Ulf Norming

Lead time associated with screening for prostate cancer

Screening serum levels of prostate‐specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value ≥10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan‐Meier) of PC in the 946 participants (ED) during 12 years of follow‐up was compared to that of an age‐matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values ≥3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the “catch‐up” point). After 12 years of follow‐up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow‐up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow‐up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection.

Diagnostic Methods in the Detection of Prostate Cancer: A Study of a Randomly Selected Population of 2,400 Men

We investigated the value of digital rectal examination, transrectal ultrasonography and prostatic specific antigen (PSA) analysis as aids in general clinical practice and in the early detection of prostate cancer. Of a randomly selected population of 2,400 men 55 to 70 years old who were offered examination with digital rectal examination, transrectal ultrasound and PSA analysis, 1,782 (74%) accepted and prostate cancer was detected in 65 (3.6%). When the transrectal ultrasound results were also considered the detection rate of digital rectal examination (2.3%) was increased by 50% and the number of stage T2A or less tumors was doubled. At reexamination due to markedly high PSA values (7 micrograms/l. or more) only a few additional cancers (5%) were detected. However, it is noteworthy that 80% of the detected cancers were found among the subgroup with abnormal PSA values (4 micrograms/l. or more) and comprising 17% of the study population, which suggests the possibility of selecting a risk group at mass screening. Moreover, the positive predictive value increased from 4% (when only digital rectal examination was positive) to 71% for the combination of positive digital rectal examination, positive transrectal ultrasound and an increased PSA concentration (that is 7 micrograms/l. or greater).

A population-based study of 538 patients with newly detected urinary bladder neoplasms followed during 5 years.

OBJECTIVE To describe in detail the diagnosis and clinical course of an unselected population-based cohort of patients with newly diagnosed bladder neoplasms. MATERIAL AND METHODS A total of 538 patients registered in the Stockholm region with newly diagnosed primary bladder neoplasms (transitional cell carcinomas) in 1995 and 1996 were followed for at least 5 years. All hospitals and urology units in the region participated in the study. Treatment and follow-up were performed according to a standard-of-care programme. Routine pathological reports were used. Original case records were scrutinized on location in 2001. In addition, a tumour bank of freshly frozen tumour tissue was established. RESULTS The calculated 5-year cancer-specific survival rate for the 538 patients in the cohort was 78%. No patient (0/29) with TaG1 tumours showed progression or died of bladder cancer. Only 2/187 patients (1%) with stage Ta and grade 2A or 2B tumours died of bladder cancer. In contrast, after 5 years of follow-up, patients with TaG3 and T1G2B tumours had disease-specific death rates of 20% and 27%, respectively. The result of the first cystoscopy examination after the initial resection of non-invasive tumours was of prognostic value. Recurrent disease was present in 62% (248/402) of all patients with Ta and T1 tumours at diagnosis and patients with T1 tumours had recurrences earlier than those with Ta tumours. Moreover, 32% (35/110) of the patients who presented with T1 tumours at diagnosis progressed to muscle-invasive disease during the follow-up period. The overall prognosis for patients presenting with muscle-invasive tumours (T2+) was dismal, with 69% (80/116) of the patients dying of the disease. CONCLUSIONS We analysed a population-based cohort of patients with urinary bladder neoplasms in order to establish a clearly defined and unselected clinical series, with the main aims of comparing and evaluating the clinical utility of new molecular biology techniques. In the present series, TaG1 tumours behaved benignly. The disease-specific mortality rate was low for initial TaG2 tumours, intermediate for initial TaG3 and T1 tumours and high for initial T2+ tumours.

15-year followup of a population based prostate cancer screening study.

PURPOSE We evaluated long-term survival in attendees and nonattendees of a 1-time screening for prostate cancer. MATERIALS AND METHODS A total of 2,400 men 55 to 70 years old in 1988 were randomly selected and invited to a screening for prostate cancer. Of the invited men 1,782 (74%) attended. Screening attendees were examined with digital rectal examination, transrectal ultrasound and prostate specific antigen analysis. When cancer was suspected, prostate biopsies were taken. A total of 65 men with prostate cancer were detected by this procedure. The entire source population comprising 27,204 men, including 618 nonattendees (26%), was followed for prostate cancer diagnosis and survival for 15 years. RESULTS Incidence rate ratios were calculated using Poisson regression models. We found no effect of this screening procedure on the risk of death from prostate cancer and other causes of death (incidence rate ratio 1.10, 95% CI 0.83-1.46 and 0.98, 95% CI 0.92-1.05, respectively) when comparing all invited men with the source population. However, attending the screening program was associated with a significantly decreased risk of death from causes other than prostate cancer (vs source population incidence rate ratio 0.82, 95% CI 0.76-0.90). In contrast, the corresponding incidence rate ratio in nonattendees was 1.53 (95% CI 1.37-1.71). CONCLUSIONS We found no evidence of a beneficial effect of this specific screening procedure but strong evidence of a difference in overall survival in screening attendees and nonattendees. These findings should be considered when interpreting previous and upcoming studies of the effect of screening programs.

Diagnostic value of percent free prostate-specific antigen: retrospective analysis of a population-based screening study with emphasis on men with PSA levels less than 3.0 ng/mL

OBJECTIVES To retrospectively investigate the use of percent free prostate-specific antigen (PSA) compared with total PSA in serum as predictor of prostate cancer in men selected randomly from the general population who underwent biopsy on the basis of abnormal findings on digital rectal examination (DRE) or transrectal ultrasound (TRUS) and/or serum PSA levels greater than 10 ng/mL. METHODS A single intervention, population-based screening study was undertaken in 1988 and 1989. Of the 2400 men aged 55 to 70 years invited to participate, 1782 men responded and were examined with DRE, TRUS, and PSA testing (Tandem-Hybritech). In 1995, frozen serum samples from 1748 men were analyzed for percent free PSA (Prostatus, Wallac OY). Five-year follow-up data on new cancers in the screened population were obtained from the Swedish Cancer Registry (SCR). RESULTS Of the 1748 men, 367 underwent TRUS-guided biopsies because of abnormal findings on either DRE or TRUS or serum PSA levels of greater than 10 ng/mL. This resulted in the diagnosis of 64 cases of prostate cancer (3.7%). PSA levels of 3.0 ng/mL or greater were found in 55 (86%) of 64 cancer cases and in 399 (24%) of the 1684 benign cases. Among the 1294 men with PSA less than 3.0 ng/mL, 9 prostate cancers were diagnosed (14% of all prostate cancers). All 9 patients with cancer and with PSA less than 3.0 ng/mL had a percent free PSA of 18% or less. In the group of 1109 patients with PSA less than 3.0 ng/mL and a percent free PSA greater than 18%, 159 biopsies were performed because of abnormal DRE or TRUS. However, no prostate cancer was diagnosed in this category of patients. Five years after the screening intervention, 7 more cases of prostate cancer were clinically diagnosed in the screened population according to the SCR. CONCLUSIONS The combination of PSA levels less than 3.0 ng/mL and percent free PSA greater than 18% defines a large part of the population at a very low risk of cancer of the prostate both at the time of screening and during the following 5 years. Men in this group may be spared DRE, and longer screening intervals may be considered. However, the risk of having prostate cancer is not negligible in men with PSA less than 3.0 ng/mL and percent free PSA of 18% or less. The results of this study indicate that biopsy should be recommended to men fulfilling these criteria, although these results should be confirmed in larger prospective studies because of the limited number of patients with prostate cancer in the present series.

Deoxyribonucleic Acid Profile and Tumor Progression in Primary Carcinoma in Situ of the Bladder: A Study of 63 Patients with Grade 3 Lesions

In 63 patients with primary grade 3 carcinoma in situ of the bladder flow cytometric deoxyribonucleic acid (DNA) analysis was performed at diagnosis and during an average followup of 63 months. The results of DNA measurements were related to disease progression, that is invasive tumor and/or metastatic disease. The DNA histograms were classified as diploid (2 patients) or aneuploid (61). A total of 3 categories of aneuploid tumors with different prognostic significance could be defined: 1) carcinoma in situ with 1 aneuploid cell population at diagnosis and with no change to multiple aneuploid cell populations throughout observation, 2) carcinoma in situ with 1 aneuploid cell population at diagnosis but with a later change to multiple aneuploid cell populations and 3) carcinoma in situ with multiple aneuploid cell populations already at diagnosis. At 5 years the progression-free survival for the 3 categories was 94%, 43% and 20%, respectively. Over-all, of the patients with multiple aneuploid cell populations (categories 2 and 3) 76% had progression, in contrast to 19% of those in category 1 (p less than 0.0005). In category 2 development of multiple aneuploid cell populations preceded progression in 8 of 11 progressive cases by an average of 20 months. Therefore, the occurrence of multiple aneuploid cell populations must be considered as a sign of high aggressiveness. We conclude that flow cytometric DNA analysis is a potent predictor of prognosis in cases of primary carcinoma in situ of the bladder.

Prognostic significance of mucosal aneuploidy in stage Ta/T1 grade 3 carcinoma of the bladder

In a prospective series of 71 patients with newly detected grade 3, stages Ta and T1 bladder carcinoma tumor characteristics, including the results of deoxyribonucleic acid (DNA) analysis as well as morphological and DNA characteristics of the grossly normal urothelium, were investigated and related to progression-free survival. The mean duration of followup was 57 months, with a minimum of 24 months. Of the 71 patients 24 underwent primary cystectomy, and 47 were conservatively treated with transurethral resection alone, or followed by instillation therapy or irradiation therapy. Of the cystectomy and conservatively treated patients 2 (8%) and 16 (34%), respectively, died of bladder carcinoma. Among the 47 conservatively treated patients tumor progression could not be predicted by the initial characteristics of tumor stage, papillary or nonpapillary growth, tumor multiplicity, tumor size, existence of 1 or multiple aneuploid cell populations, S phase value, carcinoma in situ and atypia or aneuploidy in the mucosal biopsies. Neither was progression predicted by the recurrence rate during year 1 of observation. However, a change to or persistent mucosal aneuploidy and a change to or persistent morphological abnormality of the mucosa during year 1 of observation were predictive for tumor progression (p = 0.001 and 0.045, respectively). When compared in stepwise regression analysis (Coxs proportional hazard model), DNA aneuploidy in the mucosa at 12 months after diagnosis was a highly significant predictor, whereas morphology added no further prognostic information. Therefore, progression is related to gross chromosomal abnormalities of the mucosa. High risk patients can be identified by evaluation of the grossly normal mucosa, which should be done as part of the initial diagnosis and during followup in conservatively treated patients with stages Ta and T1, grade 3 bladder carcinoma.

Prostate-specific Antigen (PSA), PSA Density and Age- adjusted PSA Reference Values in Screening for Prostate Cancer A Study of a Randomly Selected Population of 2,400 Men

Prostate cancer screening with DRE, TRUS, and PSA testing was offered to 2,400 randomly selected men 55-70 years old. Among 1,782 examined, 65 (3.6%) men with prostate cancer were diagnosed. The PSA results were correlated to the diagnosis, the mens age, and the prostate volume. Least square regression analysis was used to calculate the 95% upper confidence intervals for PSA in each year of age in men without prostate cancer. The PPV was calculated for: (i) PSA > 4 ng/ml, (ii) PSAD > 0.15, (iii) PSAD > 0.20 and (iv) age-adjusted PSA reference values. A significant correlation was found between PSA and prostate volume, between PSA and age, and between the prostate volume and age. The calculated annual growth of the prostate was 1.6% and the annual increase in PSA was 2.4%. The age-adjusted upper PSA reference values for the three age categories studied (55-59, 60-64 and 65-70 years) were 5.2, 5.8, and 6.7 ng/ml, respectively. The PPVs for PSA > 4 ng/ml, PSAD > 0.15, PSAD > 0.20, and the age-adjusted PSA reference values were 17%, 14%, 22%, and 27%, respectively. Age-adjusted PSA or PSAD may increase the PPV compared to PSA > 4 ng/ml. The detection rate is, however, inadequate. A PSA cut-off at 4 ng/ml could therefore be maintained in men 55-70 years old. The median PSA values and median prostate volumes calculated for men with benign findings may serve as a reference in future studies.

Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening

Abstract.  Kjellman A, Akre O, Gustafsson O, Høyer‐Hansen G, Lilja H, Norming U, Piironen T, Törnblom M (Department of Clinical Science, Intervention, and Technology; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark; Departments of Clinical Laboratories, Urology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; and Syrinx Bioanalytics Oy, Turku, Finland; formerly at Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark). Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening. J Intern Med 2010; 269: 299–305.

Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population‐based series. An association was found between uPA and uPAR expression (n = 172; Spearman rs = 0.60, p < 0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer‐specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0–3.3) for uPA (upper quartile cut‐line), 2.2 (1.3–4.0) for uPAR (median quartile cut‐line) and 2.5 (1.3–4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6–9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1–3.9) for uPA, 1.6 (0.8–3.3) for uPAR and 2.5 (1.1–5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies.