateral). Each zone was quantitative characterised by Gleason Score, mean
ADC value, (Cho+PA+Cr)/Cit spectral intensity ratio, and by ¹¹C acetate
uptake. Ten parameters related to the schema biopsy zones (Figure 16) were
evaluated for each patient; positive for PCa (=1) and negative (=0). One
hundred parameters were evaluated for both CNB and ¹¹C acteate PET/CT
imaging. For MRSI, 8 patients correspond to 80 parameters and 6 patients
for MR diffusion ADC maps, correspond to 60 parameters were evaluated
(Table 12). Statistical analysis for sensitivity, specificity, and accuracy,
(false positive and negative rates, positive and negative predictive values)
were made for correlation of findings at CNB, PET/CT, MRSI, and MRT
ADC with the postoperative histology, related to the 10 prostate zones.
Diagnostic parameters were calculated on a per-lesion and per-patient basis.
Ethical considerations
All studies were approved by the Ethics Review Board. Written informed
consent was obtained from all participants in Study IV. According to
regulations, all men included in the Swedish National Prostate Cancer
Register are informed about the register.
34
Results
Study I
Characteristics of study subjects are presented in Table 3. The cohort is
listed in Table 4, and the distribution and primary treatment of the 28,531
men with localised tumour are presented in Table 5. Poisson regression was
used to test association between PSA level and survival, using GS as
covariate. A positive relation between survival and serum PSA level for all
GS categories in patients with PSA level> 4 ng/ml, but a paradoxical inverse
negative association was observed among patients with PSA levels <4 ng/ml.
The inverse correlation was observed for all Gleason categories, but was
most clear for patients in the GS 8 - 10 group. Figure 7 illustrates this
relationship. A similar Poisson regression analysis with stratification for
treatment is illustrated in Figure 8. The same inverse correlation between
PSA level and survival for men with PSA levels <4 ng/mL was also
observed in this analysis and was most pronounced for men who received
definite treatment.
35
Figure 7. Poisson regression curve for the ratio between observed and expected
deaths with stratification for prostate-specific antigen (PSA) level and tumour differentiation. The regression model is based on PSA as linear splines with a breakpoint at PSA = 4 ng/ml and with tumour differentiation as a category variable
Figure 8. Poisson regression curve for the ratio between observed and expected
deaths with stratification for prostate-specific antigen (PSA) level and treatment.
The regression model is based on PSA as linear splines with a breakpoint at PSA = 4
ng/mL and with tumor differentiation as a category variable.
36
Table 3. Characteristics of 28,531 men with localised PCa in the Swedish National
Prostate Cancer Register, 1996 to 2005
Characteristic
Age, years
<55
55–59
60–64
65–69
70–75
Year of diagnosis!
1996–2000
2001–2003
2004–2005
Gleason score!
2
3
4
5
6
7
8
9
10
Missing Gleason
WHO grade 1
WHO grade 2
WHO grade 3
PSA, µg/L
<4
4 and <10
10 and <20
Tumor classification!
T0
T1 (missing abc)
T1a
T1b
T1c
T2
T3
TX
Lymph node classification
N0
NX
Metastasis classification
M0
MX
Mode of detection*!
Screening
Symptoms
Other reason
Missing information
Mean follow-up [SD], year
No. of patients (%)
1540 (5.4)
3939 (13.8)
6583 (23.1)
7872 (27.6)
8597 (30.1)
8647 (30.3)
10,020 (35.1)
9864 (34.6)
163 (0.6)
318 (1.1)
1318 (4.6)
3594 (12.6)
11,880 (41.6)
6007 (21.1)
1185 (4.2)
508 (1.8)
68 (0.2)
1857 (6.5)
1319 (4.6)
314 (1.1)
2926 (10.3)
15,688 (55.0)
9917 (34.8)
219 (0.8)
49 (0.2)
1313 (4.6)
708 (2.5)
13,068 (45.8)
10,003 (35.1)
2914 (10.2)
257 (0.9)
6062 (21.2)
22,469 (78.8)
10,630 (37.3)
17,901 (62.7)
8139 (36.3)
10,291 (45.9)
2363 (10.5)
1631 (7.3)
4.1 [2.5]
37
Table 4. Gleason Score (GS) and PSA (µg/l) at diagnosis in men excluded from
analysis because of distant metastasis (M1), regional lymph node mestastasis (N1)
or primary tumour of category T4. Some men are excluded for more than one reason
Number of patients (%)
Excluded patients
Localised tumours: to analysis
Total number
M1
N1
Non-palpable
Palpable
(T1abc, T0, TX)
(T2–T3)
T4
Gleason score 2–6
PSA <4
2342
9 (0.4)
7 (0.3)
1 (0)
1685 (71.9)
641 (27.4)
PSA 4 and <10
11272
43 (0.4)
24 (0.2)
9 (0.1)
7411 (65.7)
3789 (33.6)
PSA 10 and <20
5730
66 (1.2)
50 (0.9)
14 (0.2)
3086 (53.9)
2518 (43.9)
PSA <4
496
12 (2.4)
9 (1.8)
12 (2.4)
204 (41.1)
262 (52.8)
PSA 4 and <10
3742
58 (1.5)
65 (1.7)
12 (0.3)
1529 (40.9)
2083 (55.7)
PSA 10 and <20
3496
103 (2.9)
131 (3.7)
20 (0.6)
1065 (30.5)
2183 (62.4)
PSA <4
203
30 (14.8)
22 (10.8)
32 (15.8)
52 (25.6)
82 (40.4)
PSA 4 and <10
1048
79 (7.5)
69 (6.6)
38 (3.6)
295 (28.1)
581 (55.4)
PSA 10 and <20
1327
141 (10.6)
102 (7.7)
38 (2.9)
287 (21.6)
778 (58.6)
Total
29,656
541 (1.8)
479 (1.6)
176 (0.6)
15,614 (52.7)
Gleason score 7
Gleason score 8–10
38
4206
1318
300
270 (25.4%)
66 (6.2%)
6 (0.6%)
355 (33.3%9)
31 (2.9%)
1065
207 (23.6%)
53 (6.1%)
15 (1.7%)
205 (23.4%)
30 (3.4%)
876
25 (18.7%)
12 (9.0%)
2 (1.5%)
37 (27.6%)
2 (1.5%)
134
718 (22.1%)
165 (5.1%)
35 (1.1%)
656 (20.2%)
96 (3.0%)
3248
659 (18.2%)
188 (5.2%)
42 (1.2%)
395 (10.9%)
135 (3.7%)
3612
75 (16.1%)
21 (4.5%)
6 (1.3%)
39 (1.3%)
18 (3.9%)
466
241 (4.3%)
39 (0.7%)
593 (10.6%)
145 (2.6%)
5604
126 (1.1%)
543 (4.8%)
294 (2.6%)
11200
92 (4.0%)
69 (3.0%)
2326
Missing information
Total no of cases
184 (39.5%)
1797 (32.1%)
931 (16.6%)
4920 (43.9%)
1187 (10.6%)
518 (4.6%)
134 (5.8%)
54 (2.3%)
29 (1.2%)
Radiotherapy
(brachy)
Other curative
treatment
Hormonal treatment
803
(34.5%)
Radical
prostatectomy
Radiotherapy
(external)
28531
820
2915
10796
237 (22.3%)
281 (32.1%)
40 (29.9%)
Total
926 (28.5%)
PSA < 20 g/l
1608 (44.5%)
10 g/l
8176
PSA < 10 g/l
100 (9.4%)
PSA < 20 g/l
85 (9.7%)
585 (16.2%)
123 (26.%)
1858 (33.2%)
3612 (32.2%)
1145
(49.2%)
Watchful waiting
10 g/l
16 (11.9%)
4 g/l
4 g/l
PSA<4 g/l
Primary treatment
PSA < 10 g/l
PSA<4 g/l
PSA < 10 g/l
652 (20.1%)
PSA < 20 g/l
Poorly differentiated (Gleason score 8-10)
4 g/l
10 g/l
Moderately differentiated (Gleason score 7)
PSA<4 g/l
Well differentiated (Gleason score 2-6)
Table 5. Gleason Score, PSA (µg/l), and primary treatment of the 28 531 men with localised prostate caner in the NPCR 1996-2005.
Study II
Baseline characteristics of the study population by treatment are listed in
Table 6 and primary treatment by GS are presented in Table 7.
Altogether 31903 men fulfilled the criteria for being considered potential
candidates for radical treatment [T1-T3, N0/NX, M0/MX, age < 75 years
and PSA< 20 ng/ml]. All data presented in this report are based on this group
of men with localised tumour. The percentage of men undergoing radical
treatment was approximately the same for men with well-, moderately and
poorly differentiated tumours, but there were more men who received
palliative treatment in the high-score group (Table 7).
The RS is shown in Figures 9-11. Whereas the RS of men with welldifferentiated tumours was more than 100% during the first five years
regardless of treatment, the survival rate for moderately and poorly
differentiated tumours was dismal for men who were selected for
conservative management. The ratio between observed and expected deaths
by GS and treatment in men diagnosed 2000-2006 is shown in Figure 12.
The ratio for patients treated with curative intent varied little with tumour
grade. On the other hand, for men managed conservatively, the ratio was
considerably higher in men with poorly differentiated tumours than for men
with well-differentiated tumours. The regression analysis showed a
significant association between GS and the observed/expected mortality ratio
(p<0.05) but not between treatment and observed/expected mortality ratio
(p=0.80).
In the multivariate Cox proportional hazards analysis, treatment, age, and
GS were found to significantly and independently predict over-all survival
(table 8).
40
Table 6. .Baseline characteristics by treatment
Conservative
Curative managements
managements
Palliative
Watchful
Radical
Radiotherapy
treatments
waiting
Prostatectomy
n
%
n
%
n
%
n
%
Total
n
%
1748
4440
7571
8767
9377
4.1
11.1
20.3
27.1
37.4
Age
<55
55-59
60-64
65-69
70-75
21
77
243
686
2183
0.7
2.4
7.6
21.4
68.0
183
647
1486
2544
4575
1.9
6.9
15.7
27.0
48.5
1310
2928
4259
3433
1020
10.1
22.6
32.9
26.5
7.9
234
788
1583
2104
1599
3.7
12.5
25.1
33.4
25.3
1195
1043
972
37.2
32.5
30.3
3281
2662
3492
34.8
28.2
37.0
2361
3953
6636
18.2
30.5
51.2
1580
2148
2580
25.0 8417 28.8
34.1 9806 31.3
40.9 13680 39.9
11
26
61
243
829
896
331
190
29
173
297
124
0.3
0.8
1.9
7.6
25.8
27.9
10.3
5.9
0.9
5.4
9.3
3.9
116
168
787
1466
4004
1071
120
36
8
1132
471
56
1.2
1.8
8.3
15.5
42.4
11.4
1.3
0.4
0.1
12.0
5.0
0.6
25
74
358
1549
6556
3140
478
127
10
322
257
54
0.2
0.6
2.8
12.0
50.6
24.2
3.7
1.0
0.1
2.5
2.0
0.4
9
50
155
625
2413
1835
418
211
29
210
278
75
0.1
161
0.5
0.8
318
1.0
2.5 1361
3.9
9.9 3883 11.2
38.3 13802 39.3
29.1 6942 23.1
6.6 1347
5.5
3.3
564
2.7
0.5
76
0.4
3.3 1837
5.8
4.4 1303
5.2
1.2
309
1.5
1343
1193
674
0.4
0.4
0.2
7673
1542
220
0.8
0.2
0.0
8884
3397
669
0.7
0.3
0.1
3462
2113
733
180
1248
1782
5.6
38.9
55.5
1488
5072
2875
15.8
53.8
30.5
1275
8215
3460
9.8
63.4
26.7
365
3287
2656
5.8 3308
9.2
52.1 17822 52.0
42.1 10773 38.7
18
1
71
105
748
1267
969
31
0.6
0.0
2.2
3.3
23.3
39.5
30.2
1.0
133
18
1163
444
4536
2540
504
97
1.4
0.2
12.3
4.7
48.1
26.9
5.3
1.0
46
13
166
133
7422
4727
364
79
0.4
0.1
1.3
1.0
57.3
36.5
2.8
0.6
23
5
39
80
2494
2399
1234
34
0.4
220
0.7
0.1
37
0.1
0.6 1439
4.1
1.3
762
2.6
39.5 15200 42.0
38.0 10933 35.2
19.6 3071 14.5
0.5
241
0.8
147
3063
4.6
95.4
190
9245
2.0
98.0
4178
8772
32.3
67.7
2036
4272
32.3 6551 17.8
67.7 25352 82.2
1243
1967
38.7
61.3
1982
7453
21.0
79.0
4398
8552
34.0
66.0
3512
2796
55.7 11135 37.4
44.3 20768 62.7
389
1574
201
174
16.6
67.3
8.6
7.4
2233
3431
878
397
32.2
49.4
12.7
5.7
5275
4207
1260
648
46.3
36.9
11.1
5.7
1952
2463
514
367
36.9 9849 33.0
46.5 11675 50.0
9.7 2853 10.5
6.9 1586
6.4
4.6
(2.7)
4.8
(2.9)
4.0
(2.6)
4.4
Year of Diagnosis
1996-2000
2001-2003
2004-2006
Gleason Score (GS)
2
3
4
5
6
7
8
9
10
Missing GS, WHO grade 1
Missing GS, WHO grade 2
Missing GS, WHO grade 3
GS or WHO grade
GS 2-6, WHO 1
GS 7, WHO 2
GS 8-10, WHO 3
0.5 21362
0.3 8245
0.1 2296
0.7
0.3
0.1
PSA
PSA<4
4<=PSA<10
10<=PSA<20
T category
T0
T1 (abc missing)
T1a
T1b
T1c
T2
T3
TX
N category
N0
NX
M category
M0
MX
Mode of detection*
Screening
Symptoms
Other Reasons
Missing information
Mean follow-up years
(sd) available year 2000
(2.6)
4.3 (2.7)
41
Total no. of cases
Conservative managements
Watchful waiting
Palliative treatments
Bilateral orchiectomy
GNRH analogues
Antiandrogenes
Other palliative treatments
Curative managements
Radical prostatectomy
Radiotherapy (external)
Radiotherapy (brachytherapy)
Other curative treatments
Missing information
1328
95
5
36
8
46
1239
985
132
87
35
92
n
2754
%
4276
588
26
281
176
105
7941
5832
1240
725
144
399
n
13204
32.4
4.5
0.2
2.1
1.3
0.8
60.1
44.2
9.4
5.5
1.1
3
%
4 <= PSA < 10
2069
660
33
350
184
92
3386
2067
946
332
41
176
n
6291
32.9
10.5
0.5
5.6
2.9
1.5
53.8
32.9
15
5.3
0.7
2.8
%
10 <= PSA < 20
Gleason Score 2 - 6
48.2
3.4
0.2
1.3
0.3
1.7
45.0
35.8
4.8
3.2
1.3
3.3
PSA < 4
143
43
4
28
7
4
353
241
70
35
7
25
%
25.4
7.6
0.7
5
1.2
0.7
62.6
42.7
12.4
6.2
1.2
4.4
PSA < 4
n
564
Table 7. Distribution of primary treatment by Gleason Score (GS)
700
433
33
267
104
28
3119
2039
753
275
52
187
n
4439
15.8
9.8
0.7
6.0
2.3
0.6
70.3
45.9
17.0
6.2
1.2
4.2
%
699
717
57
462
155
43
2137
1117
751
229
40
135
n
3688
19
19.4
1.5
12.5
4.2
1.2
57.9
30.3
20.4
6.2
1.1
3.7
%
4 <= PSA < 10 10 <= PSA < 20
Gleason Score 7
17
42
6
27
4
4
92
49
26
15
2
2
n
153
11.1
27.5
3.9
17.6
2.6
2.6
60.1
32
17
9.8
1.3
1.3
96
227
19
151
39
14
656
344
219
75
18
39
n
1018
9.4
22.3
1.9
14.8
3.8
1.4
64.4
33.8
21.5
7.4
1.8
3.8
%
107
405
32
276
74
23
683
276
306
92
9
34
n
1229
8.7
33
2.6
22.5
6
1.9
55.6
22.5
24.9
7.5
0.7
2.8
%
4 <= PSA < 10 10 <= PSA < 20
Gleason Score 8 - 10
%
PSA < 4
9435
3210
215
1878
751
359
19606
12950
4443
1865
348
1089
Total
n
33340
1
0.9
0.8
Relative survival
0.7
0.6
0.5
0.4
0.3
0.2
Radiotherapy (RT)
Radical prostatectomy (RP)
Conservative managements (CM)
0.1
0
0
1
2
3
4
5
6
7
8
9
10
2198
1222
596
1465
730
334
872
394
158
414
180
60
Time (years)
No. at Risk
CM 9016 8450
RP 8884 8216
RT 3462 3284
7226
6775
2854
6014
5152
2287
4862
3705
1768
3885
2657
1354
3016
1858
950
Figure 9. Relative survival: Gleason score 2-6
1
0.9
Relative survival
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Radiotherapy (RT)
Radical prostatectomy (RP)
Conservative managements (CM)
0.1
0
0
1
2
3
4
5
6
7
8
9
10
694
482
46
402
475
316
246
269
167
124
118
72
Time (years)
No. at Risk
CM 2735 2595
RP 3397 3072
RT 2113 1980
2242
2415
1690
1881
1812
1364
1532
1312
1063
1188
938
806
922
688
584
Figure 10. .Relative survival: Gleason score 7
43
1
0.9
Relative survival
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Radiotherapy (RT)
Radical prostatectomy (RP)
Conservative managements (CM)
0.1
0
0
1
2
3
4
5
6
7
8
9
10
154
118
138
87
69
81
42
36
42
16
16
Time (years)
No. at Risk
847
CM 894
RP 669
614
RT 733
685
708
492
578
557
383
472
434
286
364
322
204
270
234
154
196
2.5
1.0
1.5
2.0
Conservative managements
Curative managements
0.0
0.5
Observed deaths/E xpected deaths
3.0
3.5
Figure 11. Relative survival: Gleason score 8-10
2
4
6
8
Gleason Score 2-10
Figure 12. Observed deaths/Expected deaths, 2000 - 2006
44
10
Table 8. Multivariate Cox proportional hazard analysis with overall survival as the
end point
Model 1
CM
RP
RT
GS 2-6
GS 7
GS 8-10
Age at diagnosis
RP* GS 7
RT* GS 7
RP* GS 8-10
RT* GS 8-10
CM
RP
RT
GS 2-6
GS 7
GS 8-10
Age at diagnosis
RP* GS 7
RT* GS 7
RP* GS 8-10
RT* GS 8-10
PSA 10-20 ng/ml
PSA 4-10 ng/ml
PSA < 4 ng/ml
HR
ref
0.36
0.54
ref
1.61
2.67
1.06
Model 3
HR
ref
0.37
0.54
ref
1.58
2.60
1.06
ref
0.82
0.96
Model 2
95 % CI
0.32 - 0.40
0.49 - 0.59
1.49 - 1.73
2.42 - 2.95
1.05 - 1.07
-
HR
ref
0.41
0.62
ref
1.72
3.00
1.06
0.78
0.81
0.65
0.71
95 % CI
0.36 - 0.47
0.54 - 0.72
1.57 - 1.88
2.67 - 3.38
1.05 - 1.07
0.63 - 0.96
0.66 - 0.99
0.47 - 0.90
0.55 - 0.91
Model 4
95% CI
0.33 - 0.41
0.49 - 0.59
1.46 - 1.70
2.35 - 2.87
1.05 - 1.06
0.77 - 0.89
0.86 - 1.08
HR
ref
0.41
0.62
ref
1.69
2.92
1.06
0.78
0.81
0.65
0.71
ref
0.83
0.97
95% CI
0.36 - 0.48
0.54 - 0.71
1.54 -1.84
2.59 - 3.29
1.05 - 1.06
0.63 - 0.97
0.66 - 0.99
0.47 - 0.90
0.55 - 0.92
0.77 - 0.89
0.87 - 1.09
Study III
A flow chart of the study population recruitment is shown in Figure 13.
Table 9 shows a multivariable Cox proportional hazard analysis of the study
cohort. It shows a significant difference in cancer-specific survival between
curative and non-curative treatments after adjusting for age, co-morbidity,
GS, T-stage and PSA level at the time of diagnosis. Age and co-morbidity
was not associated with cancer-specific survival, but, as expected, PSA, GS,
and TNM-classification had significant impact. Primary treatment is shown
in Table 10. The 10-year cause-specific mortality for patients with PSA 2050 ng/ml was 36% for patients treated without and 13% for patients treated
with curative intent. For patients with PSA 50-100 ng/ml the 10-year causespecific mortality was 55% for conservative and 20% for patients with a
curative treatment. Relative as well as over-all survival benefit was seen for
curative intent therapy compared to conservative management for the whole
PSA range up to 100 ng/ml (Figure14 and 15).
45
Figure 13. Flow chart of cohort recruitment from patients recorded in the National
Prostate Cancer Register of Sweden between 1996 and 2008.
Table 9. Cause-specific survival estimated by multivariate proportional hazard models with hazard ratios (HR) with 95% confidence intervals (CI)
PSA 20-50 nl/mg
Initially planned treatment
Conservative
Curative
Age at diagnosis (years)
<60
60-69
70-75
Log PSA (ng/ml)
Charlson Co-morbidity Index
CCI 0
CCI 1
CCI 2+
Gleason Score
GS 2-6
GS 7
GS 8-10
Clinical T-stage
T1c
T1ab
T2
T3-T4
PSA 51-100 nl/mg
PSA 20-100 nl/mg
HR
(CI 95%)
HR
(CI 95%)
HR
(CI 95%)
1.00
0.28
ref.
( 0.24 - 0.33 )
1.00
0.30
ref.
( 0.22 - 0.41 )
1.00
0.29
ref.
( 0.20 - 0.26 )
1.00
0.84
0.76
1.14
ref.
( 0.68 - 1.05 )
( 0.62 - 0.95 )
( 0.92 - 1.41 )
1.00
0.83
0.87
1.68
ref.
( 0.64 - 1.08 )
( 0.67 - 1.13 )
( 1.17 - 2.41 )
1.00
0.84
0.81
1.45
ref.
( 0.71 - 0.99 )
( 0.69 - 0.96 )
( 1.32 - 1.61 )
1.00
0.91
1.17
ref.
( 0.77 - 1.09 )
( 0.96 - 1.43 )
1.00
0.89
1.20
ref.
( 0.72 - 1.11 )
( 0.93 - 1.56 )
1.00
0.94
1.19
ref.
( 0.84 - 1.05 )
( 1.04 - 1.36 )
1.00
1.72
3.59
ref.
( 1.46 - 2.03 )
( 3.04 - 4.25 )
1.00
1.46
2.66
ref.
( 1.18 - 1.81 )
( 2.15 - 3.31 )
1.00
1.63
3.21
ref.
( 1.43 - 1.85 )
( 2.82 - 3.67 )
1.00
1.71
1.60
2.57
ref.
( 1.21 - 2.42 )
( 1.29 - 1.98 )
( 2.09 - 3.16 )
1.00
1.93
1.31
1.84
ref.
( 1.12 - 3.32 )
( 0.96 - 1.79 )
( 1.37 - 2.49 )
1.00
1.74
1.52
2.32
ref.
( 1.31 - 2.33 )
( 1.27 - 1.82 )
( 1.96 - 2.75 )
Subgroup 1. Level of PSA 20-50, M0/MX
Subgroup 2. Level of PSA 51-100, M0/MX
Subgroup 3. Level of PSA 20-100, M0/MX
46
Table 10. Clinical characteristics of patients diagnosed with primary prostate cancer
between 1996 and 2008, by level of Prostatic Specific Antigen (PSA) and planned
initial treatment
All
Calendar period
1996-2000
2001-2003
2004-2008
Age of diagnosis
<60
60-69
70-75
Mode of detection*
Screening
Symptoms
Other reason
Missing
Clinical T-stage
T0
T1ab
T1c
T2
T3
T4
TX
N-stage
N0
N1
NX/Missing
M-stage
M0
M1
MX/Missing
Gleason Score
GS 2-6
GS 7
GS 8-10
Level of PSA, mean (SD)
Charlson Comorbidity Index
CCI 0
CCI 1
CCI 2+
Initial planned treatment
Curative
Conservative
Mean follow-up time, yr (SD)
Level of Prostatic Specific Antigen (PSA)
PSA 20-50
PSA 51-100
Total
n
(%)
n
(%)
n
(%)
9263
(100)
3689
(100) 12952
(100)
3306
2362
3595
(35.7)
(25.5)
(38.8)
1483
922
1284
(40.2)
(25.0)
(34.8)
4789
3284
4879
(37.0)
(25.4)
(37.7)
1029
4036
4198
(11.1)
(43.6)
(45.3)
383
1524
1782
(10.4)
(41.3)
(48.3)
1412
5560
5980
(10.9)
(42.9)
(46.2)
1658
4057
522
458
(24.8)
(60.6)
(7.8)
(6.8)
408
1782
136
189
(16.2)
(70.9)
(5.4)
(7.5)
2066
5839
658
647
(22.4)
(63.4)
(7.1)
(7.0)
50
296
2139
3358
3054
272
94
(0.5)
(3.2)
(23.1)
(36.3)
(33.0)
(2.9)
(1.0)
17
63
423
1037
1780
314
55
(0.5)
(1.7)
(11.5)
(28.1)
(48.3)
(8.5)
(1.5)
67
359
2562
4395
4834
586
149
(0.5)
(2.8)
(19.8)
(33.9)
(37.3)
(4.5)
(1.2)
2443
591
6229
(26.4)
(6.4)
(67.2)
425
214
3050
(11.5)
(5.8)
(82.7)
2868
805
9279
(22.1)
(6.2)
(71.6)
5510
801
2889
(59.9)
(8.7)
(31.4)
1790
771
1103
(48.9)
(21.0)
(30.1)
7300
1572
3992
(56.7)
(12.2)
(31.0)
3103
3787
2158
30.8
(33.5)
(40.9)
(23.3)
(8.7)
776
1567
1255
71.7
(21.0)
(42.5)
(34.0)
(14.7)
3879
5354
3413
42.5
(29.9)
(41.3)
(26.4)
(21.4)
7191
1271
801
(77.6)
(13.7)
(8.6)
2805
547
337
(76.0)
(14.8)
(9.1)
9996
1818
1138
(77.2)
(14.0)
(8.8)
3407
5856
5.0
(36.8)
(63.2)
(3.2)
519
3170
4.5
(14.1)
(85.9)
(3.1)
3926
9026
4.8
(30.3)
(69.7)
(3.1)
47
Figure 14. Cumulative probability of all-cause mortality by PSA and initial treatment.
Figure 15. Relative survival by PSA and initial treatment.
Study IV
Baseline characteristics, including age, PSA levels CNB and PCa volumes,
are shown in Tables 11 and 12. The mean age for men with PCa was 65
years and for men without PCa was 62 years. In the whole cohort, CNB
volume was approximately 0.2% of the prostate volume. This volume was
calculated from the postoperative sequential sections for those who had
prostatectomy, and otherwise calculated by ultrasound.
PCa detection by CNB, MRSI, MRI ADC and PET/CT ¹¹C Acetate
imaging related to 10 sections of the prostate demonstrated clear conformity
of MRI ADC maps with postoperative findings (Table 13) with high
accuracy (87%) and sensitivity (95%). Results of PET/CT ¹¹C Acetate alone
(10 patients) may not give confidence for targeted biopsy due to low
resolution, however specificity of the method is high (87%). Small
extracapsular cancer 1-5 – 2 mm was not demonstrated by any of the
imaging methods (Figure 16).
48
Table 11. Patients positive or negative for PCa at routine CNB
Mean and range within
brackets
Patient age
PSA ng/ml
CNB volume mm³
CNB Ca/CNB
Vol %
Gleason Score
Prostate volume
cm³
Group A
CNB pos. PCa
Patients (N=23)
Mean, range
65 (50-75)
8 (3.8-17)
90.8 (71.9-117.2)
13.6 (0.3-84)
Group B
CNB neg. PCa Patients (N=15) Mean,
range P
62 (35-72)
5.3 (0.9-20)
71.2 (56.3-96.3)
Not available.
6.4 (5 –10)
40.5 (16-75)
Postop (10) and
TRUS calculation
(13)
Not available
52.7 (29-101)
TRUS calculation
Table 12. Patients are subdivided according to choice of treatment
CNB Volume mm³
CNB vol share of P
CNB PCa volume
mm³; mean and range;
share of Pvol.
CNBCa/CNBVol%,
range
Gleason Score
Prostate volume cm³
Way of calculation
PCa volume from
postop. serial sections, cm³
P indicates prostate
Prostatectomy
(N=10)
85.1 (71.9 -107.2)
1/450-300
13.2 (1.3-34)
mean1/2800
3.8 10-4
19 (1.1-25.3)
Radiation
(N=2)
100.6(95.1-106)
7/410
46.4 (4.3-89)
mean 1/1000
11.4 10-4
40 (5-84)
Active surviallance
(N=11)
97 (72.117.2)
490
2.7 (0.3-13.9)
mean 1/21000
0.6 10-4
3 (0.3-14)
7 (6-8)
32.2 (24 – 46.9)
Postop calculation
4.3 (1.2-8.4)
(3.6-23.5%, mean
13.4% of P volume)
8.5 (7-10)
41.5 (40-43)
US calculation
Not available
6 (5-7)
47.9 (16-75)
US calculation
Not available
49
Table 13. Imaging methods and initial CNB compared with postoperative histology
of specimen. 10 parameters from each examination: 60 parameters for ADC; 80 for
MRSI; 100 for CNB and PET/CT respectively.
CNB, PET/CT, MVSI, MRI ADC
correlated to postoperative histology
CNB
Patients (N)
10
Parameters (N)
100
Sensitivity
0.53
Specificity
0.88
Accuracy
0.64
PET/CT
10
100
0.55
0.87
0.67
MVSI
8
80
0.79
0.46
0.69
MRI ADC
6
60
0.95
0.73
0.87
Figure 16.Example schematic mapping 1-10 biopsy areas. Positive results from
CNB (yellow),PET/CT ¹¹C Acetat (green) SUV=7. MRT Diffusion ADC (red areas)
1.19 – 1.38 x 10 ¯³ mm²/s; MRSI: H= Healthy; A = Ambiguous, ≥1-2 SD deviation
from normal; S = Suspicious ≥ 2-3 SD; VS = Very Suspicious ≥3SD; S=single voxel
MRSI (whole prostate volume). Dark blue confirmed PCa at postoperative histology. Gleason 3+4, focal 3+2. TNM postoperative classification: small ectra-capsular
PCa Mid- Zone ventrolateral left side, was not detected by imaging
50
Discussion
Study I
The data from the first study were derived from a large cohort over a defined
study period. We could not estimate cause-specific survival based solely on
data from the NPCR since cause of death had not been registered
consistently. However, in a study of men with PCa in northern Sweden, it
was shown that cause-specific survival is compatible with RS [151]. Only
36.3% of the men were diagnosed with PCa following PSA screening. The
majority of the tumours were detected following symptoms from the primary
tumour. In this study we based our analyses on RS to minimise the risk of
bias regarding any uncertainly regarding the cause of death.
In general, there is an inverse relationship between the level of a tumour
marker and the prognosis. Thus, studies of tumour markers as prognostic
tools are usually based on the premise that there is a positive correlation
throughout the cursor range. However, we have shown this not always to be
the case. We noticed an inverse correlation between PSA level and survival
for patients with PSA< 4 ng/ml. This correlation was regardless of tumour
differentiation, but it was more pronounced for the high score tumours. The
U-shaped Poisson regression curve may be explained by a large number of
aggressively growing, undifferentiated tumours that have lost their ability to
secrete in the lowest PSA range. A paradoxically low PSA expressing poor
differentiation was thus observed, explaining the reverse correlation between
PSA level and survival in this group. An increasing PSA level was associated with a larger percentage of men with palpable tumours.
Tumours presenting with local or distant symptoms may have a more
aggressive behaviour than asymptomatic tumours with equivalent PSA
levels detected through screening, which could explain the poor prognosis
for men with PSA in the lowest range. This could also explain why the group
of men with PSA levels between 4 ng/ml and 10 ng/ml and with a GS
between 2 and 6 has a ratio of observed to expected deaths below 1. We also
observed a tendency towards a larger percentage poorly differentiated and
more advanced-stage tumours in the lowest PSA range. In the Prostate
Cancer Prevention Trial, there was a relatively high percentage of men with
high-grade PCa among men with PSA levels <4 ng/ml [152].
In conclusion, this study emphasizes the specific circumstance regarding
men with PSA in the lowest range. The inverse correlation noted between
51
RS and PSA level has to be taken into consideration when choosing a cut-off
level in screening and when deciding on treatment. Notwithstanding the fact
that the majority of men in this group are most likely to have small, indolent
tumours, the risk of an undifferentiated tumour with very poor prognosis
presenting without PSA elevation should not be neglected.
Study II
In Study II the RS of men with curable PCa in a large population-based
cohort was calculated. Men with intermediary and high-risk tumours were
shown to have a much poorer prognosis if left without treatment compared
to men treated with curative intent. On the other hand, men with highly
differentiated PCa had the same RS as the general male population in
Sweden. Thus, men with poorly differentiated PCa should be given highest
priority for curative treatment. The data are derived from a population-based
cohort where screening was not widely established and conservative
treatment of localised tumour was more common than it is in North America.
Only 30% of men in this cohort were diagnosed as part of PSA screening.
Almost 40% of the men in this cohort were treated conservatively. This may
be due to the scepticism towards treatment with curative intent that prevailed
before the results from the SPCG-4 trial were published [153]. The SPCG-4
study has fundamentally changed our approach to the management of PCa in
Scandinavia.
The increasing use of PSA has led to detection of PCa an earlier stage
[154]. Men in the United States who have undergone RP have GS of 8 or
greater in only 8-21% of cases, which is probably explained by a shift
towards earlier diagnosis due to widespread screening [155-157]. However,
the corresponding percentage treated with RP in our study was only 27%.
This may have an impact on the outcome of our study, since men with lowscore tumours that would have been detected in the United States and
subsequently treated with radical intent would not have been diagnosed in
the Swedish population.
Several studies have demonstrated that the vast majority of men with lowrisk PCa remain free from recurrence after curative treatment [158, 159].
However, there are no randomised controlled studies comparing the outcome
for poorly differentiated PCa after RP and RT. Tumour-free resection margins in poorly differentiated PCa is a challenging surgical accomplishment,
even in the hands of skilled surgeons. Nevertheless, the poor survival of
these men if managed conservatively should be taken into consideration in
the treatment decision. Even a very small chance of radical cure is of great
value, considering the inevitably poor prognosis of these men if left without
active treatment. We found a clear survival benefit for men with high-score
tumour when treated with curative intent compared to conservative man52
agement. The survival benefit shown in Figures 10 and 11 makes the reluctant attitude towards surgery for fear of the risk of positive margins after RP
appears very defeatist, leaving men with very aggressive tumours no hope of
survival longer than a few months. Even a small chance of cure is a better
alternative for these men than no treatment at all.
In a large analysis including 60290 men with clinically localised PCa in
the Surveillance, Epidemiology and End Results (SEER) programme [160]
the prostate cancer-specific mortality after 10 years was lower for patients
who received treatment with intent to cure than those managed
conservatively. Other studies have also provided results in accordance with
the outcome of our study [161-163].
The difference in RS between those managed conservatively and those
undergoing treatment with curative intent in our study was largest for those
with a high GS (7-10). Although such comparisons should be made with
caution, taking into consideration the risk of selection bias, this shows that
efforts to improve outcome for the whole population of men with PCa
should be focused on this group rather than the large group of patients with
well-differentiated tumours. The vast majority of GS 2-6 or WHO 1 tumours
do not shorten the life span of their hosts, whichever treatment is given,
whereas men with moderately and poorly differentiated tumours have to be
given higher priority in order to effectively reduce prostate cancer-specific
mortality.
The RS for men with GS 2-6 was higher than 100% during the first years
after diagnosis, irrespective of treatment (figure 9). For men with GS 7-10,
on the other hand, the survival was very poor for men managed
conservatively (figure 10 and 11). No definite conclusion can, however, be
drawn from these differences in survival between the different treatments
shown in this figure. Table 8 shows a significant difference in over-all
survival between men treated with RP and RT. Since the treatment decisions
may be based on several circumstances, especially co-morbidity, this
difference must be taken with caution. In addition, the development of
radiation technology has improved the outcome in term of better survival for
patients who undergo radiotherapy today compared to 10 years ago.
However, the interaction between treatment and GS can-not be explained by
co-morbidity alone unless there was a relationship between co-morbidity and
GS in conjunction with therapy.
Although it is impossible to draw definite conclusions regarding treatment
outcome in a non-randomised trial, these figures emphasise the importance
of careful treatment decision for men with moderately and poorly
differentiated tumours. Whereas randomised controlled studies are usually
considered the optimal approach for unbiased assessment of the
effectiveness of an intervention in controlled conditions, the results from
population-based studies provide information regarding the outcomes after
treatment of prostate carcinoma in the community at large that could not
53
have been achieved in a study involving patients recruited from a limited
number of units. Whereas population-based studies show the outcome of an
intervention as it is practised in the community at large, randomised
controlled trials are performed under optimised circumstances, in specialised
centres with high competence, with the best available equipment, and in
highly selected patient samples. This may limit their external validity since
the difference between the outcome after technically advanced therapies,
such as RP, and the outcome after conservative management may become
more pronounced than it would have been in an unselected population. The
outcome from surgery could be expected to diverge more between
specialised centres and the community at large than the outcome from
conservative treatment, which requires less specialist competence.
In conclusion, this study shows benefit in RS for men with intermediary
and poorly differentiated prostate cancer when treated with curative intent
compared to conservative management. Despite the lower rate of treatment
success for these men, the potential benefit in terms of increased survival
after treatment is much higher than in men with well- to moderately
differentiated tumours.
Study III
In this study we compared the cause-specific mortality and overall as well as
RS in men with PCa with PSA levels 20-100 ng/ml at the time of diagnosis
between curative intent therapy and conservative management. The study
cohort was also derived from the NPCR. The study cohort was stratified into
patients with PSA levels in the intervals 20 -50 ng/ml and 51-100 ng/ml. We
calculated the cancer-specific mortality, over-all and RS adjusting for PSA
level at the time of diagnosis, GS, T category, age and co-morbidity for each
group in relation to treatment. We found a significant difference in both
cancer-specific mortality, over-all and RS in men who were treated with
curative intent therapy at 10-year of follow-up.
The cumulative 10-year PCa mortality was 36% for patients managed
conservatively and 13% for those who were treated with curative intent
(figure 17). ADT has often been considered the treatment of choice for
patients with PSA> 20 ng/ml but our study indicates that ADT alone is not
adequate for these men. Another study also based on the NPCR and PCabase showed that men with high-risk PCa had high prostate cancer-specific
mortality if managed conservatively [164].
54
0
0.1
0.2
0.3
0.4
0
1
2
3
5
6
7
Years since diagnosis
4
Conservetive
Curative
8
9
10
Log-rank test Curetive vs Conservative: p-value <0.01
Figure 17. Prostate cancer-specific mortality
Cumulative probability of PCa death
0.5
A
0
0.1
0.2
0.3
0.4
0.5
0
B
1
2
3
5
6
7
Years since diagnosis
4
Conservetive
Curative
8
9
10
Log-rank test Curetive vs Conservative: p-value <0.01
Cumulative probability of PCa death
Cumulative probability of PCa death
0
0.1
0.2
0.3
0.4
0.5
0
C
1
2
3
5
6
7
Years since diagnosis
4
Conservetive
Curative
8
9
10
Log-rank test Curetive vs Conservative: p-value <0.01
As observed in Study II as well as in other previous studies, men with
low-risk PCa have over-all and RS almost close to the normal malepopulation regardless of treatment. On the other hand, men with high-risk PCa have
poor prognosis if they are managed -conservatively. This study indicates that
treatment with curative intent is associated with better cancer-specific survival even for patients with PSA levels of 20-100 ng/ml (Figure 18).
Figure 18. Hazard ratio for death from prostate cancer for men undergoing treatment
with curative intent, with adjustment for age at diagnosis, T category, serum PSA
level, co-morbidity and Gleason Score, and men managed conservatively as reference group. The shaded field indicated 95% confidence interval.
Whereas there are numerous studies on men with localised tumours [86, 95],
the outcome after the main treatment alternatives of men with PSA between
20-100 ng/ml and locally advanced tumours at diagnosis is less well known,
despite the fact that this group is almost as large and face a much poorer
prognosis. Whereas early PSA-relapse cannot be ruled out in the cohort of
the present study, the over-all, relative and cancer-specific survival benefit
from treatment with curative intent strongly argues against an attitude of
defeatism for this group, even if the attempt to reach radical cure may often
be followed by tumour recurrence.
In this study patients with lymph node metastasis were also included.
Even patients with lymph node metastasis have better cancer-specific, overall and RS, when treated with curative intent.
With a population of 11.380 men, our study is one the largest studies to
date analysing cancer-specific mortality of men with high-risk PCa.
However, even when adjusting for age, co-morbidity and stage of disease,
PSA level and GS, there may be residual bias that cannot be accounted for.
The diagnoses retrieved from the National Population Register (NPR) gave
information on diagnoses from hospital care only. Therefore, co-morbidity
56
may be underestimated in our study, especially for patients with minor comorbidity, i.e. Charlson Score 1. Data regarding treatment in the NPCR are
based on the first six months after diagnosis. This may have affected the
outcome of the study since delayed treatment is not included and variations
in the practice of adjuvant and salvage therapies may have confounded the
study. In studies on disease-specific survival, the uncertainties regarding
cause of death is often a source of bias. The reliability of death certificates
for patients with PCa included in the NPCR has, on the contrary, been shown
to be high [149].
Lymph node staging and screening of distant metastases was only
performed in a minority of the group. We did not find any differences in
cancer-specific or RS between NO and NX patients. Cancer-specific
mortality was, however, significantly higher for patients with MX compared
to M0. This could be explained by the presence of non-detected distant
metastases in the MX group. This emphasises the importance of screening
for distant metastases for all men with PSA > 20 ng/ml that are under
consideration for treatment with radical intent.
In conclusion, this study demonstrates a positive association between
curative intent therapy and cancer-specific mortality, and overall as well as
RS for men with a PSA between 20 and 100 ng/ml.
Study IV
In this study that was originally designed as a pilot study, our aim was to
investigate whether we could improve PCa diagnosis by comparing the MRI,
and PET/CT ¹¹C Acetate with the established methods for this purpose, i.e.
TRUS and transrectal biopsy. We found that MRI is a promising method
which may help to assess local tumour invasion in the prostate.
Although routine screening for PCa remains controversial, PSA testing is
widely used in most Western countries. Stage distribution is affected
substantially by PSA testing [165-169]. Most men nowadays (up to 70%) are
diagnosed prior to the occurrence of local or distant symptoms [170]. Biopsies targeted by ultrasound miss 60-70% of cancers of the prostate [171,
172]. Each time prostate biopsies are taken the patient risks biopsy-related
complications, such as haematuria, rectal bleeding, epididymitis, urinary
retention and, in a worse scenario, even sepsis. The number of reported
complications from prostate biopsy in the literature has been varied between
0.1and 3% [173]. Due to the increased frequency of multiresistant bacteria,
antibiotic use must be reduced and one way is to reduce the risk for infection. By improving the accuracy of ultrasound directed prostate biopsy, the
number of biopsies may be decreased and the number of times the patient is
exposed to biopsy can be reduced.
57
MR imaging and/or MR spectroscopy have, until now, not been used as a
first approach in the diagnosis of PCa, but may be useful for targeted biopsy,
especially in patients with PSA levels indicative of cancer but negative
results from previous biopsies. This situation occurs most commonly with
lesions in the anterior peripheral or transition zone (ie, regions not palpable
at digital rectal examination and often not routinely sampled or targeted
during biopsy) [174, 175]. The decision on optimal treatment for PCa is best
based on clinical TNM stage, GS, and the level of PSA. The decision to treat
should also take into account patient age, disease stage, concomitant medical
disease, and the patient’s own preference. The inclusion of MRI and/or
MRSI findings in clinical nomograms helps improve the prediction of cancer
extent, thereby improving patient selection for local therapy.
Despite this study only including a small number of patients, 3T MRI
with ADC diffusion and surface coils seems to be favourable methods indicating areas for targeted biopsy of the prostate in cancer diagnosis compared
to the routine 10 CNB. Using surface coils, reasonable resolution was
achieved with MRT3T ADC diffusion (b=1000), resolution 1.8 x 1.8 x 3 mm
and for MRSI spectroscopy 1 x 1 x 2 cm. Simple mapping of the prostate
including information from 3T MRI DW ADC combined with MRSI may
allow ultrasound guided CNB focusing on the most PCa suspicious area in
cases where In conclusion, this study indicates that MRI can improve the
diagnostic accuracy of PCa. This diagnostic tool can be especially useful in
cases of negative findings where the suspicion of cancer persists. The use of
this technique can reduce the number of biopsies and also reduce the complication rate associated with biopsy. This study is, of course, too small and
larger studies are needed to confirm these results.
58
General discussion
Data from the first three studies presented here are all derived from the
NPCR. The NPCR has a coverage of more than 90% [34] and is one of the
largest data bases on men with PCa in the world.
The results from the NPCR must, however, be interpreted with caution
and the risk of confounding factors must be taken into consideration. Decisions about treatment options may depend on selection based on the patient's
age or co-morbidity. Nevertheless, the register may help in identifying confounding variables which can be adjusted for. Although randomised controlled clinical trials are considered the most appropriate trial design for testing the outcome of a specific treatment or intervention; there are several
advantages with population-based studies. In contrary to randomised controlled trials, that is usually performed at central units with optimal resources
and best professional competence, the outcome of a population-based register study, as in the present studies, shows the effectiveness of an intervention
as practised in the community at large. External validity is not limited by the
selection mechanism associated with a randomised controlled trial. The exclusion criteria in a randomised controlled trial may also result in a selected
patient sample, not necessarily representative of all patients who are subject
to a treatment or intervention. However, adequate conclusions can only be
drawn from a population-based register if the data recorded are correct. The
reliability of the NPCR has been shown to be high [146].
Data on treatment in the NPCR are derived from the first six months after
diagnosis. This may have affected the outcome of our studies since delayed
treatment was not included and variations in the practice of adjuvant and
salvage therapies may confound these studies. With the advent of PSA
screening, PCa is increasingly being diagnosed at an earlier stage than
before. At present, 86% of newly diagnosed PCas are localised within the
gland and patients have a 5-year relative (ie, adjusted for life expectancy)
survival rate of 100% (Figure 8). The 5-year RS rate for all stages of PCa is
98%, which indicates that prostate tumours have a slow growth rate and
allow for prolonged survival, even in patients with metastases at diagnosis
[111, 176].
In Study I we explore the predictive value of PSA in a large populationbased cohort. PSA as a diagnostic tool is not ideal since neither sensitivity
nor specificity are 100%. In most cases there is a negative relationship
between the level of tumour marker and prognosis; the higher the cancer
59
marker, the poorer the prognosis. We demonstrated in our first study, that it
is not always the case. Some patients with PSA below 4 ng / ml had a poorer
prognosis than those with PSA between 4 and 10 ng / ml. Men with PSA < 4
ng / ml had poorer RS compared to those with PSA between 4-10 ng / ml.
This difference in survival was greater for men with poorly differentiated
tumours, but there was also a difference for those with well-differentiated
tumours. This difference in the RS of men with PSA < 4 ng / ml compared to
those with PSA between 4 and10 ng / ml may be explained by the fact that
these tumours are poorly differentiated , very aggressive, and have lost the
ability to produce PSA. This lack of PSA production may also explain why
these tumours are usually not detected at screening but because of symptoms
that bring the patient to the doctor.
Controversy exists as regards the appropriate management of PCa. The
choice of treatment depends on the patient’s age at diagnosis, the stage and
aggressiveness of the tumour, the potential side-effects of treatment, and
patient co-morbidity [86, 138, 177].
RP in men with poorly differentiated tumours is a particularly
controversial issue. The chance of achieving a tumour-free resection border
is much lower in men with poorly differentiated tumours, making surgery
less successful. This was one of the reasons why poorly differentiated
tumours were not included in the SPCG-4 [153].
While the RS of men with low-risk PCa is the same as the normal male
population, the RS for men with poorly differentiated tumours, was noted to
be well below 100%, reflecting excess mortality among cancer patients
compared to the general population.
In Study II, we showed that curative treatment can improve survival in
men with poorly differentiated tumours. Men with poorly differentiated
tumours actually benefit from treatment with curative intent more than men
with well-differentiated tumours.
Despite the trend towards newly diagnosed PCas being low-risk, 20-35%
of patients are still classified as high-risk, based on PSA > 20 ng/mL, GS >
8, or an advanced clinical stage [113]. A PSA of 20 ng/ml is a cut-off point
in prognostic grouping of PCa in the latest edition of the TNM-classification
[57]. Men with PSA levels higher than 20 ng/ml but without signs of distant
metastases as judged by bone scan, may, have local growth too extensive to
guarantee beneficial outcome from RT or RP. On the other hand,
considering the inevitably poor prognosis of these men if left untreated,
denying them at least a small chance of cure could be considered unethical.
In Study III, we found that men with PSA between 20 ng/ ml and 100
ng/ml without distant metastasis benefit from curative therapy, despite the
fear of tumour growth beyond the prostate. This study confirms the result
from two randomised studies which showed improved overall and cancerspecific survival in men who received combination therapy with ADT and
RT compared to those who received only ADT only [114, 115].
60
These three studies show the risks of under- as well as overtreatment of
men with PCa. Staging by DRE and TRUS together have been shown to
miss nearly 50% of T3 tumors [62]. The use of MRI may lead to
improvement in diagnostic sensitivity. MRI could play an important role in
the detection, localisation, and staging of PCa and help guide treatment
selection and planning.
The ideal diagnostic tool would be non-invasive with no associated
morbidity and 100% sensitivity for the disease of interest [178]. Diagnostic
tests for PCa meet none of these criteria. Prostate biopsy is invasive, has
associated risks and only samples a limited portion of the prostate. Current
imaging modalities are not sufficiently reliable for PCa detection or
localisation [178]. According to the latest update of EAU-guidelines the
complications rate after ultrasound-guided biopsy is low and severe postprocedural infections are around 1% [173]. Despite this, the number of cores
sampled on prostate biopsy has dramatically increased, as has Escherichia
coli resistant to standard antimicrobial therapy. For example, in a
population-based study on E. coli bloodstream isolates in Olmsted County,
Minnesota from 1998 to 2007 there was a significant linear increase in E.
coli resistance to fluoroquinolones [179]. These results highlight the need for
ongoing studies to re-evaluate the optimal antimicrobial prophylaxis regimen
for prostate biopsy, taking into consideration local resistance patterns.
In Study IV of this thesis we were able to show how MRI can be helpful
in targeting biopsies from the prostate, thus reducing the number of biopsies
required, thus minimising the risk of post- procedural complications. It can
also contribute significant incremental infomation for local PCa staging,
particularly in the preoperative identification of extracapsular extension.
However, our study could not verify extra-capsular extension of tumour as
described in the literature [180]. Nevertheless, despite its high specificity in
the identification of organ-confined disease and extra-capsular extension, it’s
lower sensitivity and substantial inter-observer variability has caused the
routine use of MRI in the local staging of PCa to remain controversial.
The final study was a pilot study aimed at exploring the field of imaging
of the prostate with different radiographic techniques. This study has increased the understanding of the pros and cons of the various radiological
techniques available, and how these methods can be used separately. This
study was basically a hypothesis-generating study intended to stimulate new
ideas about the diagnosis of PCa, but it may also be of use in larger studies
in the future.
61
Conclusion
I.
The inverse correlation noted between relative survival and PSA
level for men with PSA below 4 ng/ml should be taken into consideration when choosing a cutoff level in screening and in the treatment decision for men with low PSA. Although the majority of men
in this group will most likely have small, indolent tumors, there are a
substantial number of men with poorly differentiated tumours presenting without PSA elevation, especially those with high Gleason
Score.
II.
Outcome differs little between conservative management and treatment with curative intent in men with localised well- to moderately
differentiated tumours over a 10-yr period. For men with poorly differentiated tumours, on the other hand, treatment choice is crucial
for the outcome. Despite a lower rate of treatment success for these
men, the potential chance of benefit in terms of increased survival
after treatment is much higher than in men with well- to moderately
differentiated tumours.
III.
Treatment with curative intent is beneficial in the group of men with
prostate cancer and PSA levels between 20 and 100 ng/ml if distant
metastases have not been revealed. Many patients with such tumours
appear to be under-treated in Sweden.
IV.
A combination of MR imaging Diffusion ADC and MR spectroscopy can provide a model for imaging of the prostate for targeted
biopsy.
62
Swedish summary
(Sammanfattning på svenska)
Prostatacancer är den vanligaste cancerformen i den manliga befolkningen i
Sverige och i västvärlden. Förekomsten av sjukdomen ökar också i asiatiska
länder, främst på grund av ökande PSA-testning. Mycket talar för att män
med lågrisk prostatacancer har samma överlevnad som resten av den manliga befolkningen, oavsett behandlingsalternativ. På grund av risken för biverkningar och komplikationer efter både kirurgi och strålning, i form av
inkontinens och impotens, är det lika angeläget att undvika överbehandling
av lågriskpatienter som att undvika underbehandling av hög-riskpatienter.
Ett välgenomtänkt behandlingsbeslut är avgörande för överlevnad och hälsorelaterad livskvalitet.
Prostatacancerns bakomliggande orsak är endast delvis känd. Det finns
flera riskfaktorer, men de exakta orsakerna till att cancer utvecklas hos vissa
män är okända. Ålder tillsammans med geografiska, etniska och ärftliga
faktorer är kända riskfaktorer. Sjukdomen betraktas som ett resultat av multifaktoriell påverkan. Den västerländska livsstilen, med bland annat högt intag
av fettrik kost, verkar vara av betydelse. Kosten i Västerlandet tenderar att
ha hög andel animaliska produkter. Den är dessutom bearbetad och raffinerad, vilket resulterar i ett högt intag av mättade fetter som kan ha betydelse
för förekomsten av prostatacancer i Väst. I asiatiska länder som Japan och
Kina, där förekomsten av prostatacancer är lägre, är den traditionella kosten
främst baserad på grönsaker. Dessutom kosten är i allmänhet obearbetad.
Relativt små mängder av animaliska produkter tillsammans med grönsaker,
frukt och andra växtbaserade livsmedel leder till lägre kaloriinnehåll i kosten
än den västerländska kosten, och med stor sannolikhet innehåller den större
mängder av vissa essentiella näringsämnen. På senare tid har man även visat
på en skyddande effekt av östrogenliknande föreningar i växter, så kallade
fytoöstrogener. Intaget av fytoöstrogener är högre i Kina och Japan än i västländer. Sambandet mellan prostatacancer och fytoöstrogen har studerats och
det har påvistas att män som hade ett högt intag av fytoöstrogenrika livsmedel hade avsevärt lägre risk att drabbas av prostatacancer.
Fysisk aktivitet är viktigt för primär prevention av flera cancertyper,
bland annat cancer i tjocktarm och bröst. För prostatacancer är de epidemiologiska bevisen för en skyddande effekt av fysisk aktivitet osäkra. I vissa
63
studier har man sett både positiva och negativa effekter i samband med fysisk aktivitet, men den observerade riskreduktion är relativt liten.
Majoriteten av de studier som har gjorts om inverkan av alkoholkonsumtion och prostatacancer tyder på att alkoholkonsumtion inte påverkar utvecklingen av prostatacancer. För de flesta tumörer som drabbar urinvägarna har
rökning en avgörande betydelse, men dess roll i förekomsten av prostatacancer är fortfarande kontroversiell. Stora epidemiologiska studier har emellertid visat att rökning är förknippad med högre risk att utveckla och dö av prostatacancer.
Idag diagnostiseras prostatacancer med hjälp av ultraljudguidad biopsi
med 10-12 biopsier. Dessa vävnadsprov skickas till histologisk undersökning
och man får en Gleason summering som beskriver det histologiska utseendet
av prostatacancer. Biopsier riktade med ultraljud missar 60-70% av befintliga prostatacancrar. Vid varje biopsitillfälle riskerar patienten att drabbas av
komplikationer såsom blod i urin och sperma, blod från ändtarmen, urinvägsinfektioner och i värsta fall allvarliga infektioner som kräver intensivvård. Antalet rapporterade komplikationer i litteraturen efter prostatabiopsier
har varierat från 0.1% till 3%. På grund av den ökade frekvensen av multiresistenta bakterier i samhället måste den totala antibiotikanvändningen minskas. Ett sätt att göra det är att reducera risken att drabbas av bakteriella infektioner, som nedre urinvägsinfektioner. Genom att förbättra träffsäkerheten vid prostatabiopsi kan man både minska antalet biopsier vid varje tillfälle
samt minska antalet omgångar som patienten måste genomgå biopsitagning
eftersom patienten måste ombiopseras så länge cancermisstanken kvarstår.
Syftet med denna doktorsavhandling var att;
I.
Utvärdera det prognostiska värdet av prostataspecifik antigen (PSA) i
en populationsbaserad kohort i Sverige och även undersöka den relativa överlevnaden för patienter som är tänkbara kandidater för kurativt
syftande behandling
II.
Beräkna relativ överlevnad i en stor och oselekterad populationsbaserad grupp av män med potentiellt botbar prostatacancer
III. Undersöka relationen mellan kurativ behandling av prostatacancer
specifik dödlighet samt den totala och relativa överlevnaden hos män
som diagnostiserats med prostatacancer med PSA nivå mellan 20 och
100 ng / ml
IV. Skapa en modell för avbildning av prostata för att öka säkerheten för
ultraljudsguidade mellannålsbiopsier för män med misstänkt prostatacancer samt förbättra stadieindelningen
Ett högt PSA-värde är i allmänhet förknippat med större tumörbörda. Vanligtvis indikerar en ökning i tumörmarkörer en mer aggressiv tumör och
sämre överlevnad för cancerpatienten. Vi fann dock att en låg PSA-nivå
64
paradoxalt nog var associerad med sämre överlevnad, och ännu sämre tumördifferentiering. Detta kan förklaras av en del aggressivt växande tumörer
har förlorat sin förmåga att producera PSA.
Män med lokalt avancerad tumör och PSA-nivå under 20 ng/ml har alltså
en längre relativ överlevnad om de behandlas med kurativ behandling jämfört med konservativ behandling.
Vi fann också att män med PSA mellan 20 och 100 ng/ml hade en bättre
cancer-specifik, total samt relativ överlevnad om de behandlades med kurativ behandling jämfört med konservativ. Denna skillnad kan också ses när
efter justering för ålder, PSA-nivå vid tidpunkten för diagnos, Gleason Score, annan sjuklighet och tumörstadium.
Dessa tre studier visar riskerna för under- samt överbehandling av män
med prostatacancer. Stadieindelning med hjälp av rektalpalpation och ultraljud tillsammans riskerar att missa nästan 50% av tumörer i stadium 3. MRT
kan leda till förbättrad diagnostisk känslighet och kan spela en viktig roll i
upptäckt, lokalisering och stadieindelningen av prostatacancer. Detta skulle
kunna leda till en bättre planering och mer riktad behandling.
Den ideala diagnostiska modellen skulle vara en icke-invasiv metod utan
morbiditet, med 100% sensitivitet och specificitet. De diagnostiska tester för
prostatacancer som finns idag uppfyller inget av dessa kriterier. Transrektalt
ultraljud med biopsitagning är en invasiv och riskfylld undersökning och ger
bara prover från en minimal del av prostata. Nuvarande bilddiagnostiska
metoder är inte tillräckligt tillförlitliga för att detektera och lokalisera prostatacancer. Detta gör att man nödgas ta fler biopsier, med åtföljande infektionsrelaterade komplikationer. Antalet prostata biopsier har under de senaste åren ökat dramatiskt. I en studie med E. coli som agens visade man en
signifikant linjär ökning av resistens mot antibiotika som tidigare har varit
effektiva mot dessa bakterier. Dessa resultat belyser behovet av studier för
att omvärdera den optimala antimikrobiella förebyggandebehandling för
prostata biopsi och anpassning efter lokala resistensmönster.
MRT kan vara till stor hjälp för att ta riktade biopsier från prostatan, för
att minska antalet biopsier, och i sin tur minimera risken för biopsirelaterade
komplikationer. Det kan också bidra med viktig information om prostatacancers stadium, i synnerhet inför operation för att identifiera eventuell växt av
cancer utanför prostatakörteln.
Slutsatser
I. Det omvända sambandet som noterades mellan relativ överlevnad och
PSA-nivån för män med PSA under 4 ng/ml bör beaktas när man väljer en
cut-off nivå i screening och behandlingsbeslut för män med lågt PSA. Även
om majoriteten av män i denna grupp sannolikt har små, ofarliga tumörer,
65
finns det ett antal män med tumörer som inte producerar PSA, framförallt de
med hög Gleason Score.
II. Under de första 10 åren efter diagnosen skiljer sig överlevnaden lite
mellan konservativ och kurativt syftande behandling hos män med högt till
medelhögt differentierade tumörer där tumören är lokaliserad. För män med
lågt differentierade tumörer, å andra sidan, är behandlingsvalet avgörande
för resultatet. Trots lägre andel kurerade män är den potentiella nyttan i form
av ökad överlevnad efter behandling mycket högre än hos män med högt till
medelhögt differentierade tumörer.
III. Behandling med kurativt syftande terapi förlänger troligen överlevnaden för män med prostatacancer och PSA i nivåer mellan 20 och 100 ng
/ml utan kända fjärrmetastaser. Många patienter med sådana tumörer verkar
vara underbehandlade i Sverige.
IV. En kombination av MRT Diffusion ADC och MR-spektroskopi kan
ge en modell för avbildning av prostata för målinriktad biopsi och därmed en
reducering av antalet biopsier.
66
Recent Development and Future Perspectives
Almost 500 years have passed since the prostate was first described by
Niccolò Massa and 150 years since PCa was described as a carcinoma. The
first PCa operation was performed by Hugh H. Young at Johns Hopkins
Hospital almost 110 years ago [79]. During the eighty years that have
passed since the first RP was performed, the entire anatomy of the prostate
has gradually become clearer. A better understanding of the anatomy has
helped in preserving the neurovascular bundle, thereby reducing the risk for
postoperative impotence [89]. At the beginning of this century we also
learned the roll of Denonvilliers fascia in the continence of men who undergo RP [94]. Because of this, surgeons are now able to better preserve
continence and erectile function and increase the quality of life of men undergoing RP.
RT has also developed in recent years. The improvement in radiation
techniques, with better dose schemes and optimised doses, has resulted in
better survival rates than a decade ago. Several studies have shown an
association between higher radiation and improved biochemical outcome
after dose-escalated external beam radiotherapy [181-184].
Brachytherapy has also undergone rapid development in recent years. The
idea of Brachytherapy is to insert radioactive seeds close to or within the
target tissue. By using permanent or temporary brachytherapy alone, or in
combination with external beam radiation good cancer control can be
achieved. This technique has been revolutionised by image guidance which
helps to optimise source location. The improvement in RT alone or in
combination with ADT has also improved the survival as well as the quality
of life of men with PCa [114, 115].
Two decades ago, PSA was introduced as a new marker in the diagnosis
of PCa. Since then the diagnosis of PCa has increased rapidly. PCa is one of
the most common cancers among men in the western World and
Scandinavian, and the leading cause of cancer death in Sweden, the second
cause of cancer death in the United States and the third cause of cancer death
in many European countries. The incidence of PCa has increased in Asian
countries [31].
The diagnosis of low-risk PCa has particularly increased since the
introduction of PSA. Bill-Axelson et al. showed in a randomised control
study started in the early 1990s, that to prevent one PCa death 16 men would
67
have to be treated with RP. The patients who were included in the study
were mainly men with PSA levels below 10 ng/ml and GS of 6 [86].
In the present thesis we investigated the survival benefit of treatment with
curative intent in men with high-risk tumors. We found benefits in terms
both of cancer- specific and over-all as well as relative survival of men who
receive curative treatment, surgery as well as radiotherapy, compared to
those receiving only hormone therapy or WW.
There are two randomised studies comparing RT combined with or
without neo-adjuvant hormonal therapy [114, 115]. These studies
demonstrate the benefits in terms of cancer-specific as well as the over-all
survival of combined treatment in patients with locally advanced PCa and
PSA levels higher than 20 ng/ml.
If we are to avoid over-diagnosis and over-treatment of PCa we need to
improve prognosis prediction. To do so, we must understand the disease
better and at the same time develop better diagnostic tools in order to define
the right patient for the right treatment option.
MRI, PET and CT are of high technical quality, but none of these techniques is reliable for routine use in the assessment of local tumour invasion
[185-187]. The initial ultrasound-guided biopsy result is negative in 66%71% of cases [171, 172]. If the first biopsy is negative, but the suspicion of
PCa still remains, repeat biopsy is usually the first choice. However, the
negative detection rate at second biopsy is 81% -83% [171, 172]. Targeted
transrectal magnetic resonance imaging-guided prostate biopsy is possibly a
better choice [188].
In some cases the tumour is located in the transition zone, which makes it
difficult to obtain adequate biopsy material. The use of improved imaging
techniques is an alternative to repeated biopsies for increasing diagnostic
sensitivity.
Improvements in surgical techniques and radiotherapy have led to
widened indications for treatment with curative intent. Surgery and
radiotherapy are also offered to older men. However, a clear benefit from
treatment should be shown before elderly men, with high co-morbidity are
given such treatments, since these still have side-effects and complication
risks. The relative benefit should also be considered before attempting
treatment with curative intent for men with locally advanced cancers and
tumours with risk for undetected distant metastases. As shown in the studies
presented here, PSA, GS and clinical staging may help to guide the clinician
in decision-making. Even if PSA has been shown to be a reliable prognostic
marker, more markers and improved imaging techniques may provide an
even better base for determining prognosis and guiding management.
Numerous studies on PCa have been published in recent decades. While
this very thesis is being written, there are probably hundreds of articles on
similar subjects being prepared for publication around the world. Studies on
PCa have stimulated the development of new therapeutic strategies and have
68
strengthened and improved our knowledge about the aetiology pathogenesis
and epidemiology of PCa. However, definite answers regarding most of the
crucial issues remain distant. We know from previous studies that patients
with low- risk PCa do not need to undergo immediate active treatment for
their cancer [111, 189, 190]. Hopefully, the present thesis has provided a
contribution to our thinking about the treatment of high-risk PCa and our
understanding of how high-risk PCa should be managed.
69
Acknowledgements
I wish to express my gratitude to all whose contribution make this work possible.
I especially want to thank:
Uppsala University and the National Prostate Cancer Register for giving me
this opportunity, Johanna Hagstand and Sigfrid Linnérs Memorial Foundation, Hillevi Fries Research Foundation and Percy Falk Foundation, for financial support.
Associated Professor Gabriel Sandblom, my supervisor, who introduces
me into the register study, which I found very boring and not interesting at
all before I got the chance to work with it. I want to thank you for your never
ending enthusiasm and your guidance through the first three papers. You
were always there for me and tried to answer to my questions even you lived
far away from here for 2 years. Even if you've always had too much to do
you didn’t stop to encourage me and telling me that everything will be okay.
Associated Professor Michael Häggman, my co-supervisor and the former
head of the Department of Urology, I want to thank you for your never
ending optimism and your positive attitude about life in general. You have
taught me many things from laparoscopic surgery to how to avoid being
fined for speeding and not to lose my driving license. You have also
promised to teach me how to sail this summer which I look very forward to.
Anders Berglund, PhD, co-author, for your statistical analyses and advices.
Associate Professor Håkan Jorulf, my co-supervisor in the last study, for
all your support during these last months. You introduce me in the world of
radiology especially the Magnetic Resonance Imaging (MRI). If I had met
you 3 years ago my dissertation had perhaps dealt more about imaging of
prostate cancer. Hopefully it is never too late.
Professor Eberhard Varenhorst, co-author and co-supervisor, with your
methodic manner also helped me to understand about the National Prostate
Cancer Register, the meaning of it and how it is built. You have a sharp eye
like an eagle and things that neither Gabriel, I or Anders noticed that being
70
wrong in an article you sow it right away and could come back with a good
comment.
Professor Per-Uno Malmström, professor of Urology department of Uppsala university Hospital, for providing facilities for scientific work during
my PhD study. Thank you for listening to me and come with good advice.
Associated Professor Ola Bratt, co-author, for your long-distant advice and
support during the third study.
Ewa and Monika, research nurses, for helping me sampling my specimen
for my research and being patience with me.
All friends, Colleagues and the staff at the Department of Urology, for your
support especially during theses last months. Thank you all!
Susan and Maryam, my wonderful sisters. Thank you for your generosity
and your unconditional love. You are the best sisters anyone can ever have.
Mother’s prayers are always with you.
Mehdi, my brother in law, I will especially thank you because I can be
confident that you are always there for me when I need your help. You have
helped me with many things since I moved to Uppsala and you still do.
Arman, my brother in law, I would like to thank you for giving me the courage to take me across the border from Iran to Turkey. You were like my big
brother all the way to Turkey and even during the time we sat as prisoners in
our own house in Turkey for 6 months before we could get to Sweden.
Ann-Britt and Tore, my mother and father in low, thank you for all these
years together and for all help during the building and renovating of our
house. Tore I can never thank you enough.
Nora, Ella and Adrian, thanks for being there, make myself busy and to
give my life meaning.
Last but not least, Cecilia, the love of my life, thanks for just being there
and for your endless patience and loving supports both during our house
building and also while I wrote my doctoral thesis book.
71
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