Sakari Rannikko

MAGNETIC RESONANCE IMAGING OF CLINICALLY LOCALIZED PROSTATIC CANCER

PURPOSE We assess the accuracy of endorectal coil magnetic resonance imaging (MRI) for detecting tumor localization, capsular penetration and seminal vesicle invasion in clinically organ confined prostate cancer. We also evaluate intra-observer and interobserver agreement in interpreting MRI studies. MATERIALS AND METHODS MRI studies of 51 consecutive patients a mean of 61 years old with biopsy proved prostate cancer were retrospectively read twice by 2 radiologists in random order. Both radiologists marked tumor localization, capsular penetration and seminal vesicle invasion on standard tumor maps. These findings were compared with the histopathological results of radical prostatectomy specimens. RESULTS The overall accuracy of detecting cancer localization was 61%. The detection rate for cancer foci less than 5 mm. was only 5% but for lesions greater than 10 mm. it was 89%. There was 91 and 80% accuracy for detecting capsular penetration and seminal vesicle invasion, respectively. Sensitivity and specificity were 60 and 63, 13 and 97, and 59 and 84% for localization, capsular penetration and seminal vesicle invasion, respectively. Intra-observer and interobserver agreement ranged from fair to good (kappa coefficient 0.240 to 0.647). CONCLUSIONS Endorectal MRI seems to be better than previously reported for detecting seminal vesicle invasion and tumor foci in the anterior half of the prostate. Sensitivity in detecting minor capsular penetration of the tumor was low, which can probably be improved by methodological development. MRI may be useful for locating cancer foci in patients with high prostate specific antigen values but repeatedly negative biopsy findings.

Computerized Tomography and Transrectal Ultrasound in the Assessment of Local Extension of Prostatic Cancer Before Radical Retropubic Prostatectomy

The value of computerized tomography and transrectal ultrasound in the demonstration of local extension of prostatic cancer was evaluated in 38 patients undergoing radical retropubic prostatectomy. Transrectal ultrasound proved to be reliable for the demonstration of local extension of cancer beyond the prostatic capsule (sensitivity 86 per cent, specificity 94 per cent and accuracy 90 per cent). Invasion of the seminal vesicles was demonstrated by ultrasound, with a sensitivity of 29 per cent, specificity 100 per cent and accuracy 77 per cent. The addition of transrectal ultrasound scanning to clinical evaluation increased sensitivity in relation to detection of extraprostatic involvement from 15 to 92 per cent. When computerized tomography scanning was added to clinical examination, the sensitivity increased from 15 to only 46 per cent. Transrectal ultrasound is valuable for the preoperative evaluation of patients in whom radical prostatectomy is being considered as treatment for clinically localized prostatic cancer.

European randomized study of prostate cancer screening: first-year results of the Finnish trial.

SummaryApproximately 20 000 men 55–67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml–1 or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1–T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means.

Lead-time in prostate cancer screening (Finland).

Objective: Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial. Methods: Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model. Results: Based on findings among 10,000 men screened in 1996–1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5–7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10–14 years, given that the cancers were detected on average at the midpoint of the DPCP. Conclusions: The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.

Estimation of Prostate Cancer Risk on the Basis of Total and Free Prostate-Specific Antigen, Prostate Volume and Digital Rectal Examination

BACKGROUND AND OBJECTIVE Approximately 70% of the men with an elevated serum prostate-specific antigen (PSA) identified in prostate cancer screening do not have prostate cancer. Other available diagnostic variables may be utilized to reduce the number of false positive PSA results, but few algorithms for calculation of the combined impact of multiple variables are available. The objective of this study was to establish nomograms showing the probability of detecting prostate cancer at biopsy on the basis of total PSA, and the percentage of free PSA in serum, prostate volume and digital rectal examination (DRE) findings. METHODS In a randomized, population-based prostate cancer screening trial 10284 men aged 55-67 years were screened during 1996 and 1997 in two metropolitan areas in Finland. Results for men (n=758) with a serum PSA of 4-20 microg/l were used to establish the risk nomograms. Of these 200 (26%) had prostate cancer at biopsy. RESULTS Prostate cancer probability depended most strongly on the percentage of free PSA. Total PSA, prostate volume, and DRE also contributed to prostate cancer probability, whereas age and family history of prostate cancer did not. More false positive PSA results could be eliminated by using the multivariate risk model rather than the percentage of free PSA (p<0.001) or PSA density (p=0.003) alone. CONCLUSIONS Wide variation in probability of detecting prostate cancer among screened men with a serum PSA of 4-20 microg/l was observed. The nomograms established can be used to avoid or defer biopsy in men with a low prostate cancer probability in spite of a serum PSA level exceeding 4 microg/l.

Family History and Prostate Cancer Screening With Prostate-Specific Antigen

PURPOSE Early detection of prostate cancer has been recommended for men with affected first-degree relatives despite the lack of evidence for mortality reduction. We therefore evaluated the impact of family history in the Finnish prostate cancer screening trial. PATIENTS AND METHODS Approximately 80,000 men were identified from the population register for the first screening round. Of the 32,000 men randomized to the screening arm, 30,403 were eligible at the time of invitation. A blood sample was drawn from the participants (n = 20,716), and serum prostate-specific antigen (PSA) was determined. Men with a PSA level > or = 4.0 ng/mL were referred for prostate biopsy. Information on family history was obtained through a self-administered questionnaire at baseline. RESULTS A total of 964 (5%) of the 20,716 screening participants had a positive family history, and 105 (11%) were screening-positive. Twenty-nine tumors were diagnosed, corresponding to a detection rate of 3.0% (29 of 964) and a positive predictive value of 28% (29 of 105). Of the 19,347 men without a family history, 1,487 (8%) had a PSA level > or = 4.0 ng/mL. The detection rate was 2.4% (462 of 19,347) and the positive predictive value was 31% (462 of 1,487). The risk associated with a positive family history was not substantially increased (rate ratio, 1.3; 95% confidence interval, 0.9 to 1.8). The results were not affected by the age of the screenee or age at diagnosis of the affected relative. The program sensitivity was 6% (29 of 491) (ie, selective screening policy would have missed 94% of cancers in the population). No differences were seen in the characteristics of screen-detected cancers by family history. CONCLUSION Our findings provide no support for selective screening among men with affected relatives.

Magnetic resonance imaging of prostatic cancer: does detection vary between high and low gleason score tumors?

Both Gleason score and prostate‐specific antigen (PSA) concentration are prognostic factors for prostate cancer. We assessed our ability to localize cancer lesions based on Gleason scores and PSA values by endorectal coil magnetic resonance imaging (MRI). We also evaluated whether the size of the prostate affects tumor detectability.

Prostate cancer screening within a prostate specific antigen range of 3 to 3.9 ng./ml.: a comparison of digital rectal examination and free prostate specific antigen as supplemental screening tests.

PURPOSE Performing biopsy in all men with a serum prostate specific antigen (PSA) of 3 to 3.9 ng./ml. increases the sensitivity of prostate cancer screening compared with a PSA cutoff of 4 ng./ml. but decreases specificity and may contribute to over diagnosis. Therefore, we evaluated the detection rate and specificity attributable to digital rectal examination and percent free PSA within the PSA range of 3 to 3.9 ng./ml. MATERIALS AND METHODS Serum PSA was determined in 20,716 participants in the Finnish population based screening trial. Supplementary digital rectal examination was offered to men with a PSA of 3 to 3.9 ng./ml. during 1996 to 1998 (protocol 1). Those with a suspicious digital rectal examination finding were referred for biopsy. The screening algorithm was modified by substituting percent free PSA for digital rectal examination with a cutoff of 16% as a biopsy criterion in 1999 (protocol 2). In addition, biopsies were performed in all men with PSA 4 ng./ml. or greater. RESULTS A total of 23 cancers (2.9%) were detected by digital rectal examination among 801 men, while percent-free PSA resulted in the diagnosis of 13 cases (4.8%) among 270 men with a PSA of 3 to 3.9 ng./ml. The detection rate of tumors with a Gleason score of 5 or greater increased from 1.6% (13 of 801 cases) to 4.4% (12 of 270) in the modified screening program. The PSA cutoff of 3 ng./ml. alone showed 88.6% and 87.5% specificity in protocols 1 and 2 but specificity increased to 93.3% and 91.7% using digital rectal examination and percent free PSA, respectively. CONCLUSIONS Using percent free PSA increased the detection rate of aggressive disease compared with digital rectal examination and provided higher specificity than PSA alone.

TEST SENSITIVITY OF PROSTATE-SPECIFIC ANTIGEN IN THE FINNISH RANDOMISED PROSTATE CANCER SCREENING TRIAL

We estimated the sensitivity of serum prostate‐specific antigen (PSA) as a screening test for prostate cancer in the Finnish randomised, population‐based prostate cancer screening trial. The study population consisted of 80,458 men aged 55–67 years identified from the national population registry and randomised to the screening or control arm of the trial. The screening algorithm was based on determination of serum PSA concentration. Test sensitivity was estimated based on interval cancer incidence during the first 4 years of follow‐up among screening participants with a negative screening test. Interval cancers were defined as those occurring among men with a negative screening test. Altogether, 19 interval cancers were detected among 17,897 men with serum PSA < 3 ng/ml during the first screening interval. A further 5 cases were diagnosed among 811 men with PSA 3.0–3.9 ng/ml with a benign digital rectal examination or free total PSA ratio ≥ 0.16. Test sensitivity based on serum PSA of 3 ng/ml was estimated to be 0.89 (95% confidence interval 0.84–0.93) and that based on PSA of 4 ng/ml combined with an ancillary test (digital rectal examination or free total PSA ratio in the PSA range 3.0–3.9) was 0.87 (0.82–0.92). Test sensitivity achieved with serum PSA in prostate cancer screening appears excellent in the context of a population‐based effectiveness trial.

Histological and functional changes of the testis tissue during GnRH agonist treatment of prostatic cancer.

The purpose of this study was to examine long-term effects of GnRH agonists on human testicular histology and endocrine function. Patients with advanced prostate cancer (n = 7) were treated with the potent GnRH agonist analogue buserelin (Bu, Hoechst), 600 micrograms X 3/day intranasally. After 6 months, the patients were orchiectomized, and the testis tissue was used for histological studies and measurements of endocrine function in vitro. Fourteen other patients with matching ages and extent of the disease were castrated as the first form of therapy, and their testis tissue was used as controls (C). Severe atrophy of seminiferous tubules was seen in light microscopy in the testes of the Bu treated patients. Many tubules showed only Sertoli cells, and the seminiferous epithelium was frequently absent. In contrast, no clear changes were seen in the number of Leydig cells. Testicular content of testosterone (T) decreased greater than 95% by Bu treatment: C = 1.5 +/- 0.2 nmol/g wet wt (x +/- SE); Bu = 0.070 +/- 0.019 nmol/g. Likewise, a drop of 80% occurred in testicular high affinity receptors for FSH: C = 0.37 +/- 0.019 pmol/g; Bu = 0.067 +/- 0.009 pmol/g. In contrast, the number of LH receptors was unaffected by the treatment, C = 0.18 +/- 0.033; Bu = 0.18 +/- 0.032 pmol/g. When testis slices were incubated in the presence of maximally stimulating concentration of hCG (100 ng/ml), both groups of tissue responded similarly with a 50% increase in T production, albeit the absolute production rate was reduced by 95% in the Bu group. When several steroid precursors of T were analyzed in the incubation media, it appeared that decreased androgen synthesis was most clearly due to decreased 3 beta-hydroxysteroid dehydrogenase activity. It is concluded that long-term treatment with GnRH agonists in prostatic cancer patients brings about dramatic damage of seminiferous tubular function and reduces testicular androgen producing capacity, but has no effect on testicular capability of responding immediately to LH stimulation.