i dedicate this book to my family and my parents, who left us very …512288/fulltext02.pdf ·...
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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 Poten-tially Curable Prostate Cancer.
III Ladjevardi S, Berglund A, Bratt O, Widmark A, Varenhorst E, Sand-blom G. Treatment with curative intent, and survival in men with high-risk prostate cancer. A population-based study of 11,380 men with se-rum PSA 20-100 ng/ml.
IV Ladjevardi S, Wies J, Sörensen J, Häggman M, Tolf A, Jorulf H. Imag-ing 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
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Introduction
The aim of the present thesis was to investigate the potential benefit of cura-tive treatment compared with conservative treatment for men with the ag-gressive prostate cancer. The first study reports the concern required for men with prostate-specific antigen in the lowest range. In the second study rela-tive 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 unse-lected population-based cohort of men with prostate cancer and serum pros-tate-specific antigen levels between 20 and 100 ng/ml. The fourth study ex-plores the effectiveness of Magnetic Resonance imaging and Positron Emis-sion 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 techni-cally 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 pro-portion 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,
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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 evi-dence 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. Com-
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pared to non-drinkers, there was no difference in risk for PCa among drink-ers 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 coun-tries, 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 mor-tality 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].
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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 coun-tries, 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
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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 age-standardised 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 age-standardised 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 year-old 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
100
50
0
150
100
50
0
1960 1970 1980 1990 2000
NORDCAN
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.
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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 pros-tate.
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
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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 sym-pathetic 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].
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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 Glea-son scoring system is composed of a scale 1 to 5 (Figure 6).
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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 with-out 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 secon-dary (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].
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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 ex-amination (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 test-ing, 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]. How-ever, 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 popula-tion. In 1993, Oesterling et al. developed age-specific relevance ranges for white men [49]. Using the age-specific range for PSA can decrease the bi-opsy 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 ac-cepted 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
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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)
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As mentioned above, DRE is still the gold standard in the staging of the pri-mary tumour. DRE often underestimates tumour extension; a positive corre-lation 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 ex-ploration depends on circumstances that are involved in the decision to treat. The development and improvement of staging systems is a complex proce-dure 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 tu-mour 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 man-agement planning. This may prove to be especially useful with the emer-gence of novel and potentially less morbid targeted therapies. Recently,
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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 tu-mour 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 T2-weighted MRI scans, thus mimicking cancer. To overcome this, additional techniques, such as MRSI, dynamic contrast-enhanced MRI, and diffusion-weighted (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 contrast-enhanced 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 cen-tury 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 metas-tatic disease. ADT has been shown in several studies to reduce morbidity
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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 out-come following RP should, however, be considered in the context of the risk of over-treatment of men with slowly progressing tumours that do not bene-fit 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 tu-mours 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.
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Radiotherapy (RT) The aim of RT, as with RP, is complete cure of localised tumours. RT repre-sents an alternative to surgery since this approach may provide excellent results in patients carefully selected for the procedure [96, 97]. In the ab-sence of randomised controlled trials comparing the outcomes of RT and RP, these two approaches should be considered equal alternatives. RT is, how-ever, by tradition offered to those somewhat older and with more concomi-tant disease. Several attempts have been made to compare the outcome of the two treatments, but a major methodological obstacle has been that the treat-ment groups may have had an uneven distribution of tumour burden [98-100].
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 age-matched 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 pro-gressive disease occur, palliative hormonal therapy is initiated. Obstructive symptoms may be relieved by transurethral resection (TURP). Several stud-ies have shown that the the survival rate of older patients with localised tu-
26
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 clas-sified as high-risk, with a PSA > 20 ng/mL, Gleason Score > 8, or an ad-vanced clinical stage as criteria [113]. The treatment of men with locally advanced PCa remains controversial due to the lack of conclusive well-controlled or randomised studies comparing outcomes of conservative man-agement, RT, and RP. Men with locally advanced PCa are often not consid-ered for treatment with curative intent for fear of early relapse. As a result these men usually receive non-curative therapy, particularly hormone ther-apy. There are, however, two randomised controlled trials on men with high-risk 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].
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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 re-emergence of castration-resistant tumours. These tumours may still be sus-ceptible 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 ad-vantage 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
28
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 Co-operative Urological Research Group) randomised clinical trial was published in 1967 [135]. When first presented, no difference in survival was
29
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].
30
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 cause-specific 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
31
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
32
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.
33
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 diagno-sis, calendar period, serum PSA, co-morbidity, T-stage and GS. The Charl-son 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 asso-ciated 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
34
can be used in connection with the patient's age as a Charlson score to calcu-late a probability of survival (table 2).
Table 2. Charlson co-morbidities and their respective point scores Points
Morbidity
1 2 3 6
MI Hemiplegia Moderate–severe liver disease Metastatic solid tumourCCF Moderate–severePVD CRF AIDSCOPD DM (with end-organ damage)DM (without end-organ damage) MalignancyCerebrovascular disease LeukaemiaDementia LymphomaUlcersConnective tissue diseaseMild liver disease
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.
35
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.
36
Figure 7. Poisson regression curve for the ratio between observed and expected deaths with stratification for prostate-specific antigen (PSA) level and tumour dif-ferentiation. The regression model is based on PSA as linear splines with a break-point 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.
37
Table 3. Characteristics of 28,531 men with localised PCa in the Swedish National Prostate Cancer Register, 1996 to 2005
Characteristic No. of patients (%)Age, years<55 1540 (5.4)55–59 3939 (13.8)60–64 6583 (23.1)65–69 7872 (27.6)70–75 8597 (30.1)
Year of diagnosis!1996–2000 8647 (30.3)2001–2003 10,020 (35.1)2004–2005 9864 (34.6)
Gleason score!2 163 (0.6)3 318 (1.1)4 1318 (4.6)5 3594 (12.6)6 11,880 (41.6)7 6007 (21.1)8 1185 (4.2)9 508 (1.8)10 68 (0.2)Missing GleasonWHO grade 1 1857 (6.5)WHO grade 2 1319 (4.6)WHO grade 3 314 (1.1)
PSA, µg/L<4 2926 (10.3)
4 and <10 15,688 (55.0)10 and <20 9917 (34.8)
Tumor classification!T0 219 (0.8)T1 (missing abc) 49 (0.2)T1a 1313 (4.6)T1b 708 (2.5)T1c 13,068 (45.8)
T2 10,003 (35.1)T3 2914 (10.2)TX 257 (0.9)
Lymph node classificationN0 6062 (21.2)NX 22,469 (78.8)
Metastasis classificationM0 10,630 (37.3)MX 17,901 (62.7)
Mode of detection*!Screening 8139 (36.3)Symptoms 10,291 (45.9)Other reason 2363 (10.5)Missing information 1631 (7.3)
Mean follow-up [SD], year 4.1 [2.5]
38
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 (%)
Total number
Excluded patients Localised tumours: to analysis
M1 N1 T4Non-palpable
(T1abc, T0, TX)
Palpable
(T2–T3)
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)
Gleason score 7
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)
Gleason score 8–10
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)
Tab
le 5
. G
leas
on S
core
, PS
A (
µg/
l), a
nd p
rim
ary
trea
tmen
t of
the
28 5
31 m
en w
ith lo
calis
ed p
rost
ate
cane
r in
the
NPC
R 1
996-
2005
.
Tot
al
8176
1079
6
4206
1318 30
0
2915 82
0
2853
1
Poor
ly d
iffer
entia
ted
(Gle
ason
scor
e 8-
10) 10
g/
l P
SA <
20
g/l
100
(9.4
%)
237
(22.
3%)
270
(25.
4%)
66 (6
.2%
)
6 (0
.6%
)
355
(33.
3%9)
31 (2
.9%
)
1065
4 g/
l P
SA <
10
g/l
85 (9
.7%
)
281
(32.
1%)
207
(23.
6%)
53 (6
.1%
)
15 (1
.7%
)
205
(23.
4%)
30 (3
.4%
)
876
PSA
<4
g/l
16 (1
1.9%
)
40 (2
9.9%
)
25 (1
8.7%
)
12 (9
.0%
)
2 (1
.5%
)
37 (2
7.6%
)
2 (1
.5%
)
134
Mod
erat
ely
diff
eren
tiate
d (G
leas
on sc
ore
7) 10
g/l
PSA
< 2
0 g/
l
652
(20.
1%)
926
(28.
5%)
718
(22.
1%)
165
(5.1
%)
35 (1
.1%
)
656
(20.
2%)
96 (3
.0%
)
3248
4 g/
l P
SA <
10
g/l
585
(16.
2%)
1608
(44.
5%)
659
(18.
2%)
188
(5.2
%)
42 (1
.2%
)
395
(10.
9%)
135
(3.7
%)
3612
PSA
<4
g/l
123
(26.
%)
184
(39.
5%)
75 (1
6.1%
)
21 (4
.5%
)
6 (1
.3%
)
39 (1
.3%
)
18 (3
.9%
)
466
Wel
l diff
eren
tiate
d (G
leas
on sc
ore
2-6)
10
g/l
PSA
< 2
0 g/
l
1858
(33.
2%)
1797
(32.
1%)
931
(16.
6%)
241
(4.3
%)
39 (0
.7%
)
593
(10.
6%)
145
(2.6
%)
5604
4 g/
l P
SA <
10
g/l
3612
(32.
2%)
4920
(43.
9%)
1187
(10.
6%)
518
(4.6
%)
126
(1.1
%)
543
(4.8
%)
294
(2.6
%)
1120
0
PSA
<4
g/l
1145
(4
9.2%
)
803
(34.
5%)
134
(5.8
%)
54 (2
.3%
)
29 (1
.2%
)
92 (4
.0%
)
69 (3
.0%
)
2326
Prim
ary
trea
tmen
t
Wat
chfu
l wai
ting
Rad
ical
pr
osta
tect
omy
Rad
ioth
erap
y (e
xter
nal)
Rad
ioth
erap
y (b
rach
y)
Oth
er c
urat
ive
trea
tmen
t
Hor
mon
al tr
eatm
ent
Mis
sing
info
rmat
ion
Tot
al n
o of
cas
es
40
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 well-differentiated 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).
41
Table 6. .Baseline characteristics by treatment
Conservative managements Curative managements Total
Palliative Watchful Radical Radiotherapy
treatments waiting Prostatectomy
n % n % n % n % n %
Age<55 21 0.7 183 1.9 1310 10.1 234 3.7 1748 4.1
55-59 77 2.4 647 6.9 2928 22.6 788 12.5 4440 11.1
60-64 243 7.6 1486 15.7 4259 32.9 1583 25.1 7571 20.3
65-69 686 21.4 2544 27.0 3433 26.5 2104 33.4 8767 27.1
70-75 2183 68.0 4575 48.5 1020 7.9 1599 25.3 9377 37.4
Year of Diagnosis1996-2000 1195 37.2 3281 34.8 2361 18.2 1580 25.0 8417 28.8
2001-2003 1043 32.5 2662 28.2 3953 30.5 2148 34.1 9806 31.3
2004-2006 972 30.3 3492 37.0 6636 51.2 2580 40.9 13680 39.9
Gleason Score (GS)2 11 0.3 116 1.2 25 0.2 9 0.1 161 0.5
3 26 0.8 168 1.8 74 0.6 50 0.8 318 1.0
4 61 1.9 787 8.3 358 2.8 155 2.5 1361 3.9
5 243 7.6 1466 15.5 1549 12.0 625 9.9 3883 11.2
6 829 25.8 4004 42.4 6556 50.6 2413 38.3 13802 39.3
7 896 27.9 1071 11.4 3140 24.2 1835 29.1 6942 23.1
8 331 10.3 120 1.3 478 3.7 418 6.6 1347 5.5
9 190 5.9 36 0.4 127 1.0 211 3.3 564 2.7
10 29 0.9 8 0.1 10 0.1 29 0.5 76 0.4
Missing GS, WHO grade 1 173 5.4 1132 12.0 322 2.5 210 3.3 1837 5.8
Missing GS, WHO grade 2 297 9.3 471 5.0 257 2.0 278 4.4 1303 5.2
Missing GS, WHO grade 3 124 3.9 56 0.6 54 0.4 75 1.2 309 1.5
GS or WHO gradeGS 2-6, WHO 1 1343 0.4 7673 0.8 8884 0.7 3462 0.5 21362 0.7
GS 7, WHO 2 1193 0.4 1542 0.2 3397 0.3 2113 0.3 8245 0.3
GS 8-10, WHO 3 674 0.2 220 0.0 669 0.1 733 0.1 2296 0.1
PSAPSA<4 180 5.6 1488 15.8 1275 9.8 365 5.8 3308 9.2
4<=PSA<10 1248 38.9 5072 53.8 8215 63.4 3287 52.1 17822 52.0
10<=PSA<20 1782 55.5 2875 30.5 3460 26.7 2656 42.1 10773 38.7
T categoryT0 18 0.6 133 1.4 46 0.4 23 0.4 220 0.7
T1 (abc missing) 1 0.0 18 0.2 13 0.1 5 0.1 37 0.1
T1a 71 2.2 1163 12.3 166 1.3 39 0.6 1439 4.1
T1b 105 3.3 444 4.7 133 1.0 80 1.3 762 2.6
T1c 748 23.3 4536 48.1 7422 57.3 2494 39.5 15200 42.0
T2 1267 39.5 2540 26.9 4727 36.5 2399 38.0 10933 35.2
T3 969 30.2 504 5.3 364 2.8 1234 19.6 3071 14.5
TX 31 1.0 97 1.0 79 0.6 34 0.5 241 0.8
N categoryN0 147 4.6 190 2.0 4178 32.3 2036 32.3 6551 17.8
NX 3063 95.4 9245 98.0 8772 67.7 4272 67.7 25352 82.2
M categoryM0 1243 38.7 1982 21.0 4398 34.0 3512 55.7 11135 37.4
MX 1967 61.3 7453 79.0 8552 66.0 2796 44.3 20768 62.7
Mode of detection*Screening 389 16.6 2233 32.2 5275 46.3 1952 36.9 9849 33.0
Symptoms 1574 67.3 3431 49.4 4207 36.9 2463 46.5 11675 50.0
Other Reasons 201 8.6 878 12.7 1260 11.1 514 9.7 2853 10.5
Missing information 174 7.4 397 5.7 648 5.7 367 6.9 1586 6.4
Mean follow-up years (sd) available year 2000 4.6 (2.7) 4.8 (2.9) 4.0 (2.6) 4.4 (2.6) 4.3 (2.7)
Tab
le 7
. Dis
trib
utio
n of
pri
mar
y tr
eatm
ent b
y G
leas
on S
core
(G
S)
Gle
ason
Sco
re 2
-6
Gle
ason
Sco
re 7
Gle
ason
Sco
re 8
-10
PS
A <
44
<=
PS
A <
10
10
<=
PS
A <
20
PS
A <
44
<=
PS
A <
10
10
<=
PS
A <
20
PS
A <
44
<=
PS
A <
10
10
<=
PS
A <
20
To
tal
n%
n%
n%
n%
n%
n%
n%
n%
n%
n
To
tal n
o.
of
ca
se
s2
75
41
32
04
62
91
56
44
43
93
68
81
53
10
18
12
29
33
34
0
Con
serv
ativ
em
anag
emen
tsW
atc
hfu
l w
aitin
g1
32
84
8.2
42
76
32
.42
06
93
2.9
14
32
5.4
70
01
5.8
69
91
91
71
1.1
96
9.4
10
78
.79
43
5
Pa
llia
tive
tre
atm
en
ts9
53
.45
88
4.5
66
01
0.5
43
7.6
43
39
.87
17
19
.44
22
7.5
22
72
2.3
40
53
33
21
0
Bila
tera
l o
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0 1 2 3 4 5 6 7 8 9 10 Time (years)
0
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1
Rel
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e s
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Conservative managements (CM)
No. at Risk901688843462
CM RP RT
8450 7226 6014 4862 3885 3016 2198 1465 872 414
Radical prostatectomy (RP)
901688843462
CM RP RT
8450 7226 6014 4862 3885 3016 2198 1465 872 414 8216 6775 5152 3705 2657 1858 1222 730 394 180
Radiotherapy (RT)
901688843462
CM RP RT
8450 7226 6014 4862 3885 3016 2198 1465 872 414 8216 6775 5152 3705 2657 1858 1222 730 394 180 3284 2854 2287 1768 1354 950 596 334 158 60
Figure 9. Relative survival: Gleason score 2-6
0 1 2 3 4 5 6 7 8 9 10 Time (years)
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Conservative managements (CM)
No. at Risk273533972113
CM RP RT
2595 2242 1881 1532 1188 922 694 475 269 118
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2595 2242 1881 1532 1188 922 694 475 269 118 3072 2415 1812 1312 938 688 482 316 167 72
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2595 2242 1881 1532 1188 922 694 475 269 118 3072 2415 1812 1312 938 688 482 316 167 72 1980 1690 1364 1063 806 584 46
402246 124
Figure 10. .Relative survival: Gleason score 7
44
0 1 2 3 4 5 6 7 8 9 10 Time (years)
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Radiotherapy (RT)
894669733
CM RP RT
847 708 557 434 322 234 154 87 42 16 614 492 383 286 204 154 118 69 36 16 685 578 472 364 270 196 138 81 42
Figure 11. Relative survival: Gleason score 8-10
2 4 6 8 10
0.0
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Gleason Score 2-10
Ob
serv
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Exp
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Conservative managementsCurative managements
Figure 12. Observed deaths/Expected deaths, 2000 - 2006
45
Table 8. Multivariate Cox proportional hazard analysis with overall survival as the end point
Model 1HR 95 % CI
Model 2 HR 95 % CI
CMRPRTGS 2-6GS 7GS 8-10Age at diagnosisRP* GS 7RT* GS 7RP* GS 8-10RT* GS 8-10
ref -0.36 0.32 - 0.400.54 0.49 - 0.59ref -1.61 1.49 - 1.732.67 2.42 - 2.951.06 1.05 - 1.07- -- -- -- -
ref -0.41 0.36 - 0.470.62 0.54 - 0.72ref -1.72 1.57 - 1.883.00 2.67 - 3.381.06 1.05 - 1.070.78 0.63 - 0.960.81 0.66 - 0.990.65 0.47 - 0.900.71 0.55 - 0.91
Model 3HR 95% CI
Model 4HR 95% CI
CM ref - ref -RP 0.37 0.33 - 0.41 0.41 0.36 - 0.48RT 0.54 0.49 - 0.59 0.62 0.54 - 0.71GS 2-6 ref - ref -GS 7 1.58 1.46 - 1.70 1.69 1.54 -1.84GS 8-10 2.60 2.35 - 2.87 2.92 2.59 - 3.29Age at diagnosis 1.06 1.05 - 1.06 1.06 1.05 - 1.06RP* GS 7 - - 0.78 0.63 - 0.97RT* GS 7 - - 0.81 0.66 - 0.99RP* GS 8-10 - - 0.65 0.47 - 0.90RT* GS 8-10 - - 0.71 0.55 - 0.92PSA 10-20 ng/ml ref - ref -PSA 4-10 ng/ml 0.82 0.77 - 0.89 0.83 0.77 - 0.89PSA < 4 ng/ml 0.96 0.86 - 1.08 0.97 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 20-50 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 cause-specific 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).
46
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 mod-els with hazard ratios (HR) with 95% confidence intervals (CI)
PSA 20-50 nl/mg PSA 51-100 nl/mg PSA 20-100 nl/mg
HR (CI 95%) HR (CI 95%) HR (CI 95%)Initially planned treatment
Conservative 1.00 ref. 1.00 ref. 1.00 ref.Curative 0.28 ( 0.24 - 0.33 ) 0.30 ( 0.22 - 0.41 ) 0.29 ( 0.20 - 0.26 )
Age at diagnosis (years)<60 1.00 ref. 1.00 ref. 1.00 ref.60-69 0.84 ( 0.68 - 1.05 ) 0.83 ( 0.64 - 1.08 ) 0.84 ( 0.71 - 0.99 )70-75 0.76 ( 0.62 - 0.95 ) 0.87 ( 0.67 - 1.13 ) 0.81 ( 0.69 - 0.96 )
Log PSA (ng/ml) 1.14 ( 0.92 - 1.41 ) 1.68 ( 1.17 - 2.41 ) 1.45 ( 1.32 - 1.61 )Charlson Co-morbidity Index
CCI 0 1.00 ref. 1.00 ref. 1.00 ref.CCI 1 0.91 ( 0.77 - 1.09 ) 0.89 ( 0.72 - 1.11 ) 0.94 ( 0.84 - 1.05 )CCI 2+ 1.17 ( 0.96 - 1.43 ) 1.20 ( 0.93 - 1.56 ) 1.19 ( 1.04 - 1.36 )
Gleason ScoreGS 2-6 1.00 ref. 1.00 ref. 1.00 ref.GS 7 1.72 ( 1.46 - 2.03 ) 1.46 ( 1.18 - 1.81 ) 1.63 ( 1.43 - 1.85 )GS 8-10 3.59 ( 3.04 - 4.25 ) 2.66 ( 2.15 - 3.31 ) 3.21 ( 2.82 - 3.67 )
Clinical T-stageT1c 1.00 ref. 1.00 ref. 1.00 ref.T1ab 1.71 ( 1.21 - 2.42 ) 1.93 ( 1.12 - 3.32 ) 1.74 ( 1.31 - 2.33 )T2 1.60 ( 1.29 - 1.98 ) 1.31 ( 0.96 - 1.79 ) 1.52 ( 1.27 - 1.82 )T3-T4 2.57 ( 2.09 - 3.16 ) 1.84 ( 1.37 - 2.49 ) 2.32 ( 1.96 - 2.75 )
Subgroup 1. Level of PSA 20-50, M0/MXSubgroup 2. Level of PSA 51-100, M0/MXSubgroup 3. Level of PSA 20-100, M0/MX
47
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
Level of Prostatic Specific Antigen (PSA)
PSA 20-50 PSA 51-100 Totaln (%) n (%) n (%)
All 9263 (100) 3689 (100) 12952 (100)Calendar period
1996-2000 3306 (35.7) 1483 (40.2) 4789 (37.0)2001-2003 2362 (25.5) 922 (25.0) 3284 (25.4)2004-2008 3595 (38.8) 1284 (34.8) 4879 (37.7)
Age of diagnosis<60 1029 (11.1) 383 (10.4) 1412 (10.9)60-69 4036 (43.6) 1524 (41.3) 5560 (42.9)70-75 4198 (45.3) 1782 (48.3) 5980 (46.2)
Mode of detection*Screening 1658 (24.8) 408 (16.2) 2066 (22.4)Symptoms 4057 (60.6) 1782 (70.9) 5839 (63.4)Other reason 522 (7.8) 136 (5.4) 658 (7.1)Missing 458 (6.8) 189 (7.5) 647 (7.0)
Clinical T-stageT0 50 (0.5) 17 (0.5) 67 (0.5)T1ab 296 (3.2) 63 (1.7) 359 (2.8)T1c 2139 (23.1) 423 (11.5) 2562 (19.8)T2 3358 (36.3) 1037 (28.1) 4395 (33.9)T3 3054 (33.0) 1780 (48.3) 4834 (37.3)T4 272 (2.9) 314 (8.5) 586 (4.5)TX 94 (1.0) 55 (1.5) 149 (1.2)
N-stageN0 2443 (26.4) 425 (11.5) 2868 (22.1)N1 591 (6.4) 214 (5.8) 805 (6.2)NX/Missing 6229 (67.2) 3050 (82.7) 9279 (71.6)
M-stageM0 5510 (59.9) 1790 (48.9) 7300 (56.7)M1 801 (8.7) 771 (21.0) 1572 (12.2)MX/Missing 2889 (31.4) 1103 (30.1) 3992 (31.0)
Gleason ScoreGS 2-6 3103 (33.5) 776 (21.0) 3879 (29.9)GS 7 3787 (40.9) 1567 (42.5) 5354 (41.3)GS 8-10 2158 (23.3) 1255 (34.0) 3413 (26.4)
Level of PSA, mean (SD) 30.8 (8.7) 71.7 (14.7) 42.5 (21.4)Charlson Comorbidity Index
CCI 0 7191 (77.6) 2805 (76.0) 9996 (77.2)CCI 1 1271 (13.7) 547 (14.8) 1818 (14.0)CCI 2+ 801 (8.6) 337 (9.1) 1138 (8.8)
Initial planned treatmentCurative 3407 (36.8) 519 (14.1) 3926 (30.3)Conservative 5856 (63.2) 3170 (85.9) 9026 (69.7)
Mean follow-up time, yr (SD) 5.0 (3.2) 4.5 (3.1) 4.8 (3.1)
48
Figure 14. Cumulative probability of all-cause mortality by PSA and initial treat-ment.
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).
49
Table 11. Patients positive or negative for PCa at routine CNB
Mean and range within brackets
Group A CNB pos. PCa Patients (N=23) Mean, range
Group B CNB neg. PCa Pa-tients (N=15) Mean, range P
Patient age 65 (50-75) 62 (35-72) PSA ng/ml 8 (3.8-17) 5.3 (0.9-20) CNB volume mm³ 90.8 (71.9-117.2) 71.2 (56.3-96.3) CNB Ca/CNB Vol %
13.6 (0.3-84) Not available.
Gleason Score 6.4 (5 –10) Not available Prostate volume cm³ 40.5 (16-75)
Postop (10) and TRUS calculation (13)
52.7 (29-101) TRUS calculation
Table 12. Patients are subdivided according to choice of treatment
Prostatectomy (N=10)
Radiation (N=2)
Active surviallance (N=11)
CNB Volume mm³ 85.1 (71.9 -107.2) 100.6(95.1-106) 97 (72.117.2) CNB vol share of P 1/450-300 7/410 490 CNB PCa volume mm³; mean and range; share of Pvol.
13.2 (1.3-34) mean1/2800 3.8 10-4
46.4 (4.3-89) mean 1/1000 11.4 10-4
2.7 (0.3-13.9) mean 1/21000 0.6 10-4
CNBCa/CNBVol%, range
19 (1.1-25.3) 40 (5-84) 3 (0.3-14)
Gleason Score 7 (6-8) 8.5 (7-10) 6 (5-7) Prostate volume cm³ Way of calculation
32.2 (24 – 46.9) Postop calculation
41.5 (40-43) US calculation
47.9 (16-75) US calculation
PCa volume from postop. serial sec-tions, cm³
4.3 (1.2-8.4) (3.6-23.5%, mean 13.4% of P volume)
Not available Not available
P indicates prostate
50
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 PET/CT MVSI MRI ADC Patients (N) 10 10 8 6
Parameters (N) 100 100 80 60
Sensitivity 0.53 0.55 0.79 0.95
Specificity 0.88 0.87 0.46 0.73
Accuracy 0.64 0.67 0.69 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 histol-ogy. Gleason 3+4, focal 3+2. TNM postoperative classification: small ectra-capsular PCa Mid- Zone ventrolateral left side, was not detected by imaging
51
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 associ-ated 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
52
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 low-score 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 low-risk 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 mar-gins 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 man-
53
agement. The survival benefit shown in Figures 10 and 11 makes the reluc-tant 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
54
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 PCa-base showed that men with high-risk PCa had high prostate cancer-specific mortality if managed conservatively [164].
0.5
0.4
0.3
0.2
0.1
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Ye
ars
sin
ce
dia
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osis
12
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0
Cumulative probability of PCa deathA
BC
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Cumulative probability of PCa death
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osis
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Cumulative probability of PCa death
Log-r
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56
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 malepopula-tion 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 sur-vival 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 refer-ence 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, over-all 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
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may be underestimated in our study, especially for patients with minor co-morbidity, 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]. Biop-sies 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 infec-tion. 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.
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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 indi-cating 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 com-plication rate associated with biopsy. This study is, of course, too small and larger studies are needed to confirm these results.
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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. Deci-sions about treatment options may depend on selection based on the patient's age or co-morbidity. Nevertheless, the register may help in identifying con-founding variables which can be adjusted for. Although randomised con-trolled clinical trials are considered the most appropriate trial design for test-ing the outcome of a specific treatment or intervention; there are several advantages with population-based studies. In contrary to randomised con-trolled trials, that is usually performed at central units with optimal resources and best professional competence, the outcome of a population-based regis-ter 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 ex-clusion 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 population-based 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
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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 cancer-specific survival in men who received combination therapy with ADT and RT compared to those who received only ADT only [114, 115].
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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 post- procedural 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 in-creased 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.
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Conclusion
I. The inverse correlation noted between relative survival and PSA level for men with PSA below 4 ng/ml should be taken into consid-eration when choosing a cutoff level in screening and in the treat-ment 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 pre-senting without PSA elevation, especially those with high Gleason Score.
II. Outcome differs little between conservative management and treat-ment with curative intent in men with localised well- to moderately differentiated tumours over a 10-yr period. For men with poorly dif-ferentiated 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 spectros-copy can provide a model for imaging of the prostate for targeted biopsy.
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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 manli-ga befolkningen, oavsett behandlingsalternativ. På grund av risken för bi-verkningar 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 hälso-relaterad 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 multi-faktoriell 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 raffine-rad, 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 väst-länder. Sambandet mellan prostatacancer och fytoöstrogen har studerats och det har påvistas att män som hade ett högt intag av fytoöstrogenrika livsme-del 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 epidemi-ologiska bevisen för en skyddande effekt av fysisk aktivitet osäkra. I vissa
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studier har man sett både positiva och negativa effekter i samband med fy-sisk aktivitet, men den observerade riskreduktion är relativt liten.
Majoriteten av de studier som har gjorts om inverkan av alkoholkonsum-tion och prostatacancer tyder på att alkoholkonsumtion inte påverkar utveck-lingen av prostatacancer. För de flesta tumörer som drabbar urinvägarna har rökning en avgörande betydelse, men dess roll i förekomsten av prostatacan-cer är fortfarande kontroversiell. Stora epidemiologiska studier har emeller-tid visat att rökning är förknippad med högre risk att utveckla och dö av pro-statacancer.
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 befintli-ga prostatacancrar. Vid varje biopsitillfälle riskerar patienten att drabbas av komplikationer såsom blod i urin och sperma, blod från ändtarmen, urin-vägsinfektioner och i värsta fall allvarliga infektioner som kräver intensiv-vård. Antalet rapporterade komplikationer i litteraturen efter prostatabiopsier har varierat från 0.1% till 3%. På grund av den ökade frekvensen av multire-sistenta bakterier i samhället måste den totala antibiotikanvändningen mins-kas. Ett sätt att göra det är att reducera risken att drabbas av bakteriella in-fektioner, som nedre urinvägsinfektioner. Genom att förbättra träffsäkerhe-ten 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 relati-va överlevnaden för patienter som är tänkbara kandidater för kurativt syftande behandling
II. Beräkna relativ överlevnad i en stor och oselekterad populationsbase-rad 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 prostata-cancer samt förbättra stadieindelningen
Ett högt PSA-värde är i allmänhet förknippat med större tumörbörda. Van-ligtvis indikerar en ökning i tumörmarkörer en mer aggressiv tumör och sämre överlevnad för cancerpatienten. Vi fann dock att en låg PSA-nivå
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paradoxalt nog var associerad med sämre överlevnad, och ännu sämre tu-mördifferentiering. 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 jäm-fört 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 kura-tiv behandling jämfört med konservativ. Denna skillnad kan också ses när efter justering för ålder, PSA-nivå vid tidpunkten för diagnos, Gleason Sco-re, annan sjuklighet och tumörstadium.
Dessa tre studier visar riskerna för under- samt överbehandling av män med prostatacancer. Stadieindelning med hjälp av rektalpalpation och ultra-ljud 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 prosta-tacancer. Detta gör att man nödgas ta fler biopsier, med åtföljande infek-tionsrelaterade komplikationer. Antalet prostata biopsier har under de senas-te 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 prostatacan-cers 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,
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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 överlev-naden 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.
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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 un-dergo RP [94]. Because of this, surgeons are now able to better preserve continence and erectile function and increase the quality of life of men un-dergoing 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
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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 tech-niques 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
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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.
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Acknowledgements
I wish to express my gratitude to all whose contribution make this work pos-sible.
I especially want to thank: Uppsala University and the National Prostate Cancer Register for giving me this opportunity, Johanna Hagstand and Sigfrid Linnérs Memorial Founda-tion, Hillevi Fries Research Foundation and Percy Falk Foundation, for fi-nancial 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
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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 Upp-sala 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 cour-age 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.
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