A.L.M. Verbeek

Predictability of Recurrent and Progressive Disease in Individual Patients with Primary Superficial Bladder Cancer

The ultimate goal of prognostic assessment is optimization of individual counseling. Often, however, studies on prognostic factors focus on discriminating between high risk and low risk subgroups without considering the relevance of 1 or more factors for predicting disease outcome in individual patients. We quantified the accuracy of prediction of future recurrences and disease progression in individual patients with primary superficial bladder cancer. The study cohort consisted of 1,674 patients who were followed prospectively between 1983 and 1991 in the Netherlands. By analyzing half of the patients with proportional hazards regression, we computed relative risks of recurrence and progression. A prognostic index score based on these relative risks was then applied to the other half of the patients to determine whether group outcome could be predicted accurately. To assess the accuracy of prediction in individuals we used a method similar to the construction of receiver operating characteristic curves in diagnostic test assessment. The 3-year risk of first recurrence was 55% (95% confidence interval 51 to 59%). The 3-year risk of first progressive disease was 10% (95% confidence interval 8 to 12%). For the risk of first recurrence, tumor stage, tumor extent and multicentricity had statistically significant prognostic ability. Prognostic factors for the risk of disease progression were tumor stage, grade, multicentricity and the result of random biopsies from cystoscopically normal-appearing urothelium. For patients with a prognostic index score that suggested a low risk for recurrent and progressive disease the predicted 3-year risk of first recurrence was still 44% but the predicted 3-year risk of progression was only 3%. For patients with a prognostic index score that suggested a high risk the predicted risks were 74% and 22%, respectively. These predicted risks appeared to be fairly accurate when applied to the other half of our case series. However, in any 2 patients chosen at random the chance that the patient with the worst predicted prognosis would have a shorter recurrence-free and progression-free followup was calculated to be only 58% and 67%, respectively. Although the available prognostic factors in superficial bladder cancer may be useful to identify high risk and low risk subgroups, predictability in individuals is highly inaccurate. More relevant prognostic factors are needed to decrease current overtreatment and undertreatment rates, and to improve the followup policy.

Decreased rates of advanced breast cancer due to mammography screening in The Netherlands.

The effect of the implementation of the Dutch breast cancer screening programme during 1990–1997 on the incidence rates of breast cancer, particularly advanced breast cancer, was analysed according to stage at diagnosis in seven regions, where no screening took place before 1990. The Netherlands Cancer Registry provided detailed data on breast cancer incidence in 1989–1997 by tumour stage, age and region. Annual age-adjusted incidence rates of all breast cancers and advanced cancers, defined as large tumours T2+ with lymph node and/or distant metastases, were compared with rates in 1989. In general, breast cancer incidence rose strongly in the early 1990s, especially in the age category 50–69 years (estimated annual percentage change (EAPC) 4.25; 95% CI 1.70, 6.86). The increase was mainly due to the increase in small T1 cancers and ductal carcinoma in situ. However, in women aged 50–69, advanced cancer incidence rates showed a significant decline by 12.1% in 1997 compared with 1989 (EAPC –2.14, 95% CI −3.47, −0.80), followed by a breast cancer mortality reduction of similar size after approximately 2 years. We confirm that breast cancer screening initially leads to a temporary strong increase in the breast cancer incidence, which is followed by a significant decrease in advanced diseases in the women invited for screening. It is evident that breast cancer screening contributes to a reduction in advanced breast cancers and breast cancer mortality.

The clinical epidemiology of superficial bladder cancer. Dutch South-East Cooperative Urological Group.

Even though the majority of patients with bladder malignancies initially present with low stage disease, the clinical epidemiology of these so-called superficial bladder tumours is not well known. In this paper, disease characteristics at initial presentation and during follow-up are described in 1,745 primary cases documented prospectively in the Netherlands. The risk of recurrent disease after primary treatment is very high: in 60% of cases, at least one recurrence is diagnosed within 5 years (95% CI: 58-62%). In patients with a small solitary pTa grade 1 tumour, the 3-year recurrence risk is 37%. In patients with multiple large high grade pT1 tumours, this risk is as high as 77%, despite a significant beneficial effect of adjuvant intravesical chemotherapy. The actuarial risk of disease progression is 10.2% after 3 years (95% CI: 8.6-11.8%). This risk of progression depends on the patients age at diagnosis, tumour stage, grade, multiplicity and the presence of dysplasia or CIS in random urothelium biopsies. The use of intravesical instillations with chemotherapy or BCG vaccine after TUR does not prevent progressive disease, although this finding is difficult to interpret from a non-randomised study. The 5-year relative survival in patients with superficial TCC of the bladder is 86% (95% CI: 84-88%).

Effect of mammographic breast density on breast cancer screening performance: a study in Nijmegen, the Netherlands.

STUDY OBJECTIVE: To study the implications of breast density on mammographic screening performance. DESIGN: Screening outcomes of women with dense breast patterns were compared with those of women with lucent breast patterns (dense > 25% densities, lucent < or = 25% densities); the women were screened in different periods (before/after improvement of the mammographic technique in 1982). SETTING: Nijmegen, the Netherlands, 1977-1994. PARTICIPANTS: Between 1977 and 1994, 73,525 repeat screenings were performed in 19,152 participants (aged 50-69 years) in the Nijmegen breast cancer screening programme (repeat screenings were defined as mammographic examinations that were preceded by an examination in the previous screening round). Participants were screened biennially with mammography. There were 258 screen detected and 145 interval cancers. MAIN RESULTS: Before 1982 (rounds 2-4) the predictive value of a positive screening test (PV+) was lower in women with dense breasts than in those with lucent breasts (dense 29% v lucent 52%, p = 0.003). Also, the ratio of screen detected cancers to the total number of screen detected plus interval cancers (as a proxy for sensitivity) was lower in this group (based on a one year interval: dense 63% v lucent 92%, p = 0.001 and based on a two year interval: dense 41% v lucent 68%, p = 0.002). Moreover, the survival rate was less favourable for those with dense breasts (p = 0.07). In rounds 5-10, there were no important differences with respect to PV+ (dense 66% v lucent 62%, p = 0.57) or survival (p = 0.48). Moreover, sensitivity based on a one year interval was nearly as high in women with dense breasts as in those with lucent breasts (85% v 86%, p = 0.75). However, based on a two year interval sensitivity was lower (dense 59% v lucent 72%, p = 0.04). CONCLUSIONS: In the early screening years (rounds 2-4) high breast density had an unfavourable effect on screening performance. Nowadays, the situation has improved with respect to PV+, survival and detecting tumours in dense breasts with a lead time of up to one year, but little improvement has occurred in the detection of tumours with a lead time greater than one year.

Changes in mammographic breast density and concomitant changes in breast cancer risk

Among participants of the biennial Nijmegen breast cancer screening programme, we examined whether diminution of mammographic breast density lowered breast cancer risk. Post-menopausal breast cancer cases (n = 108), who had to have participated in all the five screening rounds prior to their diagnosis, were matched to 400 controls on year of birth and screening history. Controls had to be free of breast cancer at the time of the cases diagnosis. Changes in breast density were measured over a 10-year period, by a fully computerized method. Women in whom 5-25% or >25% of the breast was composed of fibro-glandular density showed a threefold increased 10-year risk compared to women with <5% density. In women with 5-25% density initially, we observed a trend of decreasing risk with diminishing density: when women with <5% density throughout the whole period formed the reference category, the odds ratio (OR) for those who decreased from 5-25% to <5% density was 1.9 [95% confidence interval (CI) = 0.6-6.1] in contrast to the OR of 5.7 (95% CI = 2.2-15.2) for those with persisting 5-25% density. In women who increased from 5-25% density to >25% density the OR was 6.9 (95% CI = 2.1-22.9). In women with >25% density initially, diminishing density was not clearly associated with lowering risk, which may be partly explained by the low number of women who decreased to <5% (n = 12). Due to the limited size of the study these results have to be interpreted with caution. Although the results are not conclusive, they could indicate a trend of decreasing risk with diminishing breast density. Should this effect be real, it may have great implications for the primary prevention of breast cancer or for the identification of high-risk groups who would benefit by more frequent screening. Therefore, large-scale, long-term follow-up studies on the effects of changes in breast density are needed.

Guidelines for the assessment of new diagnostic tests

RATIONALE AND OBJECTIVES. Because new diagnostic tests become available rapidly, the authors determined a need for proper assessment of tests before their implementation in clinical practice. Three factors are of pivotal importance: the selection of the proper study population, the determination of the diagnostic power including its related statistical analysis, and the relation of the new test to current diagnostic tools. Patients suspected of having a disease are those who would benefit from the application of a new test. Therefore, only those patients need be involved in the assessment study. METHODS.Summary measures of diagnostic power other than sensitivity and specificity are advocated because these conventional measures depend on cutoff points and are susceptible to selection bias. The relation between the new test and existing diagnostic tools must be established to determine if the new test contributes to the diagnostic process. RESULTS AND CONCLUSION.To avoid waste of effort and money, the authors suggest a prudent assessment approach in phases. Whereas the initial challenge consists of selection of an adequate patient population, subsequently all determinants of disease (signs, symptoms, comorbidity, and other diagnostic factors) and factors influencing the decision to use a test (patient burden and cost) are considered.

AN ADDITION TO THE CONTROVERSY ON SUNLIGHT EXPOSURE AND MELANOMA RISK: A META-ANALYTICAL APPROACH

Case control studies on the association between sunlight exposure and melanoma risk show considerable differences in design; this could be responsible for the variation in study results. In an attempt to resolve the controversy between study results, the results of 25 publications on case control studies were evaluated using meta-analytical techniques. Comparison of odds ratios between subgroups of studies revealed that the range of odds ratios was far greater for hospital-based studies than for population-based studies. For the latter type of studies, the odds ratios were homogeneous and the pooled odds ratios were 1.57 (95% confidence interval [CI], 1.29-1.91) for intermittent sunlight exposure and 0.73 (95% CI, 0.60-0.89) for chronic exposure. However, among other problems, the lack of standardized measures for sunlight exposure warrants cautious interpretation of these results. It is concluded that evidence to support the intermittent sunlight theory is still far from complete.

Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer

Random urothelium biopsies were taken at initial endoscopic surgery from 1001 patients with primary superficial bladder cancer. The clinical course of all the patients was assessed prospectively. Actuarial risks of recurrence and disease progression were determined for prognostic characteristics and comparisons were made using log-rank tests. The independent prognostic significance of concomitant intra-aurothelial dysplastic changes was examined with Coxs regression analyses. The 3-year risk of recurrence in patients with dysplasia and carcinoma in situ (CIS) in macroscopically normal-looking urothelium was only slightly higher than the risk in patients without dysplastic changes (56, 58 and 51%, respectively; P = 0.25). Concomitant dysplasia or CIS significantly increased the 3-year risk of disease progression (17 and 31%, respectively, versus 7%; P < 0.001). After adjustment for the effects of age, tumour stage, grade, size and multicentricity, the result of random biopsies had no prognostic significance regarding the risk of recurrence, but the detection of dysplasia or CIS increased the risk of progression by approximately 80%. This result suggests that random urothelium biopsies may be useful as an additional guide in defining therapy in primary superficial bladder cancer.

Polymorphisms in the Vitamin D Receptor Gene and the Androgen Receptor Gene and the Risk of Benign Prostatic Hyperplasia

Objective: Little is known about risk factors for the development of benign prostatic hyperplasia (BPH). Recently, associations were observed between prostate cancer (CaP) risk and polymorphisms in the vitamin D receptor (VDR) gene and the androgen receptor (AR) gene. Since both receptors are relevant for prostate growth, the VDR and AR are also expected to be involved in the development of BPH. The objective of this study is to establish the relationship between the risk of BPH and a polymorphism in the number of CAG repeats in the AR gene and a TaqI restriction enzyme polymorphism in the VDR gene.Methods: For this study, 98 patients who had been treated for BPH–related complaints and 61 convenience controls (predominantly bladder cancer patients) were recruited from the outpatient clinic. DNA was isolated from peripheral blood, and genotyping was performed with PCR–based methods. Means as well as odds ratios (ORs) with 95% confidence intervals (CI) were calculated using SPSS software.Results: The mean number of CAG repeats in the AR gene in patients and controls was found to be similar: 21.8 (SD = 2.8) and 21.9 (SD = 2.9), respectively. In the subgroup of patients with a prostate volume of at least 50 cm3, the mean number of repeats was 21.5 (SD = 2.6). The OR for BPH for individuals with homozygous presence of the VDR TaqI restriction fragment length polymorphism (RFLP) (tt) versus individuals with homozygous absence (TT) or heterozygotes (Tt) was found to be 1.0 (95% CI 0.4–2.4). For individuals with a prostate volume of at least 50 cm3, the OR was 1.2 (95% CI 0.5–3.2).Conclusion: Unlike earlier observations in prostate cancer, we did not find an association between the CAG repeat polymorphism in the AR gene and the TaqI RFLP polymorphism in the VDR gene and the risk of BPH.

Long term breast cancer screening in Nijmegen, The Netherlands: the nine rounds from 1975-92.

STUDY OBJECTIVE: To assess the performance of breast cancer screening in different age categories over two decades. DESIGN: Important determinants of reduced breast cancer mortality such as attendance, mammography performance, cancer detection, and disease stage were recorded. SETTING: Nijmegen, The Netherlands, 1975-92. SUBJECTS: Since 1975 more than 40,000 women aged 35 years and older have been invited biennially for breast screening in a population based project in Nijmegen. MAIN RESULTS: Rates of attendance, referral, detection, and disease stage were calculated, as well as the specificity of screening mammography and the predictive value of referral and biopsy. From round 3 onwards, the attendance rate of women younger than 50 years stabilised at 70%, in women of 50-69 years it was 62%, and in women aged 70 and over it was 22%. In these three age categories, the referral rates of a positive screening mammography per 1000 screened women were 4.9, 6.2, and 11.8, respectively. Specificity rates were between 99% and 100%. Current predictive values of referral were high: in the specific age categories 39%, 59%, and 68% of the referred women had cancer. Detection rates remained fairly stable over the rounds 4-9, at 1.9, 3.6, and 8.0 cancers per 1000 screened women. In the two year period between screening the numbers of interval cancers per 1000 screened women were 2.2, 2.2, and 2.9, for the three age categories respectively. With regard to invasive cancers detected during screening, the percentage of small tumours (< or = 20 mm on the mammogram) was 84% in each age category. For women younger than 50 years, the proportion of intraductal carcinoma in all the cancers detected at screening was 40%, while it was 15% in the other age categories. CONCLUSION: Throughout the nine rounds, the screening outcomes were found to be adequate, particularly considering the high specificity rate and the predictive value of referral without the interference of a low detection rate. Although the occurrence of interval cancers seemed high, it was similar to other screening programmes. Despite a relatively low referral rate, the ratios of screen detected versus interval cancer cases were favourable. Well organised screening programmes can achieve good mammography results without too many false positives. It is important that women continue to participate in a screening programme because cancer can still be detected even after several successive negative screening examinations.