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Biomedical subjects

Fritz H Schröder

Publications and source records attributed to Fritz H Schröder.

At least 19 recordsLinked to original sources
PubMed2007

Screening for prostate cancer at low PSA range: the impact of digital rectal examination on tumor incidence and tumor characteristics.

OBJECTIVES: To compare tumor characteristics of screen-detected prostate cancers (PCs) either by digital rectal examination (DRE) or by prostate-specific antigen (PSA) as biopsy indication at low PSA. METHODS: Two populations with PSA between 2.0 and 3.9 ng/ml were studied. Group-1 was biopsied if DRE was suspicious (1st screening round, N = 1877). In group-2 all men were offered biopsy, regardless of DRE result (side-study in 2nd screening-round, N = 801). We compared cancer detection rates (CDRs) and tumor characteristics. RESULTS: In group-1 abnormal DRE prompted biopsy in 253 (13.5%) men (236 (93.3%) actually biopsied). Forty-nine PCs were detected, CDR 49/1877 = 2.6%. In group-2 we found 120 cancers in 666 (83.1%) men actually biopsied, CDR = 120/801 = 15.0%. Of all cancers detected, organ confinement (clinical T2) was found in 77.5% (group-1) and 96.6% (group-2; of which 99 T1c). Of all PCs 46.9% in group-1 and 15.0% in group-2 had biopsy Gleason score (GS) > or = 7. In the latter, 15.2% of T1cs were classified GS > or = 7. Considering only PCs with organ confinement or GS > or = 7 for each group, CDRs amounted to 2.0% versus 14.5% and 1.2% versus 2.3% for group-1 and group-2, respectively. CONCLUSIONS: PSA-based screening detected a considerable amount (15.2%) of potentially aggressive tumors as T1cs, but in addition large numbers of possibly insignificant cancers (T1c, GS = 6) were diagnosed. DRE seemed to detect more selectively high-grade cancers, but also missed many of these. Considering both populations and the need to detect aggressive but confined cancers, PSA as biopsy indication outperformed DRE at the price of more biopsies (13.5% vs. 100% if all would comply).

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PubMed2006

Metastatic disease of screen-detected prostate cancer : characteristics at diagnosis.

BACKGROUND: Screening for prostate cancer has not only led to a stage migration, but also to a higher incidence of the disease. A decrease in mortality has occurred in several countries during the same time period. Risk stratification of screen-detected cancers at diagnosis has become more important for the anticipation and interpretation of changing incidence/mortality ratios. METHODS: From 1993 to 1998, 633 men were diagnosed with nonmetastatic prostate cancer in the prevalence screen of the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC). The characteristics at diagnosis of men who developed metastatic disease were compared with men without evidence of metastases during follow-up. RESULTS: During the median follow-up of 7.5 years, 41 men developed metastatic disease. After 10 years the metastasis-free survival rate was 89.6%, the overall survival 64.7%. In a Cox-model 2logPSA (prostate-specific antigen), biopsy Gleason score and the number of biopsy cores with prostate cancer were independent predictors for the development of metastases; the latter only predicted metastases that presented within 60 months of follow-up. CONCLUSIONS: The metastasis-free survival of men with prostate cancer detected in a prevalence screening was very high. Whether this was related to the beneficial effects of screening or to overdiagnosis due to screening (or both) remains unclear. The prognostic factors known for clinically diagnosed disease also hold for screen-detected disease.

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PubMed2006

Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, PSA doubling times, and outcome.

OBJECTIVES: To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. PATIENTS AND METHODS: We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. RESULTS: Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 yr (25-75p; 66.1-72.8); median PSA 3.6 ng/ml (25-75p; 3.1-4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 yr, 103 men (44.2%) had a PSA doubling time that was negative (ie, half-life) or longer than 10 yr. Men detected at rescreening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 yr; the cause-specific survival was 100%. CONCLUSIONS: This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men.

Adult↗
PubMed2006

Gleason score, age and screening: modeling dedifferentiation in prostate cancer.

Tumor differentiation as measured by the Gleason score is highly predictive of the course of prostatic cancer after diagnosis. Since the introduction of the prostate-specific antigen (PSA) test tumors are diagnosed with a favorable tumor stage and differentiation grade. Does screening with PSA just detect more tumors with favorable characteristics or is dedifferentiation actually being prevented by early detection and consequent treatment? The latter option implies that tumors dedifferentiate in the preclinical screen-detectable phase. To model the natural history of prostate cancer, we analyzed the age-specific distribution of clinical stage and Gleason score of 2,204 tumors diagnosed in the ERSPC-Rotterdam trial. We fitted 2 MISCAN simulation models to the observed data: Model I where tumors dedifferentiate before becoming screen-detectable and Model II where dedifferentiation occurs during the screen-detectable preclinical phase. The hypothesis of dedifferentiation during the screen-detectable phase was tested by a goodness of fit test of both models. In ERSPC-Rotterdam, we observed a significantly more favorable distribution of Gleason scores in screen-detected cancers compared to cancers found in the control arm, and in cancers detected in the second round compared to cancers detected in the first round of screening. Also, a significant association between Gleason score and age at diagnosis was found, most notably in cancers detected in the first round of screening. These findings were reproduced by Model II and less so by Model I, with a significant difference in goodness of fit between the 2 models (p < 0.001). This study provides epidemiological evidence of dedifferentiation as a major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen-detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation.

Age Distribution↗
PubMed2006

Risk of cardiovascular mortality in prostate cancer patients in the Rotterdam randomized screening trial.

PURPOSE: To estimate the risk of cardiovascular disease (CVD) mortality in prostate cancer patients in the Rotterdam section of European Randomized Study of Screening for Prostate Cancer, in both arms, and to compare this with the risk in the general population. METHODS: Standardized mortality ratios (SMRs) of cardiovascular mortality for 2,211 prostate cancer patients were calculated including analyses for treatment subgroups (surgery, radiotherapy, watchful waiting, and hormone therapy). Cardiovascular mortality was defined as death as a result of all CVD and as a result of coronary heart disease, acute myocardial infarction, other diseases of the heart, and cerebrovascular accidents. The prevalence of self-reported comorbidities at entry of the trial was evaluated as well. RESULTS: After a mean follow-up of 5.5 years, 258 prostate cancer patients (12%) had died. The SMR of all-cause mortality was 0.90 (95% CI, 0.79 to 1.01). The risk for cardiovascular mortality was low compared with that in the general population; the SMRs varied between 0.37 and 0.49. Low cardiovascular mortality risks were also seen within each treatment subgroup. CVD was the most frequently self-reported comorbidity at entry and prostate cancer patients undergoing radical prostatectomy reported the lowest rates (24%) compared with those receiving other therapies (40% to 42%). CONCLUSION: Although some self-selection has occurred, prostate cancer treatment did not increase the risk of dying as a result of cardiovascular causes in our cohort. The risk was significantly lower for all primary treatment modalities, suggesting that less emphasis should be put on CVD as a contraindication for aggressive (surgical) treatment for prostate cancer patients.

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PubMed2006

Impact of pathology review of stage and margin status of radical prostatectomy specimens (EORTC trial 22911).

Pathological staging and surgical margin status of radical prostatectomy specimens are next to grading the most important prognosticators for recurrence. A central review of pathological stage and surgical margin status was performed on a series of 552 radical prostatectomy specimens of patients, participating in the European Organisation for Research and Treatment of Cancer trial 22911. Inclusion criteria of the trial were pathological stage pT3 and/or positive surgical margin at local pathology. All specimens were totally embedded. Data of the central review were compared with those of local pathologists and related to clinical follow-up. Although a high concordance between review pathology and local pathologists existed for seminal vesicle invasion (94%, kappa=0.83), agreement was much less for extraprostatic extension (57.5%, kappa=0.33) and for surgical margin status (69.4%, kappa=0.45). Review pathology of surgical margin status was a stronger predictor of biochemical progression-free survival in univariate analysis [hazard ratio (HR)=2.16 and p=0.0002] than local pathology (HR=1.08 and p>0.1). The review pathology demonstrated a significant difference between those with and without extraprostatic extension (HR=1.83 and p=0.0017), while local pathology failed to do so (HR=1.05 and p>0.8). The observations suggest that review of pathological stage and surgical margin of radical prostatectomy strongly improves their prognostic impact in multi-institutional studies or trials.

Adenocarcinoma↗
PubMed2006

Should we replace the Gleason score with the amount of high-grade prostate cancer?

OBJECTIVES: The stage and grade shift of currently diagnosed prostate cancer has led to a diminished prognostic power of the Gleason score system. We investigated the predictive value of the amount of high-grade cancer (Gleason growth patterns 4/5) in the biopsy for prostate-specific antigen (PSA) and clinical relapse after radical prostatectomy. METHODS: PSA-tested participants (N=281) of the European Randomized Study of Screening for Prostate Cancer (ERSPC) who underwent radical prostatectomy were analyzed. Besides clinical features, and serum-PSA, histopathologic features as determined in the diagnostic biopsy and matching radical prostatectomy specimen were related to patient outcome. RESULTS: At a median follow-up of 7 yr, 39 (13.9%), 24 (8.5%), and 12 (4.3%) patients had PSA >/=0.1 ng/ml, PSA >/=1.0 ng/ml, and clinical relapse after radical prostatectomy, respectively. Using Cox proportional hazards, PSA level (p=0.002), length of tumour (p=0.040), and length of high-grade cancer (p=0.006) in the biopsy, but not Gleason score, were independent prognostic factors for biochemical relapse (PSA >/=0.1 ng/ml) when assessed as continuous variables. In radical prostatectomies, the proportion of high-grade cancer (p<0.001) was most predictive of relapse (PSA >/=0.1 ng/ml). For PSA >/=1.0 ng/ml and clinical relapse, the amount of high-grade cancer, both in the biopsy specimen (p=0.016 and p=0.004, respectively) and radical prostatectomy specimen (p=0.002 and p=0.005, respectively), but not Gleason score, was an independent predictor. CONCLUSIONS: In biopsy and radical prostatectomy specimens of surgically treated prostate cancer, the amount of high-grade cancer is superior to the Gleason grading system in predicting patient outcome. We propose that, in addition to the Gleason score, the amount of Gleason growth patterns 4/5 in the biopsy (whether absolute length or proportion) should be mentioned in the pathology report.

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PubMed2006

Overall and disease-specific survival of patients with screen-detected prostate cancer in the European randomized study of screening for prostate cancer, section Rotterdam.

INTRODUCTION: This report describes survival data of participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, diagnosed with prostate cancer (pCA) during the first round of screening, the prevalence screen. PATIENTS AND METHODS: pCA characteristics from cases diagnosed during the first screening round from December 1993 to March 2000 are shown. During follow-up, data were collected by semiannual patient chart review for the first 5 yr and annually thereafter. The causes of death are scored according to the diagnosis of the treating physician and are not based on the review of the independent causes-of-death committee. Overall and disease-specific survival graphs are shown in Kaplan-Maier projections and compared with expected survival outcomes for males in the same age categories from the Dutch provinces of North Holland and Flevoland. Statistical evaluation was based on Cox regression analysis. RESULTS: During the prevalence screening, 1014 patients were diagnosed with pCA. Median follow up was 55 mo, 126 (12.4%) patients died, 20 (2.0%) of pCA. Overall 5-yr observed and expected disease-specific survival was 97.7% and 82%, respectively. In the multivariate analysis, a Gleason sum of 4+4 or higher (p=0.025) was predictive of pCA death. CONCLUSIONS: The observed survival data are in line with the literature and the expected favorable outcome for a screened population. The proportion of men dying from pCA is still small, and a 10-yr follow-up period for the final evaluation of the ERSPC may be too short.

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PubMed2006

Biochemical progression rates in the screen arm compared to the control arm of the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) investigates the feasibility of population-based screening. This report compares the preliminary outcome of cancers detected in the screen and the control arm of its Rotterdam section, by means of biochemical progression rates. METHODS: In the screen arm of this study (21,210 men), screening was applied according to well-established protocols, and a 4-year screen interval was chosen. Widely accepted biochemical progression-criteria were used to evaluate the diagnosed cancers over time. RESULTS: Although more cancers were detected in the screen than in the control arm (1,339 vs. 298, P < 0.001), their clinico-pathological features were more favorable. Furthermore, screened men had higher 5-year survival rates for biochemical progression after surgery (84.4% vs. 58.9% in controls), radiotherapy (71.0% vs. 58.0%), and endocrine therapy (40.5% vs. 16.3%). CONCLUSIONS: The higher biochemical progression-free survival can at least in part be explained by lead and length-time. How screening will effect the mortality remains unclear.

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PubMed2006

Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials.

The prostate-specific antigen (PSA) is the most studied marker of prostate cancer. It is used for screening and as indicator of disease evolution for individual patients. PSA being a prognostic factor is however not sufficient to justify using PSA-derived endpoints as surrogate for definitive survival endpoint in phase III trials. First, we clarify the terminology and requirements for a marker to be a valid surrogate endpoint. We then review the published literature pertaining to the validation of PSA endpoints as surrogate in all disease stages. We discuss the limitations of these studies and conclude that so far, PSA is not a validated surrogate endpoint in any of the disease settings and treatment conditions considered. We give some recommendations for the planning of trials that would use PSA endpoints (in hormone refractory disease) and for the early stop of (endocrine treatment) trials on the basis of intermediate results based on PSA.

Antineoplastic Agents, Hormonal↗
PubMed2006

Detection rates of high-grade prostate cancer during subsequent screening visits. Results of the European Randomized Screening Study for Prostate Cancer.

Screening for prostate cancer using prostate-specific antigen (PSA) tests has led to a stage and grade shift as compared to the pre-PSA era. Effectiveness of screening for prostate cancer should be manifested by a reduction in detection rate of aggressive cancers during subsequent screening. In 6 centers of the European Randomized Screening study for Prostate Cancer, a total of 58,710 men were tested for prostate cancer. Screening centers differed with regard to age-range, screening interval and biopsy indications. During the 2nd visit, the proportion of Gleason score 6 cancers increased from 62.5 to 75%, mainly at the expense of Gleason score 7 cancers. High-grade (Gleason score 8-10) cancer detection rates varied per screening center during the 1st visit from 5.1 to 41.1, and during the 2nd visit from 6.4 to 29.3/10,000 men. The overall detection rate of high-grade cancers showed a reduction during the 2nd visit from 26 to 12/10,000 men, an effect mainly attributable to the screening center with the highest cancer detection rate (i.e. 507/10,000 men). Variations in detection rates among screening centers related among others to biopsy compliance and age range.

Age Factors↗
PubMed2006

Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance.

OBJECTIVE: Screening practices for prostate cancer have resulted in an increasing incidence of prostate cancers. Our knowledge about which prostate cancers are life threatening and which are not is limited. Thus, for ethical, medical, and economic reasons we need to define which patients can be managed by active surveillance. METHODS: From 1993 through 1999, men from the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC) were screened by two strict protocols, which were based on prostate-specific antigen (PSA), digital rectal examination, and transrectal ultrasound. For this study, men with criteria that reflect current active surveillance studies were selected: those with a biopsy Gleason score < or =3+3 in two or fewer cores, with a PSA density <0.2 and a maximum PSA-level of 15 ng/ml. Clinical stage had to be T1C or T2. RESULTS: Of the 1,014 prostate cancers detected in the prevalence screen, 293 men (28.9%) met the criteria for active surveillance. Their mean age was 65.7 and the mean PSA level was 4.8 ng/ml. Radical prostatectomy was elected by 136 men (46.4%), radiotherapy by 91 (31.1%), and watchful waiting by 64 (21.8%). The mean follow-up was 80.8 months. The eight-year prostate cancer-specific survival was 99.2%; the overall survival was 85.4%. Nineteen men who chose watchful waiting changed to definitive treatment during follow-up. CONCLUSION: Only three men died of prostate cancer, none of whom were on watchful waiting. Our observations provide preliminary validation of the arbitrary selection criteria for active surveillance.

Aged↗
PubMed2006

A comparison of first and repeat (four years later) prostate cancer screening in a randomized cohort of a symptomatic men aged 55-75 years using a biopsy indication of 3.0 ng/ml (results of ERSPC, Rotterdam).

BACKGROUND: The identification of predictors for prostate biopsy outcome at two screening rounds using a PSA>or=3.0 ng/ml as biopsy indication. MATERIALS AND METHODS: We compared predictors by means of descriptive statistics and logistic regression analysis in men (55-75 years) biopsied in either the 1st or 2nd screening round of ERSPC Rotterdam (interval 4 years). RESULTS: Positive predictors for biopsy outcome in both screening rounds were an increased PSA level in the absence of a previous negative biopsy (PrevNB), DRE and TRUS suspicious and a positive family history (PFH). A higher than median prostate volume was a consistent negative predictor. Having had a PrevNB at initial screening strongly reduced the chance of cancer detection at repeat screening and in addition canceled the predictive potential of PSA. CONCLUSION: If "detecting prostate cancer efficiently" were the aim, this study indicates that a "PSA only based biopsy threshold" may be replaced by another criterion incorporating, e.g., DRE, TRUS and prostate volume in men who were biopsied in the preceding 4 year interval.

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PubMed2006

Screening for prostate cancer without digital rectal examination and transrectal ultrasound: results after four years in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam.

BACKGROUND: Omission of DRE/TRUS as biopsy indication results in fewer unnecessary biopsies, but may increase the risk of missing potentially aggressive prostate cancers (PCs). In 1997, the biopsy indication within the ERSPC was changed from a PSA cut-off of 4.0 ng/ml and/or abnormal DRE/TRUS (group-1) to solely a PSA cut-off of 3.0 ng/ml (group-2). We estimated the effect of omitting DRE/TRUS by comparing the results of a re-screening 4 years after initial screening to the original policy. METHODS: We compared rate and characteristics of detected PCs in the second round in men initially screened in group-1 (N=5,957) or group-2 (N=8,044). Additionally, we compared the rate of interval cancers (ICs) after screening with and without DRE/TRUS. RESULTS: There was no significant difference in second round cancer-detection-rates (group-1, 3.0%; group-2, 2.7%), positive-predictive-values (group-1, 23.9%; group-2, 26.3%), and number of poorly-differentiated tumors (group-1, 2.6%; group-2, 3.8%). Most PCs were clinically confined to the prostate. Eleven ICs were detected in each group (0.18 and 0.14%). CONCLUSIONS: Omitting DRE/TRUS did not result in an increased IC- or PC-detection. However, considering the natural history of PC, the 4-year follow-up may be too short to draw a definitive conclusion.

Follow-Up Studies↗
PubMed2006

Does PSA velocity predict prostate cancer in pre-screened populations?

UNLABELLED: PSA-driven screening has been applied to a large part of the male population in many countries. An elevated PSA in secondary screens may indicate benign enlargement of the prostate rather than prostate cancer. In such cases the yearly rate of increase of PSA (PSA velocity [PSAV]) may improve the test characteristics of PSA. MATERIALS AND METHODS: Data from the European Randomized Study of Screening for Prostate Cancer Rotterdam are used to study the issue. Relative sensitivity, relative specificity, and positive predictive value (PPV) are calculated. Logistic regression analysis is used to compare odds ratios for positive biopsies. The relationship between PSAV and parameters of tumour aggressiveness is investigated. RESULTS: Five hundred eighty-eight consecutive participants were identified who presented at their first screening with PSA values <4.0 and who progressed to PSA values >4.0 ng/ml four years later. None were biopsied in round one, all were biopsied in round two. Relative sensitivity and specificity depend strongly on PSAV cut-offs of 0.25-1.0 ng/ml/yr. The use of PSAV cut-offs does not improve the PPV of the PSA cut-off of 4.0 ng/ml, nor do any of the PSAV cut-offs improve the odds ratio for identifying prostate cancer with respect to the cut-off value of 4.0 ng/ml. The rate of aggressive cancers seems to increase with increasing PSAV. CONCLUSIONS: PSAV does not improve the detection characteristics of a PSA cut-off of 4.0 ng/ml in secondary screening after four years.

Aged↗
PubMed2006

The actual value of the surgical margin status as a predictor of disease progression in men with early prostate cancer.

OBJECTIVES: The surgical margin status after radical prostatectomy for prostate cancer has long been considered a powerful prognostic factor, as well as an important risk factor for local recurrent disease after radical prostatectomy. In this study, a critical analysis of the predictive value of the surgical margin status was performed. METHODS: A well-described cohort of 281 participants of a population-based randomized screening trial who underwent radical prostatectomy between 1994 and 2000 was analyzed. Besides pathologic tumor stage, Gleason score, percentage of high-grade cancer, and tumor volume, the prognostic value of the surgical margin status for disease outcome (prostate-specific antigen [PSA] relapse, local recurrence) was statistically evaluated. Specifically, site ('apical' or 'circumferential') and extent of surgical margin negativity ('negative', or 'close') or positivity ('focal' or 'extensive') was assessed. RESULTS: At a median follow-up of 7 yr (range, 5-120 mo), 39 (13.9%) and 7 (2.5%) men had biochemical failure (PSA >/=0.1ng/ml), and local relapse, respectively. The surgical margin status was positive in 66 (23.5%), with 26 (9.3%) at the prostatic apex. The margin status was an independent statistically significant risk factor for biochemical relapse, though not for local relapse. Of those with positive margins, 22 (33.3%) had PSA relapse and 4 (6.1%) had local recurrence, whereas these figures were 17 (7.9%) and 3 (1.4%) for those with a negative surgical margin, respectively. The extent of margin positivity was not predictive of PSA relapse nor was the site of the surgical margin. CONCLUSIONS: In surgically treated prostate cancer, the surgical margin status has, although being a statistically significant prognostic factor, only limited predictive value for PSA relapse and local recurrent disease. The majority of men with (extensive) positive surgical margins will not experience PSA relapse nor local disease progression, even in absence of adjuvant radiotherapy. So, cases with a positive margin of resection may still be cured, although the procedure in itself was not 'radical'.

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