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To investigate time spent in hormone-sensitive and castration-resistant disease states in men with advanced prostate cancer in Sweden, and the associated health economic impact.Registry study (NCT03619980) of the Prostate Cancer data Base Sweden with data from the National Prostate Cancer Register, including the Patient-overview Prostate Cancer (PPC) and other national healthcare registries. The primary endpoint was time in each disease state. Secondary endpoints were co-medications, comorbidities and healthcare resource utilization (HRU) and cost in each disease state.In total, 1,869 men with advanced prostate cancer registered in PPC between 2014 and 2016, with data on the start of androgen deprivation therapy, were identified. Median time to progression and median survival were 4 and 11 years, respectively, for men with non-metastatic (nm) hormone-sensitive prostate cancer (HSPC); 1 and 7 years for men with metastatic (m) HSPC; and 1 and 8.5 years for men with nm castration-resistant prostate cancer (CRPC). Median survival for men with mCRPC was 4 years. Total annual mean costs for HRU per patient increased with increasing severity of disease, from 41,064 Swedish krona (SEK) for nmHSPC to 288,242 SEK for mCRPC.Progression time from mHSPC and nmCRPC to the mCRPC state was short and survival in the mCRPC state was approximately 4 years. Survival times were longer than expected, likely due to the selection of long-term survivors among prevalent cases. Healthcare costs were high for men with mCRPC. Further studies are needed to confirm our pilot study findings.

Background: There have been large changes in the pattern of detection, work-up and treatment of men with prostate cancer during the last two decades. Therefore, we aimed to investigate temporal changes in survival in men with metastatic prostate cancer. Methods: Population-based cohort study in Prostate Cancer data Base Sweden of 13,709 men with de novo metastatic prostate cancer diagnosed between 1998 and 2015. Overall survival in four calendar periods were compared by the use of Kaplan-Meier analyses and Cox regression models including age at diagnosis, T stage and serum levels of prostate-specific antigen (PSA). Results: Between 1998-2001 and 2010-2015, median survival increased with 6 months for all men. The largest increase in survival was 14 months in men age 60-69 at diagnosis and in multivariable analysis risk of death decreased for men diagnosed in 2010-2015 compared to 1998-2001, hazard ratio (HR) 0.77 (95% CI: 0.68-0.86). The median PSA at date of diagnosis decreased with 46% from 181 ng/mL in 1998 to 98 ng/mL in 2015. Conclusions: There was an increase in survival among men with de novo metastatic prostate cancer in Sweden between 1998 and 2015. This increase was due to a decreased cancer extent indicated by lower PSA levels with ensuing longer lead times and speculatively also due to an increased use of chemotherapy in the latest time period. Given the increasing use of systemic treatment for advanced prostate cancer, our results are likely heralding larger increases in survival in men with metastatic prostate cancer in the near future.

Background: Men with prostate cancer (PCa) on gonadotropin-releasing hormone agonists (GnRH) have an increased risk of cardiovascular disease (CVD) compared to men with PCa not on GnRH as well as compared with PCa-free men. Whether the addition of androgen receptor targeted (ART) drugs to GnRH further increases CVD risk, remains to be fully elucidated. Material and methods: We investigated risk of CVD for men with castration resistant PCa (CRPC) on GnRH plus ART; abiraterone or enzalutamide vs 5,127 and 12,079 respective matched comparator men on GnRH in Prostate Cancer data Base Sweden (PCBaSeTraject) 4.1 between 1 June 2015 and 31 December 2018. PCBaSeTraject links National Prostate Cancer Register of Sweden to other healthcare registries and demographic databases. We conducted multivariable Cox proportional hazard models adjusting for PCa risk category, Charlson comorbidity index (CCI), insulin or statin use, civil status, level of education, history of CVD events and number of CVD drugs, with any incident or fatal CVD as the outcome. Results and conclusion: 1,310 men were treated with abiraterone and 3,579 with enzalutamide. In multivariable analysis, CVD risk was increased in men on abiraterone (hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.03–1.38) and in men on enzalutamide (HR: 1.10; 95% CI: 1.01–1.20). Men with a recent CVD (

Background There are little and inconsistent data from clinical practice on time on treatment with the androgen receptor-targeted drugs (ART) abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). We assessed time on treatment with ART and investigated predictors of time on treatment. Material and methods Time on treatment with ART in men with mCRPC in the patient-overview prostate cancer (PPC), a subregister of the National Prostate Cancer Register (NPCR) of Sweden, was assessed by use of Kaplan-Meier plots and Cox regression. To assess the representativity of PPC for time on treatment, a comparison was made with all men in NPCR who had a filling for ART in the Prescribed Drug Registry. Results 2038 men in PPC received ART between 2015 and 2019. Median time on treatment in chemo-naive men was 10.8 (95% confidence interval 9.1-13.1) months for abiraterone and 14.1 (13.5-15.5) for enzalutamide. After the use of docetaxel, time on treatment was 8.2 (6.5-12.4) months for abiraterone and 11.1 (9.8-12.6) for enzalutamide. Predictors of a long time on treatment with ART were long duration of ADT prior to ART, low serum levels of PSA at start of ART, absence of visceral metastasis, good performance status, and no prior use of docetaxel. PPC captured 2522/6337 (40%) of all men in NPCR who had filled a prescription for ART. Based on fillings in the Prescribed Drug Registry, men in PPC had a slightly longer median time on treatment with ART compared to all men in NPCR, 9.6 (9.1-10.3) vs. 8.6 (6.3-9.1) months. Conclusions Time on treatment in clinical practice was similar or shorter than that in published RCTs, due to older age, poorer performance status and more comorbidities.

Symptoms of terminal cancer have previously been reported as undertreated. The aim of this study was to assess the use of palliative medications before death from prostate cancer.This Swedish register study included men who died from 2009 to 2012 with prostate cancer as the underlying cause of death. We assessed the proportion who collected a prescription of androgen deprivation therapy, non-steroidal anti-inflammatory drugs, paracetamol, opioids, glucocorticoids, antidepressants, anxiolytics and sedative-hypnotics and the differences in treatment related to age, time since diagnosis, educational level, close relatives and comorbidities. Data were collected from 3 years before death from prostate cancer.We included 8326 men. The proportion who received opioids increased from 30% to 72% during the last year of life, and 67% received a strong opioid at the time of death. Antidepressants increased from 13% to 22%, anxiolytics from 9% to 27% and sedative-hypnotics from 21% to 33%. Men without close relatives and older men had lower probability to receive opioids (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.47-0.66 for85 years versus70 years) and (OR 0.78, 95% CI: 0.66-0.92 for unmarried without children versus married with children).Our results represent robust epidemiological data from Sweden for comparison of palliative care quality between countries. The findings indicate that men without close relatives and older men are disadvantaged with respect to the treatment of cancer pain and need closer attention from health care providers and highlight the importance to identify psychological distress in terminal prostate cancer.

Objective To evaluate whether the effects of radical treatment in men with locally advanced prostate cancer (PCa) on PCa mortality observed in randomised clinical trials are applicable on a population basis. Patients and methods We conducted a population-based cohort study using the Prostate Cancer data Base Sweden of 20 350 men diagnosed between 2000 and 2016 with locally advanced PCa, defined as clinical local stage T3/T4, M0, Mx and a prostate-specific antigen level of

Cancer quality registers are attracting increasing attention as metrics for quality assurance and improvement. Comprehensive, high-quality data in nationwide population-based registers are also an ideal basis for observational studies. Here we describe the organization of the National Prostate Cancer Register (NPCR) of Sweden as well as some examples of reports and results from analyses based on NPCR and other health-care registers.

Given the increasing prevalence of cancer, it is vital to systematically collect data in order to monitor disease trends and quality of cancer care. For this purpose, clinical cancer registries have been developed in some countries. These registers are intended to be used as a basis for quality assurance and quality improvement, but they also constitute a rich resource of real world data for research. The aim of this mini-review was to describe the structure and the organization of the National Prostate Cancer Register (NPCR) with some examples on how data in NPCR have affected prostate cancer care in Sweden.

Objectives: The aim of this study was to examine the use of abiraterone and enzalutamide, two oral novel antiandrogens (NOVAs), in men with prostate cancer (PCa) in Sweden. Materials and methods: This cross-sectional study investigated filled prescriptions for NOVAs recorded in the Swedish Prescribed Drug Register between July 2015 and April 2016. Associations between age, comorbidity, educational level, marital status and county of residence and filled prescriptions were analyzed in the National Prostate Cancer Register (NPCR) and other health population-based registers, using multivariable logistic regression. Results: Of 91,209 men, 1650 (2%) had at least one prescription filled for NOVAs, of whom 1350 (82%) had high-risk or metastatic PCa at diagnosis.. Of 1914 men with M1 disease and a high probability of castration-resistant prostate cancer (CRPC), 22% had a prescription for NOVAs at a median 3 years after the date of diagnosis. At multivariable logistic regression analysis,, the likelihood of NOVA use was lower in older men [age >80 vs Conclusions: Less than one-third of potentially eligible men with CRPC received NOVAs in 2015–2016. There were large differences in use according to age and region of residence, indicating that efforts are needed to improve equal access to novel cancer drugs.

Low-dose metronomic chemotherapy (LDMC) is an alternative for treatment of patients with late-stage prostate cancer (PC) not susceptible to regular chemotherapy due to its severe side effects. The exact working mechanisms of LDMC have not been established, although anti-angiogenic effects have been identified. In PC, several studies show clinical effects from LDMC but the mode of action and the role of androgen signaling for its effect are not known. In this study, we used a xenograft model to evaluate the effect of LDMC on PC growth in relation to androgen deprivation.Subcutaneous human castration-resistant PC xenografts were treated with LDMC using cyclophosphamide (CPA). Treatment effect was compared to treatment with maximum tolerated dose (MTD) and also between intact and castrated mice. Microvessel density (MVD), and factors important for angiogenesis were analyzed with immunohistochemistry and real-time-PCR.Tumors treated with LDMC were 50% smaller than untreated controls. Tumors in non-castrated mice were not affected by LDMC, but in an androgen receptor (AR) negative tumor model, tumor inhibiting effect were seen in both intact and castrated animals, indicating mechanism via AR. MTD resulted in similar growth inhibition as LDMC in castrated mice, but resulted in severe weight loss. Despite that LDMC induced TSP1 mRNA expression, and the hypoxic area in the tumors was slightly increased, no decrease in MVD was detected.This study shows that a low-dose metronomic scheduling of CPA was as efficient as MTD treatment, and resulted in fewer side effects. It also demonstrates that a functional androgen signaling axis inhibits this effect despite the castration-resistance of the tumor cells. The anti-angiogenic nature of the effect of LDMC could not be confirmed and further studies to elucidate the working mechanism for treatment response are needed.

The objective of this study was to evaluate the prognostic significance of seminal vesicle invasion (SVI, pT3b) compared with extraprostatic extension (EPE) alone (pT3a) after radical prostatectomy, and to correlate pre-operative biopsy pathology with SVI and EPE. The National Prostate Cancer Register includes all prostate cancers diagnosed in Sweden. We analysed 4063 cases with stage category pT3a and 1371 cases with pT3b at radical prostatectomy between 2000 and 2012. Associations between pT3a and pT3b and progression were evaluated and adjusted for year, age, biopsy grade and s-PSA. Needle biopsy findings in these stages were compared. Patients with pT3b (n=1371) had a higher risk of death from prostate cancer (HR 2.3, 95% CI 1.5-3.3, p0.001) and death from any cause (HR 1.5, 95% CI 1.2-1.8, p0.001) than those with pT3a (n=4063). They were also more likely to be treated with post-operative radiotherapy (HR 1.5, 95% CI 1.4-1.7, p0.001) or androgen deprivation therapy (HR 3.0, 95% CI 2.5-3.7, p0.001), indicating clinical progression. Yet, disease-specific survival of patients with stage pT3b was 94% after 6 years. Median cancer extent in pre-operative biopsies of pT3a and pT3b was 14 and 24 mm (p0.001), number of positive cores was four and five, (p0.001) and biopsy Gleason score was 8-10 in 11.6% and 27.3%, respectively (p0.001). SVI of prostate cancer is associated with worse outcome after radical prostatectomy than EPE alone. However, few patients with SVI die within 6 years from surgery, suggesting that radical prostatectomy may be curative in locally advanced cancers.

BackgroundCurrent guidelines recommend androgen deprivation therapy only for men with very high-risk prostate cancer (PCa), but there is little evidence to support this stance.ObjectiveTo investigate the association between radical local treatment and mortality in men with very high-risk PCa.Design, setting, and participantsSemiecologic study of men aged InterventionProportion of men who received prostatectomy or full-dose radiotherapy in 640 experimental units defined by county, diagnostic period, and age at diagnosis.Outcome measurements and statistical analysisPCa and all-cause mortality rate ratios (MRRs).Results and limitationsBoth PCa and all-cause mortality were half as high in units in the highest tertile of exposure to radical local treatment compared with units in the lowest tertile (PCa MRR: 0.51; 95% confidence interval [CI], 0.28–0.95; and all-cause MRR: 0.56; 95% CI, 0.33–0.92). The results observed for locally advanced PCa for highest versus lowest tertile of exposure were in agreement with results from randomized trials (PCa MRR: 0.75; 95% CI, 0.60–0.94; and all-cause MRR: 0.85; 95% CI, 0.72–1.00). Although the semiecologic design minimized selection bias on an individual level, the effect of high therapeutic activity could not be separated from that of high diagnostic activity.ConclusionsThe substantially lower mortality in units with the highest exposure to radical local treatment suggests that radical treatment decreases mortality even in men with very high-risk PCa for whom such treatment has been considered ineffective.Patient summaryMen with very high-risk prostate cancer diagnosed and treated in units with the highest exposure to surgery or radiotherapy had a substantially lower mortality.

Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26–99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.

To evaluate long-term urinary, sexual and bowel functional outcomes after prostate cancer treatment at a median (interquartile range) follow-up of 12 (11-13) years.In this nationwide, population-based study, we identified 6 003 men diagnosed with localized prostate cancer (clinical local stage T1-2, any Gleason score, prostate-specific antigen20 ng/mL, NX or N0, MX or M0) between 1997 and 2002 from the National Prostate Cancer Register, Sweden. The men were aged ≤70 years at diagnosis. A control group of 1 000 men without prostate cancer were also selected, matched for age and county of residence. Functional outcomes were evaluated with a validated self-reported questionnaire.Responses were obtained from 3 937/6 003 cases (66%) and 459/1 000 (46%) controls. At 12 years after diagnosis and at a median age of 75 years, the proportion of cases with adverse symptoms was 87% for erectile dysfunction/sexual inactivity, 20% for urinary incontinence and 14% for bowel disturbances. The corresponding proportions for controls were 62, 6 and 7%, respectively. Men with prostate cancer, except those on surveillance, had an increased risk of erectile dysfunction compared with the men in the control group. Radical prostatectomy was associated with an increased risk of urinary incontinence (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.36-2.62) and radiotherapy increased the risk of bowel dysfunction (OR 2.46, 95% CI 1.73-3.49) compared with men in the control group. Multi-modal treatment, in particular treatment including androgen deprivation therapy (ADT), was associated with the highest risk of adverse effects; for instance, radical prostatectomy followed by radiotherapy and ADT was associated with an OR of 3.74 (95% CI 1.76-7.95) for erectile dysfunction and an OR of 3.22 (95% CI 1.93-5.37) for urinary incontinence.The proportion of men who experienced a long-term impact on functional outcomes after prostate cancer treatment was substantial.

Background New five-tiered Gleason grade groups (GGGs) were recently proposed, in which Gleason 6 is GGG 1, Gleason 3+4 is GGG 2, Gleason 4+3 is GGG 3, Gleason 8 is GGG 4, and Gleason 9-10 is GGG 5. Objective To examine the performance of the new GGGs in men with prostate cancer from a nationwide population-based cohort. Design, setting, and participants From the National Prostate Cancer Register of Sweden, we identified 5880 men diagnosed with prostate cancer from 2005 to 2007, including 4325 who had radical prostatectomy and 1555 treated with radiation therapy. Outcome measurements and statistical analysis Kaplan–Meier survival analysis, Cox proportional hazards models, and concordance indices were used to examine the relationship between the GGGs and biochemical recurrence after radical prostatectomy and radiation therapy. Results and limitations Among men treated with surgery, the 4-yr biochemical recurrence-free survival rates were 89%, 82%, 74%, 77%, and 49% for GGG 1–5 on biopsy, and 92%, 85%, 73%, 63%, and 51% based on prostatectomy GGG, respectively. For men treated by radiation therapy, men with biopsy GGG of 1–5 had 4-yr biochemical recurrence-free survival rates of 95%, 91%, 85%, 78%, and 70%. Adjusting for preoperative serum prostate-specific antigen and clinical stage, biopsy GGGs were significant independent predictors of biochemical recurrence after radical prostatectomy and radiation therapy. The new 5-tier system resulted in virtually no change in predictive accuracy compared with the current 3- and 4-tier classifications. Limitations include a median follow-up of 4.6 yr, precluding the ability to examine long-term oncologic outcomes. Conclusions The newly proposed GGGs offer a simplified, user-friendly nomenclature to aid in patient counseling, with similar predictive accuracy in a population-based setting to previous classifications. Patient summary The new Gleason grade groups, ranging from 1–5, provide a simplified, user-friendly classification system to predict the risk of recurrence after prostatectomy and radiation therapy.

TPS397 Background: Castrate-resistant prostate cancer (CRPC) affects around 3,000 men in Sweden every year. New drugs are available but they have moderate effect, low response rates, are expensive, and lack predictive treatment markers. This will lead to an unsustainable situation for prostate cancer care. Our hypothesis is that treatment decisions based on molecular profiling will significantly increase the response rate at 3 months compared to current clinical care, translating into improved progression free and overall survival. The vast majority of CRPC metastasize to the bone, with low success rate in obtaining sufficient material. Therefore, we will sequence circulating tumor DNA (ctDNA) being present at high levels in plasma. Methods: ProBio-II is an adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven phase 2 trial in men with CRPC . Men (n=750) will be randomized to receive either standard of care (following Swedish national guidelines) or treatment with Enzalutamide, Abiraterone, PARP inhibitors, RA-223, Cabazitaxel, or immune modulators based on molecular subtypes. The molecular subtypes are defined as tumor properties or mutations in certain genes/pathways including: Microsatellite instability; Androgen receptor alterations; DNA-repair deficiency; TP53 inactivation; PTEN inactivation etc. The molecular subtypes will be identified by ctDNA profiling. A specially designed ctDNA profile for CRPC has been developed by our group to detect: mutations, amplifications and genomic rearrangements in the androgen receptor (AR); mutations, genomic rearrangements and amplifications/deletions in 300 key genes involved in prostate cancer; and microsatellite instable and hypermutated cancers. ProBio-II’s design is novel and inspired by successful studies as I-SPY (breast cancer) and the NCI-MATCH trial (metastatic cancer). Novel aspects of the study design includes using prior probability of treatment response; re-randomization of non-responders; and adaptive design. The ProBio II study will start recruiting patients in Sweden in Q1 2018 and recruit patients during a 18 month period. All major oncology departments in Sweden will participate.

BACKGROUND Endoglin, a receptor for some of the members of the transforming growth factor-β (TGF-β) family, is expressed on proliferating endothelial cells and has been suggested as a marker of ongoing angiogenesis. In this study, endoglin was evaluated as a prognostic factor for prostate cancer progression. METHODS Immunohistochemical staining of endoglin was examined in 72 cases of prostate cancer and compared with immunohistochemical staining of the pan-endothelial marker von Willebrand factor (vWf), clinicopathological factors, and cancer-specific survival. Micro-vessels were measured in the most vascularized fields. Double staining with antibodies against smooth muscle actin and endoglin or vWf, respectively, was performed in order to evaluate vessel maturation. RESULTS Endoglin-stained tumor vessels were generally small and only 19% also stained with actin. Endoglin was a better prognostic marker than vWf. The median survival times were shorter for patients with tumor vascular count (vc) above median than for patients with vc below median (4 vs. 12 years, P = 0.0007, and 5 vs. 10 years, P = 0.018, for endoglin and vWf, respectively). Endoglin vc was associated with Gleason score (P = 0.001), local tumor stage (P = 0.0006), metastasis (P = 0.01), tumor cell immunoreactivity for TGF-β1 (P = 0.0003), and tumor cell proliferation index (rs = 0.319, P = 0.02). Endoglin, in contrast to vWf, vc was prognostic for survival in the subgroup of patients with Gleason score 5, 6, and 7 tumors. CONCLUSIONS Endoglin marks principally small, probably newly formed tumor vessels in zthe prostate, and is a promising prognostic marker for prostate cancer patients. Prostate 51: 268–275, 2002. © 2002 Wiley-Liss, Inc.

Background: Many elderly men with high-risk nonmetastatic prostate cancer (HRnMPCa) do not receive radical treatment, despite the high mortality associated with conservative management. Objective: To investigate how age and comorbidity affect treatment of men with HRnMPCa. Design, setting, and participants: This was an observational nationwide register study during 2001-2012. We identified 19 190 men of

OBJECTIVE This study was carried out to explore the capability of partial least squares (PLS) analysis, a multivariate projection method, in the evaluation of investigative prognostic biomarkers. MATERIAL AND METHODS Using PLS analysis, survival and life expectancy were prognosticated in 53 patients with prostate cancer treated with transurethral resection. The age of the patient, stage and grade of the tumours, and immunoreactivity in the tumours for p53, Bcl-2, and TGF-beta1 and its receptors type I and type II (TGFbeta-RI and TGFalpha-RII), and markers for proliferation, vascular density, and macrophage density were included as prognostic factors in the analysis. RESULTS The prognostic impact of the factors, in decreasing order, was tumour grade, proliferation, stage, vascular density, TGFbeta-RI, metastasis, TGF-beta1, and TGFbeta-RII. Macrophage staining, p53, Bcl-2, and patient age did not contribute to the model. The model explained 62% of the total variance in survival, and the standard deviation of error of prediction was 29 months. CONCLUSIONS PLS analysis may become a useful tool for evaluation of putative prognostic factors.

BACKGROUND Prostate tumors express high levels of transforming growth factor-β1 (TGF-β1) and seem to acquire resistance to its antiproliferative effects with tumor progression. Moreover, TGF-β1 could be involved in tumor-promoting processes such as angiogenesis, cell migration, and immunosuppression. METHODS Immunoreactivity for TGF-β1 and its receptors type I and type II (TGFβ-RI and TGFβ-RII), tumor vascular count, and cell proliferation were studied in 73 cases of prostate cancer, diagnosed between 1975–1983 and followed with surveillance. RESULTS Patients with tumor overproduction of TGF-β1 had shorter median cancer-specific survival than patients with normal TGF-β1 immunoreactivity (5.0 vs. 10 years, P = 0.006). Furthermore, increased TGF-β1 staining was associated with tumor grade, high vascular counts, and metastasis (P = 0.02, 0.02, and 0.01, respectively). Patients with loss of tumor TGFβ-RII expression in combination with TGF-β1 overproduction showed particularly short survival (2.6 vs. 10 years, P = 0.0000), when compared to patients with normal immunoreactivity. CONCLUSIONS Overproduction of TGF-β1 and loss of TGFβ-RII expression are associated with poor clinical outcome in prostate cancer, and TGF-β1 may promote tumor progression by stimulating angiogenesis and metastasis. Prostate 37:19–29, 1998. © 1998 Wiley-Liss, Inc.

BACKGROUND Microvessel density has been shown to give prognostic information in a variety of solid tumors, but its role in prostatic carcinoma needs further elucidation. METHODS Intratumoral density of von Willebrand factor-positive microvessels was assessed in 98 cases of prostatic carcinoma, diagnosed at transurethral resection of the prostate (TURP) between 1975–1983, using two methods: 1) volume density of microvessels and 2) vascular count in the 2–3 most vascularized fields. RESULTS Volume density and vascular counts were highly correlated. In Kaplan-Meyer analysis, mean cancer-specific survival time for patients with a vascular count 135 (P = 0.0064). The same results applied to patients with WHO grade II tumors (P = 0.01). Excluding metastasis in a multivariate analysis, both tumor stage and vascular count had an independent predictive value for cancer-specific survival in patients with WHO grade II tumors. CONCLUSIONS Microvessel density may predict cancer-specific survival in prostatic carcinoma. Prostate 33:38–45, 1997. © 1997 Wiley-Liss, Inc.

217 Background: Bone Scan Index (BSI) is a quantitative measurement that reflects the tumor burden in bone calculated from bone scintigraphy. It also represents a prognostic marker in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Abiraterone acetate (AA) has showed to prolong survival before and after chemotherapy in this group of pts. In this study we evaluated the predictive value of BSI change as a biomarker of response in mCRPC patients on treatment with AA. Methods: We retrospectively studied 62 mCRPC pats who received AA following disease progression after chemotherapy at 3 different academic hospitals. Automated baseline and follow-up BSI data was obtained from images of whole-body bone scintigraphies performed before and during AA treatment. Data on clinical overall survival (OS), blood levels of prostate-specific antigen (PSA), alkaline phosphatase (ALP) and haemoglobin (Hb) at the time of baseline and upon follow-up was collected from medical records. The association between changes in these parameters at follow-up and survival was evaluated using Cox proportional-hazards regression models and Kaplan-Meier estimates of the survival function. Discrimination between prognostic variables was assessed using the concordance index (C-index). Results: Pts with an increase in BSI of > 0.3 (n=31) had 13% one year-survival rate compared to 42% for pts with improvement or stable disease according to BSI change at follow-up (BSI change < 0.3; n=31) (p< 0.001). Among all parameters evaluated (BSI, PSA, ALP, Hb) in a univariate Cox analysis, BSI change from baseline to follow-up presented the highest and strongest association with OS (C-index=0.7, Hazard ratio= 1.3 and p=0.0001). Conclusions: Increase in BSI of ≥ 0.3 is significantly associated with reduced survival in mCRPC pts under AA treatment following disease progression in a post-chemotherapy setting. BSI is a candidate biomarker to evaluate response and survival in this group, and change in BSI could be a valuable tool in monitoring pts with mCRPC on second-line therapies. BSI could then serve as a decision making tool supporting physicians to continue current treatment or to consider alternative therapies.

49 Background: Men who are curatively treated with radiotherapy (RT) or radical prostatectomy (RP) for localized prostate cancer have long life expectancy but data on long term complications to treatment are scarce. Methods: In the nationwide, population-based Prostate Cancer data Base Sweden (PCBaSe), we identified men who underwent RT or RP between 1997 and 2012. Date of radiotherapy and dose of radiation were reassessed in an audit. For each case five controls from the background population, matched for age and county of residence, had been identified. The National Patient Register was used to identify diagnoses and surgical procedures indicating a complication to treatment, such as urinary incontinence, lower urinary tract symptoms and gastrointestinal symptoms, up to twelve years after treatment. The incidence rate ratio of complications for men who received RT and RP relative to their matched controls was calculated and relative risks (RR) were calculated for RT vs RP adjusted for treatment year, age, Charlson comorbidity index, educational level, PSA-level, clinical T stage and biopsy Gleason score. Results: In total, 37,420 men met the study criteria, of whom 12,534 had undergone RT and 24,886 had undergone RP. There were 186,624 matched controls. The risk of receiving any of the analyzed diagnoses or surgeries at 12 years after treatment was higher after RT; RT vs RP RR 1.20 (95%CI 1.08-1.34) and RT vs RP RR 1.49, (95% CI 1.36-1.64) for the diagnoses and surgical procedures respectively. At 3 years the risk of receiving any of the analyzed diagnoses was comparable between the treatments; RT vs RP RR 1.02 (95% CI 0.91-1.16) but the risk of undergoing any of the analyzed surgical procedures remained higher after RT during the entire study period. Men who underwent RP had a higher risk of being diagnosed or treated for urinary incontinence; RT vs RP RR 0.09 (95% CI 0.04-0.19) and RR 0.04 (95% CI 0.01-0.11) for the selected diagnoses and surgical procedures respectively. Conclusions: Complications after RP mostly occurred within the first 3 years after surgery whereas complications after RT were more frequent at a later date after treatment.

The vasculature plays an important role in the normal and malignant prostate. Under basal conditions both glandular epithelial and stromal prostate cells produce an abundance of blood flow and angiogenesis regulating substances and the expression of these is generally increased in prostate tumors. The proportion of proliferating endothelial cells is high in the normal prostate compared to other tissues in the body. After castration effects on the vasculature, such as decreased blood flow and vascular regression, precede effects on the glandular compartment. Correspondingly, hormone induced prostate growth is characterized by early effects on the vasculature such as increased blood flow and endothelial cell proliferation, thus indicating that the vasculature may be involved in the androgenic regulation of the prostate. Prostatic intraepithelial neoplasia (PIN) and prostate cancer are associated with increased vascular density and in experimental models prostate cancer growth is apparently angiogenesis-dependent since tumor growth and progression can be inhibited by antiangiogenic treatment. Moreover, vascular density has been related to prognosis in prostate cancer patients. A better understanding of the pathways regulating angiogenesis in the normal prostate and how these pathways change during malignant transformation can hopefully lead to better prognostic markers and therapies for the large group of patients with prostate cancer. The purpose of this review is therefore to summarize the current knowledge on the role and regulation of the vasculature in the prostate and its potential clinical applications.

Tumor associated macrophages (TAM) influence diverse processes such as angiogenesis, tumor cell proliferation, and metastasis during tumor progression. In a variety of tumor types, the amount of TAM has been associated with prognosis, but their role in prostate cancer has not been elucidated. The purpose of this study was to investigate the role of TAM in a series of 85 cases of prostatic carcinoma, diagnosed at transurethral resection of the prostate between 1975-1983, using immunohistochemistry and morphometrical techniques. Macrophage density was assessed as the maximum number of TAM per field in the three most macrophage dense areas (TAMmax) and as the average volume density of TAM in an estimate of the whole resected tumor. Furthermore, the individual cell profile area of TAM was assessed with an image analyzer. Macrophage variables were thereafter related to histological grade, tumor stage, metastasis as well as to vascular density, tumor cell proliferation and survival. Patients with a volume density of TAM in the fourth quartile had a shorter median cancer specific survival time than patients in the first to third quartile (3.3 vs. 5.9 years, p=0.005). Furthermore, an increased macrophage cell profile area was related to poor clinical outcome (4.6 vs. 5.9 years, p=0.039) whereas TAMmax gave no prognostic information. In a multivariate analysis, metastasis and the volume density of macrophages gave independent prognostic information (p=0.0008, p=0.010). However, when excluding metastasis from the analysis, only Gleason score was an independent predictor of cancer specific survival (p= 0.005). The volume density of TAM, the macrophage cell profile area and TAMmax increased with increasing Gleason score (p=0.001, p=0.0001, p=0.0001 respectively). A correlation was found between the volume density of TAM and tumor cell proliferation (rs=0.44, p=0.001) and an increased macrophage cell profile area was associated to microvessel density (rs=0.42, p=0.0001). Together these results suggest that both the functional state (as reflected by cell size), number and location of the macrophages are of importance for their influence on prostate tumors, but macrophage quantification is not a strong independent prognostic factor.