Treatment of local-regional prostate cancer detected by PSA screening: benefits and harms according to prognostic factors.

BACKGROUND: Men with screen-detected prostate cancer can choose to undergo immediate curative treatment or enter into an expectant management programme. We quantified how the benefits and harms of immediate treatment vary according to the prognostic factors of clinical T-stage, Gleason score, and patient age. METHODS: A microsimulation model based on European Randomized Study of Screening for Prostate Cancer data was used to predict the benefits and harms of immediate treatment versus delayed treatment of local-regional prostate cancer in men aged 55-74 years. Benefits included life-years gained and reduced probability of death from prostate cancer. Harms included lead time and probability of overdiagnosis. RESULTS: The ratio of mean lead time to mean life-years gained ranged from 1.8 to 31.2, and the additional number of treatments required per prostate cancer death prevented ranged from 0.3 to 11.6 across the different prognostic groups. Both harm-benefit ratios were lowest, most favourable, for men aged 55-59 years and diagnosed with moderate-risk prostate cancer. Ratios were high for men aged 70-74 years regardless of clinical T-stage and Gleason score. CONCLUSION: Men aged 55-59 years with moderate-risk prostate cancer are predicted to derive greatest benefit from immediate curative treatment. Immediate treatment is least favourable for men aged 70-74 years with either low-risk or high-risk prostate cancer.

Men's preferences for prostate cancer screening: a discrete choice experiment.

BACKGROUND: Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. METHODS: A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC-related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. RESULTS: The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay €188 per year (CI: €141-€258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. CONCLUSION: Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening.

Patients' and urologists' preferences for prostate cancer treatment: a discrete choice experiment.

BACKGROUND: Patients' preferences are important for shared decision making. Therefore, we investigated patients' and urologists' preferences for treatment alternatives for early prostate cancer (PC). METHODS: A discrete choice experiment was conducted among 150 patients who were waiting for their biopsy results, and 150 urologists. Regression analysis was used to determine patients' and urologists' stated preferences using scenarios based on PC treatment modality (radiotherapy, surgery, and active surveillance (AS)), and risks of urinary incontinence and erectile dysfunction. RESULTS: The response rate was 110 out of 150 (73%) for patients and 50 out of 150 (33%) for urologists. Risk of urinary incontinence was an important determinant of both patients' and urologists' stated preferences for PC treatment (P<0.05). Treatment modality also influenced patients' stated preferences (P<0.05), whereas the risk of erectile dysfunction due to radiotherapy was mainly important to urologists (P<0.05). Both patients and urologists preferred AS to radical treatment, with the exception of patients with anxious/depressed feelings who preferred radical treatment to AS. CONCLUSION: Although patients and urologists generally may prefer similar treatments for PC, they showed different trade-offs between various specific treatment aspects. This implies that urologists need to be aware of potential differences compared with the patient's perspective on treatment decisions in shared decision making on PC treatment.

To be screened or not to be screened? Modeling the consequences of PSA screening for the individual.

BACKGROUND: Screening with prostate-specific antigen (PSA) can reduce prostate cancer mortality, but may advance diagnosis and treatment in time and lead to overdetection and overtreatment. We estimated benefits and adverse effects of PSA screening for individuals who are deciding whether or not to be screened. METHODS: Using a microsimulation model, we estimated lifetime probabilities of prostate cancer diagnosis and death, overall life expectancy and expected time to diagnosis, both with and without screening. We calculated anticipated loss in quality of life due to prostate cancer diagnosis and treatment that would be acceptable to decide in favour of screening. RESULTS: Men who were screened had a gain in life expectancy of 0.08 years but their expected time to diagnosis decreased by 1.53 life-years. Of the screened men, 0.99% gained on average 8.08 life-years and for 17.43% expected time to diagnosis decreased by 8.78 life-years. These figures imply that the anticipated loss in quality of life owing to diagnosis and treatment should not exceed 4.8%, for screening to have a positive effect on quality-adjusted life expectancy. CONCLUSION: The decision to be screened should depend on personal preferences. The negative impact of screening might be reduced by screening men who are more willing to accept the side effects from treatment.

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts.

PURPOSE: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the (68)Ga-labelled bombesin analogue AMBA with metabolism-based targeting using (18)F-methylcholine ((18)F-FCH) in nude mice bearing human prostate VCaP xenografts. METHODS: PET and biodistribution studies were performed with both (68)Ga-AMBA and (18)F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g). RESULTS: All tumours were clearly visualized using (68)Ga-AMBA. (18)F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7 ± 1.4%ID/g (20-30 min after injection, N = 8) for (68)Ga-AMBA and 1.6 ± 0.5%ID/g (10-20 min after injection, N = 8) for (18)F-FCH, which were significantly different (p <0.001). The results in PC-3 tumour-bearing mice were comparable. Biodistribution data were in accordance with the PET results showing VCaP tumour uptake values of 9.5 ± 4.8%ID/g (N = 8) for (68)Ga-AMBA and 2.1 ± 0.4%ID/g (N = 8) for (18)F-FCH. Apart from the GRPR-expressing organs, uptake in all organs was lower for (68)Ga-AMBA than for (18)F-FCH. CONCLUSION: Tumour uptake of (68)Ga-AMBA was higher while overall background activity was lower than observed for (18)F-FCH in the same PC-bearing mice. These results suggest that peptide receptor-based targeting using the bombesin analogue AMBA is superior to metabolism-based targeting using choline for scintigraphy of PC.

Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells.

Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.

Structured robot-assisted surgery training curriculum for residents in Urology and impact on future surgical activity.

To gain insight into the availability of training for robot assisted surgery (RAS) and the possibility to perform RAS during Dutch residency curriculum and to analyze the effects on surgical skills by the introduction of an advanced course in RAS for residents. A combination of a validated snap shot survey and a prospective cohort study. Structured advanced RAS training including virtual reality (VR) simulation, dry and wet lab facility at ORSI academy (Belgium). A snap-shot survey has been sent to all the residents and specialists in Urology graduated during the years 2017-2020 in Netherlands. Among residents, only last year residents (5th and 6th year) have been considered for the RAS training. Although most of the residents (88.2%) and young urologists (95%) were asked to follow a basic training or meet basic requirements before starting RAS, the requirements set by the educators were different from center to center. Some of them were required to attend only an online course on RAS, whereas others were asked to achieve threshold scores at VR simulator and participate in a standardized course at a training institute. The attendance to a structured advanced course in RAS showed a significant increase in surgical skills. Our study shows residents in urology are allowed to perform RAS during their residency though the criteria for starting RAS differ significantly amongst the teaching hospitals. To guarantee a basic level of skills and knowledge a structured, (multi-step) training and certification program for RAS should be implemented.

Training novice robot surgeons: Proctoring provides same results as simulator-generated guidance.

To understand the influence of proctored guidance versus simulator generated guidance (SGG) on the acquisition dexterity skills in novice surgeons learning RAS (robot assisted surgery). Prospective non-blinded 3-arm randomised controlled trial (RTC). Exclusion criteria: previous experience in RAS or robotic surgery simulation. The participants were assigned to three different intervention groups and received a different form of guidance: (1) proctored guidance, (2) simulator generated guidance, (3) no guidance, during training on virtual reality (VR) simulator. All participants were asked to complete multiple questionnaires. The training was the same in all groups with the exception of the intervention part. Catharina Hospital Eindhoven, The Netherlands. A total of 70 Dutch medical students, PhD-students, and surgical residents were included in the study. The participants were randomly assigned to one of the three groups. Overall, all the participants showed a significant improvement in their dexterity skills after the training. There was no significant difference in the improvement of surgical skills between the three different intervention groups. The proctored guidance group reported a higher participant satisfaction compared to the simulator-generated guidance group, which could indicate a higher motivation to continue the training. This study showed that novice surgeons. Significantly increase their dexterity skills in RAS after a short time of practicing on simulator. The lack of difference in results between the intervention groups could indicate there is a limited impact of "human proctoring" on dexterity skills during surgical simulation training. Since there is no difference between the intervention groups the exposure alone of novice surgeons to the robotic surgery simulator could possibly be sufficient to achieve a significant improvement of dexterity skills during the initial steps of RAS learning.

Clinical impact of new prostate-specific antigen WHO standardization on biopsy rates and cancer detection.

BACKGROUND: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. METHODS: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 microg/L. RESULTS: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 microg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 microg/L, respectively). CONCLUSIONS: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.

[Gene therapy in The Netherlands]. / Gentherapie in Nederland.

Extensive research is ongoing worldwide on the clinical utility of gene therapy, particularly for the treatment of cancer and genetic disorders. Two gene therapy products have already been approved recently in China. Clinical experience with gene therapy has also been accumulating in the Netherlands: over 200 Dutch patients have now been treated in clinical trials. Published results indicate that gene therapy is generally safe. Gene therapy appears to be effective for some genetic disorders, such as severe combined immune deficiency and haemophilia B. The efficacy of gene therapy, particularly in the treatment of cancer, appears to be limited up till now.

[The search for better markers for prostate cancer than prostate-specific antigen]. / De zoektocht naar betere markers voor prostaatkanker dan prostaatspecifiek antigeen.

Prostate-specific antigen (PSA) is currently the most important biochemical marker for the diagnosis of prostate cancer. Because of the limited specificity of PSA, clinically irrelevant tumours and benign abnormalities are also detected that potentially lead to over-treatment and the accompanying physical and emotional burden for the patient. In addition, PSA is used as an indicator of progression or clinical response after treatment for prostate cancer, but the prognostic value of this marker is limited. Current studies are evaluating a number of alternative markers, such as PSA-related parameters, human kallikrein 2, osteoprotegerin and the gene DD3(PCA3), that may improve the specificity of current PSA-based diagnostics and the prognostic value of PSA.

Prostate cancer gene therapy: comparison of adenovirus-mediated expression of interleukin 12 with interleukin 12 plus B7-1 for in situ gene therapy and gene-modified, cell-based vaccines.

We have documented previously that adenovirus-mediated interleukin 12 (IL-12) gene therapy is effective for orthotopic tumor control and suppression of pre-established metastases in a preclinical prostate cancer model (Y. Nasu et al., Gene Ther., 6: 338-349, 1999). In this report, we directly compare the effectiveness of an adenovirus that expresses both IL-12 and the costimulatory molecule B7-1 (AdmIL12/B7) with one that expresses IL-12 alone (AdmIL-12) using the poorly immunogenic RM-9 orthotopic murine model of prostate cancer. We document AdmIL-12/B7-mediated secretion of IL-12 and increased surface expression of B7-1 in infected RM-9 tumor cells. A significant reduction in orthotopic tumor size and increased survival was demonstrated in mice treated with a single orthotopic injection of AdmIL-12/B7 compared with AdmIL-12 or controls. Six of 19 animals treated with AdmIL-12/B7 survived long term with apparent eradication of the primary tumor in contrast to one of 38 animals in the AdmIL-12-treated group. Orthotopic treatment of tumors with both vectors led to an infiltration of both CD4+ and CD8+ immunoreactive cells, with AdmIL-12/B7 treatment having a more prolonged infiltration of CD8+ cells. AdmIL-12/B7 was also more effective than AdmIL-12 or controls at suppression of pre-established metastases. We further developed a vaccine model based on s.c. injection of infected, irradiated RM-9 cells and found that both AdmIL-12 and AdmIL-12/B7 are effective at suppressing the development and growth of challenge orthotopic tumors using this protocol.

Elevated expression of caveolin is associated with prostate and breast cancer.

To identify genes associated with prostate cancer progression, we developed a strategy involving the use of differential display-PCR with a panel of genetically matched primary tumor- and metastasis-derived mouse prostate cancer cell lines. We isolated a cDNA fragment with homology to the mouse caveolin-1 gene. Northern blotting with this fragment revealed increased caveolin expression in metastasis-derived cell lines relative to primary tumor-derived cell lines. Western blotting with a polyclonal caveolin antibody confirmed increased caveolin protein in metastasis-derived mouse cell lines and expression in three of four human prostate cancer cell lines. Immunohistochemical analysis of a human prostate cancer cell line demonstrated a prominent granular pattern of caveolin accumulation. Subsequent analysis of mouse and human prostate specimens revealed minimal caveolin expression in normal epithelium with abundant staining of smooth muscle and endothelium. The frequency of caveolin-positive cells was increased in prostate cancer with markedly increased accumulation of caveolin and a granular staining pattern in lymph node metastatic deposits. In human breast cancer specimens, increased caveolin staining was detected in intraductal and infiltrating ductal carcinoma as well as nodal disease. Caveolin therefore appears to be associated with human prostate cancer progression and is also present in primary and metastatic human breast cancer.

The measurement properties of the five-item International Index of Erectile Function (IIEF-5): a Dutch validation study.

Erectile dysfunction (ED), affecting men worldwide, is associated with worse mental health. The severity of ED as well as the effect of its treatment can be assessed using valid self-reported outcome measures. A widely used measure is the International Index of Erectile Function short form (IIEF-5) which is not yet validated in Dutch. The objective of this study was to translate the IIEF-5 into Dutch and to investigate its reliability and validity to provide a useful evaluation tool. The IIEF-5 was translated into Dutch following standardized forward-backward procedures. To conduct this observational study, men with symptoms of ED completed the Dutch IIEF-5 at inclusion, 1 week later, and 6 months after inclusion. A population-based sample (reference group) completed the IIEF-5 once. The quality domains reliability and validity were addressed by testing the measurement properties internal consistency, reliability, measurement error, and content validity. Data of 82 patients and 253 reference group participants were analyzed. Internal consistency was adequate with Cronbach's alpha of 0.94 in both patient and reference group. In patients, the test-retest reliability was adequate with an intra-class correlation coefficient for agreement of 0.88. A floor effect was present in the patient group (42%), though not in the reference group (3%). There was no ceiling effect in patients (0%), while this was present in the reference group (17%). Analysis of responsiveness was not possible due to the limited number of patients receiving treatment. The Dutch IIEF-5 is a reliable and valid measure to determine severity of symptoms of ED. This evaluation tool is valuable for clinical use and interpreting results across international clinical studies. The context of a patient's sexual life is, however, indispensable and should be taken into account.

Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data.

BACKGROUND: The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs. METHODS: Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost-effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests. RESULTS: Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained. CONCLUSION: Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis.

Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer.

Adenovirus-mediated transduction of the herpes simplex thymidine kinase gene (HSV-tk) in conjunction with ganciclovir (GCV) has been shown to result in significant growth suppression and to enhance survival in a model of mouse prostate cancer. However, this therapeutic activity is not sustained, because in most cases tumors eventually regrow and ultimately cause the death of the host. Androgen ablation, an inducer of apoptosis in prostate cells which is used widely as palliative therapy in patients with prostate cancer, was combined with HSV-tk plus GCV using an androgen-sensitive mouse prostate cancer cell line. The combination of castration and HSV-tk plus GCV led to markedly enhanced tumor growth suppression in both subcutaneous and orthotopic models compared with either treatment alone and resulted in an enhanced survival in which combination-treated animals lived twice as long as controls in the subcutaneous model and over 50% longer than controls in the orthotopic model. Further analysis of apoptotic activity demonstrated high levels of apoptosis only in combined androgen ablation and HSV-tk plus GCV-treated tumors after 14 days of growth in an androgen-depleted environment and 8 days after HSV-tk plus GCV therapy. At this time, the apoptotic index, but not the percent of necrotic tissue, was significantly higher for combination therapy-treated tumors relative to control-treated tumors or either treatment alone. These data indicate that the therapeutic effects of androgen ablation and HSV-tk plus GCV are cooperative and that increased apoptosis may, in part, underlie these activities.

Volume adjustment for intermediate prostate-specific antigen values in a screening population.

In a screening population of 812 men, between the ages of 55 and 77 years, and prostate-specific antigen (PSA) below 10.0 ng/ml (Hybritech), digital rectal examination (DRE) and transrectal ultrasonography of the prostate (TRUS) were performed. Seventeen prostate carcinomas were detected. Four methods of prostate volumetry were used to determine volume-adjusted PSA levels. These were PSA density for the total gland volume (PSAD), for the inner zone volume (PSAT) and population-specific excess PSA values. There was a significant difference between the benign and the malignant population for age, PSA, PSAD, PSAT and excess PSA values. The maximal discriminatory potential, analysed by the area under receiver ROC curve, was 0.90, reached for prolate spheroid determined excess PSA. For PSA alone this was 0.86. Volume-adjusted PSA values have no additional benefit beyond unadjusted values in screening for prostate carcinoma in this study.

Metastasis-related genes in prostate cancer.

The identification of genes specifically related to the development of metastatic disease in prostate cancer is complicated by tumor cell heterogeneity and the presence of expressed sequences that are not related to metastasis. A system was designed to minimize these complications using differential display-polymerase chain reaction (DD-PCR) together with genetically paired cell lines derived from primary mouse prostate cancer and their associated metastases generated in vivo by the metastatic mouse prostate cancer reconstitution model. Using this system, a number of metastasis-related sequences were identified, including a cDNA that encodes caveolin-1.

Blood and serum substances for markers of prostate cancer.

Serummarkers for prostate carcinoma are widely applied for the purpose of early detection of cancer and the differentiation between benign and malignant disease, for the pre-treatment staging of detected prostatic cancers, and for the monitoring of prostate cancer after curative or palliative therapies. This review illustrates the limitations of current markers for prostatic disease in blood en serum. It gives an overview of what is known about PSA and its isoforms, hK2, PSMA, and PSCA, and discusses, based on this information, in what direction current research is developing in order to improve these markers.