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Natural history and prognostic factors in localized prostate cancer
Örebro University, School of Health and Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.

The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.

Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.

The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.

Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2008. , 78 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 15
Keyword [en]
Prostate Cancer, Natural History, Ki-67, Survival, Prognostic factor, Tumor grade, TUR-P, Incidental, Tumor volume, MUC-1, AMACR
National Category
Urology and Nephrology Surgery
Research subject
Surgery esp. Urology Specific
Identifiers
URN: urn:nbn:se:oru:diva-2109ISBN: 978-91-7668-592-1 (print)OAI: oai:DiVA.org:oru-2109DiVA: diva2:135894
Public defence
2008-05-16, Bohmanssonsalen, Hus-B USÖ, Södra Grev Rosengatan, Örebro, 08:30
Opponent
Supervisors
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2011-05-18Bibliographically approved
List of papers
1. Natural history of early, localized prostate cancer
Open this publication in new window or tab >>Natural history of early, localized prostate cancer
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2004 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, no 22, 2713-2719 p.Article in journal (Refereed) Published
Abstract [en]

Context Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting. Objective To examine the long-term natural history of untreated, early stage prostatic cancer. Design Population-based, cohort study with a mean observation period of 21 years. Setting Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984). Patients A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX MO classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms. Main Outcome Measures Progression-free, cause-specific, and overall survival. Results After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years, revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P=.01). Conclusion Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

National Category
Surgery
Research subject
Surgery esp. Urology Specific
Identifiers
urn:nbn:se:oru:diva-15599 (URN)10.1001/jama.291.22.2713 (DOI)000221862300025 ()
Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2011-05-18Bibliographically approved
2. How well does the Gleason score predict prostate cancer death?: A 20-year followup of a population based cohort in Sweden
Open this publication in new window or tab >>How well does the Gleason score predict prostate cancer death?: A 20-year followup of a population based cohort in Sweden
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2006 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 175, no 4, 1337-1340 p.Article in journal (Refereed) Published
Abstract [en]

Purpose

Adenocarcinoma of the prostate is the most common cancer among men in Western countries. Although the prognostic heterogeneity of prostate cancer is enormous, clinically insignificant aggressive prostate cancers cannot be reliably distinguished. Therefore, identifying prognostic factors is increasingly important, notably among men diagnosed with localized prostate cancer, because many of them may not require aggressive treatment.

Materials and Methods

We analyzed a population based cohort of 253 men with early stage (T1a-b, Nx, M0) initially untreated prostate cancer diagnosed between 1977 and 1991, before PSA screening was available. Tissue samples were available for 240 patients diagnosed with transurethral resection. During complete followup through September 2003, standardized criteria were used to classify histopathological characteristics, progression and causes of death.

Results

Higher Gleason grade, higher nuclear grade and larger tumor volume were independent predictors of death in prostate cancer with monotonous and statistically significant trends (p <0.05). In contrast, the level of Ki-67 – strongly correlated to Gleason score – was not an independent predictor of prostate cancer death. Given a Gleason score of 7 or greater, the probability of dying of prostate cancer was 29%. The corresponding predictive value for Gleason score 8 or greater was 48%.

Conclusions

Although a high Gleason score is a determinant of prostate cancer death, its PPV is relatively low. Thus, further efforts in finding other or complementary indicators of prostate cancer outcome are needed.

Place, publisher, year, edition, pages
Baltimore: Williams and Wilkins Co., 2006
National Category
Medical and Health Sciences Surgery Urology and Nephrology
Research subject
Surgery esp. Urology Specific
Identifiers
urn:nbn:se:oru:diva-5067 (URN)10.1016/S0022-5347(05)00734-2 (DOI)
Available from: 2009-01-26 Created: 2009-01-26 Last updated: 2011-05-18Bibliographically approved
3. Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death
Open this publication in new window or tab >>Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death
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2005 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 14, no 6, 1424-1432 p.Article in journal (Refereed) Published
Abstract [en]

alpha-Methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation > 0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cutpoints were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cutpoint on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cutpoint developed using prostate cancer-specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.

National Category
Surgery
Research subject
Surgery esp. Urology Specific
Identifiers
urn:nbn:se:oru:diva-15600 (URN)10.1158/1055-9965.EPI-04-0801 (DOI)000229766600017 ()
Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2011-05-18Bibliographically approved
4. MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden
Open this publication in new window or tab >>MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden
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2007 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 6, 730-734 p.Article in journal (Refereed) Published
Abstract [en]

Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score >=7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.

Place, publisher, year, edition, pages
London: Harcourt Publishers, 2007
National Category
Medical and Health Sciences Surgery Cancer and Oncology
Research subject
Oncology; Surgery esp. Urology Specific
Identifiers
urn:nbn:se:oru:diva-5063 (URN)10.1038/sj.bjc.6603944 (DOI)
Available from: 2009-01-26 Created: 2009-01-26 Last updated: 2017-03-27Bibliographically approved
5. Time trends and survival among men diagnosed with incidental prostate cancer in Sweden: a register-based study between 1970 and 2003
Open this publication in new window or tab >>Time trends and survival among men diagnosed with incidental prostate cancer in Sweden: a register-based study between 1970 and 2003
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(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Research subject
Surgery esp. Urology Specific
Identifiers
urn:nbn:se:oru:diva-15601 (URN)
Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2016-11-30Bibliographically approved

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