Marco Zappa

Screening and Prostate-Cancer Mortality in a Randomized European Study

BACKGROUND The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

Prostate-cancer mortality at 11 years of follow-up

BACKGROUND Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial

BACKGROUND Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. METHODS Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. FINDINGS In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two. INTERPRETATION HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. FUNDING European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

Once-Only Sigmoidoscopy in Colorectal Cancer Screening: Follow-up Findings of the Italian Randomized Controlled Trial—SCORE

BACKGROUND A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. METHODS We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. RESULTS A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. CONCLUSION A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

Results at Recruitment From a Randomized Controlled Trial Comparing Human Papillomavirus Testing Alone With Conventional Cytology as the Primary Cervical Cancer Screening Test

BACKGROUND In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year. METHODS In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24,661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24,535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided. RESULTS For women aged 35-60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25-34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44). CONCLUSIONS For women aged 35-60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25-34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.

Overdiagnosis in mammographic screening for breast cancer in Europe: A literature review

Objectives Overdiagnosis, the detection through screening of a breast cancer that would never have been identified in the lifetime of the woman, is an adverse outcome of screening. We aimed to determine an estimate range for overdiagnosis of breast cancer in European mammographic service screening programmes. Methods We conducted a literature review of observational studies that provided estimates of breast cancer overdiagnosis in European population-based mammographic screening programmes. Studies were classified according to the presence and the type of adjustment for breast cancer risk (data, model and covariates used), and for lead time (statistical adjustment or compensatory drop). We expressed estimates of overdiagnosis from each study as a percentage of the expected incidence in the absence of screening, even if the variability in the age range of the denominator could not be removed. Estimates including carcinoma in situ were considered when available. Results There were 13 primary studies reporting 16 estimates of overdiagnosis in seven European countries (the Netherlands, Italy, Norway, Sweden, Denmark, UK and Spain). Unadjusted estimates ranged from 0% to 54%. Reported estimates adjusted for breast cancer risk and lead time were 2.8% in the Netherlands, 4.6% and 1.0% in Italy, 7.0% in Denmark and 10% and 3.3% in England and Wales. Conclusions The most plausible estimates of overdiagnosis range from 1% to 10%. Substantially higher estimates of overdiagnosis reported in the literature are due to the lack of adjustment for breast cancer risk and/or lead time.

Quality-of-Life Effects of Prostate-Specific Antigen Screening

BACKGROUND After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. METHODS On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. RESULTS Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). CONCLUSIONS The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.).

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

BACKGROUND Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. OBJECTIVE To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. DESIGN, SETTING, AND PARTICIPANTS We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162,243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). INTERVENTION Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. MEASUREMENTS Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. RESULTS AND LIMITATIONS In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. CONCLUSIONS PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

Breast density as a determinant of interval cancer at mammographic screening

The association of breast density (% of breast volume involved by fibro-glandular densities) with the risk of interval cancer (IC) was investigated by reviewing a consecutive series of 346 cancers detected at screening (SDC) during 1996–1999 and of 90 ICs, reported as negative in the same period and diagnosed in the following 2 years, and comparing them to a random sample of 360 healthy controls. The probability of IC was significantly associated with breast density, whatever grouping (0/1–25/26–74/>74%; 0–25/26–60/61–74/>74%; 0–25/26–74/>74%) was considered (χ2=30.67–34.08, P<0.<0.01): 27.8% of all ICs were classified in the >74% density class, as compared to 7% of SDC and 5% of healthy controls. No significant association to IC was observed for Wolfe pattern (P2/Dy vs N1/P1: χ2=0.30, P=0.960), number of used mammographic views (single oblique vs oblique+craniocaudal: χ2=0.02, P=0.90) or screening round (first vs repeat: χ2=1.41, P=0.23). Multivariate analysis confirmed the independent association of breast density to IC, the highest risk being observed for >74% density class (OR vs 0% class=13.4, 95% CI 2.7–65.6, OR vs all other density classes=5.1, 95% CI 2.6–10.0). Age showed an independent association too, older women having a lower risk of IC (OR=0.52 95% CI 0.3–09). Breast density (>74%) resulted as being a major determinant of IC. Special screening protocols (shorter rescreening interval, routine use of ultrasonography) might be suggested for these subjects in order to improve screening sensitivity and efficacy.

Immunochemical vs guaiac faecal occult blood tests in a population-based screening programme for colorectal cancer.

Two faecal occult blood tests (FOBTs), Hemoccult II (guaiac based) and Hemeselect (immunochemical) were compared in a population screening for colorectal cancer on 24 282 subjects aged 40-70. Hemeselect was interpreted according to a lower (+ and +/-) and a higher (+) positivity threshold. A total of 8008 compliers were enrolled in the study. Positivity rates: Hemoccult = 6.0%, Hemeselect (+ and +/) = 8.2%, Hemeselect (+) = 3.1%. Among FOBT-positive subject complying with the diagnostic work-up, 22 had colorectal cancer (17 Hemeselect-positive (+), four Hemeselect-borderline (+/-), 15 Hemoccult-positive) and 166 subjects had adenomas (62 Hemeselect(+), 56 Hemeselect-borderline (+/-), 79 Hemoccult-positive) were detected. The positive predictive values (PPVs) for cancer were as follows: Hemoccult = 3.7%, Hemeselect (+ and +/-) = 3.8%, Hemeselect (+) = 8.4%. The PPVs for adenoma(s) were: Hemoccult = 19.7%, Hemeselect (+ and +/-) = 21.4%, Hemeselect (+) = 30.5%. The specificity for cancer was: Hemoccult = 94.1%, Hemeselect (+ +/-) = 92%, Hemeselect (+) = 97.1%. Ratios between detection rates of each test and expected incidence of colorectal cancer suggest that Hemoccult anticipates cancer diagnosis by approximately 2 years on average whereas the mean diagnostic anticipation of Hemeselect ranges between 2.5 and 3.2 years. Hemeselect is superior to Hemoccult as it is at least as effective but more efficient and acceptable than guaiac testing. Further evaluation of Hemeselect cost-effectiveness and sensitivity is needed in order to assess the optimal threshold of positivity and screening frequency.